Chiron Corp. v. Genentech, Inc.

• Decision Date: 30 March 2004
• Docket Number: No. 03-1158.,No. 03-1159.,03-1158.,03-1159.
• Citation: 363 F.3d 1247
• Parties: CHIRON CORPORATION, Plaintiff-Appellant, v. GENENTECH, INC., Defendant-Cross Appellant.
• Court: U.S. Court of Appeals — Federal Circuit

363 F.3d 1247

CHIRON CORPORATION, Plaintiff-Appellant, v. GENENTECH, INC., Defendant-Cross Appellant.

No. 03-1158.

No. 03-1159.

United States Court of Appeals, Federal Circuit.

DECIDED: March 30, 2004.

COPYRIGHT MATERIAL OMITTED

Harold J. McElhinny, Morrison & Foerster LLP, of San Francisco, CA, argued for plaintiff-appellant. With him on the brief were Rachel Krevans, Eric S. Walters, and Jason A. Crotty. Of counsel on the brief were Nancy J. Koch, Robert P. Blackburn, and Joseph Harry Guth, Chiron Corporation, of Emeryville, CA.

Leora Ben-Ami, Clifford Chance, of New York, NY, argued for defendant-cross appellant. On the brief were Roy E. Hofer, Cynthia A. Homan, Meredith Martin Addy, and C. Noel Kaman, Brinks Hofer Gilson & Lione, of Chicago, IL. Of counsel on the brief were John W. Keker and Daralyn J. Durie, Keker & Van Nest, of San Francisco, CA.

Before RADER, Circuit Judge, ARCHER, Senior Circuit Judge, and BRYSON, Circuit Judge.

RADER, Circuit Judge.

After a jury trial, the United States District Court for the Eastern District of California entered judgment in favor of Genentech that all claims of U.S. Patent No. 6,054,561 are invalid under 35 U.S.C. § 102 because none of the asserted claims is entitled to priority to a series of applications filed in 1984, 1985, and 1986. Chiron Corp. v. Genentech, Inc., No. Civ. S-00-1252 WBS GGH (Sept. 9 & Oct. 23, 2002). Because Chiron did not adequately disclose or support the subject matter of its '561 patent in its 1984, 1985, or 1986 applications, this court affirms the district court's denial of a motion for judgment as a matter of law (JMOL) and motion for a new trial.

I.

The '561 patent claims particular monoclonal antibodies. Specifically, independent claim 19 states:¹ "A monoclonal antibody that binds to human c-erbB-2 antigen."

According to modern understanding, a monoclonal antibody is a composition with a homogeneous antibody population. An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen. Described in terms of its structure, an antibody is a Y-shaped protein consisting of four amino acid chains, two heavy and two light. In a simplified model sufficient for this appeal, each antibody has primarily two regions: a variable region and a constant region. The variable region, located on the ends of the arms of the Y, binds to and interacts with the target antigen. This variable region includes a complementary determining region (CDR) that recognizes and binds to a specific binding site on a particular antigen. The constant region, located on the tail of the Y, is recognized by and interacts with the immune system.

A target antigen generally has numerous binding sites, also called epitopes, recognized by CDRs on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more than one corresponding antibody. In this case, claim 19 of the '561 patent reads on monoclonal antibodies that bind to human c-erbB-2 antigen (also named HER2) — an antigen associated with breast cancer cells.

There are various methods of producing monoclonal antibodies. One method uses hybridoma technology, which refers to a cloned cell line that produces a single type of antibody. The hybridoma method uses the cells of various species, including mice, hamsters, rats, and humans. Murine antibodies — derived from mouse cells — are particularly important for this invention.

Another method uses genetic engineering including recombinant DNA techniques. Monoclonal antibodies made from these techniques include, among others, chimeric antibodies and humanized antibodies. A chimeric antibody combines DNA encoding regions from more than one type of species. For example, a chimeric antibody may derive the variable region from a mouse and the constant region from a human. A humanized antibody comes predominantly from a human, even though it contains nonhuman portions. Like a chimeric antibody, a humanized antibody may contain a completely human constant region. But unlike a chimeric antibody, the variable region may be partially derived from a human. The nonhuman synthetic portions of a humanized antibody often come from CDRs in murine antibodies. In any event, these regions are crucial to allow the antibody to recognize and bind to a specific antigen.

