CRISPER–Cas9: BROAD INSTITUTE 1, BERKELEY 0 (MAYBE)

27.02.2017

By Lawrence Hoffman

The University of California, Berkeley and its allied parties (collectively below, “UC”) and the Eli and Edythe L. Broad Institute of MIT and Harvard and its allied parties (“Broad”) have been involved in an interference in the U.S. Patent and Trademark Office over the past several years to determine who was the first inventor of the CRISPER-Cas9 gene editing technology. The interference has just been terminated. Broad definitely won the battle, but just what it won, and what UC lost, is far from clear.

What is an Interference?

Back in prehistoric times before the 2011 America Invents Act (AIA), if two inventors filed applications for the same invention, or for two inventions that differed only in obvious ways, the one who made the invention first got the patent. In such a situation, priority of invention had to be determined. This was done in a proceeding called an ‘interference’.

An interference is an adversarial proceeding conducted by what was then called the Board of Patent Appeals and Interferences, reincarnated as the Patent Trial and Appeal Board (the ‘PTAB’ or ‘Board’) under the AIA. It is similar to a trial in a federal court, except that it is largely governed by its own set of rules found in Title 37 of the Code of Federal Regulations, 37 CFR Part 41, §§ 41.100-41.208 and Part 42.

Patent attorneys adept at handling interferences loved them because they made lots of money representing the parties. It has been reported that the legal fees for parties to the UC – Broad interference together exceed 15 million dollars. (My mother, who worked as an Administrator in the Patent and Trademark Office, told me that an attorney once said to her, “I always say a prayer of thanks when an examiner puts my client in an interference”.)

But the AIA changed everything. For applications governed by the AIA, the patent goes to the first inventor to file his or her application. Therefore, except for a few cases still pending under the old law, interferences are now a footnote in the history of U.S. patent law.

As an aside, though, to coin a phrase, the AIA giveth and taketh away. While we are now like the rest of the world and have races to the patent office, we also have post grant proceedings of several kinds, and some patent attorneys tout themselves as particularly qualified to handle these trial-like proceedings before the PTAB.

The CRISPER-Cas9 Technology:

For those of you (like me) not in the biotech field, CRISPER is the acronym for ‘Clustered Regularly Interspaced Short Palindromic Repeats’, a genetic phenomenon found in prokaryotic cells, i.e., those without nuclei such as those in bacteria. CRISPRs are not found in eukaryotic (plant and animal) cells. A reasonably qualitative description of the subject matter involved in this saga can be found in the Board’s opinion (the ‘opinion’) on the basis of which, it terminated the interference.

A part of this description is reproduced below for your convenience. For those of you interested in reading the entire Decision, you can find it in several places, for example, here.

According to the PTAB:

A CRISPR-Cas9 system is a combination of protein and ribonucleic acid (“RNA”) that can alter the genetic sequence of an organism. In their natural environment, CRISPR-Cas systems protect bacteria against infection by viruses. The CRISPR-Cas9 system is now being developed as a powerful tool to modify specific deoxyribonucleic acid (“DNA”) in the genomes of other organisms, from plants to animals. “With CRISPR, scientists can create mouse models of human diseases much more quickly than before, study individual genes much faster, and easily change multiple genes in cells at once to study their interactions. (Opinion, pp. 2-3. Internal citations omitted.)

The existence of CRISPRs was discovered around 1987. Not until 2007, however, was it discovered that CRISPERs, together with small clusters of Cas (CRISPR-associated system) genes located next to CRISPR sequences, conferred immunity in bacteria to invading genetic materials, for example, from viruses. Put a different way, it was found that the CRISPER-Cas combination functions as the bacterial immune system.

Several Cas sub-types had been identified. Working with one of these, Cas9, in 2012, Jennifer Doudna and Emmanuelle Charpentier, researchers at the University of California, Berkley (UC) developed a ground-breaking technique for using the CRISPER-Cas9 for precise gene editing in prokaryotic cells.

During the same period, Feng Zhang and George Church, at the Eli, (hereafter, ‘Broad’) demonstrated that CRISPER-Cas9 combinations could also be used for editing genes in eukaryotic cells. The work of Doudna, Charpentier, Feng, and Church is widely regarded as one of the most exciting biomedical research successes in recent years. Some say it has unlimited applications in the biomedical field. Others suggest that it is just the beginning of the golden years, and that more and better technologies can be expected.

Why You Should Keep Reading:

          If you are still reading, it’s because you are interested in patents or in biotechnology or both. Whichever you are, it should not surprise you that UC and Broad are both well acquainted with the benefits of obtaining patents and both Broad and UC filed patent applications around the world for the work of their respective scientists. Needless to say, the stakes are enormous – billions of dollars in royalties could easily accrue from licensing this technology. The rest of the story is fascinating, as you will see below.

The Legal Environment: 

UC had its boots on the ground first. On 15 March 2013, it filed U.S. patent application 13/842,859 (the “UC application”) claiming priority to a provisional application filed 25 May 2012.

Broad got into the game about seven months later. On 15 October 2013, Broad filed the first of its U.S. applications, 14/054,414, claiming priority from a provisional application filed 12 December 2012. The ‘414 application was issued as U.S. patent 8,697,359 on 15 April 2014 despite its later filing date. The UC application has been found to be allowable, but has not yet been issued as a patent, subject to the outcome of the interference. (Interferences are not declared unless the subject matter is deemed patentable to all the parties.)

