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

SCHEDULE 13G

Under the Securities Exchange Act of 1934
(Amendment No. 1)*

Isis Pharmaceuticals, Inc.

(Name of Issuer)

Common Stock

(Title of Class of Securities)

464330-1-09

(CUSIP Number)

December 20, 2004

(Date of Event Which Requires Filing of this Statement)

Check the appropriate box to designate the rule pursuant to which this Schedule is filed:

o Rule 13d-1 (b)

þ Rule 13d-1 (c)

o Rule 13d-1 (d)

*The remainder of this cover page shall be filled out for a reporting person’s initial filing on this form with respect to the subject class of securities, and for any subsequent amendment containing information which would alter the disclosures provided in a prior cover page.

The information required in the remainder of this cover page shall not be deemed to be “filed” for the purpose of Section 18 of the Securities Exchange Act of 1934 or otherwise subject to the liabilities of that section of the Act but shall be subject to all other provisions of the Act (however, see the notes).

13G

CUSIP No. 464330-1-09 Page 2 of 5

1. Name of Reporting Person:
Eli Lilly and Company I.R.S. Identification Nos. of above persons (entities only):
35-0470950

2. Check the Appropriate Box if a Member of a Group:

(a) o

(b) o

3. SEC Use Only: Indiana

4. Citizenship or Place of Organization:
Indiana

Number of
Shares
Beneficially
Owned by
Each Reporting
Person With

5. Sole Voting Power:
3,541,875

6. Shared Voting Power:
624,791

7. Sole Dispositive Power:
3,541,875

8. Shared Dispositive Power:
624,791

9. Aggregate Amount Beneficially Owned by Each Reporting Person:
4,166,167

10. Check if the Aggregate Amount in Row (9) Excludes Certain Shares:
o

11. Percent of Class Represented by Amount in Row (9):
7.3%

12. Type of Reporting Person:
CO


Item 1(a).		Name of Issuer:

		Isis Pharmaceuticals, Inc.

Item 1(b).		Address of Issuer’s Principal Executive Offices:

		2292 Faraday Avenue Carlsbad, CA 92008

Item 2(a).		Name of Person Filing:

		Eli Lilly and Company

Item 2(b).		Address of Principal Business Office or, if None, Residence:

		Lilly Corporate Center Indianapolis, IN 46285

Item 2(c).		Citizenship:

		Indiana

Item 2(d).		Title of Class of Securities:

		Common Stock

Item 2(e).		CUSIP Number:

		464330-1-09

Item 3.		If this statement is filed pursuant to Rule 13d-1(b), or 13d-2(b) or (c), check whether the person filing is a:

		(a)-(j) Not applicable

		If this statement is filed pursuant to Rule 13d-1(c), check this box. x

Page 3 of 5 Pages


Item 4.		Ownership.


	(a)		Amount Beneficially Owned:

			4,166,167

	(b)		Percent of Class:

			7.3%

	(c)		Number of shares as to which the person has:


Sole voting power			3,541,875

Shared voting power			624,791

Sole dispositive power			3,541,875

Shared dispositive power			624,791


Item 5.		Ownership of Five Percent or Less of a Class.

		Not applicable

Item 6.		Ownership of More Than Five Percent on Behalf of Another Person.

		Not applicable

Item 7.		Identification and Classification of the Subsidiary which Acquired the Security Being Reported on by the Parent Holding Company.

		Not applicable

Item 8.		Identification and Classification of Members of the Group.

		Not applicable

Item 9.		Notice of Dissolution of Group.

		Not applicable

Page 4 of 5 Pages


Item 10.		Certifications.

		By signing below, I certify that, to the best of my knowledge and belief, the securities referred to above were not acquired and are not held for the purpose of or with the effect of changing or influencing control of the issuer of the securities and were not acquired and are not held in connection with or as a participant in any transaction having that purpose or effect.

SIGNATURE

After reasonable inquiry and to the best of my knowledge and belief, I certify that the information set forth in this statement is true, complete and correct.

ELI LILLY AND COMPANY

By: /s/ Charles E. Golden
Charles E. Golden
Executive Vice President and
Chief Financial Officer

Date: February 11, 2005

Page 5 of 5 Pages


13G
CUSIP No. 464330-1-09					Page 2 of 5

	1.	Name of Reporting Person: Eli Lilly and Company			I.R.S. Identification Nos. of above persons (entities only): 35-0470950

	2.	Check the Appropriate Box if a Member of a Group:
		(a)	o
		(b)	o

	3.	SEC Use Only: Indiana

	4.	Citizenship or Place of Organization: Indiana

Number of Shares Beneficially Owned by Each Reporting Person With
			5.	Sole Voting Power: 3,541,875

			6.	Shared Voting Power: 624,791

			7.	Sole Dispositive Power: 3,541,875

			8.	Shared Dispositive Power: 624,791

	9.	Aggregate Amount Beneficially Owned by Each Reporting Person: 4,166,167

	10.	Check if the Aggregate Amount in Row (9) Excludes Certain Shares: o

	11.	Percent of Class Represented by Amount in Row (9): 7.3%

	12.	Type of Reporting Person: CO


	ELI LILLY AND COMPANY
	By:	/s/ Charles E. Golden
		Charles E. Golden
		Executive Vice President and Chief Financial Officer