As noted, murine antibodies play an important role in these technologies. While useful for diagnostics and short-term therapies, murine antibodies cannot be administered to people long-term without increasing the risk of a deleterious immunogenic response. This response, called Human Anti-Mouse Antibody (HAMA), occurs when a human immune system recognizes the murine antibody as foreign and attacks it. A HAMA response can cause toxic shock or even death.

Chimeric and humanized antibodies reduce the likelihood of a HAMA response by minimizing the nonhuman portions of administered antibodies. Furthermore, chimeric and humanized antibodies have the additional benefit of activating secondary human immune responses, such as antibody dependent cellular cytoxicity.

In the early 1980s, scientists at Chiron's predecessor corporation, Cetus Corp., (collectively, Chiron) began investigating monoclonal antibodies that target human breast cancer antigens. As noted above, the antigen that facilitates diagnosis and treatment of breast cancer was eventually named HER2. This investigational work led to a series of patent applications. The inventors filed their first application on February 8, 1984. Within a year, on January 11, 1985, they filed a continuation-in-part (CIP) application claiming priority based on that first 1984 application. The inventors filed another CIP application on May 21, 1986. Eventually, the application that led to the '561 patent was filed as another CIP on June 7, 1995. This appeal focuses on the '561 patent's claims to priority based on the applications filed in 1984, 1985, and 1986.

The 1984 application discloses one monoclonal antibody (454C11) that binds to HER2. The 454C11 is a murine antibody produced by the hybridoma method. While the application discloses the deposit of the hybridoma that produced the monoclonal antibody, the application does not identify the structure, function, or molecular weight of the antigen. Because the first publication that disclosed chimeric antibody technology did not appear until four months after this filing, it is not surprising that the 1984 application does not disclose any chimeric antibodies. Similarly, the first publication to disclose humanized antibodies appeared in May 1986. Thus, for good reason, this 1984 application also does not mention any humanized antibodies.

The 1985 application discloses six additional monoclonal antibodies that bind to HER2, all of which are murine antibodies. The disclosure also refers to the deposit of an additional hybridoma for one of these monoclonal antibodies, 520C9. While the application provides an approximate antigen molecular weight of 210 kilodaltons,² the application does not describe the identity, structure, or function of the antigen. The application does, however, note that six of the seven antibodies likely bind to the same epitope. By the time of this application, chimeric antibody technology was known in this art field. Although the application does not specifically disclose chimeric or humanized antibodies, it adds the following disclosure:

As used herein the term "monoclonal antibody" means an antibody composition having a homogeneous antibody population. It is not intended to be limited as regards the source of the antibody or the manner in which it is made.

The 1986 application discloses six additional murine antibodies that bind to HER2 and the deposit for three additional hybridomas. Thus, this application discloses a total of thirteen murine antibodies and deposits for five of their corresponding hybridomas, including those corresponding to 454C11 and 520C9. The application discloses that these antibodies likely bind to at least three different epitopes on HER2. Although still not identifying the antigen by name, the application discloses that its molecular weight is approximately 200 kilodaltons. Although the 1986 application makes no specific mention of chimeric or humanized antibodies, it quotes again the statement that the term monoclonal antibody "is not intended to be limited as regards the source of the antibody or the manner in which it is made."

When the '561 patent issued, Chiron sued Genentech over sales of Herceptin ®, a humanized antibody useful for the longterm treatment of breast cancer. Herceptin binds to the HER2 antigen and thus inhibits the growth of cancerous cells. Because Herceptin is a humanized antibody, it minimizes any HAMA response in patients.

Before trial, the district court broadly construed the claims of the '561 patent to embrace chimeric and humanized antibodies in addition to the murine antibodies that bind to HER2. Chiron Corp. v. Genentech, Inc., 266 F.Supp.2d 1172 (E.D.Cal. 2002). Accordingly, the district court subsequently granted Chiron's motion for partial summary judgment of infringement. Chiron Corp. v. Genentech, Inc., No. Civ. S-00-1252 WBS GGH, 2002 U.S. Dist. LEXIS 19126, 2002 WL 32123930 (E.D.Cal. June 24, 2002). Also before trial, the parties stipulated that the '561 patent would be invalid under § 102 based on intervening prior art if the patent were not entitled to claim priority to the filing date of any one of the 1984, 1985, and 1986 applications. Thus, the thirteen-day jury trial adjudicated only whether any of the priority applications satisfy the written description and enablement requirements of 35 U.S.C. § 112, first paragraph. Specifically the trial determined whether the 1980s applications adequately disclosed, and thus supported, the claim to chimeric and humanized antibodies claimed in the '561 patent (with its...