The context of the CRISPR Cas 9 legal battle had all the elements of a good soap opera: powerhouse scientists with ambitions to literally rewrite human DNA, potentially billions of dollars for the taking, a race to make history, and a surprise twist involving an unknown group of Lithuanian researchers.
It’s rare for patent cases to receive so much attention. Rarer still for research institutions to face off in court. And considering that scientists found a multitude of other ways to use CRISPR while the case was being argued — suggesting the technique in question may be only one of many — it’s easy to wonder why the case (recently tried in a Federal Appeals Court) ignited such an intense argument between scientists, research institutions, and legal theorists.
A simple explanation is that the case re-opened conversations about the economics of potentially life-saving research. But even more, simply it asked: What is an invention? And what credit is needed to establish legacy?
Six years ago, two genetic researchers, Jennifer Doudna of UC Berkeley and Emmanuelle Charpentier at the University of Vienna, published a paper that sent shockwaves through nearly every sphere of the scientific community. The premise was straightforward enough: first, they drew everyone’s attention to the tool bacteria use to kill viruses (discovered in the ’80s). The mechanism works by creating a copy of the virus, and then moves through a cell’s system, using its copy to find virus matches. Once it finds a match, it uses a protein (Cas9) to cut the virus out. Then it either inserts new chromosomes into the genome or fuses the two cut ends together. Charpentier and Doudna isolated this genetic editing tool and used it to cut and paste genes in a test tube. The technique they outlined was faster and more precise than any previous genetic edit had ever been.
Scientists lost their minds.
Clustered Regularly Interspaced Short Palindromic Repeats — thankfully called CRISPR for short — sped up experiments that used to take years and completed them in weeks and days. Soon CRISPR Cas9 was shortening the growing season of tomatoes while expanding their size and boosting their flavor. A UK-based lab used CRISPR to wipe out an entire species of mosquitoes, removing their gene that produces female offspring. In Philadelphia, researchers cut out the deadly DNA in human cells infected with HIV. There are hopes that CRISPR Cas9 can “re-program” the genes that cause diseases like Alzheimer’s, autism, and cancer, while some fear the tool will bring designer babies and biogenetic terrorism in the near future. (It’s important to note that this isn’t possible with our current knowledge of genetics. Scientists still don’t know how every gene controls and relates to other genes — but CRISPR also provides a much more efficient way to study those relationships.)
At any rate, Doudna and Charpentier were on the rise. In 2015 they won the Life Sciences Breakthrough prize (to the tune of 3 million dollars) and rumors of an eventual Nobel were circling. But then the United States Patent and Trademark Office awarded the patented application of CRISPR Cas9 in eukaryotic cells to Feng Zhang at the Broad Institute of MIT and Harvard.
Eukaryotic cells are cells with nucleuses. The cells controlling and changing plants, animals, you and me. The legal patent for applying CRISPR to many of the cells governing human health was not going to UC Berkeley or University of Vienna.
You can bet Berkeley and Vienna’s attorneys basically sprinted to the Patent and Trademark Office.
Forbes magazine estimates the value of the patent as somewhere in the realm of 265 million dollars, but experts suggest that if CRISPR lives up to the hype, its actual value could be in the billions. Beyond granting its holder the right to use the technique and sell use rights to corporations, the patent also legally establishes the original inventor.
Researchers were calling CRISPR Cas9, “the biological discovery of the century.” Holding that kind of patent could define a life, an institution. It’s the kind of achievement that gets your name in textbooks.
UC Berkeley and the University of Vienna had filed their patent application in May 2012. The Broad Institute filed in December that year. But Broad’s application was fast-tracked through a strategic — but risky — procedure known as “petition to make special”.
“So you can file a ‘petition to make special if you want a speedy review of your patent application. But!” Jacob Sherkow leans forward. “There are strategic considerations.”
Sherkow is a patent and intellectual property lawyer and professor at New York Law School. He has followed the case closely since its beginning and is able to explain convoluted patent terminology with all the excitement and style of Q showing James Bond the pros and cons of spy accessories.
Essentially, Zhang was limited to 20 claims with his patent, while Doudna and Charpentier filed 155 claims. “Usually when you prosecute patent applications, you get to say things like ‘Alright, dear examiner, you don’t like claim one? What about claim two? You don’t like claim three — I object to your analysis of claim 3!’” Sherkow throws his hand in the air and smiles. “But for ‘petitions to make special,’ the only thing you can take is an all-or-nothing vote. All yes,” he shrugs, “or all no.”
