16 Jan
2019

Five things you must know about CRISPR

Over the last six years, CRISPR-related inventions have been awarded thousands of patents. And we are only at the beginning. Catherine Coombes of HGF identifies five of the key patenting issues the revolutionary technology raises

A complex of molecular scissors with a satnav; a CRISPR associated (Cas)  protein, such as Cas9, combines with guide RNA (the satnav) to push the protein towards a DNA target. The protein can then carry out a desired function, such as gene editing; or, by deactivating the endonuclease activity of the protein, CRISPR/Cas9 can be used as a programmable DNA binding protein able to tow other proteins with desirable activity to a specific target site.

Six years on from the first scientific articles demonstrating the use of CRISPR/Cas9 to modify DNA in mammalian cells, the life sciences patent landscape has exploded into a new area which currently contains over 3,500 patent families.

Following are five key CRISPR points you need to know.

The CRISPR/Cas9 patent landscape is extremely contentious and uncertain

In Europe, there have been a number of patents issued to various parties on the underlying components of CRISPR/Cas9 as a genome editing tool, often following various third party observations. The EPO has been granting broad overlapping patents to various parties in the early CRISPR/Cas9 landscape. These are often opposed by numerous parties, with a typical opposition in this field having three to 10 opponents, and cited documents on such oppositions often exceeding 300.  

For such large oppositions, the EPO has not been keeping to the early certainty from opposition timelines. These oppositions will mean post-grant proceedings before the Opposition Division and Boards of Appeal of the EPO will ultimately decide what patent rights should be upheld in this area in Europe.

With so many opponents, a new trend of filing a Notice of Opposition on the day of grant and following this up with the grounds for opposition within the nine month window post-grant has emerged. This trend to simply file the form to secure first opponent status, which enables an opponent to speak first and have more influence on the direction of the arguments at the oral proceedings, has been accepted by the EPO. However, it could be open to abuse (eg, if firms were to file the form to secure first party as a tool to tender for a specific opposition from a client) and so it remains to be seen if the EPO will change this practice. First party status has been challenged in one of the proceedings where Opponent 1 filed a form but wasn’t the first to complete all the necessary acts for a complete opposition.

To date most oral proceedings in these oppositions have yet to occur. A year ago, the first Oral Proceedings for Broad/MIT resulted in the Opposition Division revoking EP 2 771 468 following a finding of a lack of priority which led to highly relevant documents becoming citeable against the patent. The decision was immediately appealed.

Opposition of other Broad patents having the same priority issues are still ongoing, while the EPO, in a somewhat unusual move, has encouraged the applicants to consider requesting a stay of proceedings in pending patent applications having the same priority issue as EP 2 932 421. The contentious nature of this field has resulted in third party observations objecting to such a stay of proceedings.

Outside Europe, the strength of patent portfolios of various patentees varies from jurisdiction to jurisdiction. This only adds to the complexity. Within Europe uncertainty is increased by patents granting that have inconsistent assessments of the relevance of the same cited documents.

It’s still too early to know what the key patents will be for human therapeutics

Adding to the complexity of overlapping patent rights in Europe is that the early landscape is the tip of the iceberg. Numerous patents applications aimed at improvements to CRISPR/Cas9, Cas9 orthologs, new ways of using and applications thereof have been filed.

Furthermore, despite the great scientific advances, there are still many unknowns. Considerations of how to improve efficiency, reduce off-target effects and optimise delivery are still at the forefront alongside regulatory and ethical considerations. Developments which improve the safety of CRISPR/Cas technology in human therapeutics may well be required. The dominant or essential components to be used as a scaffold for gene editing applications are yet to be confirmed. What this means in practice is that we do not know how fundamental some of the early patents currently going through oppositions and appeals will actually be in the long term.

Cas9 is just one type of Class 2 CRISPR associated protein that cleaves DNA

CRISPR systems can be divided into two classes: Class 1 systems have multi-subunit protein effector complexes, whilst Class 2 have single-protein effector modules. 

