Clash of Titans: The Fight Over the CRISPR Gene-Editing Patent Rights

As we noted in previous posts in the Genomics Law Report (now, The Privacy Report), a major dispute over patent rights to CRISPR (for Clustered Regularly Interspaced Short Palindromic Repeats)-Cas9 systems broke out in January 2016 between Feng Zhang and the Harvard–MIT-affiliated Broad Institute on one side and Jennifer Doudna and the University of California–Berkeley (UCB) along with Emmanuelle Charpentier, Krzysztof Chylinski and the University of Vienna on the other. CRISPR-Cas9 systems are powerful tools for genome editing that allow researchers to activate, deactivate or even change the sequences of target genes. The basic biology has long been known from research into the immune systems of bacteria. Subsequent research has suggested the potential use of CRISPR to edit out disease-causing mutations in embryos and living organisms, including people. Researchers in China and the United States have recently reported success in “fixing” disease-causing mutations in human embryos—reports that have generated scientific concerns about unintended “off-target” genetic changes and ethical debate over “designer babies.” (https://www.nature.com/news/crispr-fixes-disease-gene-in-viable-human-embryos-1.22382.)

The two sides have been engaged in what is called an interference proceeding. The U.S. Patent and Trademark Office (USPTO) determined preliminarily that both parties were claiming patent rights to the same technology and initiated the interference to let them fight over who had priority. Under the pre-2013 version of the Patent Act that applies here, the key question would be who first invented the claimed technology. (The old Patent Act applies because the relevant patent applications were filed before the America Invents Act took effect on March 13, 2016—in the case of Doudna’s application, the day before.) The specific issue is whether Zhang was first to invent the use of CRISPR-Cas9 in mammalian and human cells or whether Doudna’s previous invention of CRISPR-Cas9 was broad enough to encompass its application in both prokaryotic and eukaryotic cells (including mammalian and human cells). The Broad group’s patents have been granted, while the UCB applications are still pending; UCB has another issued patent that is not involved here.

In February 2017, the USPTO’s Patent Trial and Appeals Board (PTAB; the last word in the USPTO administrative process) issued a ruling that amounted to “never mind.” It held that the Broad and UCB groups were in fact claiming distinct technologies, meaning that both could keep their respective patent rights. The test was whether the Broad group’s invention was merely an obvious advance over the UCB discovery, and the PTAB used UCB scientists’ public comments against them in determining that it wasn’t.

The Federal Circuit—the national patent appeals court—has now affirmed (upheld) the PTAB’s decision, effectively ruling in favor of the Broad group. (http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/17-1907.Opinion.9-10-2018.pdf.) The narrow legal ruling is that the PTAB’s decision should not be disturbed because the PTAB had “substantial evidence” to decide as it did—not that it was necessarily right or wrong. Regardless of the Federal Circuit’s reasoning, the critical consequence is that the Broad group can control CRISPR applications in humans and other mammals.

Reasonable scientific minds are already differing on whether the PTAB and the court got the genetic facts right. (See, for example, the thoughtful perspective of patent law professor Jacob Sherkow, with equally thoughtful comments from physician Robert Cook-Deegan and others, at https://www.statnews.com/2018/09/11/crispr-patent-decision-science/.) Regardless of the scientific accuracy, there seems to be little likelihood that the Supreme Court would hear the case, meaning that the Federal Circuit’s decision on this point is almost certainly final. But I should emphasize on this point: there may be years of future litigation involving these parties and others on such questions as whether the competing inventions meet all the standards for patentability and, if so, what activities might infringe.

The ongoing dispute raises serious policy issues that go well beyond the narrow question that the PTAB and the Federal Circuit have resolved. First, the fact that some of the world’s greatest nonprofit research organizations are fighting over patent monopolies might seem, well, unseemly. They’re all massively supported by government funds, so why shouldn’t they just put CRISPR into the public domain, where it could be freely used by anyone? Shouldn’t public-sector researchers—who are very well paid by academic standards—be doing scientific research for its own sake?

The answer lies in a 1980 federal law called the Bayh-Dole Act. The legislation was prompted by growing concern that American universities weren’t bringing scientific innovations—especially federally funded ones—to market so that they could benefit the public. To cure that problem, Bayh-Dole provided that universities could seek patents that derived from federally funded research and make money from those patents. As things have evolved, promising patentable inventions are often assigned or licensed to private companies, with the universities being compensated through combinations of up-front payments and ongoing royalties. At most universities, faculty inventors are required to assign patentable inventions to their universities in exchange for a share of future income. The private companies are often startups formed by those same faculty inventors.

The CRISPR saga has played out exactly as Bayh-Dole would have it. Each of the competing research organizations has formed spin-off private companies and granted them exclusive licenses to some or all of the technology: in the case of the Broad group, Editas Medicine; and for UCB, Caribou Biosciences. Individual scientists have equity interests in these companies, and UCB inventor Charpentier has other companies of her own. These exclusive licensees have in turn granted downstream licenses, some exclusive and some nonexclusive, to a number of other companies to exploit the patented technologies in particular fields. (A clever decoding of the licensing web by Sherkow and fellow law professor Jorge Contreras can be found here: http://science.sciencemag.org/content/355/6326/698.)

So it looks like everything is going according to the Bayh-Dole plan. The Bayh-Dole scheme added the possibility of future riches to the science-for-science’s sake motivation of the researchers and their organizations. They did brilliant research and made potentially game-changing discoveries. All the private companies in the licensing chain will have a financial motive to turn the basic science into medical applications. If the researchers and their employers make a lot of money (thanks to their patent rights), then good for them.

But this optimistic narrative assumes that the Bayh-Dole game plan will work as intended. Note that the CRISPR patents at issue in the Federal Circuit case —the ones that the Broad group has and the ones UCB may get—are at a very basic level. The first claim of Zhang’s 8,697,359 patent, for example, claims the use of CRISPR-Cas9 techniques, described in very general terms, to edit a gene in a eukaryotic cell—any eukaryotic cell (https://www.broadinstitute.org/files/shared/osap/pdf/US8697359.pdf). In simplest terms, if you want to use CRISPR-Cas9 editing in human or animal cells, whether for research or medical purposes, you’ll need a license from the Broad group.

In its press release after the Federal Circuit’s decision (https://www.broadinstitute.org/crispr/journalists-statement-and-background-crispr-patent-process), the Broad Institute was reassuring: “It is time for all institutions to move beyond litigation. We should work together to ensure wide, open access to this transformative technology.” But the release ended on a more ominous note: “Over the last five years we have made multiple attempts to engage the University of California. These efforts began before UC initially licensed its IP, and have continued even after the US Patent Office ruled in favor of Broad. We have continued to reach out.” In other words, we’d like to manage these patents in the public interest, but the other side won’t cooperate. UCB might say the same thing.

As the financiers of the basic research by both sides and the putative beneficiaries of that research, we, the taxpayers and future patient community, can only hope that it all works out: that the parties manage their patents so as to get medical applications to market, without impeding basic research. But nothing in the law compels that outcome. If these nonprofit titans want to behave like aggressive for-profit companies, nothing in the Bayh-Dole scheme would prevent it.