Exhibit 4.4 SECOND AMENDMENT TO REGISTRATION RIGHTS AGREEMENT AND CONSENT THIS SECOND AMENDMENT TO REGISTRATION RIGHTS AGREEMENT AND CONSENT is made and entered into as of the 23rd day of December, 1998, by and among Maxygen, Inc., a Delaware corporation (the "Company"), and the undersigned holders (the "Investors") of the Company's Series A Preferred Stock, $0.0001 par value per share (the "Series A Preferred"), Series B Preferred Stock, $0.0001 par value per share (the "Series B Preferred") and Series C Preferred Stock, $0.0001 par value per share (the "Series C Preferred"). RECITALS The Company and certain of the Investors or their predecessors in interest (the "Series A and Series B Investors") have entered into that certain Registration Rights Agreement dated the 14th day of March, 1997, as amended the 31st day of July, 1997, attached hereto as Exhibit A (the "Rights Agreement"), that provides that such Investors are to receive certain registration rights with respect to Maxygen Common Stock ("Common Stock") and the Series A Preferred and the Series B Preferred. Pioneer Overseas Corporation, an Iowa corporation (the "Series C Investor") has agreed to purchase shares of the Series C Preferred Stock pursuant to that certain Series C Stock Purchase Agreement between the Company and the Series C Investor dated as of December 23, 1998. The undersigned Series A and Series B Investors (the "Consenting Investors") constitute the holders of a majority of the outstanding Registrable Securities for the purposes of Sections 13 and 17 of the Rights Agreement. The Company and the Consenting Investors wish to amend the Rights Agreement to add the Series C Preferred as Registrable Securities. The Consenting Investors wish to consent to the granting of registration rights to the Series C Investors. The Series C Investor wishes to become a party to the Rights Agreement, as amended hereby. NOW, THEREFORE, in consideration of the promises, mutual covenants and conditions herein contained, and of other good and valuable consideration, the receipt and sufficiency of which are hereby acknowledged, the parties hereby agree as follows: 1. Pursuant to Section 17 of the Rights Agreement, the definition of "Registrable Securities" contained in Section 1(d) of the Rights Agreement is hereby amended to read in its entirety as follows: (d) "Registrable Securities" shall mean (i) shares of Common Stock issued or issuable upon conversion of the Series A Preferred, the Series B Preferred or the Series C Preferred, (ii) shares of Common Stock held of record by any of the Investors, (iii) shares of Common Stock issued or issuable upon conversion of any other series of Preferred Stock of the Company as shall be agreed to in writing by a majority of the then outstanding Registrable Securities, and (iv) shares of Common Stock issued as a dividend or distribution with respect to, or in exchange or in replacement of, the foregoing; 2. By executing this Agreement on the Series C Investor Signature Page, the Series C Investor becomes a party to the Rights Agreement, as amended, as though the Series C Investor had executed the Rights Agreement as of the date thereof. 3. Pursuant to Section 13 of the Rights Agreement, the Consenting Investors consent to the Company entering into the Rights Agreement with the Series C Investor. This Agreement may be signed in any number of counterparts and by the parties hereto in separate counterparts, each of which when so executed shall be deemed to be an original and all of which taken together shall constitute one and the same agreement. 2 IN WITNESS WHEREOF, the parties have executed this Second Amendment and Consent as of the date first above written. MAXYGEN, INC. 3410 Central Expressway Santa Clara, California 95051 /s/ Russell Howard - ------------------ Signature Russell Howard - -------------- Name (please print) President & CEO - --------------- Title 3 SERIES A INVESTORS AFFYMAX TECHNOLOGIES N.V. Glaxo Wellcome House Berkeley Avenue Greenford, Middlesex, United Kingdom UB6 0NN Attn: ----------------- Fax: ------------------ /s/ Adrian Hennah - ----------------- Signature Adrian Hennah - ------------- Name (please print) Director - -------- Title TECHNOGEN ASSOCIATES, L.P. 525 University Avenue, Suite 700 Palo Alto, California 94301 By: TECHNOGEN MANAGERS, L.L.C., its general partner /s/ Isaac Stein - --------------- Signature Isaac Stein - ----------- Name (please print) Manager - ------- Title 4 SERIES B INVESTORS TECHNOGEN ASSOCIATES, L.P. 525 University Avenue, Suite 700 Palo Alto, California 94301 By: TECHNOGEN MANAGERS, L.L.C., its general partner /s/ Isaac Stein - --------------- Signature Isaac Stein - ----------- Name (please print) Manager - ------- Title TECHNOGEN ENTERPRISES, LLC 525 University Avenue, Suite 700 Palo Alto, California 94301 /s/ Isaac Stein - --------------- Signature Isaac Stein - ----------- Name (please print) Member - ------ Title 5 SERIES B INVESTORS continued - ---------------------- Entity (if applicable) /s/ - --- Signature - ------------------- Name (please print) - --------------------- Title (if applicable) 6 SERIES C INVESTOR SIGNATURE PAGE TO REGISTRATION RIGHTS AGREEMENT CONTINUED SERIES C INVESTOR PIONEER OVERSEAS CORPORATION 800 Capital Square 400 Locust Street Des Moines, Iowa 50309 Attn: ------------------ Fax: ------------------- /s/ Bill DeMeulenaere - --------------------- Signature Bill DeMeulenaere - ----------------- Name (please print) Assistant Secretary - ------------------- Title 7