This post will discuss the patent landscape of the groundbreaking CRISPR-Cas9 systems in the United States, including pending legal disputes. A CRISPR-Cas9 system is a combination of protein and ribonucleic acid (“RNA”) that can alter the genetic sequence of an organism. CRISPR-Cas systems occur naturally in bacteria and help the bacteria target and cut identified virus deoxyribonucleic acid (“DNA”). The CRISPR-Cas9 system is being developed as a powerful tool to modify specific DNA in the genomes of more complicated organisms, including plant and animal cells.
For the purpose of this overview, the mechanism of CRISPR-Cas9 is explained in the Patent Trial and Appeal Board (PTAB)’s Broad Institute v. The Regents of the University of California interference decision. As the decision explains, the CRISPR-Cas9 system comprises three effective parts: a guide-RNA sequence, an activator-RNA sequence, and a protein called Cas9. CRISPR-Cas9 alters a target DNA molecule by first binding the guide-RNA sequence to a specific sequence in the DNA of interest. The activator-RNA sequence then interacts with the Cas9 protein, and the Cas9 protein cuts the target DNA at a specific site. By linking a DNA-cutting protein (Cas9) to a specific site on the target DNA, the CRISPR-Cas9 system achieves specific targeted manipulation of DNA.
The U.S. Patent and Trademark Office (USPTO) has granted patents to variations of this general mechanism. At the time of this post, the USPTO had issued nearly 100 patents with “CRISPR” or “Cas9” in the abstract. The issued patents can be divided into four general categories: patents (1) directed to modifications to the components of the CRISPR-Cas9 system; (2) directed to therapeutic uses of the CRISPR-Cas9 system; (3) limited by a specific reaction environment; and (4) directed to delivering components into the cell.
1. Modifications to the Components of the CRISPR-Cas9 System
The first category of issued patents covers modifications of the general CRISPR-Cas9 system. Many of these modifications are directed to increasing the specificity and efficiency of site recognition, binding, or cleaving. The patents achieve this added efficiency by various means, such as modifying the guide RNA, the tracker RNA, or the Cas9 protein. Some patents do not purport to increase specificity or efficiency, and instead just claim a different form of the CRISPR-Cas system. For example, some patents use a protein other than Cas9 to cleave the nucleic acid. Other patents use a guide-DNA sequence instead of RNA. And other patents modify the system to cleave a single-stranded nucleic acid instead of the double-stranded one.
2. Therapeutic Uses of the CRISPR-Cas9 System
The second category covers therapeutic uses of the CRISPR-Cas9 system. Some patents use the technology to target specific diseases such as HIV infection and Alzheimer’s Disease. Other patents use the technology to target immune cells, genetically modifying the cells to make them more efficacious therapeutically.
3. CRISPR-Cas in a Specific Reaction Environment
The third category covers patents directed to the CRISPR-Cas mechanism in a specific environment. For example some are limited to the mechanism in vitro; some are limited to prokaryotes; and others are limited to eukaryotes. Some patents are even more specific and cover the CRISPR-Cas mechanism in particular organisms, including Lactococcus, E. coli, and phages.
4. Delivering the CRISPR-Cas Components into the Cell
The last category covers processes of delivering CRISPR-Cas components into the cell. These patents generally cover delivering the cleaving protein Cas9 into a cell.
This is a general overview of the current patent landscape for CRISPR-Cas9 and is not intended to be comprehensive. In fact the landscape is rapidly changing. Currently there are over 400 published patent applications containing either “CRISPR” or “Cas9” in the abstract, with new applications being added regularly.
As the CRISPR-Cas9 landscape evolves, legal disputes involving the technology will likely proliferate. There are at least two pending disputes relating to CRISPR-Cas9.
The first dispute, Regents of the Univ. of Cal. v. The Broad Institute, is currently on appeal at the Federal Circuit. In the underlying interference, the University of California (“UC”), the senior party, filed a patent application describing CRISPR-Cas9 as a gene editing technology in any environment, ostensibly covering both eukaryotic and prokaryotic cells. The Broad Institute (“Broad”), the junior party, has issued claims to CRISPR-Cas systems limited to use in eukaryotic cells. The PTAB held that there was no interference in fact because “the parties claim patentably distinct subject matter.” According to the PTAB, “the evidence shows that the invention of [CRISPR-Cas] systems in eukaryotic cells would not have been obvious over the invention of CRISPR-Cas9 systems in any environment, including in prokaryotic cells or in vitro, because one of ordinary skill in the art would not have reasonably expected a CRISPR-Cas9 system to be successful in a eukaryotic environment.” UC appealed. The Federal Circuit heard oral arguments on April 30, 2018, and a decision is forthcoming at any time.
Another dispute involves a petition for post grant review to invalidate certain CRISPR claims filed on July 17, 2018 also involving Broad. The relevant patent is directed to systems for genetic engineering eukaryotic cells using a Cpf1 cleaving protein instead of Cas9. The petition argues the claims are invalid under written description, enablement, indefiniteness, utility, and obviousness.
CRISPR-Cas9 is a potentially revolutionary biotechnology invention. As such, patent rights over the technology are being fiercely disputed around the world. This post is intended as a snapshot of the CRISPR-Cas9 legal landscape in the United States.
Gibbons will continue to monitor patenting trends and disputes involving CRISPR-Cas systems and provide periodic updates. Please contact the authors for additional information.