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Exhibit 10.68    
  

CV Therapeutics, Inc.  

 EMPLOYEE STOCK PURCHASE PLAN  

 Adopted September 23, 1996

Approved by the Stockholders in November 1996

Amended by the Board of Directors February 23 and March 31, 2000

Approved by the Stockholders on May 16, 2000

With Share Increases Effective May 30, 2001 and June 8, 2002  

1.    PURPOSE.

        (a)  The
purpose of the Employee Stock Purchase Plan (the "Plan") is to provide a means by which employees of CV Therapeutics, Inc., a Delaware corporation (the
"Company"), and its Affiliates, as defined in subparagraph 1(b), which are designated as provided in subparagraph 2(b), may be given an opportunity to purchase stock of the Company. 

        (b)  The
word "Affiliate" as used in the Plan means any parent corporation or subsidiary corporation of the Company, as those terms are defined in Sections 424(e) and (f),
respectively, of the Internal Revenue Code of 1986, as amended (the "Code"). 

        (c)  The
Company, by means of the Plan, seeks to retain the services of its employees, to secure and retain the services of new employees, and to provide incentives for such
persons to exert maximum efforts for the success of the Company. 

        (d)  The
Company intends that the rights to purchase stock of the Company granted under the Plan be considered options issued under an "employee stock purchase plan" as that
term is defined in Section 423(b) of the Code. 

2.    ADMINISTRATION.

        (a)  The
Plan shall be administered by the Board of Directors (the "Board") of the Company unless and until the Board delegates administration to a Committee, as provided in
subparagraph 2(c). Whether or not the Board has delegated administration, the Board shall have the final power to determine all questions of policy and expediency that may arise in the administration
of the Plan. 

        (b)  The
Board shall have the power, subject to, and within the limitations of, the express provisions of the Plan: 

        (i)    To
determine when and how rights to purchase stock of the Company shall be granted and the provisions of each offering of such rights (which need not be identical). 

        (ii)  To
designate from time to time which Affiliates of the Company shall be eligible to participate in the Plan. 

        (iii)  To
construe and interpret the Plan and rights granted under it, and to establish, amend and revoke rules and regulations for its administration. The Board, in the
exercise of this power, may correct any defect, omission or inconsistency in the Plan, in a manner and to the extent it shall deem necessary or expedient to make the Plan fully effective. 

        (iv)  To
amend the Plan as provided in paragraph 13. 

        (v)  Generally,
to exercise such powers and to perform such acts as the Board deems necessary or expedient to promote the best interests of the Company and its Affiliates and
to carry out the intent
that the Plan be treated as an "employee stock purchase plan" within the meaning of Section 423 of the Code. 

 

        (c)  The
Board may delegate administration of the Plan to a Committee composed of not fewer than two (2) members of the Board (the "Committee"). If administration is
delegated to a Committee, the Committee shall have, in connection with the administration of the Plan, the powers theretofore possessed by the Board, subject, however, to such resolutions, not
inconsistent with the provisions of the Plan, as may be adopted from time to time by the Board. The Board may abolish the Committee at any time and revest in the Board the administration of the Plan. 

3.    SHARES SUBJECT TO THE PLAN.

        (a)  Subject
to the provisions of paragraph 12 relating to adjustments upon changes in stock, the stock that may be sold pursuant to rights granted under the Plan
shall not exceed in the aggregate four hundred twenty-three thousand eight hundred and eighty nine (423,889) shares of the Company's common stock (the "Reserved Shares"). In addition, on the day
following each annual meeting of the Company's stockholders beginning with the meeting in 2001, and continuing through and including the meeting in 2005, the number of Reserved Shares will be
increased automatically by the least of (i) one half of one percent (0.5%) of the total number of shares of Company's common stock outstanding on
such date, (ii) one hundred thousand (100,000) shares or (iii) a number of shares determined by the Board, which number shall be less each of (i) and (ii) above. If any
right granted under the Plan shall for any reason terminate without having been exercised, the Common Stock not purchased under such right shall again become available for the Plan. 

        (b)  The
stock subject to the Plan may be unissued shares or reacquired shares, bought on the market or otherwise. 

