<SEC-DOCUMENT>0001140361-25-028020.txt : 20250730
<SEC-HEADER>0001140361-25-028020.hdr.sgml : 20250730
<ACCEPTANCE-DATETIME>20250730162504
ACCESSION NUMBER:		0001140361-25-028020
CONFORMED SUBMISSION TYPE:	S-8
PUBLIC DOCUMENT COUNT:		14
FILED AS OF DATE:		20250730
DATE AS OF CHANGE:		20250730
EFFECTIVENESS DATE:		20250730

FILER:

	COMPANY DATA:	
		COMPANY CONFORMED NAME:			IONIS PHARMACEUTICALS INC
		CENTRAL INDEX KEY:			0000874015
		STANDARD INDUSTRIAL CLASSIFICATION:	PHARMACEUTICAL PREPARATIONS [2834]
		ORGANIZATION NAME:           	03 Life Sciences
		EIN:				330336973
		STATE OF INCORPORATION:			CA
		FISCAL YEAR END:			1231

	FILING VALUES:
		FORM TYPE:		S-8
		SEC ACT:		1933 Act
		SEC FILE NUMBER:	333-289093
		FILM NUMBER:		251167454

	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>S-8
<SEQUENCE>1
<FILENAME>ef20052672_s8.htm
<DESCRIPTION>S-8
<TEXT>
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  <div style="text-align: center; color: #000000; font-weight: bold;">As filed with the Securities and Exchange Commission on July 30, 2025</div>
  <div style="text-align: right; color: #000000; font-weight: bold;">Registration No. 333-</div>
  <br>
  <hr align="center" style="border: none; border-bottom: 1px solid black; border-top: 4px solid black; height: 10px; color: #ffffff; background-color: #ffffff; text-align: center; margin-left: auto; margin-right: auto;">
  <div>
    <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold; font-size: 14pt;">UNITED STATES</div>
    <font style="font-size: 14pt;"> </font>
    <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold; font-size: 14pt;">SECURITIES AND EXCHANGE COMMISSION</div>
    <div style="text-align: center; color: rgb(0, 0, 0); font-size: 12pt;">Washington, D.C. 20549</div>
    <div style="text-align: center; color: #000000;"> <br>
    </div>
    <div>
      <hr noshade="noshade" align="center" style="height: 2px; width: 10%; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;"> </div>
    <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold; font-size: 18pt;">FORM S-8</div>
    <div style="text-align: center; color: #000000; font-weight: bold;"> <br>
    </div>
    <div style="text-align: center; color: #000000; font-weight: bold;">
      <hr noshade="noshade" align="center" style="height: 2px; width: 10%; color: #000000; background-color: #000000; margin-left: auto; margin-right: auto; border: none;"> </div>
    <div style="text-align: center; color: #000000; font-weight: bold;">REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933</div>
    <div style="text-align: center; color: #000000; font-weight: bold;"> <br>
    </div>
    <div style="text-align: center; color: #000000; font-weight: bold;">
      <hr noshade="noshade" align="center" style="height: 2px; width: 10%; color: #000000; background-color: #000000; margin-left: auto; margin-right: auto; border: none;"> </div>
    <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold; font-size: 24pt;">IONIS PHARMACEUTICALS, INC.</div>
    <div style="text-align: center; color: #000000;">(Exact name of registrant as specified in its charter)</div>
    <table cellspacing="0" cellpadding="0" border="0" id="zc5381e6ee7e84671aa9d10c8d82fd39d" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">

        <tr>
          <td style="width: 49%; vertical-align: top;">
            <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold;">Delaware</div>
          </td>
          <td style="width: 2%; vertical-align: top;">&#160;</td>
          <td style="width: 49%; vertical-align: top;">
            <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold;">33-0336973</div>
          </td>
        </tr>
        <tr>
          <td style="width: 49%; vertical-align: top;">
            <div style="text-align: center; color: rgb(0, 0, 0);">(State of Incorporation)</div>
          </td>
          <td style="width: 2%; vertical-align: top;">&#160;</td>
          <td style="width: 49%; vertical-align: top;">
            <div style="text-align: center; color: rgb(0, 0, 0);">(I.R.S. Employer Identification No.)</div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div>
      <hr noshade="noshade" align="center" style="height: 2px; width: 10%; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;"> </div>
    <div style="text-align: center; color: #000000; font-weight: bold;">2855 Gazelle Court</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">Carlsbad, CA 92010</div>
    <div style="text-align: center; color: #000000;">(Address of principal executive offices, including zip code)</div>
    <div><br>
    </div>
    <div>
      <hr noshade="noshade" align="center" style="height: 2px; width: 10%; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;"> </div>
    <div style="text-align: center; color: #000000; font-weight: bold;">Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan</div>
    <div style="text-align: center; color: #000000;">(Full title of the plan)</div>
    <div><br>
    </div>
    <div style="text-align: center; color: #000000; font-weight: bold;">Brett Monia</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">Chief Executive Officer</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">2855 Gazelle Court</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">Carlsbad, California 92010</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">(760) 931-9200</div>
    <div style="text-align: center; color: #000000;">(Name, address, and telephone number, including area code, of agent for service)</div>
    <div><br>
    </div>
    <div>
      <hr noshade="noshade" align="center" style="height: 2px; width: 10%; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;"> </div>
    <div style="text-align: center; color: #000000;">Copies to:</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">Patrick R. O&#8217;Neil, Esq.</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">Executive Vice President, Chief Legal Officer, General Counsel and Corporate Secretary</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">IONIS PHARMACEUTICALS, INC.</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">2855 Gazelle Court</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">Carlsbad, California 92010</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">(760) 931-9200</div>
    <div><br>
    </div>
    <div style="text-align: justify; color: rgb(0, 0, 0);">Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company or an emerging growth company. See the
      definitions of &#8220;large accelerated filer,&#8221; &#8220;accelerated filer,&#8221; &#8220;smaller reporting company,&#8221; and &#8220;emerging growth company&#8221; in Rule 12b-2 of the Exchange Act.</div>
    <div style="text-align: justify; color: rgb(0, 0, 0);"> <br>
    </div>
    <table cellspacing="0" cellpadding="0" border="0" id="zb8d8c09d975e4b838eaf1bd1802e13b9" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">

        <tr>
          <td style="width: 50%; vertical-align: top;">
            <div style="text-align: center; color: rgb(0, 0, 0);">Large accelerated filer &#9746;</div>
          </td>
          <td style="width: 50%; vertical-align: top;">
            <div style="text-align: center; color: rgb(0, 0, 0);">Accelerated filer &#9744;</div>
          </td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">
            <div style="text-align: center; color: rgb(0, 0, 0);">Non-accelerated filer &#9744;</div>
          </td>
          <td style="width: 50%; vertical-align: top;">
            <div style="text-align: center; color: #000000;">Smaller reporting company &#9744;</div>
          </td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="width: 50%; vertical-align: top;">
            <div style="text-align: center; color: #000000;">Emerging growth company &#9744;</div>
          </td>
        </tr>

