AMENDMENT NO. 1 TO SECOND AMENDED AND RESTATED COLLABORATION, LICENSE AND SUPPLY AGREEMENT

EXHIBIT 10.51

CONFIDENTIAL PORTIONS HAVE BEEN OMITTED BASED UPON A REQUEST FOR CONFIDENTIAL TREATMENT PURSUANT TO RULE 24b-2 OF THE SECURITIES EXCHANGE ACT OF 1934 AND HAVE BEEN SEPARATELY FILED WITH THE COMMISSION

AMENDMENT NO. 1 TO SECOND AMENDED AND RESTATED COLLABORATION, LICENSE

AND SUPPLY AGREEMENT

BETWEEN

EPOCH BIOSCIENCES, INC. (FORMERLY EPOCH PHARMACEUTICALS, INC.)

AND

APPLERA CORPORATION (SUCCESSOR TO PERKIN-ELMER CORPORATION)

This Amendment No. 1 to Second Amended and Restated Collaboration, License and Supply Agreement (the “Amendment”) is entered into this 26^TH day of July, 2002.

RECITALS

A. Epoch Biosciences, Inc. (formerly known as Epoch Pharmaceuticals, Inc.) (“Epoch”) and Applera Corporation (successor to PE Corporation (NY) (formerly known as The Perkin-Elmer Corporation)), through its Applied Biosystems Group, (“ABG”) are parties to that certain Second Amended and Restated Collaboration, License and Supply Agreement, dated August 17, 2000, (the “Collaboration Agreement”) as supplemented by that certain First Side Agreement (“First Side Agreement”), effective as of October 31, 2001.

B. As contemplated by Section 4 of the First Side Agreement, the Parties desire to further amend the Collaboration Agreement to clarify certain definitions and modify the royalty rates and the minimum royalty and minimum purchase obligations for certain categories of Licensed Products.

C. The Parties also desire to clarify certain other language of the Collaboration Agreement.

AGREEMENT

NOW, THEREFORE, the Parties agree as follows:

1. All capitalized terms not defined herein shall have the meaning set forth in the Collaboration Agreement.

2. Section 2.12 is amended to read as follows:

“2.12 “Bare Probe” means a MGB Oligonucleotide provided alone or with primers.”

3. Section 2.18 is amended to read as follows:

“2.18 “Human In Vitro Diagnostics Field (“HIVD Field”) means products and processes for the measurement of attributes, characteristics, diseases, traits or other conditions of a human being for the medical management of that human being.”

4. Section 5.04(a) is amended, effective for all Net Sales after September 30, 2001, to read as follows:

“5.04 (a) Percentage Royalties. ABG will pay to Epoch percentage royalties on the Net Sales of Licensed Products sold or otherwise disposed of under the license granted under Sections 4.01 and 4.02 of this Agreement. For purposes of determining the royalty payable with respect to a given Licensed Product, Licensed Products (other than algorithms and related software) shall be classified into three categories as follows:

The applicable royalty rates for each Licensed Product for all Net Sales from October 1, 2001 to December 31, 2002 shall be as follows:

The applicable royalty rates for each Licensed Product for all Net Sales commencing January 1, 2003 shall be as follows:

* CONFIDENTIAL POTIONS OMITTED AND FILED SEPARATELY WITH COMMISSION.

No percentage royalties will be owed under this Section 5.04 (a) for the sale by ABG of any Category 1, 2 or 3 Licensed Products not covered by a Valid Claim in the event that (i) the Licensed Know-How becomes publicly available, (ii) ABG is placed at a commercial disadvantage as a result of such know-how becoming publicly available, and (iii) such know-how was not made publicly available by ABG. In addition, no percentage royalties will be owed under this Section 5.04(a) for the sale by ABG of any Bare Probes purchased by ABG from Epoch pursuant to Section 6.02.”

5. Section 5.04(b) is amended, effective October 1, 2002, to read as follows:

“5.04(b) Quarterly Minimum Royalties. Notwithstanding the foregoing, ABG shall pay minimum quarterly royalties (each a “Quarterly Minimum Royalty”) with respect to each calendar quarter as follows:

*CONFIDENTIAL PORTIONS OMITTED AND FILED SEPARATELY WITH COMMISSION.

If total royalties paid by ABG under Section 5.04(a) above for Net Sales in any applicable calendar quarter are less than the Quarterly Minimum Royalty for such quarter, then ABG shall pay to Epoch the difference between actual royalties paid and the Quarterly Minimum Royalty within forty-five (45) days after the end of each such calendar quarter, along with the payment and statement under Section 5.06 for such quarter.”

6. Section 6.02 is amended, effective October 1, 2002, to read as follows:

“6.02 Purchases of Bare Probes. Subject to the terms and conditions of this Agreement, ABG may purchase Bare Probes from Epoch.”

The Parties acknowledge that pursuant to this Section 6, after October 1, 2002, ABG shall have no obligation to purchase Bare Probes from Epoch pursuant to Section 6.02 of the Collaboration Agreement.

7. The Parties acknowledge that the terms of Section 6.02 of the Collaboration Agreement and the First Side Agreement shall remain

in effect until September 30, 2002, and that ABG shall pay to Epoch all “Remainder Payments” (as defined in the First Side Agreement) with respect to Bare Probe purchase obligations for all quarters through the quarter ending September 30, 2002, with the last such payment due by September 30, 2002 (i.e., for example, assuming that ABG has purchased no Bare Probes from Epoch during the period of October 1, 2001 to September 30, 2002, ABG shall have paid Epoch an aggregate of $[*] in Remainder Payments for such period). No Remainder Payments will be owed by ABG to Epoch after September 30, 2002.

8. In addition, pursuant to Section 5.04(b) of the Collaboration Agreement, to the extent that the percentage royalties accrued on Net

Sales with respect to the License Year of October 1, 2001 to September 30, 2002, do not equal $[*], then ABG shall pay to Epoch such shortfall no later than November 15, 2002.

9. In all other respects, the Collaboration Agreement is hereby ratified and confirmed. In the case of direct conflict or conflict by

reason of interpretation between any provision of this Amendment and the Collaboration Agreement, the Amendment shall control and supercede the terms of the Collaboration Agreement.

[Signature page follows.]

*CONFIDENTIAL PORTIONS OMITTED AND FILED SEPARATELY WITH COMMISSION.

IN WITNESS WHEREOF, the Parties, through their authorized officers, have executed this Amendment No. 1 as of the date first written above.