Otsuka Pharm. Co. v. Sandoz, Inc.

Case Name: Otsuka Pharm. Co. v. Sandoz, Inc., Civ. Nos. 2011-1126, 2011-1127, 678 F.3d 1280 (Fed. Cir. May 7, 2012) (Circuit Judges Lourie, Moore, and Reyna presiding; Opinion by Lourie) (Appeal from D.N.J., Cooper, J.)

Drug Product and Patent(s)-in-Suit: Abilify^TM (aripiprazole); U.S. Pat. No. 5,006,528 ("the '528 patent")

Nature of the Case and Issue(s) Presented: The issue here concerned whether the '528 patent was valid as nonobvious under § 103 or the doctrine of nonstatutory double patenting. Plaintiff Otsuka Pharmaceutical Co., Ltd., ("Otsuka") is the assignee of the '528 patent, which claims the chemical compound aripiprazole, an anti-psychotic drug which is marketed by Otsuka under the brand name, Abilify^TM. Otsuka asserted that defendants Apotex Inc., Apotex Corp., Teva Pharmaceuticals USA, Inc., Barr Laboratories, Inc., and Barr Pharmaceuticals (collectively, "defendants") infringed claims 12, 17, and 23 of the '528 patent when they each filed ANDAs seeking permission to manufacture generic aripiprazole products. The cases were consolidated and tried before the United States District Court for the District of New Jersey. After a bench trial, the district court held that the asserted claims of the '528 patent were not obvious, and were not invalid under the doctrine of nonstatutory double patenting. Defendants appealed to the Federal Circuit, which affirmed the decision below.

Why Otsuka Prevailed: Defendants' first basis for appeal was that the district court's lead compound analysis violated precedent and fell into a rigid obviousness analysis that had been precluded by KSR. Specifically, defendants argued that the district court had erred when it assumed that only the most obvious choice could serve as a lead compound. Otsuka, on the other hand, argued that the district court properly rejected defendants' obviousness contentions, which were based upon improper hindsight bias. The Court first noted that, with respect to a new chemical compound, obviousness generally turns on structural similarities and differences between the claimed compound and prior art compounds. A two-part inquiry must be applied, first to determine whether a chemist of ordinary skill would have selected the asserted prior art compounds as lead compounds, or starting points, for further development efforts; and second, whether the prior art would have supplied one of ordinary skill in the art with a reason or motivation to modify a lead compound to make the claimed compound with a reasonable expectation of success. Defendants argued that particular prior art compounds, an unsubstituted butoxy, 2,3,-dichloro propoxy, and OPC-4392, had rendered the asserted claims of the '528 patent invalid for obviousness.

With respect to the unsubstituted butoxy prior art reference, the Court found that the patent in which this compound was disclosed described a genus encompassing trillions of carbostyril compounds having a laundry list of potential nervous system controlling effects. It was not obvious that one of those effects would be as a potential antipsychotic agent. Additionally, a related declaration that accompanied the file history of the unsubstituted butoxy patent reference disclosed several additional compounds that were structurally distinct from aripiprazole and the unsubstituted butoxy reference that were far more potent, and would likely have served as more promising lead compounds. The Federal Circuit held that it would not have been obvious for one skilled in the art to have selected the unsubstituted butoxy reference as a lead compound.

Next, the Court addressed the 2,3-dicholoro propoxy compound. Again, the Court found that the reference where the 2,3-dicholoro propoxy compound was disclosed listed that compound as one among hundreds of examples that may have been useful for an extensive list of potential nervous system controlling activities. The Court further found that defendants had failed to establish that the prior art reference that the disclosed the 2,3-dicholoro propoxy compound provided ample motivation to narrow the prior art genus of salt-forming anions to a few species, nor did it predict the results of such narrowing. Therefore, one of skill in the art would not have selected this compound as a lead compound.

Last, the Court addressed the OPC-4392 compound. The Court dispensed with this reference by noting that it actually taught away from using it as a starting point for further antipsychotic research. Contemporaneous clinical studies established that this compound's antipsychotic action was not strong, and that at a very low dose, it was likely to cause severe side effects. Additionally, the Court found that even if this compound had been selected for further research, the modifications necessary to arrive at the aripiprazole compound were extensive, and a skilled artisan would not have known how to modify the compound to increase antipsychotic activity.

Concerning defendants' nonstatutory double patenting argument, the Court found that while the analyses of obviousness and nonstatutory double patenting were similar, important distinctions exist. Specifically, the patent underlying a double patenting rejection need not be prior art. Additionally, when analyzing obviousness-type double patenting in cases involving claimed chemical compounds, the issue is not whether a skilled artisan would have selected the earlier compound as a lead compound. This is because the analysis must focus on the earlier claimed compound over which double patenting has been alleged, whether it is a lead compound or not. Defendants cited to cases implying that finding a motivation to combine references is unnecessary. But the Federal Circuit held that the cases defendants cited involved anticipation, which does not require an analysis of a motivation to combine references, as required under an obviousness determination. Defendants argued that it would have been obvious to start with the unsubstituted butoxy compound and substitute out the hydrogen atoms at the 2- and 3-positions with chlorine atoms to make aripiprazole. The Court rejected this argument, noting that evidence before the district court clearly established that there was a high degree of unpredictability in antipsychotic drug discovery as of the priority date of the '528 patent, and that antipsychotic research at the time was notoriously unsuccessful. Additionally, the Court noted that even though 2-3-dichloro substituted compounds were disclosed in the prior art, there was no indication that they had antipsychotic properties. The Court held that because the prior art would not have provided one of ordinary skill in the art with a reason or motivation to make aripiprazole from the unsubstituted butoxy compound, it was unnecessary to consider Otsuka's evidence of secondary considerations.