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CRISPR patent dispute - US and Europe

To date, the focus of the CRISPR patent dispute has largely been on the US dispute between UCB and the Broad in the interference action before the US Patent Trial and Appeal Board (the PTAB). In parallel, however, equally important prosecution and opposition proceedings have been in progress before the European Patent Office (the EPO). Whilst the position continues to be something of a moveable feast and may change quickly, below is a snapshot of the situation as of April 2018.

It is clear that whilst the Zhang/Harvard/Broad/MIT camp (“the Broad camp”) was not the first to file patents in respect of CRISPR technology (and specifically CRIPSR-Cas9), they have since caught up by pursuing a strategy of accelerated patent prosecution, aggressive filing and through the inventiveness of its researchers. As such, the Broad camp has been successful in:

  1. building a broad base of patent families covering a variety of aspects of CRISPR technology, including second generation Cas proteins such as Cpf1; and
  2. bringing their filed patent applications to grant, both in the U.S. and Europe.

The Broad has applied for dozens of CRISPR-related patent families with broad geographic scope (most notably including Europe, the U.S. and China – the main centres of CRISPR related research). These cover various aspects of the CRISPR system ranging from the basic molecular components through to delivery mechanisms and applications. By the time CRISPR based human therapeutic products become available, the key foundational patents owned by either UCB or the Broad may have expired, leaving the parties’ more product specific patents as the best and most relevant protection available to ensure a return on investment through product exclusivity.

However, with the grant of UCB’s key CRISPR-Cas patent in 10 May 2017 by the EPO, UCB been making up lost ground in 2017. UCB’s key filings, whilst not as numerous as Broad’s, are very broad (covering the use of the CRISPR-Cas system in both eukaryotes and prokaryotes) and were first in time. With the grant of key UCB patents being granted, the balance of power may shift, particularly as patent oppositions in relation to these patents start to play out around the world from 2018 onwards.

As the number of patent applications, granted patents and opposition actions on either side of the ledger continue to mount, barring settlement and a cross-licensing or patent pool solution being established, there is likely to be uncertainty with regards to the CRISPR patent landscape for some time to come.  The 2017 grant of broad European CRISPR patents to MilliporeSigma (in respect of the insertion of an exogenous sequence) and Cellectis (in respect of the use of CRISPR in the production of CAR-T cells) further complicates matters, but could also encourage cross-licensing.  However the discussion on this page will focus on the key actions between what has been viewed as the two main protagonists in the Broad and UCB.

Please use the links which follow to navigate to the relevant sections below for more detail on the first instance hearing in the interference between the Broad and UCB, the on-going appeal from the PTAB’s finding of no-interference-in-fact and the opposition hearing in the EPO against a key Broad patent.

U.S. interference

The U.S. interference proceeding before the PTAB (now on appeal to the Court of Appeals for the Federal Circuit) is a process which seeks to determine the priority between two parties who have made claim to the same invention within a year of one another.

Until 2013, the U.S. patent system operated under a “first to invent” priority system as opposed to “first to file”.  The relevant priority dates for the Broad and UCB patents fall just before this change, therefore the dispute falls to be determined under the old system.

First instance hearing before the PTAB

The interference was declared by the USPTO on 11 January 2016 and encompassed UCB’s key patent application over the fundamental CRISPR system as well as 12 of the Broad’s granted patents and one application. As required by the interference process, the parties conducted good-faith discussions over possible settlement on 11 April 2016 and 6 July 2016, however, no resolution was reached. On 15 February 2017, the PTAB delivered judgment on the preliminary motions sought by the parties, granting the Broad’s motion for a declaration of no interference-in-fact and effectively brought the interference proceedings to an end. Notably, this finding did not directly decide the validity of the patents, but rather indicated that the PTAB considered there were two separate inventions potentially worthy of patent protection.

We analyse the PTAB’s decision and its implications for the CRISPR landscape in the short, medium and long-term in a feature article available here.

The critical issue determinative of the finding of no interference-in-fact, was that the Broad was able to convince the PTAB that its invention, being a method for use of the CRISPR-Cas9 system in eukaryotic cells, was not obvious over the invention of CRISPR/Cas9 in any environment (including in prokaryotic cells or in vitro), as claimed by UCB’s patent application. Specifically, the PTAB found that a person of ordinary skill in the art (POSA) would not have reasonably expected the CRISPR-Cas9 system to be successful in a eukaryotic environment (one of the key limbs of the test for obviousness in the US and indeed many other jurisdictions).

Ultimately the PTAB’s decision turned on the fact that although they accepted that UCB’s evidence and arguments demonstrated a high level of motivation on the part of a POSA to try the CRISPR/Cas9 in a eukaryotic environment, this never rose to the level of a reasonable expectation of success of such experiments. By contrast, the PTAB preferred the Broad’s interpretation of each issue in almost every case.

