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        <div style="font-weight: bold;">As filed with the Securities and Exchange Commission on August 7, 2020</div>
        <div style="text-align: right; font-weight: bold;">Registration No. 333-</div>
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      <font style="font-size: 14pt;">UNITED STATES</font></div>
    <div style="text-align: center; font-family: 'Times New Roman',Times,serif; font-size: 14pt; font-weight: bold;">SECURITIES AND EXCHANGE COMMISSION</div>
    <div style="text-align: center; font-family: 'Times New Roman',Times,serif; font-size: 12pt;">Washington, D.C. 20549</div>
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    <div style="text-align: center; font-family: 'Times New Roman',Times,serif; font-size: 18pt; font-weight: bold;">FORM S-8</div>
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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933</div>
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    <div style="text-align: center; font-family: 'Times New Roman',Times,serif; font-size: 24pt; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">(Exact name of registrant as specified in its charter)</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Delaware</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">33-0336973</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">(State of Incorporation)</div>
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          <td style="width: 20%; vertical-align: top;">&#160;</td>
          <td style="width: 40%; vertical-align: top;">
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">(I.R.S. Employer Identification No.)</div>
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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2855 Gazelle Court</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Carlsbad, CA&#160; 92010</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">(Address of principal executive offices)</div>
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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Amended and Restated Ionis Pharmaceuticals, Inc. 2002 Non-Employee Directors&#8217; Stock Option Plan</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">(Full title of the plan)</div>
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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Brett Monia</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Chief Executive Officer</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2855 Gazelle Court</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Carlsbad, California&#160; 92010</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(760) 931-9200</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">(Name, address, and telephone number, including area code, of agent for service)</div>
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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Copies to:</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Patrick R. O&#8217;Neil, Esq.</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Executive Vice President, Legal, General Counsel and Corporate Secretary</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">2855 Gazelle Court</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Carlsbad, California&#160; 92010</div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">(760) 931-9200</div>
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    </div>
    <div style="text-align: justify; margin-left: 13.5pt; 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.</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Large accelerated filer&#160; &#9746;</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Accelerated filer&#160; &#9744;</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Non-accelerated filer&#160; &#9744;</div>
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          <td style="width: 50%; vertical-align: top;">
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Smaller reporting company&#160; &#9744;</div>
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Emerging growth company&#160; &#9744;</div>
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    <div style="margin-left: 13.5pt; font-family: 'Times New Roman', Times, serif;"> <br>
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    <div style="margin-left: 13.5pt; font-family: 'Times New Roman',Times,serif; text-align: justify;">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.&#160; &#160; &#9744;</div>
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    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">CALCULATION OF REGISTRATION FEE</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Title of Securities</div>
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">to be Registered</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Amount to be Registered (1,2)</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Proposed Maximum</div>
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Offering</div>
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Price per Share (3)</div>
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          <td style="width: 21.24%; vertical-align: bottom; border-left: #000000 2px solid; border-right: #000000 2px solid; border-top: #000000 4px double;">
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Proposed Maximum</div>
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Aggregate</div>
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Offering Price (3)</div>
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          <td style="width: 15.04%; vertical-align: bottom; border-left: #000000 2px solid; border-top: #000000 4px double;">
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Amount of</div>
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Registration Fee</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">Common Stock, par value $.001 per share</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">800,000 shares</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">$56.95</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">$45,560,000</div>
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            <div style="text-align: center; font-family: 'Times New Roman', Times, serif;">$5,913.69</div>
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          <td style="width: 36pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif;">(1)</td>
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            <div style="font-family: 'Times New Roman', Times, serif;">In accordance with Rule 416 under the Securities Act of 1933, as amended (the &#8220;Securities Act&#8221;),&#160;this Registration Statement on Form S-8 (this &#8220;Registration Statement&#8221;) shall be deemed
              to cover any additional securities that may from time to time be offered or issued by Ionis Pharmaceuticals, Inc. (&#8220;Ionis&#8221; or the &#8220;Registrant&#8221;) to prevent dilution resulting from stock splits, stock dividends or similar transactions.</div>
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    <table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="ze95dc8807248441f912b565b91bf53ff" cellpadding="0" cellspacing="0">

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          <td style="width: 36pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif;">(2)</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div style="font-family: 'Times New Roman', Times, serif;">Includes 800,000 shares issuable pursuant to the Registrant&#8217;s Amended and Restated Ionis Pharmaceuticals, Inc. 2002 Non-Employee Directors&#8217; Stock Option Plan (the &#8220;2002 NED Plan&#8221;).</div>
