Document:

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                                 EXHIBIT 10.15

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

                           ISIS PHARMACEUTICALS, INC.
                       SUPPLEMENTAL STOCK OPTION AGREEMENT
                                   (DIRECTOR)

Isis Pharmaceuticals, Inc. (the "Company"), pursuant to its 2000 Broad-Based
Equity Incentive 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>
<S>                                               <C>
           Number of Shares (installment)         Date of Earliest Exercise (vesting)

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

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

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

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

Exercise Price Per Share:          (1)            Expiration Date:           (2)
                         -----------                              ------------
                                                  Percentage of Full-Time Work:  100%
                                                                                ------
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) Not less than 85% of the fair market value of the Common Stock on the date
of grant of this option.

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

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                                  ATTACHMENT I
                       TERMS OF SUPPLEMENTAL STOCK OPTION
                                   (DIRECTOR)

        The grant hereunder is in connection with and in furtherance of the
Company's 2000 Broad-Based Equity Incentive Plan (the "Plan") for participation
of the Company's employees (including officers), directors or consultants and is
intended to comply with the provisions of Rule 701 promulgated by the Securities
and Exchange Commission under the Securities Act of 1933, as amended (the
"Act").

        The details of your option are as follows:

        1. The total number of shares of Common Stock subject to this option is
set forth on the first page of the Supplemental Stock Option Agreement. Subject
to the limitations contained herein, this option is exercisable with respect to
each installment indicated in the Vesting Schedule set forth on the first page
of the Supplemental Stock Option Agreement on or after the date of vesting
applicable to such installment.

        2. Notwithstanding any provision in the Plan to the contrary, in the
event of a Change in Control (as defined below) then the vesting and
exercisability of this stock option will be accelerated in full; provided,
however, that if such potential acceleration of the vesting and exercisability
of this stock option would cause a contemplated Change in Control transaction
that would otherwise be eligible to be accounted for as a "pooling-of-interests"
transaction to become ineligible for such accounting treatment under generally
accepted accounting principles as determined by the Company's independent
certified public accountants prior to the Change of Control, such acceleration
will not occur.

        For purposes of this paragraph 2 only, Change in Control means: (i) a
sale of all or substantially all of the assets of the Company; (ii) a merger or
consolidation in which the Company is not the surviving corporation and in which
beneficial ownership of securities of the Company representing at least fifty
percent (50%) of the combined voting power entitled to vote in the election of
Directors has changed; (iii) a reverse merger in which the Company is the
surviving corporation but the shares of Common Stock outstanding immediately
preceding the merger are converted by virtue of the merger into other property,
whether in the form of securities, cash or otherwise, and in which beneficial
ownership of securities of the Company representing at least fifty percent (50%)
of the combined voting power entitled to vote in the election of Directors has
changed; or (iv) an acquisition by any person, entity or group within the
meaning of Section 13(d) or 14(d) of the Exchange Act, or any comparable
successor provisions (excluding any employee benefit plan, or related trust,
sponsored or maintained by the Company or subsidiary of the Company or other
entity controlled by the Company) of the beneficial ownership (within the
meaning of Rule 13d-3 promulgated under the Exchange Act, or comparable
successor rule) of securities of the Company representing at least fifty percent
(50%) of the combined voting power entitled to vote in the election of
Directors.

        3.      (a) The Exercise Price of this option is set forth on the first
page of the Supplemental Stock Option Agreement.

                (b) Payment of the exercise price per share is due in full in
cash (including check) upon exercise of all or any part of each installment
which has become exercisable by you.

        4. The minimum number of shares with respect to which this option may be
exercised at any one time is 1,000, unless the number of shares available for
exercise (that is, the remaining vested shares pursuant to paragraph 1) equals
less than 1,000 shares, in which case the minimum number of shares exercised
must equal the number of shares then vested.

        5. Notwithstanding anything to the contrary contained herein, this
option may not be exercised unless the shares issuable upon exercise of this
option are then registered under the Act or, if such shares are not then so
registered, the Company has determined that such exercise and issuance would be
exempt from the registration requirements of the Act.

