Onyx Therapeutics, Inc. v. Cipla Ltd.

Case Name: Onyx Therapeutics, Inc. v. Cipla Ltd., No. 16-988-LPS, 2020 WL 2214443 (D. Del. May 4, 2020) (Stark, J.) 

Drug Product and Patent(s)-in-Suit: Kyprolis® (carfilzomib); U.S. Patents Nos. 7,417,042 (“the ’042 patent”), 8,207,125 (“the ’125 patent”) (collectively, “the Compound Patents), 7,737,112 (“the ’112 patent” or “the Formulation Patent”) (together with the Compound Patents, “the patents-in-suit”)

Nature of the Case and Issue(s) Presented: Onyx sued Cipla alleging infringement of the patents-in-suit based on the filing of an ANDA for a generic version of Kyprolis. Kyprolis is a proteasome inhibitor treatment for multiple myeloma. Cipla ultimately conceded that its proposed generic product would infringe the asserted claims of the patents-in-suit, but argued that the claims were invalid as obvious. After a bench trial, the district court found that Cipla failed to prove obviousness of the Compound Patents by clear and convincing evidence.

Why Onyx Prevailed: Obviousness. Cipla argued that the asserted claims of the Compound Patents were obvious over the prior art compound YU-101 and knowledge in the art. The court applied a lead compound analysis, which requires the court to determine “whether a new chemical compound would have been prima facie obvious over particular prior art compounds” and which ordinarily requires application of a two-part test: (i) “whether a chemist of ordinary skill would have selected the asserted prior art compounds as lead compounds, or starting points, for further development,” and (ii) “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.” Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1291-92 (Fed. Cir. 2012).

The court determined that YU-101 was not a lead compound for the development of a drug. The court explained that a POSA was much more likely to choose a different compound, bortezomib, as a lead compound because it was an FDA-approved drug product with human potency data and was the only FDA-approved and the most clinically advanced proteasome inhibitor at the time. YU-101, on the other hand, was studied only in vitro. Additionally, YU-101 was an irreversible inhibitor, i.e., once it bonds to its target site, the bond cannot be broken. This can cause major side effects in patients. There was therefore industry pressure to focus on only reversible inhibitors. The court explained that Cipla did not present clear and convincing evidence that a POSA would have selected an irreversible inhibitor such as YU-101 as a lead compound for a drug product.

Cipla also argued that cafilzomib would have been obvious to a POSA developing an improved molecular probe. The court declined to consider the argument because it was raised untimely.

Next, even though it noted that Cipla could not prevail on obviousness because it had failed to prove YU-101 would have been a lead compound, the court addressed the “additional failing” in the remaining portion of Cipla’s obviousness defense to the Compound Patents. Cipla argued that it would have been obvious to modify YU-101’s N-terminus with a morpholino methylene to improve solubility. The court found that it was known in the art that YU-101 had solubility problems and that adding morpholino moieties was one of the many known options for potentially increasing solubility. But the court found that a POSA would have known of many potential modifications to address solubility and Cipla failed to show that a POSA would be motivated to specifically modify the N-terminus with morpholino methylene. The court further held that Cipla failed to prove that the N-terminus was an obvious location to modify YU-101. Moreover, even assuming that a POSA selected the N-terminus for modification, Cipla failed to show that a POSA would have chosen a morpholino methylene as a modification. Onyx presented unrebutted evidence that a POSA would have had numerous options for trying to increase solubility, and it was undisputed that there was substantial uncertainty surrounding modifications to YU-101. The court held that even if Cipla had proved the modification was obvious to try, Cipla failed to prove there was a reasonable expectation of success.

The court also found that the objective indicia did not alter the its non-obviousness conclusion. Onyx had proven long-felt unmet need and industry skepticism. Kyprolis met the need of patients with multiple myeloma for improved treatment that extended lives by months. This was bolstered by FDA’s fast-track designation. Next, the inventors encountered industry skepticism in pursuing an irreversible proteasome inhibitor.

Inventorship. Cipla argued that the patents were invalid under 35 U.S.C. § 112(f) as being invented by another. The court found that Cipla failed to prove that Barry Bunin conceived of carfilzomib. To try to prove conception by Dr. Bunin, Cipla relied on memoranda where he proposed a Markush group in which “R=morpholino.” The court held that the memoranda were ambiguous at best and merely showed that Dr. Bunin had a general goal or research plan he hoped to pursue, which was not enough to show conception.

The court also held that Cipla failed to prove that a 2003 research memorandum was 102(f) prior art. § 103(c)(1) precludes the use of 102(f) prior art where the subject matter constituting the 102(f) prior art and the claimed invention were owned by the same person or under obligation of assignment to the same person at the time the claimed invention was made. The court found that everyone associated with the research memorandum had signed consulting agreements with Proteolix, the company involved in the development of cafilzomib, and were required to assign any invention made during their work for Proteolix to Proteolix. Therefore the research memoranda could not serve as invalidating prior art. The court further found that even if that were not the case, Cipla had also failed to prove that the research plan rendered carfilzomib obvious.

Double Patenting. Cipla argued that the asserted claims of the Compound Patents were invalid for obviousness type double patenting (“OTDP”) over claim 15 of the ’099 patent, which claims YU-101. The court held that Cipla’s argument failed for the same reasons its obviousness defense failed: Cipla failed to demonstrate that POSA would have been motivated to modify YU-101 to arrive at carfilzomib. Further, the court found that the ’099 patent and the Compound Patents did not share an inventive entity or common inventors, which is a requirement of OTDP.

Formulation Patent. The court held that because both asserted claims of the Formulation Patent require the active ingredient to be carfilzomib, Cipla’s obviousness argument failed. Because the court determined that carfilzomib was not obvious, a formulation containing carfilzomib could not be obvious.

Cipla argued that the asserted claims of the ’112 patent, claims 31 and 32, were invalid for OTDP over claim 25 of the ’125 patent, which claims a composition a composition of carfilzomib in water with a substituted or unsubstituted beta cyclodextrin. Since the ’125 patent expires earlier than the ’112 patent and is commonly owned, the court determined that the ’125 patent qualified as a reference for double patenting.

The court determined that Cipla did not carry its burden on OTDP for claim 31 but found claim 32 invalid due to OTDP in view of claim 25 of the ’125 patent.