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    <table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z26bf63f3682e467aa4fdd17154711c49" cellpadding="0" cellspacing="0">

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          <td style="width: 36pt; vertical-align: top; align: right; font-family: 'Times New Roman', Times, serif;">(3)</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div style="font-family: 'Times New Roman', Times, serif;">Estimated solely for the purpose of calculating the amount of the registration fee pursuant to Rule 457(c) and Rule 457(h) of the Securities Act.&#160; The price per share and the aggregate
              offering price are calculated on the basis of $56.95, the average of the high and low sales prices of Registrant&#8217;s Common Stock on August 6, 2020, as reported on the NASDAQ Global Market for the shares subject to the 2002 NED Plan.</div>
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      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">EXPLANATORY NOTE</div>
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      <div style="text-indent: 36pt; font-family: 'Times New Roman',Times,serif; text-align: justify;">Pursuant to General Instruction E of Form S-8, this Registration Statement is being filed in order to register an additional 800,000<font style="font-weight: bold;">&#160;</font>shares of Common Stock of the Registrant issuable under the 2002 NED Plan, which are securities of the same class and relate to the same employee benefit plan as those shares of Common Stock registered on the
        Registrant&#8217;s registration statements on Form S-8 previously filed with the Securities and Exchange Commission (the &#8220;Commission&#8221;) on <a href="http://www.sec.gov/Archives/edgar/data/874015/000114036115040249/forms8.htm">November 9, 2015
          (Registration No. 333-207900)</a>, <a href="http://www.sec.gov/Archives/edgar/data/874015/000110465912074771/a12-26127_1s8.htm">November 6, 2012 (Registration No. 333-184788)</a>, <a href="http://www.sec.gov/Archives/edgar/data/874015/000110465910043194/a10-15434_1s8.htm">August 9, 2010 (Registration No. 333-168674)</a>, <a href="http://www.sec.gov/Archives/edgar/data/874015/000110465906031585/a06-10506_1s8.htm">May 5, 2006
          (Registration No. 333-133853)</a> and <a href="http://www.sec.gov/Archives/edgar/data/874015/000091205702025900/a2083343zs-8.htm">June 28, 2002 (Registration No. 333-91572)</a>, all of which are hereby incorporated by reference.</div>
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      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Part II</div>
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      <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">INFORMATION REQUIRED IN THE REGISTRATION STATEMENT</div>
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      <div style="font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 3. Incorporation of Documents by Reference.</div>
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      <div style="text-indent: 36pt; font-family: 'Times New Roman',Times,serif; text-align: justify;">The following documents filed with the Commission by the Registrant are hereby incorporated by reference into this Registration Statement:</div>
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          <td style="width: 4%; vertical-align: middle;">&#160;</td>
          <td style="width: 5%; vertical-align: top;">
            <div style="font-family: 'Times New Roman', Times, serif;">(a)</div>
          </td>
          <td style="width: 91%; vertical-align: top;">
            <div style="font-family: 'Times New Roman',Times,serif; text-align: justify;">the Registrant&#8217;s Annual Report on <a href="http://www.sec.gov/Archives/edgar/data/874015/000114036120004500/form10k.htm">Form 10-K</a> for the year ended
              December 31, 2019, as filed with the Commission on March 2, 2020;</div>
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          <td style="width: 5%; vertical-align: top;">
            <div style="font-family: 'Times New Roman', Times, serif;">(b)</div>
          </td>
          <td style="width: 91%; vertical-align: top;">
            <div style="font-family: 'Times New Roman',Times,serif; text-align: justify;">the Registrant&#8217;s Quarterly Report on <a href="http://www.sec.gov/Archives/edgar/data/874015/000114036120010825/form10q.htm">Form 10-Q for the quarterly
                period ended March 31, 2020</a>, as filed with the Commission on May 6, 2020 and Quarterly Report on <a href="http://www.sec.gov/Archives/edgar/data/874015/000087401520000115/form10q.htm">Form 10-Q for the quarterly period ended June 30,
                2020</a>, as filed with the Commission on August 5, 2020;</div>
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          <td style="width: 4%; vertical-align: middle;">&#160;</td>
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            <div style="font-family: 'Times New Roman', Times, serif;">(c)</div>
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          <td style="width: 91%; vertical-align: top;">
            <div style="font-family: 'Times New Roman',Times,serif; text-align: justify;">the Registrant&#8217;s Current Reports on Form 8-K filed with the Commission on <a href="http://www.sec.gov/Archives/edgar/data/874015/000114036120000641/form8k.htm">January 10, 2020</a>, <a href="http://www.sec.gov/Archives/edgar/data/874015/000114036120001081/form8k.htm">January 17, 2020</a>, <a href="http://www.sec.gov/Archives/edgar/data/874015/000114036120004102/form8k.htm">February 26, 2020</a>, <a href="http://www.sec.gov/Archives/edgar/data/874015/000114036120010790/form8k.htm">May 6, 2020</a>, <a href="http://www.sec.gov/Archives/edgar/data/874015/000114036120013453/form8k.htm">June 10, 2020</a> and <a href="http://www.sec.gov/Archives/edgar/data/874015/000114036120017532/brhc10014107_8k.htm">August 5, 2020</a>; and</div>
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          <td style="width: 4%; vertical-align: middle;">&#160;</td>
          <td style="width: 5%; vertical-align: top;">
            <div style="font-family: 'Times New Roman', Times, serif;">(d)</div>
          </td>
          <td style="width: 91%; vertical-align: top;">
            <div style="font-family: 'Times New Roman',Times,serif; text-align: justify;">the sections of the Registrant&#8217;s Definitive Proxy Statement on <a href="http://www.sec.gov/Archives/edgar/data/874015/000114036120009606/nc10007589x2_def14a.htm">Schedule 14A</a> for the 2020 Annual Meeting of Shareholders incorporated by reference in the Annual Report.</div>
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      <div style="text-indent: 36pt; font-family: 'Times New Roman',Times,serif; text-align: justify;">All documents filed by the Registrant with the Commission pursuant to Sections 13(a), 13(c), 14 and 15(d) of the Securities Exchange Act of
        1934, as amended (the &#8220;Exchange Act&#8221;), after the date hereof and prior to the filing of a post-effective amendment which indicates that all securities offered pursuant to this Registration Statement have been sold or which deregisters all
        securities then remaining unsold, shall be deemed to be incorporated by reference herein and to be a part hereof from the date of filing of such documents.</div>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 5. Interests of Named Experts and Counsel.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif;">The validity of the issuance of the common stock offered in this Registration Statement will be passed upon for the Registrant by Patrick R. O&#8217;Neil,
