Immunogen Antibody Conjugate Patent Survives IPR


11.02.15 Posted in PTAB by

Phigenix, Inc. v. Immugen, Inc., IPR2014-00676 (PTAB 10/27/2015)

This IPR involved US Patent 8,337,856, which claims antibody-toxin immunogates for the treatment of cancer. In a final written decision by the PTAB, the patent survives an IPR challenge from Phigenix. The Board finds that “general statements” in an older reference did not offer a reasonable expectation of success. This holding suggests that the PTAB may be pro-patentee in the “unpredictable” chemical and biological arts.

The ‘856 patent (apparently filed in March, 2000) covers immunoconjugates comprising an anti-ErbB antibody, such as the humanized anti-ErbB2 antibody known as HERCEPTIN® (huMAb4D5-8, also called “trastuzumab”), linked to a maytansinoid toxin.  The ErbB family of receptor tyrosine kinases mediate cell growth, differentiation, and survival. Overexpression of ErbB2 on cell surfaces can lead to cancer in humans, such as certain breast and ovarian cancers. The maytansinoid toxin is highly cytotoxic, and not useful as a drug administered alone because of poor selectivity for tumors, which causes systematic side effects.

The IPR was instituted after the Board concluded there was a reasonable likelihood of success that the challenged claims would have been obvious under 35 U.S.C. § 103 over “Chari 1992” in view of the HERCEPTIN® label and other references. Chari 1992 is a journal article.

Chari 1992 described immunoconjugates of an anti-ErbB2 mouse monoclonal antibody conjugated to DM1, a maytansinoid toxin. Chari 1992 also stated that the development of humanized antibodies could produce more desirable therapeutic conjugates.

The HERCEPTIN® label describes trastuzumab as a humanized mouse antibody indicated for the treatment of patients with metastatic breast cancer that overexpress the HER2 protein and have been treated with other chemotherapy.

Obviousness Analysis

Phigenix contended that Chari 1992 taught all limitations of the ‘856 patent except the specific antibody huMAb4D5-8 and a pharmaceutical carrier. Relying an on expert declaration, Phigenix contended that it would have been obvious at the time the ‘856 patent was filed to substitute a humanized antibody to produce the claim-recited huMAb4D5-8. Specifically, Phigenix contended that (1) it was known (from Chari 1992) that humanized monoclonal antibodies had advantages over murine antibodies; (2) huMAb4D5-8 selectively bound to HER2 (an alternative terminology for erbB2); and (3) clinical studies have shown that huMAb4D5-8 worked well in combination with microtubule-directed chemotherapy agents. Phigenix further argued that there was a reasonable expectation of success.

Immunogen responded that Phigenix failed to make a prima facie case of obviousness, primarily because a POSA would not have had a reason to substitute the mouse antibody in Chari 1992 with huMAb4D5-8.

The Board found Immunogen’s argument persuasive, because of “Pai-Scherf 1999” (a journal article) which taught that HERCEPTIN®-maytansinoid immunoconjugates would have been expected to exhibit unacceptable levels of antigen-dependent toxicity in normal human liver tissue (hepatoxicity), presumably due to the presence of erbB2 on hepatocytes.

Phigenix responded that Pai-Scherf 1999 taught a fusion-protein, not an antibody-drug conjugate, but the Board was not persuaded by this argument because of the general teaching of targeting of tumors that express erbB2 with antibodies armed with cytoxic agents.

What is interesting here is that the Board rejects Phigenix’ main argument that the general statements (not “teachings”; emphasis added) of Chari 1992 in view of teachings years later in the HERCEPTIN® Label, Pai-Scherf 1999, and other references regarding liver toxicities, would have motivated an ordinary artisan to substitute the mouse TA.1 antibody in the immunoconjugate of Chari 1992 with HERCEPTIN® on the basis that one would have expected that modified immunoconjugate to work to treat human tumors.  The Board also was not persuaded by the other references cited by Phigenix, because such studies would not have provided an ordinary artisan with adequate (emphasis added) information regarding human toxicity in vivo. Immunogen also pointed to evidence that researchers had targeted tumors with immunoconjugates for about 40 years before the ’856 patent without success.  Immunogen also provided evidence showing that preparing any antibody-toxin immunoconjugate for use in the treatment of human tumors was difficult and unpredictable.

Lessons

The Board comes down on the side of the unpredictability of the chemical and biological arts, holding that “general statements” (emphasis added), not “teachings,” of an older reference did not offer a reasonable expectation of success in an area, antibody-drug conjugates, where many years of research were unsuccessful. Thus, despite hints in the prior art of a direction of research, those hints were insufficient to overcome the reasonable expectation prong of the KSR analysis.  The general statements and hints were not a finite number of identified, predictable solutions that would have to be satisfied to meet the reasonable expectation of success that render the claims obvious under KSR.

This holding suggests that the PTAB may be pro-patentee in the chemical and biological arts.

Contact the author: aberks@cittonechinta.com

Copyright 2015 Cittone & Chinta LLP, http://cittonechinta.com



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