11 July 2015

CRISPR – Will This Be the Last Great US Patent Interference?

Duelling PistolsOn 9 November 2014, Berkeley Professor of Chemistry Jennifer Doudna and her collaborator Emmanuelle Charpentier, currently at the Helmholtz Center for Infection Research in Germany, attended an awards ceremony at NASA’s Ames Research Center in Mountain View, California.

Not only did Doudna and Charpentier – dressed to the nines, and looking more like glamour queens than the usual white-coated scientist stereotype – mingle with celebrities including Benedict Cumberbatch, Cameron Diaz and Jon Hamm, while enjoying a live performance by Christina Aguilera, they also received the 2015 Breakthrough Prize in the life sciences category.  The award, which was sponsored by Facebook’s Mark Zuckerberg and other tech billionaires, included prize money of US$3 million apiece.

To put that in perspective, had the two scientists received a Nobel Prize last year, they would have shared 8,000,000 Swedish Kronor, or about US$1 million, between them.  Of course, it is not all – or even mostly – about the money, and the prestige attached to a Nobel prize is undoubtedly greater.  And it seems to be odds-on that the discovery for which Doudna and Charpentier received the 2015 Breakthrough Prize – and which has been called ‘the biggest biotech discovery of the century’ – will one day be the subject of a Nobel Prize as well.

All of this fuss is about a technology called CRISPR/Cas9, which is essentially a DNA ‘editing’ tool that Doudna and Charpentier developed in (around) 2012, as a result of their research into a system used by bacteria to defend themselves against viruses.  Doudna has described the CRISPR/Cas9 (which stands for Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9) tool as a ‘molecular scalpel for genomes’.  She and Charpentier demonstrated how it is possible to synthesise molecules, consisting of an engineered RNA and a ‘cutting’ protein, that can precisely target a short gene sequence within a genome, and slice the DNA open at that exact point.

Bacterial cells – in which the mechanism was first discovered – are simpler than the cells of higher organisms (known as ‘eukaryotic cells’).  However, in January 2013, Doudna and Charpentier took the next step, successfully cutting out and replacing a selected section of DNA in human cells.  In the same month, a team led by Feng Zhang at the Broad Institute, Inc and MIT reported similar success using CRISPR to edit human genes.

Which brings me to the main topic of this post.  Because, while Doudna and Charpentier have been collecting the public accolades, rubbing shoulders with the rich and famous, and banking the – doubtless well-deserved – proceeds of their success, it is Zhang who has been awarded the first patent on the basic CRISPR technology – US Patent No. 8,697,359, ‘CRISPR-Cas systems and methods for altering expression of gene products’, issued on 15 April 2015.  And that could ultimately be worth much more than $3 million!

This is now shaping up as a major battle over who will own the most basic, and potentially valuable, patent rights in relation to the CRISPR technology, and possibly the last great priority dispute of the ‘first-to-invent’ era of US patent law.

Duelling Patent Claims

Unsurprisingly, Doudna, Charpentier and their co-workers have their own patent application pending: serial no. 13/842,859 (for simplicity I shall refer to this simply as ‘Doudna’ from here on).  And this is where things get interesting, and potentially confusing, because although Zhang’s patent has issued first, Doudna was the first to file.

Specifically, the earliest filing by Doudna occurred on 25 May 2012, which was more than six months earlier than Zhang’s initial filing date of 12 December 2012.  Both of these were US provisional filings, and clearly both groups of researchers were working diligently throughout the subsequent 12 month periods.  Doudna’s group filed further provisional applications on 19 October 2012, 28 January 2013 and 15 February 2013, before filing their final nonprovisional application on 15 March 2013.  Meanwhile, Zhang filed further provisional applications on 2 January 2013, 15 March 2013 and 17 June 2013, with his final nonprovisional application being filed on 15 October 2013.

The reason Zhang’s application was examined first – and has already issued as a granted patent – is because he (or, more likely, his backers) requested prioritised examination under the USPTO’s Track One program.

As an attentive reader, you are no doubt thinking that if Doudna filed first, surely her application should have been cited as prior art against Zhang’s claims to the CRISPR/Cas9 technology.  And you would be absolutely correct.

It’s All About The Eukaryotic Cells…

So this is where the plot thickens, and it all comes down to those eukaryotic cells I mentioned earlier (i.e. cells from more complex organisms, such as human beings).  Zhang’s claims are specifically directed to methods and systems for ‘altering expression of at least one gene product comprising introducing into a eukaryotic cell containing and expressing a DNA molecule having a target sequence…’.  In overcoming the citation of Doudna’s application, Zhang argued that Doudna’s earlier filings disclosed only the effectiveness of CRISPR/Cas9 in simpler bacterial cells, and that it was not obvious from those disclosures that the technique could also be applied in eukaryotic cells.