The patent office accepted all of the Broad Institute’s claims. When UC Berkeley protested the decision, Broad needed to prove that their application of CRISPR Cas9 was their invention — or in lawyer terms: that their invention did not “interfere” with Doudna and Charpentier’s invention. This made the case an interference procedure, which, while rare in patent law, happens with groundbreaking technology. For us non-lawyers: interference means an invention was not particularly inventive, that it was an obvious copy or extension of someone else’s invention so it “interfered” with theirs.
If a court decides there is no “interference” in an invention, then the court never listens to arguments over who the original inventor is — in this case, the different applications of CRISPR Cas9 are considered discrete inventions.
Towin a patent, the invention must meet three requirements. It must be new, useful, and non-obvious. For a year, both sides sent the court all of their “prior art” — journal articles, applications, studies, and so on, to prove the obviousness or novelty of the invention.
Right in the midst of what otherwise might have been a montage of lawyers preparing for a trial — a la Tom Cruise in A Few Good Men — a group of Lithuanian researchers, led by Virginijus Šikšnys, were suddenly awarded the CRISPR Cas9 patent for prokaryotic cells — the other major cell type, the kind without nucleuses that make up bacteria, among other things.
In the patent world, there is an 18-month secrecy statute surrounding all applications. Sherkow compares this lag of knowledge to the way we see a star from Earth. You’re never seeing the star as it is, but as it was when the light started traveling. For those looking at patents: “You are always dealing with an 18-month lag from reality,” he says. “You’re only seeing the light that was emanating 18 months ago.” Since the Lithuanians did not publish a paper prior to filing a patent application, none of the attorneys, institutions, researchers had any idea that Šikšnys actually filed his application two months before Berkeley.
(To be fair, Šikšnys had tried to publish his paper earlier — none of the local journals thought it was worth running.)
There was no fighting the Šikšnys patent. His came first and was very specific about its method. With one of two major cell types out of the running, all eyes turned toward the Berkeley vs. Broad dispute.
The hearing was held in a small room in Alexandria, Virginia on a wet day in early December of 2016. Fifty-five people crammed into Hearing Room A. Those unable to fit inside were forced to wait in the hall, raincoats dripping onto the floor.
Charpentier, Doudna and Zhang were not in attendance.
Each side took 20 minutes to present their case. Two months later, the Board awarded Zhang the patent. Their finding was that Doudna and Charpentier invented the technique of applying CRISPR Cas9 to cells in a test tube, while Zhang invented the technique of applying it to human DNA.
Berkeley quickly appealed.
Getting a sense of what was at stake is difficult. Sure, potentially billions of dollars could go along with this patent. But knowledge of CRISPR was expanding quickly beyond the Cas9 protein, and new techniques have the potential to be just as effective. While only 126 papers on CRISPR were published in 2012, by 2016 over 21,000 papers were in circulation. The slices of CRISPR patent pie might be getting smaller. Not only that, the technology is evolving so unprecedentedly fast that it’s impossible to know if the techniques will work in the ways researchers hope they will.
Just this year, a study found that Cas9 sometimes damages the genome. The scientists published their findings in June and stocks in CRISPR biotech companies fell dramatically.
Dr. Greg Licholai, a biotechnology consultant and co-director of the Yale Center for Digital Health, says that these findings are not shocking, but a typical part of science. Since CRISPR use increased so dramatically within such a short time, the discoveries weren’t tested and confirmed in the same way new scientific findings are typically evaluated. Licholai sees these recently published studies and warnings simply as evidence that the field is catching up to itself, “business as usual when it comes to science.”
In other words, the bugs might be worked out…but time will tell. In the meantime, the awards are flowing. In 2014, 2016 and 2017 Doudna, Charpentier and Zhang shared three awards while receiving others separately. The three also founded several CRISPR therapeutics companies, seeking to treat diseases such as autism and cancer. In an interesting turn, Doudna and Zhang had originally founded Editas Medicine together in 2013. Citing family obligations, Doudna left the Massachusetts-based corporation to start a company in her home state of California soon after Broad won the patent.
