in a class — even the ones they don’t know about?
The U.S. Supreme Court will decide in early 2019 whether to consider a patent dispute over monoclonal antibodies. At issue is whether a company, namely the pharmaceutical giant Amgen, can patent every antibody that binds a given epitope — even if there might be thousands of such antibodies and not all are yet discovered.
Amgen filed the patents in question in 2008. They cover a class of antibodies that bind to the proprotein convertase subtilisin/kexin type 9, or PCSK9, and thereby lower cholesterol. Amgen markets one PCSK9 inhibitor as Repatha. The company is suing rival pharmaceutical giant Sanofi over its competing drug, Praluent, which targets the same part of PCSK9.
If Amgen goes before the high court and prevails, it will get to lay claim to a whole therapeutic approach. If it loses, patenting groups of antibodies will get much harder, especially for research teams that aren’t bankrolled by pharmaceutical companies and represented by high-dollar legal teams.
But it’s not clear yet that the high court will even take up the case, Amgen Inc. v. Sanofi et al. Some experts predict the precedent-loving court will send it back to the lower court. Others see it as a potentially important test case.
Fifteen years ago, PCSK9 was a barely known gene defined by homology to a family of proteases and by an interesting phenotype in a few humans with mutations. It developed with unusual speed into a drug target and a legal battleground that may set important precedent for the biotech industry.
The story starts with the discovery that some patients with familial hypercholesterolemia, or very high levels of low-density lipoprotein cholesterol, also known as LDL, carried mutations in a newly identified gene called PCSK9. A group of French scientists led by Catherine Boileau published that finding in the journal Nature Genetics in 2003.
Scientists all over the world took notice. Within a year and a half, three groups had shown in mice that overexpression of PCSK9 in the liver raised blood levels of cholesterol because of a reduction in LDL receptors in the liver.
Tom LagaceTom Lagace, an American who had just finished his Ph.D. at Dalhousie University in Canada, joined one of those research groups at the University of Texas Southwestern Medical Center in 2004. He had hoped to focus on transcription factors called SREBPs, but his mentors had a different project in mind for him.
Michael Brown (left) and Joseph GoldsteinUTSW’s department of molecular genetics had a storied history in cholesterol research. It was home to the lab of Nobel laureates Michael Brown and Joseph Goldstein, who had discovered the LDL receptor.
The receptor, expressed on the surface of liver cells, ferries low-density lipoproteins rich in cholesterol from the blood into liver cells through endocytosis. The LDL receptor then is recycled to the cell surface, while the lipoproteins are metabolized. Mutations in the receptor that disrupt this metabolic pathway are linked to high blood cholesterol. Brown and Goldstein’s description of this cycle had paved the way for the development of a class of drugs called statins, and they shared a Nobel Prize for the work in 1985.
Brown and Goldstein continued to research mechanisms of cholesterol homeostasis in a growing department at UTSW, which Goldstein chaired, staffed by many of their former trainees.
Jay Horton Lagace went to work for one of Brown and Goldstein’s former postdocs, Jay Horton, by then a UTSW professor. Horton had come across PCSK9 independently in a study published in 2003, finding that its RNA level responded to SREBP.
After that study and Boileau’s were published, the Horton lab began to investigate mice that overexpressed PCSK9, which had higher cholesterol.
Horton shared his study results with UTSW colleagues Helen Hobbs, a physician-scientist who had also trained in the Brown and Goldstein lab, and Jonathan Cohen. Hobbs and Cohen had just established the Dallas Heart Study, using population genetics to search out rare genetic variants with significant effects on cardiovascular disease.
Jonathan Cohen and Helen Hobbs After hearing about the effects of PCSK9 overexpression in mice, Hobbs said, she and Cohen decided to look for mutations in PCSK9 that would kill its function. They reasoned that such mutations should appear in people with more LDL receptor activity and lower blood cholesterol.
“We went to our (heart study) population and sequenced the coding regions of PCSK9 in the individuals with the lowest LDL levels and hit pay dirt right away when we found a nonsense mutation,” Hobbs told the Journal of Clinical Investigation in 2015.
