On August 23, 2016, the PTAB denied Mylan Laboratories Limited’s (Mylan) petition for IPR (IPR2016-00627) against a patent owned by Aventis Pharma S.A. (Aventis). In doing so, the PTAB offered guidance regarding what is required to successfully make out a claim of obviousness regarding a new chemical compound. In particular, the PTAB’s decision offers insight into the threshold a petitioner will need to meet in order to establish that a person of ordinary skill in the art would have recognized a prior art reference as “promising to modify.”
The petition sought cancellation of claims of U.S. Patent No. 5,847,170, asserting they were obvious in view of numerous references. The ‘170 patent is directed to new taxoids that inhibit abnormal cell proliferation and have antitumor properties on tumors that are resistant to paclitaxel or docetaxel. The ‘170 patent discloses and claims a compound known as cabazitaxel, pharmaceutical compositions containing cabazitaxel, and processes to prepare cabazitaxel. Cabazitaxel is sold under the brand name Jetvana® by Aventis, for use in treating prostate cancer.
The Board was not persuaded that a person of skill would ignore Klein’s substitution of a hydroxyl for a carbonyl at this position, given the touted superior properties. The PTAB agreed with Aventis that Mylan had used hindsight to formulate their obviousness arguments
Of particular interest in cabazitaxel is the presence of a methoxy group at both the C-7 position and C-10 position, and a carbonyl at the C-9 position. In contrast to cabazitaxel, neither prior art paclitaxel nor docetaxel has a methoxy group at C-7 or C-10, although both have a carbonyl at C-9. Both paclitaxel and docetaxel are synthesized from precursor “10-DAB.”
Mylan relied primarily on two prior art references in their petition – Kant et al. and Klein et al. Kant disclosed the introduction of a variety of substituents at the C-10 position of 10-DAB in the synthesis of various paclitaxel analogues, including one analogue that contained a methoxy group at C-10. Klein disclosed a new family of compounds exhibiting antitumor activity having increased water solubility and stability as compared to paclitaxel. Klein disclosed substituting the C-7 hydroxyl group with various substituents, including a methoxy group at C-7. However, Klein also disclosed the replacement of the C-9 carbonyl in both paclitaxel and docetaxel with a hydroxyl for increased water solubility.
Kant does not describe the C-7 methoxy substitution of cabazitaxel, and Klein does not disclose the C-10 methoxy substitution of cabazitaxel. Mylan argued, however, that a person of skill in the art would have selected Kant’s C-10 methoxy analogue for further modification because of its superior binding ability and cytotoxicity among the chemical analogues disclosed. Mylan further argued that a skilled person would have modified the C-7 position of Kant’s analogue in view of Klein’s C-7 methoxy analogue that increased anti-tumor potency, which would have led to the synthesis of cabazitaxel.
The PTAB was not persuaded that Mylan’s petition established a reasonable likelihood of prevailing with respect to its assertions of obviousness. The Board first noted that for compositions containing new chemical compounds, there must have been a reason for a skilled person to: (1) select the prior art “most promising to modify,” and (2) make all of the necessary modifications to arrive at the claimed invention. The Board further noted that there also must have been a “reasonable expectation” both of making the new compound, and of its advantageous properties. [IPR2016-00627, Paper 10, page 11] Considering Kant, the Board noted that the authors did not teach or suggest further modifications to their analogue, beyond alterations at the C-10 position. The PTAB concluded that this factcut against using this analogue as a starting point for further modification. The Board further noted that Kant does not teach or suggest simultaneous substitutions of C-7 and C-10. Turning to Klein, the Board observed that Klein expressly taught the reduction of the C-9 carbonyl to a C-9 hydroxyl in order to achieve superior water solubility. The Board was not persuaded that a person of skill would ignore Klein’s substitution of a hydroxyl for a carbonyl at this position, given the touted superior properties. The PTAB agreed with Aventis that Mylan had used hindsight to formulate their obviousness arguments:
Petitioner does not address persuasively the question of why a POSA would have disregarded Klein’s teachings to reduce the C-9 carbonyl to a hydroxyl group to improve aqueous solubility and chemical stability …Nor does Petitioner persuasively rationalize Kant’s teaching of selective substitution at only the C-10 position to increase cytotoxicity, with Klein’s teaching to functionalize the C-7 and/or C-9 positions,…Weighing the evidence as a whole, Petitioner’s argument that a POSA would have selectively methylated both the C-7 and C-10 positions … to create a more potent analogue (cabazitaxel) based on the teachings of Klein and Kant, is not persuasive. [Paper 10, pages 19-20]
The PTAB’s decision in this case illustrates the challenge in proving obviousness of a claim directed to a new chemical compound with pharmaceutical activity, even in view of prior art that describes structurally-similar compounds.