FIFTH AMENDMENT TO RESEARCH COLLABORATION AND LICENSE AGREEMENT DATED MAY 31, 1991

Exhibit 10.4

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(4)

and 240.24b-2.

FIFTH AMENDMENT TO RESEARCH COLLABORATION AND LICENSE

AGREEMENT DATED MAY 31, 1991

This Fifth Amendment (“Fifth Amendment”), entered into this 8th day of September, 2005 (“Amendment Effective Date”), between Merck & Co., Inc. (“MERCK”) and Vical Incorporated (“VICAL”), amends the Research Collaboration and License Agreement between MERCK and VICAL dated May 31, 1991, as previously amended on April 27, 1994, December 13, 1995, November 3, 1997 and August 20, 2003 (such August 20, 2003 amendment referred to as the “Fourth Amendment”) (collectively, including all amendments, the “Agreement”).

RECITALS:

WHEREAS, pursuant to the Agreement, MERCK obtained an exclusive license under VICAL PATENT RIGHTS and VICAL KNOW-HOW to develop, make, have made, use and sell LICENSED PRODUCTS in the TERRITORY upon the terms and conditions set forth therein; and

WHEREAS, AIDS VACCINE is a LICENSED PRODUCT and TREATMENT VACCINE is a LICENSED PRODUCT; and

WHEREAS, the parties wish to amend the Agreement to provide for the reversion of non-exclusive rights to VICAL under the VICAL PATENT RIGHTS and VICAL KNOW-HOW for AIDS VACCINE and TREATMENT VACCINE for human immunodeficiency virus (“HIV-1”), subject to certain conditions described herein; and

WHEREAS, under the Fourth Amendment, VICAL granted MERCK an option to obtain up to three (3) CANCER TARGET LICENSES; and

WHEREAS, MERCK has recently exercised its option to obtain all three (3) CANCER TARGET LICENSES available to MERCK pursuant to the Fourth Amendment;

WHEREAS, MERCK and VICAL have agreed that MERCK shall have an option to obtain up to [***] additional CANCER TARGET LICENSES, and to extend the Option Period (as such term is defined in the Fourth Amendment) for such CANCER TARGET LICENSES, on the same terms as applicable to CANCER TARGET LICENSES under the Fourth Amendment, as further set forth herein;

NOW, THEREFORE, in consideration of the premises and covenants set forth herein, the parties hereto agree as follows:

“DNA HIV VACCINE” shall mean a bulk or finished vaccine containing a plasmid nucleic acid that encodes for an antigenic protein, where such vaccine is utilized for prevention and/or treatment of human immunodeficiency virus and/or diseases or medical conditions involving infection with human immunodeficiency virus.

“ELECTROPORATION” shall mean the use of an electrical pulse to temporarily disturb membranes of a cell or cells.

“ELECTROPORATION EXCLUSIVITY PERIOD” shall mean the [***] period immediately following the Amendment Effective Date.

“ELECTROPORATION HIV FIELD” shall mean the use of ELECTROPORATION TECHNOLOGY to assist with the in vivo delivery of the DNA HIV VACCINE into human tissue.

“ELECTROPORATION TECHNOLOGY” shall mean any device for use in ELECTROPORATION, such device including any software, applicators or custom components used in such ELECTROPORATION.

“VICAL ELECTROPORATION KNOW-HOW” shall mean all information and data in the ELECTROPORATION HIV FIELD, which are not generally known to the public, including, but not limited to, formulae, procedures, protocols, techniques and results of experimentation and testing, which are necessary or useful in the ELECTROPORATION HIV FIELD to make, use, develop, sell or seek regulatory approval to market a composition, or to practice any method or process related to information or data claimed or disclosed in any issued patent or pending patent application within the VICAL ELECTROPORATION PATENT RIGHTS, (i) which are in existence as of the Amendment Effective Date or thereafter during the ELECTROPORATION EXCLUSIVITY PERIOD and (ii) in which VICAL has a licensable or sublicensable interest and which is in the possession or control of VICAL (including but not limited to any such rights obtained by VICAL from Inovio Biomedical Corporation or its subsidiary). For clarification, VICAL ELECTROPORATION KNOW-HOW shall not include any information and data pertaining to the DNA HIV VACCINE itself, and VICAL ELECTROPORATION KNOW-HOW shall not be included in the VICAL KNOW-HOW or VICAL PATENT RIGHTS.

“VICAL ELECTROPORATION PATENT RIGHTS” shall mean any and all patents and patent applications in the TERRITORY which are necessary or useful in the ELECTROPORATION HIV FIELD and in which VICAL has a licensable or sublicensable interest as of the Amendment Effective Date or thereafter during the ELECTROPORATION EXCLUSIVITY PERIOD, including any patent issued from any such patent application, including utility, model and design patents and certification of invention, and all divisionals, continuations, continuations-in-part, reissues, renewals, extensions, or additions to any such patents and patent applications claiming benefit of the priority date thereof to the extent the foregoing are applicable to the ELECTROPORATION HIV FIELD. For clarification, VICAL ELECTROPORATION PATENT RIGHTS shall not include any patents or patent applications claiming the DNA HIV VACCINE or its manufacture or use, and VICAL ELECTROPORATION PATENT RIGHTS shall not be included in the VICAL KNOW-HOW or VICAL PATENT RIGHTS.

Article 3.1 is amended by reorganizing the existing text of Article 3.1 into different subsections, and revising the text of such provision, as follows:

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