The study subjects whose PCSK9 genes included a nonsense mutation had LDL levels much lower than those without the mutation. The team also discovered a missense mutation that changed a single amino acid in PCSK9. They tested the effects of these sequence variations in a different group and found that people with PCSK9 mutations had a reduced rate of heart disease.
Meanwhile, the Horton lab continued to investigate the molecular mechanisms that led to PCSK9’s effect.
“I was quite lucky that a former postdoc was just leaving” the lab, Lagace said, “so I came at the right time.” His predecessor left him a collection of plasmid constructs and a big question to work on: How did PCSK9 reduce cell-surface levels of the LDL receptor?
PCSK9 is a member of a family of proteases, enzymes that break down other proteins. It stood to reason, and some mechanistic work from other labs suggested, that its effect on cholesterol came through breaking down another protein — but which? What was PCSK9’s substrate?
Lagace set about finding out.
He did not have much luck.
Frustrated and increasingly worried that he had nothing positive to present at the lab’s weekly meeting, Lagace decided to try isolating the protein from mammalian cells instead of the bacterial or insect cells he had been using. Post-translational protein modifications are known to differ among species; perhaps, he thought, some crucial tweak to PCSK9 was missing in the protein purified from bacteria.
After setting up a system in the lab to express and purify the protein from human cells, he said, “I was really struck that the PCSK9 in the medium was much greater than the PCSK9 in the cells.” That led him to hypothesize that the protein is mostly secreted — and that the previously published work suggesting PCSK9 operated inside of cells was somehow incorrect.
To test the idea, Lagace asked a nurse who worked nearby to draw some of his blood. He checked it for PCSK9; the protein was definitely in his plasma. Then he asked a colleague who processed and fractionated patient samples to run his plasma through a size-exclusion column, which separates macromolecules in a solution according to their mass.
“All I was going to do was see how big PCSK9 was (in case it oligomerized), but he also gave me the lipoprotein profiles. I was really struck that a lot of the PCSK9 was in a perfect overlap with low-density lipoprotein in the blood,” Lagace said. A quick experiment using isolated proteins and lipoproteins confirmed that PCSK9 bound to low-density lipoprotein particles.
Thinking that PCSK9 might piggyback on LDL particles and attack LDL receptors once it was internalized, he set up an experiment controlled with PCSK9 alone in LDL receptor-positive and -negative cells. To his surprise, even without LDL, PCSK9 could make it into the cells — but only if the receptor was present.
His project took off. The next steps were clear, and the Horton lab, with the Hobbs and Cohen lab, was on the way to publishing a series of papers in the Journal of Biological Chemistry defining the mechanism by which PCSK9 affects LDL receptors.
In short, circulating PCSK9 binds to the LDL receptor’s extracellular domain. When the LDL receptor is internalized by endocytosis, PCSK9 directs it to the lysosome for degradation. If circulating PCSK9 is blocked, the number of LDL receptors on the surface of liver cells goes up — providing a way to remove more LDL cholesterol from the blood.
The potential value of a PCSK9 inhibitor was clear both to Horton and to scientists at pharmaceutical companies. When the 2003 Nature Genetics paper came out, Simon Jackson was working at a biotechnology startup called Tularik. He read the paper, chatted with his supervisor about it and put it away. It wasn’t the right time, he said in court in 2016.
In 2004, Amgen bought Tularik. Jackson stayed on as a scientist. PCSK9 came back to his attention in 2005, when Goldstein visited Amgen and gave a lecture on findings from the Horton lab.
Horton’s group had found not only that mice without PCSK9 had lower cholesterol but also that giving them blood from a mouse that did carry the gene raised cholesterol again, suggesting that PCSK9 operates in the bloodstream and not within liver cells. Hobbs and Cohen’s discovery that humans with nonfunctional PCSK9 have lower cholesterol was not yet published, but Jackson saw evidence in Goldstein’s talk that that reducing PCSK9 in the blood could be beneficial to patients.
“So I presented to the senior team at Amgen,” Jackson testified in 2016. He earned their approval to begin research on ways to block PCSK9 activity, focusing on its hypothetical protease activity.
At around the same time Lagace was making his discoveries, Jackson and his team at Amgen were arriving at the same conclusion: PCSK9 bound directly to the LDL receptor, reducing its presence on the surface of liver cells.
