More Money, More Problems: The Science, the Law, and the Fight over CRISPR Patents

From Lab Bench to Court Bench: The Science, the Law, and the CRISPR Patent Dispute

Whenever a new technology has the potential to be ground-breaking and extremely valuable, there are bound to be disputes about invention and ownership. From Nikola Tesla and Thomas Edison to the new space race, scientists and inventors are often driven into competition and conflict. Recently, one such conflict has arisen over one of the biggest scientific discoveries of the Twentieth Century.

Clustered regularly interspaced palindromic repeats (CRISPR) are a molecular system whose harnessing is transforming the science, with important applications in medicine, biotechnology and other areas. By repurposing the natural biological system, scientists are able to target and make precise changes to specific strands of DNA at a more cost-efficient and faster rate than ever before. While CRISPR has spurred the development of a host of new technologies, there has been significant controversy over who actually owns the “invention.” A winner-takes-all dispute over the technology’s patent rights is in full swing between the Broad Institute and the University of California, Berkeley, and the spoils are plenty.

Serendipity and bacterial immunity

First discovered in Japan in 1987, CRISPR was subsequently shown to be an adaptive system used by bacteria to defend against viral infection. Francisco Mojica identified these repeating sequences of DNA in 1993, while working as a graduate student in Santa Pola, Spain. Mojica isolated CRISPR loci in over forty different microbes and identified their key features.

Just as Mojica was publishing his paper, Gilles Vergnaud—at the time, a geneticist for the French ministry of defence—was also completing research illuminating the function of the CRISPR system. Vergnaud found that the CRISPR locus often contained new spacers similar to those in prophages in bacterial genomes. It was Vergnaud and his colleagues who first hypothesized that CRISPRs serve as a defence mechanism for viral infection.

Subsequent work by researchers such as Philippe Horvath and Rodolphe Barrangou, working in the dairy industry to identify bacteria in yogurt and cheese production, developed our understanding of the cas9 protein. A seminal paper by Marrifini and Sontheimer, two researchers then at Northwestern contributed to identifying DNA as the target of CRISPR. These researchers were also the first to predict that CRISPR could be used for genome editing.

This serendipitous adventure from Spain to Chicago, which involved scientists working in industries as diverse as defence and food processing, predated the work done by the Berkeley’s Jennifer Doudna, and Feng Zhang of the Broad Institute. These varied fields which led to the development of the CRISPR-Cas9 system are telling of the wide impact the CRISPR system could have.

Not your average scientific debate

It is not surprising that arguments arose over the ownership of rights to CRISPR-based inventions which remove or alter “bad” bits of DNA contributing to diseases and genetic disorders. “Cancer-fighting” and “HIV-curing” are attention-grabbing phrases, and the implications and value of the science are both high-profile and high-value. For instance, there has been much debate over the The Human Fertilisation and Embryology Authority’s decision to allow a research team to engage in germ line editing of human embryos. The popular press—usually infrequently interested in complex scientific discussions—is attune to the importance of the dispute and the stakes.

So, what is the problem? The problem is that two major academic and scientific institutions, along with their scientists, cannot agree about the patents for CRISPR technology.

Big league players

The debate is more an institutional one than one between competing scientists. At the highest level, it is The Broad Institute and the University of California, Berkeley who are fighting a patent (and publicity) war over CRISPR. At issue are patents filed by Broad’s Zhang and Berkeley’s Doudna. Whoever owns the technology can expect a windfall in royalties and license fees.

The researchers

In 2012, Doudna et al. published a paper that elaborated on the mechanism used by the associated CRISPR system to insert breaks in target DNA. In this publication they discussed the possibility of applying the CRISPR-Cas9 system to genome editing in eukaryotic cells. However, as confirmed by Dr. Ron Pearlman, a biologist at York University, this paper described only the possibility of using CRISPR Cas9 for genome editing in eukaryotic cells and in that paper, the authors did not in fact do genome editing in eukaryotic cells.

