June 1, 2018 (Vol. 38, No. 11)
An Interview with Law Professor Jacob Sherkow
Given the exciting applications of CRISPR in fields ranging from gene therapy to genetically modified foods, there has naturally been intense scrutiny of the ongoing dispute regarding the discovery and patenting of CRISPR gene editing technology. No one has covered this story more intensively or adeptly than Jacob Sherkow, an academic law professor at the New York Law School. In this interview, Professor Sherkow provides a brief accessible history of the ongoing CRISPR patent dispute, and he discusses this dispute’s implications as well as other legal issues impacting biotechnology. (This is an edited version of the interview, which was conducted March 20, 2018, by Kevin Davies, Ph.D., executive editor of The CRISPR Journal.)
Dr. Davies: What is your interest in CRISPR?
Mr. Sherkow: I am an intellectual property scholar interested in patent disputes, especially in the biotech area. Needless to say, the huge patent dispute regarding the foundational patents on CRISPR and Cas9 are of particular interest.
Dr. Davies: When did you first get interested in CRISPR or recall hearing the term?
Mr. Sherkow: It was at the end of 2013 or the beginning of 2014. I was a research fellow at Stanford Law School, and one of the professors I was working with, Hank Greely, had a student in his seminar course, Chris Weyant, who was interested in biotech patent issues. He approached Hank and me and said, “Hey, there is this really interesting new technology. It is called CRISPR, and there may be some priority dispute over foundational patents in the area.” Chris helped me write a Nature Biotechnology article that appeared in early 2015. And we were off to the races.
Dr. Davies: You’ve called this whole saga “the biggest biotech patent dispute in decades.” Is that still your view?
Mr. Sherkow: Certainly. It is hard for me to think of another piece of technology in the biotech area with such a public focus, with such potential to perform the kind of Holy Grail of genetic engineering that many scientists are looking for. If you go back a number of years, there are a couple of moments that really stand out, and this seems to be one of those: the development of recombinant DNA in the late ’70s and the early ’80s; the advent of PCR in 1985. You may also believe that the discovery of induced pluripotent stem cells or RNA interference in the early 2000s was important. And here we are in 2013/2014 with CRISPR. So the fact that there is this crystalline patent dispute between groups of well-known scientists piques people’s interest.
Dr. Davies: Let’s start with the two seminal papers and what happened in terms of the patent applications surrounding them—the Doudna/Charpentier paper in the summer of 2012 and then the Zhang paper from the Broad Institute in early 2013. What were some of the major signposts around that?
Mr. Sherkow: On one side you have Emmanuelle Charpentier and Jennifer Doudna, who share a patent application; on the other side, Feng Zhang and his collaborators. Both sides filed for patent applications in 2012, and it was apparent at the time that the two institutions—the University of California, Berkeley, and the Broad Institute—were trying to resolve between themselves what looked like a potential patent dispute. Those efforts did not come to fruition. And so, in April 2015, the University of California files a request with the U.S. Patent and Trademark Office (PTO) that it declare an interference between the yet-issued University of California application and between some of the Broad Institute’s patents, which were already granted by the PTO.
That kicked off the interference proceeding, which is the trial before the PTO as to exactly what the particular technology is that may have been invented and who the first inventor of that technology was—if it is necessary to answer that particular question.
Dr. Davies: Is it significant that the Zhang patent application was awarded before the University of California application, even though it was filed afterwards?
Mr. Sherkow: Yes. In general, interference proceedings are structured to include a junior party and a senior party. It is a complicated terminology … One way to envision it is that my grandparents are senior citizens and I am a junior citizen, so the senior party is the kind of earlier-birthed application, and the junior party is the later-birthed one. This changes whose burden it is to prove their particular case at the PTO.
If you already have an issued patent application, or patent, while you can still be the junior party or the senior party, I am under the impression that the PTO is more reluctant to invalidate or cancel a patent that has already been issued, relative to an application that has not even gone through all the paces. So there is some significance to the Broad Institute’s patent being awarded first, although maybe not a whole lot.
Dr. Davies: And did that come about because of an expedited review?
Mr. Sherkow: Yes and no. It is decidedly true that the Broad Institute’s patent application would not have been issued in time for the interference proceeding had they not filed for expedited review. But I do not think that that has changed who the ultimate winner and loser of the patent dispute either was at the interference proceeding or is eventually going to be after all the appeals are exhausted.
I think a lot of people have focused, in some cases unnecessarily, on the fact that the Broad Institute used this expedited procedure in what we would call the prosecution of their patents application. But I do not think it has really changed anything with respect to the interference proceeding itself. It is a relatively minor detail in a sea of otherwise important details.
Dr. Davies: So, this interference proceeding culminated in a live hearing, a court hearing, at the patent office in Virginia at the end of 2016. Correct?