      Executive Vice President, Legal, General Counsel and Corporate Secretary of Ionis.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif;">Mr. O&#8217;Neil holds or has the right to acquire shares of Ionis&#8217; Common Stock in an aggregate amount that is less than 1% of Ionis&#8217; outstanding Common
      Stock.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 6. Indemnification of Directors and Officers.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif;">Under Section 145 of the Delaware General Corporation Law (the &#8220;DGCL&#8221;), we have broad powers to indemnify our directors and officers against liabilities
      they may incur in such capacities, including liabilities under the Securities Act.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif;">Our certificate of incorporation and bylaws include provisions to (i) eliminate the personal liability of its directors for monetary damages resulting
      from breaches of their fiduciary duty to the extent permitted by Section 102(b)(7) of the DGCL and (ii) require us to indemnify our directors and officers to the fullest extent permitted by Section 145 of the DGCL, including circumstances in which
      indemnification is otherwise discretionary. Pursuant to Section 145 of the DGCL, a corporation generally has the power to indemnify its present and former directors, officers, employees and agents against expenses incurred by them in connection with
      any suit to which they are, or are threatened to be made, a party by reason of their serving in such positions so long as they acted in good faith and in a manner they reasonably believed to be in, or not opposed to, the best interest of the
      corporation, and with respect to any criminal action, they had no reasonable cause to believe their conduct was unlawful.&#160; We believe that these provisions are necessary to attract and retain qualified persons as directors and officers. These
      provisions do not eliminate the directors&#8217; duty of care, and, in appropriate circumstances, equitable remedies such as injunctive or other forms of non-monetary relief will remain available under Delaware law.&#160; In addition, each director will
      continue to be subject to liability for breach of the director&#8217;s duty of loyalty to us, for acts or omissions not in good faith or involving intentional misconduct, for knowing violations of law, for acts or omissions that the director believes to be
      contrary to the best interests of Ionis or our stockholders, for any transaction from which the director derived an improper personal benefit, for acts or omissions involving a reckless disregard for the director&#8217;s duty to Ionis or our stockholders
      when the director was aware or should have been aware of a risk of serious injury to Ionis or our stockholders, for acts or omissions that constitute an unexcused pattern of inattention that amounts to an abdication of the director&#8217;s duty to Ionis or
      our stockholders, for improper transactions between the director and us and for improper distributions to stockholders and loans to directors and officers.&#160; The provision also does not affect a director&#8217;s responsibilities under any other law, such as
      the federal securities law or state or federal environmental laws.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif;">We have entered into indemnity agreements with each of our directors and executive officers that require us to indemnify such persons against expenses,
      judgments, fines, settlements and other amounts incurred (including expenses of a derivative action) in connection with any proceeding, whether actual or threatened, to which any such person may be made a party by reason of the fact that such person
      is or was a director or an executive officer of Ionis or any of our affiliated enterprises, provided such person acted in good faith and in a manner such persons reasonably believed to be in, or not opposed to, the best interests of Ionis and, with
      respect to any criminal proceeding, has no reasonable cause to believe his conduct was unlawful. The indemnification agreements also set forth procedures that will apply in the event of a claim for indemnification thereunder.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif;">We have an insurance policy covering our officers and directors with respect to certain liabilities, including liabilities arising under the Securities
      Act or otherwise.</div>
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      <div id="DSPFPageFooter"></div>
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    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 8. Exhibits.</div>
    <div><br>
    </div>
    <table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="ze08a7bc15d0e40638927d14083f12b9f" cellpadding="0" cellspacing="0">

        <tr>
          <td style="width: 10.55%; vertical-align: bottom;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Exhibit</div>
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Number</div>
          </td>
          <td style="width: 89.45%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Description</div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><a href="nt10014191x2_ex5-1.htm">5.1</a></div>
          </td>
          <td style="width: 89.45%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">Opinion of Patrick R. O&#8217;Neil</div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><a href="nt10014191x2_ex23-1.htm">23.1</a></div>
          </td>
          <td style="width: 89.45%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">Consent of Independent Registered Public Accounting Firm</div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><a href="nt10014191x2_ex5-1.htm">23.2</a></div>
          </td>
          <td style="width: 89.45%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">Consent of Patrick R. O&#8217;Neil. <font style="font-variant: small-caps;">&#160;</font>Reference is made to Exhibit 5.1</div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><a href="#SIGNATURES">24.1</a></div>
          </td>
          <td style="width: 89.45%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">Power of Attorney is contained on the signature pages</div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><a href="http://www.sec.gov/Archives/edgar/data/874015/000114036120009606/nc10007589x2_def14a.htm">99.1</a></div>
          </td>
          <td style="width: 89.45%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">Amended and Restated Ionis Pharmaceuticals, Inc. 2002 Non-Employee Directors&#8217; Stock Option Plan (1)</div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><a href="nt10014191x2_ex99-2.htm">99.2</a></div>
          </td>
          <td style="width: 89.45%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">Form of Option Agreement for options granted under the Amended and Restated Ionis Pharmaceuticals, Inc. 2002 Non-Employee Directors&#8217; Stock Option Plan (2)</div>
          </td>
        </tr>
        <tr>
          <td style="width: 10.55%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;"><a href="nt10014191x2_ex99-3.htm">99.3</a></div>
          </td>
          <td style="width: 89.45%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">Form of Restricted Stock Unit Agreement for restricted stock units granted under the Amended and Restated Ionis Pharmaceuticals, Inc. 2002 Non-Employee Directors&#8217;
