AstraZeneca’s ONGLYZA product patent is not invalid due to obviousness

United States District Court For The District Of Delaware has issued a memorandum opinion in favour of Astrazeneca, which states that Saxagliptin product patent is not invalid due to obviousness.

Background:
Saxagliptin product description:
Saxagliptin(BMS-477118) is a once-daily, oral CD26 antigen (dipeptidyl peptidase IV, DPP IV) inhibitor discovered by Bristol-Myers Squibb and patented through USRE44186 E1 (reissue of 6,395,767).

Saxagliptin was developed by Bristol-Myers Squibb in collaboration with AstraZeneca for the treatment of type 2 diabetes mellitus (T2DM). However, AstraZeneca subsequently acquired all rights to the drug from Bristol-Meyers Squibb.

Saxagliptin FDA approval information:
FDA approved Saxagliptin hydrochloride (N022350)tablets 2.5mg and 5mg on Jul 31, 2009, which is marketed by Astrazeneca under the trade name ONGLYZA.

FDA also approved Saxagliptin hydrochloride and Metformin hydrochloride combination (N200678) on November 5, 2010, which is also marketed by Astrazeneca under the trade name KOMBIGLYZE XR.

US RE44186 is listed in Orange Book for ONGLYZA and KOMBIGLYZE, US ‘186 claims Saxagliptin and its salts including hydrochloride salt, US ‘186 is set to expire in July 2023 including PTE.

ANDA litigations:
On July 31, 2013 ANDA with a paragraph IV certification has been filed to market generic version of ONGLYZA and KOMBIGLYZE XR.

In 2014 Astrazeneca sued several generic companies such as Aurobindo, Wockhardt, Watson, Actavis, Sun Pharma, Mylan, Amneal under the patent infringment of US ‘186, US 7,951,400 and US 8,628,799. Stipulations were filed and all the claims concerning the ‘400 and ‘799 patents (formulation patents) were dismissed.

All the lawsuits were consolidated and a three-day bench trial in this matter has been held on September 19 through September 21, 2016. Defendants stipulated to infringement of all asserted claims. Thus, the sole issue is defendants obviousness defense with respect to the RE’186 patent.

The structure of Saxagliptin is given below:

new-picture-4

The defendants has argued that the RE’186 patent is obvious in light of the prior art and the asserted claims of the RE’186 patent are valid under 35 U.S.C.§ 103.

35 U.S.C.§ 103 states that a patent may not be obtained thought the invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which said subject matter pertains.

The defendants argued that the asserted claims were obvious for three reasons:

1) a person of ordinary skill in the art would have been motivated to select Vildagliptin as a lead compound;

2) a person of ordinary skill in the art would have been motivated to move the hydroxy admantyl group; and

3) a person of ordinary skill in the art would have added a cyclopropyl ring.
Vildagliptin is claimed as a product in US 6,166,063 B2 which claims the priority date as December 10, 1998, the publication date of its PCT equivalent WO 2000/034241 A1 is June 15, 2000, whereas the US RE’186 claims the priority date as Mar 10, 2000.
The structural difference between Saxagliptin and Vildagliptin is given below:
image
The major differences between the two moieties are highlighted in red colour.
The defendants argued that the POSA would have moved the hydroxyadamantyl group from the nitrogen of the glycine to the alpha-carbon of the glycine in order to improve potency. Dr. Powers testified that a person of ordinary skill would have been motivated to do so because the prior art taught that DPP4 preferred bulky groups, with a free amino group, at its P2-substrate binding pocket. (Tr.79:13-14 (Powers).)
According to defendants a POSA would have been motivated to make this modification for three reasons directed to increasing the potency of the molecule:
(1) primary  amines more closely resemble the natural substrates for DPP4,
(2) beta-branching was known to increase potency, and
(3) primary amines were generally more potent than secondary amines.
Specifically, the defendants relies on the teachings of Mentlein and Ashworth I. Mentlein disclosed that natural substrates of DPP4 enzymes are peptides with primary amines at N-terminus. Ashworth I taught that the most potent, reversible DPP4 inhibitors were primary amines.

AstraZeneca responds that there was no such motivation and no reasonable expectation of success in making this modification.

The court found that Dr. Powers failed to show a motivation to move the hydroxadamantyl group of his lead compound with any reasonable expectation of success (cited Medichem, S.A. v. Rolablo).

The court also stated that Dr. Powers failed to explain why a POSA would introduce the problem of instability into a DPP4 inhibitor by moving from N-linkage to C-linkage and then adding a cyclopropyl group to solve the newly created stability problem. The combination of “several sequential modifications” is not obvious where there is no reason in the prior art to make the subsequent modification (cited Pfizer Inc., v. Mylan Pharm. Inc) and also stated that the defendants has not shown a motivation to try cyclopropanation.

AstraZeneca highlighted that there were no data available to show the effect of cyclopropanation on the stability of a DPP4 inhibitor, because no one other than the inventors proposed cycloproponation in the context of DPP4 inhibitors.

After the above arguments of the both the parties the court has stated that the defendants failed to present a primafacie case that the asserted claims of the patent-in-suit are invalid as obvious.

The court further denies AstraZeneca’s request for an award of attorney’s fees.
Apart from ANDA litigations there are several IPR’s filed by pharma companies such as Mylan, Wockhardt, Amnea, Aurobindo and Teva challenging the validity of US RE44186. PTAB has ordered to institute the IPR’s.
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