NEW YORK – The legal battle over the ownership rights to foundational patents for CRISPR-Cas9 technology took a nasty turn this week after the University of California and its co-plaintiffs in the case accused the Broad Institute's Feng Zhang and his collaborator Neville Sanjana of making "untrue" and "materially false" declarations in the Broad's original patent applications.
In January 2017, the US Patent and Trademark Office (USPTO) declared an interference at UC's request to settle certain claims related to the CRISPR patent battle. In the proceedings, the USPTO said it would collect, consider, and compare historical documentary evidence to establish the dates of the technology's invention and who had invented it first. Because the applications were filed before the US moved to a "first to file" patent system in 2013 under the Leahy-Smith America Invents Act (AIA), the patent rights would be granted under the old "first to invent" system.
In February, however, the three-judge panel from the Patent Trial and Appeal Board (PTAB) issued a judgement of no interference-in-fact, leaving the Broad to control the key IP estate for targeted genome editing applications in several areas, especially gene therapy, drug discovery and development, and ag-bio, which rely on editing in eukaryotic cells.
Although UC filed an appeal, the US Court of Appeals for the Federal Circuit ruled in favor of the Broad in September 2018.
But the USPTO reignited the case this June when it initiated a new patent interference. The proceeding — which was started by the USPTO rather than one of the parties — involves one patent application filed by and 13 patents issued to the Broad in 2014, 2015, and 2017, and 10 patent applications filed by UC Berkeley in 2018, all on the use of CRISPR-Cas9 to edit eukaryotic genomes.
At the time, UC released a statement saying it welcomed the new proceeding. "The initiation of this interference proceeding highlights that previous decisions involving the Broad did not determine who was the first to invent this technology," Eldora Ellison, lead patent strategist on CRISPR matters for UC and a director at the law firms of Sterne, Kessler, Goldstein and Fox, said in an email. "We are confident that the USPTO will ultimately recognize that the [Jennifer] Doudna and [Emmanuelle] Charpentier team hold the priority of invention specific to eukaryotic cells."
In its newest brief, UC identified a list of motions it would like permission to file with the PTAB. Among these motions, UC has asked the PTAB to judge all the Broad's claims involved in the interference unpatentable.
First, UC alleges that the Broad's patents fall under the provisions of AIA's "first to file" system. All of the Broad's involved cases issued from applications with a filing date on or after March 16, 2013 when the AIA took effect, but claim priority benefit to one or more applications filed before that date, the motion said. However, the Broad's involved cases and/or the applications involved in the cases "contains or contained at one time at least one claim that was not supported by Broad's applications filed before March 16, 2013," the university added. "Thus, Broad's involved cases, the application from which each of Broad's involved patents issued, and/or a parent application to which each of Broad's involved cases claims benefit, contains or contained at one time at least one claim to subject matter having an effective filing date on or after March 16, 2013 — thereby subjecting each of Broad's involved cases to AIA prior art provisions."
In its filing, UC noted that this motion should be enough for the PTAB to decide the unpatentability of the Broad's claims. However, the filing adds, if this argument isn't enough, there are other provisions that would render the Broad's claims unpatentable.
In the next motion, UC claims that "Broad deliberately misidentified the inventors on its involved patents and application, as demonstrated by the fact that its own prosecuting attorney's sworn declaration contradicts the inventive entities named during prosecution of the involved applications."
The Broad's patents name either Zhang as the sole inventor or Zhang in combination with Le Cong, Fei Ran, Randall Platt, Patrick Hsu, and/or Sanjana. However, UC claims, Broad attorney Thomas Kowalski identified "a substantially different set of inventors" in a declaration provided to the European Patent Office." Specifically, Kowalski's declaration attests that several individuals who weren't listed on the official patents "had contributed in a not insubstantial manner" to various CRISPR inventions, including Cong, Ran, Shuailiang Lin, Platt, Ophir Shalem, Matthias Heidenreich, and Lukasz Swiech.
"As one example, Broad's attorney determined that Dr. Cong contributed to the invention of 'the CRISPR-Cas9 system adapted in for [sic] uses in eukaryotic cells,' a critical feature of every involved claim in the Interference. But Dr. Cong is not named on 8 of the 14 patents/application involved," UC's motion notes. "If all inventors are not named, then a patent or application is unpatentable unless it is corrected."
