Advances in CRISPR are happening at breakneck speed. IPM’s editor Maura O’Malley talks to industry experts to shed light on the complex licensing and patenting landscape that surrounds this powerful technology
In 1999, an 18-year old boy called Jesse Gelsinger died after having a violent immune response to a viral vector. He was being treated for a rare metabolic disorder and it was the first publicly recognised fatality in a clinical trial for gene therapy. The tragedy set back gene therapy for years. How could we find the holy grail? A way to alter or knock out genes with precision so that it would not give rise to unintended and potentially tragic side effects?
The gene editing technology known as CRISPR offers this hope. It offers not just hope in the human therapeutics field, but in animal heath, agriculture and bioindustry. Naturally, a complex patent and licensing landscape has mushroomed up around it. On 5 December, IPM editor Maura O’Malley in association with Informa’s Pharma Intelligence group gathered a stellar panel to discuss the many issues. She was joined by:
- The CEO of ERS Genomics Eric Rhodes. ERS Genomics is one of the five main spin-out companies that have been created, all founded by pioneering CRISPR researchers.
- Daniel Lim, a senior associate at Allen & Overy, with particular focus on patent litigation in the life sciences sector.
- Mike Ward, head of content in Pink Sheet and Scrip at Informa. Mike has been writing, analysing and commenting on the life sciences sector for over 30 years.
CRISPR stands for ‘Clustered Regularly Interspaced Short Palindromic Repeats’, and it is a naturally occurring defence mechanism in bacteria used to fight viruses. Although it feels like the 'hottest new thing in town' CRISPR, as Ward pointed out, has been around for a long time.
Ward said, “It may come as a surprise to many that the CRISPR literature dates back to the late 1980s when several groups observed repeated arrays of DNA repeats in the genome of both bacteria and archaea. It wasn’t until the advent of genome sequencing technologies that we saw a large set of microbial genomes that were carrying these strange sequences, but nobody knew what the function was.
He added that industry’s first interest in CRISPR actually began in the Danish food company Danisco, (now part of DuPont), while they were developing molecular methods for strain differentiation of yogurt bacteria.
Scientists were able to establish that CRISPRs were regions in the bacterial genome that help defend against invading viruses. When the target DNA is found (in bacteria the DNA of the invading viruses) Cas9 – one of the enzymes produced by the CRISPR system – binds to the target DNA (it is guided by CRISPR RNA to the correct spot) and cuts it, shutting the targeted gene off and disabling the virus.
In January 2013, the first method to engineer CRISPR to edit the genome in mouse and human cells was published.
IP landscape surrounding CRISPR is increasingly broad and complex (scroll to end to see the main players). Rhodes pointed out that ERS Genomics was formed by one of the original inventors of the technology Emmanuelle Charpentier, “and her mandate to us was to make the technology as broadly available as possible, but to do it in a commercial way so that companies wanting to have freedom to operate would know they were appropriately licensed to be carrying out commercial opportunities”.
Charpentier also formed CRISPR Therapeutics; this is focused on the human therapeutics side. ERS Genomics covers all of the other applications, like R&D, tools, kits, reagents and agriculture.
“ERS Genomics is a strictly out licensing engine and exists to make the technology more broadly available under appropriate commercial licences”, Rhodes said. It has done deals with tool providers like Oxford Genetics, Horizon, US-based Cellecta, pharma companies like Merck and Bayer, and with companies that are modifying animals for research purposes or in the livestock area.
“All our deals have been non-exclusive, with the exception of one - DuPont.” ERS Genomics signed this agreement as it felt it needed to form a partnership with a bigger partner for an area that, ”they did not understand quite as well".
“Having done an exclusive with DuPont we don’t have any other IP licences to give. They have sub licensing rights from us so they are now the focus for agricultural licences. We will not be doing additional ag deals anyway,” he added.
Commenting on the agreement between DuPont Pioneer (a division of DuPont) and the Broad Institute to jointly provide non-exclusive licences to foundational CRISPR Cas9 IP, Rhodes stated they are bringing together those two IP portfolios and trying and make them available.
