Carfilzomib - USA

On May 07, 2020, in an unsealed opinion,  Delaware court found Kyprolis® patents valid in a Hatch-Waxman litigation challenged by Cipla.

Plaintiff (Onyx Therapeutics Inc) sued Defendants (Apotex, Aurobindo, Breckenridge, Cipla, Dr. Reddy’s, Fresenius Kabi, Innopharma, MSN, Qilu Pharma and Sagent) as they sought to bring to market generic versions of Plaintiffs' Kyprolis ® (Carfilzomib), a drug indicated for the treatments for relapsed multiple myeloma. Carfilzomib is a novel epoxyketone-based irreversible proteasome inhibitor. All of the defendants other than Cipla entered into consent judgments with Onyx and thus cases were dismissed. Cipla stipulated that its proposed ANDA product infringes Onyx’s U.S. Patent Nos. 7,417,042 and 8,207,125 (Compound Patents) expiring on Jul. 20, 2026 & Apr. 14, 2025 respectively as well as Onyx’s U.S. Patent No. 7,737,112 (Formulation Patent) expiring on Dec. 07, 2027. Cipla, however, contends that the Asserted claims are invalid. In May 2019, the Court held a five-day bench trial.

Onyx asserted claims 23 and 24 (specific compound or its salt) of the ’042 Patent. Onyx asserted claims 1 (specific compound) and 25 (composition with cyclodextrin) of the ’125 patent. Onyx also asserted claims 31 (composition with SBECD and 10 mM citric acid adjusted to pH 3.5) and 32 (composition with SBECD in lyophilized form) of the ’112 Patent.

1. Compound patents:

Obviousness

Cipla sought to invalidate the asserted claims of the Compound Patents as obvious in view of YU-101 (lead compound under development by Proteolix) disclosed in the US 6,831,099 Patent. The addition of a morpholine ring to the N-terminus of YU-101 made it more soluble & thus new compound Carfilzomib was produced. It was known in the art that morpholino acts as a solubilizing substituent.

        [Image source: https://cen.acs.org/articles/90/i35/Carfilzomib-Discovery-Drug.html]

Court said that lead compound analysis (Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1291; Fed. Cir. 2012) is applied while determining the obviousness of a new chemical compound. A lead compound is a compound in the prior art that would be “most promising to modify in order to improve upon its activity and obtain a compound with better activity. Once a lead compound has been identified, a party seeking to invalidate a patent must then show the reason or motivation for modifying the lead compound, which “may come from any number of sources and need not necessarily be explicit in the prior art.”

Court said that POSA would not have viewed YU-101 as a lead compound for developing a carfilzomib drug. Because, POSA looking for a lead compound would have preferred a compound that had human potency data and not just test tube data. YU-101 is an irreversible epoxyketone proteasome inhibitor and the early 2000s were a period of strong industry aversion to irreversible inhibitors. If an irreversible inhibitor like YU-101 inadvertently binds to an off-target site, a patient may suffer catastrophic side effects that cannot be alleviated. Thus, there was significant pressure in the industry to focus only on reversible inhibitors. Cipla argued that YU-101’s chymotrypsin-like activity (“CT-L”) specificity was so overwhelming that it would have outweighed general industry concerns of off-site toxicity. But court said that this contention is not supported by the record evidence. Cipla has not shown that POSAs in the industry would have correlated proven CT-L site specificity with increased safety. Nor has Cipla proven that a POSA would have believed YU-101 would not bind off-tissue and would not cause an adverse immune response.

Instead, POSA looking to develop a new drug product would have much more likely pursued modifying other known reversible inhibitors, such as bortezomib which was approved by USFDA as first proteasome inhibitor in May 2003. The FDA approval of bortezomib not only validated the CT-L site as a therapeutic target, but also proved to the industry that proteasome inhibition could provide high-impact therapeutic uses. POSA would also have known that bortezomib had an established data package, had been safely and effectively administered to humans, and was the most clinically-advanced proteasome inhibitor at the pertinent time. Therefore, court held that Cipla has failed to prove that a POSA would have viewed YU-101 to be a lead compound for a POSA looking to develop a carfilzomib drug product.