    </table>
    <div style="text-align: justify; color: rgb(0, 0, 0);"> <br>
    </div>
    <div style="text-align: justify; color: rgb(0, 0, 0);">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. &#9744;</div>
    <div style="text-align: justify; color: rgb(0, 0, 0);"> <br>
    </div>
    <div style="text-align: justify; color: rgb(0, 0, 0);">
      <hr align="center" style="border: none; border-bottom: 4px solid black; border-top: 1px solid black; height: 10px; color: #ffffff; background-color: #ffffff; text-align: center; margin-left: auto; margin-right: auto;"> </div>
    <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div class="BRPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: center; color: #000000; font-weight: bold;">PART I</div>
    <div>&#160;</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">INFORMATION REQUIRED IN THE SECTION 10(A) PROSPECTUS</div>
    <div>&#160;</div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000;">The information called for by Part I of Form S-8 is omitted from this Registration Statement in accordance with Rule 428 of the Securities Act and the instructions to Form S-8. In
      accordance with the rules and regulations of the Securities and Exchange Commission (the &#8220;<font style="font-weight: bold; font-style: italic;">Commission</font>&#8221;) and the instructions to Form S-8, such documents are not being filed with the
      Commission either as part of this Registration Statement or as prospectuses or prospectus supplements pursuant to Rule 424.</div>
    <div>&#160;</div>
    <div style="text-align: center; color: #000000; font-weight: bold;">Part II</div>
    <div><br>
    </div>
    <div style="text-align: center; color: #000000; font-weight: bold;">INFORMATION REQUIRED IN THE REGISTRATION STATEMENT</div>
    <div><br>
    </div>
    <div style="color: #000000; font-weight: bold;">
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="z07e98eb3f34340dcbcb86615aaa93746">

          <tr>
            <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0); font-weight: bold;">Item 3.</td>
            <td style="width: auto; vertical-align: top;">
              <div style="color: #000000; font-weight: bold;">Incorporation of Documents by Reference.</div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000;">The following documents filed with the Commission by the Registrant are hereby incorporated by reference into this Registration Statement:</div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z14664d035d8e459ebe680397e13cca3f" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;">&#160;</td>
          <td style="width: 27pt; vertical-align: top;">(a)</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div>the Registrant&#8217;s Annual Report on Form 10-K for the year ended December 31, 2024, as filed with the Commission on<font style="color: rgb(5, 99, 193);">&#160;</font><a href="https://www.sec.gov/ix?doc=/Archives/edgar/data/0000874015/000087401525000089/form10k.htm">February 19, 2025</a>,<font style="color: rgb(0, 0, 0);"> and the information specifically incorporated by reference into the Registrant&#8217;s
                Annual Report on Form 10-K for the year ended December 31, 2024, from the Registrant&#8217;s Definitive Proxy Statement on Schedule 14A, as filed with the Commission on</font><font style="color: rgb(5, 99, 193);">&#160;</font><a href="https://www.sec.gov/ix?doc=/Archives/edgar/data/0000874015/000114036125015771/ny20041859x1_def14a.htm">April 25, 2025</a>;</div>
          </td>
        </tr>

    </table>
    <table cellspacing="0" cellpadding="0" id="zdf26e5d5c3f24920b7e40a020fe7ab5d" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;"></td>
          <td style="width: 27pt; vertical-align: top;">(b)</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div>the Registrant&#8217;s Quarterly Report on Form 10-Q for the quarterly period ended March 31, 2025, as filed with the Commission on<font style="color: rgb(5, 99, 193);">&#160;</font><a href="https://www.sec.gov/ix?doc=/Archives/edgar/data/0000874015/000087401525000123/form10q.htm">April 30, 2025</a> and Quarterly Report on Form 10-Q for the quarterly period ended June 30, 2025, as filed with the Commission on<font style="color: rgb(5, 99, 193);"> <font style="background-color: rgb(255, 255, 255); font-weight: normal; font-style: normal; font-variant: normal; text-transform: none;"><a href="https://www.sec.gov/ix?doc=/Archives/edgar/data/874015/000087401525000167/form10q.htm">July 30, 2025</a></font></font><font style="color: rgb(0, 0, 0);">;</font></div>
          </td>
        </tr>

    </table>
    <table cellspacing="0" cellpadding="0" id="z2a73f136bc16461eb4a1d86f3d10fa1a" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;"></td>
          <td style="width: 27pt; vertical-align: top;">(c)</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div>the Registrant&#8217;s Current Reports on Form 8-K filed with the Commission on<font style="color: rgb(5, 99, 193);">&#160;</font><a href="https://www.sec.gov/ix?doc=/Archives/edgar/data/0000874015/000114036125008178/ef20045255_8k.htm">March 12, 2025</a>,<font style="color: rgb(5, 99, 193);">&#160;</font><a href="https://www.sec.gov/ix?doc=/Archives/edgar/data/0000874015/000114036125019620/ef20049265_8k.htm">May 19, 2025</a>,<font style="color: rgb(5, 99, 193);">&#160;</font><a href="https://www.sec.gov/ix?doc=/Archives/edgar/data/0000874015/000114036125022001/ef20050437_8k.htm">June 10, 2025</a> and <a href="https://www.sec.gov/ix?doc=/Archives/edgar/data/0000874015/000114036125022267/ef20050532_8k.htm">June 12,
                2025</a>; and</div>
          </td>
        </tr>

