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Editing the future: A brief introduction to CRISPR

 

23 February 2017

​For those with an interest in life sciences, the rise to prominence of CRISPR has been impossible to ignore.  It seems a day does not go by without the discovery of a new application for the technology or a new variant of one of the essential components of the system, or a yet another twist in the on-going patent dispute between the would-be inventors of the foundational IP. 

On 15 February 2017 the USPTO’s Patent Trial and Appeal Board (PTAB) handed down its decision in the interference proceedings between the Broad Institute of MIT and Harvard (the Broad) and the University of California Berkeley (UCB), discussed further below.  This decision represents perhaps the most significant event in the legal and licensing side of the CRISPR story since the Broad’s key patents were granted ahead of those sought by UCB.
 
For those not closely following the CRISPR landscape, the pace of developments can be overwhelming and, for those looking to catch up on the latest in the CRISPR field, it can be difficult to know where to look.  This article aims to set out the basic principles behind the technology, why it has taken the scientific world by storm and outline why the patent dispute matters.

What is CRISPR?

CRISPR is short for Clustered Regularly Interspaced Short Palindromic Repeats, a system of adaptive immunity first characterised in bacteria and archaea which has now been harnessed by the scientific community for a host of applications.  Its most well-known application is to facilitate accurate and targeted cutting of DNA to enable editing of genes.

Although there are many variants of the CRISPR system, which differ subtly but importantly from species to species, the first and still most widely used variety is the CRISPR/Cas9 system, which is derived from proteins found in the bacterium Streptococcus pyogenes.  Since then many more CRISPR systems have been discovered and are in the process of being characterised, some of the most promising being the Cpf1 and C2c2 systems.

The power of the CRISPR system lies in the ease with which it can target regions or genes of interest in the genome of target cells.  Unlike existing gene manipulation techniques (i.e. Zinc Finger Nucleases and TALENs), which require entire bespoke proteins to be constructed to interact with a particular target sequence, the CRISPR system simply requires the synthesis of a different 20 base pair RNA guide, which is fed into the relevant protein complex and guides it to the specific target site.  There, the endonuclease activity of the Cas protein (e.g. Cas9) causes a double stranded break which researchers can then take advantage of to remove or insert genetic material, through DNA repair mechanisms such as non-homologous end joining or homology directed repair. 

The CRISPR system had first begun to be characterised in the 80s, but its potential was not realised until 2012 when Jennifer Doudna and Emmanuelle Charpentier developed a method to simplify the RNA guide component of the CRISPR/Cas complex.  Later Feng Zhang and George Church’s labs, separately but simultaneously (in the same issue of Science), were the first groups to publish a method for its use in eukaryotic cells.  This was followed very shortly after by the publication of independent work by other labs, including those of Jennifer Doudna and Jin-Soo Kim, which also described the successful use of the CRISPR system in eukaryotes.

What can CRISPR do?

It is difficult to overstate the realm of potential applications for CRISPR based technology.  Although much of the media coverage to date has tended to focus on the potential medical applications for CRISPR technology, equally there is a wealth of potential applications in the agricultural and bioindustrial sectors.  CRISPR could potentially revolutionise any industry in which molecular biology and genetic technology plays a part. 

In particular, the convergence of the rise of CRISPR technology and personalised medicine is a perfect match – CRISPR enables the accurate and (relatively) inexpensive editing of nucleic acids on a scale which was unimaginable using the previous generation of gene editing techniques.  One of the most exciting early areas of research is in using CRISPR to create “killer” T-cells specifically targeted to antigens displayed by a particular patient’s cancer.  Indeed, a clinical trial involving CRISPR edited T-cells in cancer therapy has already been commenced in China and a similar trial has been approved in the US. 

Genetic modification has never been far from controversy and never has it been so easy to do, or potentially so easy to abuse.  And as much as the power and ease of use of CRISPR technology is a boon to research and development, there is a corresponding risk and concern that such technology may be abused and misused.   

The biggest concern expressed in industry is over the potential for CRISPR to be used to make modifications to the germ line of organisms – i.e. gene edits not to the somatic, adult cells of an organism (which will only affect that organism), but to the reproductive cells, such that those modifications will be passed down to offspring of the organism (and potentially their offspring, and so on down the line).  The spectre of eugenics and uncertainty of the long term consequences of such germ line modification is unlikely to be dispelled any time soon.

Who are the key players?

As with any new transformative technology, questions of access, control, inventorship and ownership are often central, and CRISPR is no exception.  Major patent office disputes are currently underway on both sides of the Atlantic, the outcome of which could have huge implications for the future direction of the technology and the significant economic interests in play.

The protagonists are some of the leading lights in the scientific world today and the powerful academic institutions from which they hail.  They can roughly be divided into one of three camps:

  • Jennifer Doudna, UCB and spin-out companies Caribou Biosciences and Intellia Therapeutics.  Together with the Charpentier group the Doudna group co‑owns the first filed patent applications in the US and Europe in relation to the key components of the CRISPR/Cas9 system currently in use, however their key patents are yet to be granted.
  • Emmanuelle Charpentier, the University of Vienna and spin-out companies CRISPR Therapeutics, ERS Genomics and joint venture (with Bayer) Casebia Therapeutics.
  • Feng Zhang, MIT, Harvard, the Broad Institute and spin-out company Editas Medicine.  The Zhang group owns a range of patents and patent applications concerning the CRISPR process, including granted patents in the US and Europe for the fundamental CRISPR technology in eukaryotes.

