Photo by Sangharsh Lohakare ()

Emily Prieur is an IPilogue Writer and a 3L JD Candidate at Queen’s University Faculty of Law.

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Introduction

In to Drs. Emmanuelle Charpentier and Jennifer A. Doudna for “the development of a method for genome editing” otherwise known as CRISPR gene editing.

CRISPR’s discovery was a revolutionary breakthrough that has the potential to . CRISPR has been widely discussed within the scientific community for years for both its scientific and .

But in late February 2022, CRISPR entered the news for an entirely different reason. After a decade-long dispute, the United States that Drs. Charpentier and Doudna were not the rightful owners of the CRISPR-Cas9 patent, concluding that the gene editing technology belonged to Dr. Feng Zheng and his team of scientists at the Broad Institute of MIT and Harvard.

What is CRISPR?

CRISPR is an acronym for “” and Cas9 is short for “CRISPR-associated protein 9”. CRISPR are specialized repeats of genetic information (i.e., DNA). . The protein that is added to the DNA ; however, it is the protein that is most often used by scientists when employing this technique. In essence, the finding a “bad” piece of DNA, removing that bad piece, and then correcting the DNA sequence by inserting a new gene.

The Patent Dispute History

Drs. Charpentier and Doudna from the University of California-Berkeley (“UCB”) showed the genius of the CRISPR editing method in their paper in 2012, specifically on gene-editing in test tubes. Dr. Zhang and his group at the Broad Institute of MIT and Harvard also published in in 2013, showing the promise of CRISPR/Cas9 in humans.

Following the scientists’ publications, the United States transitioned from a first to invent patent system to a first inventor to file system, . This is relevant as all patent disputes between the scientists revolved around the issue of who invented CRISPR, and, more specifically, who was able to prove CRISPR’s application in humans, first.

In 2014, the United States Patent and Trademark Office (“USPTO”) granted U.S. Patent to Dr. Zhang and his group at the Broad Institute of MIT and Harvard. There were two interferences at the PTAB, in 2015 and 2019, both triggered by the UCB through and For the first interference, the that there was no interference because of the invention’s (i.e., eukaryotic human cells versus non-human cells in a test tube). For the second interference, UCB requested that the PTAB reverse the prior first instance decision and conclude that successful experiments in human cells is not necessary to successfully obtain the patent.

The PTAB’s Decision

Following the scientists’ oral arguments on February 4, 2022, the that Dr. Zheng and his team at the Broad Institute of MIT and Harvard were the rightful owners of the patent. UCB was unable to prove that their invention was applicable in human cells prior to the Broad Institute’s invention in 2013.

Conclusion

The battle may not be over. Drs. Charpentier and Doudna, along with the University of California Berkley, have the option to appeal to the U.S. Court of Appeals Federal Circuit. In a , the University of California Berkley said it was to challenge the PTAB decision, making an appeal even more likely. In addition to UCB, Dr. Zheng and his colleagues at the Broad Institute of MIT and Harvard are also embroiled in

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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 to the , scientists and inventors are often driven into competition and conflict. Recently, one such conflict has arisen over one of the biggest of the Twentieth Century.

Clustered regularly interspaced palindromic repeats () 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 , 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 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.

, which involved scientists working in industries as diverse as defence and food processing, predated the work done by the Berkeley’s , and 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 contributing to . “Cancer-fighting” and are attention-grabbing phrases, and the implications and value of the science are both . For instance, there has been much debate over the to allow a research team to engage in germ line editing of human embryos. The —usually infrequently interested in complex scientific discussions—is attune to the importance of the 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 and the who are fighting a patent (and ) 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 .

The researchers

In 2012, Doudna et al. published 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 , a biologist at 91ŃÇÉ«, 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 utilizing the CRISPR system to accomplish genome editing in mammalian cells. Soon after, George Church, a leading geneticist from Harvard, Ěýpublished that outlined possible applications of CRISPR in editing human cells. 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 application was filed on March 15, 2013 by Doudna and . Zhang filed his application seven months later on October 15, 2013. Zhang expedited the review of his application (under a “”), which would otherwise as conflicting with the earlier one. He was 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 91ŃÇÉ« Law School’s notes, Doudna’s initial application “”, while Zhang’s “.” Although Doudna’s initial filing may not have conflicted directly with Zhang’s, her , 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 and, in early January of this year, . An interference proceeding is used to assist in the determination of priority: “.”

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 “” 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 , based on . This interference has lessened the possibility of a 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, 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 to the research community, a lot of money remains at stake in the control of these patents, especially for founded to develop the technology. Interference proceedings are , making them unusual for academic institutions. While the technology is , commercialization is another matter altogether.

The commercial applications of this technology mean that more than just academic institutions are taking notice. As , CRISPR-related companies are already making significant investments in the technology. For instance, (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 of the technology, but the uncertainty engendered by the 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 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.

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