FORM 4

UNITED STATES SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549

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Check this box if no longer subject to Section 16. Form 4 or Form 5 obligations may continue. See Instruction 1(b).

STATEMENT OF CHANGES IN BENEFICIAL OWNERSHIP

Filed pursuant to Section 16(a) of the Securities Exchange Act of 1934, Section 17(a) of the Public Utility Holding Company Act of 1935 or Section 30(h) of the Investment Company Act of 1940

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1. Name and Address of Reporting Person* Cole Douglas L.	2. Issuer Name and Ticker or Trading Symbol Isis Pharmaceuticals, Inc. (ISIS)		6. Relationship of Reporting Person(s) to Issuer (Check all applicable) Director 10% Owner X Officer (give title below) Other (specify below) Vice President
(Last) (First) (Middle) 2292 Faraday Avenue	3. I.R.S. Identification Number of Reporting Person, if an entity (voluntary)	4. Statement for Month/Day/Year 101/142/0203
(Street) Carlsbad, CA 92008		5. If Amendment, Date of Original (Month/Day/Year)	7. Individual or Joint/Group Filing (Check Applicable Line) X Form filed by One Reporting Person Form filed by More than One Reporting Person
(City) (State) (Zip)	Table I — Non-Derivative Securities Acquired, Disposed of, or Beneficially Owned

1. Title of Security (Instr. 3)	2. Trans- action Date (Month/ Day/ Year)	2A. Deemed Execution Date, if any (Month/Day/ Year)	3. Trans- action Code (Instr. 8)		4. Securities Acquired (A) or Disposed of (D) (Instr. 3, 4 & 5)			5. Amount of Securities Beneficially Owned Follow- ing Reported Transactions(s) (Instr. 3 & 4)	6. Owner- ship Form: Direct (D) or Indirect (I) (Instr. 4)	7. Nature of Indirect Beneficial Ownership (Instr. 4)
			Code	V	Amount	(A) or (D)	Price
Common Stock	101/141/0203	101/142/0203	MJ	V	~~8400~~327(1)	A	$5.56015	8,966	D
Common Stock	10/14/02	10/14/02	S(1)		8400	D	$8.8999	8639	D

Reminder: Report on a separate line for each class of securities beneficially owned directly or indirectly.
* If the form is filed by more than one reporting person, see Instruction 4(b)(v).

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FORM 4 (continued)

Table II - Derivative Securities Acquired, Disposed of, or Beneficially Owned
(e.g., puts, calls, warrants, options, convertible securities)

1. Title of Derivative Security (Instr. 3)

2. Conver- sion or ~~Excercise~~Exercise Price of Derivative Security

3. Trans- action Date (Month/ Day/ Year)

3A. Deemed Execution Date, if any (Month/ Day/ Year)

4. Trans- action Code (Instr. 8)

5. Number of Derivative Securities Acquired (A) or Disposed of (D) (Instr. 3, 4 & 5)

6. Date Exercisable and Expiration Date (Month/Day/ Year)

7. Title and Amount of Underlying Securities (Instr. 3 & 4)

8. Price of Derivative Security (Instr. 5)

9. Number of Derivative Securities Beneficially Owned Following Reported Transaction(s) (Instr. 4)

10. Owner- ship Form of Deriv- ative Security: Direct (D) or Indirect (I) (Instr. 4)

11. Nature of Indirect Beneficial Ownership (Instr. 4)

Code

(A)

(D)

Date Exer-cisable

Expira- tion Date

Title

Amount or Number of Shares

Employee Stock Option (right to buy)

$56.584

~~10/14/02~~1-2-03

9,000

~~8400~~

~~10/16/97~~(2)

~~10/15/02~~1-1-13

Common Stock

~~8400~~9,000

09,000

Explanation of Responses: (1) ~~The~~Reporting ~~sale~~327 ~~reported~~shares inacquired ~~this~~under ~~Form~~the 4Isis ~~was~~Pharmaceuticals, ~~effected~~Inc. ~~pursuant~~2000 toEmployee aStock ~~Rule~~Purchase ~~10b5-~~Plan on January 1, ~~trading~~2003.(2) ~~plan~~25% ~~adopted~~of bythe shares subject to the ~~reporting~~option ~~person~~will vest and become exercisable on ~~March~~1-2-04. 20Thereafter, ~~2002~~the remaining shares subject to the option vest and become exercisable in 36 equal monthly installments, at the rate of 2,250 shares per year. The option is exercisable as to 0 shares on 1-2-03.

By: /s/ Douglas L. Cole ~~Douglas L~~B. ~~Cole~~Lynne Parshall **Signature of Reporting Person ~~10/14/02~~1-3-03 Date

**Intentional misstatements or omissions of facts constitute Federal Criminal Violations.
See 18 U.S.C. 1001 and 15 U.S.C. 78ff(a).

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Filing Compare · COLE DOUGLAS L