The Broad Institute of MIT and Harvard today withstood a closely watched challenge to its CRISPR-Cas9 patents as the U.S. Court of Appeals for the Federal Circuit (CAFC) sided with The Broad over the University of California (UC), the University of Vienna, and Emmanuelle Charpentier, Ph.D., of the Max Planck Institute for Infection Biology, in the bitter battle royal over who invented the gene-editing technology.
The CAFC upheld a unanimous finding last year by a three-judge panel of the Patent Trial and Appeal Board (PTAB) that there was “no interference in fact” between 12 patents related to CRISPR technology that list as inventor Feng Zhang, Ph.D., of The Broad, and a patent application by Jennifer Doudna, Ph.D., of UC Berkeley, and Dr. Charpentier.
The Doudna/Charpentier application stated claims covering the use of CRISPR in a bacterial system, while The Broad's patents focus on the use of CRISPR in eukaryotic systems, such as plants and higher animals. UC Berkeley, Dr. Doudna, and Dr. Charpentier challenged The Broad patents, contending that the application of CRISPR to eukaryotic systems represented an obvious rather than an inventive invention, and was thus nonpatentable. The Broad has defended its patents.
The court noted that an obviousness determination would require finding that a person of ordinary skill in the art would have been motivated to combine or modify the teachings in the prior art, and would have had a reasonable expectation of success in doing so. Using the standard of “substantial evidence,” the PTAB found a person of ordinary skill in the art would not have had a reasonable expectation of success in applying the CRISPR-Cas9 system in eukaryotic cells.
“The (PTAB) Board’s underlying factual findings are supported by substantial evidence and the Board did not err in concluding that The Broad’s claims would not have been obvious over UC’s claims,” a three-judge panel of the CAFC including Chief Circuit Judge Sharon Prost stated in its 19-page decision, written by Circuit Judge Kimberly A. Moore.
While the CAFC decision can be appealed for rehearing to the appeals court, or appealed to the U.S. Supreme Court, it is unknown whether the high court would accept the case: “Because I don't think this case presents any novel *legal* issues, I don't think either is going to happen,” Jacob Sherkow, an academic law professor at the New York Law School, stated on Twitter. Absent overturning by the Supreme Court, the CAFC decision ends the legal challenge to the Broad’s CRISPR patents in the U.S.
“The Federal Circuit made the correct decision in upholding the United States Patent Trial and Appeal Board’s ruling,” The Broad stated on its website. “The patents and applications of Broad Institute and UCB are about different subjects and do not interfere with each other. The PTAB decision was clearly supported by sufficient evidence and followed applicable legal standards.”
Added The Broad: “It is time for all institutions to move beyond litigation. We should work together to ensure wide, open access to this transformative technology.”
UC Berkeley responded to the CAFC decision with a statement saying that it is “evaluating further litigation options.”
“We also look forward to proving that Drs. Doudna and Charpentier first invented usage in plant and animal cells—a fact that is already widely recognized by the global scientific community—as the Doudna-Charpentier team’s several pending patent applications that cover use of CRISPR-Cas9 in plant and animal cells are now under examination by the patent office,” UC Berkeley stated.
In June, UC Berkeley, the University of Vienna, and Dr. Charpentier were granted a U.S. patent for intellectual property related to CRISPR-Cas9 genome-editing technology.
“We are gratified that our dominant applications for the groundbreaking invention of the use of CRISPR-Cas9 in all environments, including plant and animal cells, will continue to issue as patents, adding to the patents recently granted in the United States and other countries around the world for this work,” UC Berkeley added.
The “substantial” evidence, according to the CAFC, included statements by the UC Berkeley inventors acknowledging doubts and frustrations about engineering CRISPR-Cas9 systems to function in eukaryotic cells and noting the significance of The Broad’s success.
In a 2013 UC Berkeley press release, Dr. Doudna acknowledged, “The techniques for making these modifications in animals and humans have been a huge bottleneck in both research and the development of human therapeutics.”
Following publication of the initial UC Berkeley research, she stated in Catalyst, a publication of UC Berkeley’s College of Chemistry, that: “[o]ur 2012 paper was a big success, but there was a problem. We weren’t sure if CRISPR-Cas9 would work in eukaryotes.” The Broad also cited a 2014 article in which Dr. Doudna cited “many frustrations” in getting CRISPR-Cas9 to work in human cells, and that she thought success in doing so would be “a profound discovery.”
The substantial evidence cited by the CAFC also included testimony from Paul Simons, Ph.D., Reader in Experimental Genetics and Molecular Medicine at University College London, about differences between prokaryotic systems and eukaryotic systems that rendered the application of the CRISPR-Cas9 system in eukaryotic cells unpredictable.
Differences in cellular conditions can cause differences in folding of the Cas9 protein, Dr. Simons testified, adding that the functionality of CRISPR-Cas9 in eukaryotes was unpredictable based on factors that included intracellular temperature, the concentration of various ions, pH, and the presence of other molecules that may be present in one type of cell, but not the other. “He explained that folding is particularly important for the CRISPR-Cas9 system because of the conformational changes the Cas9 protein undergoes in performing its function,” the appellate court summarized.
Also, Dr. Simons testified, a skilled artisan would not have a reasonable expectation that CRISPR-Cas9 would work in eukaryotic cells, since a person of ordinary skill in the art would have been concerned the CRISPR-Cas9 system could result in an excessive number of double-stranded DNA breaks given factors such as the greater size of the human genome compared to typical bacterial genome and the frequency with which similar DNA sequences appear in the human genome.
“We conclude that substantial evidence supports the Board’s finding that there was not a reasonable expectation of success, and the Board did not err in its determination that there is no interference-in-fact.”
UC contended that substantial evidence supported its view that a person of ordinary skill would have had a reasonable expectation of success in implementing CRISPR-Cas9 in eukaryotes.
“There is certainly evidence in the record that could support this position,” CAFC acknowledged—such as numerous techniques found in prior art that were used for adapting prokaryotic systems for use in eukaryotic cells, and the surmounting of obstacles adopting other prokaryotic systems—techniques that UC Berkeley's expert witness Dana Carroll, Ph.D., of University of Utah School of Medicine, suggested could be used to implement CRISPR-Cas9 in eukaryotes.
“We are, however, an appellate body. We do not reweigh the evidence. It is not our role to ask whether substantial evidence supports fact-findings not made by the Board, but instead whether such evidence supports the findings that were in fact made,” the CAFC asserted. “Here, we conclude that it does.”