Mr. Sherkow: Yes. It was a rainy Tuesday, December 6, 2016. It was probably the most well-attended interference proceeding in U.S. PTO history!
Dr. Davies: How did that proceeding play out? Was the onus on California to somehow invalidate the Broad’s application or pa-tent? Who was litigating who at that time?
Mr. Sherkow: The University of California being the earlier-birthed application (under this ridiculous analogy that I trafficked out earlier), the burden was on the Broad Institute, being the junior party, to prove that they were entitled to their particular patent. The strategy the Broad used successfully was to argue that Feng Zhang’s invention was, at least from a patent law perspective, distinct from the invention that was described in Doudna and Charpentier's application.
Zhang’s patent application really only described how to use the technology in eukaryotic cells: the methods of using the technology in eukaryotic cells—for example, by making use of a nuclear localization signal and by optimizing codons to be more accurately translated in a eukaryotic cell system. This was different, Broad’s attorneys argued, from the stuff that was described in Doudna and Charpentier’s application.
The Patent Trial and Appeals Board bought that argument. They said, “Yeah, right. So the Broad Institute’s patent application is something separate. It is a more specific application of the technology than Doudna and Charpentier described in their patent application.” Therefore, the Broad is entitled to their patents, independent of what happens to Doudna and Charpentier’s application once it gets assessed finally by a PTO examiner.
The way this ruling was described by the patent trial and appeal board was that there was “no interference in fact.” Even though it seemed like both parties were there at the same time, and even though they seemed to be working in relatively the same area, their patent applications, at the very least, did not interfere with one another.
So Doudna, Charpentier, and the University of California can continue prosecuting their application before the PTO, and whatever the outcome of that application may be, Zhang and the Broad Institute get to keep their patents.
Dr. Davies: We are still waiting for that outcome?
Mr. Sherkow: That decision has been appealed, as all major patent disputes are. There is one court in the United States that hears all of these appeals—the U.S. Court of Appeals for the Federal Circuit. Right now, all the papers are in. All of the appellate papers are in. We are just waiting for an oral argument date to be set by the federal circuit … [Ed. note: The oral argument took place on April 30, 2018.] The way the federal circuit typically works, that means we are probably going to get a decision by April of 2019.
Dr. Davies: There was a time when the rules of how a patent is awarded were changed from “first to invent” to “first to file.” Did that have any bearing on this case?
Mr. Sherkow: Yes and no. The actual changing of the rules did not have a bearing on this case because those rules did not become effective until March 16, 2013. Both sides had filed their earliest patent applications back in 2012. So we were still, and are still—in first-to-invent land.
Had this been a first-to-file case, there would not be any interference for University of California to suggest—so they would have just had to deal with whatever the examiner said in the initial round of applications. There was nothing that they could do to hamper the Broad’s efforts in obtaining their patent prior to obtaining theirs if we were in first-to-file land.
Dr. Davies: The Zhang paper was published in 2013, some six months after Doudna’s paper, but the Broad published internal documents showing that he independently came up with this CRISPR genome editing strategy and application back in February 2011. Was that an important strand in the Broad’s arguments showing independent discovery of CRISPR gene editing?
Mr. Sherkow: Not for this particular case, or not for the case in the United States. All interference proceedings are split into two phases. The first is the interlocutory phase, and the second is the testimonial phase. In the interlocutory phase, the Patent Trial and Appeal Board is not asking who was there first, or “Okay, who came out with the first paper? Who has the first documentary evidence to demonstrate they were in possession of the invention?” Rather, the Board is trying to figure out what the what is—whether you really have the same invention and two parties fighting over that, or whether you have two separate inventions. If you have two separate inventions, you don’t have to get into this fight about who came first. You have two separate inventions with their own separate timelines.
But if you have the same invention, that is when you have to start getting into who was really there first. You have to look at pieces of paper that are signed. This is one of the reasons why Bell Laboratories required all engineers to have every page of their notebooks dated and signed before they left home for the evening—in the event there was an interference proceeding, they would have some documentary evidence to bring to it.
Dr. Davies: Meanwhile, what is going on in Europe?
Mr. Sherkow: The rules in Europe regarding priority for inventors are very different from what they are in the United States. In Europe, at the very least, Doudna and Charpentier’s principle patent application was granted by the European Patent Office (EPO). They won out of the gate in contrast to what happened here in the United States.
After patents get granted in Europe, parties can object—the formal word is “oppose” —a granted patent by the EPO, and so there are some opposition proceedings surrounding Doudna and Charpentier’s patent application. Those take a long time—as long as five years. We are not going to get a final-final decision on Doudna and Charpentier’s European patent application for a long time.
