he US patent office ruled on Wednesday that hotly disputed patents on the revolutionary genome-editing technology CRISPR-Cas9 belong to the Broad Institute of Harvard and MIT, dealing a blow to the University of California in its efforts to overturn those patents.
In a one-sentence judgment by the Patent Trial and Appeal Board, the three judges decided that there is “no interference in fact.” In other words, key CRISPR patents awarded to the Broad beginning in 2014 are sufficiently different from patents applied for by UC that they can stand. The judges’ full 51-page decision explaining their reasoning stated that the Broad had persuaded them “that the parties claim patentably distinct subject matter.”
“The Broad landed a knock-out punch,” said Jacob Sherkow of New York Law School, an expert on patent law who has followed the CRISPR case.
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The ruling means that, in the eyes of the patent office, breakthrough work by UC biochemist Jennifer Doudna and her colleagues on CRISPR — an ancient bacterial immune system that they repurposed to easily and precisely edit DNA — was not so all-encompassing as to make later advances “obvious.” That is at odds with how much of the science world has viewed their work. Doudna and her chief collaborator, Emmanuelle Charpentier, won the $3 million Breakthrough Prize in the life sciences in 2015, the $500,000 Gruber Genetics Prize in 2015, and the $450,000 Japan Prize in 2017.
The patent board said in its decision that the achievement of the Broad’s Feng Zhang in inventing a way to use CRISPR to edit the genomes of mouse and human cells “would not have been obvious” from the invention by Doudna and Charpentier “because one of ordinary skill in the art would not have reasonably expected a CRISPR-Cas9 system to be successful” in those higher-order cells.
Although today’s molecular biologists, especially those doing genome editing, have a good idea of who made which seminal discoveries, the patent decision will likely shape how history views the CRISPR pioneers: now, Zhang will be the scientist who invented the form of CRISPR that has revolutionized humans’ ability to make wholesale changes in an organism’s blueprint of life, for purposes ranging from cancer therapy to turning pigs into organ donors for humans on transplant waiting lists.
The ruling also has big consequences for a phalanx of biotech startups racing to commercialize CRISPR technology. Companies that backed the wrong horse will have to scramble to shore up their intellectual property portfolio. Berkeley-based Caribou Biosciences, Inc., holds the exclusive license on the CRISPR-Cas9 inventions made by Doudna and her colleagues, while Basel, Switzerland-based CRISPR Therapeutics licensed essentially the same inventions from the University of Vienna, where Charpentier once worked and which sided with UC in the patent case.
But champagne corks should pop at the dozen-plus companies that won non-exclusive licenses from the Broad for its CRISPR patents, ranging from GE Healthcare and Monsanto to German drug-developer Evotec and, arguably the biggest winner, Cambridge, Mass.-based Editas Medicine. Co-founded by the Broad’s Zhang (and also by Doudna, in more collegial days), Editas holds the exclusive license on what may be the most lucrative prize of all: applications of Zhang’s CRISPR-Cas9 inventions to diseases. Only if Editas passes on a certain disease-related application can another company license the Broad’s patents.
Shares of Editas jumped 29 percent by the close of trading.
In a statement, the University of California said it was pleased that its patent application, which it described as covering “the invention and use of CRISPR gene editing in all cells,” can move forward. “We continue to maintain that the evidence overwhelmingly supports our position that the Doudna/Charpentier team was the first group to invent this technology for use in all settings and all cell types,” it said, “and that the Broad Institute’s patents directed toward use of the CRISPR-Cas9 system in particular cell types are not patentably distinct from the Doudna/Charpentier invention.”
UC said it is considering its legal options, including the possibility of an appeal, but it contended that anyone who wants to develop CRISPR-based treatments for human diseases would have to license not only the Broad’s patents but also those that UC expects to be awarded. “Ours,” Doudna told reporters, “is for the use [of CRISPR] in all cells,” including human ones.
The Broad said in a statement that the decision “confirms that the patents and applications of Broad Institute and UC Berkeley are about different subjects and do not interfere with each other.”
The CRISPR case began in January 2016, when the patent office granted UC’s request to launch an “interference” proceeding. That means the patent office was willing to entertain the possibility that the CRISPR-Cas9 patent application that UC filed in May 2012, but which the patent office had not issued, claimed essentially the same invention as the patent awarded to the Broad in April 2014. The award to the Broad might therefore have “interfered” with UC’s application.