4.    GRANT OF RIGHTS; OFFERING.

        (a)  The Board or the Committee may from time to time grant or provide for the grant of rights to purchase Common Stock of the
Company under the Plan to eligible employees (an "Offering") on a date or dates (the "Offering Date(s)") selected by the Board or the Committee. Each Offering shall be in such form and shall contain
such terms and conditions as the Board or the Committee shall deem appropriate, which shall comply with the requirements of Section 423(b)(5) of the Code that all employees granted rights to
purchase stock under the Plan shall have the same rights and privileges. The terms and conditions of an Offering shall be incorporated by reference into the Plan and treated as part of the Plan. The
provisions of separate Offerings need not be identical, but each Offering shall include (through incorporation of the provisions of this Plan by reference in the document comprising the Offering or
otherwise) the period during which the Offering shall be effective, which period shall not exceed twenty-seven (27) months beginning with the Offering Date, and the substance of the provisions
contained in paragraphs 5 through 8, inclusive. 

        (b)  If an employee has more than one right outstanding under the Plan, unless he or she otherwise indicates in agreements or
notices delivered hereunder: (1) each agreement or notice delivered by that employee will be deemed to apply to all of his or her rights under the Plan, and (2) a right with a lower
exercise price (or an earlier-granted right, if two rights have identical exercise prices), will be exercised to the fullest possible extent before a right with a higher exercise price (or a
later-granted right, if two rights have identical exercise prices) will be exercised. 

5.    ELIGIBILITY.

        (a)  Rights
may be granted only to employees of the Company or, as the Board or the Committee may designate as provided in subparagraph 2(b), to employees of any Affiliate of
the Company. Except as provided in subparagraph 5(b), an employee of the Company or any Affiliate shall not be eligible to be granted rights under the Plan, unless, on the Offering Date, such employee
has been in the employ of the Company or any Affiliate for such continuous period preceding such grant as the Board or the 

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Committee may require, but in no event shall the required period of continuous employment be equal to or greater than two (2) years. In addition, unless otherwise determined by the Board or
the Committee and set forth in the terms of the applicable Offering, no employee of the Company or any Affiliate shall be eligible to be granted rights under the Plan, unless, on the Offering Date,
such employee's customary employment with the Company or such Affiliate is for at least twenty (20) hours per week and at least five (5) months per calendar year. 

        (b)  The
Board or the Committee may provide that each person who, during the course of an Offering, first becomes an eligible employee of the Company or designated Affiliate
will, on a date or dates specified in the Offering which coincides with the day on which such person becomes an eligible employee or occurs thereafter, receive a right under that Offering, which right
shall thereafter be
deemed to be a part of that Offering. Such right shall have the same characteristics as any rights originally granted under that Offering, as described herein, except that: 

        (i)    the
date on which such right is granted shall be the "Offering Date" of such right for all purposes, including determination of the exercise price of such right; 

        (ii)  the
period of the Offering with respect to such right shall begin on its Offering Date and end coincident with the end of such Offering; and 

        (iii)  the
Board or the Committee may provide that if such person first becomes an eligible employee within a specified period of time before the end of the Offering, he or
she will not receive any right under that Offering. 

        (c)  No
employee shall be eligible for the grant of any rights under the Plan if, immediately after any such rights are granted, such employee owns stock possessing five
percent (5%) or more of the total combined voting power or value of all classes of stock of the Company or of any Affiliate. For purposes of this subparagraph 5(c), the rules of Section 424(d)
of the Code shall apply in determining the stock ownership of any employee, and stock which such employee may purchase under all outstanding rights and options shall be treated as stock owned by such
employee. 

        (d)  An
eligible employee may be granted rights under the Plan only if such rights, together with any other rights granted under "employee stock purchase plans" of the
Company and any Affiliates, as specified by Section 423(b)(8) of the Code, do not permit such employee's rights to purchase stock of the Company or any Affiliate to accrue at a rate which
exceeds twenty-five thousand dollars ($25,000) of fair market value of such stock (determined at the time such rights are granted) for each calendar year in which such rights are
outstanding at any time. 

