United States: Expected Toxicity Of Claimed Immunoconjugates Thwarts Showing Of Prima Facie Obviousness

Phigenix, Inc. v. Immunogen, Inc., (PTAB October 27, 2015)

In an inter partes review (IPR) proceeding, the Patent Trial and Appeal Board (Board) upheld the patentability of Phigenix's patent claims that were challenged on the basis of obviousness. Phigenix, Inc. v. Immunogen, Inc., Case IPR-2014-00676, Final Written Decisions dated October 27, 2015 (Paper 39).

Phigenix's U.S. Patent No. 8,337,856 is directed to immunoconjugates (antibodies bound to toxins) used to target and kill cancer cells that express the ErbB2 family of receptors, such as breast cancer. Independent claim 1 of the '856 patent is specifically directed to "an immunoconjugate comprising an anti-ErbB2 antibody conjugated to a maytansinoid, wherein the antibody is huMAb4D5-8." Dependent claims 2 through 8 include specific forms or numbers of the conjugated maytansinoid toxin molecules and the use of specific chemical linkers.

In the IPR proceeding based on a theory of unpatentability due to obviousness, the Board found that Phigenix did not show by a preponderance of evidence that claims 1 through 8 of the '856 patent are unpatentable (page 3). Specifically, the Board determined that Phigenix did not demonstrate a prima facie case of obviousness of the challenged claims, even though Phigenix presented evidence that the primary prior art reference (Chari 1992) disclosed "all limitations recited in [claim 1] ... except [the specific antibody] huMAB4D5-8" (page 11) Chari 1992 disclosed the use of a mouse antibody (TA.1) in an immunoconjugate with the claimed toxin maytansinoid (pages 7–8). Further, huMAB4D5-8 had been commercialized in the prior art product, Herceptin®, which was known for use in treating breast cancer, including in combination with other cytotoxic agents (pages 8–9). Phigenix argued that one of skill in the art would have been motivated to substitute the mouse TA.1 antibody of Chari 1992 with huMAB4D5-8 because: human antibodies were preferred to mouse antibodies for clinical applications; huMAB4D5-8 was receptor selective and approved by the U.S. Food and Drug Administration; and huMAB4D5-8 worked synergistically with other chemotherapeutic agents (pages 12–13). 

Significantly, the Board found persuasive Immunogen's rebuttal evidence on the issue of expectation of success. Immunogen presented prior art showing that at the time the '856 patent was filed (2000), "Herceptin-maytansinoid immunoconjugates would have been expected to exhibit unacceptable levels of antigen-dependent toxicity in normal human liver tissue in patients" (pages 16–22). Consequently, the Board concluded that Phigenix "did not establish by a preponderance of evidence that those general statements in Chari 1992 [that maytansinoid conjugates may effectively treat human cancer] in view of teachings years later in the Herceptin Label ... and other references regarding liver toxicities, would have motivated an ordinary artisan to substitute" in the human antibody safely and effectively treat tumors (pages 19–22).

Additionally, the Board found dependent claims 6 and 8 relating to non-cleavable linkers non-obviousness for the reasons set forth above, in addition to prior art teaching the benefit of cleavable linkers and evidence of secondary inidicia of non-obviousness, including long-felt and unmet need, industry praise and commercial success of the purported commercial embodiment, Kadcycla®.

With regarding to Phigenix evidentiary objections to the admission of Immunogen's evidence of commercial success, the Board accepted the submission by Immunogen's economist of voluminous data summaries relating to marketing and sales information for Kadcycla (consistent with Fed. R. Evid. 703), but also accepted certain paragraphs of the expert's declaration objected to as hearsay "[b]ecause that Declaration corresponds to Mr. Jarosz's direct testimony in this trial" (page 28).

In December 2015, Phigenix filed a notice of appeal from the final decision including as the basis for appeal: the Board's ruling that the challenged claims were not obvious under the preponderance of evidence standard and the Board's denial of Phigenix's motion to exclude evidence relating to commercial success.

The Board declined to institute an IPR in response to Phigenix's petition on related U.S. Patent No. 7,575,748 (IPR2014-00842).

Expected Toxicity Of Claimed Immunoconjugates Thwarts Showing Of Prima Facie Obviousness

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