On September 10, a US court settled an increasingly churlish patent dispute between two research institutions in the country, the University of California (UC) in Berkeley and the Broad Institute, Massachusetts, with great consequence for the commercial use of a powerful gene-editing technology called CRISPR-Cas9.
The dispute centred on CRISPR’s usability in two different kinds of biological lifeforms: prokaryotes and eukaryotes. UC had devised a way to edit the genetic makeup of prokaryotes using CRISPR in 2014. Broad followed a year later with a method to use CRISPR in eukaryotes. UC had subsequently contested the patentability of Broad’s method saying that it was a derivative of UC’s method and couldn’t be patented separately.
The court as well as the US patent office have disagreed and upheld Broad’s patent.
The following FAQ breaks the case down to its nuclear components and assesses the verdict’s implications and future courses of action.
What are CRISPR and CRISPR-Cas9?
CRISPR is a natural defensive mechanism that prokaryotes use to protect themselves against viruses. Prokaryotes are smaller, less complex lifeforms and include bacteria and archaea: they are unicellular, the cells lack a membrane as well as membrane-bound organelles. The bigger lifeforms are classified as eukaryotes, which are multicellular, whose cells have a membrane and the cells also contain membrane-bound organelles. Because of these and other differences (see here, p. 8), it wasn’t clear if a CRISPR system built for use in prokaryotes could be adapted by a person of reasonable skill for use in eukaryotes with a reasonable chance of success. This distinction is at the heart of the patents dispute.
CRISPR-Cas9 is essentially a technology that combines CRISPR with a protein called Cas9 to form a molecular tool. This tool can swim to a eukaryote’s DNA, pick out a specific section of the genes and snip it at both ends, removing it from the DNA sequence. Once the section is out, the DNA strand repairs itself to restore the genes. If the original section of genes was faulty (e.g. containing an undesirable mutation), then CRISPR-Cas9 can be used to remove it from the DNA and force the DNA strand to repair itself to a healthier version.
Researchers have already reported that they are close to using this technology to treat a debilitating condition called Duchenne muscular dystrophy.
Of course, there are other gene-editing technologies, including zing-finger nucleases and transcription activator-like effector nucleases, but CRISPR-Cas9 has proved to be more efficient, effective and easier to use. At the same time, a few concerns are starting to emergeabout unintended side-effects.
What was the case timeline?
The UC team, led by Jennifer Doudna, published a paper in August 2012 describing how an RNA-based system called CRISPR-Cas9 could be used to edit DNA in prokaryotic cells. Editing DNA is a lucrative prospect – then and now – because it allows us in theory to modify the fundamental constitution of biological life, curing debilitating illnesses as much as modifying crops. And what the UC team had found, together with Emmanuelle Charpentier, then of the University of Umea in Sweden, was the first tool that could achieve this. After their paper was published, the UC team filed a patent with the US Patent and Trademarks Office (USPTO) for the use of CRISPR in prokaryotes.
While UC’s patent was pending, a team led by Feng Zhang from the Broad Institute, setup by the Massachusetts Institute of Technology and Harvard University, Boston, published a paper in 2013 and then built a CRISPR system in 2014 that could work in eukaryotes. Zhang and co. then filed for an expedited patent that was granted in 2017. At this point, UC complained to the USPTO that the Broad patent infringed on its own – that, effectively, Zhang et al’s work was not patentably distinct from Doudna et al’s work. UC’s own patent for CRISPR use in prokaryotes was granted in early 2018.
In late 2017, the Patent Trial and Appeal Board (PTAB) of the USPTO upheld the Broad patent, effectively stating that the DNA-editing technologies used in prokaryotes and eukaryotes were “patentably distinct”. Specifically, it had ruled that there was no interference-in-fact, i.e. that UC’s general description of use of CRISPR in biological systems could not have anticipated, under reasonable circumstances, Broad’s more specific CRISPR invention for use in eukaryotes. An interference-in-fact check is pegged on a so called ‘obviousness review’. A 1966 SCOTUS case defines four factors using which it can be undertaken:
(1) the scope and content of the prior art; (2) the differences between the claims and the prior art; (3) the level of ordinary skill in the art; and (4) objective considerations of non-obviousness
UC decided to appeal the PTAB’s verdict with the US Court of Appeals of the Federal Circuit (CAFC). The latter came to its decision on September 10, ruling in favour of the USPTO and upholding the Broad patent.
What happens next?
A lot of things. Let’s classify them as financial, academic, legal and administrative.
Financial – Where there’s a patent, there’s money. However, there’s more money for Broad than for UC because almost all application of the CRISPR technology will happen in eukaryotes, a domain that includes humans and plants. And because the Broad patent has been upheld, this effectively means the UC patent can apply only to prokaryotes and not to eukaryotes.
Public attitudes to this affirmation were partly reflected in the share values of three companies intent on commercialising CRISPR tech: Crispr Therapeutics AG (cofounded by Charpentier) and Intellia Therapeutics have licenses with UC and their shares fell by 5.3% and 2.5% respectively; Editas Medicine Inc., which has licenses with Broad, climbed by 6.8%.
A review in 2017 stated that although “CRISPR IP ownership is claimed by at least seven different parties”, the Broad patent could be a “blocking patent” because of its ancestral nature. This is one reason why the Broad Institute has already issued 13 licenses, more than any of the other patent-holders. In all, the review estimated that the American gene-editing industry will be worth $3.5 billion by 2019, with CRISPR propelling biotechnology to the status of “second highest funded sector in the United States”.