              Stock Option Plan (3)</div>
          </td>
        </tr>

    </table>
    <div style="text-align: justify;"><br>
    </div>
    <div style="text-align: justify;"><font style="font-family: 'Times New Roman', Times, serif;">(1)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;">Filed as an appendix to the Registrant&#8217;s <a href="http://www.sec.gov/Archives/edgar/data/874015/000114036120009606/nc10007589x2_def14a.htm">Notice of 2020 Annual Meeting of Stockholders and Proxy Statement</a> filed with the SEC on April 24, 2020, and incorporated herein by reference.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-family: 'Times New Roman', Times, serif;">(2)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;">Filed herewith.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify;"><font style="font-family: 'Times New Roman', Times, serif;">(3)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;">Filed herewith.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -36pt; margin-left: 36pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Item 9. Undertakings.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -36pt; margin-left: 36pt; font-family: 'Times New Roman', Times, serif;">(a) The undersigned Registrant hereby undertakes:</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-family: 'Times New Roman', Times, serif;">(1)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;">To file, during any period in which offers or sales are
        being made, a post-effective amendment to this Registration Statement:</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-family: 'Times New Roman', Times, serif;">(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;">To include any prospectus required by section 10(a)(3) of
        the Securities Act;</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-family: 'Times New Roman', Times, serif;">(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;">To reflect in the prospectus any facts or events arising
        after the effective date of the Registration Statement (or the most recent post-effective amendment thereof) which, individually or in the aggregate, represent a fundamental change in the information set forth in the Registration Statement.&#160;
        Notwithstanding the foregoing, any increase or decrease in volume of securities offered (if the total dollar value of securities offered would not exceed that which was registered) and any deviation from the low or high end of the estimated maximum
        offering range may be reflected in the form of prospectus filed with the Commission pursuant to Rule 424(b) if, in the aggregate, the changes in volume and price represent no more than a 20% change in the maximum aggregate offering price set forth
        in the &#8220;Calculation of Registration Fee&#8221; table in the effective Registration Statement;</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-family: 'Times New Roman', Times, serif;">(iii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;">To include any material information with respect to the
        plan of distribution not previously disclosed in the Registration Statement or any material change to such information in the Registration Statement;</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; margin-left: 36pt; font-family: 'Times New Roman', Times, serif;"><font style="font-style: italic;">Provided, however,</font> that paragraphs (a)(1)(i) and (a)(1)(ii) of this section do not apply if
      the information required to be included in a post-effective amendment by those paragraphs is contained in reports filed with or furnished to the Commission by the Registrant pursuant to section 13 or section 15(d) of the Securities Exchange Act of
      1934 (the &#8220;Exchange Act&#8221;) that are incorporated by reference in the Registration Statement; and</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt;"><font style="font-family: 'Times New Roman', Times, serif;">(2)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;">That, for the purpose of determining any liability under
        the Securities Act, each such post-effective amendment shall be deemed to be a new registration statement relating to the securities offered herein, and the offering of such securities at that time shall be deemed to be the initial <font style="font-style: italic;">bona fide</font> offering thereof.</font></div>
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    <div style="text-align: justify; text-indent: 36pt;"><font style="font-family: 'Times New Roman', Times, serif;">(3)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;">To remove from registration by means of a post-effective
        amendment any of the securities being registered which remain unsold at the termination of the offering.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; margin-left: 36pt; font-family: 'Times New Roman', Times, serif;">(4)&#160; &#160; &#160;&#160; That, for the purpose of determining liability of the Registrant under the Securities Act to any purchaser in the initial distribution of the
      securities: The undersigned Registrant undertakes that in a primary offering of securities of the undersigned Registrant pursuant to this Registration Statement, regardless of the underwriting method used to sell the securities to the purchaser, if
      the securities are offered or sold to such purchaser by means of any of the following communications, the undersigned Registrant will be a seller to the purchaser and will be considered to offer or sell such securities to such purchaser:</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-family: 'Times New Roman', Times, serif;">(i)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;">Any preliminary prospectus or prospectus of the undersigned
        Registrant relating to the offering required to be filed pursuant to Rule 424;</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-family: 'Times New Roman', Times, serif;">(ii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;">Any free writing prospectus relating to the offering
        prepared by or on behalf of the undersigned Registrant or used or referred to by the undersigned Registrant;</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-family: 'Times New Roman', Times, serif;">(iii)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;">The portion of any other free writing prospectus relating
        to the offering containing material information about the undersigned Registrant or its securities provided by or on behalf of the undersigned Registrant; and</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 72pt;"><font style="font-family: 'Times New Roman', Times, serif;">(iv)</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<font style="font-family: 'Times New Roman', Times, serif;">Any other communication that is an offer in the offering
        made by the undersigned Registrant to the purchaser.</font></div>
    <div><br>
    </div>
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">(b) The undersigned Registrant hereby undertakes that, for purposes of determining any liability under the Securities Act, each filing of the Registrant&#8217;s annual report
      pursuant to Section 13(a) or Section 15(d) of the Exchange Act (and, where applicable, each filing of an employee benefit plan&#8217;s annual report pursuant to Section 15(d) of the Exchange Act) that is incorporated by reference in the Registration