Each of these camps has partnered variously with big pharma, venture capitalists and fellow disruptive biotech start-ups in a complex series of exclusive licensing deals, joint ventures and strategic collaborations to commercialise the CRISPR/Cas system.  Each has received substantial funding through early funding rounds and partnerships, and each undertook an IPO in 2016.  Even with the ongoing patent dispute, they represent the vanguard of CRISPR companies, given their stake in the patent dispute and the reputation and expertise of their big name founders.  Leading companies such as Novartis, Regeneron, Bayer and Monsanto have already aligned themselves with one side or the other, and it seems merely a matter of time before others enter the CRISPR field.

Importantly, the Doudna and Charpentier camps share the same estate of foundational CRISPR IP, whereas the Zhang/Broad camp holds a separate, competing portfolio.  This forms the basis of the patent dispute around the globe. On 16 December 2016, the Doudna and Charpentier camps formalised their alliance, signing a global cross-licensing and patent prosecution co-operation agreement.

Why this patent dispute matters

Thus far, most of the focus on the CRISPR patent dispute has been on the US dispute between UCB and the Broad Institute in the interference action before the PTAB.  Commentators have sought to use the PTAB’s 15 February 2017 decision to draw conclusions about the balance of power in the CRISPR dispute more broadly and the future direction of the technology.  

Pursuant to a motion brought by the Broad on 23 May 2016, the PTAB found that there is no interference-in-fact between the Broad’s and UCB’s relevant CRISPR patents and applications, effectively bringing the interference proceedings to an end, subject to any appeal by UCB.  This means that the PTAB considered that the respective inventions claimed by UCB and the Broad are sufficiently different and distinct from one another as to be separately patentable.  The claims of UCB’s patent application cover the use of the CRISPR/Cas9 system in any setting, whilst the claims of the Broad’s patents are limited to the system’s use in eukaryotic cells.  In a separate article, we examine the PTAB decision in detail and its ramifications in the short, medium and long term for the parties and their current and prospective licensees and collaborators.  In particular, we will consider how useful the PTAB decision really is as an indication of how other courts and tribunals may view the patents and the parties’ arguments.

However, whilst the position of the parties’ patents in the US is undoubtedly of key significance, it must be remembered that, in parallel, equally important prosecution and opposition proceedings have been in progress before the European Patent Office (EPO) and a key UCB patent is on the verge of being granted in Europe (Case No. EP2800811).  With so many granted and pending patents, at different stages in prosecution or opposition around the world, and subject to different patent law systems in different jurisdictions, we expect the patent landscape will continue to shift for some time yet.

What is clear, however, is that whilst the Harvard/Broad/MIT camp was not first off the line, in the sense that UCB was first to file, they have since more than caught up, by pursuing a strategy of accelerated patent prosecution and aggressive filing. 

With good reason, life sciences industry press, companies large and small, and even the mainstream media have been keenly observing what has been billed as the biggest biotech patent dispute in history.  The outcome of the dispute in the patent offices will have significant consequences and may come to define the developmental path of this transformational technology.

For those seeking to enter the CRISPR field, uncertainty over the ownership of the foundational IP may delay or deter their entry, thus having a chilling effect on innovation and participation in the CRISPR revolution.  The lack of one clear winner will lead to a fragmented landscape globally or even within a single jurisdiction, with prospective industry entrants forced to take licences from multiple parties unless some single licensing platform or pool could be formed.

For those who have already taken a licence, they will be keen to know whether they have backed the winner in the patent dispute, and how much their licence and/or collaboration is really worth.  Clinical programs being developed in conjunction with a loser in the patent dispute could be jeopardised, and additional licences may need to be sought from the winners.  Significantly, the PTAB’s decision as to the separate patentability of UCB and the Broad’s respective inventions leaves open the possibility that ultimately both UCB and the Broad will retain valid CRISPR/Cas9 patents of broad scope.  In that circumstance, users of CRISPR/Cas9 technology (including UCB and the Broad themselves) will need licences to both CRISPR/Cas9 patent portfolios.  Should this come to pass, we may see more commercially attractive cross-licensing options emerge.

For IP counsel and their external advisors, the dispute will provide plenty to digest, and the way it is fought could set the tone for future breakthrough technologies, either as an example to be followed or a cautionary tale.  By the end, the dispute will no doubt have yielded plenty of lessons to be learned which can be applied more broadly, including:

  • What is the optimal early filing strategy?
  • How should secondary patent protection be developed for biotechnology platforms?
  • How should big pharma approach collaborations with startups holding transformational IP (and vice versa)?
  • How can the risk from such patent disputes be mitigated or accounted for in licensing/collaboration agreements?

At any rate, given the current stage of the case in both the US and Europe and the avenues available to both sides for appeal, oppositions and litigation, barring settlement and cross-licensing, we are unlikely to see any certainty as to the ownership landscape for CRISPR’s foundational IP for some time yet.

 
 

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