CRISPR Systems: Natural Occurrences & the Trans-Atlantic Divide over Patent Rights
Clorox sells a product, “disinfecting wipes,” that boasts on its container, “Kills 99.9% of Viruses & Bacteria.” It’s a great product, and I use it every day. But it’s a good thing there’s plenty more bacteria around. Scientists have begun deferring to them for inspiration, and it turns out, bacteria just might provide the panacea for an array of genetic afflictions.
Yes, I’m talking about “CRISPR,” a class of adaptive anti-viral systems that naturally occur in bacteria and archaea and that, recently, scientists have learned to manipulate as non-natural biomedical tools for genetic engineering in plants and animals — including humans.
To be clear, in many ways, biomedical genetic engineering of humans has become a reality even without the inception of CRISPR-based technologies. And aside from that, it’s also true that there is already a steady stream of articles highlighting the prospective implications of this “second generation” suite of biomedical tools, including a hefty dose of both fanfare publications and calls for alarm alike. In fact, CRISPR-based patent filings have existed for six years now and considering not just the 24/7 media cycle we’ve grown accustomed to, but even more so the breakneck speed of biomedical innovation, that’s a lifetime ago. But with the dust starting to settle after the latest round in a cross-jurisdictional epic of patent disputes, the landscape of patent-holders well-slated to dominate the market for genetic medical technology is beginning to materialize on both sides of the Atlantic — and it now seems likely that different titans are in the making on one side versus the other. If you plan to continue living on Earth in the near future, this warrants your attention.
Bacteria and archaea are the two sorts of biomolecular organisms that together comprise the family of prokaryotic organisms. “Prokaryotes” are unicellular lifeforms characterized by a DNA complex called a “nucleoid,” which lacks a nuclear membrane; cf. all other biological lifeforms, which fall under the domain of “eukaryotes,” organisms defined by cellular structures that contain their DNA in membrane-bound nuclei. Notably, nucleoids’ lack of nuclear walls results in their extreme susceptibility to infectious agents – specifically, bacteriophage, a family of gene-changing viruses that first invade, and then replicate through, the genetic encoding of bacteria and archaea. While exclusively found in prokaryotes, bacteriophage are by far “the most abundant organisms in the biosphere,” so the fact that prokaryotic populations remain resilient in spite of the ubiquity of the parasites that inflict them is an impressive testament to the powerful anti-viral capacities that pertain to CRISPR systems.
Fundamental to CRISPR systems is the pairing of CRISPR-affiliated forms of RNA(“crRNA”) with certain types of crRNA-guided endonuclease, which are so-called “restriction” enzymes. All forms of endonuclease are enzymes that cleave segments from polynucleotide chains, and in so doing, cause either the deletion, insertion, or reordering of targeted chromosomal segments of either RNA or DNA. This cleaving function effectively reconstitutes the biomolecular elements of organisms. The reason that restriction forms of endonuclease are particularly remarkable, aside from the fact that they only naturally occur in prokaryotic organisms, is that they are exceptionally specific in terms of the particular segments of the polynucleotide chain they sever.
By far the most discussed form of restriction enzyme is the “Cas9” protein. This enzyme is essential to “CRISPR-Cas9” — and it’s generating headlines for good reason. That’s because CRISPR-Cas9 has been technologically harnessed to create patented CRISPR tools for gene-editing applications for eukaryotic organisms, a broad biological domain that encompasses the entirety of plant, fungi, and animal kingdoms. Notwithstanding the likely proliferation of statutory, regulatory and judicial restrictions on genome editing, this controversial development suggests that the feasibility of commercially-marketable procedures for the genetic engineering of humans is apparently more imminent than not. To some, this sounds like a promising route to the good riddance of a whole slew of genetic afflictions (e.g., Huntington’s disease; Parkinson’s disease; hemophilia; etc.). To others, it raises serious existential fears (e.g., bioterrorism; environmental destruction; extinctions; homogenization of natural resources; etc.).
Patent Rights Across the Atlantic:
One of the major umbrella entities that has been involved in recent CRISPR patent disputes is the Berkeley group, a research collective led by a faculty member of UC-Berkeley, Jennifer Douda, who is a co-founder of both Caribou Biosciences and Intellia Therapeutics; Emmanuelle Charpentier, who is a co-founder of CRISPR Therapeutics and a director of the Max Planck Institute for Infection Biology; and Krzysztof Chylinksi of the University of Vienna. In May, 2012, the Berkeley group filed patents for non-natural methods of programming CRISPR gene-editing systems and, that same year, published the groundbreaking research that led to their patent filings.