      Statement shall be deemed to be a new registration statement relating to the securities offered therein, and the offering of such securities at that time shall be deemed to be the initial <font style="font-style: italic;">bona fide</font> offering
      thereof.</div>
    <div><br>
    </div>
    <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">(c) Insofar as indemnification for liabilities arising under the Securities Act may be permitted to directors, officers and controlling persons of the Registrant pursuant
      to the foregoing provisions, or otherwise, the Registrant has been advised that in the opinion of the Securities and Exchange Commission such indemnification is against public policy as expressed in the Securities Act and is, therefore,
      unenforceable.&#160; In the event that a claim for indemnification against such liabilities (other than the payment by the Registrant of expenses incurred or paid by a director, officer or controlling person of the Registrant in the successful defense of
      any action, suit or proceeding) is asserted by such director, officer or controlling person in connection with the securities being registered, the Registrant will, unless in the opinion of its counsel the matter has been settled by controlling
      precedent, submit to a court of appropriate jurisdiction the question whether such indemnification by it is against public policy as expressed in the Securities Act and will be governed by the final adjudication of such issue.</div>
    <div><br>
    </div>
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    </div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;"><a name="SIGNATURES"><!--Anchor--></a>SIGNATURES</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif;">Pursuant to the requirements of the Securities Act of 1933, as amended, the Registrant certifies that it has reasonable grounds to believe that it meets
      all of the requirements for filing on Form S&#8209;8 and has duly caused this Registration Statement to be signed on its behalf by the undersigned, thereunto duly authorized, in the City of Carlsbad, State of California, on August 7, 2020.</div>
    <div><br>
    </div>
    <table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="zf356e171573c4430a7dd601c8735e276" border="0" cellpadding="0" cellspacing="0">

        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td colspan="2" style="vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif; font-variant: small-caps; font-weight: bold;">Ionis Pharmaceuticals, Inc.</div>
          </td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="width: 6%; vertical-align: top;">&#160;</td>
          <td style="width: 44%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="width: 6%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">By:</div>
          </td>
          <td style="width: 44%; vertical-align: top; border-bottom: 2px solid black;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">&#160;/s/ Brett Monia</div>
          </td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td colspan="2" style="vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">Brett Monia</div>
          </td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td colspan="2" style="vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">Chief Executive Officer</div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">POWER OF ATTORNEY</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif;"><font style="font-weight: bold; font-variant: small-caps;">Know All Persons By These Presents</font><font style="font-variant: small-caps;">,</font> that
      each person whose signature appears below constitutes and Brett Monia and Elizabeth Hougen, and each or any one of them, his or her true and lawful attorney-in-fact and agent, with full power of substitution and resubstitution, for him or her and in
      his or her name, place and stead, in any and all capacities, to sign any and all amendments (including post-effective amendments) to this Registration Statement, and to file the same, with all exhibits thereto, and other documents in connection
      therewith, with the Securities and Exchange Commission, granting unto said attorneys-in-fact and agents, and each of them, full power and authority to do and perform each and every act and thing requisite and necessary to be done in connection
      therewith, as fully to all intents and purposes as he or she might or could do in person, hereby ratifying and confirming all that said attorneys-in-fact and agents, or any of them, or their or his or her substitutes or substitute, may lawfully do or
      cause to be done by virtue hereof.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; font-family: 'Times New Roman', Times, serif;">Pursuant to the requirements of the Securities Act of 1933, as amended, this Registration Statement has been signed by the following persons in the
      capacities and on the dates indicated.</div>
    <div><br>
    </div>
    <table style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;" id="zf7d5e94dc16d4fbeb08557f8d5323577" border="0" cellpadding="0" cellspacing="0">

        <tr>
          <td style="width: 40%; vertical-align: top;">
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Signature</div>
          </td>
          <td style="width: 35%; vertical-align: top;">
            <div style="text-align: center; margin-left: 9pt; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Title</div>
          </td>
          <td style="width: 25%; vertical-align: top;">
            <div style="text-align: center; font-family: 'Times New Roman', Times, serif; font-weight: bold;">Date</div>
          </td>
        </tr>
        <tr>
          <td style="width: 40%; vertical-align: top; border-bottom: 2px solid black;">
            <div style="text-align: justify;"><font style="font-family: 'Times New Roman', Times, serif;">/s/ Brett Monia</font>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;</div>
          </td>
          <td rowspan="2" style="width: 35%; vertical-align: top;">
            <div style="margin-left: 9pt; font-family: 'Times New Roman', Times, serif;">Chief Executive Officer</div>
            <div style="margin-left: 9pt; font-family: 'Times New Roman', Times, serif;">(Principal Executive Officer)</div>
          </td>
          <td rowspan="2" style="width: 25%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">August 7, 2020</div>
          </td>
        </tr>
        <tr>
          <td style="width: 40%; vertical-align: top;">
            <div style="text-align: justify; font-family: 'Times New Roman', Times, serif;">Brett Monia</div>
          </td>
        </tr>
        <tr>
          <td style="width: 40%; vertical-align: top;">&#160;</td>
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{"company-data": {"conformed-name": "IONIS PHARMACEUTICALS INC", "cik": "0000874015", "assigned-sic": "2834", "irs-number": "330336973", "state-of-incorporation": "DE", "fiscal-year-end": "1231"}, "filing-values": {"form-type": "S-8", "act": "33", "file-number": "333-242386", "film-number": "201085677"}, "business-address": {"street1": "2855 GAZELLE COURT", "city": "CARLSBAD", "state": "CA", "zip": "92010", "phone": "7609319200"}, "mail-address": {"street1": "2855 GAZELLE COURT", "city": "CARLSBAD", "state": "CA", "zip": "92010"}, "former-company": {"former-conformed-name": "ISIS PHARMACEUTICALS INC", "date-changed": "19930328"}}
As filed with the Securities and Exchange Commission on August 7, 2020
Registration No. 333-
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM S-8
REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933
IONIS PHARMACEUTICALS, INC.
