CRISPR One giant breakthrough; a mass of complexities

The discovery and successful harnessing of the gene editing technology, CRISPR, promises to be one of the most significant breakthroughs of our age. But a complex series of hurdles - legal, technical, commercial, regulatory and ethical - must be leapt to safely realise its vast potential.

The trajectory of scientific discovery often follows a similar pattern, with years of slow progress within individual disciplines suddenly giving way to a moment of extraordinary breakthrough and a giant leap forward.

The discovery and successful harnessing of the CRISPR (clustered regularly interspaced short palindromic repeats) system looks to be one of those step-change moments, particularly in its application in the field of gene editing. It promises to be of massive importance, not just in the treatment of genetic disorders, but in drug development, animal health, crop science and across the bio-industrial sector.

“The potential applications are so wide-ranging that it is hard to scope them out fully,” says Marc Döring, head of our IP Litigation practice in London. “But I think it’s fair to say that CRISPR has the potential to revolutionise just about any industry in which biology and genetic technology play a part.”

Part of that is because the technology is relatively low cost and easy to use, says Daniel Lim, a senior associate in the IP Litigation practice.

“Gene editing technology is not a new idea and after more than a decade of trying we were getting close to creating one or two viable products. Then CRISPR – a Johnny-come-lately technology – arrives and really throws the cat among the pigeons because it represents such an important paradigm shift.”

The previous technologies were cumbersome, expensive and just very difficult to develop, he explains.

As a gene editing tool, CRISPR is a lot easier to handle, and cheaper to develop and to use.

“Within a year or two of its arrival CRISPR was quickly being put to work by researchers in labs around the world at a fraction of the cost of previous methods. In the research sense, it has democratised gene editing.”

There are now many variants of the technology but the most widely used is the CRISPR/Cas9 system, with other promising variants now being developed, including the Cpf1 and C2c2 systems.

The power of these systems lies in the relative ease with which they can be adapted specifically to target regions or genes of interest in the genome of target cells. The activity of the Cas protein causes a double-stranded break in the DNA at the target site, allowing researchers to remove or insert genetic material through DNA repair mechanisms.

Much of the media coverage of CRISPR has focused on its potential medical applications, particularly in the field of personalised medicine. For example, we are already seeing CRISPR being applied in a number of promising fields of research, such as in so-called ‘killer’ T-cell therapy designed to target cancer cell antigens specific to an individual patient’s cancer.

In the only trial to be cleared in the U.S., the University of Pennsylvania plans to use CRISPR to introduce three different modifications to T-cells taken from the patient’s body, which are then reintroduced in modified form to hone in on and attack tumour cells.

Clinical trials have already begun in China to investigate the use of similarly CRISPR-modified T-cells to treat patients with aggressive lung cancer. And in an indication of how quickly China is becoming a global force in biotech, clearance has also been given for the world’s first trial of a direct in vivo (within the body) application of the technology, significantly ahead of Western trials.

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Patent uncertainties

In any area of rapid scientific advancement, questions of ownership and control are rarely far behind. That’s certainly the case with CRISPR, with patent battles being fought in both the U.S. and Europe. The most prominent disputes centre on the foundation IP behind the technology.

Two rival groups have laid claim to inventing the fundamental components of the CRISPR system.

On one side are Jennifer Doudna of the University of California, Berkley (UCB) and Emmanuelle Charpentier who first described the use of the Cas9 system in single-celled organisms.

On the other side are Feng Zhang and the Broad Institute of MIT and Harvard who were the first to publish work on the use of the system in eukaryotes – higher-level organisms (including humans) with cells in which DNA is stored as chromosomes within a membrane-enclosed nucleus.

Some hailed a widely reported ruling by the U.S. Patent Trial and Appeal Board (PTAB) in February 2017 as a win for the Broad Institute. But, taking a global view and in light of subsequent patent grants for UCB, that decision (currently under appeal) was actually less decisive than many media commentators had suggested and, crucially, ruled that both teams’ approaches were separately patentable.

That is an important ruling because each of the three main players have separately created spin-out companies to commercialise CRISPR-based technology. Doudna has set up Caribou Biosciences and Intellia Therapeutics, which cross-license their foundational CRISPR IP with Charpentier’s CRISPR Therapeutics and ERS Genomics. Meanwhile, Zhang is associated with Editas Medicine.