A competing affiliation of CRISPR researchers is the “Broad Institute.” Partnered with MIT and Harvard University, the Broad Institute is a well-funded nonprofit research center that has a portfolio of CRISPR-related patents based on the work of one of its members, a biochemist named Feng Zhang, who, along with the Broad Institute, co-founded Editas Medicine, a pharmaceutical company established to develop CRISPR-based gene therapies for human subjects. In 2014, while the Berkeley patents pended approval, Zhang and the Broad Institute filed applications for patents for CRISPR technology as applied to eukaryotic organisms. Approved in 2017, these patents were the subject of interference claims, as well as an appeal on the administrative judgment thereof, both brought by affiliates of the Berkeley Group – specifically, the Regents of the University of California; the University of Vienna; and Emmanuelle Charpentier.
Then, in Regents of Univ. of Cal. v. Broad Inst., Inc. (Sept. 10, 2018), the U.S. Court of Appeals for the Federal Circuit held that the USPTO’s Patent Trial and Appeal Board (PTAB) had not erred in finding no interference-in-fact. In doing so, the court backed PTAB’s judgment that the Berkeley group’s USPTO patent claims for the use of CRISPR-Cas9 did not render obvious the Broad Institute’s portfolio of U.S. patents covering CRISPR technology as applied to eukaryotic organisms. Considering this ruling, it seems that, within the context of U.S. jurisdictional matters, the Broad Institute is better positioned than the Berkeley group when it comes to reaping the benefits of CRISPR-related bio-engineering treatments and services.
Elsewhere in the world of CRISPR patents, however, it is the Berkeley umbrella group that has the clear edge. The Berkeley group holds patents that appear to broadly cover the use of CRISPR for the editing of cells under the jurisdictions of the European Patent Office (EPO), as well as similar holdings in the U.K., China, Japan, Australia, New Zealand and Mexico. As for the Broad Institute, earlier this year, the EPO revoked one of its CRISPR patents, “EP 2771468 B1,” which was essentially the European counterpart to its foundational patent covering use-cases for eukaryotic cells. Further damning the Broad Institute, the EPO’s grounds for revoking this one patent concerned a technical defect that is shared by most of the Broad Institute’s other European CRISPR patents: specifically, its initial patent application documents listed a co-inventor, with whom the Institute subsequently settled an intellectual property dispute ahead of the EPO’s decision, whereas other documentation, related to the same application and submitted after the settlement, did not do so. As noted by Daniel Lim, a senior associate of Allen & Overy who attended the EPO hearing, the Broad Institute’s IP settlement “did not have retroactive effect and could not cure that key deficiency at the time of filing after the fact.” Responding to news of the EPO decision, Eric Rhodes, the CEO of ERS Genomics, a company affiliated with Charpentier of the Berkeley group, stated, “We’re on the backfoot in the U.S. [but] I think the Broad [Institute] is on the backfoot in most of the rest of the world.”
Joshua Perkins is a J.D. candidate, 2020, at NYU School of Law.
 “CRISPR” is an often-used truncation of the abbreviation “CRISPR-Cas,” which stands for “Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated.”
 See, e.g.,Sara Reardon, Baby’s DNA Mix Revealed, 544 Nature 17 (2017) (discussing the live birth of a baby whose conception was engineered from the DNA of three people through an experimental mitochondrial replacement therapy known as “oocyte spindle transfer”).
 “RNA” is an acronym for ribonucleic acid, which, like deoxyribonucleic acid (“DNA”), is an essential molecular component of all lifeforms. Both RNA and DNA consist of polymeric chains of nucleic acids, which in turn are composed of molecular monomers known as nucleotides. In total, there are five types of nucleotides that account for the bases of DNA and RNA: whereas thymine is only found in DNA, and uracil only in RNA, adenine, guanine, and cytosine exist in both.
 There are many forms of endonucleases that naturally occur in eukaryotes (i.e., “deoxyribonuclease I”), but unlike “restrictive enzymes”, these sever nucleotides from DNA at sites targeted with a relatively low level of specificity. In other words, the chromosomal loci where such enzymes cleave is a function of targeting that is, at most, “biased” or “preferential” to a certain nucleotide sequence.
 The Eli and Edy L. Broad Institute of MIT and Harvard.