(Exact name of registrant as specified in its charter)
Delaware
33-0336973
(State of Incorporation)
(I.R.S. Employer Identification No.)
2855 Gazelle Court
Carlsbad, CA  92010
(Address of principal executive offices)
Amended and Restated Ionis Pharmaceuticals, Inc. 2002 Non-Employee Directors' Stock Option Plan
(Full title of the plan)
Brett Monia
Chief Executive Officer
IONIS PHARMACEUTICALS, INC.
2855 Gazelle Court
Carlsbad, California  92010
(760) 931-9200
(Name, address, and telephone number, including area code, of agent for service)
Copies to:
Patrick R. O'Neil, Esq.
Executive Vice President, Legal, General Counsel and Corporate Secretary
IONIS PHARMACEUTICALS, INC.
2855 Gazelle Court
Carlsbad, California  92010
(760) 931-9200
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 "large accelerated filer," "accelerated filer," "smaller reporting company," and "emerging growth company" in Rule 12b-2 of the Exchange Act.
Large accelerated filer  ☒
Accelerated filer  ☐
Non-accelerated filer  ☐
Smaller reporting company  ☐
Emerging growth company  ☐
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.    ☐
CALCULATION OF REGISTRATION FEE
Title of Securities
to be Registered
Amount to be Registered (1,2)
Proposed Maximum
Offering
Price per Share (3)
Proposed Maximum
Aggregate
Offering Price (3)
Amount of
Registration Fee
Common Stock, par value $.001 per share
800,000 shares
$56.95
$45,560,000
$5,913.69
(1)
In accordance with Rule 416 under the Securities Act of 1933, as amended (the "Securities Act"), this Registration Statement on Form S-8 (this "Registration Statement") shall be deemed
              to cover any additional securities that may from time to time be offered or issued by Ionis Pharmaceuticals, Inc. ("Ionis" or the "Registrant") to prevent dilution resulting from stock splits, stock dividends or similar transactions.
(2)
Includes 800,000 shares issuable pursuant to the Registrant's Amended and Restated Ionis Pharmaceuticals, Inc. 2002 Non-Employee Directors' Stock Option Plan (the "2002 NED Plan").
(3)
Estimated solely for the purpose of calculating the amount of the registration fee pursuant to Rule 457(c) and Rule 457(h) of the Securities Act.  The price per share and the aggregate
              offering price are calculated on the basis of $56.95, the average of the high and low sales prices of Registrant's Common Stock on August 6, 2020, as reported on the NASDAQ Global Market for the shares subject to the 2002 NED Plan.
EXPLANATORY NOTE
Pursuant to General Instruction E of Form S-8, this Registration Statement is being filed in order to register an additional 800,000
shares of Common Stock of the Registrant issuable under the 2002 NED Plan, which are securities of the same class and relate to the same employee benefit plan as those shares of Common Stock registered on the
        Registrant's registration statements on Form S-8 previously filed with the Securities and Exchange Commission (the "Commission") on
November 9, 2015
          (Registration No. 333-207900)
,
November 6, 2012 (Registration No. 333-184788)
,
August 9, 2010 (Registration No. 333-168674)
,
May 5, 2006
          (Registration No. 333-133853)
and
June 28, 2002 (Registration No. 333-91572)
, all of which are hereby incorporated by reference.
Part II
INFORMATION REQUIRED IN THE REGISTRATION STATEMENT
Item 3. Incorporation of Documents by Reference.
The following documents filed with the Commission by the Registrant are hereby incorporated by reference into this Registration Statement:
(a)
the Registrant's Annual Report on
Form 10-K
for the year ended
              December 31, 2019, as filed with the Commission on March 2, 2020;
(b)
the Registrant's Quarterly Report on
Form 10-Q for the quarterly
                period ended March 31, 2020
, as filed with the Commission on May 6, 2020 and Quarterly Report on
Form 10-Q for the quarterly period ended June 30,
                2020
, as filed with the Commission on August 5, 2020;
(c)
the Registrant's Current Reports on Form 8-K filed with the Commission on
January 10, 2020
,
January 17, 2020
,
February 26, 2020
,
May 6, 2020
,
June 10, 2020
and
August 5, 2020
; and
(d)
the sections of the Registrant's Definitive Proxy Statement on
Schedule 14A
for the 2020 Annual Meeting of Shareholders incorporated by reference in the Annual Report.
All documents filed by the Registrant with the Commission pursuant to Sections 13(a), 13(c), 14 and 15(d) of the Securities Exchange Act of
        1934, as amended (the "Exchange Act"), after the date hereof and prior to the filing of a post-effective amendment which indicates that all securities offered pursuant to this Registration Statement have been sold or which deregisters all
        securities then remaining unsold, shall be deemed to be incorporated by reference herein and to be a part hereof from the date of filing of such documents.
Item 5. Interests of Named Experts and Counsel.
The validity of the issuance of the common stock offered in this Registration Statement will be passed upon for the Registrant by Patrick R. O'Neil,
      Executive Vice President, Legal, General Counsel and Corporate Secretary of Ionis.
Mr. O'Neil holds or has the right to acquire shares of Ionis' Common Stock in an aggregate amount that is less than 1% of Ionis' outstanding Common
      Stock.
