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Exhibit 10.56  

	Optionee:	 	    
	 	Date:	 	    

 
 

Isis Pharmaceuticals, Inc.
  2000 Plan Supplemental Stock Option Agreement    
    

        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:  

	Number of Shares (installment)
	 	Date of Earliest Exercise (vesting)(1)

	    	 	 
	    	 	 
	    	 	 
	    	 	 

	

Exercise Price Per Share:(2)	
 	

    
	
 	

Expiration Date:(3)	
 	

    

	Percentage of Full-Time Work:	 	100%

	(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. 

	Isis Pharmaceuticals, Inc.	 	 	 	 
	

By:	
 	

    
	
 	

Optionee:	
 	

    

	Duly authorized on behalf of

    the Board of Directors	 	Address:	 	 

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. 

ATTACHMENT I

TERMS OF SUPPLEMENTAL STOCK OPTION  

        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 employment 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 employment is due to your Disability, in which event the option shall terminate on the earlier of the termination date set forth above or
1 year following such termination of employment; 

        (b)   such
termination of employment 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)   (i) such
termination of employment is due to your retirement; and (ii) you were over the age of 55 at the
time of such retirement; and (iii) you had been an employee, director or consultant (or any combination thereof) of the Company for a continuous
and uninterrupted period of at least 5 years prior to such retirement, in which event (i.e having satisfied all of the conditions set forth in
clauses (i) through (iii) above) the option shall terminate on the earlier of the termination date set forth above or 18 months after such retirement; or 

        (d)   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
employment; or 

        (e)   exercise
of the option within 3 months after termination of your employment 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 employment with the Company or an Affiliate. 

However,
this option may be exercised following termination of employment only as to that number of shares as to which it was exercisable on the date of termination of employment 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 an employment contract and nothing in this option shall be deemed to create in any way whatsoever any obligation on your part to continue in the employ
of the Company, or of the Company to continue your employment 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 employment, 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 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

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Exhibit 10.57  

 
 

2002 NON-EMPLOYEE DIRECTORS' STOCK OPTION PLAN
  GRANT NOTICE    
    

	Optionee:	 	    
	 	Date:	 	    

 
 

Isis Pharmaceuticals, Inc.
  Non-Statutory Stock Option Agreement    
    

        ISIS PHARMACEUTICALS, INC. (the "Company"), pursuant to its 2002 Non-Employee Directors' Stock
Option Plan (the "Plan"), hereby grants to Optionholder an option to purchase the number of shares of the Company's Common Stock set forth below. This option is subject to all of the terms and
conditions as set forth herein and in the Stock Option Agreement (Attachment I hereto), the Plan and the Notice of Exercise, all of which are attached hereto and incorporated herein in their
entirety. 

	 	 	Number of Shares Subject to Option:	 	    

Vesting Schedule:  

	Number of Shares (installment)
	 	Date of Earliest Exercise (vesting)

	    	 	 
	    	 	 
	    	 	 
	    	 	 

	

Exercise Price Per Share:(1)	
 	

    
	
 	

Expiration Date:(2)	
 	

    

	(1)
	Not
less than 100% 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. 

	Isis Pharmaceuticals, Inc.	 	 	 	 
	

By:	
 	

    
	
 	

Optionee:	
 	

    

	Duly authorized on behalf of

    the Board of Directors	 	Address:	 	 

Optionee:  

        Additional Terms/Acknowledgements:    The undersigned Optionholder acknowledges receipt of, and understands and agrees to, this
Grant Notice, the Stock Option Agreement and the Plan. Optionholder further acknowledges that as of the Date of Grant, this Grant Notice, the Stock Option Agreement and the Plan set forth the entire
understanding between Optionholder and the Company regarding the acquisition of stock in the Company and supersede all prior oral and written agreements on that subject with the exception of
(i) options previously granted and delivered to Optionholder under the Plan, and (ii) the following agreements only: 

	OTHER AGREEMENTS:	 	    

	 	 	    

ISIS PHARMACEUTICALS, INC.

2002 NON-EMPLOYEE DIRECTORS' STOCK OPTION PLAN  

STOCK OPTION AGREEMENT

(NONSTATUTORY STOCK OPTION)  

        Pursuant to your Stock Option Grant Notice ("Grant Notice") and this Stock Option Agreement, Isis Pharmaceuticals, Inc. (the "Company") has granted you an
option under its 2002 Non-Employee Directors' Stock Option Plan (the "Plan") to purchase the number of shares of the Company's Common Stock indicated in your Grant Notice at the exercise
price indicated in your Grant Notice. Defined terms not explicitly defined in this Stock Option Agreement but defined in the Plan shall have the same definitions as in the Plan. 

