Sitagliptin – USA

Sitagliptin – USA

On May 07, 2021, PTAB found phosphate salt patent of sitagliptin valid in IPR proceeding.

 

Petitioner (Mylan) on Oct 30, 2019 filed inter partes review (IPR) for claims 1–4, 17, 19, and 21–23 of US 7,326,708 patent. On May 12, 2020, PTAB instituted the IPR & subsequently Dr. Reddy’s & Sun Pharma joined the proceeding. US’708 patent is assigned to Merck & it claims dihydrogenphosphate (DHP) salt of sitagliptin. This patent is listed in Orange Book for sitagliptin related products & is under Hatch-Waxman litigation. In litigation, Merck sued fourteen ANDA generic drug companies in District of Delaware. Petitioner here in IPR, based on different prior arts asserted that claims are unpatentable under anticipation & obviousness.

 

Claim 1 of US’708 mentions structural formula for the DHP salt of sitagliptin as shown below in 1:1:

Sitagliptin Phosphate API | CAS 654671-77-9 Supplier - Dr. Reddys

 

Anticipation:

Petitioner asserted that claims are unpatentable as anticipated by WO03004498 (family of OB listed US 6,699,871). WO’498 discloses several examples of DPP-IV inhibitors among which sitagliptin base is one & in general discloses pharmaceutically acceptable salts. WO ’498 identifies 26 illustrative acids which can form salts with base. Among the 26 acids named, WO ’498 discloses that “particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids”. Example 7 of WO’498 specifically discloses hydrochloride salt of sitagliptin. WO ’498 does not describe or exemplify any specific phosphate salt of sitagliptin.

 

Petitioner argued that WO ’498 teaches the phosphoric acid salt of sitagliptin and a specific example is not needed. This case involves anticipation by disclosure of “lists,” not necessarily anticipation where the art discloses a genus and a species within that genus are claimed. Specifically, petitioner contended that WO ’498 provides two closed lists, where “the primary list (i.e., Claim 15) provides 33 DPP-IV compounds” and the “secondary list identifies eight preferred acids.” Petitioner argued that neither list leaves anything to the imagination and WO ’498 anticipates claims 1 and 2.

 

PTAB, however, said that petitioner does not address the 1:1 stoichiometry limitation of the claimed salt. All the challenged claims require a 1:1 sitagliptin DHP salt. It is undisputed that a 1:1 sitagliptin DHP salt is not expressly disclosed in WO ’498. No phosphate salts of sitagliptin, or any of the other thirty-two exemplary DPP-IV compounds, are shown in WO ’498, nor are there details given about making them. Example 7 of WO ’498 describes a process for making a hydrochloride salt of sitagliptin, which appears to form in a 1-to-1 ratio. But, POSA would not simply conclude that whatever applies for hydrochloric acid and sitagliptin also applies to phosphoric acid. Petitioner’s “lists” and “envisage” theories do not make up for the absence of express disclosure of the claimed 1:1 sitagliptin DHP salt on this record. Because, POSA would not and could not at once envisage all the possible salts, nor the claimed 1:1 sitagliptin DHP salt.

 

With respect to “Inherency”, PTAB said that petitioner did not provide any experimental results or data to show that sitagliptin can only be mono-protonated and will form the 1:1 DHP salt every time when reacted with phosphoric acid. On the other hand, Patent Owner expert, Dr. Matzger made non-1:1 salts. Dr. Matzger’s results showed production of 2:1 and 3:2 phosphate salts of sitagliptin in the solvent system. PTAB finally said that the evidence confirmed experimentally and undeniably showed that non-1:1 sitagliptin phosphate salts do exist and that the claimed 1:1 sitagliptin DHP does not form “every time” sitagliptin and phosphoric acid are reacted. Therefore, petitioner has not shown by a preponderance of the evidence that claims are unpatentable for anticipation.

 

Obviousness:

Petitioner asserted that claims are unpatentable as obvious in view WO03004498 alone or in combination with other prior arts such as Bastin & Brittain. But, Patent Owner argued that it reduced to practice the subject matter of claims before WO ’498 published (Jan 2003). Thus, WO ’498 is not § 102(a) prior art, and it is merely a § 102(e) reference. PTAB said that it was corroborated by documentary evidence, which shows the creation of a 1:1 sitagliptin DHP salt in Dec 2001, with experimental confirmation of the salt’s form and stoichiometry documented in early 2002. This evidence showed successful reduction to practice of the subject matter of claims 1 and 2. Therefore, WO ’498 qualifies as prior art only under §102(e), but Patent Owner also showed common ownership of the claimed subject matter and WO ’498. Thus, it also eliminated as a § 102(e) reference from the obviousness inquiry for claims 1, 2, 17, 19, and 21–23.

 

That leaves only claims 3 and 4, for which Patent Owner does not assert a prior reduction to practice. Claim 3 recites “the salt of claim 1 having the (S)-configuration at the chiral centre”. Petitioner argued the claim 3 would have been obvious over WO ’498 alone or over a combination of WO ’498 and Bastin (teaches how to choose the salts based on acidity or basicity of the ionisable group).  Claim 4 recites ““salt of claim 2 characterized in being a crystalline monohydrate.” Petitioner asserts that claim 4 would have been obvious over the combination of WO ’498, Bastin, and Brittain (book focused on Polymorphism in Pharmaceutical Solids). PTAB held that Petitioner advances no expected or even theoretical benefit to making an (S)-enantiomer or crystalline monohydrate of 1:1 sitagliptin DHP. WO ’498’s general disclosure, which encompasses millions of potential compounds and salts, does not show a motivation to make, with a reasonable expectation of success, 1:1 (S) or crystalline monohydrate of sitagliptin DHP specifically as claimed—especially where the evidence also shows that forming such salts is highly unpredictable. Therefore, petitioner has not proved by a preponderance of the evidence that claims 3 & 4 would have been obvious.

 

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