Biopharma Industry Sharply Divided Over Supreme Court Antibody Patent Brawl
Executive Summary
Big biologic makers line up on opposite sides of dispute between Amgen and Sanofi over whether Amgen’s Repatha patents cover analogous antibodies with the same functional characteristics.
The biopharmaceutical industry is in intense conflict over a case that could determine how broadly a patent can cover a cutting edge invention. More than a dozen companies have taken opposite sides in the dispute between Amgen, Inc. and Sanofi over their PCSK9-targeting antibodies.
The US Supreme Court is to hear oral argument in the case, Amgen v. Sanofi, on 27 March. The case focuses on the standard for the enablement requirement in the Patent Act, which requires a patent to disclose the claimed invention in the specification in sufficient detail so that a person skilled in the art would be enabled to make and use the invention. Amgen is challenging the US Court of Appeals for the Federal Circuit’s decision invalidating patents covering its cholesterol-lowering drug Repatha (evolocumab) for lack of enablement.
At issue is the scope of genus claims, which cover a group of related chemicals. Amgen alleges that Sanofi and Regeneron Pharmaceuticals, Inc.’s Praluent (alirocumab) infringes two patents that cover a genus of monoclonal antibodies that bind one or more of the amino acids on PCSK9, thereby blocking the protein PCSK9 from binding and destroying LDL receptors, which remove cholesterol from the bloodstream.
“This is a tremendously significant case and probably one of the most important ones of the past several years,” Adam Mosoff, a law professor at George Mason University's Antonin Scalia Law School, said in an interview. “If the court rules against Amgen it will severely hamper the ability of inventors to create and commercialize the miracle drugs and high technology products and services that have made life in the 21st Century a miracle.”
Mosoff said genus claims are written broadly to cover the functional value of the invention and cover many different examples (embodiments) of the particular invention. If patent protection is limited to a specific example detailed in the patent, he said it would effectively make the patent valueless. Those in support of Sanofi contend that genus claims are being used to stake ownership far beyond the scope of an invention.
Natasha Daughtrey, a partner at Goodwin Procter, said depending on how the court frames its decision, if the Federal Circuit decision is affirmed, it could impact what companies disclose for genus claims. "There could be a trend toward making narrower claims and putting more embodiments in the patent, or delaying the filing of an application until you have more embodiments to put in," she said.
Amgen’s patent specification discloses amino acid sequences for 26 antibodies, including Repatha. Amgen contends that this disclosure provides a roadmap for making antibodies with binding properties similar to the examples in its specification. But the Federal Circuit held that it would require “substantial time and effort” and “undue experimentation” to “practice the full scope of these claims.”
The question before the Supreme Court is whether enablement requires the specification to teach those skilled in the art to “make and use” the claimed invention or whether it must enable those skilled in the art “to reach the full scope of claimed embodiments without undue experimentation, i.e. to cumulatively identify and make all or nearly all embodiments of the invention without ‘substantial time and effort.’”
On Amgen’s side are AbbVie Inc., Biogen, Inc., Bristol Myers Squibb Company, GlaxoSmithKline Biologicals SA, and Merck & Co., Inc.. While AstraZeneca PLC, Bayer AG, Eli Lilly and Company, Genentech, Inc. , Gilead Sciences, Inc. and Johnson & Johnson and Pfizer Inc. support Sanofi.
Arguing For Amgen
GlaxoSmithKline contends in its amicus brief that the Federal Circuit’s “newly minted enablement standard has called the validity of genus claims into question and undermines the incentives to innovation that the patent system was designed to foster.”
“A patent does not need to literally teach every variation of an invention to satisfy the enablement requirement nor is a claim’s breadth dispositive – even if the variations included in the scope are numerous or infinite” – GlaxoSmithKline
“Without the ability to secure patent protection over a genus, competitors could make closely related species or modifications to a patented compound to avoid infringement while still appropriating the heart of the invention,” GSK said.
“A patent does not need to literally teach every variation of an invention to satisfy the enablement requirement nor is a claim’s breadth dispositive – even if the variations included in the scope are numerous or infinite,” the company stated.
Biogen, Bristol Myers Squibb Company and Merck Sharp & Dohme Corp. asserted that the scope of patent protection “should not be limited to the first antibody made by the innovator but should also cover analogous antibodies that share the unique functional characteristics of the first.”
They submitted a brief with the Association of University of Technology Mangers Inc., Corning Inc. and St. Jude Children’s Hospital in support of Amgen’s petition for certiorari. (Also see "Supreme Court May Consider Ruling Invalidating Amgen’s Repatha Patents" - Pink Sheet, 19 Apr, 2022.)
AbbVie said in its brief that nothing in Section 112 of the Patent Act suggests that enablement depends on the cumulative time and effort required to make virtually all variations of the invention.
An inventor who has taught a person having ordinary skill in the art how to make and use individual embodiments across the scope of the claim “should not lose patent protection simply because substantial time and effort would be required to make almost every one of them,” AbbVie stated.
