Who owns CRISPR?

As CRISPR establishes a firm foothold as the gene editing technique of choice, the patent lawyers are braced for what may shape up to be science’s bloodiest commercial battle. Dermot Martin gets into the mired battle ground to give us an update…

Science history is pock-marked with disputes about originality, inventions, unique discoveries that lead to bitter intricate legal wrangles. Newton fought tooth and nail with Leibniz over the discovery of calculus. More recently Roger Guillemin fought what became known as ‘the Nobel Duel’ with Poland’s Andrew Schally over the true discoverer of the brain hormone thyrotropin-releasing hormone (TRF). And there was the titanic dispute between Robert Gallo and Luc Montagnier about the credit for the discovery of the human T-lymphotropic virus type III. That was the mother of all scientific legal battles heightened by the early eighties panic over AIDS. It was a dispute which eventually took a meeting of the French and US presidents to resolve.

Science history is pock-marked with disputes about originality, inventions, unique discoveries that lead to bitter intricate legal wrangles

Now we have the spectacle of another grinding dispute in the courts in the US over, potentially, the greatest discovery so far in the world of gene editing. CRISPR, discovered and developed as a tool for site-specific gene editing, took off in 2012 and some see it as vital for helping understand the role of specific genes in DNA. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) deserves a better name, since it is now regarded as the biggest breakthrough in gene manipulation since Watson and Crick’s first structural interpretation of DNA – itself a discovery mired in controversy about sexism and who did what when.

The CRISPR rumpus is centred on patents submitted for the technique. It is important not just for the financial implications to individuals and institutions involved, but also for the unwritten history of CRISPR. When it comes to Nobel Prizes – and most commentators agree is only a matter of time before CRISPR pioneers are on the receiving end – there’s a desire to be certain who has the strongest claim.

The ‘theatre of war’ is centred around the research of Feng Zhang at the Broad Institute in Massachusetts, and Jennifer Doudna of the University of California, Berkeley, working with Emmanuelle Charpentier. Although Jennifer Doudna and UC Berkeley applied for CRISPR patents before Feng Zhang and the Broad Institute, the US Patent and Trademark Office quietly awarded Zhang something like 13 out of 20 patents, while Doudna and Charpentier have been left largely empty-handed when it comes to protecting their intellectual property. This IP could attract hundreds of billions of dollars to their research institutes.

When it comes to Nobel Prizes – and most commentators agree is only a matter of time before CRISPR pioneers are on the receiving end – there’s a desire to be certain who has the strongest claim

Last December, UC Berkeley successfully convinced the US Patent and Trademark Office (PTO) to allow “patent interference”. This meant that the row was being kicked into the long grass to await the deliberations of a higher US court which could take years to reach a decision. The Broad Institute, a marriage between Harvard University and the Massachusetts Institute of Technology, is believed to hold 13 CRISPR patents that are under fire from the University of California (UC) and two other competitors. In September 2016, lawyers for the Broad Institute submitted fresh motions that may have opened the door to a compromise of sorts. Broad asked patent office officials to separate four of its issued patents from the case. The move was seen as significant because if patent officials rule in its favour there may be a way for both sides to emerge with both cash and kudos.

Then, in October of last year, a new player entered the ring, injecting fresh fuel into an already incendiary dispute. The French biopharmaceutical company Cellectis, announced at the end of October that it had just been issued patents that broadly cover genome-editing methods, including CRISPR. Patent specialists said before the Broad request to separate off four specific patents that it had the look of an ‘all or nothing affair’ in that whoever was going to win would control the most important aspects of the CRISPR patents landscape.

Cellectis’ patents appear to cover all gene-editing technologies that depend on chimeric endonucleases to alter and repair DNA, providing the DNA sequence has at least 12 base pairs, and is only for in vitro applications. In the press release on the announcement, Cellectis CEO Andre Choulika stated that this definition “covers most of the gene editing procedures done with a nuclease,” including those based on CRISPR-Cas9. Cellectis’ patents have already triggered challenges from other companies so the chaos looks likely to get worse long before it gets better. One patent specialist, Jacob Sherkow – who works at New York Law School and has closely monitored the CRISPR landscape so far – does not agree that CRISPR is covered by Cellectis’ umbrella patent. “I think Cellectis is taking an overly generous view of both the validity and scope of its new patent,” he said. “And given the state of the chimeric restriction endonuclease art prior to the patent’s 1999 date, there are some serious doubts as to its validity. We’ll see what Cellectis does with it.”

Other CRISPR patent watchers believe that commercial interests and the future of licence ownership is the driving force – rather than pure academic rivalry – behind all the rancour and it will be a fight to the bitter end. We owe the discovery of CRISPR to the quest to understand bacterial resistance to antibiotics and their defence mechanism to attack by viruses. Behind the acronym sit two molecules, which effectively work as a pair of scissors and a microscopic sat nav. The protein Cas9 is the ‘scissors’ which can chop up DNA. But precisely where it does so is directed by a short strand of ribonucleic acid (RNA). These two components evolved to help bacteria identify – and destroy – invading viruses’ DNA.

Behind the acronym sit two molecules, which effectively work as a pair of scissors and a microscopic sat nav

Researchers worked out how to isolate and adapt these ‘tools’ to let them edit any gene they wish, in any cell they like, with precision. First, the RNA ‘sat nav’ precisely matches up with a particular stretch of DNA. It brings the Cas9 molecule along with it, allowing the scissors to cut at that exact point in the DNA sequence. CRISPR’s power as a research tool comes from being able to engineer bespoke versions of the RNA sat nav, allowing Cas9 to be directed to any gene a researcher wishes. But it’s what happens next that makes the CRISPR system a cellular version of the “find and replace” tool in a word processor. Once Cas9 has cut the DNA, the cell’s built-in repair machinery swings into action. Researchers can use this response to disrupt the gene that has been cut, essentially switching it off to see what happens.

Or they can do more sophisticated experiments that precisely change the DNA code. Here they can make ‘spelling mistakes’ in a gene, like certain faults seen in cancer cells, which alter the gene’s function rather than merely scrambling it. Fortunately, the legal dispute and battles over intellectual property rights have not stalled pioneering studies using the CRIPSR techniques and variants.

A Chinese group has just announced (Nature) that it has injected a human with cells that contain genes edited using the revolutionary CRISPR–Cas9 technique. On October 28 2016, the report says, a team led by oncologist Lu You at Sichuan University in Chengdu delivered the modified cells into a patient suffering aggressive lung cancer as part of a clinical trial at the West China Hospital, also in Chengdu.

Earlier trials using cells edited with a different technique have excited clinicians. The introduction of CRISPR, which is simpler and more efficient than other techniques, is likely accelerate the efforts to get gene edited cells in to clinical trials. CRISPR still has a long way to go before it can be used safely and effectively to repair – not just disrupt – genes in people. That is particularly true for most diseases, such as muscular dystrophy and cystic fibrosis, which require correcting genes in a living person because if the cells were first removed and repaired then put back, too few would survive. The need to treat cells inside the body means gene editing faces many of the same delivery challenges as gene transfer – researchers must devise efficient ways to get a working CRISPR into specific tissues in a person, for example.

CRISPR also poses its own safety risks. Most often mentioned is that the Cas9 enzyme that CRISPR uses to cleave DNA at a specific location could also make cuts where it’s not intended to – potentially causing genetic damage. However, CRISPR promises a cheaper, quicker and more accurate way of studying the inner workings of our genome – a bit like exchanging a stone tablet and chisel for a fast laptop running modern publishing software.

Author: Dermot Martin is a freelance science writer specialising in analytical and medicinal chemistry