The argument at the Patent Trial and Appeal Board in April reveals the tension at the heart of the case. Yes, a lot of money was possibly on the line — but that doesn’t generally interest so many people across so many different fields. This case was exposing a fault line. Legal and scientific fields often determine standards of fact for countries and cultures. Yet in the case of CRISPR Cas9, the definitions of invention and discovery — nouns that often serve as the bedrock of science and law — could be contested, and were seemingly on trial themselves.
Berkeley hired a new, big-name attorney for the appeal — Donald Virilli, the former Solicitor General of the United States who successfully argued President Obama’s Affordable Care Act before the Supreme Court — and when he took the floor, the courtroom was packed once again.
Even listening to a recording of the proceeding, without having been present, you can feel the tension in the room. When Judge Kimberly Moore goes into a coughing fit, her casual request that Virilli continue argument since speakers were broadcasting the hearing to the back room is met with an unexpected roar of laughter, not unlike a sitcom’s laugh track. Virilli’s voice is actually shaking at points through his 15-minute argument, while Broad’s attorney, Raymond Nimrod, sounds like the epitome of calm assurance.
Virilli was the one facing an uphill legal battle. He needed to prove that the original court had weighed the evidence incorrectly. He insisted the patent should hinge on the discovery of CRISPR being a tool, that Doudna and Charpentier’s ability to demonstrate its application in a test tube — solving the “problem” — put Broad just a step away from applying CRISPR to human cells. The technique was the game changer — not where it was used.
“All of them faced with this problem took the conventional off-the-shelf techniques.” To make his point, Virilli starts throwing out terms like “codon optimization”, but before he can continue, Judge Moore interrupts.
“And guess what? They didn’t work.” Her voice is strained from her cold and she speaks faster. “So it took years and innovation. That’s how science works, Mr. Virilli!” Her voice is almost electric in the still courtroom. She outlines how Zhang used traditional experimentation and failure to refine and refine until successfully using CRISPR in human cells. The same way Doudna and Charpentier took the discovery of CRISPR’s existence and refined it into a tool.
Virilli tries to speak again, but the judge silences him and the hearing ends.
Berkeley lost the case, and in the process defined lines of where one discovery ends and another begins.
Having lost significant patents to both Broad and Šikšnys, UC Berkeley and University of Vienna are now left picking up the crumbs. In the legal world, Doudna and Charpentier are not likely to be big names, despite being the first ones to demonstrate CRISPR’s use. Simply put: what they accomplished in test tubes has very little legal value.
Since the court’s September decision, the attorneys and representatives of UC Berkeley, MIT, and Harvard have issued a slew of statements. The Broad Institute called upon everyone to join forces: “It is time for all institutions to move beyond litigation. We should work together to ensure wide, open access to this transformative technology.” Unsurprisingly, UC Berkeley suggested they would continue to look into their legal options, but chances of moving forward in the courts are slim to none.
While nearly everyone seemed to be arguing and poring over every detail of the case, the inventors themselves have remained almost completely silent. In her book on CRISPR, Doudna mentions the patents only briefly when describing the “heady time” that all of them experienced in the lab during 2012. “Only later would the contents and publication dates of these papers be dissected to support arguments in a dispute over CRISPR patent rights, a disheartening twist to what had begun as collegial interactions and genuine shared excitement about the implications of the research.”
In all interviews following the case, the three always shift the topic when patent rights come up. They don’t want to talk about their feelings — “disheartening” is the most open Doudna has ever been on the subject-they want to talk about CRISPR. About what’s next, and where the research could be going. They want to argue about what it should be used for, or outline what their lab is doing now.
The scientific community is continuing to recognize all the inventors, honoring them with awards and asking them to speak at key summits on gene editing. All research institutions involved are under agreement to share CRISPR Cas9 editing rights freely for education and non-profit purposes.
And while Charpentier, Doudna, and Zhang certainly must have felt something when the patent decisions were delivered, their only observable reaction was to stay at work — they never attended a single hearing. Instead, they remained in the lab, publishing papers on their most recent CRISPR discoveries, and conducting experiment after experiment. In the landmark 2012 paper that started it all, Doudna and Charpentier wrote that CRISPR Cas9, “highlights the potential to exploit the system”, the “system” being the genome of living things. It’s apparent that this is where the inventors would like the rest of us to keep our focus: on our future and the potential for what could be.
by Kaitlyn Nicholas