This was not the first patent application to mention CRISPR: in April 2004, the Danisco group of Barrangou and Horvath described a method for sequencing CRISPR regions in a dairy sample to fingerprint variants of Lactobacillus acidophilus. “The origins of the CRISPR patent estate, far from being forged in combat, were gently cultured in distant tuns,” observes Sherkow.4 Another interesting application was one from Erik Sontheimer and Luciano Marraffini. In his office at the University of Massachusetts Medical School, Sontheimer rifles through his computer files searching for what he calls “the best grant I’d ever written,” which mirrored his patent application.
In January 2009, Sontheimer submitted a five-year, $1.8 million grant application to the NIH, entitled “RNA-Directed DNA Targeting in Eukaryotic Cells.” “CRISPR interference could provide unique capabilities, if it can be ported to eukaryotic cells,” Sontheimer wrote. “It could be easily programmed (and, when desired, reprogrammed) by the introduction of small RNA molecules.” The goal was to manipulate the structure and activity of genomes of higher organisms using RNA that recognizes its target DNA using the well understood rules of Watson-Crick base pairing. The method “would have transformative and disruptive potential in biotechnology and medicine.”5 There were parallels to RNA interference, the technology codiscovered by the Nobel laureate next door, Craig Mello. But “CRISPR interference” was exciting because of the sequence specificity conferred by the twenty-four- to forty-eight-base spacers. Sontheimer and Marraffini’s discovery of “a natural, highly specific, RNA-directed, DNA-targeting machinery in bacteria” suggested a route toward a “reprogrammable genome targeting system in eukaryotic cells.”
Sontheimer’s plan was to port CRISPR into eukaryotic cells and test its ability to target specific genes. He would start small, working in yeast, then progress to Drosophila, and eventually mammalian cells in the final two years of the funding by 2012–13. RNA-directed genome targeting “has the potential to transform biomedical research, biotechnology, genetic medicine, and stem cell therapeutics,” he wrote. In retrospect, it was too much too soon. The proposal “hit a brick wall” and was rejected, and his companion patent application was abandoned. “The vision and idea were out there, but we hadn’t reduced it to practice,” said Sontheimer wistfully.6
Six months after CVC filed their patent application (’772) just prior to publication of their Science paper, the Broad Institute followed the same playbook, as Zhang filed an application covering the use of CRISPR editing in eukaryotic cells in December 2012. But in a nifty legal maneuver, the Broad lawyers paid the princely sum of $70—a round of cocktails at the local Meadhall gastropub—for an expedited “fast track” review, thereby leaping ahead of UC’s application. In January 2014, the United States Patent and Trademark Office (PTO) provisionally denied the application, citing the “prior art” of the CVC application. Zhang quickly filed a forty-page “personal declaration” rebuttal. It paid off: three months later, in April, the PTO awarded patent number 8,697,359 to the Broad. The decision sent shockwaves across the biotech communities. Doudna resigned as an advisor to Editas, the all-star company she had cofounded with Zhang and others. CVC filed for an interference proceeding, seeking a PTO ruling to establish who truly invented the technology.
The Broad responded by filing a “priority statement” with the PTO in May 2016. Exhibit A was an internal Broad document—a “Confidential Memorandum of Invention”—that Zhang had signed in February 2011. In this document, Zhang declared he had the initial idea for CRISPR gene editing on February 4, 2011—shortly after hearing Gilmore’s lecture—and first documented those ideas four days later.7 Zhang wrote:
The key concept of this invention is based on the CRISPR [repeats] found in many microbial organisms. Enzymes associated with the CRISPR complex use short RNA sequences to recognize specific target sites on the host genome and performs site-specific cleavage. The key novel feature of this invention is that it does not rely on the design of site-specific DNA binding proteins (i.e., zinc finger or TAL effector) and can be easily targeted to multiple sites through the use of multiple sequence-specific CRISPR spacer elements.
The Broad mounted an effective campaign to sway public opinion. “CRISPR itself cannot be patented,” explained communications director Lee McGuire. “Cas9 is a naturally occurring protein and part of a naturally-occurring bacterial process, but this process, on its own, does not work in mammalian cells. What [Zhang] has patented are engineered components and compositions specifically altered from their naturally-occurring form to be useful in methods for editing the genomes of living mammalian cells.”8 There were shortcomings in both the CVC application as well the earlier Šikšnys application. These applications, the Broad argued, merely showed that “purified Cas9 protein and a certain purified RNA could cut a short piece of DNA in a solution in a test tube.” And then the Broad dropped the hammer. Both applications “contained no disclosure of work in cells, no genomes, and no editing.”9
No cells, no genomes, no editing. It was a brutal rebuttal to the CVC appeal. But would it work in court?
Showtime came on a rainy Tuesday morning in December 2016. Legal scholars including Sherkow and Robert Cook-Deegan, attorneys and journalists formed an orderly queue more than an hour before the doors opened at the PTO’s headquarters in Alexandria, Virginia. They were there to witness history in the making: such courtroom dramas would likely become a thing of the past under the “first to file” rule.10 The Patent Trial and Appeal Board (PTAB) was unprepared for the crush of spectators who rapidly filled the courtroom and two overflow rooms. “It was probably the most well-attended interference proceeding in USPTO history,” said Sherkow.
The purpose of the hearing was not to establish who invented CRISPR genome editing. Rather, the three judges on the PTAB were trying to determine “what the what is,” as Sherkow put it. If the PTAB concluded that there were indeed two separate inventions with two distinct timelines, then the question of who came first was redundant. But if the dispute was over the same invention, then all bets were off. There is a reason, says Sherkow, that for example Bell Laboratories required all its engineers to sign and date every page of their notebooks before they left work each day to ensure there was documentary evidence in the event of an interference proceeding.
The panel of three judges, led by Judge Deborah Katz, who has a doctorate in molecular biology, fired their sharpest questions at the CVC lawyer, who insisted that Doudna’s discovery, restricted to DNA in a test tube, could be extrapolated to all organisms including humans.11 Among hundreds of research papers, emails, PDFs, patents, and other documents, UC submitted statements from a pair of expert witnesses. One was from Nobel laureate Carol Greider, a Berkeley grad herself, who discovered telomeres (the DNA aglets that protect the ends of chromosomes from fraying). The other was from gene-editing pioneer Dana Carroll, who was compensated $500/hour to compile a brief totaling nearly two hundred pages.
Much of the deliberation centered on the contemporaneous commentaries of Carroll and other experts on the initial prospects of translating CRISPR gene targeting to human cells. Recall that in his September 2012 commentary, Carroll mulled over the prospects for CRISPR genome editing in human cells. In conclusion he wrote: “Whether the CRISPR system will provide the next-next generation of targetable cleavage reagents remains to be seen, but it is clearly well worth a try. Stay tuned.”12