Court: District Court, D. Delaware; February 1, 2017; Federal District Court
AstraZeneca has initiated a consolidated patent infringement action against several pharmaceutical companies, collectively referred to as "Aurobindo," alleging infringement of U.S. Reissue Patent No. RE44,186, known as the RET86 patent. A three-day bench trial was conducted from September 19 to September 21, 2016, focusing on the validity of the RET86 patent and whether its asserted claims are invalid due to obviousness under 35 U.S.C. § 103. The court, after reviewing the case record and applicable law, determined that the asserted claims of the RET86 patent are not invalid for obviousness. The memorandum also details the parties involved, including AstraZeneca and its subsidiary AstraZeneca Pharmaceuticals LP, along with various entities associated with Aurobindo, such as Aurobindo Pharma Ltd., Aurobindo Pharma U.S.A. Inc., Wockhardt Bio AG, Wockhardt USA LLC, Amneal Pharmaceuticals LLC, Sun Pharmaceutical Industries Ltd., Sun Pharma Global FZE, Mylan Pharmaceuticals Inc., Watson Laboratories, Inc., and Actavis Laboratories FL, Inc. The court confirmed its jurisdiction over all parties involved in the case.
Consolidated actions involve Defendants submitting multiple Abbreviated New Drug Applications (ANDAs) under § 505(j) of the Federal Food, Drug, and Cosmetic Act to the FDA, seeking to market generic saxagliptin drugs before AstraZeneca’s RE'186 patent expiration. Saxagliptin is an FDA-approved DPP4 inhibitor for type 2 diabetes, characterized by a cis-4,5-cyclopropyl group fused to a cyanopyrrolidine ring as the P1 group and a C-linked 3-hydroxyadamantyl group forming the P2 group. AstraZeneca holds NDA No. 022350 for 2.5 mg and 5 mg saxagliptin hydrochloride tablets, marketed as "Onglyza," approved for improving glycemic control in adults with type 2 diabetes. The RE'186 patent is listed in the FDA's Orange Book for Onglyza. Additionally, AstraZeneca holds NDA No. 200678 for saxagliptin and metformin hydrochloride extended-release tablets in various strengths, marketed as "Kombiglyze™ XR," which is also covered by the RE'186 patent in the Orange Book.
U.S. Reissue Patent Number RE44,186, known as the RET86 patent, was issued on April 30, 2013, and is titled "Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method." The inventors listed are Jeffrey A. Robl, Richard B. Slusky, David J. Augeri, David R. Magnin, Lawrence G. Hamann, and David A. Betebenner. AstraZeneca is the assignee and owner of the RE'186 patent, which grants them standing to initiate legal action regarding this patent.
The RE'186 patent stems from U.S. Application No. 13/308,658, filed on December 1, 2011, and is a reissue of U.S. Patent No. 6,395,767, originally issued on May 28, 2002. The '767 patent was filed on February 16, 2001, and claims priority to provisional application 60/188,155, filed on March 10, 2000.
AstraZeneca has asserted claims 25 and 26 of the RE'186 patent against the defendants. Claim 25 describes "a compound that is or a pharmaceutically acceptable salt thereof," while Claim 26 specifies that the compound mentioned in Claim 25 is the hydrochloride salt, specifically identifying saxagliptin hydrochloride salt.
On May 23, 2014, AstraZeneca initiated legal action against Aurobindo for infringing the RE'186 patent. Similar complaints were filed on the same day against Wockhardt concerning both the RE'186 and '400 patents. Subsequently, on August 15, 2014, AstraZeneca filed suits against Watson, Actavis, and Actavis LLC for infringement of the same patents. On June 2, 2014, additional suits were filed against Sun Pharma, Mylan, and Amneal for infringement of the RE'186 and '400 patents. Another complaint was filed on October 31, 2014, against Actavis Laboratories FL, Inc., Actavis, and Actavis LLC regarding the RE'186 and '799 patents.
