<PAGE>
                                                                 EXHIBIT 10.29.1

                     FIRST AMENDMENT TO EMPLOYMENT AGREEMENT

          This FIRST AMENDMENT TO EMPLOYMENT AGREEMENT (the "Amendment") is made
and entered into this 19th day of August, 2004, by and between EPOCH
BIOSCIENCES, INC., a Delaware corporation (the "Employer"), and Dr. Walter
Mahoney, an individual (the "Employee").

                                    RECITALS:

          A. Employee and Employer are parties to that certain Employment
Agreement dated as of January 7, 2002 (the "Employment Agreement"); and

          C. The parties desire to amend the Employment Agreement to correct and
clarify certain provisions relating to Employee's ability to terminate his
employment for "Good Reason" following a Change in Control of the Company.

                                   AGREEMENT:

          NOW, THEREFORE, in consideration of the foregoing premises and the
respective covenants and agreements of each party to the other set forth herein,
the parties hereto, intending to be legally bound, hereby agree as follows:

          1. Amendment to Section 4.1(f). The parties hereby amend, as of the
Effective Date of the Employment Agreement, Section 4.1(f) of the Employment
Agreement, such that Section 4.1(f) of the Employment Agreement shall read in
its entirety as follows:

                         "(f) For the purposes of this Agreement, "Good Reason"
             shall mean the assignment of Employee to a position within the
             Company, upon or within twelve (12) months following a Change in
             Control, which (i) is not equivalent in all material respects with
             the Employee's position with the Company prior to such Change in
             Control (taking into account the relative size of the Company prior
             to such Change in Control and the size of the acquiring entity, and
             other than actions that are not taken in bad faith and are remedied
             by the Company within five (5) business days after receipt of
             notice thereof from the Employee), (ii) requires the Employee to
             work at a location not within 50 miles of the Company's
             headquarters immediately prior to the Change in Control (the
             "Existing Location"), provided that Employee, if requested in
             writing by the Company, continues working at the Company at the
             Existing Location under the terms of this Agreement for a period of
             up to six (6) months following the Change in Control, or (iii)
             results in any reduction in the Employee's Base Salary.
             Notwithstanding the foregoing, in the event the Board of Directors
             reassigns Employee to another senior executive officer position
             with the Company, such reassignment shall not constitute "Good
             Reason" under clause (i) of this Section 4.1(f)."

<PAGE>

          2. Defined Terms. Unless otherwise defined herein, all capitalized
terms in this Amendment shall have the respective meanings ascribed to them in
the Employment Agreement.

          3. Effect on Employment Agreement. Except as specifically amended in
the manner and to the extent provided in Section 1 above, the Employment
Agreement shall remain unchanged and the Employment Agreement shall continue, as
and to the extent amended by this Amendment, in full force and effect.

          4. Conflicts. This Amendment shall be governed by all the terms and
conditions of the Employment Agreement. In the event of any conflict between the
terms of the Employment Agreement and the terms of this Amendment, the terms of
this Amendment will control.

          5. Counterpart Execution. This Amendment may be executed by facsimile
and in counterparts, each of which shall be deemed an original and all of which
when taken together shall constitute but one and the same instrument.

          IN WITNESS WHEREOF, the parties have executed this First Amendment to
Employment Agreement as of the day and year set forth above.

                                             "EMPLOYER"

                                             EPOCH BIOSCIENCES, INC.,
                                             a Delaware corporation


                                             By:   /s/ William G. Gerber
                                                   -----------------------------
                                                   William G. Gerber
                                                   Its: Chief Executive Officer

                                             "EMPLOYEE"


                                             /s/ Dr. Walter Mahoney
                                             ---------------------------------
                                             Dr. Walter Mahoney



                                       2