Amgen Inc. v. Amneal Pharms. LLC

Case Name: Amgen Inc. v. Amneal Pharms. LLC, Civ. No. 16-0853 (MSG), 2018 U.S. Dist. LEXIS 125631 (D. Del. July 27, 2018) (Goldberg, J.)

Drug Product and Patent(s)-in-Suit: Sensipar® (cinacalcet HCl); U.S. Patent No. 9,375,405 (“the ’405 patent”)

Nature of the Case and Issue(s) Presented: The ’405 patent is assigned to Amgen and listed in the FDA’s Orange Book as covering Sensipar. Claim 1 of the ’405 patent recites a pharmaceutical composition combining Markush groups of specific excipients, namely, a diluent, a binder, and a disintegrant, in specific amounts, with the active ingredient cinacalcet HCl. The court construed three terms in claim 1 of the ’405 patent. Importantly, it construed the Markush groups for the binder and disintegrant elements as “closed to unrecited binders and disintegrants” and found that “there could be no literal infringement if the Defendants’ ANDA product contained an unrecited (or unlisted) binder or disintegrant.”

Amgen accused defendants Amneal, Watson, Piramal, and Zydus of infringing the ’405 patent by filing ANDAs seeking FDA approval to manufacture, use and/or sell generic versions of Sensipar. The court bifurcated the infringement claims and invalidity counterclaims for trial, and held a four-day bench trial on infringement. The court’s trial order found Amneal, Watson, and Piramal did not infringe the ’405 patent, and that Zydus’s proposed ANDA did infringe the ’405 patent.

Why Amneal, Watson, and Piramal Prevailed: The court found that Amneal’s ANDA did not infringe the binder and disintegrant claim limitations. Amneal’s ANDA contains as its binder an excipient called Opadry. Claim 1 of the ’405 patent does not list Opadry in the Markush group for binders. Amgen nonetheless attempts to prove literal infringement by arguing that Opadry is a pseudonym for hydroxypropyl methylcellulose (“HPMC”), which is a listed binder, and, alternatively, that Amneal’s ANDA infringes under the doctrine of equivalence. Crediting Amneal’s expert over that of Amgen, the court found that a POSA would not consider Opadry and HPMC synonymous. The court also found that Opadry and HPMC have different chemical structures, physical characteristics, binding mechanisms, and commercial sources. With respect to the doctrine of equivalents argument, the court found Amgen’s expert’s opinion conclusory, given without explanation or corroborating evidence, and thus persuasive. Next, Amneal’s ANDA discloses the use of the unlisted disintegrant pregelatinized starch. Amgen therefore argued that the pregelatinized starch in Amneal’s product was not functioning as a disintegrant, but as a diluent. The court rejected this argument because Amneal’s expert explained that Amneal’s ANDA product did not need another diluent, its manufacturing process runs contrary to Amgen’s expert’s opinion, and the ANDA included testing that showed pregelatinized starch in Amneal’s product functioning as a disintegrant.

The court next addressed Amgen’s arguments against Watson. Watson uses an unlisted disintegrant, low substituted hydroxypropyl cellulose (“L-HPC”) in its formulation. Amgen therefore argues that L-HPC infringes claim 1 under the doctrine of equivalence. The court analyzed Amgen’s arguments under both the “function-way-result” test and the “insubstantial differences” test. As it had with Amneal, the court found that Amgen’s expert did not identify at trial what he considered to be the function, way, or result of the disintegrants being compared. Instead, Amgen relies on a brief assertion by its expert that the disintegrants listed in claim 1 are “superdisintegrants,” and LHPC is “another superdisintegrant” with “similar disintegrant capability to other superdisintegrants.” The court found that opinion alone could not form the basis for meeting Amgen’s burden of proving infringement under the doctrine of equivalents. Similarly, Amgen’s expert did not provide an opinion regarding the insubstantial differences between L-HPC and crospovidone. So the only particularized testimony in the trial record regarding the differences between L-HPC and crospovidone was presented by Watson’s expert, which the court credited.

With respect to Piramal, Amgen argued that the unlisted binder in Piramal’s ANDA product—pregelatinized starch—has two components; a native starch fraction that actually functions as a diluent; and a cold-water soluble fraction that functions as a binder. Neither pregelatinized starch nor its cold-water soluble fraction is listed in the Markush group for binders. Accordingly, Amgen argued that cold-water soluble fraction is equivalent to povidone. But the court found that Amgen was foreclosed by prosecution history estoppel from asserting the doctrine of equivalents against Piramal’s use of pregelatinized starch as a binder.

Finally, Amgen’s dispute with Zydus comes down to the function of pregelatinized starch. Amgen argued that it functions as a diluent, as stated in Zydus’ ANDA. Zydus takes the position that it functions as a binder, which is the same opinion that Amgen’s expert asserted against other defendants. “Thus, we are in a counterintuitive world where Amgen wins against Zydus only if the opinion of Amgen’s expert—which Amgen relies on to prove infringement against the other defendants—is unpersuasive.” The court, however, was not persuaded that Amgen’s expert’s opinion regarding pregelatinized starch was “scientifically sound.” For one thing, Amgen was not consistent in asserting where Dr. Davies’ fractions opinion operated. On the one hand, he claimed that three defendants literally infringed claim 1, because the fractions opinion applied to Aurobindo and Piramal, but not to Zydus. All of the experts agreed that the particular function of pregelatinized starch in any given formulation “depends on the context,” including the amount of pregelatinized starch, the other excipients present, and the manufacturing process. But Amgen did not have its expert give testimony that applied those same contextual factors to each specific defendant.