Arguing For Sanofi
In a joint brief, Genentech, AstraZeneca, Bayer, Gilead and J&J said the Supreme Court should preserve the Federal Circuit’s flexible enablement standard, which requires a patentee to enable the full invention over which it claims exclusive rights.
“This court’s caselaw does not support the notion, offered by some of Amgen’s amici, that teaching how to make and use merely one embodiment (or ‘species’) should generally suffice to enable a claim that encompasses an entire category (or ‘genus’) of diverse embodiments identified not by common structure but by a particular function recited in the claims,” they asserted.
The Federal Circuit’s enablement standard “is not a death knell for functional genus claims,” they said, noting that the court upheld such claims against an enablement challenge in its 2021 decision in Bayer Healthcare LLC v. Baxalta. The patent at issue in that case claimed a functionally defined genus of Factor VIII proteins with PEGylation used in the treatment of hemophilia A.
"By defining its claimed antibodies purely by their functional effect, through a natural mechanism on a naturally-occurring protein, Amgen intentionally seeks to lay claim to all PCSK9 antibody therapeutics" – Eli Lilly
Pfizer noted in its brief that it was among a number of pharmaceutical companies that conducted independent, contemporaneous clinical research on anti-PCSK9 antibodies to treat hypercholesterolemia. Pfizer discontinued Phase III trials of its anti-PCSK9 antibody bococizumab in 2016.
Pfizer said Amgen’s patents claim a broad genus of monoclonal antibodies not by any structural terms or amino acid sequence, but solely by reference to their function of binding to a broadly defined target and the resulting effect of such binding.
“The claims encompass millions of antibodies having no identifiable common structural features,” Pfizer stated. “While genus patent claims are important for the life sciences industry, patent claims that define a genus of molecules solely by reference to functional characteristics threaten innovation and preempt future development and commercialization of novel therapeutics.”
Pfizer said Amgen’s patents are an attempt to monopolize a highly competitive therapeutic market. “Amgen did not discover PCSK9, its sequence, or its function, nor teach the world that it was a therapeutic target for monoclonal antibodies,” the company stated.
Eli Lilly, in a brief submitted with Ipsen Bioscience and Innovent Biologics, Inc., said the number of antibodies that could be preempted by Amgen’s claims are in the millions, if not billions or more. “Moreover, by defining its claimed antibodies purely by their functional effect, through a natural mechanism on a naturally-occurring protein, Amgen intentionally seeks to lay claim to all PCSK9 antibody therapeutics,” they stated.
Government’s Position
The Supreme Court decided to take up the case against the advice of the US Solicitor General. (Also see "Will Genus Claims Be Resuscitated? Supreme Court To Decide In Amgen PCSK9 Patent Dispute" - Pink Sheet, 7 Nov, 2022.)
In its amicus brief in support of Sanofi, the government said an inventor whose novel product achieves a widely shared goal may not obtain a patent for the entire genus of products that perform the same function, thereby foreclosing others form inventing potentially better products that achieve the same goal, unless the inventor provides the information necessary to enable others to make and use the full range of products within the genus.
The government cited the Supreme Court’s 1916 decision in Minerals Separation, Ltd. v. Hyde, in which the court rejected an enablement challenge to a patent that claimed the process for separating metal from mineral ores, even though a person using the process would need to conduct some preliminary tests to adapt the process to the particular ore.
Amgen contends that it has satisfied the enablement requirement because its “roadmap will produce claimed antibodies every time, and that the 26 examplars they have already produced are representative of the structural diversity within the genus,” the government stated. But the Federal Circuit “correctly determined that no reasonable juror could conclude that the roadmap would produce antibodies within the full scope of the claim without undue experimentation.”
Patent Bar Split
Patent lawyers also sharply disagree on the Federal Circuit’s interpretation of the enablement requirement.
Fourteen intellectual property law professors led by Mark Lemley, Stanford Law School, submitted a brief in support of Amgen asserting that the Federal Circuit has changed the law dramatically in recent years, to the point where it is not longer possible to have a valid genus claim in the chemical and biotechnology industries.
The court “now rejects claims as invalid because the genus contains thousands or millions of possible chemicals, unless the patent itself identifies exactly which of those myriad species will work. It is an impossible burden, and it is not one the law imposed until recently,” they stated. They cited an article Lemley co-authored, "The Death of the Genus Claim," published in Harvard Journal of Law & Technology in 2021.
Another group of 10 law professors and scholars, including Bernard Chao, Denver University Sturm College of Law and Arti Rai, Duke Law School, made a counter argument in a brief in support of Sanofi.
“There is no paradox, no death of anything or otherwise a need for alarm,” they asserted. “This case presents a classic example of a narrow invention that is coupled to overbroad claims.”
They said Amgen’s patent explicitly discloses and enables a limited set of 26 antibodies but the claims at issue extend well beyond those 26 antibodies and any antibodies derived from them. “To fill that huge gap, Amgen argues that its disclosed ‘roadmap’ teaches how to ‘make’ all the claimed antibodies.”
