The CRISPR/Cas9 system, and variants of it, allows for in-vivo modifications including gene knockouts, certain knockins and the introduction of conditional alleles. One field which has seen exponential growth in the use of CRISPR/Cas9 is the generation of custom genetically engineered mouse and rat models. As compared to other genetic modification techniques, the use of CRISPR/Cas9 in the development of rodent models requires less time, effort and expense, enabling investigators to obtain a study cohort sooner and more cost-effectively.
By obtaining access to the CRISPR/Cas9 patents, rodent model generation companies can offer researchers custom models developed using this technology. However, there are key issues that researchers must be aware of when requesting a model created using CRISPR/Cas9. An understanding of the patent history and intellectual property (IP) landscape surrounding the use of the CRISPR/Cas9 system is critical for any researcher considering designing a mouse or rat model using this technology.
History of patent filings
Similar to many other inventions, the CRISPR/Cas9 system has multiple claims to inventorship since its discovery as a genome-editing tool. Researchers Dr. Jennifer Doudna from UC Berkeley and Dr. Emmanuelle Charpentier, previously at the University of Vienna and now at the University of Umea in Sweden, both worked on CRISPR/Cas9 independently for years. In 2011, Charpentier’s lab published an article in Nature titled, “CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III.”
Later that year, these researchers decided to investigate CRISPR/Cas9 together, and their combined work led to the submission of a patent application to the United States Patent and Trademark Office (USPTO) on May 25, 2012. The patent, titled “Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription” (USPTO No. 10,000,772), cited Jennifer Doudna (Berkeley, CA), Martin Jinek (Berkeley, CA), Emmanuelle Charpentier (Braunschweig, DE), and Krzysztof Chylinski (Vienna, AT) as inventors, and The Regents of the University of California, The University of Vienna and Emmanuelle Charpentier as the applicants.
Separately, Dr. Feng Zhang was working in the CRISPR/Cas9 field at the Massachusetts Institute of Technology and The Broad Institute, using the CRISPR/Cas9 system in eukaryotic cells. In December 2012, the Broad filed a patent listing Dr. Zhang as the inventor, titled, “CRISPR-Cas systems and methods for altering expression of gene products” (Patent No. 8,697,359). The related paper published in Science in February 2013 was titled, “Multiplex Genome Engineering Using CRISPR/Cas Systems.” Although the Broad was technically fourth to file a patent relating to CRISPR/Cas9 gene editing, it opted to pay for an “accelerated examination,” resulting in the Broad being the first to obtain a granted patent on April 15, 2014.1
Shortly after the Broad’s patent was issued, UC Berkeley requested that the USPTO declare an interference, claiming that the Broad’s patent was too similar to its original patent application and that UC Berkeley was the first inventor of CRISPR/Cas9 for genome editing.
The U.S. Patent, Trial and Appeal Board (PTAB) evaluated the patents and ruled in favor of the Broad Institute in February 2017, holding that the inventions were patentably distinct. UC Berkeley appealed this decision to the US Court of Appeals for the Federal Circuit, which ruled in September 2018 that the Broad patent represents a non-obvious development of the CRISPR/Cas9 tool that is not covered by the UC Berkeley patent. Specifically, the UC Berkeley patent claims that the CRISPR/Cas9 system would be used “outside of a bacterial cell and outside of an archaeal cell,” while the Broad patent claimed the use of CRISPR/Cas9 genome editing in eukaryotic cells.2,3 The UC Berkeley patent issued in June 2018.
Companies with exclusive licenses
Multiple spinout companies have been created by the inventors of the CRISPR/Cas9 technology to license the tool to commercial clients. Created by Charpentier, ERS Genomics can license the technology to companies working on all fields of research except those using CRISPR/Cas9 to directly treat human disease (human therapeutics). Charpentier’s second company, CRISPR Therapeutics, licenses the technology to companies developing human therapeutics. There exists a similar setup from Doudna’s side, with Caribou Biosciences representing the non-human therapeutic licensor and Intelia Therapeutics having the ability to license to companies developing human therapeutics. On the Broad’s side, Editas Medicine was granted an exclusive license to utilize the CRISPR/Cas9 system in the development of human therapeutics.