The Broad Institute also had a number of patent applications covering some foundational aspects of the CRISPR technology that was issued by the EPO. But there was a dispute over whether Luciano Marraffini (Rockefeller University) should have been listed on some follow-on patent applications that the Broad had filed. This was one of the bigger mysteries about the CRISPR patent case. Marraffini was a co-author on the Zhang group’s 2013 paper in Science [Cong et al.].
But he is not a listed inventor on many of the United States patents with Zhang. In Europe, some of the earlier patent applications had Marraffini listed, but later ones did not. This is not a huge deal in the United States.
If you believe that you have mistakenly listed inventors, you can remove them. This does not affect the priority of the patent. That is not true in Europe: they are very rigid about exactly who can be listed as an inventor and when, and whether that effects the priority of a patent application.
Last January, the EPO revoked many of the Broad's patents covering foundational aspects of CRISPR-Cas9 technology precisely because these patents did not have priority over Doudna’s application, and they did not have priority of Doudna’s application because Marraffini was not listed as an inventor on them. That is, needless to say, currently being appealed in Europe to an outfit colorfully called The Board of Appeal. And so obviously we are waiting for a decision on that. You know, there are at least two other rounds of appeals afterward if the Broad Institute is not satisfied with a decision there.
Dr. Davies: Is there a scenario whereby both groups may get US patents for different things, because as you explained, the courts have viewed them as non-interfering?
Mr. Sherkow: Yeah, that is certainly true. As more nucleases are discovered, there are more patents covering those particular nucleases, or uses of those nucleases, in new systems. For example, there is Cpf1, where Zhang is an inventor. There is CasX and CasY, discovered by Doudna and Jillian Banfield at Berkeley. On top of that, there are some Cas9 orthologs that seem to be protected under separate patents right now owned by an institute in Korea. There is another nuclease, Cas13a, useful in some diagnostic systems like SHERLOCK… So with more iterations of the technology, there are more and more patents covering these variations on the technology.
Dr. Davies: So relative importance with this CRISPR-Cas9 saga may start to recede as some of these other more recently characterized nucleases take on more commercial significance?
Mr. Sherkow: Yeah, I think that is true. If you want to take a historical analogy, you could think of this as patents covering first-generation DNA sequencing patents, or DNA amplification patents following the discovery of PCR, relative to some of the really cool, high-tech stuff in the sequencing world that we are seeing today, you know, like Oxford Nanopore sequences that are also covered by patents now too.
Dr. Davies: Why have the Broad and University of California not found a way to reach some sort of agreement?
Mr. Sherkow: This is anybody's guess… Typically, when these disputes are just about how much money could be received from royalties, that is usually when the lawyers hammer out a number that is acceptable to both parties, and everyone goes on their own separate ways. When there is a reluctance to settle cases like these, typically speaking it is about something more. I do not know if that is the case here, but it has left many people wondering.
Dr. Davies: Are there other CRISPR patents that perhaps we should spend time talking about?
Mr. Sherkow: There is one patent application that I think is particularly important that does not get nearly enough discussion — Virginijus Šikšnys's patent. If you take a look at the patent landscape in the US, Šikšnys was really the first owner of a patent to claim using CRISP Cas9 as a gene-editing technology. His patent application predates Doudna's by roughly six weeks. For some complicated reasons, this may be particularly bad for Doudna and Charpentier's application if they have to go back to the PTO…
We tend to view the patent dispute being between these two principal parties. But in reality, even in the US. where things are more crystalline than in Europe, there are more patents, more parties out there that may have an effect on the dispute than we may give them credence for.
As far as the ag/bio space goes, prior to their being a decision with respect to the interference proceeding, essentially Monsanto on one side, and DuPont Pioneer on the other took bets as to who was going to win the interference proceeding, with Monsanto siding with the Broad Institute and DuPont Pioneer siding with University of California.
After the interference proceeding was decided, Monsanto and DuPont Pioneer entered into a pretty interesting arrangement with the Broad Institute where they agreed to share their patents and cross-license them to any other agricultural companies interested in using a particular technology.
This is something that is commercially viable for them to do because, unlike in the therapeutic space, licenses tend to be non-exclusive anyway (it is not just one company doing one iteration of the particular technology to the exclusion of others. Rather, it is kind of everyone jumping in and developing the technology on their own ambit.)
So by DuPont Pioneer and Monsanto signing those cross-licenses, they have essentially resolve the patent dispute for new entrants in a way that it is not resolved in the human therapeutics space. We will get to see whether the ag/bio companies in the US are able to kind of make use of this cross-licensing deal.
The full interview was originally published as "The Evolving Law of CRISPR" in the Biotechnology Law Report.
The podcast with Mr. Sherkow is available at The CRISPR Journal.
