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                                  EXHIBIT 10.10

Optionee:                                                        Date:
         ---------------------------                                  ----------

                           ISIS PHARMACEUTICALS, INC.
                       SUPPLEMENTAL STOCK OPTION AGREEMENT

Isis Pharmaceuticals, Inc. (the "Company"), pursuant to its 1989 Stock Option
Plan (the "Plan") has this day granted to the undersigned optionee, an option to
purchase shares of the common stock of the Company ("Common Stock") as described
herein. This option is not intended to qualify and will not be treated as an
"incentive stock option" within the meaning of Section 422 of the Internal
Revenue Code of 1986, as amended from time to time (the "Code"). This option is
subject to all of the terms and conditions as set forth herein and on Attachment
I hereto, which is incorporated herein in its entirety.

                  Number of Shares Subject to Option:__________

VESTING SCHEDULE:

<TABLE>
<CAPTION>
Number of Shares (installment)              Date of Earliest Exercise (vesting)(1)
------------------------------              ------------------------------------
<S>                                         <C>

          ------------                                  --------------

          ------------                                  --------------

          ------------                                  --------------
                                                                    >>
          ------------                                  --------------
                                                        <<          >>
          ------------                                  --------------
</TABLE>

*THIS OPTION WILL NOT BE EXERCISABLE, INCLUDING ANY VESTED SHARES, UNTIL THE
FOLLOWING OBJECTIVES ARE MET: (1) AS OF DECEMBER 31, 2000, THE AMOUNT OF CASH
AVAILABLE TO THE COMPANY IS GREATER THAN $40 MILLION; (2) THE COMPANY REACHES A
"GO/NO GO" DECISION ON FOUR PRODUCT OPPORTUNITIES (INDICATIONS); (3) THE
RESTRUCTURING OF THE COMPANY, AS DESCRIBED IN THE RESTRUCTURING PLAN PRESENTED
TO THE BOARD OF DIRECTORS ON JANUARY 6, 2000, IS SUCCESSFUL; AND (4) THE COMPANY
HAS COMPLETED AT LEAST ONE NEW CORPORATE PARTNERSHIP. IF SUCH OBJECTIVES ARE NOT
MET BY JANUARY 6, 2002 OR WAIVED BY THE BOARD OF DIRECTORS, THIS OPTION WILL
TERMINATE.

<TABLE>
<S>                                                    <C>
Exercise Price Per Share: <<                   >>(2)   Expiration Date:<<             >>(3)
                          -----------------------                      -----------------

Isis Pharmaceuticals, Inc.


By:                                                    Optionee:
   ---------------------------------                            -------------------------
Duly authorized on behalf of                           Address:
   the Board of Directors
</TABLE>

OPTIONEE:

Acknowledges receipt of the option as described herein and the attachments
referenced therein and understands that all rights and liabilities with respect
to this option are set forth in the option and the Plan; and acknowledges that
as of the date of grant of this option, it sets forth the entire understanding
between the optionee and the Company regarding the acquisition of stock in the
Company and supersedes all prior oral and written agreements on that subject.

(1) After the first year, the option will vest monthly with 2.08% of the total
grant vesting each month; provided, however, that during any period in which the
undersigned provides service at less than the Percentage of Full-Time Work set
forth above, a reduced number of shares will vest as follows: the percentage of
shares which will vest during such period of reduced service will equal (a) the
percentage of shares that would vest as set forth on this schedule, multiplied
by (b) the percentage of full-time work furnished during the period of reduced
service divided by the Percentage of Full Time Work as set forth above.
Increases of work percentage up to but not in excess of the Percentage of Full
Time Work specified above will result in a corresponding increase in the
percentage of shares vesting. This reduction in vesting will not apply during
any period of paid leave or the first 20 weeks of a period of unpaid leave. No
shares will vest during unpaid leave after the first 20 weeks of such leave.
Shares which do not vest because of reductions in work percentage or unpaid
leave will be canceled and no longer subject to this option.

(2) Not less than 85% of the fair market value of the Common Stock on the date
of grant of this option.

(3) Less than 10 years from the date of grant of this option.



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                           ISIS PHARMACEUTICALS, INC.
                       SUPPLEMENTAL STOCK OPTION AGREEMENT

                                    SCHEDULE



<TABLE>
<CAPTION>
               NAME OF OPTIONEE                    NUMBER OF SHARES
               ----------------                    ----------------
<S>                                                <C>
               Stanley T. Crooke                        250,000
               B. Lynne Parshall                        170,000
               Debby Jo Blank                           100,000
</TABLE>