        (e)  Officers
of the Company and any designated Affiliate shall be eligible to participate in Offerings under the Plan, provided, however, that the Board may provide in an
Offering that certain employees who are highly compensated employees within the meaning of Section 423(b)(4)(D) of the Code shall not be eligible to participate. 

6.    RIGHTS; PURCHASE PRICE.

        (a)  On
each Offering Date, each eligible employee, pursuant to an Offering made under the Plan, shall be granted the right to purchase up to the number of shares of Common
Stock of the Company
purchasable with a percentage designated by the Board or the Committee not exceeding fifteen percent (15%) of such employee's Earnings (as defined by the Board for each Offering) during the period
which begins on the Offering Date (or such later date as the Board or the Committee determines for a particular Offering) and ends on the date stated in the Offering, which date shall be no later than
the end of the Offering. The Board or the Committee shall establish one or more dates during an Offering (the "Purchase Date(s)") on which rights granted under the Plan shall be exercised and
purchases of Common Stock carried out in accordance with such Offering. 

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        (b)  In
connection with each Offering made under the Plan, the Board or the Committee may specify a maximum number of shares that may be purchased by any employee as well as
a maximum aggregate number of shares that may be purchased by all eligible employees pursuant to such Offering. In addition, in connection with each Offering that contains more than one Purchase Date,
the Board or the Committee may specify a maximum aggregate number of shares which may be purchased by all eligible employees on any given Purchase Date under the Offering. If the aggregate purchase of
shares upon exercise of rights granted under the Offering would exceed any such maximum aggregate number, the Board or the Committee shall make a pro rata allocation of the shares available in as
nearly a uniform manner as shall be practicable and as it shall deem to be equitable. 

        (c)  The
purchase price of stock acquired pursuant to rights granted under the Plan shall be not less than the lesser of: 

        (i)    an
amount equal to eighty-five percent (85%) of the fair market value of the stock on the Offering Date; or 

        (ii)  an
amount equal to eighty-five percent (85%) of the fair market value of the stock on the Purchase Date. 

7.    PARTICIPATION; WITHDRAWAL; TERMINATION.

        (a)  An
eligible employee may become a participant in the Plan pursuant to an Offering by delivering a participation agreement to the Company within the time specified in the
Offering, in such form as the Company provides. Each such agreement shall authorize payroll deductions of up to the maximum percentage specified by the Board or the Committee of such employee's
Earnings (as defined by the Board for each Offering) during the Offering. The payroll deductions made for each participant shall be credited to an account for such participant under the Plan and shall
be deposited with the general funds of the Company. A participant may reduce (including to zero) or increase such payroll
deductions, and an eligible employee may begin such payroll deductions, after the beginning of any Offering only as provided for in the Offering. A participant may make additional payments into his or
her account only if specifically provided for in the Offering and only if the participant has not had the maximum amount withheld during the Offering. 

        (b)  At
any time during an Offering, a participant may terminate his or her payroll deductions under the Plan and withdraw from the Offering by delivering to the Company a
notice of withdrawal in such form as the Company provides. Such withdrawal may be elected at any time prior to the end of the Offering except as provided by the Board or the Committee in the Offering.
Upon such withdrawal from the Offering by a participant, the Company shall distribute to such participant all of his or her accumulated payroll deductions (reduced to the extent, if any, such
deductions have been used to acquire stock for the participant) under the Offering, without interest, and such participant's interest in that Offering shall be automatically terminated. A
participant's withdrawal from an Offering will have no effect upon such participant's eligibility to participate in any other Offerings under the Plan but such participant will be required to deliver
a new participation agreement in order to participate in subsequent Offerings under the Plan. 

        (c)  Rights
granted pursuant to any Offering under the Plan shall terminate immediately upon cessation of any participating employee's employment with the Company and any
designated Affiliate, for any reason, and the Company shall distribute to such terminated employee all of his or her accumulated payroll deductions (reduced to the extent, if any, such deductions have
been used to acquire stock for the terminated employee), under the Offering, without interest. 

        (d)  Rights
granted under the Plan shall not be transferable by a participant otherwise than by will or the laws of descent and distribution, or by a beneficiary designation
as provided in paragraph 14 

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and, otherwise during his or her lifetime, shall be exercisable only by the person to whom such rights are granted. 