Court further said even assuming that a POSA would have selected YU-101 as a lead compound, Cipla has not proven by clear and convincing evidence that a POSA would have modified YU-101’s N-terminus with a morpholino methylene. Cipla argued that morpholino methylene would have been an obvious modification to improve YU-101’s solubility because it was well known in the art. But, court said that Cipla’s contention that a POSA designing a drug product would have been motivated to increase YU-101’s solubility improperly rests on hindsight reasoning. In this case, Cipla has shown that numerous potential modifications were available to a POSA who desired to increase YU-101’s solubility, but the record does not demonstrate that a POSA would have been motivated specifically to place a morpholino methylene on the N-terminus. Cipla has not proven even that the N-terminus was the obvious location to modify YU-101 to increase solubility. On the contrary, Onyx presented unrebutted evidence that a POSA would have had numerous options, including prodrugs or other side-chain or N-terminal modifications, at her disposal as mechanisms for trying to increase solubility. Further, while adding a morpholino methylene to the N-terminus may have increased solubility, it is undisputed that substantial uncertainty surrounded the biological implications of any modification to YU-101, and it was unknown whether the morpholino methylene N-terminus modification would actually produce a better drug product. Given the uncertainty and relative lack of data surrounding YU-101 as a whole, the Court was persuaded by Onyx’s expert that modifying the N-terminus of YU-101 with a morpholino methylene was not obvious.

Incorrect Inventorship

Cipla sought to invalidate the asserted claims of the ’042 and ’125 Patents as being invented by another, pursuant to 35 U.S.C. § 112(f). Cipla relied on Dr. Bunin’s purported conception of carfilzomib. Dr. Bunin was chemistry consultants hired by Proteolix to generate ideas for possible analogs of YU-101. In September 2003, Dr. Bunin emailed some proposals for creating epoxomicin/YU-101 analogs. The 2003 Research Plan does not describe the synthesis of any specific compound, but instead lists approaches for potentially modifying epoxomicin and YU-101 at multiple locations. Cipla relied on the September Memoranda, in which Dr Bunin proposed a Markush group in which “R=morpholino.” But, court found that Dr. Bunin’s proposal of “R=morpholino” is ambiguous. The Court was persuaded by Onyx’s expert, Dr. Lipinski, that a POSA would interpret “R=morpholino” in the September Memoranda as referring literally to a urea linkage (a morpholino carbonyl), and not carfilzomib (a morpholino methylene).

Court said that clear and convincing evidence required to demonstrate that Dr. Bunin had the idea for carfilzomib “that was definite and permanent enough” that a POSA could have understood it. To the contrary, the September Memoranda show merely that Dr. Bunin had “just a general goal or research plan” he (and Proteolix) hoped to pursue, which is insufficient to constitute conception. The documents and associated communications repeatedly refer to the September Memoranda as research plans or proposals. At the time of the September Memoranda, Dr. Bunin had conducted no testing and had no particular expectation of success. For at least these reasons, Cipla has failed to prove that Dr. Bunin conceived of every modification he proposed, and, most pertinently, has failed to prove, by clear and convincing evidence, that he conceived of carfilzomib.

Obviousness-Type Double Patenting

Cipla sought to invalidate claims 23 and 24 of the ’042 Patent and claim 1 of the ’125 Patent as being an obvious double-patenting (OTDP) of claim 15 of the ’099 Patent, which claims YU-101. Court said that while double patenting does not per se require a complete overlap of inventors or common ownership, there must be some commonality between the earlier and later patents. It is undisputed that the ’099 Patent does not share any common inventors with the Compound Patents, Nor does Onyx own the ’099 Patent, Yale does. Cipla argued that Onyx’s exclusive license with Yale gave Onyx “all substantial rights” to the ’099 Patent, such that Onyx is effectively an owner of the ’099 Patent. Specifically, Cipla points to Onyx’s “first right to sue for infringement” as evidence of Onyx’s effective ownership. Court, however, said that Cipla is asking the Court to extend the effective ownership doctrine from the realm of standing to non-statutory double patenting. The Court is not persuaded to do so, as Cipla’s position ignores the fundamental nature and purpose of the non-statutory double patenting doctrine. Court said that the licensed patent will always be made by another who is not the licensee (e.g., the licensor) and the licensed patent will, therefore, constitute § 102 prior art to the licensee’s patent. The licensee cannot take advantage of the gap which OTDP is directed at filling, so there is no reason to extend OTDP in the manner Cipla proposes.

