Who Owns CRISPR?
By Natalie Bratset
-Featured Image by Natalie Bratset
On June 28th, 2012, a paper in the AAAS journal, Science, titled A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity began the CRISPR revolution. However, with this magnificent discovery came an ongoing patent battle between the MIT-Harvard Broad Institute and UC Berkeley/the University of Vienna over who the rightful owner of CRISPR is, which is still going on to this day.
THE CRISPR ORIGIN STORY
The CRISPR/Cas9 system was discovered in bacteria as a form of immunity against viruses. It works by recognizing harmful viral DNA and stopping the virus from making copies of itself by cutting that DNA out.1 In 2005, Francisco Mojica at the University of Alicante characterized CRISPR as an adaptive immune system in specific bacteria.2 Around the same time, Alexander Bolotin at the French National Institute for Agricultural Research discovered the Cas9 protein while studying the bacteria Streptococcus thermophilus—a probiotic that you might have in your microbiome right now!2 After years of work and many different hypotheses on the exact inner workings of CRISPR/Cas9, Emmanuelle Charpentier at Umea University Sweden and University of Vienna Austria, finally unraveled a mechanism for this bacterial immune system in March of 2011. She identified two small RNAs ,crRNA and tracrRNA, that served as a template for where to cut the DNA.2
At the same time, Charpentier teamed up with Jennifer Doudna from UC Berkeley to understand the CRISPR/Cas9 DNA cutting mechanism.3 Shortly after, their infamous 2012 paper was published. The authors of this paper showed that with some clever re-engineering of this bacterial mechanism and its RNAs, CRISPR/Cas9 can be used to cut any sequence we desire out of DNA. This groundbreaking discovery unlocked a vital tool that, when combined with a variety of procedures, can perform specialized genetic modifications—such as gene deactivation, gene deletion, gene replacement, and more. CRISPR/Cas9 are the “genetic scissors” that scientists now have in their arsenal.
Charpentier and Doudna were recognized in 2020 when they received the Nobel Prize in Chemistry for their discovery of the CRISPR/Cas9 genetic scissors.4 With this new and amazing technology, a whole world of possibilities opened up in research and clinical applications. Now, scientists can use this reliable and customizable tool to make precise cuts in a DNA sequence without being too destructive to the target cell.
Charpentier and Doudna were not the only two interested in CRISPR; another team on the East Coast was also investigating CRISPR in 2012. Led by Feng Zhang at the Broad Institute of MIT and Harvard, Zhang and his team published a paper in February 2013 that outlined the methods and use of CRISPR/Cas9 specifically for genome editing with two engineered versions of the bacterial Cas9 protein.2 Without getting into semantics, Doudna and Charpentier made a hybrid RNA sequence to customize CRISPR cutting. In contrast, Zhang and his team used two modified Cas9 proteins in mammalian, or eukaryotic, cells to do the same thing.3,6 The major difference is that Doudna and Charpentier’s original paper did not have evidence of their CRISPR technique working in eukaryotic cells. After these two discoveries hit the press, there was a resounding uproar about the potential of CRISPR/Cas9 editing systems. Alongside this positive response, however, a storm began to brew over the ownership of CRISPR.
A BATTLE OF PATENTS
The exact details of the patent-related events get a little blurry. According to UC Berkeley’s website, Doudna, Charpentier, and Martin Jinek of UC Berkeley—with Krzystof Chylinski of the University of Vienna—were the first to file their patent on May 25th, 2012.3 Whereas Zhang with the MIT-Harvard Broad Institute filed their patent on October 15th, 2013, over a year later.5 Although UC Berkeley filed their patent first, the Broad Institute paid for the expedited application, so its patent was awarded first in 2014.3
In 2015, UC Berkeley requested that the United States Patent and Trademark Office (USPTO) review the Broad Institute and their patents to determine who invented CRISPR first—called a patent interference proceeding. In February 2017, the USPTO Patent Trial and Appeal Board (PTAB) decided that the Broad Institute and UC Berkeley patents did not overlap. They cited that both can keep their patents because the Broad Institute version is specific to eukaryotic cells, while the UC Berkeley patent applied to all cells.7 Although this seemed like a fair compromise at first, it did not end the debate.
