Antibody-patent row could have far-reaching impact on biotech

3D computer generated graphic of proprotein convertase subtilisin kexin type 9 (PCSK9) shown as spiral and ribbon structures

The PCSK9 protein is the target of several antibodies that are used to treat high cholesterol.Credit:

An unusual patent case before the US Supreme Court could have wide-reaching impacts on drug prices and technology.

On 27 March, the court heard arguments in a dispute over rights to therapeutic antibodies that are used to treat high cholesterol in people at risk of cardiovascular disease. Although the court’s justices spent much of their time wrestling with the details of how these antibodies are isolated, their decision — expected by the end of June — could affect how specific patents of any ilk must be when they describe an invention, and how broad they can be.

“It could spill over into all types of biotechnology cases,” says Sean Tu, a legal scholar at West Virginia University in Morgantown. “Today we’re talking about antibodies, tomorrow we might be talking about CRISPR or CAR T-cell therapies.”

Cholesterol clearance

At the core of the current case are antibodies that bind to a protein called PCSK9, which decreases the clearance of ‘bad’ cholesterol from the blood. The antibodies block PCSK9 activity, resulting in lower levels of this cholesterol. The first such antibody, called Praluent (alirocumab), was approved by the US Food and Drug Administration in July 2015 and was developed by two pharmaceutical companies: Sanofi in Paris and Regeneron in Tarrytown, New York.

Since then, several other PCSK9 therapies have come to market, including a rival antibody called Repatha (evolocumab) made by Amgen in Thousand Oaks, California, that was approved in August 2015. Sales of Repatha reached US$1.3 billion last year; sales of Praluent were $467 million.

In the case before the US Supreme Court, Amgen is appealing a federal court ruling that struck down one of its key patents on Repatha. The patent claims not only a handful of specific antibodies, as defined by their amino-acid sequence, but also any other antibodies, regardless of their structure, that bind to the same region of the PCSK9 protein.

This, said the lower court, was insufficiently detailed. US law requires that a patent contains a written description of the invention that provides enough detail that someone “skilled in the art” could use the patent as a recipe to recreate the invention. But Amgen’s patent, the federal court argued, merely disclosed how to sift through antibodies found in mouse serum for those that bind to a region of the PCSK9 protein, rather than first specifying what the sequence of those antibodies would be. “They have not given the information that a person skilled in the art would need to make and use all of the antibodies,” said Colleen Sinzdak, assistant to the US solicitor-general, during oral arguments before the Supreme Court. “The amino acid sequence is the recipe.”

Discouraging development

A win by Amgen could hinder the development of new medicines by restricting competition and discouraging the development of multiple therapeutic antibodies that bind to the same target, says Gregory Winter, a molecular biologist at the University of Cambridge, UK. The availability of multiple antibodies helps keep the price of such drugs — already among the world’s most expensive medicines — in check, while also providing treatment options for people who develop an immune response against one particular therapeutic antibody.

In 2018, Winter shared the Nobel Prize in Chemistry for his work on therapeutic antibodies. When a colleague showed him the patent at issue in the Supreme Court case, he decided to submit a brief to the court explaining the science underlying such medicines.

In the brief, Winter and his co-authors compare antibodies to an attempt to make calorie-free ice cream. Amgen, they said, made vanilla and chocolate ice cream that it determined, after the fact, to contain no calories. “But rather than patent only those two flavors, Amgen claims to have invented all calorie-free frozen dessert, be it ice cream, sorbet, sherbet, or gelato,” they wrote.

Amgen’s attorneys, however, have argued that striking down its patent will harm, not help, future development of therapeutic antibodies. Broad patent protection is necessary to justify the company’s hefty investment in a specific medicine, said Jeffrey Lamken, an attorney who represented Amgen before the Supreme Court. “We’ve reached an endpoint where, frankly, the industry can’t take it any longer,” he said. “You can’t invest $2.6 billion if the breadth of your claims is such that it means you can’t get adequate protection.”

Patents ‘squeezed’

A decision against Amgen could discourage investors from taking a risk on other biotechnology companies as well, said Michael Penn, vice president of intellectual property at Instil Bio, a company that is developing cell therapies in Dallas, Texas, at a meeting hosted by the American University Washington College of Law after oral arguments. “When they see patents getting squeezed and patent breadth getting squeezed year for year, that investment goes elsewhere,” he said. “That’s the fear.”

The debate divides the industry into those who focus on discovering drug targets, and favour broad patent protection for their findings, and those that develop specific molecules to drug the targets, says Ulrich Storz, a patent attorney at the Michalski Hütterman and Partner law firm in Düsseldorf, Germany. Universities are more likely to patent drug targets than actual candidate drugs, and the Association of University Technology Managers in Washington DC has filed a brief in support of Amgen.

Even so, there is little evidence that the prevailing practice — which over the past few years has favoured relatively narrow patent claims on antibodies — needs to change to allow such broad patents, says Tu, especially given the potential effect on drug prices and treatment options for patients. “The system that we have right now is working pretty well,” he says. “Everybody’s getting paid.”

2023-03-28 17:16:23