FIRST SUPPLEMENTAL INDENTURE

Exhibit 10.1

FIRST SUPPLEMENTAL INDENTURE

     This First Supplemental Indenture (this “ First Supplemental Indenture ”) is made and entered into as of this 11th day of December 2008, by and between Vermillion, Inc., formerly Ciphergen Biosystems, Inc., a Delaware corporation (the “ Company ”), and U.S. Bank National Association, a national banking association duly organized and existing under the laws of the United States, as trustee under the Indenture (as defined below) (the “ Trustee ”).

RECITALS

     A. The Company and the Trustee entered into that certain Indenture dated as of August 22, 2003 (the “ Indenture ”) governing the 4.50% Convertible Senior Notes due 2008 (the “ Notes ”) issued by the Company to Holders thereof.

     B. The Notes matured on September 1, 2008, at which time all principal and interest on the Notes came due. The Company made a partial payment of $56,250 to the Trustee on September 1, 2008, which amount was equal to accrued interest on the Notes through August 31, 2008.

     C. Section 7.2 of the Indenture provides that the Indenture and the Notes may be amended to change the stated maturity of the principal of the Notes with the written consent of the Holders of the Notes so affected (the “ Requisite Consents ”).

     D. Pursuant to Section 7.2 of the Indenture, the Company desires to amend the Indenture to extend the maturity of the Notes, and to make such other changes to the terms of the Notes, as set forth herein.

     E. The Company has obtained the Requisite Consents to amend the Indenture and waive noncompliance with certain provisions therein all as set forth in this First Supplemental Indenture.

     F. The Company has requested that the Trustee execute and deliver this First Supplemental Indenture, all requirements necessary to make this First Supplemental Indenture a valid, binding and enforceable instrument in accordance with its terms have been done and performed, and the execution and delivery of this First Supplemental Indenture have been duly authorized in all respects.

     G. Upon consummation of the First Supplemental Indenture, the Trustee will distribute the partial payment of $56,250 to the Holders, which payment shall constitute accrued interest through August 31, 2008. Interest on the Notes shall continue to be payable semiannually in arrears on March 1 and September 1 in each year, and the next interest payment shall be payable by the Company on March 1, 2009.

STATEMENT OF AGREEMENT

     NOW, THEREFORE, in consideration of the foregoing recitals and of the mutual covenants and agreements hereinafter set forth, and intending to be legally bound, the parties hereto hereby agree as follows:

     1. Unless otherwise defined herein, all capitalized terms used herein have the meanings given to them in the Indenture.

     2. Each reference to the term “Change of Control” in the Indenture shall be replaced with the term “Change in Control.”

     3. The second paragraph of Section 2.1 of the Indenture is hereby amended and superseded in all respects by the provisions of this First Supplemental Indenture. As amended and restated, the second paragraph of Section 2.1 of the Indenture reads in its entirety:

“The Notes shall mature on September 1, 2009.”

     4. Section 10.1(b) of the Indenture is hereby amended and superseded in all respects by the provisions of this First Supplemental Indenture. As amended and restated, Section 10.1(b) of the Indenture reads in its entirety:

“On or after September 1, 2006, the Company may, at its option, redeem the Notes in whole at any time or in part from time to time, except upon the occurrence of a Change in Control, on any date prior to maturity, upon notice as set forth in Section 10.4 at the redemption price (expressed as a percentage of the principal amount) set forth below (the “Redemption Price”) if redeemed during the 24-month period beginning on the date indicated:

     5. Section 11.1 of the Indenture is hereby amended and superseded in all respects by the provisions of this First Supplemental Indenture. As amended and restated, Section 11.1 of the Indenture reads in its entirety:

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