The Controversial Genome-Editing Technique CRISPR-Cas9

On February 15, 2017, the Patent Trial and Appeal Board (PTAB) of the United States Patent and Trademark Office (USPTO) issued a ruling on a patent dispute about a genome-editing technique called CRISPR-Cas9.  The Regents of the University of California, University of Vienna, and a scientist named Emmanuelle Charpentier (collectively “UC”) initiated this legal proceeding, called an interference, against the Broad Institute, Inc., Massachusetts Institute of Technology, and President and Fellows of Harvard College (collectively “Broad”). The three-judge panel unanimously sided with Broad concluding, although temporarily, a legal battle closely watched by scientists, legal professionals and the biotechnology industry. On April 12, 2017, UC filed an appeal to the United States Court of Appeals for the Federal Circuit.

An acronym for “clustered, regularly interspaced short palindromic repeats,” CRISPR is short sequences of ribonucleic acid (RNA) that can recognize and bind to complementary deoxyribonucleic acid (DNA) sequences in the genome of an organism. Cas9, a protein functioning like a pair of molecular scissors, can cut through the genomic DNA at the binding site.  The CRISPR-Cas9 system, functioning like a cut and paste tool in a word processor, can be employed to permanently modify the genome of an organism by removing deleterious genes or inserting beneficial ones.  UC’s patent application, which was filed earlier than Broad’s, described the functions of CRISPR-Cas9 in prokaryotes−single-cell organisms without cellular nucleus such as bacterium−in a non-cellular environment, while Broad’s patents demonstrated the applications of CRISPR-Cas9 in the more complex cellular environment of eukaryotes−humans, animals and plants.  During the PTAB hearings, UC argued that its patent claims anticipated or rendered Broad’s obvious, therefore making Board’s invention indistinct from UC’s.  Relying on expert testimonies, PTAB declared that the two parties claimed patentably distinct subject matter.  In consideration of CRISPR-Cas9’s future applications in developing novel therapies for human diseases or pest-resistant plants, the PTAB ruling was widely considered a decisive win for Broad.

In the upcoming appeal, the obviousness issue will likely to be continuously contested. The criterion for determination of obviousness is whether the prior art would have suggested to one of ordinary skill in the art that a process would have a reasonable likelihood of success if being carried out in the light of the prior art.  The evidence that persuaded the PTAB judges to rule for Broad was UC inventors’ various comments which were made right after their discovery and suggested that they were unsure whether CRISPR-Cas9 would work in eukaryotes.  Although these comments undermined UC’s position, UC could still have an argument that an inventor is not one of ordinary skill in the art due to their superior expertise in the relevant field, therefore it is improper to use their comments to determine the obviousness issue. Additionally, UC could present evidence and expert testimonies that an inventor usually holds a more rigorous standard than one of ordinary skill in the art in respect to expectations of future success due to their more detailed knowledge of potential obstacles in the art.

The patent war between UC and Broad also spills across the Pacific and Atlantic Ocean. Weeks after the conclusion of the PTAB proceeding, both the European Patent Office (EPO) and China’s State Intellectual Property Office (SIPO) granted a patent to UC covering the use of CRISPR-Cas9 in both eukaryotes and prokaryotes, giving UC exclusive right to use and license the technology in human therapy development and adding another twist to this legal battle.  The legal rulings from different continents create uncertainty and ramifications in the business world. The final outcome of this legal battle will likely have impact on the millions of dollars of investments and licensing fees.  Startups have already been set up by both sides to commercialize the technology.  Others who want to use the technology will have to decide which side they will have to pay the licensing fees to.

Finally, the potential of CRISPR-Cas9 to create inheritable human genomic alterations raises bioethical concerns.  Germline editing−the deletion of a disease gene from a human embryo genome to prevent it from being passed on to future generations−is among the most pressing ones.  From the scientific perspective, two major hurdles exist before this technique can to be safely applied to human genome editing: off-target mutations or unwanted genetic changes and risk of mosaics or different genetic sequences in different cells of an embryo.  Recently, CRISPR-Cas9 has been demonstrated by scientists in the laboratory environment to successfully correct disease-causing mutations in human embryos without findings of any off-target effect or mosaics, making a major breakthrough and posing serious legal and bioethical challenges.  In anticipation of future advances of CRISPR-Cas9 toward its clinical application, coordinated efforts among the international communities of law, science, business, medicine and public policy are needed to provide guidelines to deal with these challenges.

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