Here, the ’099 Patent lists different inventors and different assignees/owners than the Compound Patents and, thus, will always constitute § 102 prior art, even without invoking the doctrine of OTDP. The Compound Patents are not invalid based on OTDP.

2. Formulation patents:

Obviousness

Court held that given the conclusions already stated above in connection with the Compound Patents, it follows that Cipla’s contention that the ’112 Patent, the Formulation Patent, is invalid due to obviousness must also fail. This is because both asserted claims of the Formulation Patent, claims 31 and 32, have as a claim limitation that the active ingredient of the claimed formulation is carfilzomib. Because carfilzomib was not obvious, for the reasons explained above, a formulation containing carfilzomib also cannot have been obvious.

Obviousness-Type Double Patenting

Cipla also sought to invalidate claims 31 and 32 of the ’112 Patent as being an obvious double-patenting of claim 25 of the ’125 Patent.

The substantive differences between claim 31 of the ’112 Patent and claim 25 of the ’125 Patent are that the carfilzomib of claim 31 is: (1) complexed with a specific cyclodextrin, SBECD, at 10% w/v, (2) at a pH of 3.5, (3) with 10mM citric acid, (4) in a single formulation. 

With respect to 10% SBECD court said that there is no patentably distinct difference between claiming substituted or unsubstituted beta cyclodextrin, as claim 25 of the ’125 Patent and claiming 10% w/v SBECD, as claim 31 of the Formulation Patent. It would have been obvious to a POSA formulator at least to start with SBECD, given its proven track record with the FDA. With respect to pH of 3.5, court said that there is a patentably distinct difference between claiming carfilzomib in a formulation with no specific pH, as does claim 25 of the ’125 Patent, and a formulation with carfilzomib with a pH of 3.5. The record contains substantial evidence that a POSA would have had concerns with whether carfilzomib could be stable at a pH of 3.5. With resepct to 10mM of Citric Acid limitation, court said that there is also a patentably distinct difference between claiming carfilzomib and claiming a specific formulation with 10mM of citric acid. And court finally said that even if all the elements of claim 31 of the Formulation Patent were obvious and patentably indistinct from the elements of claim 25 of the ’125 Patent (which they were not), Cipla has not shown that the combination as a whole was obvious.

The only substantive differences between claim 32 of the ’112 Patent and claim 25 of the ’125 Patent are that claim 32: (1) is directed at a “pharmaceutical composition” (rather than just a “composition”); (2) recites SBECD instead of substantiated or unsubstantiated β-cyclodextrin; and (3) requires lyophilization. 

Court said that Onyx does not argue that there is a difference between the claimed “pharmaceutical composition” of claim 32 and the “composition” of claim 25 of the ’125 Patent. The Court has also found in connection with claim 31 that there is no patentably distinct difference between claiming substantiated or unsubstantiated beta cyclodextrin and SBECD. So, all that is left as potentially patentably distinct between claim 32 of the Formulation Patent and claim 25 of the earlier ’125 Patent is lyophilization. With respect to this, Cipla has also shown that a POSA would have had a reasonable expectation of success in lyophilizing proteasome inhibitors, as evidenced approbed Bortezomib. Cipla has further proven that a POSA would have had a reasonable expectation of success that SBECD complexes may be lyophilized. For these reasons, claim 32 of the ’112 Patent is invalid due to obviousness-type double patenting, in view of claim 25 of the ’125 Patent.