The Patent Dispute Over Gene Editing Technologies: The Broad Institute, Inc. vs. The Regents of the University of California

CRISPR-Cas9 editing of the genomeThe patent dispute already called “the biggest in biotech history” is only getting started. On January 11, 2016, Administrative Law Judge (ALJ) Deborah Katz officially declared an interference over patents for the CRISPR-Cas gene editing technologies. An interference is a U.S. Patent and Trademark Office (USPTO) administrative proceeding conducted to determine which of multiple claimants to a particular invention has priority rights. Since the patents in question were filed before the March 2013 effective date of the America Invents Act, priority will be awarded to the claimant who was the first to invent the technology in question. This dispute pits Feng Zhang, the Broad Institute, and MIT against Jennifer Doudna and the University of California-Berkeley as well as Emmanuelle Charpentier, Krzysztof Chylinski, and the University of Vienna. Law professor Jacob S. Sherkow has followed the case closely and has provided useful background information on Stanford’s Law and Biosciences Blog.

CRISPR-Cas systems (including CRISPR-cas9 and CRISPR-cpf1) offer a potentially powerful tool for gene editing, essentially offering cut-and-paste capability to correct errors throughout the human genome. CRISPR stands for “Clustered Regularly Interspaced Short Palindromic Repeats,” and Cas refers to “CRISPR-associated” nucleases (such as cas1 – cas10). Licenses for use of these gene editing technologies are predicted to bring the patent holders significant financial gains. According to the Washington Post, no one seems sure who will win this patent dispute and intellectual property (IP) licenses for the technologies are all over the map: for example, Caribou licenses its gene editing IP from UC Berkeley and the University of Vienna, while Editas licenses its gene editing IP from the Broad.

Zhang, Broad Institute, and MIT hold a dozen patents (the first issued on April 15, 2014 and the most recent issued on April 7, 2015). The declaration of interference filed this month suggests that ALJ Katz believes the patents may have been wrongly issued because Zhang et al. were not the true first inventors. The burden of proof will be on the patent holders to show there is no interference and that they are entitled to the patents as the first to invent. For procedural details of the patent interference and a reading of the tea leaves from the declaration of interference, see the continued analysis by Jacob S. Sherkow. According to Sherkow, Zhang’s application was processed before Doudna’s thanks to Zhang’s attorneys’ savvy strategic Petition to Make Special (a filing that allows for an accelerated process). Furthermore, Sherkow notes, Doudna’s attorneys had added amendments to their provisional patent application to cover use of the gene editing technologies in human cells with the specific intent to bring the application in direct conflict with the patents issued to Zhang.

Why are we talking about first to invent? With the passage of the America Invents Act in 2011, Congress swapped the Patent Act’s “first to invent” approach for a “first inventor to file” approach. This change took effect on March 16, 2013. Today, the USPTO issues patents on a streamlined “first inventor to file” basis; however, at the time Doudna’s provisional patent application was filed (on March 15, 2013—the day before the AIA took effect), the rule was still “first to invent.” The old rule thus applies to this case, and the panel of administrative law judges will have to determine who really invented CRISPR-Cas gene editing.

Patent interference procedures are virtually unknown to everyone except patent lawyers, and a useful introduction to patent interference is available here. It is important to keep in mind that not only will the three-judge panel determine priority of invention between the disputing parties, but the panel will also determine patentability. In other words, there is a possibility for the panel to determine that neither party is entitled to a patent because the subject matter is not patentable. As a reminder from our coverage of the battles over Myriad’s patents, the following requirements must be met for a valid patent to issue to anyone:

In addition to the initial § 101 determination that there is a potentially patentable invention, the subsequent sections set detailed requirements that must be met before a patent can properly issue. Still, section 101 has been doing the “heavy lifting” in determining the outcome of recent litigation. Recall that in Mayo v. Prometheus, 132 S. Ct. 1289, 1298 (2012), the Supreme Court explained that a methods claim must include an “inventive concept” (a process involving more steps than those “well-understood, routine, or conventional activity already engaged in by the scientific community” at the time the patent application was filed) that transforms a natural law into a patentable application of that natural law. The key is whether the steps are “meaningful limitations” that restrict a patent’s scope. Also recall that in AMP v. Myriad, 133 S. Ct. 2107 (2013), the Supreme Court held that isolated DNA was not patentable subject matter, but that cDNA was, and left untouched the Federal Circuit’s rulings that limited Myriad’s methods patents.

The CRISPR patent dispute involves both methods and composition of matter claims. Specifically, this dispute focuses on patent claims regarding CRISPR-Cas9, not all nucleases (like Cpf1). The patent claims by the two sides are not identical and Doudna’s claims have changed over time, as Patent Attorney Mark Summerfield has thoroughly reviewed on his blog (with hyperlinks to the relevant patent application documents). According to Summerfield, Doudna originally referenced the CRISPR-Cas9 as applied to prokaryotic cells, and Zhang referenced eukaryotic cells. Doudna’s application (No. 13/842,859) originally contained 155 claims when it was filed, but it was amended multiple times (on January 8, 2015 to replace the 155 original claims with 9 new ones and again on April 13, 2015 to replace the prior 9 claims with 82 new ones) so that it specifically includes CRISPR-Cas9 “in a desired cell type,” presumably without regard to whether that cell type is prokaryotic or eukaryotic. Zhang’s application (No. 14/054,414) contained 20 claims, including specifically the application of CRISPR-Cas9 “in mammalian or human cells.” In contrast to the interpretation by Sherkow and Summerfield, science blogger Paul Knoepfler offers an interview with an “anonymous expert” who holds a different reading of the claims and insists that Doudna’s original application did contemplate CRISPR-Cas9 as applied to eukaryotic and mammalian cells. Biotech patent Attorney Kevin Noonan has also shared a view of the patent claims now in dispute, as those claims are currently phrased and without regard to the amendment history for Doudna’s application.

The plot just keeps getting thicker, too. The specific facts and history of CRISPR-Cas systems will be extensively scrutinized to determine whether Doudna was really the first inventor and thus entitled to foundational patent protections for the gene editing technologies. But where will those facts about the history of CRISPR be gleaned? The patent filings will certainly be important, but other sources (such as lab notes as well as dates of presentations and publications) could be considered. In what could very well become an “instant classic” case study of research ethics, Cell published a perspective piece on the history of gene editing technologies. The author was Eric Lander…of the Broad Institute and MIT. The perspective piece on “The Heroes of CRISPR” omits any disclosure that the Broad Institute is involved in pending litigation on the subject matter of the article or cautioning readers that the facts as set forth could be skewed or perceived to be skewed by this significant financial interest. Criticisms were quickly launched against the publication, including accusations that the piece is inaccurate at best and a deliberate manipulation of the facts at worst. GenomeWeb reported the author did disclose the potential conflicts of interest, including the Broad’s patent interests in CRISPR technologies, during the submission process but that it is the journal’s policy to disclose only personal interests and not institutional ones. Robert Cook-Deegan (author of several pieces published on Genomics Law Report) has been quoted as saying, “Science can be a blood sport.”

Science named CRISPR 2015’s “breakthrough of the year,” and there are billions of dollars at stake in this patent dispute. Patent Attorney Mark Summerfield has called this “the last great US patent interference.” With reputations and money on the line, it is safe to assume that the story will only get juicier. The case is set to proceed before the panel of three administrative law judges on March 9, 2016.

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Filed under: Genomics & Society, Legal & Regulatory, Patent Litigation, Patents & IP, Pending Litigation