"Inequitable… untrue… materially false"
UC's next motion, alleging the Broad engaged in "inequitable conduct" is the most explosive, however.
The university said that the Broad's claims are unpatentable because it made "at least one affirmative material misstatement" in each of its applications. Specifically, UC alleges that Zhang made statements he knew to be "untrue" at the time he made them, and that Sanjana had made a "materially false declaration."
Zhang alleged in his declaration that he had a complete conception and reduction to practice of the technology he'd claimed he'd invented, USC said. But the university alleges that the evidence shows Zhang's experiments failed to include tracrRNA, which is a required component of a functional CRISPR-Cas9 cleavage complex.
"The evidence shows that Dr. Zhang did not include tracrRNA in his experiments to form a CRISPR-Cas9 complex at that time and therefore could not have had a complete conception, much less a reduction to practice, of a functional CRISPR-Cas9 system for cleaving DNA," UC wrote.
The university also claimed that Zhang didn't include tracrRNA in his CRISPR-Cas9 complex until after he'd read a 2012 Science paper co-authored by Doudna, Charpentier, and Martin Jinek, which showed that tracrRNA is essential for cleavage of target DNA.
"Dr. Zhang was aware of the Jinek paper, and cited it in his own publications before he signed his declaration and before his counsel submitted it to the [USPTO]," UC said.
UC also accused Zhang of omitting unfavorable data and context from a summary panel the Broad showed the patent office. The full data would have showed the experimental failure of not including tracrRNA, as well as Zhang's "failure to understand the criticality of tracrRNA at the time he conducted the experiments," UC said.
"The Broad's affirmative mischaracterization of data… is part of a larger pattern of deception," the university added. In filing a claim for one of the involved patents, the Broad submitted a declaration from Sanjana, stating that the researchers had achieved successful cleavage of target DNA in eukaryotic cells by a CRISPR-Cas9 system comprising a single-guide RNA. As evidence, the team included a copy of an experimental gel. But UC said that gel was misrepresented, and clearly shows that Zhang and Sanjana's experiment was "a failure."
By presenting the gel as proof of a successful experiment, UC added, "Sanjana materially misstated facts in an attempt to prove an even earlier date of invention. Those acts evidence Broad's pattern of deceptive behavior in its dealings with the patent office."
In its supporting documents, UC submitted a February 2015 email from Shuailiang Lin, a researcher who had worked in Zhang's lab from 2011 to 2012 and who was listed as an inventor on the Broad's provisional applications.
"The 15-page declaration of [Feng Zhang] and Le Cong's luciferase data is mis- and overstated to change the examiner's decision, which seems to be a joke. After seeing your in virto [sic, in vitro] paper, Feng Zhang and Le Cong quickly jumped to the project without letting me know. My lab notebooks, emails and other files like dropbox or gel pictures recorded every step of the lab's failure process. I am willing to give more details and records if you are interested or whoever is interested to clear the truth. We did not work it out before seeing your paper, it's really a pity," the e-mail said, according to UC's filing.
The bottom line, UC concluded, is that the Broad's patents should be canceled.
In a statement, the Broad denied UC's allegations, calling the university's chosen legal strategy "deeply unfortunate for the entire field." UC has chosen to avoid the issue of who invented the technology first because "all of the evidence demonstrates that UC was not the first to invent any method of using CRISPR in eukaryotic cells," the institute added. "Instead, UC casts baseless claims at the Broad patents and inventors in the hope of avoiding having to provide any actual evidence of UC's work in eukaryotic cells."
According to the Broad, for example, UC's claim that Zhang's work is based on Jinek's paper is wrong. "It is obvious from the records and scientific papers that Broad did not rely on this work, because it used a clearly different approach," the institute said.
Further, the Broad dismissed Lin's email as being "from a student with an expiring visa who emailed Dr. Doudna seeking a job and promising information. The student was hired by the UC system within days. The email was inaccurate and contrary to all records."
The Broad stood behind its scientific claims and the filings it has made to the patent office. It also called on UC to "move beyond litigation" and work with the institute to "ensure wide, open access to this transformative technology" through the use of patent pools and licensing deals.