8.    EXERCISE.

        (a)  On
each Purchase Date specified therefor in the relevant Offering, each participant's accumulated payroll deductions and other additional payments specifically provided
for in the Offering (without any increase for interest) will be applied to the purchase of whole shares of stock of the Company, up to the maximum number of shares permitted pursuant to the terms of
the Plan and the applicable Offering, at the purchase price specified in the Offering. No fractional shares shall be issued upon the exercise of rights granted under the Plan. The amount, if any, of
accumulated payroll deductions remaining in each participant's account after the purchase of shares which is less than the amount required to purchase one share of stock on the final Purchase Date of
an Offering shall be held in each such participant's account for the purchase of shares under the next Offering under the Plan, unless
such participant withdraws from such next Offering, as provided in subparagraph 7(b), or is no longer eligible to be granted rights under the Plan, as provided in paragraph 5, in which case
such amount shall be distributed to the participant after such final Purchase Date, without interest. The amount, if any, of accumulated payroll deductions remaining in any participant's account after
the purchase of shares which is equal to the amount required to purchase whole shares of stock on the final Purchase Date of an Offering shall be distributed in full to the participant after such
Purchase Date, without interest. 

        (b)  No
rights granted under the Plan may be exercised to any extent unless the shares to be issued upon such exercise under the Plan (including rights granted thereunder)
are covered by an effective registration statement pursuant to the Securities Act of 1933, as amended (the "Securities Act") and the Plan is in material compliance with all applicable state, foreign
and other securities and other laws applicable to the Plan. If on a Purchase Date in any Offering hereunder the Plan is not so registered or in such compliance, no rights granted under the Plan or any
Offering shall be exercised on such Purchase Date, and the Purchase Date shall be delayed until the Plan is subject to such an effective registration statement and such compliance, except that the
Purchase Date shall not be delayed more than twelve (12) months and the Purchase Date shall in no event be more than twenty-seven (27) months from the Offering Date. If on the Purchase
Date of any Offering hereunder, as delayed to the maximum extent permissible, the Plan is not registered and in such compliance, no rights granted under the Plan or any Offering shall be exercised and
all payroll deductions accumulated during the Offering (reduced to the extent, if any, such deductions have been used to acquire stock) shall be distributed to the participants, without interest. 

9.    COVENANTS OF THE COMPANY.

        (a)  During
the terms of the rights granted under the Plan, the Company shall keep available at all times the number of shares of stock required to satisfy such rights. 

        (b)  The
Company shall seek to obtain from each federal, state, foreign or other regulatory commission or agency having jurisdiction over the Plan such authority as may be
required to issue and sell shares of stock upon exercise of the rights granted under the Plan. If, after reasonable efforts, the Company is unable to obtain from any such regulatory commission or
agency the authority which counsel for the Company deems necessary for the lawful issuance and sale of stock under the Plan, the Company shall be relieved from any liability for failure to issue and
sell stock upon exercise of such rights unless and until such authority is obtained. 

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10.  USE OF PROCEEDS FROM STOCK.

        Proceeds
from the sale of stock pursuant to rights granted under the Plan shall constitute general funds of the Company. 

11.  RIGHTS AS A STOCKHOLDER.

        A
participant shall not be deemed to be the holder of, or to have any of the rights of a holder with respect to, any shares subject to rights granted under the Plan unless and until the
participant's shareholdings acquired upon exercise of rights hereunder are recorded in the books of the Company. 

12.  ADJUSTMENTS UPON CHANGES IN STOCK.

        (a)  If
any change is made in the stock subject to the Plan, or subject to any rights granted under the Plan (through merger, consolidation, reorganization, recapitalization,
stock dividend, dividend in property other than cash, stock split, liquidating dividend, combination of shares, exchange of shares, change in corporate structure or other transaction not involving the
receipt of consideration by the Company), the Plan and outstanding rights will be appropriately adjusted in the class(es) and maximum number of shares subject to the Plan and the class(es) and number
of shares and price per share of stock subject to outstanding rights. Such adjustments shall be made by the Board or the Committee, the determination of which shall be final, binding and conclusive.
(The conversion of any convertible securities of the Company shall not be treated as a "transaction not involving the receipt of consideration by the Company.") 