In October 2014, the patent infringement claims against various defendants were consolidated into Civil Action No. 14-664. On October 8, 2014, multiple civil actions were also consolidated under this same number. A stipulated order to further consolidate Civil Action No. 14-cv-1356 with the consolidated action was filed on November 17, 2014, and granted by the court. On January 23 and 27, 2015, further stipulated orders were filed to consolidate additional actions and dismiss certain defendants without prejudice, all of which were granted.
A three-day bench trial took place from September 19 to September 21, 2016, during which Aurobindo admitted to infringing all asserted claims, leaving only the issue of the patent’s obviousness for consideration. The court, after reviewing the evidence and applicable law, determined that the defendants did not demonstrate that the asserted claims of the RE'186 patent were obvious as of the filing date, thus ruling the claims valid under 35 U.S.C. § 103. Aurobindo’s motion was denied, while AstraZeneca’s motion was granted.
A patent cannot be granted if the differences between the claimed invention and prior art render the invention obvious to a person of ordinary skill in the art (POSA) under 35 U.S.C. § 103(a). Obviousness is a legal question based on several factual inquiries, as outlined in Richardson-Vicks v. Upjohn Co. The evaluation involves four key considerations: 1) scope and content of prior art; 2) level of ordinary skill in the art; 3) differences between the claimed invention and prior art; and 4) secondary considerations of non-obviousness, which include commercial success, unmet needs, failure of others, industry acquiescence, and unexpected results, as established in Graham v. John Deere Co. A patent is presumed valid under 35 U.S.C. § 282(a), and the burden of proof to challenge a patent's validity based on obviousness lies with the challenger, who must provide clear and convincing evidence that the invention was obvious at the time it was made, avoiding hindsight bias as cautioned in KSR Int’l Co. v. Teleflex, Inc. The KSR ruling also emphasizes that there must be a reason for a POSA to combine prior art elements in the claimed manner, without requiring an explicit teaching or motivation. Obviousness does not demand absolute predictability of success, but rather a reasonable expectation of success, as reflected in Medichem, S.A. v. Rolabo, S.L. The Federal Circuit acknowledges that while pharmaceuticals can be unpredictable, evidence of a limited number of predictable solutions may indicate obviousness, as seen in Eisai Co. Ltd. v. Dr. Reddy’s Labs. Ltd. Regarding the determination of the level of ordinary skill in the art for the RE'186 patent, both parties agree that it pertains to a medicinal chemist with either a Ph.D. and practical experience or a Bachelor’s/Master’s degree with significant experience, with no meaningful differences in their definitions.
The court will evaluate whether Aurobindo has demonstrated a prima facie case of obviousness based on trial evidence. For new chemical compounds, the accused infringer must present a known "lead" compound, the rationale for its selection, and a reason that would prompt a chemist to modify it in a manner that results in the claimed invention. Aurobindo claims the asserted patents are obvious for three specific reasons: first, that a person of ordinary skill would have been motivated to choose vildagliptin as a lead compound; second, that there would have been a motivation to relocate the hydroxyadamantyl group; and third, that there would have been a motivation to incorporate a cyclopropyl ring. The court will examine each of these claims individually.
To establish a prima facie case of obviousness, Aurobindo must demonstrate that a person of ordinary skill in the art (POSA) would have selected vildagliptin as a lead compound. Aurobindo argues that vildagliptin was a strong candidate due to its potency, favorable history, and biological efficacy, supported by Dr. Powers' testimony. They claim that existing literature on DPP4 inhibitors indicated vildagliptin’s structural suitability as a lead compound. However, AstraZeneca counters that selecting vildagliptin lacks justification without hindsight, referencing Dr. Weber's testimony that two more advanced compounds, P32/98 and NVP-DPP728, were already in clinical development. Dr. Weber emphasized the importance of in vivo data over in vitro data, asserting that human data is paramount.
The court agrees with AstraZeneca, stating Aurobindo has not shown that a POSA would have chosen vildagliptin over other compounds. Aurobindo's analysis is criticized for being overly focused on potency, neglecting other critical pharmacokinetic and pharmacodynamic factors essential for determining a compound's final dosage. The court finds that a POSA would not dismiss the clinical data for P32/98 and NVP-DPP728 in favor of limited rat data. The court identifies hindsight bias in Dr. Powers' analysis, noting that he selectively reviewed prior art without a comprehensive assessment. Ultimately, the court concludes that a POSA would consider additional compounds alongside P32/98 and NVP-DPP728 in their evaluation.