The early patent landscape for gene editing applications referred to Class 2, Type II CRISPR/Cas systems in which a single protein (Cas9) can effect cleavage. Since then V and VI systems have emerged which also are single-protein effector molecules. Examples include Cas12a (Cpf1), which has been used widely, and Cms1, which has garnered interest in mainly agricultural applications. Cas13 and Cas12 have found utility in diagnostics using techniques, such as: specific high sensitivity reporter unlocking (SHERLOCK), and DETECTR, which harness the ability of these proteins to detect, bind and cleave specific sequences and then cleave oligonucleotides having a detectable signal.

These Cas proteins were not part of the early landscape which centres on Type II systems. Hence, numerous discrete patent landscapes are emerging. It is useful to consider the applicability of other Class 2 CRISPR/Cas systems when considering IP strategies in this area.

Class 1 systems are garnering scientific interest and investment

Class 1 systems are not desirable for the gene editing applications envisioned in the early CRISPR/Cas landscape as they require multiple proteins to effect cleavage of DNA. Thus, these systems would present more challenges for delivery and use. However, Class 1 systems have garnered a lot of interest in the fight against antimicrobial resistance.

CRISPR/Cas systems are naturally present in bacteria as part of a bacterium’s adaptive immune response to foreign genetic elements, such as bacteriophages. Unlike Cas9, which is an endonuclease, CASCADE/Cas3 of Type 1 systems is a powerful exonuclease which shreds the target DNA. Companies such as Locus Biosciences are harnessing this technology by combining bacteriophages with a CRISPR/cas3 that is designed to target a specific pathogenic species or strain.

The ability to generate selective antimicrobials so that infections may be treated whilst protecting a subject’s microbiome has generated both interest and investment, with Locus Biosciences recently licensing their proprietary technology to Janssen in a deal worth a potential $818 million.

Patentability requirements in Europe

Considerations for changes to drafting practice in this field are very much dependent on how CRISPR/Cas is used in the context of the invention. For applications where the invention is not CRISPR technology at all, with CRISPR technology being simply used to generate a desired modification, it may be that no changes are required to drafting practice. A paragraph in the description disclosing various genome-editing tools including CRISPR may be sufficient together with checking that the examples disclose enough details for the experiment to be repeated.

The EPO has made it clear that merely carrying out known modifications using CRISPR, instead of traditional methods, will not be enough to render methods patentable. Comparing CRISPR to other genome-editing techniques to correct known mutations in EP 3 019 595, the examiner stated: “Of course applicant will try and argue that it was not a one-way street situation because he could have chosen other options … However, where one option is akin to a motorway while the other is winding unpaved roads, the applicant is presented with a clear one-way street situation.” Such inventions are likely to require unexpected technical effects to be demonstrated in the patent application as filed to be granted.

But what about improvements in the use of CRISPR technology such as to reduce off-target effects or increase efficiencies of the successful modification occurring that are accompanied by data showing such improvements? These require a lot of careful consideration in drafting, both in considering the likely breadth of claims and fulfilling the requirements of clarity and sufficiency in the description.

While a number of the terms used in this field have become common general knowledge and so much more is now known about how such CRISPR systems work, it can be deceptive. For example “Cas9 polypeptide” is a very well-known term used in scientific literature to refer to naturally occurring Cas9 polypeptides and is often used in patent applications to cover both natural proteins and those altered in some way, such as functional fragments, variants etc.

Yet what are the defining features that make a Cas9 polypeptide considerable as a Cas9 when departing from naturally occurring proteins? In a patent that utilises Cas9 to cleave DNA this may be easy to define but in one which also encompasses the use of dead Cas9, care should be so that the metes and bounds of the term is clear.

How broad can you plausibly define your claims without encountering sufficiency issues? For example, it may be desirable to consider references to key papers which explain the structural requirements for the Cas protein(s) used, together with the structural requirements for the various components to interrelate, to function to bind target DNA and carry out the desired function. Such guidance may be useful in drafting a patent application which is enabled across the whole scope of the claims.

CRISPR is one of the topics that will be under discussion at IAM's forthcoming Pharma and Biotech IP conference taking place in London on 28th January. More details here:

http://www.iam-events.com/events/pharma-and-biotech-ip-2019/event-summary-b74377f3494e4c629161bff58450e12e.aspx

Catherine Coombes

Patent director | HGF

York, UK