In particular, the PTAB placed “significant weight” on contemporaneous statements made by those in the art at and after the publication of the seminal Jinek 2012 paper (in which UCB’s inventors had demonstrated the CRISPR/Cas9 system working in vitro). These statements (including some from the UCB inventors and one of their expert witnesses) were found to support the Broad’s case and in some cases undermined UCB’s expert evidence.

The PTAB were also convinced by the technical arguments made by the Broad as to the difficulty and uncertainty in transferring a prokaryotic system into a eukaryotic environment. The packaging of eukaryotic DNA in chromatin structures was particularly singled out as a factor, but the Broad were also able to point to other prokaryotic, RNA-based systems which had only been transferred into eukaryotes with limited success and/or with great difficulty. Although UCB was able to establish that some of the techniques used to transfer systems into eukaryotes were known and routine to the POSA, this was found not to be sufficient to give rise to a reasonable expectation of success.

The judgment and full text of the decision is available on the PTAB’s website here as documents 894 and 893, respectively.

Appeal to the Court of Appeal for the Federal Circuit

On 12 April 2017, UCB filed its appeal against the no-interference-in-fact decision made by the PTAB on 15 February 2017.  It subsequently filed its appeal brief in chief on 25 July 2017.

In the brief, UCB (together with Emmanuelle Charpentier and University of Vienna) allege multiple errors in the PTAB’s judgment that the use of CRISPR-Cas in eukaryotes is separately patentable to UCB’s claim to the use of CRISPR-Cas more generally.

In particular, UCB argue that:

  1. The PTAB applied the incorrect legal standard in assessing the obviousness of the Broad’s invention.
  2. The PTAB committed a legal error in failing to consider what UCB characterises as “critically relevant evidence of simultaneous invention” by six different labs working independently across the world.
  3. The PTAB fell into legal error in giving “near-dispositive weight” to contemporaneous statements made by Jennifer Doudna and UCB’s expert witness Dana Carroll, which UCB says were taken out of context and misinterpreted.
  4. On the application of the correct legal standard, the Broad’s implementation of the CRISPR-Cas system in eukaryotes is obvious in light of the claims of UCB’s patent (which are not limited to eukaryotes).

UCB have characterised the alleged errors of the PTAB as legal in nature. Many commentators seem to be of the view that, due to the extensive factual findings made by the PTAB at first instance, UCB are fighting an uphill battle on appeal.

UCB’s legal points about the misapplication of the law on obviousness may be their most promising argument.  UCB say that the PTAB placed too much weight on the lack of specific instructions relevant to CRISPR-Cas in the prior art and effectively elevated the “reasonable expectation of success” test to a requirement of virtual certainty of success prior to experimentation, in circumstances where it was obvious to try those experiments.

The Broad’s reply brief was filed on 25 October 2017 and seeks to make the most of the advantage of having succeeded at first instance. The Broad’s Counter-Statement of Issues, characterises the appeal as boiling down to the single question of whether substantial evidence supports the PTAB’s finding that a person of skill in the art in 2012 would not have had a reasonable expectation of success in engineering prokaryotic-based CRISPR-Cas systems to function in eukaryotic cells.

The Broad’s brief devotes significant time to highlighting the PTAB’s “extensive” factual findings which supported their decision, recounting the five categories of evidence on which the PTAB based its finding:

  1. Contemporaneous statements by the UCB inventors.
  2. Contemporaneous statements by skilled artisans.
  3. Evidence of other research groups.
  4. Extensive scientific evidence of the fundamental differences between prokaryotic and eukaryotic cells.
  5. Extensive evidence of obstacles and failures encountered in prior art attempts.

The Broad argues that UCB has not refuted that the PTAB relied on substantial evidence (the only relevant question on appeal according to the Broad) and seeks to cast UCB’s legal arguments as the final resort of a party which knows the factual findings are against them.

UCB’s response filed on 22 November 2017 refutes the Broad’s characterisation of the standard of review to be applied and attacks the Broad’s account of the evidence and historical record, labelling it as “revisionist” and “a tendentious alternative history”.  In respect of the standard of review, UCB considers that the Broad’s “scintilla” of evidence standard is incorrect and that the agency’s decision must be supported by substantial evidence when considered in light of the whole record, including countervailing evidence.

The disagreement between the parties both as to the nature of the key question to be addressed on appeal as well as the historical context that forms the factual backdrop to the interference is likely symptomatic of the approach UCB has been forced to take in light of the factual findings of the PTAB.

The oral hearing of the appeal before the Court of Appeals for the Federal Circuit was heard on 30 April 2018.  The arguments focused on the key legal question of whether the PTAB had “sufficient evidence” to support its decision of non-obviousness in respect of the application of CRISPR-Cas9 to eukaryotes.  Consistent with their submissions in the lead up to the hearing, UCB stressed the point that the PTAB had not properly considered the fact that multiple labs had attempted and succeeded in applying the CRISPR-Cas9 system to editing in eukaryotes in a very short space of time, whilst the Broad continued to argue that the PTAB made extensive factual findings and had taken all of the parties’ arguments into account.