Aurobindo's attempt to demonstrate that modifying vildagliptin to create saxagliptin was obvious to a person of ordinary skill in the art (POSA) was not substantiated by clear and convincing evidence. The court emphasized that establishing obviousness requires proof that a skilled chemist would be motivated to select and modify a prior art compound to achieve a new compound with similar or improved properties. Aurobindo's argument, which included the idea that relocating the hydroxyadamantyl group would enhance potency, was countered by Dr. Weber's testimony. Dr. Weber argued that prior art discouraged such modifications, as eliminating the N-linkage from vildagliptin would remove a stabilizing feature and that existing N-linked compounds demonstrated good potency and stability. The court found Dr. Weber's perspective more credible, noting that the prior art indicated that the proposed modification was unlikely to yield successful results. Ultimately, the court concluded that Aurobindo failed to demonstrate a reasonable expectation of success in making the modification, ruling that it was not obvious.
Aurobindo contends that a person of ordinary skill in the art (POSA) would have anticipated stabilizing modifications to vildagliptin by introducing a primary amine and a 4,5 cyclopropyl ring. They argue that the synthesis method from the Hanessian 1998 reference would facilitate this modification and that selecting the attachment point for the cyclopropyl ring would be straightforward. However, the analysis is deemed flawed. Dr. Powers did not adequately justify the rationale behind introducing instability by changing the linkage type before adding the cyclopropyl group. The court finds that the sequential modifications lack obviousness due to insufficient prior art justification. Furthermore, Aurobindo did not demonstrate motivation for cyclopropanation, noting a lack of data on its effects on DPP4 inhibitor stability, with AstraZeneca asserting that prior art favored five-membered rings and warned against increasing ring size. The court highlights that expert testimony indicated no reasonable expectation of success in this modification, as the prior art did not suggest that cyclopropyl addition would enhance DPP4 inhibitors. Thus, the court concludes that Aurobindo failed to establish a prima facie case of obviousness for the claims of the RET86 patent, emphasizing that Dr. Powers' motivations contradict prior art teachings and reflect hindsight reasoning.
AstraZeneca sought attorney’s fees under Section 285 of the Patent Act, arguing that the case was exceptional due to the substantive weakness of Aurobindo’s position. The court evaluates whether a case is "exceptional" based on the overall circumstances, particularly the strength of the litigating position, as established in Octane Fitness. AstraZeneca contended that Aurobindo's case was flawed by hindsight bias and contradictions with prior art, yet the court noted that these elements alone do not qualify the case as exceptional. The determining factor in this matter was the credibility of expert witnesses rather than the substantive strength of Aurobindo's litigation. Although the definition of an exceptional case has broadened, the absence of misconduct or other negative factors also weighs against awarding fees. Ultimately, the court concluded that the case did not meet the criteria for exceptional status and denied AstraZeneca's request for attorney’s fees.
The court has determined that the asserted claims of the patent-in-suit are not invalid due to obviousness, leading to a judgment in favor of the plaintiffs against the defendants. AstraZeneca's claims involve the RET 86 patent, specifically claims 25 and 26. Two other patents, U.S. Patent No. 7,951,400 and U.S. Patent No. 8,628,799, were previously part of the case but were dismissed following stipulations. The court based its findings primarily on a set of uncontested facts submitted by the parties and made minor edits for clarity without altering the original meanings. Key findings regarding disputed matters are addressed in the Discussion and Conclusions of Law section. The court recognized the definition of a person of ordinary skill in the art (POSA) based on testimony from Dr. Powers and Dr. Weber, with Dr. Weber’s definition being favored due to his relevant experience in the field. AstraZeneca challenged Dr. Powers' qualifications, but the court acknowledged him as a POSA. Aurobindo failed to establish a prima facie case of obviousness, rendering AstraZeneca's secondary considerations unnecessary to address.
