Merck overcomes the inherent challenge of PTAB anticipation
Overcoming claims of prior art is a hurdle that many patent holders face, both during examination and later when challenged before the PTAB. Merck Sharp & Dohme Corp. (“Merck”), however, recently overcame an anticipatory challenge inherent by Mylan Pharmaceuticals (“Mylan”) by relying on the complexities of chemical salt formation.
The relevant patent, US Patent No. 7,326,708 (“the 708 Patent”) claims a “1: 1 sitagliptin DHP”, a salt composed of “a phosphate anion” in conjunction with “an amine cation sitagliptin”. DHP is a dipeptidyl peptidase-IV inhibitor used to lower blood sugar and is the main ingredient in the drug Januvia from Merck for type 2 diabetes.
By filing IPR2020-00040 in October 2019, Mylan sought to make the claims of the ‘708 patent unpatentable for reasons of anticipation, inherent anticipation and obviousness. While the PTAB methodically went through each of Mylan’s arguments, this article, part 1, focuses on Mylan’s unsuccessful inheritance arguments. Part 2 will focus on Mylan’s equally unsuccessful obvious arguments.
In asserting inherent anticipation, Mylan relied primarily on WO 03/004498 (“publication WO ‘498”) as the prior art. WO ‘498 is also owned by Merck. WO ‘498 claims peptidase-IV enzymes, or DP-IV inhibitors, used to treat hyperglycemia. Mylan Pharma. vs. Merck Sharp & Dohme Corp., DPI n ° 2020-00040, p. 16 (PTAB May 7, 2021).
Mylan asserted that publication WO ‘498 taught a 1: 1 phosphoric sitagliptin salt by disclosing two “closed lists”. Identifier. to 20. Mylan argued that one listing included sitagliptin as one of 33 potential compounds, and another listing identified phosphoric acid as one of the eight preferred acids. Mylan asserted that a person of ordinary skill would see these two lists closed, be able to combine the two compounds and, as with the chewing gum combination in Wrigley, create the 1: 1 sitagliptin DHP claimed in the ‘708 patent.
In response, Merck distinguished the argument from Mylan’s “lists of combinations”. Merck insisted that a list-based analysis Wrigley was incorrect with respect to the ‘708 patent. In Wrigley, the Federal Circuit found anticipation because two chewing gum components, the flavoring agent and the cooling agent, were both disclosed in the prior art in closed lists as “preferred agents.” and therefore a person of ordinary skill would have thought of combining them to create the claimed product. Here, to create sitagliptin DHP 1: 1, a skilled artisan would not only have to combine sitagliptin and phosphoric acid, but he would also have to achieve an exact 1: 1 stoichiometric ratio, which the prior art did not teach. Merck asserted that the salt formation in the ‘708 patent was far too unpredictable and complex to rely on simple combination analysis. Merck relied on County, a district court case that distinguished complex chemical reactions from the simple combination of prior art lists in Wrigley.
Merck argued that in the absence of a simple combination argument, Mylan struggled, attempting to bridge the gap between the disclosed sitagliptin and the claimed 1: 1 sitagliptin DHP. Merck insisted that a ‘considering’ argument only works when the ‘gender resulting from the combination of the two lists is of a’ class so defined and limited ” that a person of ordinary skill might ‘immediately consider each member of the genus ”. With respect to the Merck ‘708 patent, a person of ordinary skill “does not know — what kind of salts will form,” let alone what members of the genus would result. Identifier. to 21.
In making their inheritance argument, Mylan also relied on tests performed by Dr. Chyall, for purposes of another procedure, allegedly following the protocols in an example disclosed in publication WO ‘498. Identifier. at 26. Mylan claimed that the 1: 1 salt form of sitagliptin DHP would form “all time ”and, therefore, claims were inherently anticipated. Dr. Chyall, however, made “at least eight changes between” his tests and Example WO ‘498. Primarily, the exchange of hydrochloric acid (disclosed in publication WO ‘498) for phosphoric acid (the salt form of which is claimed in the’ 708 patent).
Merck expert Dr Matzger in response explained that there is no guarantee that a 1: 1 salt form of sitagliptin DHP would form. all time. Identifier. at 24, FN 17. Dr Matzger explained that sitagliptin has several proton acceptor sites and that phosphoric acid can donate “up to three protons”, which means that the two compounds can also form a salt 2 : 1. Additionally, Merck cited experts, including Dr Chyall and Dr Atwood of the University of Missouri, who had trained no 1: 1 salts of sitagliptin and phosphoric acid in their tests. Counter-evidence from Merck, as well as the lack of “experimental results or data to show that sitagliptin can only be monoprotonated” demonstrated that a DBH of sitagliptin 1: 1 not form all time. Identifier. at 35 years old.
PTAB decision: The PTAB concluded that Mylan had “failed to prove inheritance by a preponderance of evidence”. The PTAB explained that an invention is inherent only if “it is the natural result of the explicit disclosure of the state of the art”. Schering Corp. vs. Geneva Pharm., Inc., 339 F.3d 1373, 1379 (Fed. Cir. 2003). The “inherent outcome must inevitably result from the disclosed steps” and “cannot be established by probabilities or possibilities”. In Montgomery, 677 F.3d 1375, 1379-80 (Cir. Fed. 2012). Identifier. to 37.
In discussing Mylan’s reliance on Dr Chyall’s testing, the PTAB noted that Dr Chyall “did not follow the example” in publication WO ‘498, as there was no explicit disclosure in publication ‘498 to apply the process used for acid hydrochloride to phosphoric acid. The PTAB found that Chyall’s experiment was very different from the “simple exchange” of acids, “and Dr. Chyall had to” necessarily modify “the procedures described in WO ‘498 to achieve the desired result. Therefore, the PTAB noted that the prior art and technical literature showed “undeniably” that there are non-1: 1 sitagliptin phosphate salts and that the claimed 1: 1 ratio will not be formed every time, which guarantees that the claim is not inherently anticipated. . Identifier. to 41.
Take away food
The unpredictability of chemical reactions and salt formation remains favorable to patent holders in their fight against invalidity / patentability challenges. PTAB is easily distinguished Wrigley, both under a combination of lists and doctrine analyzes envisaged. In particular, this case signifies a victory for pharmaceutical patent holders who seek to build on their own previous research and discover polymorphic species.
Additionally, petitioners should be careful about relying on bold claims, such as “every” in their inheritance arguments. Mylan claimed that the 1: 1 ratio would form all time, an argument that collapsed when the complexities of sitagliptin and phosphoric acid reactions were exposed by experts on both sides.
Finally, applicants and patentees should take note of PTAB’s criticism of the modified expert testing procedures. The PTAB found that the two experts, Dr Chyall and Dr Matzger, had changed the example procedures in such a drastic way that an ordinary person would not have thought of making these changes without the desire to obtain a specific result. In general, it is a bad idea to rely on modified experiences of the prior art in an attempt to satisfy the “necessarily and inevitably” demands of inherent anticipation.
Mylan filed an appeal on July 8, 2021. You usually don’t know what a particular panel on the Federal Circuit will do, so we’ll wait and see.
Jordan Cowger, Summer Associate at Finnegan, and Stacy Lewis, Legal Assistant at Finnegan, contributed to this article.
© 2021 Finnegan, Henderson, Farabow, Garrett & Dunner, LLPRevue nationale de droit, volume XI, number 264