University of California v. Broad Institute: Court Affirms Broad’s Patent on Complex Cell Gene-Editing Tool

Reports Patent

Regents of the Univ. of Cal. v. Broad Inst., No. 2017-1907 (Fed. Cir. Sep. 10. 2018), opinion hosted by Court of Appeals for the Federal Circuit.

In 2012, researchers from the University of California, University of Vienna, and Emmanuelle Charpentier (collectively, “UC”) published their use of CRISPR-Cas9 to precisely cut the DNA of prokaryotes (single-celled organisms without distinct nuclei). Shortly thereafter, researchers from the Broad Institute, Inc., Massachusetts Institute of Technology, and the President and Fellows of Harvard College (collectively, “Broad”) published their successful use of CRISPR-Cas9 in eukaryotic cells—cells with a distinct nucleus containing their genetic material, which comprise multicellular organisms. The Patent Trial and Appeal Board (“Board”) found that Broad’s invention was patentably distinct from UC’s. UC appealed, and the Federal Court of Appeals affirmed.

CRISPR-Cas9 has its roots in bacterial immune systems. CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) refers to repeating sequences of bacterial DNA. When a virus infects a bacterium, the bacterium stores portions of that virus’ DNA in these spaces. If the virus infects the bacterium again, the corresponding RNA sequence combines with Cas9, a DNA-cutting protein. Using the RNA as a guide, Cas9 slices the virus’ DNA, rendering it ineffective. Already in 2012, UC acknowledged CRISPR-Cas9’s potential for use in gene-editing.

Prior to the America Invents Act, which applies to patents with a priority date after March 2013, patents were awarded on a first inventor basis, rather than a first-to-file. This allowed claims that patents “interfered” with each other, meaning that one “anticipated or rendered obvious the subject matter” of the other. Finding obviousness pursuant to this standard required that “a person of ordinary skill in the art would have been motivated to combine or modify the teachings of the prior art and would have had a reasonable expectation of success”. Accordingly, the court first reviewed the Board’s finding of no obviousness. It then assessed UC’s two grounds for appeal: that the Board improperly required specific instructions for obviousness, and that it erroneously ignored the evidence of simultaneous invention.

 The court found substantial evidence that a person ordinarily skilled in the art would not have expected to succeed in using CRISPR-Cas9 in eukaryotic cells. Broad’s expert, Dr. Paul Simons, had described significant differences from prokaryotic cells which could impact the Cas-9’s folding or degrade the RNA on which the system relies. The human genome is also larger and more repetitive than that of bacteria, which could reduce Cas9’s accuracy. Dr. Dara Carroll, UC’s expert witness, had reiterated these concerns. UC’s researchers themselves had expressed the difficulty of using CRISPR-Cas9 in animals. Furthermore, comparison to other gene-editing tools suggested that crossover from prokaryotic to eukaryotic cells was uncertain. The court acknowledged UC’s evidence, but concluded that the Board’s factual findings were adequately supported, and deferred to its judgment.

The court rejected UC’s contention that the Board erred in requiring specific instructions, finding that it had imposed no such restrictions. Instead, it had noted that generalized instructions, like those contained in UC’s application, in conjunction with evidence of a method’s non-transferability, pointed to non-obviousness. Its precedents for such a balancing test included In re Rinehart, 531 F.2d 1048 (C.C.P.A. 1976) and Amgen, Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1207-08 (Fed. Cir. 1991).

Finally, the court disagreed that the Board incorrectly dismissed evidence of simultaneous invention—here, six groups’ use of CRISPR-Cas9 in eukaryotic cells shortly after UC’s article. The court conceded that simultaneous invention may suggest obviousness. However, it remarked that if this alone were dispositive, “any claim involved in an interference would be unpatentable for obviousness”, mandating analysis of the whole context. Accordingly, the court held that the Board did not ignore this evidence, but rather considered it and deemed it uncompelling. For these reasons, it affirmed the Board’s reasonable finding of no interference.

This dispute’s duration and virulence signals the expected importance of CRISPR-Cas9—patent disputes usually settle out of court. Already, the tool is used not only locally in human genomes, but also in human embryos, creating heritable genetic changes. Yet the speed of advances in the gene-editing sphere could soon render the technology, and Broad’s patent, obsolete. As legal scholar Jacob Sherkow remarked, “[t]his is still an incredibly important case for the present, [b]ut it may not be an incredibly important case for the future.”