Table: Key Dates in the CRISPR-Cas9 Patent Dispute
YEAR
DATE
EVENT
2012
March 20
Šikšnys files patent (’739)
May 25
CVC files patent application (’772)
December 6
MilliporeSigma files patent
December 12
Broad files first patent (’527)
2013
March 15
CVC files patent application (’859)
2014
April 15
Broad awarded ’527 patent
July 7
Rockefeller files CRISPR patent
2015
April 13
CVC files “suggestion of interference”
2016
January 11
PTO declares an interference
December 6
PTAB interference oral argument
2017
February 15
PTAB interference decision favors Broad
March 23
EPO grants CVC patent
April 12
CVC appeals Interference in federal court
2018
January 18
EPO revokes Broad patent in Europe (’468)
April 30
Appeal oral argument
June 19
PTO awards CVC its first patent (’772)
Sept 10
Court upholds PTAB appeal decision
2019
February 8
PTO awards CVC ’859 patent
June 24
PTO declares interference
2020
January 16
EPO dismisses Broad appeal of ’468
February 7
EPO upholds CVC
May 18
PTAB hearing
* CVC, University of California/University of Vienna/Charpentier; EPO, European Patent Office; PTAB, Patent Trials and Appeals Board; PTO, U.S. Patent and Trademark Office.
Incredibly, the PTAB judges tried to unpack just what Carroll meant by “Stay tuned.” Was Carroll skeptical that CRISPR would work in human cells, or suggesting it was only a matter of time? The judges dissected another line from Carroll’s article where he said: “there is no guarantee that Cas9 will work effectively on a chromatin target.” The judges summed it up: “We fail to see how ‘no guarantee’ indicates an expectation of success”—especially for someone having ordinary skill in the art. They concluded sternly that Carroll “did not have a reasonable expectation that the system would work.” And if it had been a formality, then one would have to question why the editors of Science wanted to publish the Zhang and Church reports six months after they published the Doudna-Charpentier masterpiece.
Among the hundreds of documents and exhibits made public in the Broad-CVC saga, was a bizarre email that Doudna received in February 2015. It was sent by Lin Shuailiang, a Chinese student who had spent nine months at the Broad from October 2011 through June 2012 and was a coauthor on Zhang’s Science article. Lin raised allegations about the provenance of the CRISPR work in Zhang’s lab. Lin called the PTO decision “a joke” and claimed, “Feng is not only unfair to me but also the science history.” He continued:
I began the CRISPR project solely the first day I came to Feng Zhang’s lab in 2011 as a side project for a visiting student. At that time, the whole lab except me focused on TALEN projects. I was working on the CRISPR project until I went back to China [in] 2012 June for my PhD… After seeing your [Science] paper, Feng Zhang and Le Cong quickly jumped to the project without letting me know. My lab notebooks, emails and other files… recorded every step of the lab’s failure process… We did not work it out before seeing your paper, it’s really a pity. But I think we should be responsible for the truth. That’s science.13
The Broad dismissed Lin’s assertions, noting that his visa was about to expire and he was out of a job at the Broad. Lin ended up joining a San Francisco nanomedicine biotech company called Ligandal. On the company’s website, he was described as “the very first scientist in the world to work with CRISPR.”
On February 15, 2017, the PTAB ruled decisively in favor of Zhang and the Broad Institute, finding no “interference-in-fact”—the Broad’s patent did not overlap significantly with the CVC application.14 Zhang’s invention of CRISPR genome editing was “not obvious” because “one of ordinary skill in the art would not have reasonably expected a CRISPR-Cas9 system to be successful in a eukaryotic environment.” As the rival patent applications did not overlap, the Broad’s patents could stand. “Even though it seemed like both parties were there at the same time and they seemed to be working in relatively the same area, their patent applications, at the very least, did not interfere with one another,” Sherkow summarized.15 Editas’s stock surged 30 percent, pushing its market cap above $1 billion.
Three months later, I was in Vilnius, meeting Šikšnys for the first time. On his desk was a newly arrived FedEx envelope. Before I left, he agreed to open it. Inside was an official copy of his newly approved U.S. patent, filed back in March 2012: “RNA-directed DNA cleavage by the Cas9-crRNA complex.” DowDuPont (now Corteva) wasted no time in licensing the rights to Šikšnys’ IP.
CVC might have lost the Battle of Alexandria, but it was still determined to win the war. Doudna put her own spin on the verdict: “They have a patent on green tennis balls. We will have a patent on all tennis balls.”16 The players regrouped and dug in for another nail-biting set.
Two months later, CVC filed an appeal in federal court, confident it would establish definitively that the Doudna-Charpentier partnership “was the first to engineer CRISPR-Cas9 for use in all types of environments” including human cells.17 It was an uphill battle—the federal court’s task was not to retry the case but merely to assess whether the PTAB had committed a legal error. At the appeal hearing in April 2018, UC’s lawyer Donald Verrilli, a former U.S. solicitor general, argued that if Doudna and colleagues hadn’t demonstrated the feasibility of genome editing in higher organisms, the multiple publications in early 2013 would have used different techniques. “This was like the California Gold Rush,” Verrilli said. The competing researchers were all trying to demonstrate genome editing first. “If they thought making changes was necessary, they would have.”18
But the three judges didn’t bite. “You start with the common technology,” declared Judge Kimberly Moore. She highlighted statements by Doudna and others expressing frustration about getting CRISPR to work in human cells. For example, in a profile for a Berkeley College of Chemistry magazine, Doudna openly admitted: “Our 2012 paper was a big success, but there was a problem. We weren’t sure if CRISPR-Cas9 would work in eukaryotes.”19 In the end, the flood of reports in early 2013 showed that it was fairly easy to get genome editing to work in human cells based on the UC methods. But the key question according to Moore wasn’t “Did it turn out to be easy to do?” It was: “What was the perception of the skilled artisan at the time?”
On September 10, 2018, the Court ruled in favor of the PTAB’s earlier judgment. Sherkow said that while legally correct, he wasn’t sure the decision meshed with the way biomedical research is actually practiced. “The PTAB’s decision and Šikšnys’s patent sit as the Scylla and Charybdis for UC’s continued prosecution of its application,” Sherkow wrote.20 Some reporters thought it was game over: NPR declared “East Coast scientists” the victors.21
But not so fast: in another surprising twist in February 2019, the PTO assigned the CVC ’859 patent—in limbo for six years—to a new examiner, who promptly allowed it with minimal comment.22 By the end of 2019, CVC had been awarded some twenty CRISPR-related patents, gleefully punctuating each award with a press release. But questions lingered: was the key CVC patent overly broad (no pun intended)? And did it meet the enablement clause? Did it provide sufficiently detailed instructions to allow someone to edit a genome?