“They are still separate as I understand it but you can deal with DuPont in order to get an understanding of the commercial terms to get access to both sets of IP. I believe you still have to get two licences...but I do know they are trying to be a ‘single stop’ where people can go and get all the information they need to get an agricultural licence.”
Discussing the University of California, Berkeley (UCB) and the Emmanuelle Charpentier parties appeal against the US Patent and Trademark Office’s (USPTO) decision finding of no interference-in-fact in its dispute with the Broad Institute, Rhodes said, “It is very difficult to predict and I am very biased in what I believe the outcome should be!"
“The Berkeley side is pushing hard to have the patent office recognise that there were six groups that simultaneously used the information that Berkeley had basically disclosed to get it to work in eukaryotic cells, and there was nothing inventive in what the Broad Institute did and that the patent should actually go to Berkeley for use in eukaryotic cells rather than to the Broad.
“I am hoping that the appeal will at least go back and the decision that there was not an interference will be reversed.” So, that the patent office can examine the details and try and determine who the actual inventor was in this technology.
He said all the formal filings have been done and the next step is to have oral arguments scheduled sometime in the second quarter of 2018. “And then the appeals board will make a decision at that point, the expectation is that this will come in Q3 or Q4. There isn’t a firm deadline for when they need to make that decision. They understand the importance of this case too.”
Lim pointed out that the USPTO dispute is dealing mainly with the foundational patents which cover the CRISPR system as a whole. And when it comes to time for enforcement in relation to actual products, “there is the chance that a lot of these patents we have been hearing so much about in the media will have expired by then”.
He said that if you look at the lead time and approval to launch of in vivo human therapeutic applications of CRISPR, there is a very real chance that the 20-year protection offered to platform -level patents will have expired by then.
European Patent Office
Lim added that the interference judgment has little influence elsewhere in the world. “It is also not an analysis of validity, the key question in the action is whether there is one, single patentable invention here or two inventions both worthy of patent protection.
“And in the course of that inquiry, it does not consider formal matters like priority which is a real issue for the board. And the obviousness analysis is just the obviousness of the Broad patents over the UCB first-file patents as prior art. It is not going to consider other prior art in particular, intervening prior art, he commented.”
This brings us to the European Patent Office (EPO) Opposition Division, which has issued a preliminary non-binding opinion that a key Broad Institute patent appears to be invalid in Europe, the intervening prior art is a key issue in this. Lim noted that in January 2018, the first oral hearing will be heard. “A decision from the EPO will be a lot more in line with the way things are analysed over here (ie, in Europe)."
The prevailing discourse has centred around two main parties: the UBC/Charpentier parties on the one hand and the Broad on the other. But the EPO has recently granted broad, fundamental patents to MilliporeSigma (a division of Merck) and Cellectis. This further crowds the rosta of parties that are laying claim to broad foundational patents, said Lim. “It does complicate the already difficult question around freedom to operate... People are going to have to seek licences from multiple parties or ‘hold out’ until someone picks up the phone.”
The Broad Institute has submitted 10 of its fundamental CRISPR/Cas9 patent families to MPEG-LA’s patent pool initiative. Could this be a new way of creating certainty around freedom to operate? Lim wondered about the status of this initiative. “One would expect that if others had submitted patents to that pool, they would be making a lot more noise about it. There is a deafening silence.
“There are serious practical issues to overcome. Instead of a formalised patent pool we might see collaborations around particular subsets of applications like what we have seen recently from the Broad and DuPont where they have brought together these two very significant patent portfolios and are now seeking proposing to offer a comprehensive non-exclusive licensing solution for agriculture.”
Rhodes said, “I can’t speak for all the companies on the Berkeley and Charpentier side, but we did not participate in that. My understanding was that the Broad Institute having submitted their patents, this was a ticket to come to the table for a discussion, it wasn’t a commitment to participate in the patent pool."
He believed patent pools were a more natural fit in the technology, media and telecommunications sector where technology moves fast and products are out of date in three or four years. In the case of pharmaceuticals and biologics it usually takes 10 years to get approval of a new drug or approach, “there is not the same time pressures”.
Products and research
The speed in which these technologies are being developed is tremendous, said Ward. “We expect to see the first candidates in the clinic in the CRISPR space maybe next year.”