        6. The term of this option commences on the date hereof and, unless
sooner terminated as set forth below or in the Plan, terminates on the
Expiration Date. This option shall terminate prior to the expiration of its term
as follows: 3 months after the termination of your service as a Director with
the Company or an Affiliate of the Company (as defined in the Plan) for any
reason or for no reason unless:

                (a) such termination of service is due to your Disability, in
which event the option shall

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terminate on the earlier of the termination date set forth above or 1 year
following such termination of service;

                (b) such termination of service is due to your death, in which
event the option shall terminate on the earlier of the termination date set
forth above or 18 months after your death; or

                (c) during any part of such 3 month period the option is not
exercisable solely because of the condition set forth in paragraph 5 above, in
which event the option shall not terminate until the earlier of the termination
date set forth above or until it shall have been exercisable for an aggregate
period of 3 months after the termination of service; or

                (d) exercise of the option within 3 months after termination of
your service with the Company or with an Affiliate would result in liability
under Section 16(b) of the Securities Exchange Act of 1934, in which case the
option will terminate on the earlier of the termination date set forth above,
the 10th day after the last date upon which exercise would result in such
liability or 6 months and 10 days after the termination of your service with the
Company or an Affiliate.

However, this option may be exercised following termination of service only as
to that number of shares as to which it was exercisable on the date of
termination of service under the provision of paragraph 1 of this option.

        7.      (a) This option may be exercised, to the extent specified above,
by delivering a notice of exercise (in a form designated by the Company)
together with the exercise price to the Secretary of the Company, or to such
other person as the Company may designate, during regular business hours.

                (b) By exercising this option you agree that:

                        (i) the Company may require you to enter an arrangement
providing for the cash payment by you to the Company of any tax withholding
obligation of the Company arising by reason of: the exercise of this option; the
lapse of any substantial risk of forfeiture to which the shares are subject at
the time of exercise; or the disposition of shares acquired upon such exercise.

        8. This option is not transferable except by will or by the laws of
descent and distribution, and is exercisable during your lifetime only by you;
notwithstanding the foregoing, you may transfer part or all of this option to
any of the following:

                (i) your spouse, children (by birth or adoption), stepchildren,
grandchildren, or parents;

                (ii) a trust or other entity established solely for your benefit
or the benefit of your spouse, children (by birth or adoption), stepchildren,
grandchildren, or parents for estate planning purposes; or,

                (iii) an organization which is exempt from taxation under
Section 501(c)(3) of the Code or to which tax-deductible charitable
contributions may be made under Section 170 of the Code.

        Furthermore, you may, by delivering written notice to the Company, in a
form satisfactory to the Company, designate a third party who, in the event of
your death, will thereafter be entitled to exercise the option.

        9. This option is not a service contract and nothing in this option
shall be deemed to create in any way whatsoever any obligation on your part to
continue as a Director of the Company, or of the Company to continue your
service with the Company. In the event that this option is granted to you in
connection with the performance of services as a consultant or director,
references to service, employee and similar terms shall be deemed to include the
performance of services as a consultant or a director, as the case may be,
provided, however, that no rights as an employee shall arise by reason of the
use of such terms.

        10. Any notices provided for in this option or the Plan shall be given
in writing and shall be deemed effectively given upon receipt or, in the case of
notices delivered by the Company to you, 5 days after deposit in the United
States mail, postage prepaid, addressed to you at the address specified on the
attached or at such other address as you hereafter designate by written notice
to the Company.

        11. This option is subject to all the provisions of the Plan, a copy of
which is attached hereto and its provisions are hereby made a part of this
option, including without limitation the provisions of paragraph 6 of the Plan
relating to option provisions, and is further subject to all interpretations,
amendments, rules and regulations which may from time to time be promulgated and
adopted pursuant to the Plan. In the event of any conflict between the

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provisions of this option and those of the Plan, the provisions of the Plan
shall control.