    </table>
    <table cellspacing="0" cellpadding="0" id="z0cad05f0dab24041a7ed52a390d21220" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;"></td>
          <td style="width: 27pt; vertical-align: top;">(d)</td>
          <td style="width: auto; vertical-align: top;">
            <div>the description of the Registrant&#8217;s Common Stock contained in the Registrant&#8217;s registration statement on Form 8-A filed with the SEC on April 12, 1991, as updated by its Certificate of Amendment of its Restated Certificate of Incorporation
              filed with its Definitive Proxy Statement on Schedule 14A filed on <a href="https://www.sec.gov/Archives/edgar/data/874015/000114036114017588/formdef14a.htm">April 25, 2014</a>, and its Certificate of Amendment of its Restated Certificate of
              Incorporation filed with its current report on Form 8-K filed on <a href="https://www.sec.gov/Archives/edgar/data/874015/000114036115045083/ex3_1.htm">December 18, 2015</a>.</div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000;">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;<font style="font-weight: bold; font-style: italic;">Exchange Act</font>&#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; provided, however, that documents or information or portions thereof
      deemed to have been furnished and not filed in accordance with Commission rules shall not be deemed incorporated by reference into this Registration Statement. Any statement contained herein or in a document, all or a portion of which is incorporated
      or deemed to be incorporated by reference herein, shall be deemed to be modified or superseded for purposes of this Registration Statement to the extent that a statement contained herein or in any other subsequently filed document which also is or is
      deemed to be incorporated by reference herein modifies or supersedes such statement. Any statement so modified or superseded shall not be deemed, except as so modified or superseded, to constitute a part of this Registration Statement.</div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000;"> <br>
    </div>
    <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div class="BRPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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    <table cellspacing="0" cellpadding="0" id="zc068878462c640adb3daec47bf29289f" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0); font-weight: bold;">Item 5.</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div style="color: rgb(0, 0, 0); font-weight: bold;">Interests of Named Experts and Counsel.</div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000;">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, Chief
      Legal Officer, General Counsel and Corporate Secretary of Ionis.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000;">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>
    <table cellspacing="0" cellpadding="0" id="z2a38abcf62cd4445a2d9e5efb3fd6e70" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0); font-weight: bold;">Item 6.</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div style="color: rgb(0, 0, 0); font-weight: bold;">Indemnification of Directors and Officers.</div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000;">Under Section 145 of the Delaware General Corporation Law (the &#8220;<font style="font-weight: bold; font-style: italic;">DGCL</font>&#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; color: #000000;">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&#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. 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. 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; color: #000000;">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; color: #000000;">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>
    <div style="text-align: justify; text-indent: 36pt; color: #000000;"> <br>
    </div>
    <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div class="BRPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div>
      <table cellspacing="0" cellpadding="0" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;" class="DSPFListTable" id="zb4f9be16a10442b5a7bcefa070c1a13f">

          <tr>
            <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0); font-weight: bold;">Item 8.</td>
            <td style="width: auto; vertical-align: top;">
              <div style="color: #000000; font-weight: bold;">Exhibits.</div>
            </td>
          </tr>

      </table>
    </div>
    <div><br>
    </div>
    <table cellspacing="0" cellpadding="0" border="0" id="z463f1e82ce38488fac521cafd5636159" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">

        <tr>
          <td style="width: 12%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: justify; color: rgb(0, 0, 0); font-weight: bold;">Exhibit Number</div>
          </td>
          <td style="width: 1.4%; vertical-align: top;">&#160;</td>
          <td style="width: 87%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: justify; color: rgb(0, 0, 0); font-weight: bold;">Description</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;">4.1</div>
          </td>
          <td style="width: 1.4%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 87%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;">Amended and Restated Certificate of Incorporation (1).</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top;">
            <div style="text-align: justify;">4.2</div>
          </td>
          <td style="width: 1.4%; vertical-align: top;">&#160;</td>
          <td style="width: 87%; vertical-align: top;">
            <div style="text-align: justify;">Certificate of Amendment to Restated Certificate of Incorporation (2).</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;">4.3</div>
          </td>
          <td style="width: 1.4%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 87%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;">Certificate of Amendment to Restated Certificate of Incorporation (3).</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top;">
            <div style="text-align: justify;">4.4</div>
          </td>
          <td style="width: 1.4%; vertical-align: top;">&#160;</td>
          <td style="width: 87%; vertical-align: top;">
            <div style="text-align: justify;">Amended and Restated Bylaws (4).</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;">4.5</div>
          </td>
          <td style="width: 1.4%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 87%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;">Certificate of Designation of the Series C Junior Participating Preferred Stock (5).</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top;">
            <div style="text-align: justify;">4.6</div>
          </td>
          <td style="width: 1.4%; vertical-align: top;">&#160;</td>
          <td style="width: 87%; vertical-align: top;">
            <div style="text-align: justify;">Specimen Common Stock Certificate (6).</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><a href="ef20052672_ex5-1.htm">5.1</a></div>
          </td>
          <td style="width: 1.4%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 87%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;">Opinion of Patrick R. O&#8217;Neil.</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top;">
            <div style="text-align: justify;"><a href="ef20052672_ex23-1.htm">23.1</a></div>
          </td>
          <td style="width: 1.4%; vertical-align: top;">&#160;</td>
          <td style="width: 87%; vertical-align: top;">
            <div style="text-align: justify;">Consent of Independent Registered Public Accounting Firm.</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;"><a href="ef20052672_ex5-1.htm">23.2</a></div>
          </td>
          <td style="width: 1.4%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 87%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;">Consent of Patrick R. O&#8217;Neil. Reference is made to Exhibit 5.1.</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top;">
            <div style="text-align: justify;"><a href="#POWEROFATTORNEY">24.1</a></div>
          </td>
          <td style="width: 1.4%; vertical-align: top;">&#160;</td>
          <td style="width: 87%; vertical-align: top;">
            <div style="text-align: justify;">Power of Attorney is contained on the signature pages.</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;">99.1</div>
          </td>
          <td style="width: 1.4%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 87%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan (7).</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top;">
            <div style="text-align: justify;">99.2</div>
          </td>
          <td style="width: 1.4%; vertical-align: top;">&#160;</td>
          <td style="width: 87%; vertical-align: top;">
            <div style="text-align: justify;">Form of Option Agreement for Options granted under the Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan (8).</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;">99.3</div>
          </td>
          <td style="width: 1.4%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 87%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Form of Time-Vested Restricted Stock Unit Agreement for Restricted Stock Units granted under the Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan (9).</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top;">
            <div style="text-align: justify;">99.4</div>
          </td>
          <td style="width: 1.4%; vertical-align: top;">&#160;</td>
          <td style="width: 87%; vertical-align: top;">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Forms of Performance Based Restricted Stock Unit Grant Notice and Performance Based Restricted Stock Unit Agreement for Performance Based Restricted Stock Units granted prior to January 1,
              2023 under the Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan (10).</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify;">99.5</div>
          </td>
          <td style="width: 1.4%; vertical-align: top; background-color: rgb(204, 238, 255);">&#160;</td>
          <td style="width: 87%; vertical-align: top; background-color: rgb(204, 238, 255);">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Forms of Performance Based Restricted Stock Unit Grant Notice and Performance Based Restricted Stock Unit Agreement for Performance Based Restricted Stock Units granted beginning January 1,
              2023 under the Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan (11).</div>
          </td>
        </tr>
        <tr>
          <td style="width: 12%; vertical-align: top;">
            <div style="text-align: justify;"><a href="ef20052672_ex107.htm">107</a></div>
          </td>
          <td style="width: 1.4%; vertical-align: top;">&#160;</td>
          <td style="width: 87%; vertical-align: top;">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Filing Fee Table.</div>
          </td>
        </tr>

