' The CRISPR War Drags On: How the Fight to Patent CRISPR-Cas9 Creates Uncertainty in the Biotechnology Sphere | MTLR

The CRISPR War Drags On: How the Fight to Patent CRISPR-Cas9 Creates Uncertainty in the Biotechnology Sphere

On September 10, 2018, the Federal Circuit Court of Appeals (“Federal Circuit”) affirmed the ruling of the United States Patent Trial and Appeals Board (“the Board”) in Regents of the University of California v. Broad Institute, finding that there was no interference-in-fact between competing patents that claimed methods of using CRISPR-Cas9 to modify cellular DNA. Rather than settling the patentability issue, however, exhaustive litigation has continued, as both parties seek to protect the results obtained from costly research. Such protracted litigation has created significant uncertainty among members of the scientific, legal, and biotechnology communities as to the exact demarcation of patent ownership and may ultimately reduce the amount of innovation in CRISPR-based technologies and stifle developing industries.

Clustered Regularly Interspaced Short Palindromic Repeats (“CRISPR”) are a family of DNA sequences found naturally in bacteria that, when paired with guiding RNA sequences and CRISPR-associated proteins (Cas), can selectively modify an organism’s genetic material (genome) more effectively and cheaply than comparable gene-editing systems. Since the discovery of CRISPR’s gene-editing capacity by researchers at the University of California, the University of Vienna, and Emmanuelle Charpentier, innovators have applied CRISPR technology in diverse industries, including the medical, industrial, and agricultural sectors. Several thousand CRISPR-related patent applications have already been filed worldwide, with the majority being filed in the United States, China, and Europe.

Researchers at the University of California were the first to (“UC”) demonstrate that isolated CRISPR-Cas9 components could effectively function in an in vitro environment. UC subsequently filed a patent application in May 2012 broadly claiming a method to using CRISPR-Cas9 without referencing specific cellular environments. In December 2012, a research team led by Feng Zhang at the Broad Institute filed a patent application directed to a method of using CRISPR-Cas9 in mammal cells. UC unsuccessfully sought to invalidate Dr. Zhang’s patents in an interference proceeding in front of the Board. UC appealed the Board’s ruling to the Federal Circuit, arguing that the Board employed an improperly rigid obviousness test and that it erred in dismissing evidence that other researchers simultaneously applied CRISPR-Cas9 to non-bacterial (eukaryotic) .

The Federal Circuit rejected UC’s arguments and affirmed the Board’s finding that substantial evidence indicated there was no reasonable expectation of success a person of ordinary skill in the relevant art (POSITA) could successfully apply CRISPR-Cas9 to eukaryotic genomes. The Federal Circuit approved of the wide range of evidence the Board used to make its determination, including expert testimony, evidence of past failures in the field, simultaneous invention, and statements by members of UC’s research team expressing doubt that CRISPR-Cas9 could be successfully implemented in eukaryotic systems. The Federal Circuit also rejected UC’s contention that evidence of simultaneous evidence alone sufficiently demonstrated an invention’s obviousness. While the fact that six independent research teams successfully applied CRISPR-Cas9 within months of its disclosure by UC was useful evidence in determining obviousness, the weight of such evidence must “be carefully considered in light of all the circumstances.

It is unclear what the Federal Circuit’s decision means for the non-obviousness standard of CRISPR-related patents. Some observers have praised the ruling as affirming the Board’s comprehensive analysis of available factual evidence while noting that some evidence existed that could support a finding of obviousness. While the Federal Circuit rejected UC’s argument that simultaneous invention alone could not demonstrate a showing of obviousness, it was careful to state that such evidence had not demonstrated “a reasonable expectation of success given the ‘specific context of the art at the time.” This may suggest that evidence of simultaneous invention may gain greater significance in future decisions as advances are made in CRISPR technology. The Federal Circuit further clarified that its ruling determined that the competing sets of patent claims comprised distinct subject matter and did not rule on the validity of either parties’ claims.

The Federal Circuit’s holding has also generated a heated discussion outside of the legal field. Many members of the scientific community have criticized the decision, with some indicating that they believe the Board’s factual determination does not reflect the practices found within the field of molecular biology. The uncertainty resulting from the Federal Circuit’s decision is also reflected in the confusion among third party innovators regarding who they should seek a license from in order to commercially exploit existing CRISPR patents. This confusion is further compounded by the fact that the “surrogate companies” the Broad Institute and UC have created to manage the licensing of their patents grant differing levels of exclusivity when licensing their patents.

Further complicating the determination of patent rights in the foundational CRISPR-Cas9 patent is a lack of uniformity among the various national (and multinational) patent offices. Even before the Federal Circuit’s ruling, China’s State Intellectual Property Office (now renamed National Intellectual Property Administration or CNIPA) granted UC a patent for its CRISPR technology, and the European Patent Office (EPO) granted UC a patent for use CRISPR-Cas9 in both prokaryotic and eukaryotic organisms. The EPO subsequently rescinded a patent grant it had issued to the Broad Institute in 2015, finding that the prior art from UC’s patent demonstrated a lack of novelty for the invention. On January 17, 2020, the EPO’s Board of Appeal dismissed the Broad Institute’s appeal against the rescission, and in February, the Board of Appeal rejected the Broad Institute’s opposition proceeding against UC’s patent. Rather than creating a clear standard within Europe, however, the EPO’s rulings have resulted in greater uncertainty, with both the Broad Institute and UC, as well as other patentholders, having overlapping patent rights that may result in further litigation. In addition, several of the Broad Institute’s EPO patents for CRISPR remain valid and the CNIPA has granted three patents to the Broad Institute for CRISPR technologies.

Perhaps the most worrying development has been the renewal of UC and the Broad Institute’s legal battle in the United States. In June 2019, the Board filed documents to commence interference proceedings between the Broad Institute and UC’s patents that will address the question of priority. These new interference proceedings, which will examine who first invented the use of CRISPR-Cas9 in eukaryotic organisms, have already begun with both parties accusing the other of engaging in questionable legal conduct. Although some observers are optimistic that the new interference proceedings may induce the parties to reach a settlement, it is equally possible that the proceedings may result in a protracted legal battle and another appeal to the Federal Circuit. The protracted legal battles surrounding the UC and the Broad Institute’s CRISPR patents have created significant uncertainty as to the final determination of ownership and patentability. What is certain, however, is the need for greater clarity in patent rights in order to make researchers feel secure in developing further technological innovations using CRISPR-.

* Ian Sterlin is an Associate Editor on the Michigan Technology Law Review.

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