Genome editing, also referred to as genome editing with engineered nucleases (GEEN) is a category of genetic engineering, in which DNA is inserted, replaced, or removed from a genome using artificially engineered nucleases, or “molecular scissors.” The nucleases create specific double-stranded break (DSBs) at desired locations in the genome, and harness the cell’s endogenous mechanisms to repair the induced break by natural processes of homologous recombination (HR) and nonhomologous end-joining (NHEJ). Amongst four specific families of engineered nucleases, CRISPR/Cas system has gained immense importance in recent years. Generally, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) and CRISPR-associated (Cas) proteins are found in many bacteria and most archaea. With respect to high flexibility and specific targeting, it is possible to manipulate and redirect CRISPR-Cas systems and render them as powerful tools for genome editing. CRISPR-Cas9 is notable because this gene editing technology allows scientists to insert defective portions of DNA with healthy sequences. This kind of DNA technology holds immense potential than just curing individuals stricken with genetic diseases. It is hypothesized that this precious technology can completely eliminate the faulty genes by erasing them from germline cells. Already, scientists have employed the technology to disable HIV, cure muscular dystrophy in mice, and make wheat that is resistant to crop diseases.
An inadvertent discovery of first genomic CRISPR locus in Escherichia coli dates back to 1987, when a group of scientists led by Ishino (J. Bacteriol. 169, 5429–5433) stated “The Biological Significance of These Sequences Is Not Known, while sequencing the iap gene. Since January 2013, an outbreak of studies demonstrated that site-specific DNA editing in eukaryotic cells could be achieved through the heterologous expression of Cas9 together with a guide RNA. Two years and after more than1,000 publications, the technology has gone viral in bioscience.
Nevertheless, considering patent rights of this wonderful technology, incongruity persists between scientists at UC Berkeley, Harvard and the Massachusetts Institute of Technology. UC Berkeley, Harvard, and MIT are all now battling for the IP rights to CRISPR-Cas9. The legal team of the UC Board of Regents asked the United States Patent and Trademark Office (USPTO), an agency in the US Department of Commerce (USPTO) to reconsider award of patents to Harvard, MIT, and the Broad Institute in April this year. Their position is that the rights belong to Jennifer Doudna of UC Berkeley, the technology’s rightful inventor. The UC Regents’ legal team disputes the Zhang team’s evidence with respect to essentiality of proof for independent innovation to award patent. According to the legal team, the rights to the process belong to the team of Jennifer Doudna, Professor of chemistry and molecular and cell biology at the UC Berkeley. However, since April 2014, the patent to develop the technology for commercial use has been under dispute, after Feng Zhang of the Broad Institute was awarded a patent that gave him and his research center commercial control over CRISPR-Cas9 technology. Zhang used lab notebooks as evidence to argue that his team invented the process on its own. Zhang told MIT Technology Review in December 2014 that other evidence, like grant applications and correspondence, could offer further proof. However, lawyers for UC Berkeley, in counterclaims filed with the patent office say pages and diagrams from Zhang’s lab notebooks demonstrate fewer related experiments, and do not prove that he has invented the system. “Dr. Zhang is wrong,” they conclude. Their conclusions rely, in part, on a technical analysis provided to the patent office by Dana Carroll, a gene-editing expert at the University of Utah. This evidence in fact has provided the Broad Institute team with a cutthroat advantage before the USPTO. According to Brett Staahl, a UC Berkeley postdoctoral associate with the Doudna Lab, “We have a technology that in one treatment can cure the underlying cause of a genetic disease and it could change the game for academic research. The technology is one treatment that is capable of curing the underlying cause of a genetic disease.” Ever since Doudna’s team published a paper in the journal, Science in 2012, which describes the technique, scientists worldwide have employed the experimental method on plant, animal and human cells, and also to test potential cures for life-threatening diseases like sickle-cell anemia and cancer. According to the National Library of Medicine, the number of papers published on CRISPR last year was more than quadruple the number compared to the ones, which appeared in 2012. It is an appreciable fact that Doudna and one of her collaborators, Emmanuelle Charpentier from the Helmholtz Centre for Infection Research, won the Breakthrough Prize in Life Sciences and were included in Time magazine’s list of the most influential people of the year because of their CRISPR-related research. Some of the potential uses of CRISPR-Cas9 technology have been clearly stated by Ryan Clarke, a biochemistry PhD candidate and published scientist, along with James Hyun, a PhD student in the life sciences. The specific application of the technology may be instrumental to several breakthroughs: finding a cure for HIV; the a cellular ion pump, CFTR, which causes cystic fibrosis; the modification of the SHANK3 genes suspected of causing autism; the dystrophin gene, which is typically mutated in muscular dystrophy; engineering of CAR T cells used to find and attack specific kinds of cancer; and various drug studies and discoveries. An email by Michael Botchan, Professor of Biochemistry, UC Berkeley humbly states, “Despite patent issues, transparency and sharing are characterizing the way this very rapidly advancing technology is spreading”.