    </table>
    <div> <br>
    </div>
    <table cellspacing="0" cellpadding="0" id="z6359f1abf55c4f96a36647a26ab77929" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;">&#160;</td>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(1)</td>
          <td style="width: auto; vertical-align: top;">
            <div><font style="color: #000000;">Filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended </font><a href="https://www.sec.gov/Archives/edgar/data/874015/000087401518000047/exhibit3_1.htm">December 31, 2017</a><font style="color: rgb(0, 0, 0);">, and incorporated herein by reference.</font></div>
          </td>
        </tr>

    </table>
    <table cellspacing="0" cellpadding="0" id="z003e0b316ad54652aca552494f299b1f" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;"></td>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(2)</td>
          <td style="width: auto; vertical-align: top;">
            <div>Filed as an appendix to the Registrant&#8217;s Notice of 2014 Annual Meeting of Stockholders and Proxy Statement filed on <a href="https://www.sec.gov/Archives/edgar/data/874015/000114036114017588/formdef14a.htm">April 25, 2014</a>, <font style="color: rgb(0, 0, 0);">and incorporated herein by reference.</font></div>
          </td>
        </tr>

    </table>
    <table cellspacing="0" cellpadding="0" id="ze445abd61c6740f78fbb805703508bf8" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;"></td>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(3)</td>
          <td style="width: auto; vertical-align: top;">
            <div><font style="color: #000000;">Filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed </font><a href="https://www.sec.gov/Archives/edgar/data/874015/000114036115045083/ex3_1.htm">December 18, 2015</a><font style="color: rgb(0, 0, 0);">, and incorporated herein by reference.</font></div>
          </td>
        </tr>

    </table>
    <table cellspacing="0" cellpadding="0" id="z9b57d237830247c3b80b3fa73251aeb4" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;"></td>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(4)</td>
          <td style="width: auto; vertical-align: top;">
            <div><font style="color: #000000;">Filed as an exhibit to the Registrant&#8217;s Current Report on Form 8-K filed </font><a href="https://www.sec.gov/Archives/edgar/data/874015/000114036121010402/brhc10022399_ex3-1.htm">March 29, 2021</a><font style="color: rgb(0, 0, 0);">, and incorporated herein by reference.</font></div>
          </td>
        </tr>

    </table>
    <table cellspacing="0" cellpadding="0" id="z26357195c9a24279b014ccc32e0a8d95" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;"></td>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(5)</td>
          <td style="width: auto; vertical-align: top;">
            <div><font style="color: #000000;">Filed as an exhibit to Registrant&#8217;s Current Report on Form 8-K filed </font><a href="https://www.sec.gov/Archives/edgar/data/874015/000091205700053343/a2032851zex-4_2.txt">December 13, 2000</a><font style="color: rgb(0, 0, 0);">, and incorporated herein by reference.</font></div>
          </td>
        </tr>

    </table>
    <table cellspacing="0" cellpadding="0" id="z92cd5b41f50f41a3a6ce8be1880ac4cd" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;"></td>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(6)</td>
          <td style="width: auto; vertical-align: top;">
            <div><font style="color: #000000;">Filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended </font><a href="https://www.sec.gov/Archives/edgar/data/874015/000087401518000047/exhibit4_2.htm">December 31, 2017</a><font style="color: rgb(0, 0, 0);">, and incorporated herein by reference.</font></div>
          </td>
        </tr>

    </table>
    <table cellspacing="0" cellpadding="0" id="za3917cf0d2cf41baa00de1b9ce314968" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;"></td>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(7)</td>
          <td style="width: auto; vertical-align: top;">
            <div><font style="color: #000000;">Filed as an appendix to the Registrant&#8217;s </font>Notice of 2025 Annual Meeting of Stockholders and Proxy Statement filed with the SEC on <a href="https://www.sec.gov/ix?doc=/Archives/edgar/data/0000874015/000114036125015771/ny20041859x1_def14a.htm">April 25, 2025</a><font style="color: rgb(0, 0, 0);">, and incorporated herein by reference.</font></div>
          </td>
        </tr>

    </table>
    <table cellspacing="0" cellpadding="0" id="z67027eb821b94143a53e00af5d95cb85" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;"></td>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(8)</td>
          <td style="width: auto; vertical-align: top;">
            <div><font style="color: #000000;">Filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year December 31, 2022, filed with the SEC on </font><a href="https://www.sec.gov/Archives/edgar/data/874015/000087401523000105/exhibit10-13.htm">February 22, 2023</a><font style="color: rgb(0, 0, 0);">, and incorporated herein by reference.</font></div>
          </td>
        </tr>

    </table>
    <table cellspacing="0" cellpadding="0" id="z97c66d588a4948d4b8dc95ce21713389" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;"></td>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(9)</td>
          <td style="width: auto; vertical-align: top;">
            <div><font style="color: #000000;">Filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year December 31, 2022, filed with the SEC on </font><a href="https://www.sec.gov/Archives/edgar/data/874015/000087401523000105/exhibit10-14.htm">February 22, 2023</a><font style="color: rgb(0, 0, 0);">, and incorporated herein by reference.</font></div>
          </td>
        </tr>

    </table>
    <table cellspacing="0" cellpadding="0" id="z236149fe4570463d9158c067295d372c" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;"></td>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(10)</td>
          <td style="width: auto; vertical-align: top;">
            <div><font style="color: #000000;">Filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended </font><a href="https://www.sec.gov/Archives/edgar/data/874015/000087401522000079/exhibit10-19.htm">December 31, 2021</a><font style="color: rgb(0, 0, 0);">, and incorporated herein by reference.</font></div>
          </td>
        </tr>

    </table>
    <table cellspacing="0" cellpadding="0" id="z7434f51cacbe4ea48bb6a15fa1705053" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 18pt;"></td>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(11)</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div><font style="color: #000000;">Filed as an exhibit to the Registrant&#8217;s Annual Report on Form 10-K for the year ended </font><a href="https://www.sec.gov/Archives/edgar/data/874015/000087401523000105/exhibit10-16.htm">December 31, 2022</a><font style="color: rgb(0, 0, 0);">, and incorporated herein by reference.</font></div>
          </td>
        </tr>

    </table>
    <div> <br>
    </div>
    <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div class="BRPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <table cellspacing="0" cellpadding="0" id="z536c4e0501d44677939b477b9d75ced0" class="DSPFListTable" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000;">

