The code breaker, p.21
The Code Breaker, page 21
The modern biotechnology industry was born a century later, when a Stanford attorney approached Stanley Cohen and Herbert Boyer and convinced them to file for a patent on the method they had discovered for manufacturing new genes using recombinant DNA. Many scientists, including Paul Berg, the discoverer of recombinant DNA, were horrified at the idea of patenting a biological process, but the royalties that flowed to the inventors and their universities quickly made biotech patents popular. Stanford, for example, made $225 million in twenty-five years by granting hundreds of biotech companies non-exclusive licenses to the Cohen-Boyer patents.
Two major milestones occurred in 1980. The U.S. Supreme Court ruled in favor of a genetic engineer who had derived a strain of bacteria capable of eating crude oil, which made it useful in cleaning up oil spills. His application had been rejected by the Patent Office on the theory that you could not patent a living thing. But the Supreme Court ruled, in a 5–4 decision written by Chief Justice Warren Burger, that “a live, human-made micro-organism is patentable” if it is “a product of human ingenuity.”1
Also that year, Congress passed the Bayh-Dole Act, which made it easier for universities to benefit from patents, even if the research was funded by the government. Until then, universities often were required to assign the rights to their inventions to the federal agencies that had funded them. Some academics feel that the Bayh-Dole Act cheats the public out of the proceeds from inventions funded with taxpayer money and distorts the way universities work. “Encouraged by a small number of patents that made huge sums, universities developed massive infrastructure to profit from their researchers,” argues Michael Eisen, Doudna’s colleague at Berkeley. He believes that the government should put all work funded by federal dollars into the public domain. “We all would benefit returning academic science to its roots in basic discovery oriented research. We see with CRISPR the toxic effects of turning academic institutions into money hungry hawkers of intellectual property.”2
That’s an appealing argument, but I believe that, on balance, American science has benefited from the current mix of federal funding and commercial incentives. To turn a basic scientific discovery into a tool or a drug can cost billions of dollars. Unless there is a way to recoup that, there won’t be as much investment in research.3 The development of CRISPR and the therapies it led to are a good example.
CRISPR patents
Doudna did not know much about patents. Little of her previous work had practical application. When she and Charpentier were finishing their June 2012 paper, she reached out to the woman at Berkeley in charge of intellectual property, who set her up with a lawyer.
For research professors in the U.S., the patents to their inventions are usually assigned to the academic institution, in Doudna’s case Berkeley, with the inventors having a lot of say over how it will be licensed and taking a portion (in most universities about one-third) of the royalties. In Sweden, where Charpentier was then based, the patent goes directly to the inventor. So Doudna’s application was filed jointly by Berkeley, Charpentier personally, and the University of Vienna, where Chylinski was based. Shortly after 7 p.m. on May 25, 2012, just as they were finishing their paper for Science, they filed their provisional patent application and used a credit card to pay the $155 fee for processing. It did not occur to them to spend a little extra to have the application expedited.4
The 168-page application, which included diagrams and experimental data, described CRISPR-Cas9 and made more than 124 claims for ways that the system could be used. All of the data in the application were from experiments done with bacteria. However, it mentioned delivery methods that could work in human cells, and it made the claim that the patent should cover the use of CRISPR as an editing tool in all forms of life.
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As I noted earlier, Zhang and the Broad submitted their own patent application in December 2012, when his paper about editing in humans was accepted by Science.5 It specifically described a process for using CRISPR in human cells. Unlike Berkeley, the Broad made use of a neat little provision in the patent process: it paid a small additional fee and agreed to a few conditions in order to expedite consideration under what was known as an Accelerated Examination Request or, more poetically, a Petition to Make Special.6
Initially, the Patent Office did not grant Zhang’s application, asking for more information. Zhang responded by supplying a written declaration. In it, he made an allegation that infuriated Doudna. He pointed out that Church had sent her a preprint of his paper, and he implied that she used his data in her patent application. “I respectfully question the origin of the example,” Zhang said. In one of their legal filings, Zhang and the Broad asserted, “It was only after the Church laboratory shared unpublished data that Dr. Doudna’s laboratory reported they were able to adapt a CRISPR-Cas9 system” for use in human cells.
Doudna was outraged at Zhang’s declaration because it implied that she had plagiarized Church’s data. She called Church at his home on a Sunday afternoon, and he shared her anger at what his former student had alleged. “I’m happy to go public and say you didn’t improperly use my data,” Church told her. She had been polite to include a sentence about him in her acknowledgments, and it was “outrageous,” he later told me, that Zhang would turn that small act of collegiality against her.7
Marraffini dropped
As Zhang was waiting for a ruling on his patent applications, he and the Broad did something unusual: they dropped the name of his collaborator Luciano Marraffini from the main application. The somewhat mystifying tale is a sad example of the distorting effects that patent law can have on scientific collaboration. It’s also a tale of competitiveness, perhaps even greed, overwhelming kindness, and collegiality.