Rhodes could not believe the breath of application. “People are using CRISPR in spaces where I never thought they would use gene editing.” The main areas were in the human therapeutics side - in target discovery and target validation.
He said it is also being used to look at extinct species and trying to understand what genetic changes have occurred over time that has driven the species to extinction or allowed a species to urvive. Were there changes for example that could be introduced into a population of insects that might render them less harmful to humans? In the agricultural space they could be used to produce drought resistant plants in areas of the world where there is not enough water.
Lim believes that the key patents of the future “won’t be these foundation-level patents, but probably a mix of more product specific patents directed towards things like the particular guide sequence that you are using to target a gene, potentially modified forms of Cas proteins, particular delivery vectors, target sequences and various optimisation techniques.”
Relative newcomer Cellectis is using CRISPR to produce chimeric antigen receptor T cells (CART cells), MilliporeSigma is focusing on the use of CRISPR to insert exogenous sequence into eukaryotic cells. “Inserting exogenous sequences will allow you to replace defective sequences with healthy’ wild type sequences to create gene therapies,” said Lim.
“There has been a huge amount of buzz around CART cells, with the first set of approvals in the US. There is huge potential there for life changing therapies.”
There has also been increased interest in alternative Cas proteins, Lim added. “When we talk about CRISPR, people typically mean the Cas9 CRISPR system. It is the one that was first reported on and remains to this day the best characterised. But there are a whole host of different variations of even just the Cas9 in different organisms.”
Rhodes believed that the creation of other gene editing techniques like zinc fingers and talens have paved the way for CRISPR regulation. “I don’t see anything more challenging than what the zinc finger and talen folks have already faced.
CRISPR is essentially equal to these other technologies, it is just that it is much easier to build something from the start with CRISPR. To make a zinc finger takes quite a bit of expertise.
“Talens are a bit bulky, they are a bit more difficult to manufacture but they all work well in cutting DNA. All three technologies share the same level… I don’t see a huge advantage of any one over the other, but CRISPR is so much easier and faster to implement,” he stated.
For all three technologies the biggest worry is around off target effects: are they cutting somewhere where they shouldn’t be? And, if they do, what are the consequences of that happening?
Hearts and minds
The zinc finger technique promises many of the same advantages as CRISPR and is now being used to treat patients; if this suffers some setbacks could the backlash extend to CRISPR? Rhodes believed it could. “So you are looking at putting the technology into a human and having a change occur on the body so obviously there is great risk of something goes wrong so it could have an impact on CRISPR. “But it will depend on factors contributing to any negative responses, hopefully there won’t be and it will provide a path for others to follow.”
He added that ERS Genomics hasn’t been that active in encouraging public discussion surrounding the gene editing tool.
“We have opinions but for the most part we’re trying to let the experts, such as DuPont in the case of agriculture, lead the way but we hope to provide support and offer our opinions on things, but it is a broad public discussion that has to happen on several ethical fronts.
Lim concluded, “People have learnt the lessons from the past in relation to the PR surrounding genomes and the potential missed opportunities and I think people don’t want to see CRISPR with all of its great potential become another missed opportunity. They want to see it fulfil its potential. and I think everyone is on the same side in terms of that battle for hearts and minds”
The main players
There are five spin-out companies each formed by pioneering CRISPR researchers. They are loosely divided up into two groups: the UBC/Charpentier parties on the one hand and the Broad Institute on the other.
Spin-outs associated with the Broad and Feng Zhang
- Editas Medicine, note that Doudna of University of California, Berkeley (UCB) was formerly a founding scientific advisor– active in the field of human therapeutics (note that the Broad itself licenses for other uses of the technology – ie, no separate spin out licensing/commercial development body for those applications)
Spin-outs associated with Emmanuelle Charpentier
- CRISPR Therapeutics – human therapeutics
- ERS Genomics – Fields other than human therapeutics
Spin-outs associated with UCB and Jennifer Doudna
- Intellia Therapeutics – Human therapeutics (exclusive sub-licence from Caribou)
- Caribou Biosciences – In practice, fields other than human therapeutics