17 January 2016

Who Will Get the CRISPR Patent?

CrispyAs has been widely reported, the US Patent and Trademark Office (USPTO) has instituted interference proceedings to determine who is entitled to own foundational patent rights in relation to CRISPR/Cas9 ‘gene editing’ technology.  I wrote about this brewing dispute back in July 2015, when I predicted that this would be ‘the last great US patent interference’, given that the US patent system changed from first-to-invent to first-inventor-to-file on 16 March 2013. 

As the number of applications filed under the former first-to-invent system dwindles, the opportunities for new interference proceedings – which are all about figuring out who invented first when separate applications with competing claims are filed – are becoming scarce.  Even less likely is another interference over a genuinely groundbreaking and immensely valuable invention.

For the full story, you should really go back and read my earlier article.  But if you lack the time or stamina, here is the TL;DR recap:
  1. Berkeley Professor of Chemistry Jennifer Doudna and her collaborator Emmanuelle Charpentier were the lead researchers on a team that, in around 2012, developed so-called CRISPR/Cas9 – a biotechnology system consisting of an engineered RNA and a ‘cutting’ protein that can be used for highly-targeted gene editing;
  2. Doudna, Charpentier and their co-workers have a US patent application pending (serial no. 13/842,859), which is based on a series of filings beginning in May 2012;
  3. Doudna and Charpentier’s original work related to the discovery of the CRISPR system in relatively simple bacterial cells, but in January 2013 they were successful in applying the technology to human cells;
  4. roughly in parallel, however, a team led by Feng Zhang at the Broad Institute, Inc and MIT reported similar success using CRISPR to edit human genes;
  5. Zhang and his team also filed a US patent application, based on a series of their own filings beginning in December 2012 (i.e. more than six months later than Doudna’s earliest filing);
  6. to complicate matters, Zhang requested prioritised examination under the USPTO’s Track One program and, as a result, was 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, even though Doudna’s group had been the first-to-file;
  7. Doundna and Charpentier subsequently requested the USPTO to institute interference proceedings, in order to determine who is really entitled to own the patent rights to the CRISPR/Cas9 technology.
That request has now been granted.  So who will get the CRISPR patent?  Well, if I knew that I could save the USPTO a whole lot of work, and the parties a great deal of time and money.  Ultimately, only time and the evidence will tell.  But what I can do is to outline the basics of interference proceedings, and make a few tentative predictions.

A Quick Update

A brief summary of developments in Doudna’s patent application since last July is in order.  In September an Official Action (i.e. an examination report) was issued, which contained a number of rejections of the claims that were pending at that time.  In October, the applicants’ attorneys conducted an interview with a panel of examiners (four USPTO staff participated in the interview, which is unusual and shows that the Office is well-aware of the importance of this case).  It appears that agreement was reached in the interview regarding amendments to the application in order to overcome the rejections.

In November a formal response to the Office Action was filed.  This response, including the agreed claims, is publicly available via the USPTO’s PAIR system, and I have obtained a copy of the relevant documents [PDF, 726kB].  Doudna and Charpentier have also identified a number of further related patents and applications filed by Zhang/Broad/MIT that they say contain interfering subject matter.

On 23 December 2015, the USPTO issued a notice indicating that all of Doudna’s claims are in condition for allowance (i.e. no outstanding rejections or objections) pending a potential interference.

With the claims of both parties finalised, the stage is set, and the interference can, and will, proceed.

What Are the Parties Claiming?

The patent claims of the Doudna and Zhang parties are not identical.

Put simply (perhaps too simply, but I am no expert in this technical field) Doudna is claiming the CRISPR/Cas9 system without any limitation on the RNA and/or DNA involved.  Recall that Doudna’s team originally discovered the mechanism in bacterial cells, which are simpler than the cells of higher organisms (known as ‘eukaryotic cells’).  They are, however, claiming more broadly, to cover all types of cells.  This is legitimate so long as an oridinary skilled person working in the field would have anticipated that the same mechanism could be made to work in eukaryotic cells (such as human cells) without requiring further inventive activity.  It is notable that the US examiners, at least, seem satisfied that this is the case, because they consider Doudna’s claims to be allowable.

Zhang’s claims – again, grossly simplified – are limited to use of the CRISPR/Cas9 mechanism in eukaryotic cells.  Remember, Doudna filed first and that earlier application was therefore prior art to Zhang’s claims.  Doudna’s earlier filing disclosed the use of the CRISPR/Cas9 mechanism in bacterial cells, so what Zhang said was new and patentable in his team’s work was the application to eukaryotic cells.  Thus Zhang’s examiners were satisfied that the extension to eukaryotic cells was not obvious, and his team could therefore be granted a patent for this advance.

This explanation makes it seem as though resolving the interference will simply be a matter of figuring out who is right: if there is nothing surprising or inventive in showing that the CRISPR/Cas9 system works in eukaryotic cells, then Doudna and Charpentier win; otherwise Zhang is victorious.