        <tr>
          <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0); font-weight: bold;">Item 9.</td>
          <td style="width: auto; vertical-align: top; text-align: justify;">
            <div style="color: rgb(0, 0, 0); font-weight: bold;">Undertakings.</div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: -36pt; margin-left: 36pt; color: #000000;">(a) The undersigned Registrant hereby undertakes:</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000;">(1) To file, during any period in which offers or sales are being made, a post-effective amendment to this Registration Statement:</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 72pt; color: #000000;">(i) To include any prospectus required by section 10(a)(3) of the Securities Act;</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 72pt; color: #000000;">(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 &#8220;Calculation of Filing Fee Tables&#8221; or &#8220;Calculation of Registration Fee&#8221; table, as applicable, in the effective
      Registration Statement; and</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 72pt; color: #000000;">(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;</div>
    <div><br>
    </div>
    <div style="text-align: justify; color: #000000;"><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 Exchange Act that are incorporated by reference in the Registration Statement.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000;">(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 <font style="font-style: italic;">bona fide</font> offering thereof.</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000;">(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.</div>
    <div><br>
    </div>
    <div style="text-align: justify; color: #000000;">(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 style="text-align: justify; color: #000000;"> <br>
    </div>
    <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div class="BRPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
    </div>
    <div style="text-align: justify; color: #000000;">(h) 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 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.</div>
    <div style="text-align: justify; color: #000000;"> <br>
    </div>
    <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div class="BRPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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    <div style="text-align: center; color: #000000; font-weight: bold;">SIGNATURES</div>
    <div><br>
    </div>
    <div style="text-align: justify; text-indent: 36pt; color: #000000;">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 July 30, 2025.</div>
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        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="vertical-align: top;" colspan="2">
            <div style="text-align: justify; color: rgb(0, 0, 0); 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: 5%; vertical-align: top;">
            <div style="text-align: justify; color: rgb(0, 0, 0);">By:</div>
          </td>
          <td style="width: 45%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: justify; color: rgb(0, 0, 0);">/s/ Brett Monia</div>
          </td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="vertical-align: top;" colspan="2">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Brett Monia</div>
          </td>
        </tr>
        <tr>
          <td style="width: 50%; vertical-align: top;">&#160;</td>
          <td style="vertical-align: top;" colspan="2">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Chief Executive Officer</div>
          </td>
        </tr>

    </table>
    <div><br>
    </div>
    <div style="text-align: center; color: #000000; font-weight: bold;"><a name="POWEROFATTORNEY"><!--Anchor--></a>POWER OF ATTORNEY</div>
    <div><br>
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    <div style="text-align: justify; text-indent: 36pt; color: #000000;"><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 Brett Monia and Elizabeth Hougen, and each or any one of them, as 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; color: #000000;">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>
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        <tr>
          <td style="width: 37.51%; vertical-align: top;">
            <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold;">Signature</div>
          </td>
          <td style="width: 39.06%; vertical-align: top;">
            <div style="text-align: center; margin-left: 9pt; color: rgb(0, 0, 0); font-weight: bold;">Title</div>
          </td>
          <td style="width: 23.44%; vertical-align: top;">
            <div style="text-align: center; color: rgb(0, 0, 0); font-weight: bold;">Date</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="color: rgb(0, 0, 0);">/s/ Brett Monia</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;" rowspan="2">
            <div style="text-align: center; margin-left: 9pt; color: #000000;">Chief Executive Officer</div>
            <div style="text-align: center; margin-left: 9.35pt; color: #000000;">(Principal Executive Officer)</div>
          </td>
          <td style="width: 23.44%; vertical-align: bottom;" rowspan="2">
            <div style="text-align: center; color: rgb(0, 0, 0);">July 30, 2025</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">
            <div style="color: rgb(0, 0, 0);">Brett Monia</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">&#160;</td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="color: rgb(0, 0, 0);">/s/ Elizabeth Hougen</div>
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          <td style="width: 39.06%; vertical-align: bottom;" rowspan="2">
            <div style="text-align: center; text-indent: 4.5pt; margin-right: 13.4pt; margin-left: 32.95pt; color: #000000;">Chief Financial Officer</div>
            <div style="text-align: center; text-indent: 4.5pt; margin-right: 13.4pt; margin-left: 32.95pt; color: #000000;">(Principal Financial Officer and Principal Accounting Officer)</div>
          </td>
          <td style="width: 23.44%; vertical-align: bottom;" rowspan="2">
            <div style="text-align: center; color: rgb(0, 0, 0);">July 30, 2025</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">
            <div style="color: rgb(0, 0, 0);">Elizabeth Hougen</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">&#160;</td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="color: rgb(0, 0, 0);">/s/ Joseph Loscalzo</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">
            <div style="text-align: center; margin-left: 9pt; color: rgb(0, 0, 0);">Chairman of the Board</div>
          </td>
          <td style="width: 23.44%; vertical-align: bottom;">
            <div style="text-align: center; color: rgb(0, 0, 0);">July 30, 2025</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">
            <div style="color: rgb(0, 0, 0);">Joseph Loscalzo</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">&#160;</td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="color: rgb(0, 0, 0);">/s/ Spencer R. Berthelsen</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">
            <div style="text-align: center; margin-left: 9pt; color: rgb(0, 0, 0);">Director</div>
          </td>
          <td style="width: 23.44%; vertical-align: bottom;">
            <div style="text-align: center; color: rgb(0, 0, 0);">July 30, 2025</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">
            <div style="color: rgb(0, 0, 0);">Spencer R. Berthelsen</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">&#160;</td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="color: rgb(0, 0, 0);">/s/ Allene Diaz</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">
            <div style="text-align: center; margin-left: 9pt; color: rgb(0, 0, 0);">Director</div>
          </td>
          <td style="width: 23.44%; vertical-align: bottom;">
            <div style="text-align: center; color: rgb(0, 0, 0);">July 30, 2025</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">
            <div style="color: rgb(0, 0, 0);">Allene Diaz</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">&#160;</td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="color: rgb(0, 0, 0);">/s/ Michael Hayden</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">
            <div style="text-align: center; margin-left: 9pt; color: rgb(0, 0, 0);">Director</div>
          </td>
          <td style="width: 23.44%; vertical-align: bottom;">
            <div style="text-align: center; color: rgb(0, 0, 0);">July 30, 2025</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">
            <div style="color: rgb(0, 0, 0);">Michael Hayden</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">&#160;</td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="color: rgb(0, 0, 0);">/s/ Joan Herman</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">
            <div style="text-align: center; margin-left: 9pt; color: rgb(0, 0, 0);">Director</div>
          </td>
          <td style="width: 23.44%; vertical-align: bottom;">
            <div style="text-align: center; color: rgb(0, 0, 0);">July 30, 2025</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">
            <div style="color: rgb(0, 0, 0);">Joan Herman</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>