Item 6. Indemnification of Directors and Officers.
Under Section 145 of the Delaware General Corporation Law (the "DGCL"), we have broad powers to indemnify our directors and officers against liabilities
      they may incur in such capacities, including liabilities under the Securities Act.
Our certificate of incorporation and bylaws include provisions to (i) eliminate the personal liability of its directors for monetary damages resulting
      from breaches of their fiduciary duty to the extent permitted by Section 102(b)(7) of the DGCL and (ii) require us to indemnify our directors and officers to the fullest extent permitted by Section 145 of the DGCL, including circumstances in which
      indemnification is otherwise discretionary. Pursuant to Section 145 of the DGCL, a corporation generally has the power to indemnify its present and former directors, officers, employees and agents against expenses incurred by them in connection with
      any suit to which they are, or are threatened to be made, a party by reason of their serving in such positions so long as they acted in good faith and in a manner they reasonably believed to be in, or not opposed to, the best interest of the
      corporation, and with respect to any criminal action, they had no reasonable cause to believe their conduct was unlawful.  We believe that these provisions are necessary to attract and retain qualified persons as directors and officers. These
      provisions do not eliminate the directors' duty of care, and, in appropriate circumstances, equitable remedies such as injunctive or other forms of non-monetary relief will remain available under Delaware law.  In addition, each director will
      continue to be subject to liability for breach of the director's duty of loyalty to us, for acts or omissions not in good faith or involving intentional misconduct, for knowing violations of law, for acts or omissions that the director believes to be
      contrary to the best interests of Ionis or our stockholders, for any transaction from which the director derived an improper personal benefit, for acts or omissions involving a reckless disregard for the director's duty to Ionis or our stockholders
      when the director was aware or should have been aware of a risk of serious injury to Ionis or our stockholders, for acts or omissions that constitute an unexcused pattern of inattention that amounts to an abdication of the director's duty to Ionis or
      our stockholders, for improper transactions between the director and us and for improper distributions to stockholders and loans to directors and officers.  The provision also does not affect a director's responsibilities under any other law, such as
      the federal securities law or state or federal environmental laws.
We have entered into indemnity agreements with each of our directors and executive officers that require us to indemnify such persons against expenses,
      judgments, fines, settlements and other amounts incurred (including expenses of a derivative action) in connection with any proceeding, whether actual or threatened, to which any such person may be made a party by reason of the fact that such person
      is or was a director or an executive officer of Ionis or any of our affiliated enterprises, provided such person acted in good faith and in a manner such persons reasonably believed to be in, or not opposed to, the best interests of Ionis and, with
      respect to any criminal proceeding, has no reasonable cause to believe his conduct was unlawful. The indemnification agreements also set forth procedures that will apply in the event of a claim for indemnification thereunder.
We have an insurance policy covering our officers and directors with respect to certain liabilities, including liabilities arising under the Securities
      Act or otherwise.
Item 8. Exhibits.
Exhibit
Number
Description
5.1
Opinion of Patrick R. O'Neil
23.1
Consent of Independent Registered Public Accounting Firm
23.2
Consent of Patrick R. O'Neil.
Reference is made to Exhibit 5.1
24.1
Power of Attorney is contained on the signature pages
99.1
Amended and Restated Ionis Pharmaceuticals, Inc. 2002 Non-Employee Directors' Stock Option Plan (1)
99.2
Form of Option Agreement for options granted under the Amended and Restated Ionis Pharmaceuticals, Inc. 2002 Non-Employee Directors' Stock Option Plan (2)
99.3
Form of Restricted Stock Unit Agreement for restricted stock units granted under the Amended and Restated Ionis Pharmaceuticals, Inc. 2002 Non-Employee Directors'
              Stock Option Plan (3)
(1)
Filed as an appendix to the Registrant's
Notice of 2020 Annual Meeting of Stockholders and Proxy Statement
filed with the SEC on April 24, 2020, and incorporated herein by reference.
(2)
Filed herewith.
(3)
Filed herewith.
Item 9. Undertakings.
(a) The undersigned Registrant hereby undertakes:
(1)
To file, during any period in which offers or sales are
        being made, a post-effective amendment to this Registration Statement:
(i)
To include any prospectus required by section 10(a)(3) of
        the Securities Act;
(ii)
To reflect in the prospectus any facts or events arising
        after the effective date of the Registration Statement (or the most recent post-effective amendment thereof) which, individually or in the aggregate, represent a fundamental change in the information set forth in the Registration Statement. 
        Notwithstanding the foregoing, any increase or decrease in volume of securities offered (if the total dollar value of securities offered would not exceed that which was registered) and any deviation from the low or high end of the estimated maximum
        offering range may be reflected in the form of prospectus filed with the Commission pursuant to Rule 424(b) if, in the aggregate, the changes in volume and price represent no more than a 20% change in the maximum aggregate offering price set forth
        in the "Calculation of Registration Fee" table in the effective Registration Statement;
(iii)
To include any material information with respect to the
        plan of distribution not previously disclosed in the Registration Statement or any material change to such information in the Registration Statement;
Provided, however,
that paragraphs (a)(1)(i) and (a)(1)(ii) of this section do not apply if
      the information required to be included in a post-effective amendment by those paragraphs is contained in reports filed with or furnished to the Commission by the Registrant pursuant to section 13 or section 15(d) of the Securities Exchange Act of
      1934 (the "Exchange Act") that are incorporated by reference in the Registration Statement; and
(2)
That, for the purpose of determining any liability under
        the Securities Act, each such post-effective amendment shall be deemed to be a new registration statement relating to the securities offered herein, and the offering of such securities at that time shall be deemed to be the initial
bona fide
offering thereof.
