In this month's Letter to the Readers, ONCOLOGy co-editor-in-chief Howard Hochster, MD, reviews the implications of legal disputes surrounding patents for CRISPR technology.
CRISPR is a way of editing genes very efficiently. Standing for clustered regularly interspaced short palindromic repeats, CRISPR began with investigations by bacteriologists, including Danish yogurt makers, into repetitive segments of bacterial DNA. The repeated segments were unusual because they were not sequential—but had other coding regions between them. Eventually these coding regions were understood to represent a means of repelling viral or bacteriophage infections and, for example, led to a much more stable strain of yogurt culture.
However, researchers in the mid-2000s realized that when coupled with an editing enzyme, Cas9, the CRISPR system could be used to direct specific sites for genes to be deleted or modified. The technique became even more efficient when Jennifer Doudna and Emmanuelle Charpentier (Nobel Prize winners) combined 2 kinds of RNA to form a single RNA guide for the Cas9 enzyme and were able to specifically code for precisely where the guide would bind to DNA and direct the Cas9 enzyme. They published the key papers in 2012, in which they showed the system worked in vitro and in bacteria.1
The University of California (UC), with the University of Vienna, filed a patent early in 2012 for this technology based on the work of these 2 scientists. Shortly thereafter, Feng Zhang, PhD, of the Broad Institute in Boston, Massachusetts, made additional modifications to allow the CRISPR-Cas9 system to work in mammalian or eukaryotic cells,2 so a patent was filed a few months later by the Broad Institute. This work now gave a technique by which DNA could be easily modified at precise locations, and companies were founded to use this technology.
These patent filings have now led to a decade of extensive legal battles between these 2 groups about who “owns” the patent for CRISPR technology. UC claims that eukaryotic cell application is an obvious extension of the science they patented, and the Broad Institute claims that essential changes were made to enable the process in mammalian cells, resulting in its patent.
After several years of back-and-forth hearings in front of the United States Patent and Trademark Office (USPTO) and several federal court lawsuits, the USPTO finally decided in March 2022 to award the patent to the Broad Institute. This decision represents a potential loss of many millions of dollars to the UC system should CRISPR ever be used commercially. It also represents a setback for companies already licensing the technology from UC (CRISPR Therapeutics AG and Intellia Therapeutics, Inc) and a boon to Editas Medicine, Inc, and other companies working off the Broad Institute license.
Some European patent offices, however, have decided differently regarding the patent ownership, so the story continues.3
These fascinating events leads us, of course, to consider what a patent means and its intended purpose. The justification for giving patent rights for scientific discovery is to encourage scientists to innovate and companies to invest in discoveries and research, which could eventually turn into a profitable venture for public benefit.
This makes sense for drugs and other material inventions, but should researchers be allowed to patent nature herself, such as a gene or an enzymatic process? Consider discovery of nucleophilic substitution reactions in chemistry, published by Edward Hughes and Christopher Ingold in 1935. Should this “technology” have been patented, and should every chemical synthesis leading to a marketable product pay a royalty to these chemists for 20 years? We’ve already seen attempts to patent the BRCA2 gene itself, which were eventually overturned.
Also imagine if the “technology” of restriction enzymes had been patented instead of published as a scientific discovery? This technique for DNA manipulation led to the very fundamental discoveries in molecular biology over the past 30 years that produced understanding of cellular process underlying cancer and targeted therapy. Should researchers put a dollar in the“patent kitty” every time they use restriction enzymes in the production of a new biomolecule?
Finally, we need to consider that we, as US taxpayers, are usually funding these basic research efforts. The basic research behind the messenger RNA vaccines, such as Moderna’s COVID-19 vaccine, has been funded for more than a decade with tens of millions of dollars from US taxpayers—yet, we, the taxpayers, do not share in the financial profits of this research.
I would, therefore, like to draw a distinction between patenting processes and natural structures and those chemicals or biomolecules that are the potentially marketable products of known processes. Is it in fact reasonable to patent basic aspects of nature that exist in nature when discovered by man? When dealing with a technology platform such as CRISPR that has involved decades of work by numerous scientists, eventually becoming more practical by work of individual scientists, should these last scientists be able to patent the natural process?
We need to distinguish between patenting the process of CRISPR gene editing versus the actual gene-editing product—resulting in a treatment or better plants or tastier fruits—which clearly should be patentable. I believe the patenting of natural processes or molecules, such as a gene, is not good public policy because this will put a brake on additional use of the process. Additionally, considering the investment that we, the taxpayers, make into the research that leads to these discoveries, I question these patent rulings.
It is time to revisit many aspects of patent law and to reconsider how the law benefits the public and the advancement of science more generally.