Academic – The contest between UC and Broad has only worsened the mutual, and deleterious, embitterment between the institutions. In 2015, Broad launched an acrimonious campaign to turn public opinion in its favour, which included attempts to rewrite the history of DNA-editing research and present Zhang’s achievement in stronger light. The possibly most damaging thing Broad did was to quote UC’s Doudna herself as having expressed frustration and doubt about whether a CRISPR system for use in bacteria could be adapted for use in eukaryotic cells.
These quotes were used in Broad’s filings for the patent dispute, undermining UC’s case. However, scientists have argued that science is almost never free of frustration and that Doudna was also right to express doubt because that’s what any good scientist would do: lead with the uncertainty until something to the contrary could be demonstrated. However, Broad effectively penalised Doudna for being a good scientist – an action that Michael Eisen, a biologist in Doudna’s department at UC, has said is rooted in universities being able to profit from patents created with taxpayer dollars.
Legal – It’s important to recognise what UC has actually lost here. UC appealed the PTAB verdict, bringing it to the CAFC, who in turn ruled that the PTAB had not wronged in its conclusion. The judge did not reevaluate the evidence and did not hear arguments from the two parties; no new evidence was presented. The court only affirmed that UC, in the eyes of the law, did not have grounds to contend the PTAB verdict. A salient portion from the judgment follows, where the judge writes that some parts of the CRISPR/Cas9 system as used in prokaryotes could have been adapted for use in eukaryotes but that that’s besides the point (emphasis added):
UC expended substantial time and effort to convince this court that substantial evidence supports the view it would like us to adopt, namely, that a person of ordinary skill would have had a reasonable expectation of success in implementing the CRISPR-Cas9 system in eukaryotes. There is certainly evidence in the record that could support this position. The prior art contained a number of techniques that had been used for adapting prokaryotic systems for use in eukaryotic cells, obstacles adopting other prokaryotic systems had been overcome, and Dr. Carroll suggested using those techniques to implement CRISPR-Cas9 in eukaryotes. We are, however, an appellate body. We do not reweigh the evidence. It is not our role to ask whether substantial evidence supports fact-findings not made by the Board, but instead whether such evidence supports the findings that were in fact made. Here, we conclude that it does.
Therefore, this is a judgment of the law, not a judgment of the science.
According to Jacob Sherkow, a professor at the New York Law School, UC can either petition the CAFC for a rehearing or appeal to the Supreme Court. Sherkow added that neither strategy is likely to work because he doesn’t think “this case presents any *novel* legal issues” (emphasis in the original). This means UC will likely return to the patent office and attempt to “salvage what they can from their patent application”.
There is also another problem. To quote Chemical and Engineering News,
… it recently became clear that another CRISPR scientist, Virginijus Šikšnys of Vilnius University [Lithuania], filed a patent for CRISPR/Cas9 just weeks before UC Berkeley filed its patent in 2012. While UC Berkeley and Broad were entangled in their dispute, the Šikšnys patent was approved and made public, meaning that USPTO can now hold the Šikšnys patent against UC Berkeley. “That has the potential to sink whatever is left from Berkeley’s patent application,” Sherkow says.
Administrative – This part is confusing. In the US, the USPTO upheld the Broad patent in February 2017. But in Europe, the European Patent Office (EPO) ruled in favour of Doudna and Charpentier in March 2017. So depending on the jurisdiction, companies that want to commercialise CRISPR technology (for eukaryotes) will have to work with UC in Europe and the Broad Institute in the US. At least one company, DowDuPont, which is using CRISPR to engineer corn and soybean crops to be cultivable without pesticides, has purchased licenses with both institutions.
The different judgments arise from one difference in how the EPO and the USPTO evaluate ‘no interference-in-fact’. According to a May 2017 report by Sherkow, “In Europe, one is entitled to a broad patent on a new technique, if it demonstrates an ‘inventive step’ over prior methods, even if there [is] no guarantee that it will work for all of its claimed applications.” In the US, on the other hand, each “claimed application” has to be demonstrated and is separately patentable if one application doesn’t follow obviously from the previous. The EPO decision is open to challenge and Broad is likely to use the opportunity to do so.
By the way, the country with the second-most patents related to CRISPR is China, after the US. Chinese research institutions and industry players have been focusing mostly on knockout mechanisms of CRISPR, which control how undesirable genes in a DNA sequence are removed. To quote at length from the 2017 review,
The Chinese government has been actively involved in gene-editing funding. The National Natural Science Foundation of China (NNSF), invested $3.5 million in over 40 CRISPR projects during 2015. Through the NNSF and the National Basic Research Program, the Chinese government has funded the first use of CRISPR for the modification of human embryos. Additionally, Shenzhen Jinjia Color Printing Group Co., a public company, has pledged $0.5 million to fund Sun Yat-sen University for studying CRISPR in embryos.
What do scientists say?
Scientists’ reactions are still coming in, although no consensus is likely to emerge soon. In the meantime, awards make for a reasonable proxy to determine what scientists think is laudable. On this count, Doudna and Charpentier are clear leaders. Since 2014, Doudna has won 20 awards (excluding one from UNESCO), Charpentier has won dozens and Zhang, nine (although must be noted that Doudna and Charpentier have been scientists for longer than Zhang has). Doudna, Charpentier and Šikšnys were also jointly awarded the 2018 Kavli Prize in Nanoscience.
September 11, 2018