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As our understanding of CRISPR technology grows, the extraordinary potential of this gene-editing system in the realm of therapeutic development comes closer and closer to realization. However, ownership of the intellectual property (IP) behind this technology is set to spark a protracted patent feud between the most prominent scientists in the field. Who will reap the financial rewards if CRISPR revolutionizes the pharmaceutical industry and launches a new era of human medicine?

CRISPR holds incredible therapeutic promise
The CRISPR/Cas9 system holds several advantages over existing gene-editing technologies. Firstly, RNA-guided gene targeting via CRISPR/Cas9 is fundamentally easier and vastly cheaper when compared with Zinc-finger nucleases or TALENs, both of which require recombinant protein engineering. Experimentally, the system has been simple enough to introduce into various tissues and organisms, including human cell lines, which is an enormous boon moving forward into clinical development.

Thus far, genetic editing through CRISPR/Cas9 has already shown quantifiable success in several mouse models of human disease, including liver disease, cataracts and muscular dystrophy. In these cases, CRISPR/Cas9 components were directly injected into cells to correct single gene mutations, resulting in ameliorated disease phenotypes. Given CRISPR’s site-specificity and functionality in living cells, the technology holds great promise for treating human diseases that are, for the time being, incurable. Prime targets include those caused by a single genetic mutation such as hemophilia and Huntington’s disease.

The patent race begins
The potential of CRISPR has not gone unnoticed by investors looking to capitalize on the most important biotechnology discovery since RNA interference. Three brand-new, heavily financed startup companies have been created with the ultimate goal of applying this gene-editing technique to develop the next blockbuster therapeutic. The successful launch of any clinical development programs based on CRISPR/Cas9 technology would require these companies to tie down the IP claims of the scientists on their advisory boards in the form of patents.

Co-discoverers of the CRISPR/Cas9 system, Jennifer Doudna of the University of California, Berkeley, and Emmanuelle Charpentier of the Helmholtz Centre for Infection Research in Braunschweig, Germany, first filed a patent together in 2012 alongside their seminal Science paper. This patent names them as co-inventors of the methods of using CRISPR/Cas9 to generate targeted deletions or mutations of DNA sequences. Although their patent claims a priority date that goes back to May 25, 2012, it has yet to be accepted by the US Patent and Trademark Office (PTO) at the time of writing.

Meanwhile, Feng Zhang of MIT and the Broad Institute, who was the first to successfully integrate the CRISPR/Cas9 system into mouse and human cells, filed his own patent with a priority date of December 12, 2012. By November 2013, Zhang had founded the Boston-based consortium Editas Medicine backed by $43m of venture capitalist investment from three separate firms, including Doudna as an original board member. However, the US PTO initially rejected the Zhang patent as it “anticipated existing technology”, noticeably overlapping with IP claims made by Doudna and Charpentier’s patent application. In other words, the authors of the two patents both claim to have invented a similar novel technology. However, Zhang managed to successfully appeal this rejection by submitting an addendum that listed the dates of his own lab’s experiments—dates that declare Zhang to be the first to use CRISPR/Cas9 in eukaryotic cells. By April 2014, the Broad Institute announced that Zhang’s patent had been accepted by the US PTO and subsequently licensed to his company, Editas Medicine.

In response, Charpentier co-founded CRISPR Therapeutics, a start-up based in Basel, Switzerland, backed by $25m of financing in late April 2014. To make matters more interesting, Doudna left Editas Medicine later in 2014 in order to share her IP rights to CRISPR with a Berkeley start-up, Caribou Biosciences. In November 2014, Intellia Therapeutics was formed with financing to the order of $15m to apply Caribou’s CRISPR platform to novel applications in the clinical market. Thus, Doudna and Charpentier, the two scientists considered founders of the CRISPR/Cas9 gene-editing field, now find themselves as potential competitors in different boardrooms. Meanwhile, as both wait for the US PTO to validate the strength of their IP claims, Zhang and his company Editas forges ahead with the only accepted CRISPR patent thus far.

A drawn-out IP battle looms large
The award of the first CRISPR patent to Zhang and Editas took many by surprise. It was later revealed that Zhang petitioned to the US PTO for expedited assessment of his patent, perhaps anticipating complications due to existing competition or simply acknowledging the sheer importance of the CRISPR/Cas9 invention. Possibly unaware of this loophole or unsuspecting of the ruthlessness of their scientific rivals, Doudna and Charpentier forewent this route when filing their original patent. Nevertheless, neither Doudna nor Charpentier are willing to throw in the towel in the conflict of ownership for what they, and the majority of the scientific community, believe is their invention. In an interview with The Independent, Charpentier remained defiant: “I have to be careful what I say here. It is very surprising. But the fundamental discovery comes from my laboratory and no-one has told me that they have scooped me.”

The incredible potential of CRISPR/Cas9 and the financial reward for control of its ownership is primed to take the scientific dispute of who invented what and when into a battlefield of patent litigation. As of September 2014, the lawyers for the Doudna-Charpentier patent group have asked the US PTO to open an interference proceeding against Zhang’s patent. This legal procedure allows one to challenge an existing patent if both groups share overlapping IP claims. If the interference is accepted, then the authors on the Zhang and Doudna-Charpentier patents will need to provide evidence for their claimed inventions in the form of dates – found in letters, lab notes, and emails. Understandably, an investigation of this nature would likely be protracted, tedious and accumulate a small fortune’s worth of legal fees. The financial future of start-ups Editas, Intellia, and CRISPR Therapeutics, whose entire R&D programs are built to exploit CRISPR/Cas9 gene-editing, may very well hinge on the outcome of this IP dispute.

Through uncertainty the field marches on
Ever since its revolutionary discovery as a gene-editing tool in 2012, the CRISPR/Cas9 field has moved at an incredible pace. CRISPR/Cas9 systems have and will continue to see widespread use in academic research laboratories around the world for a variety of scientific programs – thanks to the availability and affordability of these reagents from databases like Addgene. Rapid progress has already been made in mitigating technical issues that could otherwise hold CRISPR back as a therapeutic, such as off-target cleavage, inefficient delivery methods, and suboptimal expression. As a result, many expect clinical trials involving CRISPR-based therapies to emerge in as little as three years. Whether the impending legal arguments have an impact on these predictions remains to be seen.

On the one hand, the IP competition between rival companies may lead to their specialization in distinct areas and thus improve the quality of their CRISPR-based treatments. On the other, back-and-forth legal disputes over CRISPR’s IP landscape could dissuade further investment and delay these companies from committing to their drug discovery programs. Will the involved parties manage to find a common ground that allows them to operate independently? Will the scientific legacy of CRISPR/Cas9 be defined by who wins in the courtroom? Either way, researchers and investors alike are sitting on the sidelines, eager to witness the outcome.

http://www.immpressmagazine.com/controlling-crispr/

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