Attachments:   2000 Broad-Based Equity Incentive Plan
               Notice of Exercise<PAGE>   1

                                  EXHIBIT 10.16

January 11, 2000

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

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

Isis Pharmaceuticals, Inc.
2292 Faraday Ave.
Carlsbad, CA  92008

Dear
    ----------------------

Isis Pharmaceuticals, Inc. ("Isis") is pleased to offer you certain severance
benefits in light of your contributions to Isis. As Isis has no policy or
procedure requiring such benefits, we request that you keep the terms and
conditions of this letter agreement confidential.

In the event that your employment is terminated without "cause" (as defined
herein) by Isis on or before December 31, 2001 (the "Severance Period"), you
will be eligible to receive a severance payment equal to a minimum of six (6)
months of your then current base salary, less payroll deductions and
withholdings. For purposes of this letter agreement, "cause" will be defined as
follows: (i) engaging or in any manner participating in any activity which is
competitive with or intentionally injurious to Isis or which violates any
provision of the Proprietary Information and Inventions Agreement; (ii)
commission of any fraud against Isis or use or appropriation for personal use or
benefit of any funds or properties of Isis not authorized by the Company to be
so used or appropriated; (iii) conviction of a crime involving dishonesty or
moral turpitude; (iv) conduct by you which in the good faith and reasonable
determination of the Company demonstrates gross unfitness to serve in your then
current capacity at Isis. In order to be eligible to receive the severance
payments described herein, you will be required to execute an Employee
Separation Agreement substantially in the form attached hereto as Exhibit A.

In the event that your employment is terminated during the Severance Period as a
result of a reduction of the Company's workforce or you elect to terminate your
employment with Isis as a result of substantial change in your primary job
duties, your severance payment shall be increased such that you receive a total
payment equal to twelve (12) months of your then current base salary, less
payroll deductions and withholdings.

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In the event that your employment is terminated by Isis during the Severance
Period as a result of a Change in Control (as defined herein), your severance
payment shall be increased such that you receive a total of twenty-four (24)
months of your then current base salary, less payroll deductions and
withholdings. For purposes of this letter agreement, Change in Control will be
defined as follows: (i) a sale of all or substantially all of the assets of
Isis; (ii) a merger or consolidation in which Isis is not the surviving
corporation and in which beneficial ownership of securities of Isis representing
at least fifty percent (50%) of the combined voting power entitled to vote in
the election of Directors has changed; (iii) a reverse merger in which Isis is
the surviving corporation but the shares of Common Stock outstanding immediately
preceding the merger are converted by virtue of the merger into other property,
whether in the form of securities, cash or otherwise, and in which beneficial
ownership of securities of Isis representing at least fifty percent (50%) of the
combined voting power entitled to vote in the election of Directors has changed;
or (iv) an acquisition by any person, entity or group within the meaning of
Section 13(d) or 14(d) of the Exchange Act, or any comparable successor
provisions (excluding any employee benefit plan, or related trust, sponsored or
maintained by Isis or subsidiary of Isis or other entity controlled by Isis) of
the beneficial ownership (within the meaning of Rule 13d-3 promulgated under the
Exchange Act, or comparable successor rule) of securities of Isis representing
at least fifty percent (50%) of the combined voting power entitled to vote in
the election of Directors.

Please keep in mind that this letter agreement is not intended to change your
status as an at-will employee with Isis. As with all employees at Isis, you or
Isis may terminate your employment at any time, for any reason whatsoever, with
or without cause or advance notice subject to the provisions set forth herein.

If you have any questions or comments regarding the terms and conditions of this
letter, please do not hesitate to contact me.

Very truly yours,

Isis Pharmaceuticals, Inc.

Patricia M. Lowenstam
Vice President, Human Resources

PML/jk

attachment
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                               SEVERANCE AGREEMENT

                                    SCHEDULE

        NAMES OF EXECUTIVE OFFICERS
        WHO ARE PARTIES TO THE SEVERANCE AGREEMENT
        ------------------------------------------
        Stanley T. Crooke
        B. Lynne Parshall
        Debby Jo Blank
        C. Frank Bennett
        David J. Ecker
        Patricia Lowenstam

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