Zhang et al. appear to have been first to report utilizing the CRISPR system to accomplish genome editing in mammalian cells. Soon after, George Church, a leading geneticist from Harvard,  published a paper that outlined possible applications of CRISPR in editing human cells. Church has emphasized that, while Doudna and Zhang were instrumental in the application of CRISPR technology, the gene-editing project was a collaborative effort. However, aside from this anecdotal evidence, it is not clear that this was the case.

The patents

The Berkeley patent application was filed on March 15, 2013 by Doudna and Emmanuelle Charpentier. Zhang filed his patent application seven months later on October 15, 2013. Zhang expedited the review of his application (under a “Petition to Make Special”), which would otherwise likely have been flagged as conflicting with the earlier one. He was granted a patent in April 2014.

In addition to determining who filed first, there are further questions concerning the scope of the patent claims in question. As New York Law School’s Jacob S. Sherkow notes, Doudna’s initial application “contained 155 broad claims to the CRISPR technology, but described only ‘genetically modified cells that produce Cas9’”, while Zhang’s “specifically contemplated adapting CRISPR in eukaryotic cells.” Although Doudna’s initial filing may not have conflicted directly with Zhang’s, her amended application did, because—her lawyers argue—the application covered gene-editing in mammalian (including human) cells.

Science goes to court

In April 2015, Doudna (Berkeley) took the issue of the competing patents to the United States Patent and Trademark Office and, in early January of this year, interference was declared. An interference proceeding is used to assist in the determination of priority: “which party first invented the commonly claimed invention.”

Administrative Patent Judge Deborah Katz, who declared the interference, now refers the matter to the Board of Patent Appeals and Interferences, which will consider evidence from both parties (such as laboratory notes and publications from both parties) in order to determine dates of invention. Today, the United States has a “first to file” patent system, but at the time Doudna filed her patent application, it was “first to invent,” so the interference proceedings will go forward on that basis.

The decision of the panel will determine who, if anyone, owns the patent rights to CRISPR-Cas9 editing in animal cells, based on whether Doudna’s application covered that aspect of the technology and on who invented it first. This interference has lessened the possibility of a settlement. The panel can decline to award the patent to either party.

Moreover, the decision may be appealed to the US Court of Appeals for the Federal Circuit. Recently, both parties filed their proposed motions for the interference proceedings, though the patent board trial judge has yet to rule on them. So, while the dispute may have moved from the lab to the courts, it is far from over for the institutions or their scientists.

Big money anxiety

Though the Broad Institute has made the technology widely available to the research community, a lot of money remains at stake in the control of these patents, especially for start-ups founded to develop the technology. Interference proceedings are rare and expensive, making them unusual for academic institutions. While the technology is freely available to academic researchers, commercialization is another matter altogether.

The commercial applications of this technology mean that more than just academic institutions are taking notice. As The Washington Post noted, CRISPR-related companies are already making significant investments in the technology. For instance, Editas Medicine (founded by both Zhang and Doudna) has planned a $100 million IPO. Other biologics firms, such as CRISPR Therapeutics, Intellia and Caribou Biosciences (which has raised nearly $90 million) are partnering with large pharmaceutical companies.

All of this raises questions about the benefits and drawbacks regarding the ownership of science, especially when there may be so much to be gained for peoples’ health. Researchers and start-ups alike appear to have every intention of making the most of the possibilities of the technology, but the uncertainty engendered by the Broad Institute-UC Berkeley patent fight does little to advance the science.

CRISPR clearly has the potential to be a game-changing medical technology, but clearly even ground-breaking discoveries have to wade through the legal muck sometimes.

Recent updates

The Patent Trial and Appeal Board ruled on several motions on March 17, from both Berkeley and Broad. Broad will be able to argue that there was no interference because of the specificity of its patents as to eukaryotic cells, while Berkeley will not be able to argue malfeasance on Zhang’s part at this time but will be allowed to argue for a reworded count. These early rulings are not determinative and serve to show how unpredictable the outcome is at this stage.

 

Sebastian Beck-Watt and Daniel Quainoo are IPilogue Editors and JD Candidates at Osgoode Hall Law School.

Leave a reply

Your email address will not be published. Required fields are marked *