Obtaining genetically engineered models made via CRISPR/Cas9 technology
Depending on the type of entity using the technology and the intended use of a mouse or rat model designed using the CRISPR/Cas9 technology, there are different requirements with regard to the licenses that need to be obtained. As stated earlier, the UC Berkeley patent covers the use of CRISPR/Cas9 for genome editing outside of bacterial and archaeal cells. While the team’s original research was conducted in vitro in test tubes, this language does not exclude the use of the technique in eukaryotic cells. The Broad patent specifically covers the use of CRISPR/Cas9 in eukaryotic cells only.
Taken together, this means that if an R&D or model generation company wants to ensure proper coverage, obtaining licenses to both patents would be the best route. Investigators interested in purchasing models created with CRISPR/Cas9 should ensure such licenses are in place prior to obtaining these animals for their research.
The Broad Institute permits not-for-profit researchers to use the CRISPR/Cas9 technology for genome editing without requiring them to obtain a license to the patent portfolio. However, this is limited to researchers who do not intend to commercialize their models. These permissions help advance basic research in genetically modified rodents, as it does not require an intense financial commitment on behalf of the researcher. These murine models can be bred by and transferred between non-for-profit institutions and government agencies under the terms of the Uniform Biological Material Transfer Agreement without requiring any licenses from the Broad. However, if the model is to be sold at any point, the institution would need to obtain licenses to one or both of the CRISPR/Cas9 patents.
Commercial companies may also generate their own CRISPR/Cas9-modified mice and rats; however, they require a license to one or both patents in order to practice the patented technology. They may test potential drug candidates and therapeutics in these mice as well as breed them internally. However, if the model is then to be sold to another for-profit company, the purchaser would also need to obtain their own licenses to the appropriate patent(s).
Designing a CRISPR/Cas9-modified murine model has been advertised as an easy, fast and cheap alternative to traditional genetic engineering methods. However, there are extensive knowledge and resources required in order to achieve the correct result. Companies that specialize in custom model generation are often relied upon to develop models using the CRISPR/Cas9 technology because they are able to combine the components essential for successful model creation: experience with genome-editing tools, broad technical resources, and PhD-level research teams with extensive experience and the capability to create well-designed models. This is beneficial for both academic and commercial investigators who would like to conduct research in a mouse or rat, but do not have the skillset or tools to do so. For investigators in commercial organizations, the added benefit is that their companies do not need to pay for licenses to the patents to conduct research in genetically modified rodents.
What’s next?
Modifications to the original CRISPR/Cas9 technology have already begun, with multiple patents being issued for specific alterations to the protein and/or nucleic acid sequence used (e.g., the addition of a nuclear localization signal to the Cas9 protein). These unique developments refine and perhaps enhance the technology. However, with every new invention related to CRISPR/Cas9, there is likely a follow-on patent for which a license needs to be obtained prior to using the new aspect of this technology to generate a model. Most model generation companies maintain licenses to the basic CRISPR/Cas9 patents mentioned previously, but as the technology evolves, researchers need to be mindful of how they are designing their model and what patents need to be obtained to avoid obstacles down the road.
Caroline Horizny, Ph.D., is a scientific technical writer at Taconic Biosciences. Her background consists of experience in RNA biology, nanotechnology and scientific content creation.
References
- Broad Communications. For Journalists: Statement and background on CRISPR patent process https://www.broadinstitute.org/crispr/journalists-statement-and-background-crispr-patent-process (accessed Jun 5, 2019).
- Feng Zhang. CRISPR-Cas Systems and Methods for Altering Expression of Gene Products. 8,697,359, 2013.
- Doudna, et al. Methods and Compositions for RNA-Directed Target DNA Modification and for RNA-Directed Modulation of Transcription. 10,000,772, 2012.
