The CRISPR patent dispute between the University of California, Berkeley, and the Broad Institute is finally over. As almost everyone following the case predicted, the U.S. Court of Appeals for the Federal Circuit affirmed Monday the U.S. patent office’s decision that there was “no interference-in-fact” between UC Berkeley’s patent application and more than a dozen Broad patents. In plain English: Broad researcher Feng Zhang’s CRISPR patents were sufficiently inventive over the UC Berkeley’s patent applications with Jennifer Doudna and Emmanuelle Charpentier.
Many scientists disagree with the decision, believing that it fails to comport with how molecular biology is actually practiced. I agree with them. But that doesn’t make the Federal Circuit’s decision wrong. In fact, I think its decision is absolutely correct.
The reason has to do with standards of review — the standards courts use to weigh evidence, limit their authority, and make decisions. Like criminal law’s “beyond a reasonable doubt” standard, standards of review are incredibly important for many legal cases. They’re how much one side needs to prove something and, failing that, who should win.
The standard of review in the CRISPR patent dispute was the “substantial evidence” standard: whether a reasonable trier of fact (one or more people who determine the facts in a legal proceeding) based its opinion on substantial evidence. To be clear, that doesn’t mean the trier of fact got things correct, or even whether there was more evidence for the other side. Rather, the substantial evidence standard means only that a fact-finder based its decision on substantial enough evidence to be reasonable.
And there was substantial enough evidence for the Patent Office to determine that Zhang’s application of Doudna and Charpentier’s CRISPR-Cas9 system, which they developed in bacteria, to more complex eukaryotic cells (cells like human cells that have nuclei) constituted a significant enough advance to be its own invention. The patent office considered the scientific difficulties in getting other nucleic acid gene-editing systems to work in eukaryotes; statements submitted by experts from both sides, such as UC Berkeley’s own expert saying that there was “no guarantee that Cas9 would work effectively on a chromatin target or that the required DNA-RNA hybrid can be stabilized in that context,” and ultimately statements by Doudna herself that called the gap between bacteria and human cells a “huge bottleneck.”
I, and many scientists as well, think that holding these offhanded statements against Doudna is both unfortunate and bad as a matter of policy. But they were evidence, and the patent office was correct to consider them as such. Considered as a whole, those statements, the testimony of experts, and scientific difficulties in getting previous gene-editing systems to work in eukaryotic cells represent at least substantial evidence.
This doesn’t mean I agree with the patent office’s interpretation of the science. In its original decision, the patent office wrote that moving previous gene-editing systems from bacteria to eukaryotic cells suffered from numerous problems: “differences in gene expression, protein folding, cellular compartmentalization, chromatin structure, cellular nucleases, intracellular temperature, intracellular ion concentrations, intracellular pH, and the types of molecules in prokaryotic versus eukaryotic cells.”
These problems were real and shouldn’t be discounted. But, as I wrote in article for EMBO Reports last year, they were widely known to scientists at the time who could have solved each with a road map of solutions. “[D]ifferential gene expression can be controlled by selecting appropriate promoters; protein folding can, in some instances, be made uniform by certain optimization techniques; chromatin structure can be altered by histone modification; nucleases can be blocked; temperature can be regulated; pH can be buffered; and so on,” I wrote. As a matter of patent law, however, this experimental road map isn’t enough — it does not provide, in patent parlance, a “reasonable expectation of success.”
This illustrates, I think, a classic disconnect between the legal standards of patent law and the realities of scientific research. There are others, which I have also written about at length: on how science and patent law treat reproducibility; how they treat genetic datasets; on what, exactly, is a “law of nature.”
You could say that as a former laboratory scientist turned patent law professor, this is a particular academic interest of mine. But my view of what’s best is not the same as what the law actually is. The CRISPR patent decision may not have gotten the science right. But that doesn’t make it wrong as a legal matter.
If you don’t agree with the Federal Circuit’s decision, you may be in good company. The law can sometimes be wrong as a matter of both policy and practicality. But, at least ideally, the law provides a previously agreed-upon, neutral set of rules to decide disputes. When the law no longer works, it’s ultimately the job of Congress to change the law. And although this ideal is routinely flaunted in practice, it’s still a model to live by.