Was the discovery completely independent?
In any case, once it was clear that PCSK9 functioned by binding to the LDL receptor, and not as an enzyme, the next step was to come up with a protein product that could block that binding. By doing that, researchers could block LDL receptor internalization and degradation, leaving the protein able to suction more LDL out of the bloodstream. That would lower patients’ risk of heart attack.
To find proteins that block PCSK9 from binding to the LDL receptor, Jackson called on Amgen’s antibody team, led by Chadwick King.
With a clever assay design, however, the team didn’t need to know the exact binding location. They just needed to find out which of about 3,000 antibodies they had raised against PCSK9 in mice could block the protein from also binding the LDL receptor.
“What we were asking was, if we had PCSK9 in solution and we allowed that (experimental) antibody to bind, could that complex then bind to the LDLR on the plate?” King explained at trial.
The team found 85 antibodies that block PCSK9–LDL receptor binding. They continued to characterize that subset, looking for antibodies that would make promising drug targets.
Papers on protein crystal structures and patent applications indicate that teams at Novartis, Pfizer and Regeneron also were hard at work trying to block PCSK9. Adding urgency to their studies, everyone knew that statins, the blockbuster cholesterol-lowering drugs that included Lipitor, soon would come to the end of their patent protection and become much less profitable.
Amgen won the race to the patent office. It took Jackson’s team about a year and a half, from June 2006 to January 2008, to collect all the data they used in a patent filing. Beginning late in 2007, Amgen filed 30 patents for antibodies to PCSK9 with the U.S. Patent and Trademark Office, and a total of 81 worldwide.
Ari Zytcer According to Ari Zytcer, an intellectual property lawyer and trained pharmacist based in Ohio who prepares patent applications, that flurry of patents is a typical strategy.
The most important of Amgen’s patents, filed in January 2008, described the screen that King and colleagues had performed to winnow the 3,000 antibodies to a few leading drug candidates. The patent laid claim to a class of antibodies that block PCSK9’s interaction with the LDL receptor. The patent filing also included crystal structures of two of those candidates in complex with PCSK9 and amino acid sequences of about two dozen more.
The two runners-up, Regeneron and Pfizer, filed applications before the end of 2009 to patent antibodies to PCSK9 to treat high cholesterol. Regeneron, the smallest of the three companies, licensed its product to pharmaceutical giant Sanofi for clinical development and commercialization.
In the race to launch a PCSK9 inhibitor, three of the year’s top 15 drug companies were now in the running.
By the fall of 2014, both Amgen and Sanofi had demonstrated that their PCSK9 inhibitor antibodies were safe and effective treatments for patients with elevated LDL cholesterol, and both companies had submitted data from large efficacy trials to the Food and Drug Administration. They expected final FDA decisions around the same time on whether they could sell the molecules as drugs. Pfizer was a few years behind them, and later scuttled its drug candidate.
That October, the patent office finally approved Amgen’s 2008 application on its PCSK9 inhibitor antibody screen. Just days later, Amgen sued Sanofi for patent infringement.
The patents Amgen held, the company’s lawyers said, described a whole class of antibodies — any antibody that would bind to the LDL receptor-binding region of PCSK9, often referred to in court as the protein’s “sweet spot.” Sanofi was preparing to market an antibody that bound exactly there, meaning it fell into the protected class. Amgen’s lawyers insisted that Sanofi stop.
Sanofi hired the best possible lawyer for its particular case. Dianne Elderkin, a patent litigator in Philadelphia, had represented Janssen Biotech in an important antibody patent case settled earlier that year. Abbvie, which owned the patent on a class of antibodies against a cytokine, had sued Janssen for developing an antibody that binds to the same target. Elderkin led the legal team defending Janssen from charges of patent infringement. Her team’s case convinced the jury to find Abbvie’s patent invalid.
Sanofi faced a problem similar to Janssen’s: It was being sued for infringing on a patent that claimed a class of antibodies. Working as lead counsel with a team of lawyers and paralegals from three law firms, Elderkin became the face of Sanofi’s argument that Amgen’s patent was invalid.