(3)
To remove from registration by means of a post-effective
        amendment any of the securities being registered which remain unsold at the termination of the offering.
(4)       That, for the purpose of determining liability of the Registrant under the Securities Act to any purchaser in the initial distribution of the
      securities: The undersigned Registrant undertakes that in a primary offering of securities of the undersigned Registrant pursuant to this Registration Statement, regardless of the underwriting method used to sell the securities to the purchaser, if
      the securities are offered or sold to such purchaser by means of any of the following communications, the undersigned Registrant will be a seller to the purchaser and will be considered to offer or sell such securities to such purchaser:
(i)
Any preliminary prospectus or prospectus of the undersigned
        Registrant relating to the offering required to be filed pursuant to Rule 424;
(ii)
Any free writing prospectus relating to the offering
        prepared by or on behalf of the undersigned Registrant or used or referred to by the undersigned Registrant;
(iii)
The portion of any other free writing prospectus relating
        to the offering containing material information about the undersigned Registrant or its securities provided by or on behalf of the undersigned Registrant; and
(iv)
Any other communication that is an offer in the offering
        made by the undersigned Registrant to the purchaser.
(b) The undersigned Registrant hereby undertakes that, for purposes of determining any liability under the Securities Act, each filing of the Registrant's annual report
      pursuant to Section 13(a) or Section 15(d) of the Exchange Act (and, where applicable, each filing of an employee benefit plan's annual report pursuant to Section 15(d) of the Exchange Act) that is incorporated by reference in the Registration
      Statement shall be deemed to be a new registration statement relating to the securities offered therein, and the offering of such securities at that time shall be deemed to be the initial
bona fide
offering
      thereof.
(c) Insofar as indemnification for liabilities arising under the Securities Act may be permitted to directors, officers and controlling persons of the Registrant pursuant
      to the foregoing provisions, or otherwise, the Registrant has been advised that in the opinion of the Securities and Exchange Commission such indemnification is against public policy as expressed in the Securities Act and is, therefore,
      unenforceable.  In the event that a claim for indemnification against such liabilities (other than the payment by the Registrant of expenses incurred or paid by a director, officer or controlling person of the Registrant in the successful defense of
      any action, suit or proceeding) is asserted by such director, officer or controlling person in connection with the securities being registered, the Registrant will, unless in the opinion of its counsel the matter has been settled by controlling
      precedent, submit to a court of appropriate jurisdiction the question whether such indemnification by it is against public policy as expressed in the Securities Act and will be governed by the final adjudication of such issue.
SIGNATURES
Pursuant to the requirements of the Securities Act of 1933, as amended, the Registrant certifies that it has reasonable grounds to believe that it meets
      all of the requirements for filing on Form S‑8 and has duly caused this Registration Statement to be signed on its behalf by the undersigned, thereunto duly authorized, in the City of Carlsbad, State of California, on August 7, 2020.
Ionis Pharmaceuticals, Inc.
By:
/s/ Brett Monia
Brett Monia
Chief Executive Officer
POWER OF ATTORNEY
Know All Persons By These Presents
,
that
      each person whose signature appears below constitutes and Brett Monia and Elizabeth Hougen, and each or any one of them, his or her true and lawful attorney-in-fact and agent, with full power of substitution and resubstitution, for him or her and in
      his or her name, place and stead, in any and all capacities, to sign any and all amendments (including post-effective amendments) to this Registration Statement, and to file the same, with all exhibits thereto, and other documents in connection
      therewith, with the Securities and Exchange Commission, granting unto said attorneys-in-fact and agents, and each of them, full power and authority to do and perform each and every act and thing requisite and necessary to be done in connection
      therewith, as fully to all intents and purposes as he or she might or could do in person, hereby ratifying and confirming all that said attorneys-in-fact and agents, or any of them, or their or his or her substitutes or substitute, may lawfully do or
      cause to be done by virtue hereof.
Pursuant to the requirements of the Securities Act of 1933, as amended, this Registration Statement has been signed by the following persons in the
      capacities and on the dates indicated.
Signature
Title
Date
/s/ Brett Monia
Chief Executive Officer
(Principal Executive Officer)
August 7, 2020
Brett Monia
/s/ Elizabeth Hougen
Chief Financial Officer (Principal Financial Officer)
August 7, 2020
Elizabeth Hougen
/s/ Stanley T. Crooke
Executive Chairman
August 7, 2020
Stanley T. Crooke
/s/ Breaux B. Castleman
Director
August 7, 2020
Breaux B. Castleman
/s/ Spencer R. Berthelsen
Director
August 7, 2020
Spencer R. Berthelsen
/s/ Joseph Klein, III
Director
August 7, 2020
Joseph Klein, III
/s/ Joseph Loscalzo
Director
August 7, 2020
Joseph Loscalzo
/s/ Frederick T. Muto
Director
August 7, 2020
Frederick T. Muto
/s/ Joseph H. Wender
Director
August 7, 2020
Joseph H. Wender
/s/ B. Lynne Parshall
Director
August 7, 2020
B. Lynne Parshall
/s/ Peter Reikes
Director
August 7, 2020
Peter Reikes
/s/ Michael Hayden
Director
August 7, 2020
Michael Hayden
/s/ Joan E. Herman
Director
August 7, 2020
Joan E. Herman