The Federal Circuit Weighs in on CRISPR

Gene editing was once quite difficult.  Though it was not impossible to insert a new sequence of DNA into a bacterium and measure the effects, as recently as a decade ago, the process consumed unsustainably large amounts unlucky graduate students’ time and effort.  In 2012, a groundbreaking paper from the group led by Dr. Jennifer Doudna at the University of California demonstrated that the bacterial immune protein CRISPR Cas-9 could revolutionize gene editing. See Martin Jinek et al., A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity, 337 Science 816 (2012).  However, a dispute over in what context Dr. Doudna and her collaborators thought that CRISPR Cas-9 could revolutionize gene editing could determine the fate of the biotech sector’s greatest technological achievement since the sequencing of the human genome.

CRISPR Cas-9 is a protein that protects some types of bacteria from viruses.  Viruses, which are much smaller than bacteria, consist of little more than genetic material in an envelope of protein and cannot replicate themselves.  Instead, viruses eject their genetic material into an unlucky bacterium and hijack the bacterium’s cellular machinery to do the replication.  This means that, at least some of the time, viral genetic material is exposed to the environment of the bacterial cell.  When viral genetic material is exposed, the bacterium can sample it, and store short sequences of it between Clustered Regularly Interspaced Short Palindromic Repeats (“CRISPR”).  CRISPR Cas-9 recognizes if DNA that it encounters matches a sequence of stored viral DNA, and if it does, cuts the DNA in half.  Because the virus needs an intact DNA sequence to replicate itself, when CRISPR cuts a viral DNA sequence, it neutralizes the viral threat.

CRISPR is essential to bacterial health, but research since Doudna’s seminal paper has also enabled it to be used as a tool in the biological laboratory setting. Disrupting genes is incredibly useful in the lab, as comparing the behavior of cells with modified genes can reveal unexpected genetic function, as well as probe the efficacy of drug treatments, .  Since it was first was first recognized that CRISPR Cas-9 could cut DNA in a reliable and controllable way, numerous modifications have been made to protein itself to make it a better tool.  In some labs, CRISPR Cas-9 systems have been developed that can reliably insert genetic material into a sequence, allowing the creation of customized organisms on demand.

The most exciting, and potentially revolutionary use of CRISPR, however, is not as a laboratory tool.  While many scientists rejoice at the increase in speed in their experiments now that CRISPR Cas-9 is available for use in their bacterial experiments, CRISPR Cas-9 based gene therapy could cure many untreatable diseases if it lives up to its promise.

CRISPR-based gene therapies would dramatically increase the value of a CRISPR patent’s licensing potential.  At the time of her initial paper, Dr. Doudna, however, was skeptical that CRISPR Cas-9, a bacterial protein, would maintain its world-changing effects in human cells.  Dr. George Church and Dr. Feng Zhang of the Broad Institute at Harvard and MIT proved that it could.  The University of California and the Broad Institute teams both filed for a patent: the California team’s on using CRISPR Cas-9 to edit DNA, and the Broad team’s on doing so within a human cell.

The Patent Trial and Appeal board instituted an interference proceeding to determine whether Dr. Doudna’s patent application rendered the Broad Institute claim unpatentably obvious.  Broad Institute, Inc. v. Board of Regents of the University of Cal., No. 106,048 (DK) (PTAB Feb 15, 2017).  On Sept. 10, 2018, the Court of Appeals for the Federal Circuit ruled that, contrary to the University of California’s appeal, the PTAB had applied the correct standard when it determined that the Broad’s claim to CRISPR in mammal cells was not obvious in light of the University of California’s application. Regents of Univ. of California v. Broad Inst., Inc., No. 2017-1907, 2018 WL 4288968 (Fed. Cir. Sept. 10, 2018). The PTAB’s decision gave great, but not dispositive weight, to Dr. Doudna’s statements indicating that, although there was no reason to believe that CRISPR Cas-9 could not work in a human cell, the differences between the bacterial cells and those of higher organisms are so great that there is no guarantee of successful application of the technique in human cells.

The University of California’s lawyer, Don Verilli, noted that six labs concurrently demonstrated that CRISPR Cas-9 worked in human cells, and argued that this degree of concurrent invention was sufficient to demonstrate that any person having ordinary skill in the art of biochemistry would believe Dr. Doudna’s protein to work in human cells.  However, per Federal Circuit precedent, evidence of  simultaneous invention may only be used to demonstrate the level of skill of the person alleged to have ordinary skill in the art, and the degree to which those in the art understand that a problem and a possible solution exist.  See Monarch Knitting Mach. Corp. v. Sulzer Morat GmbH, 139 F.3d 877 (Fed. Cir. 1998).  The mere fact of simultaneous CRISPR experimentation is legally insufficient to demonstrate that success was obvious to a person having ordinary skill in the art.  Because the University of California’s success with CRISPR outside human cells did not render the Broad Institute’s success in human cells obvious, the Broad Institute’s patent application was not anticipated by the University of California’s application.

While the Federal Circuit’s ruling is a major victory for the Broad Institute, the litigation is far from over.  The court explicitly disclaimed having decided the validity of either set of patent claims. As it stands now, anyone wishing to use CRISPR Cas-9 in human cells must obtain a license from both the Broad Institute for use of their patent covering the use of the protein to edit genes in the cells of higher organisms, and from the University of California for use of their patent covering use of the protein to edit any kind of genetic material.

Jacob Sherkow, a professor at New York Law School, has observed, that the Federal Circuit’s reliance on Dr. Doudna’s own cautious words to render a ruling adverse to her parent application “has now echoed throughout laboratories across the USA as a cautionary tale against critical reflections of one’s work—at least while patents are pending.” Jacob S. Sherkow, Patent Protection for CRISPR: an ELSI Review, 4 J.L. Bioscience 565, 569 (2017). Only time will tell if the first (likely of many) of the Federal Circuit’s swings at the CRISPR patent’s curveball will cause major changes in the scientific discourse.  What is certain is that neither the University of California nor the Broad Institute will rest until they have exhausted their litigation options—including seeking review by a Supreme Court in flux.

The law of interferences too, is in flux.  The America Invents Act’s move to a first to file system will gradually winnow away the importance of interference proceedings, but fundamental questions about obviousness will remain.  In the meantime, litigation over patents by universities will continue to shape science—possibly in ways that merit review of the assumptions about “curiosity driven” research that underlie our current patent system.

Gabriel Ferrante is a J.D. candidate, 2020, at NYU School of Law.