U.S. jury upheld validity of two patents for Amgen Inc’s cholesterol-lowering drug Repatha® (evolocumab)

US healthcare giant Amgen has successfully defended two of its patents related to cholesterol-lowering drug Repatha® (evolocumab). Amgen announced on February 25, 2019 that a U.S. District Court jury in Delaware delivered a verdict in the company’s favor upholding the validity of two patents related to its anti-cholesterol drug, Repatha®. The patent challenge was brought by Sanofi and Regeneron, which had contended that Amgen’s patents on Repatha® were invalid “for lack of written description and enablement”. Sanofi and Regeneron make a competing anti-cholesterol drug called Praluent® that prevents PCSK9 binding to LDLR.

The Delaware jury verdict follows recent decisions in the European Patent Office and the Japanese Patent Office which also rejected challenges to the validity of the Amgen’s patents brought by Sanofi and Regeneron.

Praluent® and Repatha® belong to a category of drugs known as PCSK9 inhibitors, designed to help patients with ultra-high bad, or LDL, cholesterol who can’t get their condition under control with widely used statins such as atorvastatin. Praluent® is designed to reduce cholesterol levels without allowing them to go so low that they might be harmful.

Repatha® is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). Repatha® binds to PCSK9 and inhibits circulating PCSK9 from binding to the low-density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, Repatha® increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels. Repatha® is indicated to reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease. It is also indicated as an adjunct to diet, either alone or in combination with other lipid-lowering therapies for treatment of adults with primary hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C), and as an adjunct to diet and other LDL-lowering therapies in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C. The drug is approved in more than 60 countries, including the USA, Japan, Canada and all 28 countries that are members of the European Union.

Amgen filed suit against Sanofi and Regeneron Pharmaceuticals on October 17, 2014. Amgen asserted that Sanofi and Regeneron’s manufacture and sale of Praluent, a drug that treats patients with high levels of low density lipoprotein cholesterol, infringes claims of Amgen’s U.S. Patent Nos. 8,829,165 and 8,859,741. The parties stipulated to infringement of certain claims on February 22, 2016. During trial, the Court issued two Rule 50(a) rulings. The Court determined that as a matter of law, the patent claims were non-obvious and Amgen had failed to meet the burden of showing that Sanofi and Regeneron’s infringement was willful. The case was submitted to the jury on the remaining issues: written description and enablement of the patent claims. The trial resulted in a judgment for Amgen that the patents are not invalid. After trial, Sanofi and Regeneron moved for renewed judgment as a matter of law on patent validity and for a new trial. Amgen moved for a permanent injunction. The Court denied Sanofi and Regeneron’s post-trial motions and entered final judgment in favor of Amgen under Rule 54(b) on January 3, 2017. The Court granted Amgen’s motion for a permanent injunction on January 5, 2017. Sanofi and Regeneron appealed. The Federal Circuit determined that the Court had erred in precluding post-priority date evidence relevant to written description and enablement, and had improperly instructed the jury on written description. The Federal Circuit remanded for a new trial on written description and enablement. The parties then moved for summary judgment. Sanofi and Regeneron moved for summary judgment that the asserted patents are “invalid on written description and enablement grounds.” Amgen moved for partial summary judgment to “estop Defendants from arguing that Amgen’s selected claims lack written description and enablement”.

Sanofi and Regeneron asserted that no disputes of material fact exist and that the patent is invalid for lack of written description. Amgen argued that there are genuine disputes of material facts under both the common structural features test and representative species test. The Court agreed with Amgen that genuine issues of material fact preclude summary judgment on the written description defense.

The parties disputed whether the specification discloses a common structural feature of the claimed antibodies. Sanofi and Regeneron argued that the Federal Circuit’s opinion in Amgen stands for the proposition that an antibody cannot be described by its function- binding to an antigen. However, in Amgen, the Federal Circuit recognized that it is “hotly disputed [whether] knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies.” The parties’ experts continued to dispute whether the function of binding correlates to the structure of the antibody. Additionally, the defendants’ expert, Dr. Petsko, has testified that the pattern of hydrophobic and non-hydrophobic residues is a common structural feature of the claimed antibodies.

The Delaware jury found that genuine disputes of material facts exist under the representative species test. Amgen’s patents “describe at least 32 antibodies by sequence that fall within the claimed genus by binding to the fifteen amino acid sweet spot on PCSK9.” Sanofi and Regeneron argued that these patent claims do not meet the representative species test because 1) the patents disclose antibodies that bind to no more than eight PCSK9 residues, but claim antibodies binding up to fifteen residues, 2) the patents fail to disclose antibodies that bind to any of the combination of residues to which the competitor antibodies bind, and 3) the patents only disclose four antibodies that share sixty percent or more of its heavy or light chain CDR sequences with any of the competitor antibodies. However, Amgen’s experts, Dr. Petsko and Dr. Rees, testified that a person of ordinary skill in the art would understand the exemplary antibodies to be representative of the claimed genus due to common key sequence characteristics with post-priority antibodies. The Delaware jury found the disclosed antibodies to be sufficiently representative of the genus.

As regards enablement, Sanofi and Regeneron asserted that no dispute of material fact remains and that they have proven no enablement by clear and convincing evidence. Amgen argued that 1) the patent claims are enabled and 2) there are material disputes of fact as to whether the specification’s disclosed process is a “trial and error” process and whether Amgen practiced the full scope of the claims. Specifically, Sanofi and Regeneron argued that the post-priority evidence shows that Amgen were attempting to make more antibodies within the claimed genus and were unable to do so. Amgen asserted that this post-priority evidence shows their attempts to make novel antibodies with different properties from the claimed genus. The Delaware jury agreed with Amgen and concluded that the patent claims are enabled.

The latest court verdict said that Amgen’s patents on Repatha® are in line with the legal requirements of written description and enablement. On February 25, 2019, jurors in Wilmington, Delaware, rejected the argument of Sanofi and Regeneron that the Amgen’s patents didn’t adequately describe the invention or explain how to make the full scope of antibodies the patents cover, though they agreed that some aspects of one of the patents were invalid.

Commenting on the verdict, Sanofi and Regeneron said they strongly disagree with some aspects of the jury’s decision and intend to file post-trial motions to overturn the verdict and request a new trial.

In the Sanofi release, Karen Linehan, executive vice president and general counsel, said “We are disappointed in today’s verdict,” “It is our longstanding belief that all of Amgen’s asserted U.S. patent claims are invalid and we believe the law and the facts support our positions.”

Amgen’s chief executive officer, Robert A. Bradway, said “This decision protects intellectual property which is essential to innovators who are bringing forward new medicines for patients with serious diseases. Amgen scientists discovered and developed Repatha, which can play a key role in the fight against cardiovascular disease,”…”We are thankful that the jury weighed the evidence carefully and recognized the validity of Amgen’s patents.”.

Author: Mr. Antony David, Principal Associate – Pharmaceutical-Life Sciences Practice Group, at Khurana & Khurana, Advocates and IP Attorneys. In case of any queries please contact/write back to us at antony@khuranaandkhurana.com.

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