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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What is CRISPR?

Some scientists believe the design and development of new biomolecules is as much an art as it is science. The Ěýdiscussed, and used, by Dr. Pearlman capitalizes on an adaptive immunity system found naturally in bacteria and archaea that uses clustered, regularly interspaced short palindromic repeat (CRISPER) DNA segments to fend off invading viruses. In naturally adapting to a virus invading the cell, CRISPR associated proteins (Cas proteins) will create a spacer unit of genetic code that is unique to the invading virus and incorporate this spacer into the CRISPR region of the cell’s genome. This unique spacer unit will then be transcribed (that is, converted from double stranded DNA to RNA), associate with Cas proteins to form a functional complex, and then target and inactivate the very same type of virus that led to the creation of the spacer unit.

In the laboratory, genome editing uses the functional complex found in this adaptive immunity mechanism to insert or remove genetic code from the genome of a cell. By attaching a synthetic, guiding portion of RNA (sgRNA) to Cas proteins they can be directed to a portion of the genome, through complimentary base pairing with the sgRNA, where Cas will recognize a portion of the genome and cut it to either insert a new region or to remove a portion and disrupt the expression of a gene. By cutting out sections of DNA a gene can be disrupted and lose its functional expression in the cell. In other words, it will no longer be able to produce the molecular products responsible for its former physical trait. By inserting new regions of DNA, the genome can be expanded to confer resistance to invading pathogens, such as viruses, or to express new protein products that can add or enhance the cell’s function. For example, a new portion of DNA may be inserted that codes for a digestive protein not normally found in the cell and, consequently, grant a new molecular digestive mechanism.

What does Genome Editing have to do with Law?

Dr. Pearlman noted that there has been an explosion of scientific literature covering the CRISPR system of genome editing since 2010 and it appears that the momentum will only grow in the coming years. The ability to edit genomes can allow for the expression of new protein products that can be of great commercial value as well as pave the way for new medical treatments that circumvent traditional pharmaceuticals. Additionally, Dr. Pearlman noted that the CRISPR system can be used to produce heritable traits – that is, changes that can be transferred from a parent to their offspring. With this sort of molecular modification becoming more pragmatic, it becomes paramount to have a thorough understanding of the biochemical expression pathways that govern genomic expression to keep an eye on the ethical implications of modification. If human genome editing were to become available, should those with advantageous genomic modifications be treated differently by public health systems? To whom should these technologies be made available, if ever? These questions are beyond the scope of current genomic technology but, with the growing pace of CRISPR methodologies, designs may soon start to reach more readily into the macroscopic domain.

What Makes Scientific Designs Different?

With the cost of biochemical research and development increasing and a billion-dollar entry fee for the drug and biomolecular development market it follows that when an industrially relevant molecule is finally created the developer should be able to recuperate their investment and benefit from their work. Normally, the boundaries of property rights require contextual understanding: what is the nature of comparable products, if the new product’s design is generic or obvious, and if the new product can have a place in its intended market. The differentiating criteria of the sciences become pronounced when considering the esoteric nature of the discipline. How can one reasonably expect a thorough consideration of the distinguishing criteria for obscure scientific concepts, like base pair fidelity, when the requisite knowledge is held only by a few people, like Dr. Pearlman, who have committed years, if not decades, to the study? The nuanced nature of genetics can make innovations in genome editing or CRISPR technology appear to be near imitation; however, the modification of a single nucleotide in the genetic code can have a profound impact on the success and possible application of a biotechnology.

Synthesis, Structure, and Industry

What amount of scientific knowledge is sufficient in legal practice? that a special breed of IP lawyer will arise to confront the high demands of contemporary science and technology patents. Considering the high financial stakes and the significant likelihood that a new molecule or molecular technique will fail the requisite safety tests at any of a multitude of stages, a lot of designs are left in the laboratory. A re-engineering of the approach or scrapping the project in its entirety may follow, meaning product patents should not be initiated until after the molecule has been proven safe for its regular use instead of when it is first designed or synthesized in the lab. Additionally, research and development can indirectly prioritize self-benefit over scientific collaboration since scientists rely on design details to learn about their ever-developing field and most details are kept secret until after a patent has been granted.

This is where innovation becomes conservative and structure becomes especially important. Does a single elemental substitution in the genetic code constitute a new product if the application remains the same? What about changing a single gene to modify a physical characteristic that relies on multiple genes? While certain business practices, such as non-competition deals, are commonly found outside of the sciences, unique can arise from small chemical modifications which effectively extend a patent beyond its expiry date through the issuing of a new patent for a highly similar molecule. Furthermore, patents may be sought for generic parts of biotechnology procedures that are nonessential to its action, prohibiting competitors from including strategies in their approach and significantly , or even demolishing, a competing synthesis. Lastly, meeting the testing and safety demands of different communities poses an for introduction into a global market due to different national regulatory standards.

So, What Makes It My Molecule?

The same fundamental concepts that apply to patents outside of genome engineering also apply to those inside the discipline but with a stringent demand to understand the nuances of molecular design. An integration of mechanistic knowledge may prove to be key when evaluating possible distinguishing criteria among patents filed for similar compounds but it is ultimately up to practicing lawyers to integrate sufficient scientific knowledge to accurately capture the scope of their client’s designs.

Dominic Cerilli is the Content Editor for the IPilogue and a JD Candidate at Osgoode Hall Law School.

[1] Dr. Pearlman's talk was organized by The 91ŃÇÉ« Collegium for Practical Ethics and The 91ŃÇÉ« Centre for Public Policy and Law under the leadership of Ian Stedman.Ěý Support for the event was provided by IP Osgoode, McLaughlin College, 91ŃÇÉ« - Faculty of Health, 91ŃÇÉ« - Faculty of Science, and 91ŃÇÉ«'s Office of the VPRI.

The post What Makes It My Molecule: A Look at Professor Ronald Pearlman’s Genome Editing Work appeared first on IPOsgoode.

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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