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                           CERTIFICATE OF AMENDMENT OF
                    RESTATED CERTIFICATE OF INCORPORATION OF
                           ISIS PHARMACEUTICALS, INC.

          Isis Pharmaceuticals, Inc., a corporation organized and existing under
and by virtue of the General Corporation Law of the State of Delaware, does
hereby certify:

          FIRST: The name of the Corporation is Isis Pharmaceuticals, Inc. (the
"Corporation").

          SECOND: The date on which the Corporation's original Certificate of
Incorporation was filed with the Secretary of State of the State of Delaware is
March 25, 1991.

          THIRD: The Board of Directors of the Corporation, acting in accordance
with the provisions of Sections 141 and 242 of the General Corporation Law of
the State of Delaware, adopted resolutions at a meeting held on December 8, 2000
to amend Article V of the Restated Certificate of Incorporation of the
Corporation to read in its entirety as follows:

                      The Corporation is authorized to issue two classes of
                shares designated respectively "Common Stock" and "Preferred
                Stock." The total number of shares of all classes of stock which
                the Corporation has authority to issue is 115,000,000 shares,
                consisting of 100,000,000 shares of Common Stock, each having a
                par value of $.001, and 15,000,000 shares of Preferred Stock,
                each having a par value of $.001. The Preferred Stock may be
                issued in one or more series. The Board of Directors is
                authorized to fix the number of shares of any such series of
                Preferred Stock and to determine the designation of any such
                series (a "Preferred Stock Designation"), subject to (a) such
                stockholder approvals as may be provided for herein and (b) the
                number of shares of Preferred Stock authorized at that time by
                this Article V. Subject to such stockholder approvals as may be
                provided for herein, the Board of Directors is further
                authorized to determine or alter the rights, preferences,
                privileges and restrictions granted to or imposed upon any
                wholly unissued series of Preferred Stock, and to increase or
                decrease (but not below the number of shares of such series then
                outstanding) the number of shares of any series of Preferred
                Stock. In case the number of shares of any series shall be so
                decreased, the shares constituting such decrease shall resume
                the status that they had prior to the adoption of the resolution
                or amendment originally fixing the number of shares of such
                series.

          FOURTH: The foregoing amendment was submitted to the stockholders of
the Corporation for their approval and was duly adopted in accordance with the
provisions of Section 242 of the General Corporation Law of the State of
Delaware.

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          IN WITNESS WHEREOF, Isis Pharmaceuticals, Inc. has caused this
Certificate of Amendment to be signed by its duly authorized officers this 9th
day of April, 2001.


                                        By:  /s/ Stanley T. Crooke
                                             -----------------------------
                                             Stanley T. Crooke
                                             Chairman of the Board of Directors
                                             and Chief Executive Officer

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