U.S. Pat. No. 8,337,856B2
October 27, 2015
Brief Summary: Claims 1-8 of the ‘856 directed to metastatic HER2-positive breast cancer treatment Kadcyla® (ado-trastuzumab emtansine (huMAb4D5-8/ maytanisoid conjugate)) not found unpatentable because prior art taught risk of hepatic toxicity for similar immunoconjugates and convincing secondary considerations (unexpected results and long-felt, unmet need with nexus to claimed subject matter).
Summary: Phigenix filed a Petition requesting IPR of Immunogen’s US 8,337,856 relating to the metastatic HER2-positive breast cancer treatment Kadcyla® (ado-trastuzumab emtansine), alleging obviousness in view of a prior art publication (“Chari”) the HERCEPTIN® label (aka Trastuzumab or huMAb4D5-8), and other references, which was granted on October 29, 2014. The challenged claims are directed to “[a]n immunoconjugate comprising an anti-ErbB2 antibody conjugated to a maytanisoid, wherein the antibody is huMAb4D5-8.” Maytanisoid are cytotoxic compounds and the specification includes an example of one type, termed “DM1”, in Figure 3, which is claimed in dependent claim 2 (immunoconjugate “comprises from 3 to 5 maytanisoid molecules per antibody molecule”). Only “pharmaceutically-acceptable carrier” was specifically construed; the other claim terms were construed to “carry their ordinary meaning”. Relying on an expert declaration, Phigenix alleged that it would have been obvious to substitute huMAb4D5-8 for the mouse antibody in the antibody-DM1 conjugates of Chari. It also alleged a motivation to do so because humanized antibodies such as huMAb4D5-8 were known to be preferred over mouse-derived antibodies, huMAb4D5-8 selectively bound to with high affinity to HER2, was approved for use to treat breast cancer, and breast cancer clinical trials indicated it worked well with microbtubule-directed chemotherapy agents. It argued the ordinary artisan would have had a reasonable expectation of success because it was known that huMAb4D5-8 was more effective when combined with paclitaxel, Chari targeted the same cells as huMAb4D5-8, and humanized antibodies were less immunogenic than mouse antibodies. Other references were also cited to show similar immunoconjugates, similar antibody/chemotherapy combinations were suggested by the prior art to be “rational…to test in human clinical trails” and/or synergistic. The Decision summarized these arguments as relying “on the position that an ordinary artisan would have expected such an immunoconjugate to work clinically to treat tumors in humans upon reading the cited references.” But the Board found that Immunogen “provide[d] persuasive evidence…that…at the time the ‘856 patent was filed, prior art indicated HERCEPTIN®- maytanisoid would have been expected to exhibit unacceptable levels of [ADCC] in normal human liver tissue in patients” (e.g., reference describing Phase I erb-38 (portion of antibody e23 fused to Pseudomonas exotoxin A) clinical trial showing “unacceptable hepatoxicity in all patients” treated and warning that “targeting of tumors with antibodies to erbB2 that are armed with..toxic agents may result in unexpected organ toxicities due to erbB2 expression on normal tissues.”) It concluded Phigenix did not “establish by a preponderance of the evidence that [the] general statements in Chari 1992, in view of teachings year later” regarding liver toxicity would have motivated the substitution with an expectation “that modified immunoconjugate [would] work to treat human tumors” (citing Par, FC 2014). The Board also found Immunogen’s evidence of secondary considerations persuasive (e.g., unexpected results, long-felt/unmet need with a nexus to the claims). Thus, it did not hold claims 1-8 of the ‘856 unpatentable.