March 8, 2021
Torrent Pharmaceuticals and Indoco Remedies Ltd. (Defendant-Appellant) appealed from the district court’s final judgment on Takeda’s (Plaintiffs-Appellees) invalidity challenges to claims 4 and 12 of U.S. Patent No. 7,807,689, owned by Takeda. In a non-precedential opinion, the Federal Circuit (“the Court”) affirmed the district court’s final judgment that Torrent and Indoco had failed to prove that the claims asserted by Takeda were invalid for statutory obviousness or non-statutory obviousness-type double patenting.
Takeda’s patent ‘689 is listed in the Orange Book as protecting Takeda’ alogliptin benzoate formulations, marketed under the brand names Nesina®, Kazano®, and Oseni®. Indoco filed Abbreviated New Drug Application (“ANDA”) Nos. 210002 and 209998, seeking approval to market generic versions of Nesina® and Kazano®. Torrent filed ANDA Nos. 21-0159, 21-0160, and 21-0161, seeking approval to market generic versions of Nesina®, Kazano®, and Oseni®. Takeda filed a law suit against Torrent and Indoco. Takeda complained that by filing these ANDAs, Torrent and Indoco had infringed the ’689 patent. The parties had stipulated to a finding that the proposed generic products infringe claims 4 and 12 of the ’689 patent.
Claims 4 and 12 of the ’689 patent are as follows:
4. A compound of the formula
or pharmaceutically acceptable salts thereof.
12. A compound of the formula
wherein the compound is present as a benzoate salt.
The claims at issue are directed to alogliptin, a uracil-containing DPP-IV inhibitor useful for treating type II diabetes, and pharmaceutical salts thereof. The district court concluded that Appellants had failed to prove by clear and convincing evidence that the challenged claims were invalid for either statutory obviousness or non-statutory obviousness-type double patenting. Appellants challenged several different fact findings by the district court. The Court held that “[e]ven assuming some of those challenges have merit, we discern no clear error in the district court’s finding that a skilled artisan would not have been motivated to make Appellants’ proposed scaffold and isosteric replacements with a reasonable expectation of success.” The Court pointed out that it was the undisputed factual finding that “in the relevant art of pharmaceutical development, very small changes in molecular structure can have dramatic effects on the properties of the molecule.”
Torrent presented two obviousness-type double patenting theories using Feng’s F162 compound as the lead compound for further modification. First, Torrent argued that a skilled artisan would have found it obvious to replace F162’s pyrimidinone scaffold with uracil, citing Böhm and Kim. Böhm disclosed that scaffold replacement techniques were known in the prior art as of the relevant priority date. Kim reported that administering uracil lowers blood glucose in an animal model of diabetes but did not mention DPP-IV or DPP-IV inhibitors or scaffold hopping or the use of uracil as a scaffold. These references, along with other evidence of record, did not demonstrate that uracil was known to possess DPP-IV inhibitory activity or other characteristics desirable in a scaffold for DPP-IV inhibition as of the relevant priority date. The district court pointed out that none of the evidence presented by Torrent’s counsel disclosed that uracil was a known DPP-IV inhibitor. “Given that Torrent fails to establish that uracil was known at the time of invention to lower blood glucose by inhibiting DPP-IV, or was otherwise understood to be a desirable scaffold for DPP-IV inhibition,” the Court concluded that the district court did not clearly err in finding that a skilled artisan would not have been motivated to replace F162’s pyrimidinone scaffold with a uracil scaffold with a reasonable expectation of success.
Torrent contended that a skilled artisan would have been motivated to replace a fluoroolefin unit in F162’s pyrimidinone scaffold with an amide unit. Torrent argued that fluoroolefin and amide were known isosteres in the prior art, and because skilled artisans are medicinal chemists looking for new compounds, they would have been motivated to replace F162’s fluoroolefin with its isostere with a reasonable expectation to develop a new DPP-IV inhibitor. The district court determined that “Torrent had not identified anything in the prior art that would have motivated a skilled artisan to dispose of F162’s fluoroolefin unit, let alone replace it with an amide, given myriad more conservative and predictable modifications that were available for transforming F162 into a ‘novel’ compound.” The Court agreed and stated that “we discern no clear error in the district court’s finding that a skilled artisan would not have been motivated to make Appellants’ proposed scaffold and isosteric replacements with a reasonable expectation of success.”
As for statutory obviousness, Indoco argued that a skilled artisan would have been motivated to use DCAX as a lead compound and to replace DCAX’s xanthine scaffold with uracil because xanthine and uracil are interchangeable naturally occurring nitrogenous bases. The Court disagreed, because even if the prior art would have motivated a skilled artisan to modify DCAX by replacing its xanthine scaffold with uracil, “we agree with the district court that Indoco ‘failed to show that a [skilled artisan] who did so would have [had] a reasonable expectation of success’ with this particular scaffold replacement.” “The interchangeability references on which Indoco relies do not pertain to DPP-IV inhibitors or diabetes, nor do they, or any other prior art of record, teach substituting an existing xanthine scaffold for uracil.”
Torrent and Indoco also argued that the district court materially erred with respect to the level of ordinary skill in the art and improperly ignored the parties’ dispute over whether a skilled artisan must have specific experience developing DPP-IV inhibitors and/or type II diabetes drugs. This specific experience is a material difference as it is critical to the district court’s findings regarding motivation and reasonable expectation of success. The Court disagreed.
The Court recognized that the district court had considered the prior art from both perspectives, that of a skilled artisan with and without specific experience with DPP-IV inhibitors or type II diabetes drugs, and concluded that Appellants had failed to prove invalidity under either definition of a skilled artisan.
Given the substantive gaps in establishing motivation and reasonable expectation of success, the Court held that the record supported the district court’s conclusion that it would have reached the same outcome under either definition of a skilled artisan. Appellants, moreover, failed to show how applying a level of ordinary skill that requires experience with DPP-IV inhibitors or type II diabetes drugs would have remedied its failures of proof. “While motivation and reasonable expectation of success need not be expressly disclosed by the prior art itself and may instead come from the background knowledge of the skilled artisan, merely asserting that a given modification would have been obvious to a skilled artisan does not make it so.” The Court affirmed the district court’s judgment upholding the validity of claims 4 and 12 of the ’689 patent.