On Apr. 11, 2022, Federal Court of Canada found sitagliptin phosphate patent valid and infringed.

 

This case arises from a patent infringement action brought by Plaintiff (Merck) against Defendant (Pharmascience) for Canadian Patent No. 2529400, as defendant sought to market generic version of Plaintiff’s drug, JANUVIA®. Pharmascience asserted in defense that the 400 Patent is invalid for obviousness and/or insufficiency. The 400 Patent is directed to the dihydrogenphosphate [DHP] salt of sitagliptin and its crystalline monohydrate form, its process and formulation of same.

 

Court said that at the priority date (June 24, 2003) of 400 patent, Person Skill in Art (PSA) would have some clinical knowledge about DPP-4 inhibitors and treatment of type 2 diabetes. PSA also would have known about prior art, WO’498 and class of compounds disclosed (including sitagliptin HCl) as being inhibitors of DPP-4, with the potential to be used in the treatment or prevention of type 2 diabetes. PSA would also possess certain knowledge relating to salt formation and polymorph screening at the time of priority date. Court also agreed with Experts that that the selection of a salt and its appropriate form that exhibits the desired pharmacological, toxicological and therapeutic properties was a multidisciplinary task of varying complexity. Court identified WO498 and the Deacon, Augustyns and Drucker references as being prior art that is relevant.

 

Court applying ‘inventive concept’ rule said that inventive concept of 400 patent is the identification of the compound sitagliptin dihydrogenphosphate (DHP) monohydrate with its enhanced chemical and physical properties over sitagliptin free base and the hydrochloride salt. Court then found differences between prior arts and inventive concept as:

• identifying sitagliptin from amongst the other compounds disclosed within WO498 as a promising DPP-4 lead compound for further development;
• the choice to proceed with further salt screening and with polymorph screening;
• the formation and selection of the DHP salt of sitagliptin;
• the isolation of the crystalline monohydrate form of the DHP salt and the recognition of its enhanced chemical and physical properties for formulation over sitagliptin free base and the hydrochloride salt.

Court said that an invention to be obvious to try, the evidence must show, on a balance of probabilities, that it was more or less self-evident for the skilled person to try to obtain the invention. Mere possibility that something might turn up is not enough. Court further said that it is undisputed that phosphoric acid is one of the preferred acids referenced in WO498 for possible salt formation with the basic compounds of the application. As agreed by the Experts, phosphoric acid would have been one of the preferred acids that a PSA would include in a salt screening experiment with sitagliptin free base because of their differences in pK_a (i.e. the level of acidity of the acid). However, the experts disagreed as to whether it was possible to predict that the DHP salt would form. The possibility of isolating the salt as a solid, or a crystalline solid of particular stoichiometry, remained unpredictable. It would not have been possible to predict whether a given salt would possess advantageous properties for formulation into a dosage form.

 

At the priority date, PSA would be aware that phosphate salts had a high propensity to form hydrates. However, hydrates were also known to have low solubility, which was undesirable for formulation. Moreover, whether a crystalline monohydrate could be isolated and reliably made, and found to provide advantageous chemical and physical properties, added unpredictability that was not disputed by any of the Experts. There was no motivation arising from WO498 or the prior art to take further steps with sitagliptin specifically, including by conducting a salt and polymorph screen. WO498 does not point directly or indirectly to sitagliptin as being a preferred compound of the compounds disclosed. Nor does it provide any data or scientific justification for selecting any of the compounds it discloses over any of the others as a lead compound. The skilled team would need to make all 33 example compounds in order to properly determine if any of the compounds were appropriate to be a lead compound for further development. Thus, the evidence indicates that the PSA would not have any specific motivation arising from WO498 to focus on the particular crystalline form of a salt of sitagliptin over the other compounds disclosed within WO498. Therefore, the asserted claims are not obvious.