        The
details of your option are as follows: 

        1.    VESTING.    Subject to the limitations contained herein, your
option will vest as provided in your Grant Notice, provided that vesting will cease upon the termination of your Continuous Service. 

        2.    NUMBER OF SHARES AND EXERCISE PRICE.    The number of shares of
Common Stock subject to your option and your exercise price per share referenced in your Grant Notice may be adjusted from time to time for Capitalization Adjustments, as provided in the Plan. 

        3.    METHOD OF PAYMENT.    Payment of the exercise price is due in
full upon exercise of all or any part of your option. You may make payment of the exercise price in cash or by check. 

        4.    WHOLE SHARES.    You may exercise your option only for whole
shares of Common Stock. 

        5.    SECURITIES LAW COMPLIANCE.    Notwithstanding anything to the
contrary contained herein, you may not exercise your option unless the shares of Common Stock issuable upon such exercise are then registered under the Securities Act or, if such shares of Common
Stock are not then so registered, the Company has determined that such exercise and issuance would be exempt from the registration requirements of the Securities Act. The exercise of your option must
also comply with other applicable laws and regulations governing your option, and you may not exercise your option if the Company determines that such exercise would not be in material compliance with
such laws and regulations. 

        6.    TERM.    You may not exercise your option before the
commencement of its term or after its term expires. Unless otherwise provided in Section 11(d) of the Plan, the term of your option commences on the Date of Grant and expires upon the  earliest of the following:

         (a)   3 months after the termination of your Continuous Service for any reason other than your Qualified Retirement (as defined in
Section 6(d) below), Disability or death, provided that if during any part of such 3 month period your option is not exercisable solely because of the condition set forth in the
preceding paragraph relating to "Securities Law Compliance," your option shall not expire until the earlier of the Expiration Date or until it shall have been exercisable for an aggregate period of
3 months after the termination of your Continuous Service; 

         (b)   12 months after the termination of your Continuous Service due to your Disability; 

         (c)   18 months after your death if you die either during your Continuous Service or within 3 months after your Continuous Service
terminates; 

        (d)   18 months after the termination of your Continuous Service due to your retirement, where (i) you were over the age of 55 at the
time of such retirement; and (ii) you had been an employee, director or consultant (or any combination thereof) of the Company for a continuous and uninterrupted period of at least
5 years prior to such retirement (having satisfied all of the conditions set forth in clauses (i) and (ii) above, "Qualified Retirement"); or 

        (e)   the day before the 10th anniversary of the Date of Grant. 

        7.    EXERCISE.    

         (a)   You may exercise the vested portion of your option during its term 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, together with such additional documents as the
Company may then require. 

         (b)   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 equals less than 1,000 shares, in which case the minimum number of shares exercised must equal the number of shares then vested. 

        (c)   By exercising your option you agree that, as a condition to any exercise of your option, the Company may require you to enter into an
arrangement
providing for the payment by you to the Company of any tax withholding obligation of the Company arising by reason of (1) the exercise of your option, (2) the lapse of any substantial
risk of forfeiture to which the shares of Common Stock are subject at the time of exercise, or (3) the disposition of shares of Common Stock acquired upon such exercise. 

        8.    TRANSFERABILITY.    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.    RIGHT OF REPURCHASE.    To the extent provided in the Company's
bylaws as amended from time to time, the Company shall have the right to repurchase all or any part of the shares of Common Stock you acquire pursuant to the exercise of your option. 

        10.    OPTION NOT A SERVICE CONTRACT.    Your option is not an
employment or service contract, and nothing in your option shall be deemed to create in any way whatsoever any obligation on your part to continue in the employ of the Company or an Affiliate, or of
the Company or an Affiliate to continue your employment. In addition, nothing in your option shall obligate the Company or an Affiliate, their respective stockholders, Boards of Directors, Officers or
Employees to continue any relationship that you might have as a Director or Consultant for the Company or an Affiliate. 

        11.    WITHHOLDING OBLIGATIONS.    You may not exercise your option
unless the tax withholding obligations of the Company and/or any Affiliate are satisfied. Accordingly, you may not be able to exercise your option when desired even though your option is vested, and
the Company shall have no obligation to issue a certificate for such shares of Common Stock or release such shares of Common Stock from any escrow provided for herein. 

        12.    NOTICES.    Any notices provided for in your 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 mail by the Company to you, 5 days after deposit in the United States mail,
postage prepaid, addressed to you at the last address you provided to the Company. 

        13.    GOVERNING PLAN DOCUMENT.    Your option is subject to all the
provisions of the Plan, the provisions of which are hereby made a part of your option, 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 provisions of your option and those of the Plan, the provisions of the Plan shall control. 

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2002 NON-EMPLOYEE DIRECTORS' STOCK OPTION PLAN GRANT NOTICE

Isis Pharmaceuticals, Inc. Non-Statutory Stock Option Agreement

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