        (b)  In
the event of: (1) a dissolution or liquidation of the Company; (2) a merger or consolidation in which the Company is not the surviving corporation;
(3) a reverse merger in which the Company is the surviving corporation but the shares of the Company's 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; or (4) the acquisition by any person, entity or group within the meaning of Section 13(d) or 14(d) of
the Securities Exchange Act of 1934, as amended (the "Exchange Act") or any comparable successor provisions (excluding any employee benefit plan, or related trust, sponsored or maintained by the
Company or any Affiliate of 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, then, as determined by the Board in its sole discretion
(i) any surviving or acquiring corporation may assume outstanding rights or substitute similar rights for those under the Plan, (ii) such rights may continue in full force and effect, or
(iii) participants' accumulated payroll deductions may be used to purchase Common Stock immediately prior to the transaction described above and the participants' rights under the ongoing
Offering terminated. 

13.  AMENDMENT OF THE PLAN.

        (a)  The
Board at any time, and from time to time, may amend the Plan. However, except as provided in paragraph 12 relating to adjustments upon changes in stock, no
amendment shall be effective unless approved by the stockholders of the Company within twelve (12) months before or after the adoption of the amendment, where the amendment will: 

        (i)    Increase
the number of shares reserved for rights under the Plan; 

        (ii)  Modify
the provisions as to eligibility for participation in the Plan (to the extent such modification requires stockholder approval in order for the Plan to obtain
employee stock purchase plan treatment under Section 423 of the Code or to comply with the requirements of Rule 16b-3 promulgated under the Securities Exchange Act of 1934,
as amended ("Rule 16b-3")); or 

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        (iii)  Modify
the Plan in any other way if such modification requires stockholder approval in order for the Plan to obtain employee stock purchase plan treatment under
Section 423 of the Code or to comply with the requirements of Rule 16b-3. 

It
is expressly contemplated that the Board may amend the Plan in any respect the Board deems necessary or advisable to provide eligible employees with the maximum benefits provided or to be provided
under the provisions of the Code and the regulations promulgated thereunder relating to employee stock purchase plans and/or to bring the Plan and/or rights granted under it into compliance therewith. 

        (b)  Rights
and obligations under any rights granted before amendment of the Plan shall not be altered or impaired by any amendment of the Plan, except with the consent of
the person to whom such rights were granted, or except as necessary to comply with any laws or governmental regulations, or except as necessary to ensure that the Plan and/or rights granted under the
Plan comply with the requirements of Section 423 of the Code. 

14.  DESIGNATION OF BENEFICIARY.

        (a)  A
participant may file a written designation of a beneficiary who is to receive any shares and cash, if any, from the participant's account under the Plan in the
event of such participant's death subsequent to the end of an Offering but prior to delivery to the participant of such shares and cash. In addition, a participant may file a written
designation of a beneficiary who is to receive any cash from the participant's account under the Plan in the event of such participant's death during an Offering. 

        (b)  Such
designation of beneficiary may be changed by the participant at any time by written notice. In the event of the death of a participant and in the absence of a
beneficiary validly designated under the Plan who is living at the time of such participant's death, the Company shall deliver such shares and/or cash to the executor or administrator of the estate of
the participant, or if no such executor or administrator has been appointed (to the knowledge of the Company), the Company, in its sole discretion, may deliver such shares and/or cash to the spouse or
to any one or more dependents or relatives of the participant, or if no spouse, dependent or relative is known to the Company, then to such other person as the Company may designate. 

15.  TERMINATION OR SUSPENSION OF THE PLAN.

        (a)  The
Board in its discretion, may suspend or terminate the Plan at any time. No rights may be granted under the Plan while the Plan is suspended or after it is
terminated. 

        (b)  Rights
and obligations under any rights granted while the Plan is in effect shall not be altered or impaired by suspension or termination of the Plan, except as
expressly provided in the Plan or with the consent of the person to whom such rights were granted, or except as necessary to comply with any laws or governmental regulation, or except as necessary to
ensure that the Plan and/or rights granted under the Plan comply with the requirements of Section 423 of the Code. 

