CRISPR gene-editing technology promises to be one of the most significant scientific and medical breakthroughs in modern history. Its precision and relative ease-of-use have already transformed how scientists study disease and the human genome. Such powerful technology also brings with it the promise of tremendous wealth, fame, and scientific prestige. With so much at stake, it’s little surprise that CRISPR technology has been mired in intellectual property (IP) rights disputes from the get-go.The protracted CRISPR patent fight took yet another turn when the United States Patent and Trademark Office (USPTO) issued a “notice of allowance” to UC Berkeley last month. The allowance grants the university additional CRISPR IP rights which include the single guide RNA-Cas9 complex in both cellular and non-cellular environments. This is a significant win for Berkeley. The single guide RNA molecule has become one of the most popular CRISPR tools.The CRISPR IP battle falls mainly into two camps: UC Berkeley and the Broad Institute at Harvard and MIT. Both claimed IP rights to CRISPR technology shortly after its initial discovery in 2012. Though Jennifer Doudna from Berkeley and Emanuelle Charpentier from the Max Planck Institute filed their patent applications with the USPTO first, the Broad Institute paid for their applications to be expedited. The USPTO has since switched to a first-to-file system, but it did not take effect until 2013. As a result, the Broad patents were awarded first, and the legal firestorm began shortly thereafter.There was a brief period in which it seemed that the core of early CRISPR scientists would be able to partner and share intellectual property. But disagreements over academic credit, company locations, loyalty, ego, financial gain, and even Nobel Prize aspirations splintered the CRISPR pioneers.Berkeley’s notice of allowance may be the first sign of relative peace. The Broad Institute does not appear to dispute the allowance, announcing that the decision “does not affect the CRISPR patent estate held by Broad, MIT, and Harvard in any way.”But Berkeley’s newly established rights may also make it more challenging to develop CRISPR-based technologies or therapeutics. It is more than likely that anyone wishing to use CRISPR will need to obtain licenses from multiple parties.Several companies were founded on the initial CRISPR IP rights granted to various individuals and institutions. These companies include Intellia Therapeutics and its parent company, Caribou Biosciences (Berkeley), CRISPR Therapeutics and ERS Genomics (Emmanuelle Charpentier), and Editas Medicine (Broad) as well as the Broad Institute itself. Anyone aiming to commercialize CRISPR technology must obtain licenses from one or more of these companies. However, Broad and Berkeley have followed the long-standing recommendations that federally funded academic institutions grant non-exclusive licenses to university researchers and nonprofits.ERS Genomics also offers non-exclusive licenses for research purposes and the commercialization of certain services and products, including, specifically, synthetic biology. Additionally, the Broad Institute offers non-exclusive licenses for companies selling reagents and other genome editing tools and for in-house commercial research. But they are clear they only offer exclusive licenses for human therapeutics. Editas holds most of the Broad’s IP rights for therapeutics but companies can potentially obtain licenses through what the Broad calls their “inclusive innovation” model.If all of that weren’t complex enough, there are certain overlaps between the patents. For example, Editas, CRISPR Therapeutics, and Intellia all offer licenses to treat human diseases. But ERS Genomics specifically excludes a therapeutics option. Meanwhile, both Editas and Intellia offer licenses for stem cells, CAR-T cells, and Alpha-1 antitrypsin while Caribou Biosciences and the Broad Institute do not. In short, navigating the CRISPR IP thicket can be extremely confusing. And, unfortunately, it is likely to become even more so.

Image credit: Labiotech and Science News.

While Berkeley’s notice of allowance does help put out the flames, until recently, most of the fights have centered on the Cas9 protein. But, in the last several years, research has shown that the CRISPR-Cpf1 protein, also known as Cas12a, is potentially more effective than Cas9. Companies like Mammoth Biosciences have already been founded off of Cas12a technology. Patents involving the Cas12a-RNA complex are already pending on behalf of Berkeley and the Broad Institute.And, in the true style of the seemingly breakneck pace of CRISPR developments, yet another new Cas protein, CasX, could overshadow both Cas9 and Cas12a. First discovered in 2017 by Jill Banfield in collaboration with Jennifer Doudna’s lab at Berkeley, CasX is significantly smaller than other Cas proteins. This could give it an advantage getting when into cells. And, because it originates from bacteria not found in humans, the human immune system is more likely to accept it than Cas9. When patents for CasX and it’s sibling, CasY, come through, the entire CRISPR IP rights landscape could change once again.

What is the future of CRISPR IP rights?

Most likely, a complex one. Genomic breakthroughs are on the rise as CRISPR unlocks the secrets of the human genome. The CRISPR-Cas9 IP battle seems settled for now. And there is no indication that Cas12a will kick up nearly the same kinds of patent fights. But that is no guarantee for the future. With a potential worth of billions of dollars, CRISPR has the capability to break scientific partnerships as easily as it does DNA.The best way to stay out of the IP rabbit hole is to use CRISPR for research or non-profit purposes. But even commercial companies looking to build CRISPR-based platforms should carefully review the relevant licenses from each institution, especially as there are often non-exclusive options for certain kinds of CRISPR products and services. Unsurprisingly, the most complex CRISPR IP rights seem to center around therapeutics. But other industries including agriculture should be clear on their licensing options as well.We are still in the early days of CRISPR technology and there is a lot to learn both in and out of the lab. The hope is that licensing CRISPR will become more straightforward or at least clearer and more organized. Synthego CSO Rich Stoner spoke with SynBioBeta’s Kevin Costa about the current atmosphere surrounding CRISPR IP rights. “Yes, there’s a lot of litigation and contention around the core patents. But the pace of innovation to create new nucleases, new ways to edit and more predictability means that we’re very optimistic about the future of the technologies we’re deploying now as well as over the next few years.”But that future remains a little way off—the dust is still settling.