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In CRISPR Patent Battle, U of California Downed by Doudna's Own Words


NEW YORK (GenomeWeb) – On Wednesday, the University of California suffered a major setback in its bid to secure CRISPR patents in the US based on the work of UC-Berkeley Professor Jennifer Doudna.

The Broad Institute, with more than a dozen patents already issued in the US based on work led by Feng Zhang, also of the Massachusetts Institute of Technology, gained the high ground in the CRISPR patent battle when the US Patent and Trademark Office's Patent Trial and Appeal Board (PTAB) determined that CRISPR/Cas9 genome editing in eukaryotic cells was a separately patentable invention.

The no interference-in-fact decision surprised at least one legal expert who has argued patent interferences before the PTAB. But perhaps just as surprising was that the Broad's lawyers were able to use Doudna's own words against her.

Citing quotes attributed to Doudna in multiple interviews and publications in the years after her pivotal papers, co-authored with microbiologist Emmanuelle Charpentier, now at the Max Planck Institute for Infection Biology, the judges concluded that there was no reasonable expectation of success in attempts to move CRISPR/Cas9 into eukaryotic cells.

"Specifically, the evidence shows that the invention of such systems in eukaryotic cells would not have been obvious over the invention of CRISPR/Cas9 systems in any environment, including in prokaryotic cells or in vitro, because one of ordinary skill in the art would not have reasonably expected a CRISPR-Cas9 system to be successful in an eukaryotic environment," the judges wrote in their decision.

As a result, the Broad now controls the key IP estate for companies pursuing targeted genome editing applications in several areas, especially gene therapy, drug discovery and development, and ag-bio, which rely on editing in eukaryotic cells.

UC must re-evaluate its strategy for acquiring CRISPR IP, which almost seemed designed to force an interference. As New York Law School Professor Jacob Sherkow wrote in December 2015, UC rewrote the claims of its patent application several times to capture broad use of CRISPR/Cas9, and in April of that year petitioned for an interference, which the USPTO examiners also recommended to the PTAB.

In January 2016, the PTAB declared an interference and the UC- and Broad-led parties spent most of the last year arguing over the shape and scope of the court battle. When declared, the interference was explicitly set up to cover CRISPR in eukaryotic cells. UC felt that was too limited and argued for a broader scope of invention, outside of such cells.

But the Broad argued that there was nothing to argue over, that getting CRISPR/Cas9 to work in eukaryotic cells was something above and beyond what Doudna and her co-inventors had come up with.

It was unlikely to work, Brent Babcock, a lawyer at Knobbe Martens who has argued several PTAB interference proceedings, said in a phone call before the judges issued their decision. "A priori, no interference-in-fact is one of the harder motions to win," he said. Given that the PTAB had already decided there was an interference, it's generally difficult to effect an about-face.

Ironically, it was Doudna's own words that helped convince the judges to rule in the Broad's favor.

Because UC hadn't included the eukaryotic limitation, the judges said that the Broad only needed to "provide persuasive argument supported by a preponderance of the evidence that UC's claims would not render Broad's claims obvious if UC’s claims are considered to be prior art to Broad's claims."

At oral arguments, held Dec. 7, 2016 at the USPTO offices in Alexandria, Virginia, much was made over whether it was obvious — or not — that CRISPR/Cas9 would work in eukaryotic cells.

In the end, the judges put a lot of weight on comments made by Doudna and Martin Jinek, then her postdoc, around the time of their 2012 discovery that a chimeric guide RNA could make Cas9 target DNA in vitro.

The judges pointed to several statements made between 2012 and 2014 where Doudna was quoted expressing reservations that CRISPR/Cas9 would work in human or animal cells.

In January 2013, Jinek and Doudna co-authored a publication in eLife demonstrating CRISPR/Cas9's ability to work in human cells. However, they said that while their earlier work in vitro "suggested the exciting possibility" of genome editing in human cells, "it was not known whether such a bacterial system would function in eukaryotic cells."

In a 2014 profile of her on, Doudna was quoted saying she had "many frustrations" using CRISPR in human cells. And in a 2014 story in UC-Berkeley's Catalyst magazine, she was quoted as saying, "Our 2012 paper was a big success, but there was a problem. We weren't sure if CIRSPR/Cas9 would work in eukaryotes — plant and animal cells."

While Doudna and her colleagues had also expressed optimism that CRISPR/Cas9 could be a broadly applicable genome-editing tool as early as their 2012 paper, the judges said they agreed with the Broad's arguments that those statements "do not demonstrate a reasonable expectation of success."

"We pay particular attention to the statements made contemporaneously to [Doudna and Jinek's 2012 paper] because where such statements conflict with testimony prepared for litigation, contemporaneous statements have been considered to be stronger evidence of a particular situation," they said. "Accordingly, we give significant weight to the statements by those in the art at the time of [the paper] regarding expectation of success in using a CRISPR-Cas9 system in eukaryotic cells."

When asked to comment on the decision and how those quotations contributed to it, Doudna declined. "There will be an opportunity for my views to be known at some point in the future," she wrote in an email. "I expect that when all the facts are ultimately evaluated in the appropriate context, the University of California position will prevail."

It wasn't just Doudna's words that the Broad used to create an air of doubt. Broad's lawyers pointed out that Dana Carroll, a professor at the University of Utah and an expert witness for UC, wrote in 2012 in Molecular Therapy: "There is no guarantee that Cas9 will work effectively on a chromatin target or that the required DNA–RNA hybrid can be stabilized in that context." The judges referenced this line three times in their decision to discount UC's arguments about the expectation of success.

In the Catalyst profile, journalist Richard Sanders wrote, "CRISPR/Cas9 has tremendous potential, but Doudna is careful not to overpromise." He was referencing clinical applications, specifically, but it's possible Doudna's unwillingness to guarantee results there came from the same mindset that led her to recount her early doubts. Ultimately, it wasn't just her words that swayed the judges. Repeatedly, they rejected UC's arguments for why a researcher would expect success.

The UC-led party can still appeal the decision with the Federal Circuit Court, and the decision doesn't prevent it from receiving patents for use of CRISPR/Cas9 outside of eukaryotic cells. It's possible that the single-guide RNA could still be patentable and any patents could be included in a pool, which the licensing firm MPEG LA is pursuing for CRISPR.

Companies including Intellia Therapeutics and Crispr Therapeutics, which have licensed IP from the UC-led party, have suggested that a second interference could be triggered. However, the judgment brings this interference proceeding to a close after just over a year, far shorter than many had expected.