The genome editor CRISPR, whose invention is at the heart of a fierce patent battle, typically uses an RNA molecule (red) to guide a DNA-cutting enzyme such as Cas9 (orange) to a DNA sequence (blue) targeted for cutting.

By Jon CohenSep. 11, 2020 , 6:40 PM

The long-running patent battle over CRISPR, the genome editor that may bring a Nobel prize and many millions of dollars to whoever is credited with its invention, has taken a new twist that vastly complicates the claims made by a team led by the University of California.

The Patent Trial and Appeal Board (PTAB) ruled 10 September that a group led by the Broad Institute has priority in its already granted patents for uses of the original CRISPR system in eukaryotic cells, which covers potentially lucrative applications in lab-grown human cells or in people directly. But the ruling also gives the University of California group, which the court refers to as CVC because it includes the University of Vienna and scientist Emmanuelle Charpentier, a leg up on the invention of one critical component of the CRISPR tool kit.

This is a major decision by the PTAB, says Jacob Sherkow, a patent attorney at the University of Illinois at Urbana-Champaign who has followed the case closely but is not involved. Theres some language in the opinion from today thats going to cast a long shadow over the ability of the [CVC] patents going forward.

Jennifer Doudna, a biochemist at the University of California at Berkeley, and Charpentier, now with the Max Planck Institute, first published evidence that the bacteria-derived CRISPR system could cut targeted DNA in June 2012, seven months before the Broad team led by Feng Zhang published its own evidence it could be a genome editor. But the CVC team did not show in its initial paper that CRISPR worked inside eukaryotic cells as Zhangs team did in its report, even though the original CVC patent application broadly attempted to cover any use of the technology. The U.S. Patent and Trademark Office issued several CRISPR-related patents to Broad beginning in 2014, sparking a legal a battle in 2016 based on CVC claims of patent interference. That led to a first PTAB trial, which seemed to deliver a mixed verdict, ruling that the eukaryotic CRISPR and other uses of the genome editor were separate inventions, patentable by Broad and CVC respectively. Unsatisfied, CVC took the issue to a federal court, which denied its appeal.

CVC subsequently filed new claims that led PTAB to declare a second interference. The board this time did a more direct comparison of which group had the best evidence for the first demonstration that CRISPR worked in eukaryotic cells. The PTAB ruling did not accept CVC arguments that it crossed this line first, giving the priority edge to the Broad.

This doesnt settle the dispute, however, but instead requires that CVC provide more evidence at a future hearing that it was first. The interference [hearing] is going ahead all the way this time to determine who was the first to invent, says Catherine Coombs, a patent attorney at the U.K legal firm Murgitroyd who has not been involved in the case but handled other CRISPR litigation in Europe. Coombs notes that theres a large gap between the CRISPR patent environment in the United States and Europe, where CVC has won the upper hand in the European Union patent office.

Sherkow anticipates the PTAB will face a tough, complex decision. Its going to need to subpoena Doudna and subpoena Zhang and subpoena a bunch of graduate students and put a bunch of eight-year-old lab notebooks in evidence, says Sherkow.

CRISPR, which typically comprises a DNA-cutting enzyme known as Cas9 and a molecule that guides it to a specific DNA sequence, often is compared to molecular scissors. A key dispute in the patent battle focuses on the guide component. Zhangs first description of CRISPR working in eukaryotic cells used a guide that combined two RNA molecules while CVCs use relied on a single RNA to do the same thing. This single molecule guide RNA now is the standard tool in the field.

A statement from a University of California spokesperson says it is "pleased" with the new ruling, noting that it denied several of the Broads motions. The PTAB "has ruled in our favor in most instances and will continue with the interference proceeding to determine which party was the first to invent CRISPR in eukaryotes, the statement says. [W]e remain confident that the PTAB will ultimately recognize that the Doudna and Charpentier team was first to invent the CRISPR-Cas9 technology in eukaryotic cells.

A statement issued by the Broad calls for something akin to a peace treaty. Although we are prepared to engage in the process before the PTAB and are confident these patents have been properly issued to Broad, we continue to believe it is time for all institutions to move beyond litigation and instead work together to ensure wide, open access to this transformative technology, the statement says. The best thing, for the entire field, is for the parties to reach a resolution and for the field to focus on using CRISPR technology to solve todays real-world problems.

Many observers of the patent battle long have hoped that the Broad and CVC will reach a settlement, but Sherkow thinks its less likely now. Almost every outcome is stacked in Broads favor, he says. If the CVC wins, he says, they will have the patent for the single molecule guide, but the Broad will not lose its eukaryotic patent and, at worst, will have to share it. If CVC loses, theyre toast, they come away empty, says Sherkow. But Ive been wrong about settlement before so theres every expectation that Ill be wrong again.

The PTAB ruling does not specify a date for its next hearing.

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The latest round in the CRISPR patent battle has an apparent victor, but the fight continues - Science Magazine

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