16.  EFFECTIVE DATE OF PLAN.

        The
Plan shall become effective on the same day that the Company's initial public offering of shares of common stock becomes effective (the "Effective Date"), but no rights granted under
the Plan shall be exercised unless and until the Plan has been approved by the stockholders of the Company within twelve (12) months before or after the date the Plan is adopted by the Board or
the Committee, which date may be prior to the Effective Date. 

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Exhibit 10.1  

        CONFIDENTIAL TREATMENT REQUESTED

UNDER 17 C.F.R. §§ 200.80(b)4, AND 240.24 

 
 

AMENDMENT NO. 1 TO
  SECURITIES PURCHASE AGREEMENT    
  

        This Amendment No. 1 to Securities Purchase Agreement (the "Amendment"), is effective as of April 25, 2002 ("Effective Date") between Isis
Pharmaceuticals, Inc., a Delaware corporation ("Isis"), and Elan International Services, Ltd., a Bermuda exempted limited liability company ("EIS") and a wholly-owned subsidiary of Elan
Corporation, plc, an Irish public limited company. 

	A.
	WHEREAS,
Isis and EIS entered into that certain Securities Purchase Agreement dated January 14, 2000 (the "Original Agreement"); and

	B.
	WHEREAS,
Isis and EIS wish to amend the Original Agreement to decrease the Second Common Stock Purchase Price and to provide for a Third Subsequent Purchase Date, as more fully
described below. 

        NOW
THEREFORE, in consideration of the mutual promises contained in this Amendment, Isis and EIS agree to amend the Original Agreement as follows: 

        All
capitalized terms not otherwise defined herein, will have the meanings ascribed to them in the Original Agreement. 

 
 

ARTICLE 1. AMENDMENTS    
  

        1.1    Recital A.    Recital A of the Original Agreement is hereby amended such that the language
"Section 1(b)(ii) and (iii)" appearing in clauses (ii) and (iii) of Recital A is replaced by the following language "Sections 1(b)(ii), 1(b)(iii) and
1(b)(iv)." All other provisions of Recital A will remain unchanged and will continue in full force and effect. 

        1.2    Amendment and Restatement of Section 1(b)(iii).    Section 1(b)(iii) of the Original
Agreement is hereby amended, restated and replaced in its entirety by the following language: 

"(iii) On
any day within 5 trading days after the Completion Date (the "Second Subsequent Purchase Date"), the Company shall issue and sell to EIS, and EIS shall purchase from the Company, for
an aggregate purchase price of US$3,750,000 (the "Second Common Stock Purchase Price"), (A) 126,092 shares of Common Stock and (B) a Warrant to purchase 6,304 shares of Common Stock,
pursuant to a warrant certificate in the form attached hereto as Exhibit G. "Completion Date" will mean April 22, 2002. The purchase by
EIS of the securities to be issued on the Second Subsequent Purchase Date is conditioned upon EIS obtaining requisite approval, if any, pursuant to the Mergers Act." 

        1.3    Addition of Section 1(b)(iv).    The Original Agreement is hereby amended to include the following
language as Section 1(b)(iv) thereto: 

"(iv) On
any day within 5 trading days after the receipt by EIS from the Company of notification of the occurrence of the Additional Completion Date (the "Third Subsequent Purchase Date"), the
Company shall issue and sell to EIS, and EIS shall purchase from the Company, for an aggregate purchase price of [***] (the "Third Common Stock Purchase Price"), (A) the
number of shares of Common Stock determined by dividing the Third Common Stock Purchase Price by [***] of the average closing price of the Common Stock for the
[***] trading days ending two days prior to the Additional Completion Date and (B) a Warrant to purchase a number of shares of Common Stock equal to
[***] of the aggregate 

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number of shares of Common Stock to be purchased by EIS pursuant to clause (iv)(A) above, pursuant to a warrant certificate in the form attached hereto as Exhibit G (except that the
warrant will reference the Third Subsequent Purchase Date). "Additional Completion Date" will mean either (a) the date upon which the clinical
trial ISIS 14803-CS2 is completed with results sufficient to demonstrate [***]. The purchase by EIS of the securities to be issued on the Third Subsequent Purchase
Date is conditioned upon EIS obtaining requisite approval, if any, pursuant to the Mergers Act." 