Squaring off against Elderkin, Amgen’s lead counselors were Sarah Columbia, a Boston litigator whose prior experience tended more to devices than large molecules, and William Gaede, a colleague at Columbia’s firm who was experienced in biotech. The two headed up a team of lawyers and paralegals from two law firms.
Lawyers on both sides began to review each company’s laboratory records, recruit professors to serve as expert witnesses, build their arguments and dispute which evidence was admissible in court.
As the case lumbered toward a trial, the FDA approved both drugs for the treatment of high LDL cholesterol in 2015. The two drugs launched commercially, Sanofi’s as Praluent and Amgen’s as Repatha, about a month apart that summer. Less than six months later, the patent-infringement suit went to trial in Delaware as Amgen Inc. v. Sanofi et al.
The legal issues were dense, but Amgen’s core argument was simple. According to trial records, its lawyers argued that Sanofi and Regeneron had infringed on two of Amgen’s patents, which protect any antibody that targets a specific LDL receptor-binding region of PCSK9. (Amgen’s media relations office did not respond to a request for comment).
Everyone agreed that if the patent was valid as written, Sanofi had infringed upon it, so the issue before the jury was whether the patent was valid. In other words, did Amgen own every monoclonal antibody that binds the LDL receptor-binding region in PCSK9? To answer that question, the jury first needed to decide whether Amgen had described adequately a class of antibodies and how to make them.
The law states what can’t be patented: You can’t patent something that’s obvious, something that occurs naturally or — in most cases — an idea that hasn’t been made real.
A patent needs to include a description of the product and a reasonable amount of information about how to make it, called enablement. These rules are a little relaxed for antibodies.
Also important in this case is that an inventor can patent a class of products — provided the patent application discloses enough examples in the class’ written description that a colleague could see how they’re related and imagine the rest of the class.
Being able to patent a class is useful in biotechnology. Otherwise, a competitor could tweak just enough of an antibody’s sequence to fall outside of a patent’s claims, profiting off an inventor’s work. But it also raises a problem, because imagining all of the possible antibodies that could bind to a given epitope — all of the members of a class — is all but impossible.
variation that leads to structural variation in the variable region, here indicated in purple.Wikimedia/Digital Shutter MonkeyIn an influential antibody case decided in 2011, the U.S. Court of Appeals for the Federal Circuit described an epitope not as a lock with a single key, but a lock and “a ring with a million keys on it.” And legal precedent, including the case Elderkin had won for Janssen, held that to own a class of antibodies, the inventor needs to describe a broad cross-section of the class, representing the diversity of those keys.
Sanofi’s lawyers contended that Amgen had not provided enough information about how its family of antibodies was made or description of the antibodies themselves to qualify as a thorough description of the class. The team argued that the antibodies disclosed in the patent bound only to the edges of the PCSK9–LDL receptor binding site and, more importantly, that there was no way to envision what other antibodies would fit into the class.
Besides written description and enablement, one more important legal concept was in play. At the time Amgen had filed its patent, the part of PCSK9 that bound to the LDL receptor was not widely known. That meant Amgen’s claims were also subject to a patent office assessment called the newly characterized antigen test, which protects inventors who find antibodies binding to a new and important antigen, even if the rest of the invention is routine.
Amgen convinced the jury that its patent claims were valid. The U.S. District Court for the District of Delaware ruled that Amgen’s patent was indeed valid, and Robinson issued an injunction that would stop Sanofi from selling its PCSK9 inhibitor, Praluent. The website Law.com named Columbia and Gaede litigators of the week for the victory.
Just as Robinson had predicted, Sanofi immediately appealed. The U.S. Court of Appeals for the Federal Circuit took up the case and suspended the injunction before it went into effect. During the appeal, Sanofi parted ways with Elderkin’s firm. Amgen added a few lawyers but kept its trial team otherwise intact.
In October 2017, the appeals court overturned parts of the lower court’s ruling. It concluded that the lower court had been wrong to exclude some information that Sanofi had hoped to use to convince the jury that Amgen’s written description and enablement were insufficient. That information, from Regeneron’s patent application, was intended to illustrate the gap between what Amgen disclosed and the antibodies that subsequently were discovered to bind to PCSK9. It is key to a thorny question: What if a team of inventors discloses everything they have discovered, but they haven’t yet discovered everything?