In fact, it’s something scientists themselves should be familiar with. When the facts stop fitting the model, you change the model, not the facts. You dust yourself off, come up with new hypotheses and new experiments to explain the world, and try again.
Jacob S. Sherkow, J.D., is professor of law at the Innovation Center for Law and Technology at New York Law School.
So Doudna and Charpentier will win Nobels while Zhang/Broad will keep the billions.
Jake, I quite agree about the CAFC doing what was expected, and that it would have been quite surprising if they reversed, given the detailed analysis that the PTAB judges devoted to the facts in the case.
But one point about science and the law. It is indeed quite sad if this case becomes a basis for tech licensing offices at universities muzzling their scientists to protect broad patent rights. Jennifer Doudna spoke the truth about uncertainty about whether CRISPR-Cas9 would work in eukaryotes. And her work with Emmanuele Charpentier and others is truly monumental. I hope earns them both a trip to Stockholm. But publication and scientific credit are all about building things and putting them in the world for others to build upon, which is exactly what has happened.
Patent rights, in sharp contrast, are government-granted licenses to sue if someone uses your invention. They serve a useful purpose. But the problem with the UC claims is that they extend to inventions that Doudna and Charpentier had not yet invented. This is customary in patent practice, but it’s particularly destructive with a powerful and broad platform technology. In my view, the PTAB got it right, including the science. And it’s good they did because extending the right to exclude beyond what an inventor has actually invented thwarts the social value of patents. Do we really think that UC should be able to block someone who uses CRISPR to develop a mosquito that does not transmit Zika virus or a cancer therapeutic, based on having demonstrated a powerful new platform method in molecules extracted from bacteria? Yet that is precisely what a patent right can do; that is its power.
I do not agree that the courts got the science wrong; I think the PTAB judges got the science right—accurately determining that it took actual experimentation and real work to show genome editing in nucleated cells was possible, and that “pioneer patent” claims were too broad. UC’s patent claims-drafting over-reached, and someone in the UC complex decided to play winner-take-all instead of forging a reasonable deal with Broad and the other early inventors (let’s not forget about Univ Vilnius, Mollica and others who should rightly get some of the benefits).
UC may be dominant in Europe because of how the European Patent Office interprets patent rights (although it will take a long time to work through all the opposition proceedings), but with the CAFC decision, perhaps the parties can finally come to the kind of open, straightforward nonexclusive licensing framework they could and should have crafted five years ago. The sabre-rattling about “litigation” from UC’s legal team sounds ominous, and I truly hope they do not go down that expensive, conflict-ridden, slow, and destructive path.
Jennifer Doudna spoke the truth. Let this be a heroine story, not a money-grubbing story. There’s plenty of money to be had. At this point, before the dollars start rolling in, it might be possible for everyone to feel like they got a fair deal. That would entail developing a framework that justly rewards the various inventors for what they contributed—but not more.
I disagree with the scientific methodological parsing that you heavily weigh your opinion on. With the molecular biology tools that were available in place 5-10 years ago and the modularity of proteins that are widely known to even graduate students, it is not too much of a stretch to expect a way of applying bacterial technologies to Eukaryotes. As an example, key technologies for generating mouse knockout/knockins available at the time were borrowed from Prokaryotes/viruses. I cannot comment on the legal benchmarks used. The potential of the applied scientific implications of Doudna/Charpentier’s work was known after their Science publication in 2012.
Albeit my technical background is not in molecular biology so I cannot comment on how “obvious” it is to adapt an expression pathway that is successful in prokaryotes in eukaryotes.
But based on the record and the CAFC’s opinion, I 110% agree with you.
The rights UC are asking for are definitely not commensurate with the disclosure they provided. Clearly there was still a need for tremendous amounts of experimentation to be performed to adapt the system in eukaryotes at the time UC filed.
As to Mendel Roth’s comment below: it seems as if you’re describing the need for further experimentation in order to determine if expression in eukaryotes would be successful.
The exact wording of our Patent Rules are “undue experimentation”
Saying “it’s not too far of a stretch…” may or may not be “undue experimentation” but don’t you think UC should’ve undertaken whatever experimentation required in order to be successful? Further, if the Broad researchers merely “beat the UC researchers to the punch,” shouldn’t the Broad researchers be awarded the patent?
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