But it is not so simple as this, because we know that both teams were successful in demonstrating operation of the CRISPR mechanism in human cells.  What is more, we know they both did so at around the same time, i.e. in about January 2013.  So by the time each party filed their ‘final’ patent applications later that year, they could both arguably lay claim to rights over the CRISPR/Cas9 system in eukaryotic cells.

Advantage Doudna!

Interference proceedings are complex, and the rules arcane.  But the first, and perhaps most important thing to understand is this: the burden of proof to establish earlier inventorship lies with Zhang.  This is because Doudna’s team were the first-to-file and, even in a nominally ‘first-to-invent’ system, this makes them the ‘senior party’.

The rules of patent interference start from a presumption that the first-to-file is entitled to a patent, placing the initial onus upon the later filer (the ‘junior party’) to provide persuasive evidence of an earlier date of invention.  Only if the junior party is able to do this will the senior party need to establish its own date of invention.

As a result of this procedural ‘bias’, being senior party is something of an advantage.  Historically, in interferences decided by the USPTO Board the senior party has been victorious around 75% of the time.  (This is not the whole story.  In a paper published in 2003, legal academics Colleen Chien and Mark Lemley found that when ‘true’ priority disputes in US Federal District Courts, and at the Court of Appeal for the Federal Circuit were taken into account, it appeared that the junior party was awarded priority in about 43% of cases.  But, even so, one would clearly rather be the senior party than the junior party in an interference!)

Conception and Reduction to Practice

Some readers may be wondering what it means to establish a specific date of invention… and I am glad you asked!

‘Invention’ may lie almost entirely in a flash of inspiration, in which a new product springs fully-formed into the inventor’s mind.  More commonly, however, invention is a process.  Initially, the inventor may conceive of an idea, and/or make a new discovery, but it is only after some time, effort and experimentation that a final, practical working form of an invention is devised.  In US patent law these two steps are called, respectively, ‘conception’ and ‘reduction to practice’.  You might think of them, in more colloquial terms, as ‘inspiration’ and ‘perspiration’.

The date of invention could therefore be regarded as either the date of conception, or the date of final reduction to practice.  There is, it should be noted, no requirement that an invention actually be reduced to practice in order to obtain a patent.  It is enough that the inventor can explain, e.g. in a patent specification, how the invention can be made to work, regardless of whether or not they have actually done so in the ‘real’ world.  Filing a patent application with a sufficient description is therefore regarded as a ‘constructive reduction to practice’.

OK, if you have grasped all of that, then you are all set to understand how the date of invention is determined:
  1. the date of invention is the date of conception if (and only if) the inventor has then proceeded to reduce the invention to practice without further inventive activity and with sufficient diligence;
  2. if the inventor cannot prove a date of invention, or is unable to show diligent reduction to practice, then the date of invention is the date of final reduction to practice; and
  3. if no earlier date can be established by sufficient evidence, then the date of invention is taken to be the date of filing the patent application, i.e. the date of constructive reduction to practice.
Simple, isn’t it?!

The gold standard for proof of conception and diligent reduction to practice is the keeping of detailed, consistent, dated, tamper-proof and witnessed laboratory notebooks.  You all have those, right?  Fingers crossed that both Doudna’s and Zhang’s teams had implemented best-practice in lab-notebook-keeping!

Conclusion – Who Will Get the Patent?

The main prize here is the patent covering use of CRISPR/Cas9 in eukaryotic cells (including human cells).  There does not seem to be any dispute that Doudna and Charpentier first discovered and applied the mechanism in bacterial cells, but that is not where the big commercial opportunities lie.  Still, a patent is a patent, and this, at least, looks to be Doudna’s for the taking.

Beyond this, the odds also appear to be in Doudna’s favour.  Her team is the senior party in the interference, which is always the best place to be.  In addition, absent evidence to the contrary, it seems logically to be more likely than not that they were first to conceive of the idea of applying the CRISPR/Cas9 system in eukaryotic cells.  That, surely, would be one of the first things anyone in their position would think of.

If so, then the dispute will come down to whether or not Doudna’s team showed sufficient diligence in reducing the idea to practice, and possibly to who actually got there first.  Because if team Doudna is able to show that it was, in fact, the first to successfully apply CRISPR/Cas9 in eukaryotic cells, then team Zhang will almost certainly lose.

Interestingly, another outcome of the study by Chien and Lemley mentioned above was that around 70% of priority contests were ultimately decided on a showing of first reduction to practice, so it would seem that this is indeed Zhang’s best hope for success.  But there are undoubtedly a number of evidentiary obstancles to overcome to get to this point.

So, if pressed for a prediction, my best guess right now is that team Doudna will prevail – they have the odds on their side.  But there is really no way to know until all the evidence is in, so neither party should really be counting their (genetically modified) chickens just yet.

And there is an alternative outcome that may be better for all concerned: the parties could get together and reach an agreement to share the patent rights.  It would not matter which patent had priority if they were both collectively owned by all claimants.  My true hope, therefore, is that wiser heads will prevail because, quite aside from anything else, interference proceedings can be spectacularly expensive, and will inevitably leave one team of brilliant scientists as the losers.


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