In June 2019, the PTO declared its own interference, hoping to resolve the dispute. In one corner, a dozen patents owned by the Broad (the senior party); in the other, ten awarded to CVC.23 As the junior party, CVC still has the uphill task. The core of the case, Sherkow explains, is who can claim priority for the single-guide RNA?
Many have wondered why UC and the Broad have spent so many millions of dollars on this dragged-out patent fight? The bills are actually paid by the biotech companies; Editas has paid tens of millions of dollars on legal fees on behalf of the Broad Institute. The thought that the Nobel committee is unlikely to award the inevitable CRISPR prize to the loser in the patent drama “could be one factor in the Broad’s litigation strategy,” says Hank Greely.24 The Broad insists it has been open to a settlement for years, but UC hasn’t shown any appetite for compromise. Indeed, CVC has filed motions alleging that Zhang did not include tracrRNA until after Doudna’s paper was published, also questioning authorship discrepancies in some of Broad’s patents in the United States and Europe.25
In the run-up to the latest PTAB hearing in May 2020, the Broad filed an expert brief by Chad Mirkin, a chemistry professor at Northwestern University. Mirkin, who runs a massive lab of seventy people, charged his standard consulting rate of an eye-watering $1,600/hour in support of the Broad’s claims. He argued that the hypothetical “person of ordinary skill in the art” would not have successfully achieved genome editing in mammalian cells based on the CVC. During a deposition in early 2020, UC lawyers laid into Mirkin’s CRISPR credentials. He was forced to admit that his lab had not actually performed a CRISPR experiment until 2016.
Whether this legal sparring will have any material bearing on the case is unclear. At the PTAB encore hearing in May 2020, the judges did not tip their hand. Whoever wins the next round, the other side is still likely to come out swinging.
In Europe, CVC has fared better, thanks in part to a curious event that happened early on in the legal drama. The original Broad application in 2012 listed four co-inventors: Zhang plus Le Cong, Ann Ran, and Marraffini, all coauthors on the 2013 Science paper. But in the later ’359 patent application, Zhang was flying solo.II In July 2014, the Rockefeller University filed its own patent, essentially a carbon copy of the Broad’s application, only with Marraffini’s name restored.26 It was an unorthodox gambit that violated PTO rules because Zhang’s name had been included in this later filing without his notification or permission.
The dispute went to binding arbitration behind closed doors. On January 15, 2018, the Broad announced that it had prevailed. This meant that Marraffini, the microbiologist who had collaborated with Zhang throughout 2012, would not be listed as a co-inventor on the Broad’s major patents regarding eukaryotic editing.27 The Broad’s press release stating that the two sides had “settled their disagreement” gave the appearance of an amicable resolution. But when I even broached the subject with Marraffini in his office months later, he shot me the universal my-lips-are-sealed gesture.
But the Broad’s celebrations lasted barely seventy-two hours, as it was dealt a major setback in Europe. In March 2017, the European Patent Office (EPO) had awarded CVC a wide-ranging patent across all organisms—microbes, plants, and animals.28 Just a few days after the Broad-Rockefeller arbitration results, EPO announced that it was revoking the Broad patents ironically because of the Marraffini dispute. As the list of inventors of the Broad applications had changed from the earliest application in December 2012, EPO deemed the earliest application to be invalid. With that off the table, the Broad’s applications did not predate CVC. The EPO upheld that decision in January 2020 and reaffirmed the CVC patent three weeks later.29
The dispute has driven a wedge between the two biggest names and ex-industry colleagues in CRISPR in the United States. It’s not a subject Doudna cares to discuss, saying only it is “very disappointing for me, as a scientist and as a person.”30 Lurking in the wings is another patent application, originally filed on December 6, 2012, by MilliporeSigma researchers, who claim they were the first to perform CRISPR editing in eukaryotes. Ironically, the PTO judged that claim to be obvious in light of the CVC work, in contrast to the history of the Broad application. MilliporeSigma has petitioned the PTO to declare another interference with CVC.31
Hopefully this saga won’t be repeated as more CRISPR technologies are developed. In more recent iterations like base editing and prime editing (see chapter 22), the patent situation looks much cleaner. And the first to file rule is less contentious than first to invent. As patent attorney Joe Stanganelli says: “If there is any universally good news to take away from the CRISPR patent saga, it is this: It is unlikely to happen again.”32
What hinges on these patent disputes? In the coming years, the CRISPR biotech companies will likely have several gene-editing therapies on the market, all using garden-variety Cas9. “There will be a lot of money changing hands to make sure those drugs get into patients’ veins without infringement,” says Sherkow, who is now a law professor at the University of Illinois. What about 2040? “We’ll have a million CRISPR therapeutics on the market, every nuclease, RNA editors, a complete riot of options. Will we look back and say, ‘What a godawful waste of money’? Absolutely. It’s a joke.”33
Joke or not, the patent wars hold an “inside baseball” fascination that will at some point result in some momentous decisions about who will be paying licensing fees to whom. But in 2018, a new danger flared up. Some scientists and observers considered it nothing short of an existential threat to the fledgling CRISPR industry as it took its first nervous steps into the clinic.
I. The correct answer is “genes.”
II. The U.S. PTO is usually quite forgiving about such adjustments; less so in Europe.
PART III
“What more powerful form of study of mankind could there be than to read our own instruction book?”
—Francis Collins
“Humankind ascended to the top so quickly that the ecosystem was not given time to adjust. Moreover, humans themselves failed to adjust.”
—Yuval Noah Harari
Rita: Don’t you worry about cholesterol, lung cancer, love handles?
Phiclass="underline" I don’t worry about anything anymore.
Rita: What makes you so special? Everybody worries about something.
Phiclass="underline" That’s exactly what makes me so special. I don’t even have to floss.
—Groundhog Day
CHAPTER 14 #CRISPRBABIES
In April 2018, more than 15,000 scientists and physicians arrived in Chicago for the American Association of Cancer Research annual convention. In a hotel lobby, Marilynn Marchione, the chief medical correspondent for the Associated Press (AP), met an acquaintance, Ryan Ferrell. The year prior, Ferrell, working for a public relations company that represented Sangamo, had arranged for Marchione to have exclusive access to the launch of the first in vivo gene editing clinical trial in the United States.1 Marchione’s story shadowed Brian Madeux, an Arizona man with Hunter syndrome, who became the first patient to receive the groundbreaking therapy.