CAFC Affirms Merck’s Win at PTAB over Mylan Challenge to Diabetes Treatment Claims

“We agree with Merck…that a class of 957 predicted salts that may result from the 33 disclosed compounds and eight preferred acids…is insufficient to meet the ‘at once envisage’ standard.” – CAFC

CAFCIn its third precedential patent opinion this week, the U.S. Court of Appeals for the Federal Circuit (CAFC) earlier today upheld a Patent Trial and Appeal Board (PTAB) decision finding that Mylan Pharmaceuticals, Inc. failed to show that certain claims of Merck Sharp & Dohme Corp.’s patent for a Type 2 Diabetes treatment were anticipated or would have been obvious over the cited prior art. Judge Lourie authored the opinion.

Sitagliptin DHP

U.S. Patent 7,326,708 describes sitagliptin dihydrogenphosphate (“sitagliptin DHP”), belonging to the class of dipeptidyl peptidase-IV (“DP-IV”) inhibitors, which can be used for treating Type 2 diabetes. Mylan petitioned the PTAB for inter partes review (IPR) of claims 1–4, 17, 19, and 21–23 of the ‘708 patent, arguing that: 1) claims 1–3, 17, 19, and 21–23 were anticipated by  International Patent Publication WO 2003/004498, owned by Merck, and the equivalent U.S. Patent 6,699,871 (collectively, “Edmondson”); and 2) that claims 1–4, 17, 19, and 21–23 would have been obvious over Edmondson and two additional publications titled “Structural Aspects of Hydrates and Solvates” (“Brittain”) and “Salt Selection and Optimisation Procedures for Pharmaceutical New Chemical Entities” (“Bastin”). The PTAB ultimately disagreed and held that Mylan had failed to demonstrate that the claims were anticipated or would have been obvious.

On appeal to the CAFC, Mylan argued the PTAB: 1) “erred in determining that a 1:1 stoichiometry of sitagliptin DHP was not anticipated, either expressly or inherently, by Edmondson”; 2) “that the Board erred in determining that the ’708 patent antedates Edmondson”; and 3) “that the Board erred in determining that it failed to prove that claims 3 and 4 of the ’708 patent would have been obvious over Edmondson, Brittain, and Bastin.”

The ‘At Once Envisage’ Theory

As to the first argument, Mylan said that Edmondson anticipates the relevant claims because “it discloses sitagliptin in a list of 33 compounds” and also “discloses acids forming ‘pharmaceutically acceptable salts,’ including phosphoric acid in a list of eight ‘particularly preferred’ acids.” Mylan argued “sitagliptin DHP is effectively disclosed in Edmondson, and Edmondson thus anticipates the challenged claims.” Furthermore, a skilled artisan would “’at once envisage’ a 1:1 stoichiometry of the sitagliptin DHP salt” because it is disclosed in Example 7 of Edmondson and because “experimental data presented by Mylan’s expert Dr. Chorghade illustrate that only a 1:1 sitagliptin DHP stoichiometry forms under conditions allegedly similar to those disclosed in Edmondson.”

Merck argued in response that this approach does not meet the standard of the “at once envisage” theory and would inappropriately expand that theory by using hindsight to focus on one compound out of a large class.

The CAFC agreed with Merck, explaining that the PTAB’s decision was supported by substantial evidence, including when Mylan’s own expert stated “that nothing in Edmondson directs a skilled artisan to sitagliptin from among the 33 listed DP-IV inhibitors.” Additionally, nothing in Edmondson “singles out phosphoric acid or any phosphate salt of any DP-IV inhibitor, and the list of ‘pharmaceutically preferred’ salts comes 44 pages earlier in the specification,” said the CAFC.

The court further agreed with Merck that the PTAB didn’t err in finding that nothing in Edmondson inherently disclosed a 1:1 sitagliptin DHP salt. In re Petering, 301 F.2d 676, 681 (C.C.P.A. 1962), from which the “at once envisage” theory stems, “stands for the proposition that a skilled artisan may ‘at once envisage each member of [a] limited class, even though the skilled person might not at once define in his mind the formal boundaries of the class,’” wrote the court. Here, “the list of 33 compounds… plus the eight ‘pharmaceutically preferred’ acids and various stoichiometric possibilities, results in 957 salts, some of which may not exist. That is a far cry from the 20 compounds ‘envisaged’ by the narrow genus in Petering.” The opinion concluded on this point:

“We cannot provide a specific number defining a ‘limited class.’ In re Petering, 301 F.2d at 681. It depends on the “class.” But we agree with Merck and hold that the Board did not err in finding that a class of 957 predicted salts that may result from the 33 disclosed compounds and eight preferred acids, some of which may not even form under experimental conditions, is insufficient to meet the ‘at once envisage’ standard set forth in Petering.”

Obviousness

Turning to Mylan’s argument that the PTAB erred in finding that it had failed to prove obviousness for claims 1–4, 17, 19, and 21–23, the court first agreed with Merck that the PTAB’s antedation determination for claims 1, 2, 17, 19, and 21-23 was supported by substantial evidence, as Merck had shown that it developed a 1:1 sitagliptin DHP salt in December 2001, with experimental confirmation in early 2002, one year before Edmondson was published. The CAFC summarized Merck’s argument on this point:

“Because it is undisputed that the invention claimed in the ’708 patent and the subject matter of Edmondson were commonly owned by Merck at the time of the invention, the exception in § 103(c)(1) applies. Section 103(c)(1) (pre-AIA) provides that ‘[s]ubject matter developed by another person, which qualifies as prior art only under one or more subsections (e), (f), and (g) of section 102, shall not preclude patentability under this section where the subject matter and the claimed invention were, at the time the claimed invention was made, owned by the same person or subject to an obligation of assignment to the same person.’”

If Edmondson cannot serve as an obviousness reference for the claims, the obviousness challenge fails, said Merck, and the CAFC agreed.

As to claims 3 and 4, the court also agreed with Merck that the PTAB’s finding that Mylan had failed to prove obviousness was supported by substantial evidence. With respect to claim 3, the Board “adequately credited” Mylan’s expert testimony, “which stated that the (S)-enantiomer was not disclosed in Edmondson,” and noted that “Mylan advanced no expected or theoretical benefit to making the (S)-enantiomer of 1:1 sitagliptin DHP, and that the general disclosure on diastereomers in Edmondson encompasses millions of potential compounds and salts with no motivation to make the (S)-enantiomer with a reasonable expectation of success, particularly in an unpredictable activity like salt formation.”

And looking at claim 4, the CAFC said the PTAB’s finding that there was no motivation to combine Edmondson, Bastin, and Brittain was supported by substantial evidence, including the Board’s credit to Mylan’s expert, its reference to “the numerous downsides of hydrates reported in the literature, including those stating that a skilled artisan would have several reasons for avoiding hydrates,” and credit to Merck’s expert.

Finally, the CAFC said the Board did not err in its evaluation of purported objective indicia of nonobviousness. “Although the Board did not consider in detail the alleged unexpected properties of the claimed crystalline monohydrate of claim 4, the Board stated that such unexpected results served as further evidence undermining Mylan’s challenge to claim 4,” explained the court.

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