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    <div class="BRPFPageBreakArea" style="clear: both; margin-top: 10pt; margin-bottom: 10pt;">
      <div class="BRPFPageBreak" style="page-break-after: always;">
        <hr noshade="noshade" style="margin: 4px 0px; width: 100%; border-width: 0; height: 2px; color: #000000; background-color: #000000; clear: both;"></div>
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        <tr>
          <td style="width: 37.51%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="color: rgb(0, 0, 0);">/s/ Joseph Klein, III</div>
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          <td style="width: 39.06%; vertical-align: bottom;">
            <div style="text-align: center; margin-left: 9pt; color: rgb(0, 0, 0);">Director</div>
          </td>
          <td style="width: 23.44%; vertical-align: bottom;">
            <div style="text-align: center; color: rgb(0, 0, 0);">July 30, 2025</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Joseph Klein, III</div>
          </td>
          <td style="width: 39.06%; vertical-align: top;">&#160;</td>
          <td style="width: 23.44%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">&#160;</td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="color: rgb(0, 0, 0);">/s/ B. Lynne Parshall</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">
            <div style="text-align: center; margin-left: 9pt; color: rgb(0, 0, 0);">Director</div>
          </td>
          <td style="width: 23.44%; vertical-align: bottom;">
            <div style="text-align: center; color: rgb(0, 0, 0);">July 30, 2025</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">
            <div style="text-align: justify; color: rgb(0, 0, 0);">B. Lynne Parshall</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">&#160;</td>
          <td style="width: 39.06%; vertical-align: bottom;">&#160;</td>
          <td style="width: 23.44%; vertical-align: bottom;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="color: rgb(0, 0, 0);">/s/ Joseph Wender</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">
            <div style="text-align: center; margin-left: 9pt; color: rgb(0, 0, 0);">Director</div>
          </td>
          <td style="width: 23.44%; vertical-align: bottom;">
            <div style="text-align: center; color: rgb(0, 0, 0);">July 30, 2025</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Joseph Wender</div>
          </td>
          <td style="width: 39.06%; vertical-align: top;">&#160;</td>
          <td style="width: 23.44%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td rowspan="1" style="width: 37.51%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 39.06%; vertical-align: top;">&#160;</td>
          <td rowspan="1" style="width: 23.44%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: bottom; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="color: rgb(0, 0, 0);">/s/ Michael Yang</div>
          </td>
          <td style="width: 39.06%; vertical-align: bottom;">
            <div style="text-align: center; margin-left: 9pt; color: rgb(0, 0, 0);">Director</div>
          </td>
          <td style="width: 23.44%; vertical-align: bottom;">
            <div style="text-align: center; color: rgb(0, 0, 0);">July 30, 2025</div>
          </td>
        </tr>
        <tr>
          <td style="width: 37.51%; vertical-align: top;">
            <div style="text-align: justify; color: rgb(0, 0, 0);">Michael Yang</div>
          </td>
          <td style="width: 39.06%; vertical-align: top;">&#160;</td>
          <td style="width: 23.44%; vertical-align: top;">&#160;</td>
        </tr>

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      <hr noshade="noshade" align="center" style="height: 2px; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;"> </div>
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</DOCUMENT>
<DOCUMENT>
<TYPE>EX-5.1
<SEQUENCE>2
<FILENAME>ef20052672_ex5-1.htm
<DESCRIPTION>EXHIBIT 5.1
<TEXT>
<html>
  <head>
    <title></title>
    <!-- Licensed to: Broadridge Financial Solutions, Inc.
         Document created using Broadridge PROfile 25.7.1.5324
         Copyright 1995 - 2025 Broadridge -->
  </head>
<body bgcolor="#ffffff" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000;">
  <hr noshade="noshade" align="center" style="height: 4px; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;">
  <div>
    <div style="text-align: right; font-weight: bold;">Exhibit 5.1</div>
    <div><br>
    </div>
    <div style="text-align: justify;">July 30, 2025</div>
    <div style="text-align: justify;"> <br>
    </div>
    <div style="text-align: justify;">Ionis Pharmaceuticals, Inc.</div>
    <div style="text-align: justify;">2855 Gazelle Court</div>
    <div style="text-align: justify;">Carlsbad, CA 92010</div>
    <div style="text-align: justify;"> <br>
    </div>
    <div style="text-align: justify;">Ladies and Gentlemen:</div>
    <div style="text-align: justify;"> <br>
    </div>
    <div style="text-align: justify;">You have requested my opinion with respect to certain matters in connection with the filing by Ionis Pharmaceuticals, Inc.&#160; (the &#8220;<font style="font-weight: bold; font-style: italic;">Company</font>&#8221;) of a Registration Statement on Form S-8 (the &#8220;<font style="font-weight: bold; font-style: italic;">Registration
        Statement</font>&#8221;) with the Securities and Exchange Commission, covering the offering of an additional 4,000,000 shares of the Company&#8217;s Common Stock, $.001 par value (the &#8220;<font style="font-weight: bold; font-style: italic;">Shares</font>&#8221;), of which, 4,000,000 Shares are issuable pursuant to its Amended and Restated 2011 Equity Incentive Plan (the &#8220;<font style="font-weight: bold; font-style: italic;">2011 Plan</font>&#8221;) as described in the Registration Statement.</div>
    <div style="text-align: justify;"> <br>
    </div>
    <div style="text-align: justify;">In connection with this opinion, I have examined and relied upon the Registration Statement, the Company&#8217;s Restated Certificate of Incorporation, as amended, and Bylaws
      and the originals or copies certified to my satisfaction, of such records, documents, certificates, memoranda and other instruments as in my judgment are necessary or appropriate to enable me to render the opinion expressed below.</div>
    <div style="text-align: justify;"> <br>
    </div>
    <div style="text-align: justify;">On the basis of the foregoing, and in reliance thereon, I am of the opinion that the Shares, when issued and sold in accordance with the 2011 Plan and related
      prospectuses, will be validly issued, fully paid and nonassessable.</div>
    <div style="text-align: justify;"> <br>
    </div>
    <div style="text-align: justify;">I consent to the reference to myself under the caption &#8220;Interests of Named Experts and Counsel&#8221; in the Registration Statement and to the filing of this opinion as an
      exhibit to the Registration Statement.</div>
    <div style="text-align: center;"> <br>
    </div>
    <table cellspacing="0" cellpadding="0" border="0" id="z63193ade68b442949815a4c6825021fb" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; border-collapse: collapse; text-align: left; color: #000000;">