In light of that ongoing dispute, the appeals court ruled that describing an antigen could not suffice as written description of the antibody that binds it.
That ruling will guide the judge who hears the case if it returns to the lower court in Delaware. Judge Robinson has since retired; at the retrial, scheduled for February, the new judge cannot tell the jury that written description of an antigen suffices to describe the antibody it binds. The jury will consider the same question: Does Amgen’s disclosure of 384 PCSK9 inhibitors that block the protein’s interaction with the LDL receptor describe a class of antibodies well enough to claim it?
But whether the retrial will go forward as scheduled is uncertain. In July, Amgen appealed to the U.S. Supreme Court to review the federal appeals court’s decision.
“In Amgen’s petition to the Supreme Court, they’re essentially raising a new issue,” Royzman said.
Other pharmaceutical companies, notably Bristol–Myers Squibb, weighed in with an amici curiae (“friends of the court”) brief, arguing the Supreme Court should hear the case. The companies argued that the appeals court’s ruling impedes innovation, because once an inventor has one antibody to an epitope, it’s trivially easy to make what they called follow-on antibodies. Moreover, the brief said, compiling a “representative number of examples” could be quite subjective — just how many examples is that? — and might involve a lot of rote work.
On Nov. 19, Sanofi filed a response to Amgen’s Supreme Court petition, calling the case “an exceptionally poor candidate” on the grounds that Amgen had never questioned the interpretation of patent law in the lower courts. Moreover, Sanofi argued, even if the Supreme Court did review how the appeals court is applying the law, it would not settle the central question of whether Amgen’s patent is valid. Now it’s up to the Supreme Court to decide whether to intervene in the case.
He sees uncertainty in how patent law is interpreted among legal practitioners and patent examiners that could be settled by a Supreme Court decision. “I think from a litigator’s perspective, though, this is plain and simple.” There is plenty of precedent upholding separate enablement and written description requirements for patent applications, he said.
The case has major implications for a type of patent dispute that comes up again and again — and is poised to become even more common as antibody drugs proliferate. Not long after the Delaware court’s initial decision in Amgen v. Sanofi, Merck and Bristol–Myers Squibb settled a similar case over antibodies against the cancer antigen PD-1. Merck paid Squibb $625 million and will pay royalties on its drug Keytruda for the next eight years.
At least two other cases await litigation to determine whether competitors’ drugs infringe on patents covering classes of antibodies defined by antigens. Bristol–Myers Squibb, one of the friends of the court advocating for the Supreme Court to hear Amgen’s case, recently hired Elderkin and her team to sue AstraZeneca over PD-L1 inhibitors, which target PD-1’s ligand and are also used to treat cancer. In July, Genentech filed suit against Eli Lilly and Co. over Lilly’s interleukin-17 antibody just after Genentech’s patent for a class of humanized monoclonal antibodies to the interleukin was granted.
As antibody drugs proliferate, there is more and more opportunity for companies’ patent claims to overlap. The number of FDA-approved antibody drugs has surged in recent years, and many are in legal dispute. Challenges concerning approved drugs that target the EGF receptor, cytokine IL-12 and cancer-related receptor Her2 have shaped the patent landscape, and many infringement cases concerning drugs to other targets are ongoing.
In 2017, the U.S. Patent and Trademark Office granted 964 patents with titles that contained the words “antibody” or “antibodies.” Those titles sometimes described a broadly applicable method or specified a drug-antibody conjugate, but the majority simply described an antibody or group of antibodies and left the details for the claims.
Only about 2 percent of U.S. patents granted in 2017 were assigned to the world’s largest pharmaceutical companies by revenue — a group to which both Amgen and Sanofi belong. About a quarter were assigned to universities or academic–commercial partnerships, and more than half went to smaller biotech and pharmaceutical companies, and in some cases individual inventors, from around the world. Academic and small commercial inventors may lack the resources to protect their intellectual property with the vigor that Amgen and Sanofi have shown in litigation.
According Lukacher and Kurz, the retrial at the lower court in Delaware and consideration at the Supreme Court level will proceed in parallel unless the judge in Delaware chooses to stay the trial — which Kurz said would be likely if lawyers for Amgen or Sanofi asked for a pause.