UC Berkeley, amongst many others, began filing more patents for various applications and interactions of the original CRISPR/Cas9 system. As a result, the USPTO began looking more into exactly who was the first to develop the infamous genetic scissors. On February 28th, 2022, the USPTO decided that Zhang and the Broad Institute were the first to show that CRISPR worked in eukaryotic cells, and therefore they were the inventors of the CRISPR/Cas9 technique for agricultural and medical uses.8 This monumental decision has resounding effects on many aspects of both academic and clinical use of CRISPR/Cas9.
LOCKED BEHIND A LICENSE
Why are these two fighting over CRISPR in the first place? And why does this matter? Maybe it’s the prestige. CRISPR-based therapies have extreme potential, and perhaps the Broad Institute and UC Berkeley ultimately wanted the crowning achievement of “we invented that” and the money that follows. Unfortunately, the aftershocks of this decision have major implications for the development of these CRISPR therapies since UC Berkeley’s patents no longer hold for eukaryotic uses of these treatments. Companies that have licenses with UC Berkeley—and are the farthest along in clinical trials—such as Crispr Therapeutics, Intellia Therapeutics, Caribou Biosciences, and more, are no longer able to use their licenses.9 According to Jacob Sherkow, a professor of law at the University of Illinois, “They will need a license from the Broad Institute before they launch any product approved by the FDA… This patent decision casts a shadow over whether and when the first CRISPR therapies will be launched onto the market.”8 The decision also has detrimental financial implications, with UC Berkeley facing an estimated $100 million to $10 billion in losses from licensing revenues.9 This decision is not the end of the patent dispute. As of April 4th, 2022, Charpentier, UC Berkeley, and the University of Vienna have already appealed.10 So the final decision on the fate of CRISPR has yet to be determined.
Locking this revolutionary technology behind patents and licenses will only detriment the resounding efforts to try to help people with new and innovative therapies. Hopefully, as this complicated patent debacle unfolds, the enforcement and paywalls of CRISPR/Cas9 techniques will be relaxed, and this technique will be able to help millions of people.
So, in the end, who really owns CRISPR? In my opinion, I’d say it’s the bacteria.
References
1. Jinek, M. & et. al. (2012, August 17). A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. doi: 10.1126/science.1225829.
2. CRISPR Timeline. Broad Institute. Retrieved from https://www.broadinstitute.org/what-broad/areas-focus/project-spotlight/crispr-timeline
3. (2019, June 25). CRISPR Timeline. UC Berkeley. Retrieved from https://news.berkeley.edu/2019/06/25/crispr-timeline/
4. (2020, October 7). Press Release: The Nobel Prize in Chemistry 2020. NobelPrize.org. Retrieved from https://www.nobelprize.org/prizes/chemistry/2020/press-release/
5. Zheng, F. (2014). CRISPR-Cas systems and methods for altering expression of gene products. (US. Patent No. 8,697,359 B1). U.S. Patent and Trademark Office. Retrieved from https://patents.google.com/patent/US8697359B1/en
6. Cong, L. & et. al. (2013, February 15). Multiplex genome engineering using CRISPR/Cas systems. Science. doi: 10.1126/science.1231143.
7. Jewell, C. & Balakrishnan, V.S. (2017, April). The battle to own the CRISPR–Cas9 gene-editing tool. World Intellectual Property Organization Magazine. Retrieved from https://www.wipo.int/wipo_magazine/en/2017/02/article_0005.html
8. Cross, R. (2022, April 4). The Broad won the biggest CRISPR patent fight yet, but the rivalry over gene editing is still simmering. The Boston Globe. Retrieved from https://www.bostonglobe.com/2022/04/04/business/broad-won-biggest-crispr-patent-fight-yet-rivalry-over-gene-editing-is-still-simmering/
9. McGrail, S. (2022, March 7). UC Berkeley Loses CRISPR Gene-Editing Patent Appeal. PharmaNews Intelligence. Retrieved from https://pharmanewsintel.com/news/uc-berkeley-loses-crispr-gene-editing-patent-appeal
10. Armstrong, A. (2022, April 4). CRISPR patent dispute not over yet as Emmanuelle Charpentier, universities appeal. Fierce Biotech. Retrieved from https://www.fiercebiotech.com/biotech/crispr-patent-dispute-not-over-yet-charpentier-universities-appeal