The case therefore turned in large part on whether UC’s claims about what Doudna and Charpentier invented were essentially the same as the Broad’s claims about what Zhang invented, as detailed in the Broad’s December 2012 patent application. Although the Broad filed months after UC, it paid a small fee for accelerated review and got its patents — eventually, 13 of them. UC has not challenged the other 30 or so CRISPR patents that the office has awarded, including those to Harvard for inventions by geneticist George Church, largely because they cover narrower innovations. Zhang’s patents are considered foundational, covering virtually all uses of CRISPR-Cas9 in mammalian cells.
UC’s application described how Doudna, Charpentier, and their team constructed CRISPR-based molecules able to cut DNA in a test tube, which they reported in 2012. The gist of UC’s legal argument was that constructing such molecules to edit DNA inside living eukaryotic cells (those whose DNA is inside a cell nucleus), as scientists led by the Broad’s Zhang and, separately, by Harvard’s Church did in two 2013 papers, was an obvious extension of Doudna’s work — even though her feat wasn’t performed in living cells. It could have been accomplished, UC argued, by “persons of ordinary skill in the art” of molecular genetics.
In other words, Doudna worked out the recipe, Zhang just applied and extended it. An obvious add-on would not be eligible for patents. If the three judges on the Patent Trial and Appeal Board agreed that extending CRISPR to eukaryotic cells was obvious, then key patents awarded to the Broad would have essentially been clawed back.
After 13 months, the judges did not agree with UC. In their decision, they concluded that using CRISPR-Cas9 to simultaneously edit the genomes of eukaryotic cells at multiple locations represented an invention that could not have been made by just any scientist of ordinary skill. What Zhang accomplished was therefore separately patentable: The patent office’s decision to award the Broad CRISPR patents did not interfere with UC’s pending patent applications.
Neither the commercial consequences nor the reputational ones will hit immediately. While UC said it was weighing an appeal, experts on intellectual property said they couldn’t imagine the university not appealing, given the stakes. If the use of CRISPR to treat genetic disorders, including cancer, lives up to the hopes that scientists and biotechnology companies have for it, this form of genome editing is expected to be a multibillion-dollar annual market. Agricultural uses, from tweaking mushroom genes so the fungi never turn brown to editing corn genes so its oil is as healthful as olive oil, are expected to be another billion-dollar market.
PTAB appeals are heard by the US Court of Appeals for the Federal Circuit, which sits in Washington. In recent years, more than half of PTAB’s decisions have been upheld.
“The Federal Circuit heard three appeals of interferences in 2016,” said Sherkow. “All three were at least affirmed in part. It’s completely unclear whether that’s meaningful — it’s an N of 3–but there you go.” Overall, on 155 appeals since PTAB was created in 2012, the Federal Circuit affirmed 120 on every issue, dismissed or reversed 21 on every issue, and issued partial decisions (that is, upholding parts of a PTAB decision and reversing others) in the other 14.
An appeal would, of course, keep the legal bills growing. The Broad’s legal costs, paid by Editas, topped $15 million last summer. UC’s, paid by Caribou, have passed $5 million. Neither party has said what they have spent since then.
The dispute turned ugly quickly. Last summer, UC found a former member of Zhang’s lab who, in asking Doudna for a job, claimed that he could document “the [Zhang] lab’s failure process,” and that Zhang succeeded in making CRISPR edit human and mouse genes only after he read Doudna’s 2012 paper. In March, UC argued that the Broad obtained its patents fraudulently, because it “withheld or misrepresented material information with the intent to deceive the USPTO” into believing that Zhang had accomplished more than he really did. The Broad disputed all of this, and PTAB denied UC’s motions to take testimony of these points.
Close watchers of the CRISPR patent fight have expected the Broad to prevail since early December, when, during the only oral arguments in the case, the three-judge PTAB panel directed many more skeptical questions at UC’s attorney than they did at the Broad’s. At the time, Sherkow said the grilling “was bad for UC.”
The patent battle has caused entire rivers of bad blood between the institutions. A year ago, Broad president Eric Lander wrote a history of CRISPR that critics perceived as giving too little credit to the UC group, leading Doudna to call his account “factually incorrect.” When STAT asked Rush Holt, CEO of the American Association for the Advancement of Science, whether the patent decision cemented the Broad’s preeminent reputation, he joked, “Eric would say it never needed cementing.”