Four other law professors led by Joshua Sarnoff, DePaul University College of Law, also submitted a brief in support of Sanofi. The American Intellectual Property Law Association submitted a brief suggesting affirmance of the Federal Circuit’s decision that Amgen’s patents are invalid. It said the decision was based on established law for judging the enablement of genus claims that use functional language and did not rewrite or create a new test for determining the sufficiency of an enablement disclosure.
Scientists Side With Sanofi
Sir Gregory Paul Winter, who won the 2018 Nobel Prize in Chemistry and is known for his work on the therapeutic use of monoclonal antibodies, asserted that Amgen has claimed ownership of the natural binding site of PCSK9 itself by writing its patent claims so broadly in purely functional terms.
“No entity should be able to contribute only a few drops and claim ownership of the ocean” – Nobel Prize winner Sir Gregory Paul Winter
In a brief submitted with six other scientists in support of Sanofi, Winter said that these patents, if upheld, “would give Amgen the exclusive right to market antibody therapies blocking PCSK9, despite Amgen not having discovered any of the underlying biology or contributed anything beyond naming the existing residues of the natural binding site.”
They said purely functional claims like Amgen’s are enormously harmful to scientists who seek to understand, research, and develop new therapies for known targets, particularly where the technology at issue is complex and unpredictable.
“No entity should be able to contribute only a few drops and claim ownership of the ocean,” they declared.
Function Versus Structure Claims
In their brief, Sanofi and Regeneron said that Praluent and Repatha differ substantially in their amino-acid sequences and where they bind to PCSK9. Each company patented its respective antibody by amino-acid sequence, but years later “in a blatant attempt to corner the market, Amgen obtained additional patents that broadly claim the entire genus of PCSK9 antibodies by function, rather than structure,” they stated.
Amgen asserted in its 6 March reply brief that its claims cover only antibodies that block the interaction between PCSK9 and LDL receptors by binding PCSK9’s sweet spot. It said Merck and Novartis AG developed cholesterol-reducing antibodies that, binding elsewhere, function through a different mechanism. It noted that Novartis developed a non-antibody, siRNA-based therapeutic that inhibits PCSK9 production and lowers LDL cholesterol and Novo Nordisk A/S is developing small molecule PCSK9 inhibitors.
The Association for Accessible Medicines, Fresenius Kabi USA LLC, Viatris Inc. and a group of four small-and-medium sized biotechnology companies – ABL Bio Corp., Kiniksa Pharmaceuticals Corporation, Opko Health and SK Bioscience – filed briefs supporting Sanofi. Instil Bio, Inc., a clinical stage biotech company, filed a brief in support of Amgen and three other clinical stage biotech companies jointly filed a brief in support of neither party arguing against the Federal Circuit's reach-the-full scope standard of enablement. They include Regenxbio Inc., IGM Biosciences, Inc. and Adaptive Phage Therapeutics Inc.
AAM said the court should restrict overbroad, functional claims because such claims improperly impede generic and biosimilar manufacturers from designing noninfringing variations of drugs or drug-dosing regimens. It also criticized the practice of brandname manufacturers obtaining a secondary patent not only on the “backbone” peptide sequence of a biologic but also on secondary characteristics, such as glycan profile and functional activities. AAM said this practice violates the enablement requirement because the first patent fails to explain to the public how to use the invented peptide sequence.
Decade Of Twists And Turns
Amgen filed suit against Sanofi and Regeneron in October 2014 and the case went through two jury trials. In the first trial the jury found that Sanofi and Regeneron failed to show that Amgen’s patents were invalid for lack of written description and enablement. A Delaware district judge then issued a permanent injunction to block US sales of Praluent, which was stayed and never went into effect. (Also see "‘Between A Rock And A Hard Place,’ Court Issues Injunction To Halt Praluent Sales" - Pink Sheet, 5 Jan, 2017.)
On appeal, the Federal Circuit vacated the judgment and remanded the case for a new trial, finding that the district court’s erroneous evidentiary rulings and jury instructions necessitated a new trial. Amgen then petitioned the Supreme Court to review the Federal Circuit’s standard for determining the adequacy of an invention’s written description but the court declined to take up the case.
In the second trial, the jury again found that Sanofi failed to prove the asserted claims were invalid for lack of written description and enablement. The district court entered judgment as a matter of law overturning the jury’s enablement verdict while upholding its written description verdict. (Also see "After Two Jury Verdicts, Court Finds Repatha Patents Invalid" - Pink Sheet, 28 Aug, 2019.) The Federal Circuit upheld that ruling in a February 2021 opinion.
Amgen is represented by Jeffery Lamken, MoloLamken LLP, and counsel from Cravath, Swaine & Moore and McDermott Will & Emery. Sanofi is represented by Paul Clement, Clement & Murphy PLLC, and counsel from Kirkland & Ellis, Arnold & Porter Kaye Scholer, and Stroock & Stroock.
The Solicitor General will participate in oral argument as amicus curiae.