In January 2014, Doudna piloted a team of ethical, legal, and scientific experts and discussed on the implications of editing germline cells using the CRISPR-Cas9 technology, and stated, “The issue is especially human germline editing and the appreciation that this is now a capability in everyone’s hands.” This conference attempted to maintain the use of the technology as transparent as possible and dispel fears about “designer babies” enough to ensure that the technology can continued to be used for important disease-related applications. As per an published article by participants, “Given the speed with which the genome engineering field is evolving, the Napa meeting concluded that there is an urgent need for open discussion about the merits and risks of human genome modification by a broad cohort of scientists, clinicians, social scientists, the general public, and relevant public entities and interest groups”. In addition, several guidelines were produced for the use of the CRISPR-Cas9 technology.
As per present rules, known as “first to file,” patent rights are imparted to anyone, who submits a patent application first. Accordingly, this rule will pave an easy victory for Doudna and Charpentier, because their earliest application is dated May 2012, seven months before Zhang’s. But, because of the dates of the discoveries, the case is being carried out under older “first to invent” rules, where the winner is whoever is able to show by any means that they were first to make an invention work, or simply conceive it. “That person gets the patent,” says Aharonian.
The prevailing perplexity around CRISPR patents has slowed down commercial efforts. Tom Adams, vice president of global biotechnology at Monsanto, says his company had initiated working with the technology to create plants with useful traits, but remained reluctant to employ it widely. “It’s a very complicated set of inventions,” says Adams. “Until we understand the intellectual property it’s hard to do much.” A published report states that if products or treatments are delayed, the high-profile legal fight could end up reflecting badly on the universities, which have employed public tax dollars or philanthropic gifts to make the inventions. A spokesperson for the Broad Institute, Paul Goldsmith, said that Broad has made “repeated efforts and trips since the beginning of 2013 to resolve this situation outside the legal system.”
According to Dan Voytas, a gene-editing researcher at the University of Minnesota, it has been possible to resolve other technology disputes by creating patent pools, which offer wide access to basic innovations, or via cross-licensing. Nevertheless, that has not happened yet with CRISPR-Cas9, precisely because still the owner of the key rights is not decided. It has also been stated that, “It would be mutually beneficial to develop as many products as possible with the technology, because it’s the products that will generate the revenue”. As per a published report, interestingly, both Zhang and Doudna have dedicated significant time and efforts in terms of supporting and publicizing CRISPR. Doudna has created a video, which is being passed around social media sites, while Zhang’s lab has organized a website and loaded laboratory materials, which can be accessed by other scientists, worldwide. The stakes involved are huge. Not only does a Nobel Prize for gene editing seem likely, but also several heavily financed startups have been created to start developing gene-therapy treatments. In addition, Zhang is involved in Editas Medicine, Doudna’s startup is called Caribou Biosciences, and Charpentier is a founder of CRISPR Therapeutics. There has been a proportional and tremendous increase in the number of scientific publications on the technique, and is likely to exceed 1,100 this year.
Ryan Honick, a spokesperson for the patent office, says a special board of examiners, which hears evidence in about 100 cases a year, decides interference proceedings and the process can take as much as two years to resolve. Greg Aharonian, director of the Center for Global Patent Quality, which works on patent issues says, “Expect this battle to be very expensive, very contentious, given the stakes involved. I can see many hundreds of thousands of dollars being spent. This is far from over”.
It could be hypothesized that if the patent office approves the request by Regents for a “patent interference,” an argument about who actually originated the CRISPR-Cas9 process will take place before a panel. This particular legal battle could cost millions and stretch out over the course of years. Either the Broad Institute, or the University of California and two co-petitioners, including the University of Vienna, will be benefited with rights to the gene-editing system, leaving their rival with nothing. Undeniably, the simplicity with which this technology can be practiced, and owing to its marvelous efficacy, it is proposed that CRISPR-Cas9 will increasingly become a tool of choice for the next generation of biologists. However, based on the existing scenario, it can be concluded that the prevailing legal fights could end up serving very little rationale. Improved versions of CRISPR-Cas9 have already been invented, and entirely new methods are likely to emerge in scientific field.