Alogliptin & combinations – USA

On Feb 04, 2020, Judge Stanley R. Chesler of New Jersey found claims of alogliptin compound patent valid & infringed.

Takeda (Plaintiff) own U.S. Patent No. 7,807,689 (compound), which is listed in the Orange Book as protecting Plaintiffs’ alogliptin benzoate formulations, marketed under the brand names Nesina®, Kazano®, and Oseni®. Indoco & Torrent (Defendants) filed ANDAs seeking approval to market generic products. The defendants stipulated infringement of claims 4 and 12 of the ’689 patent & contested invalidity challenge. Claim 4 covers alogliptin & claim 12 covers specific benzoate salt.

Defendants presented case on obviousness-type double patenting and on obviousness. Specifically, Defendants’ invalidity theories relied heavily on a chemistry technique termed “scaffold hopping” or “scaffold replacement” and “isosteric replacement theory”. For this defendants relied on “Böhm” reference. Bohm states that,

“Scaffold hopping approach requires the availability of a template – a chemical structure displaying the desired biological activity, and it is based on the assumption that the same biological activity can be exerted by other compounds that maintain some essential features of the template but are structurally different otherwise”.      

   

Defendants argued that claims 4 and 12 are invalid, under the doctrine of obviousness-type double patenting, because they are not patentably distinct from F162, the compound disclosed in claim 162 of the ’344 patent. Defendants argued that the POSA would have been motivated to replace the scaffold of the claim 162 compound with the goal of developing a new DPP-IV inhibitor for the treatment of Type 2 diabetes, because ‘scaffold replacement’ is one of ‘a range of strategies’ used by medicinal chemists to design and identify novel structures.”

But court said that Defendants has offered no support for the proposition that the POSA would have been motivated to choose scaffold replacement to develop a novel compound from F162. Defendants have not yet identified some reason which would have led a POSA to select scaffold replacement to modify F162 to make F162u with a reasonable expectation of success. As of the Priority Date, the art did not have available the structural information needed to perform scaffold replacement to produce a non-peptidic molecule that was active as a DPP-IV inhibitor with a reasonable expectation of success. The cited testimony says no more than that scaffold replacement was one of a “range” of options. Furthermore, Defendants relies substantially on the testimony of Dr. Rotella, whose credibility was damaged on cross-examination. During the direct examination, Dr. Rotella stated that the substituents of F162 and alogliptin are the same, but the scaffolds differ. On cross-examination, Dr. Rotella agreed that F162 contained a fluorine atom as a substituent, while alogliptin does not. Dr. Rotella’s credibility also suffered from inconsistent testimony. Court also did not find second isosteric replacement theory convincing & denied the challenge.

With respect to obviousness theory, Defendants argued that POSA searching for a promising drug development candidate would have focused on non-peptidic inhibitors and specifically on xanthine-based compounds, which a POSA would recognize as “particularly promising.” Defendants argued that, in short, two references suggest DCAX as lead compound, the WO ’496 patent and the CA ’730 patent. Plaintiffs contended that Defendants’ theory is based on hindsight. Plaintiffs argued that Defendants rely principally on the testimony of their expert, Dr. Ferraris, but that his credibility is undermined by, and is inconsistent with, his own work. Dr. Ferraris testified that a POSA seeking a candidate for drug development would have ignored peptidic inhibitors, but his own work during this time was on peptidic inhibitors. His actual work thus contradicts his opinions in this case. Next, Plaintiffs point to the fact that Dr. Ferraris admitted that he did not actually do an independent lead compound analysis. Dr. Ferraris testified that the choice of DCAX and the two references supporting that choice, the WO ’496 and CA ’730 patents, were given to him by Defendants’ counsel; he did not search through the prior art to find them.

Court next said that, Defendants’ path to the selection of DCAX is unpersuasive. Defendants argue, in short, that there are eight compounds that are mentioned in both the WO ’496 and the CA ’730 patents and that, of those eight compounds, DCAX has the greatest potency. Defendants did not explain why a POSA would believe that a compound mentioned in two patents is more worthy of development than a more potent compound listed in one. The prior art did not supply a POSA with a reason to select DCAX as a lead compound over other compounds in the prior art. Court said that the Defendant’s argument has a number of major gaps, missing connections or steps with inadequate support. This is a theory with major defects and does not come close to meeting the clear and convincing standard for successful validity challenges.

The Court thus concluded that Defendants have failed to prove, by clear and convincing evidence, that claims 4 and 12 of the ’689 patent are invalid under their theories based on § 103 obviousness or the doctrine of obviousness-type double patenting.