The U.S. Patent and Trademark Office has taken what steps it can to prevent a repeat of this battle. In a memo issued after the appeals court made its decision, the patent office instructed patent examiners that “adequate written description of a newly characterized antigen alone should not be considered adequate written description of an antibody to that antigen,” officially putting the appeals court’s ruling into practice at the patent office.
However, lawyers say there is still confusion among patent examiners about what suffices as description.
Amgen’s petition to the Supreme Court argued that the appeals court’s ruling has “left innovators no way of predicting what disclosures will be sufficient” to secure patent protection for their inventions.
Craik once wrote an application for a class of antibodies that was denied on the grounds that it claimed more than he possessed when he submitted the application. (He had hoped to claim antibodies that could bind to any protease and prevent conformational shifting from an active to an inactive form, but he secured a patent for antibodies against the active form of just one protease.) He worries that narrowing the scope of the average patent to protect specific epitope-binding sequences will harm the commercial possibilities of monoclonal antibodies.
According to Zytcer, if the appeals court’s ruling holds, it may dampen universities’ enthusiasm for patenting antibodies, especially for technology transfer offices with limited resources.
From a lawyer’s point of view, a patent is essentially a trade. An inventor tells the government what they have invented and how it’s made; the federal government protects the inventor’s exclusive rights to the invention for a set amount of time, usually 20 years.
In most fields, that means a structural definition of the product, perhaps with some diagrams.
As anyone who has taken a biochemistry course knows, protein sequence determines structure, and protein structure determines function. So for protein inventions, applications that include the protein’s amino acid sequence or its function have been accepted as reasonable proxies to structure. This is especially true for monoclonal antibodies, which are invented specifically to bind to other proteins.
Until recently, the U.S. Patent and Trademark Office would consider granting a patent application that described in detail the function of an antibody — by describing the epitope it bound. This was known as the “newly characterized antigen test.” The Amgen v. Sanofi patent-infringement case, however, has forced the patent office to stop using that test.
Nobel laureate César Milstein invented an efficient method for generating monoclonal antibodies, which he never patented.UK Medical Research CouncilBefore scientists developed methods to produce monoclonal antibodies, researchers who needed antibody activity relied on antisera, heterogeneous mixtures of antibodies isolated from immunized animals. In 1975, Argentinian biologist César Milstein developed a method to make a single antibody species, or monoclonal antibody, by fusing a single antibody-producing cell from an immunized animal with an immortalized cancer cell. Milstein shared the 1984 Nobel Prize in Medicine for the finding.
Although the invention, called a hybridoma, spawned drug industry profits now estimated at $90 billion a year, Milstein never applied to patent it.
That decision was famous and controversial. Though Milstein did go into business with a local antiserum producer to sell monoclonals, the outfit couldn’t compete with larger biotechnology companies. He developed the method while working at the Laboratory of Molecular Biology in Cambridge, England. British Prime Minister Margaret Thatcher later criticized what she called Milstein’s failure to patent the invention. Milstein, who had disclosed the hybridoma technology to his funding agency before publishing it in the journal Nature, blamed the bureaucracy for not pursuing a patent.
When Amgen Inc. v. Sanofi et al. went to trial in the District Court of Delaware, expert witnesses — many of them members of the American Society for Biochemistry and Molecular Biology — gathered at the courthouse in Dover to explain the scientific dispute to the jury and give their opinions on whether Amgen held a valid patent. A selection of their statements, in which they tried to bridge the legal and biochemical worlds, is offered below.
Patent law can be confusing. In this primer, lawyers introduce the patent application process, international patent protections, and what can and cannot be patented.
A professor’s first step is to go to the university tech-transfer office. Who works there, and what does the job look like? Find out from tech transfer agent Rachel Cassidy.
Antibodies are just one of many types of therapy that take advantage of the immune system. Learn about some others in this feature on the field, which got its start in the late 1800s.
An increasing number of antibody inventions are bispecific, or engineered to bind two distinct epitopes. A recent article in the Journal of Biological Chemistry reports an advance in manufacturing of bispecific antibodies.