The spin-outs have all moved quickly to form ties with (variously) disruptive biotech groups, venture capitalists and some of the very biggest pharma and agriscience companies, among them Bayer, Novartis, Regeneron, Allergan, DuPont and Monsanto, attracting thousands of millions of dollars of investment into specific areas of research.

But the PTAB ruling is by no means the end of the story and Marc and Daniel are clear that the patenting issue, complex enough already, will only become more so.

Already hundreds if not thousands of CRISPR-related patents have been filed worldwide, they argue, and if even a small fraction of them are granted, the field will be left with an incredibly complex web of patent rights that must be navigated.

Reflecting on the PTAB ruling, Marc says: “I think we’ve come to the view that the ruling is effectively letting both sides have some of the IP – it’s not knocking out one side or the other.”

Daniel agrees, but adds: “On the commercial side, a huge number of questions have already been raised about what players need to do to ensure they have the freedom to operate given the complexity of the current landscape in terms of licensing and rights over ownership.

“And the key questions for a business seeking freedom to operate in the CRISPR space are: should I be jumping in now and with whom? If I do, what are the short, medium and long-term risks of backing one side over the other? And, if I don’t, will I get left behind?”

Although both are agreed that the legal landscape will remain uncertain, they suggest a more rational outcome might be possible, given the importance of the technology and its potential uses to society. Sure, there will be a proliferation of patents, often involving overlapping scopes of protection, but how many in reality will end up being the subject of litigation and when?

As Daniel puts it: “I think the really interesting question is what sort of patent pools will form, what sort of cross-licensing and other innovative licensing solutions will we see being explored, and what groups will, in the end, band together to take different applications of the technology forward.”

Notably, the Broad Institute appears to have flagged its willingness to participate in such patent pooling initiatives, recently submitting 22 of its foundational CRISPR patents for consideration in a pool proposed by MPEG-LA, the company best known for administrating the patent pools behind the MPEG video codec standards. This could be a strategic move to corral other patent holders to move towards patent pooling. However, it is still early days for such initiatives. The many exclusive licences to the Broad Institute’s patents alone may well scupper any such deal.

Regulatory and ethical doubts

That, however, leaves one other area of complexity.

Genetic modification has always been a deeply controversial issue, as we’ve seen most clearly, perhaps, in the field of GM foods.

It is an area where regulation is lagging behind the rapid pace of technological change, with existing rules, devised for an older generation of GM technology, failing to address the new landscape of which CRISPR is just a part. The future direction of regulation will have huge implications for therapeutic applications of CRISPR as well as its uses in food production and agriculture.

Ethical questions could prove even more controversial. In particular, there are deep concerns that the technology could be used eugenically.

It’s an area where some of the breakthrough scientists in the field have expressed their own real concerns, including Jennifer Doudna of UCB who has spoken powerfully of her fears of science running way ahead of ethics. Despite asking scientists to refrain from clinical use of human germline editing (editing the genome in human embryos, sperm or egg cells), at least one research team has done just that in an attempt to show that diseases might be stopped before they ever start.

Marc says governments, policymakers and regulators need to perform a delicate balancing act here – introducing regulation that, on the one hand, encourages free and open research, but also protects against reckless or nefarious uses of the technology.

“It might seem straightforward. If you could edit the genome to remove coding for leukaemia in a patient – terrific, who wouldn’t want that? Similarly, if you can use gene technology to eradicate malaria-carrying mosquitoes in Africa, the case for that might seem pretty clear.

“But is this morally right, and where do you stop? If germline editing (to prevent inheriting a disease) is permitted in the name of alleviating human suffering, why would genetic enhancement facilitating a ‘better’, ‘improved’ life be impermissible? Who ultimately is going to decide what ethical codes and legal regulations are needed to put the right limits on this technology? And if gene editing has become democratised, how are we going to be sure common ethical standards will be applied from country to country?”

On the one hand, there are stories of those who have seen family members suffer from a devastating genetic disease rejoicing at the prospect that CRISPR will potentially be able to remove the inherited genetic mutation. On the other hand, genome editing is seen by some as potentially undermining humanity itself, and has even been described by the U.S. intelligence community as one of the six weapons of mass destruction that nation-states might seek to deliberately or unintentionally misuse, leading to far-reaching economic and national security implications.

Certainly CRISPR epitomises how advances in science and technology can profoundly disrupt the world around us – and at such speed thattmany businesses, governments, policy-makers and regulators are struggling to keep up.