Marraffini is the soft-spoken Argentinian-born bacteriologist at Rockefeller University who collaborated with Zhang beginning in early 2012 and was a coauthor on his Science paper. When Zhang initially filed for his patents, Marraffini was listed as one of the co-inventors.8
A year later, Marraffini was called into the office of the president of Rockefeller and told, to his shock and profound sadness, that Zhang and the Broad had decided to narrow some of the patent applications and focus one of them only on the process of making CRISPR-Cas9 work in human cells. Marraffini did not contribute enough to that work to deserve being on the patent, the Broad unilaterally decided, so they were dropping him.
“Feng Zhang didn’t even have the politeness to tell me directly,” Marraffini says, shaking his head, still looking shocked and sad after six years. “I’m a reasonable guy. If they said my contribution was not worth an equal share, I would have accepted a smaller share. But they didn’t even tell me.” What particularly pains him is that he views the story of his work with Zhang as an inspiring American tale: two young rising stars who were immigrants, one from China and the other from Argentina, joining forces to show how CRISPR could be used in humans.9
When I ask Zhang about this, he likewise speaks quietly and sorrowfully, as if he’s the one who is hurt. “I focused on Cas9 from the beginning,” he insists when I ask if Marraffini should get some credit for getting him to concentrate on that enzyme. It may have been ungenerous to take Marraffini off the patent, but in Zhang’s mind it was not unwarranted. Therein lies one of the problem with patents: they prod people to be less generous in sharing credit.10
Conflict
The Patent Office decided to grant Zhang’s patent application on April 15, 2014, even though Doudna’s applicationI was still being considered.11 When she heard, she called Andy May, her business associate, who was driving. “I remember pulling over in the car and taking the call and getting this blast,” he says. “ ‘How did this happen?’ she asked. ‘How did we get beaten?’ She was livid, absolutely livid.”12
Doudna’s application was still languishing at the Patent Office. That raised a question: What happens if you apply for a patent and, before the decision gets made, another person is granted a similar patent? Under U.S. law, you have a year to request an “interference” hearing. So in April 2015, Doudna filed a claim that Zhang’s patents should be disallowed because they interfered with the patent applications that she had previously submitted.13
Specifically, Doudna submitted a 114-page “Suggestion of Interference” detailing why some of Zhang’s claims were “not patentably distinct” from her own pending claims. Even though her team’s experiments had involved bacteria, she argued that their patent application “specifically states” that the system can be applied in “all organisms” and provides “detailed descriptions of numerous steps that could be taken to apply the system” to humans.14 Zhang argued in his response declaration that Doudna’s application “did NOT [emphasis in the original] have the features required for Cas9 binding and DNA target site recognition in a human cell.”15
Thus the battle lines were drawn. Doudna and her colleagues had identified the essential components of CRISPR-Cas9 and engineered a technique to make it work using components from bacterial cells. Their contention was that it was then “obvious” how it would work in a human cell. Zhang and the Broad Institute countered that it was not obvious that the system would work in humans. It required another inventive step to make it work, and Zhang had beaten Doudna to it. In order to resolve this issue, the patent examiners in December 2015 launched an “interference proceeding” to be decided by a panel of three patent judges.
When Doudna’s lawyers asserted it was “obvious” that a system that worked in bacteria would also work in humans, they were using a term of art. In patent law, the term “obvious” refers to a specific legal concept. Courts have declared that the “criterion for determination of obviousness is whether the prior art would have suggested to a person of ordinary skill in the art that this process would have a reasonable likelihood of success.”16 In other words, you don’t deserve a new patent if you merely modified a prior invention in a way that was so obvious that a person with ordinary skill in the field could have done the same with a reasonable likelihood of success. Unfortunately, phrases such as “person of ordinary skill” and “reasonable likelihood of success” are fuzzy when applied to biology, where experiments are less predictable than in other forms of engineering. Unexpected things happen when you start fiddling with the innards of living cells.17
The trial
It took a full year for all the briefs, declarations, and motions to be filed, after which a hearing was held in December 2016 before a three-judge panel at the Patent and Trademark Office in Alexandria, Virginia. With its blond-wood dais and simple tables, the hearing room looks like a sleepy county traffic court. But on the day of the trial, a hundred journalists, lawyers, investors, and biotech fans, most of them bespectacled and looking a bit nerdy, began lining up at 5:45 a.m. to get seats.18
Zhang’s lawyer opened the hearing by stating that the key issue was “whether the use of CRISPR in eukaryotic cells was obvious” after the Doudna-Charpentier 2012 article.19 To make the case that it was not, he put up a series of posters with statements made earlier by Doudna and her team. The first was from an interview Doudna gave to a Berkeley Chemistry Department magazine: “Our 2012 paper was a big success, but there was a problem. We weren’t sure if CRISPR-Cas9 would work in plant and animal cells.”20
Zhang’s lawyer then put up a quote that was not merely an offhand comment but a statement that Doudna and Martin Jinek made in the eLife paper that they had rushed into publication in January 2013. Their earlier paper had “suggested the exciting possibility” that the CRISPR system could be used for editing human genes, they wrote, but then they added, “However, it was not known whether such a bacterial system would function in eukaryotic cells.” As Zhang’s lawyer told the court, “These comments at the time belie this idea that this was all obvious.”