        1.4    Addition of Section 1(d)(iv).    The Original Agreement is hereby amended to include the following
language as Section 1(d)(iv) thereto: 

"(iv) On
the Third Subsequent Purchase Date, EIS shall pay the Third Common Stock Purchase Price by wire transfer to an account designated by the Company and the parties hereto shall execute
and deliver to each other, as applicable: (A) a certificate or certificates for the Common Stock to be purchased on the Third Subsequent Purchase Date, as determined pursuant to
Section 1(b)(iv) hereof; (B) the Warrant to be issued pursuant to Section 1(b)(iv) hereof; (C) a secretary certificate of the Company, in substantially the
form of Exhibit H; and (D) any other documents or instruments reasonably requested by a party hereto." 

        1.5    Amendment and Restatement of Section 17.    Section 17 of the Original Agreement is hereby
amended, restated and replaced in its entirety by the following language: 

"Assignments and Transfers.    This Agreement and all of the provisions hereof shall be binding upon and inure to the benefit of the parties
hereto and their respective successors and permitted assigns. This Agreement, the shares of Series B Preferred Stock and the shares of Common Stock being purchased hereunder by EIS, the Note,
the Warrants, and the shares of Common Stock underlying the Series B Preferred Stock, the Note and the Warrants may be transferred by EIS to its affiliates and subsidiaries, as well as any
special purpose financing or similar vehicle established by EIS or its affiliates, provided, however, that EIS shall remain liable for its obligations hereunder after any such assignment. Other than
as set forth above, no party shall transfer or assign this Agreement, the shares of Series B Preferred Stock and Common Shares being purchased hereunder by EIS, the Note, the Warrants, and the
shares of Common Stock underlying the Series B Preferred Stock, the Note and the Warrants, or any interest therein, without the prior written consent of the other party; provided, however, that
(a) no consent shall be required in connection with any such transfer or assignment by a party pursuant to a sale of all or substantially all of the business of such party whether by merger,
sale of stock, sale of assets or otherwise and (b) the restriction on the transfer of the Common Shares being purchased hereunder by EIS and the shares of Common Stock underlying the
Series B Preferred Stock, the Note and the Warrants will not apply to (i) Securities registered under the Securities Act, (ii) Securities sold pursuant to 144 under the Securities
Act, and (iii) Securities sold in private transaction to an entity that is primarily engaged in the business of investing in publicly-traded securities." 

        1.6  The
parties agree that the Common Stock purchased on the Third Subsequent Purchase Date and the Common Stock issuable upon the exercise of the Warrant purchased on the
Third Subsequent Purchase Date are included in the definition of Registrable Securities under that certain Registration Rights Agreement between Isis and EIS dated January 14, 2000. 

 
 

ARTICLE 2. GENERAL PROVISIONS    
  

        2.1    Original Agreement.    Except as specifically provided in this Amendment, all other terms and conditions of the
Original Agreement will remain in full force and effect. 

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        2.2    Entire Agreement.    This Amendment, the Original Agreement and the other Transaction Documents contain the
entire understanding of the parties with respect to the subject matter hereof and thereof and supersede all prior agreements and understandings among the parties with respect thereto. 

        2.3    Other General Provisions.    Section 8 and Sections 10 through 18 of the Original Agreement, will apply
to this Amendment. 

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        IN
WITNESS WHEREOF, the parties hereto have executed this Amendment as of the date first written above: 

	ISIS PHARMACEUTICALS, INC.	 	 	 	ELAN INTERNATIONAL SERVICES, LTD
	

    	
 	

 	
 	

 
	

    
 Name	
 	

 	
 	

    
 Name
	

    	
 	

 	
 	

 
	

/s/  B. LYNNE PARSHALL      
 Signature	
 	

 	
 	

/s/  DEBRA MOORE BURYS      
 Signature
	

    	
 	

 	
 	

 
	

    
 Title	
 	

 	
 	

    
 Title

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AMENDMENT NO. 1 TO SECURITIES PURCHASE AGREEMENT

ARTICLE 1. AMENDMENTS

ARTICLE 2. GENERAL PROVISIONS

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