And when I say ‘Zhang argued’, I mean precisely that, and not merely that the patent attorneys acting on behalf of Zhang’s backers or employers made this argument.  On 30 January 2014, an affidavit executed by Zhang was filed, in which he personally set out the analysis of the prior art, and the reasons why (in his opinion) ‘the CRISPR-Cas system was not known to function in eukaryotic cells at the time’ of filing of Doundna’s earlier provisional applications.

Thus was Zhang awarded a patent covering the CRISPR/Cas9 technology for use in eukaryotic cells, which is (presumably) the main area of application that people are interested in commercially.

Who Has Priority Over CRISPR?

So where does all this leave Doudna, Charpentier, their assignees as the Universities of Vienna and California, and the commercial entities that have already begun taking licenses to their CRISPR intellectual property?  Well, that depends…

On 16 March 2013 provisions of the America Invents Act came into effect, changing the US patent system from the world’s only ‘first-to-invent’ patent priority regime into a ‘first-inventor-to-file’ regime, much like the rest of the world.  A first-to-file system is simpler to administer than a first-to-invent system – if there are two conflicting applications claiming the same invention, the patent goes to whoever filed first.  But both Doudna and Zhang filed prior to 16 March 2013, and their applications are therefore subject to the former priority regime.

Under the old ‘first-to-invent’ system, however, priority goes to whoever can demonstrate that they were the first to conceive of the invention, subject to them also demonstrating that they were then diligent in ‘reducing it to practice’.  This whole notion of ‘invention’ as ‘conception’ plus ‘reduction to practice’ is mired in legal history, and dependent upon a fairly high standard of proof.  Suffice to say (for those with experience at the bench) that this is where the whole practice of keeping detailed, formal, dated, numbered, witnessed and signed-off laboratory notebooks originated.

‘Suggestion of Interference’

The formal process of determining who is entitled to a patent under the first-to-invent regime is called an ‘interference proceeding’.  An interference can be initiated if one patent applicant presents claims that are not ‘patentably distinct’ from those of another applicant, which essentially means that the subject matter of one set of claims would (assuming it is prior art) anticipate, or render obvious, one or more of the claims in the other application.

On 13 April 2015, the interested parties in the Doudna application sought to provoke an interference by filing hundreds of pages of documentation, including:
  1. a set of amended claims, encompassing the broad application of CRISPR/Cas9 without limitation to any particular type of cell, and thus including within their scope the application to eukaryotic cells;
  2. a (106 page) ‘Suggestion of Interference’ explaining why certain ones of Zhang’s issued claims are not patentably distinct from Doudna’s amended claims; and
  3. a written declaration from Professor Dana Carroll of the University of Utah, who is considered a pioneer in the field of gene editing, in which he asserts that not only do the earlier Doudna provisional applications (and equivalent scientific publications) provide ‘clear disclosure of the use of the compositions in eukaryotic cells, they also provide detailed descriptions of numerous steps that could be taken to apply the system to a eukaryotic cell environment.’
Since then, an unidentified third party (almost certainly connected to Zhang, the Broad Institute and/or MIT) has filed a stack of prior art that they assert is relevant to the amended Doudna claims, along with accompanying statements outlining the relevance.  These statements include various assertions, including that the amended claims are ‘overly broad’, and that the Doudna applicants have failed to comply with the duty to disclose information (e.g. prior art) pertinent to the patentability of their claims.  For those unfamiliar with the US system, such a failure provides grounds to refuse a patent, under 37 CFR 1.56.

So, it looks like things are getting heated!

Conclusion – Fortunes Hanging on USPTO Decision

The USPTO has yet to make a decision on the Suggestion of Interference, but if I were a betting person my money would be on the Office declaring an interference in this case, setting in train a procedure that could carry on for a couple of years, and cost the parties in excess of a million dollars between them.

There does not seem to be any question that Doudna and Charpentier were the first to develop and demonstrate the CRISPR/Cas9 technique in bacterial cells, so their place in the scientific firmament is no doubt safe.

But ultimately, the big money is going to be in the application of CRISPR/Cas9 in higher life forms, whether that is curing genetic defects and diseases in humans, engineering genetic modifications to animals and plants, combatting viruses (such as HIV), or other applications not yet imagined.  And since the ultimate value of a patent is commercial, it is going to matter very much who ends up ‘owning’ the use of CRISPR/Cas9 in eukaryotic cells.

Right now, the likely outcome in this regard is unclear.  Professor Carroll is clearly of the view that Doudna and Charpentier’s early work in bacteria pointed the way to application in eukaryotic cells without need for further ‘invention’.  If he is correct, then the spoils should go to team Doudna.  Professor Zhang, understandably enough, holds a different opinion.

Since this seems to be an issue upon which experts might legitimately disagree, this electrical engineer is not going to express a view.  But if you are a geneticist or biochemist, please feel free to share your opinion in the comments below!

Acknowledgement: I am grateful to Sophia Frentz (@sofaf) for piquing my interest in this topic, and pointing me in the direction of some useful background reading.  Having said that, any scientific errors or gross oversimplifications are entirely mine!

Image Copyright (c) 7fotfoto / 123RF Stock Photo


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