Commentators present at the appeal have observed that one of the judges on the three judge bench seemed to favour the Broad’s arguments, another appeared to have some sympathy for UCB’s criticism of the standard applied by the PTAB and the other asked few questions and did not indicate any leanings one way or the other.  The decision of the court is expected by late summer. 


Although much of the public focus on the CRISPR patent dispute has centred on the US interface proceedings, the dispute has been simmering in Europe for some time and the first in what is likely to be a long series of opposition hearings in relation to the various granted European CRISPR patents will shift the spotlight to Europe at least temporarily.

Each of (at least) the Broad, UCB, Cellectis, MilliporeSigma have managed to obtain the grant of European Patents which cover a broad and fundamental range of CRISPR technology activities and now enter the opposition phase of the life of a patent, where other parties may launch challenges to the validity of a granted patent within the nine month opposition period from its grant.  Prior to the grant of a patent, third parties looking to make life difficult for a patent applicant may submit “Third Party Observations” in relation to the application, but not make direct oral submissions to the office.

For an opposition to run its full course from filing, through to a first instance decision by the Opposition Division (OD) then appeal to the Technical Board of Appeal, and possibly even further to the Enlarged Board of Appeal takes years, particularly where there are many opponents and the issues are complex.

The first oral hearing in the Opposition Division (OD) of the EPO for a fundamental CRISPR patent (the Broad’s EP2771468) was heard in Munich on 16 and 17 January 2018.  Unlike the interference proceedings in the U.S., which are effectively limited to an analysis of obviousness over the claims of a single piece of notional prior art (the claims of the UCB patent), the OD heard full opposition arguments from six opponents, comprising a mixture of “strawman” parties as well as named opponents including CRISPR Therapeutics.

In its preliminary, non-binding opinion dated 13 April 2017, the OD indicated that:

  • Claims 1, 2, 14 and 15 added matter.
  • The claims lacked priority over all but the latest dated priority document (P12, with a priority date of 17 June 2013), on the basis of a combination of arguments as to the ineffective transfer of priority rights (from Luciano Marraffini of Rockefeller University) and lack of disclosure of the same invention as between the priority document and patent as filed (the latter in relation to the disclosure of a guide sequence between 10–30 nucleotides in length).
  • Only claims 7 and 8 were novel over the cited documents D3 (Mali), D4 (Hwang), D6 (Cho), D28 (DiCarlo) and D29 (Chang).
  • Claims 7 and 8, which survived the novelty attack, were nonetheless obvious in light of the common general knowledge that one can use viral vector systems to express proteins and RNA constructs.
  • The patent was sufficient.

The OD in its decision revoked EP2771468 and found all claims of the patent to be invalid, upholding the preliminary opinion. The revocation of the patent will be suspended pending the completion of the appeal process, which the Broad immediately flagged that it would pursue.

The key issue discussed was whether the EPO had the power to decide on entitlement to priority.  The Broad considered that national law (in this case US law) should apply; under the relevant US law inventorship (and valid claim to priority) would be defined by the person’s contribution to the subject matter of the invention and so the omission of Marraffini could be justified on the basis that he did not contribute to the later filed invention.  The opponents argued that the EPO is competent to rule on priority and bound to do so by Article 87 of the European Patent Convention (EPC), invoking the case law of the EPO and suggesting that the Broad was asking the OD to “throw 100 years of case law out the window”.

The OD declined to do so, despite the Broad’s best efforts, finding that the EPO was entitled to rule on the priority of a patent claiming priority from a US provisional, and could apply European law in doing so.  Despite the Broad’s late evidence in relation to a settlement between the Broad and Rockefeller University, the EPO found that under European patent law there had to have been an assignment of Marraffini’s right to claim priority to the applicants named on the patent application before the date of its filing.

Following the decision on priority the Broad immediately issued a press release which indicated that they would appeal the decision to the EPO’s Technical Board of Appeal (TBA) and clearly foreshadowed the line of attack to be taken in the appeal, stating that the decision “affects many other European patents that rely on U.S. provisional patent applications, and is inconsistent with treaties [i.e. Paris Convention] designed to harmonize the international patent process, including that of the United States and Europe”.

The consequence of the OD’s decision is that some of the Broad’s other European patents will also be vulnerable this same priority point – i.e. seeking to claim an early priority date from earlier filings where Marraffini was listed as an inventor, without having named him as an inventor on the later application.  It is likely that the claims of those patents will also be substantially or wholly revoked, in light of this decision.  However, the Broad has other patents covering later, more specific inventions and different Cas proteins like Cpf1 which will not be affected.

The detailed grounds for the decision were made available on 26 March 2018.  No date has yet been set for the hearing of the appeal from the OD’s decision, but it is unlikely that the appeal will be heard before mid-2019 at the earliest.

Introduction to CRISPR

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