        <tr>
          <td style="width: 45%; vertical-align: top;">
            <div style="text-align: justify;">Very truly yours,</div>
          </td>
          <td style="width: 55%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 45%; vertical-align: top;"><br>
          </td>
          <td style="width: 55%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 45%; vertical-align: top; border-bottom: 2px solid rgb(0, 0, 0);">
            <div style="text-align: justify;">/s/Patrick R. O&#8217;Neil</div>
          </td>
          <td style="width: 55%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 45%; vertical-align: top;">&#160;</td>
          <td style="width: 55%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 45%; vertical-align: top;">
            <div style="text-align: justify;">Patrick R. O&#8217;Neil</div>
          </td>
          <td style="width: 55%; vertical-align: top;">&#160;</td>
        </tr>
        <tr>
          <td style="width: 45%; vertical-align: top;">
            <div style="text-align: justify;">Executive Vice President, Chief Legal Officer, General Counsel and Corporate Secretary</div>
          </td>
          <td style="width: 55%; vertical-align: top;">&#160;</td>
        </tr>

    </table>
    <div><br>
    </div>
    <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>
  </div>
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</html>
</TEXT>
</DOCUMENT>
<DOCUMENT>
<TYPE>EX-23.1
<SEQUENCE>3
<FILENAME>ef20052672_ex23-1.htm
<DESCRIPTION>EXHIBIT 23.1
<TEXT>
<html>
  <head>
    <title></title>
    <!-- Licensed to: Broadridge Financial Solutions, Inc.
         Document created using Broadridge PROfile 25.7.1.5324
         Copyright 1995 - 2025 Broadridge -->
  </head>
<body bgcolor="#ffffff" style="font-family: 'Times New Roman'; font-size: 10pt; text-align: left; color: #000000;">
  <hr noshade="noshade" align="center" style="height: 4px; color: #000000; background-color: #000000; text-align: center; margin-left: auto; margin-right: auto; border: none;">
  <div>
    <div style="text-align: right; margin-left: 36pt; font-weight: bold;">Exhibit 23.1</div>
    <div><br>
    </div>
    <div style="text-align: center; margin-left: 36pt; font-weight: bold;">Consent of Independent Registered Public Accounting Firm</div>
    <div><br>
    </div>
    <div>We consent to the incorporation by reference in the Registration Statement (Form S-8) pertaining to the Amended and Restated Ionis Pharmaceuticals, Inc. 2011
      Equity Incentive Plan of our reports dated February 19, 2025, with respect to the consolidated financial statements of Ionis Pharmaceuticals, Inc. and the effectiveness of internal control over financial reporting of Ionis Pharmaceuticals, Inc.
      included in its Annual Report (Form 10-K) for the year ended December 31, 2024, filed with the Securities and Exchange Commission.</div>
    <div><br>
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    <div>/s/ Ernst &amp; Young LLP</div>
    <div>&#160;</div>
    <div>San Diego, California</div>
    <div>July 30, 2025</div>
    <div><br>
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    <div style="text-align: right; font-weight: bold;">Exhibit 107</div>
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    <div style="text-align: center; color: #000000; font-weight: bold;">Calculation of Filing Fee Table</div>
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    <div style="text-align: center; color: #000000;">(Exact Name of Registrant as Specified in its Charter)</div>
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    <div style="text-align: center; color: #000000;"><span style="text-decoration:underline">Table 1: New Registered Securities</span></div>
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vertical-align: bottom; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);"> <div style="text-align: center; font-weight: bold;">Amount</div> <div style="text-align: center; font-weight: bold;">Registered</div> <div style="text-align: center; font-weight: bold;">(1)(2)</div> </td> <td style="width: 11.98%; vertical-align: bottom; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);"> <div style="text-align: center; font-weight: bold;">Proposed</div> <div style="text-align: center; font-weight: bold;">Maximum</div> <div style="text-align: center; font-weight: bold;">Offering</div> <div style="text-align: center; font-weight: bold;">Price Per</div> <div style="text-align: center; font-weight: bold;">Share (3)</div> </td> <td style="width: 16%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);"> <div style="text-align: center; font-weight: bold;">Maximum</div> <div style="text-align: center; font-weight: bold;">Aggregate</div> <div style="text-align: center; font-weight: bold;">Offering Price</div> </td> <td style="width: 11.94%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);"> <div style="text-align: center; font-weight: bold;">Fee Rate</div> </td> <td style="width: 11.96%; vertical-align: top; border-width: 2px; border-style: solid; border-color: rgb(0, 0, 0);"> <div style="text-align: center; font-weight: bold;">Amount of</div> <div style="text-align: center; font-weight: bold;">Registration</div> <div style="text-align: center; font-weight: bold;">Fee</div> </td> </tr> <tr> <td style="width: 9%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);"> <div style="text-align: center;"><ix:nonNumeric contextRef="c1" format="ixt:fixed-false" name="ffd:PrevslyPdFlg" id="ixv-138"><ix:nonNumeric contextRef="c1" name="ffd:OfferingSctyTp" id="ixv-139">Equity</ix:nonNumeric></ix:nonNumeric></div> </td> <td style="width: 15%; 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vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);"> <div style="text-align: center;">$<ix:nonFraction contextRef="c1" decimals="2" format="ixt:num-dot-decimal" name="ffd:FeeAmt" scale="0" unitRef="usd" id="ixv-146">25,249.25</ix:nonFraction></div> </td> </tr> <tr> <td colspan="4" style="vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);"> <div style="text-align: center;">Total Offering Amounts</div> </td> <td style="width: 11.98%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0);">&#160;</td> <td style="width: 16%; vertical-align: top; border-left: 2px solid rgb(0, 0, 0); border-right: 2px solid rgb(0, 0, 0); border-bottom: 2px solid rgb(0, 0, 0); text-align: center;"><span style="letter-spacing: normal; text-decoration-thickness: initial; 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            <div>Includes 4,000,000 shares issuable pursuant to the Registrant&#8217;s Amended and Restated 2011 Equity Incentive Plan<span style="color: #000000;">.</span></div>
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<span style="display: none;">v3.25.2</span><table class="report" border="0" cellspacing="2" id="id2">
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<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Submission<br></strong></div></th>
<th class="th"><div>Jul. 30, 2025</div></th>
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<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_dei_EntityCentralIndexKey', window );">Central Index Key</a></td>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>A unique 10-digit SEC-issued value to identify entities that have filed disclosures with the SEC. It is commonly abbreviated as CIK.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityCentralIndexKey</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The exact name of the entity filing the report as specified in its charter, which is required by forms filed with the SEC.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Exchange Act<br> -Number 240<br> -Section 12<br> -Subsection b-2<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">dei_EntityRegistrantName</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ffd_FeeExhibitTp</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ffd_FormTp</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ffd_SubmissionLineItems</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>na</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>No definition available.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ffd_SubmissnTp</td>
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<span style="display: none;">v3.25.2</span><table class="report" border="0" cellspacing="2" id="id2">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Offerings - Offering: 1<br></strong></div></th>
<th class="th">
<div>Jul. 30, 2025 </div>
<div>USD ($) </div>
<div>shares </div>
<div>$ / shares</div>
</th>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ffd_OfferingTable', window );"><strong>Offering:</strong></a></td>
<td class="text">&#160;<span></span>
</td>
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<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ffd_PrevslyPdFlg', window );">Fee Previously Paid</a></td>
<td class="text">false<span></span>
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</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ffd_FeesOthrRuleFlg', window );">Other Rule</a></td>
<td class="text">true<span></span>
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<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ffd_OfferingSctyTp', window );">Security Type</a></td>
<td class="text">Equity<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ffd_OfferingSctyTitl', window );">Security Class Title</a></td>
<td class="text">Common Stock, par value $.001 per share<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ffd_AmtSctiesRegd', window );">Amount Registered | shares</a></td>
<td class="nump">4,000,000<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ffd_MaxOfferingPricPerScty', window );">Proposed Maximum Offering Price per Unit | $ / shares</a></td>
<td class="nump">41.23<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ffd_MaxAggtOfferingPric', window );">Maximum Aggregate Offering Price</a></td>
<td class="nump">$ 164,920,000<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ffd_FeeRate', window );">Fee Rate</a></td>
<td class="nump">0.01531%<span></span>
</td>
</tr>
<tr class="ro">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ffd_FeeAmt', window );">Amount of Registration Fee</a></td>
<td class="nump">$ 25,249.25<span></span>
</td>
</tr>
<tr class="re">
<td class="pl" style="border-bottom: 0px;" valign="top"><a class="a" href="javascript:void(0);" onclick="Show.showAR( this, 'defref_ffd_OfferingNote', window );">Offering Note</a></td>
<td class="text"><table cellpadding="0" class="DSPFListTable" id="z4d17dd8b73b944f7bffd9e8288b8a175" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000; border-spacing: 0px;"> <tr> <td style="width: 27pt;">&#160;</td> <td style="width: 36pt; vertical-align: top; color: rgb(0, 0, 0);">(1)</td> <td style="width: auto; vertical-align: top;"> <div style="color: #000000;">In accordance with Rule 416(a) under the Securities Act, 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. to prevent dilution resulting from stock splits, stock dividends or similar transactions.</div> </td> </tr> </table><table cellpadding="0" class="DSPFListTable" id="zfd120b11d3014389a7b5cdfb7b11a49a" style="font-family: 'Times New Roman'; font-size: 10pt; width: 100%; text-align: left; color: #000000; border-spacing: 0px;">