Doudna’s lawyers rebutted that her comments were simply the mark of a careful scientist. This did not impress the lead judge, Deborah Katz. “Are there any statements,” she asked Doudna’s lawyer, “in which anybody said they did believe it would work?” The best the lawyer could do was point to Doudna’s statement that it was “a real possibility.”
Fearing that he was playing a losing hand, Doudna’s lawyer shifted the argument. Five labs had made the system work in eukaryotic cells within six months of the publication of the Doudna-Charpentier discovery, he said, which was an indication of how “obvious” such a step was. He displayed a chart showing that they all used well-known methods. “There’s no special sauce here,” he told the judge. “These labs would not have embarked on this quest unless they had a reasonable expectation of success.”21
The three-judge panel ended up siding with Zhang and the Broad. “Broad has persuaded us that the parties claim patentably distinct subject matter,” the judges declared in February 2017. “The evidence shows that the invention of such systems in eukaryotic cells would not have been obvious.”22
Doudna’s side appealed to the federal courts, beginning a process that took another nineteen months. In September 2018, the U.S. Court of Appeals for the Federal Circuit upheld the ruling of the patent board.23 Zhang was entitled to his patent; it did not interfere with Doudna and Charpentier’s application.
But as happens with many complex intellectual property cases, these rulings did not end the case or give Zhang a total victory. Because there was “no interference” between the two sets of applications, they could be considered separately, which meant that it was still possible that the Doudna-Charpentier application would be granted as well.
Patent priority dispute, 2020
That is what happened. In the final two sentences of its 2018 decision affirming Zhang’s patent, the U.S. Court of Appeals had emphasized a significant point. “This case is about the scope of two sets of applied-for claims and whether those claims are patentably distinct,” the judge wrote. “It is not a ruling on the validity of either set of claims.” In other words, there was no “interference” between the patents granted to Zhang and the pending ones that had been applied for by Doudna and Charpentier. They could be considered as two distinct inventions, and it was possible that both could deserve patents or that the Doudna-Charpentier ones would take priority.
Of course such a result would be messy and somewhat paradoxical. If both sets of patents got granted and then seemed to overlap, that would fly in the face of the decision that there was no interference between them. But sometimes life, and in particular life inside of cells and courtrooms, can be paradoxical.
In early 2019, the U.S. Patent Office granted fifteen patents based on the applications that Doudna and Charpentier had filed in 2012. By then, Doudna had hired a new lead attorney, Eldora Ellison, who had blazed an educational path that was tailor-made for the age of biotech. She earned her undergraduate degree at Haverford in biology, then a doctorate at Cornell in biochemistry and cell biology, and finally a law degree at Georgetown. I often suggest to my students that they consider studying both biology and business, as Rachel Haurwitz did, or biology and law, as Ellison did.
When she analyzed the case for me over breakfast, Ellison was able to explain the nuances of both the biology and the law, and she readily cited from memory arcane footnotes in various scientific articles and court decisions. I came to the conclusion that Ellison would be great on the Supreme Court, which nowadays could use at least one justice who understands biology and technology.24
Ellison was able to prod the Patent Office in June 2019 to launch a new case.25 Unlike the first case, which looked only at whether Zhang’s patents interfered with the ones that Doudna had applied for, this new case would involve adjudicating the fundamental issue: which side had made the key discoveries first. This new “priority dispute” would attempt to pinpoint, using notebooks and other evidence, precisely when each applicant had invented CRISPR-Cas9 as an editing tool.
In a May 2020 hearing, done by phone because of the coronavirus closures, Zhang’s lawyer argued that the issue had already been decided: it was not “obvious” that the CRISPR-Cas9 system discovered by Doudna and Charpentier in 2012 would work in human cells, and therefore Zhang was entitled to a patent for being the first to show how it would. Ellison responded that the legal issues in the new case were not the same. The patent that was granted to Doudna and Charpentier was for the use of CRISPR-Cas9 in all organisms, from bacteria to humans. The question, she said, was whether their patent application from 2012 contained enough evidence to show they had discovered this. She contended that even though their experimental data came from using bacterial components in a test tube, their patent application, when considered in its entirety, described how to use the system in any organism.26 By late 2020, the case was still dragging along.
In Europe, there was initially a similar situation: Doudna and Charpentier were granted a patent, and then Zhang was also given one.27 But at that point Zhang’s dispute with Marraffini popped up again. After Zhang’s applications were revised and Marraffini’s name dropped, the European patent court ruled that Zhang could not use the date of his original application as his “priority date.” As a result, other patent applications were deemed to have an earlier priority date, and the court revoked Zhang’s patent. “Feng’s European patent was nullified because of the way he took me off,” Marraffini says.28 By 2020, Doudna and Charpentier had been awarded the major patents also in Britain, China, Japan, Australia, New Zealand, and Mexico.
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Were all of these patent battles worth it? Would Doudna and Zhang have been better off coming to a deal rather than battling in court? In retrospect, Doudna’s business partner Andy May thinks so. “We would have saved a lot of time and money around all of the legal arguments if we had managed to come together,” he says.29
