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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Filed By Romeo & Dye's Instant Form 4 Filer
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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 1/2/03
(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	1/1/03	1/2/03	J	V	327⁽¹⁾	A	$5.6015	8,966	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
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)

$6.84

1-2-03

9,000

⁽²⁾

1-1-13

Common Stock

9,000

Explanation of Responses:

(1) Reporting 327 shares acquired under the Isis Pharmaceuticals, Inc. 2000 Employee Stock Purchase Plan on January 1, 2003.
(2) 25% of the shares subject to the option will vest and become exercisable on 1-2-04. Thereafter, 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
B. Lynne Parshall
**Signature of Reporting Person

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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If space is insufficient, See Instruction 6 for procedure.

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COLE DOUGLAS L 4