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Exhibit 10.53

AMENDMENT

        This Amendment to the Collaborative Research and License Agreement dated
July 9, 2001, ("Agreement"), by and between ISIS PHARMACEUTICALS, INC. ("Isis"),
a Delaware corporation, with its principal office at 2292 Faraday Avenue,
Carlsbad, California 92008 and PE CORPORATION (NY), a New York corporation,
through the CELERA GENOMICS GROUP, ("Celera"), having a principal place of
business at 45 West Gude Drive, Rockville, Maryland 20850. Celera and Isis may
be referred to herein individually as a "Party" and collectively as the
"Parties".

        WHEREAS, Celera and Isis entered into the Agreement to collaborate to
generate information on gene function for up to 250 gene targets; and

        WHEREAS, Celera and Isis desire to amend the Agreement.

        NOW, THEREFORE, in consideration of the mutual covenants and promises
contained herein, the Parties agree to amend the Agreement as follows:

1.Section 1.4(a) is added as follows:

1.4(a)   "Celera Conditional Target" means a Gene selected by Celera and
included by Isis in the HTGF queue under the conditions set forth in
Section 3.1(b).

2.Section 3.1(b) is amended by adding the following:

Upon approval by Celera, Isis will include a Gene in the HTGF queue
notwithstanding the right of Isis under this Section to exclude such Gene
provided that such Gene will not become: (i) part of the Celera Gene
Availability Pool, or (ii) a Celera Exclusive Target (such Gene a "Celera
Conditional Target"). Except as provided in the preceding sentence, all Celera
Conditional Targets will be treated equally hereunder with any other Gene
included in the HTGF queue. Isis will notify Celera in writing of the identity
of any Gene which Isis would include in the HTGF queue only as a Celera
Conditional Target within ten (10) business days of Celera's selection of such
Gene. If Celera wishes to approve such Gene as a Celera Conditional Target,
Celera will notify Isis in writing within fifteen (15) business days of receipt
of Isis's notification, provided, however, that Isis will have no obligation to
reserve such Gene for Celera prior to receiving notification of Celera's
approval of such Gene as a Celera Conditional Target. If Celera does not approve
such Gene as a Celera Conditional Target, such Gene will become a Rejected Gene.

        This Amendment will be attached to the Agreement and incorporated
therein. All other terms of the Agreement will remain in full force and effect.

PE CORPORATION (NY)   ISIS PHARMACEUTICALS, INC.
By:
/s/  MARK D. ADAMS      

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By:
/s/  B. LYNNE PARSHALL      

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  Mark D. Adams, Ph.D.
Vice President, Genome Programs     B. Lynne Parshall
Executive Vice President
Date: 4/19/02
 
Date: 4/22/02

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Exhibit 10.53