        <tr>
          <td style="width: 27pt;">&#160;</td>
          <td style="width: 36pt; vertical-align: top; color: #000000;">(2)</td>
          <td style="width: auto; vertical-align: top;">
            <div>Includes 4,000,000 shares issuable pursuant to the Registrant&#8217;s Amended and Restated 2011 Equity Incentive Plan<span style="color: #000000;">.</span></div>
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          <td style="width: 27pt;">&#160;</td>
          <td style="width: 36pt; vertical-align: top; color: #000000;">(3)</td>
          <td style="width: auto; vertical-align: top;">
            <div style="color: #000000;">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 $41.23, which is the average of the high and low price per share of Registrant&#8217;s Common Stock on July 29, 2025, as reported on the Nasdaq Global Market.</div>
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<table border="0" cellpadding="0" cellspacing="0" class="authRefData" style="display: none;" id="defref_ffd_AmtSctiesRegd">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The amount of securities being registered.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ffd_AmtSctiesRegd</td>
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<td>na</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="Show.toggleNext( this );">- Definition</a><div><p>Total amount of registration fee (amount due after offsets).</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ffd_FeeAmt</td>
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<td>na</td>
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<td>duration</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The rate per dollar of fees that public companies and other issuers pay to register their securities with the Commission.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ffd_FeeRate</td>
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<td>duration</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Checkbox indicating whether filer is using a rule other than 457(a), 457(o), or 457(f) to calculate the registration fee due.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ffd_FeesOthrRuleFlg</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>
<td>duration</td>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The maximum aggregate offering price for the offering that is being registered.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ffd_MaxAggtOfferingPric</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>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_ffd_MaxOfferingPricPerScty">
<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
<tr><td><div class="body" style="padding: 2px;">
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The maximum offering price per share/unit being registered.</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
<td><strong> Name:</strong></td>
<td style="white-space:nowrap;">ffd_MaxOfferingPricPerScty</td>
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<tr>
<td style="padding-right: 4px;white-space:nowrap;"><strong> Namespace Prefix:</strong></td>
<td>ffd_</td>
</tr>
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<td><strong> Data Type:</strong></td>
<td>ffd:nonNegativeDecimal4lItemType</td>
</tr>
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<td><strong> Balance Type:</strong></td>
<td>na</td>
</tr>
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<td><strong> Period Type:</strong></td>
<td>duration</td>
</tr>
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<tr><td class="hide"><a style="color: white;" href="javascript:void(0);" onclick="Show.hideAR();">X</a></td></tr>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
<tr>
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<td style="white-space:nowrap;">ffd_OfferingNote</td>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>The title of the class of securities being registered (for each class being registered).</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- Definition</a><div><p>Type of securities: "Asset-backed Securities", "ADRs/ADSs", "Debt", "Debt Convertible into Equity", "Equity", "Face Amount Certificates", "Limited Partnership Interests", "Mortgage Backed Securities", "Non-Convertible Debt", "Unallocated (Universal) Shelf", "Exchange Traded Vehicle Securities", "Other"</p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ References</a><div style="display: none;"><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<span style="display: none;">v3.25.2</span><table class="report" border="0" cellspacing="2" id="id2">
<tr>
<th class="tl" colspan="1" rowspan="1"><div style="width: 200px;"><strong>Fees Summary<br></strong></div></th>
<th class="th">
<div>Jul. 30, 2025 </div>
<div>USD ($)</div>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br></p></div>
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br></p></div>
<a href="javascript:void(0);" onclick="Show.toggleNext( this );">+ Details</a><div style="display: none;"><table border="0" cellpadding="0" cellspacing="0">
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<a href="javascript:void(0);" onclick="Show.toggleNext( this );">- References</a><div><p>Reference 1: http://www.xbrl.org/2003/role/presentationRef<br> -Publisher SEC<br> -Name Securities Act<br> -Number 230<br></p></div>
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    <dei:EntityCentralIndexKey contextRef="c0" id="ixv-153">0000874015</dei:EntityCentralIndexKey>
    <ffd:FeeExhibitTp contextRef="c0" id="ixv-154">EX-FILING FEES</ffd:FeeExhibitTp>
    <ffd:SubmissnTp contextRef="c0" id="ixv-155">S-8</ffd:SubmissnTp>
</xbrl>
</XML>
</TEXT>
</DOCUMENT>
</SEC-DOCUMENT>