Subsequent to the filing of the ‘414 application, Broad filed 12 additional U.S. applications, 11 of which have issued as U.S. patents as of the present time. The Examiner handling the still-pending application has determined that it is also directed to patentable subject matter. All of these claim priority to the 12 December 2012 provisional, among others.

Needless to say, UC wasn’t happy to see that Broad was winning the race to get patents on what UC regarded as Doudna’s and Charpentier’s invention.  Once it was confirmed that the UC application was allowable, it began an effort to overcome Broad’s advantage by persuading the Patent and Trademark Office to declare the interference between the UC application and the 12 Broad patents. When Broad’s still-pending application was indicated to be allowable, it was added to the interference.

Are the UC and Broad Inventions Really The Same?

The terminology of the claims in the UC application and in the Broad patents and application are very different. However, the real difference is that the disclosure of UC application is limited to a prokaryotic environment. Also, the experiments disclosed were only in vitro. There is no mention or a suggestion in the application that the CRISPER-Cas9 technology will work, or should be used for editing  genes in eukaryotic cells.

Importantly, the claims of the UC application do not specify the environment. Broad’s claims, however, are directed specifically to use with eukaryotic cells. The UC claims are thus generic while the Broad claims are directed to the eukaryotic species, of the genus. The question the PTAB had to decide, and did decide, is whether the Broad species is patentable over the UB genus.

What Was the Outcome?

In brief, the PTAB said the eukaryotic species is patentable over UC’s generic claims.

How the PTAB Got to its Decision:

Interferences and other adversarial proceedings before the PTAB are governed by a set of rules set forth in Parts 41 and 42 of title 37 of the U.S. Code of Federal Regulations. Under the rules, evidence is presented in the form of expert declarations, depositions and other documentary exhibits. Live testimony may be permitted under some (rare) circumstances.

Interferences consist of two phases. In the first phase, the parties are permitted, subject to prior PTAB approval, to file motions which will allow the case to be decided without a full examination of the priority issues. Among these are so-called ‘threshold issues’. 37 CFR 41.201 defines a threshold issue as “an issue that, if resolved in favor of the movant, would deprive the opponent of standing in the interference”.

One of the permitted threshold issues is that there is ‘no- interference-in-fact’, i.e. that the inventions involved are not the same, and are not obvious variations of each other. In due course, Broad filed a motion to have the interference terminated for this reason.

To this observer, this was Broad’s best possible strategy. Although Broad was permitted to file a motion arguing that the UC application does not support its generic claims, Broad chose not to file such a motion. There appears to be a reasonable argument that this would not qualify as a threshold issue under the facts of this case. UC was going to get a patent one way or another and the best Broad could hope for was that its patents would not be taken away.

Broad’s strategy proved correct; the PTAB decided that there was no ‘interference-in-fact and terminated the interference without reaching the question of priority. That is certainly a major victory for Broad, and, as of now, not a complete loss for UC. But the final outcome is still very much in doubt, as we will explain later.

The PTAB first considered Broad’s no “interference-in-fact” motion, since a decision in Broad’s favor would mean that other issues raised in the pending motions need not to be decided.

In determining if an “interference-in-fact” exists, the claims of the parties must be compared. For this purpose, PTAB uses a “two-way test” where in the subject matter of a claim of one party would, if prior art, have anticipated or rendered obvious the subject matter of a claim of the opposing party and vice versa.  For its motion to be granted, Broad therefore had to demonstrate (by a preponderance of the evidence) that:

if considered to be prior art to UC’s claims, Broad’s involved claims would not anticipate or render obvious UC’s involved claims, or that, if considered to be prior art to Broad’s claims, UC’s involved claims would not anticipate or render obvious Broad’s claims (Opinion, p. 9).

Broad’s argument was that UC’s claims would not anticipate or render obvious Broad’s claims if considered to be prior art.

As to anticipation, the PTAB relied on the rule that that each limitation of a claim must be found in a single reference, either expressly or inherently. UC admitted that because none of its claims recites a limitation to a eukaryotic environment and each of Broad’s claims contains this limitation, the requirement for anticipation was not met. Thus, the outcome would turn on whether Broad could demonstrate persuasively, i.e., by a preponderance of the evidence, that UC’s claims would not render Broad’s claims obvious.

Specifically, the Board considered if UC’s claims, which did not explicitly refer to a eukaryotic environment, would have suggested to one of ordinary skill in the art that the claimed process should be carried out in and would have a reasonable likelihood of success, in a eukaryotic environment. Stated differently, did the UC claims reasonably suggest that the generic process could be successful in a eukaryotic environment?

UC and Broad both relied on opinion testimony of expert witnesses with extensive experience in the field of molecular biology, and also on contemporaneous statements and publications by the UC inventors and others in the field of molecular biology at the time the work of UCs scientists was made public. After reviewing the evidence, the Board agreed with Broad that those working in the art did not have a reasonable basis to expect at the time CRISPR-Cas9 technology would work outside of a prokaryotic environment.

In its opinion, the Board made several interesting observations. For example, the Board paid particular attention to the contemporaneous statements because it regarded these statements to conflict with testimony prepared for the interference.

One such statement mentioned by the Board, in a 2012 publication by the inventors suggested the “exciting possibility” that CRISPR-Cas9 complexes might constitute a simple and versatile RNA-directed system for site-specific genome editing, but “it was not known whether such a bacterial system would function in eukaryotic cells”.

The Board further referred to statements by UC inventor Doudna mention that “there was a problem. We weren’t sure if CRISPR-Cas9 would work in eukaryotes…”, and another statement by her that “she had experienced “many frustrations” getting CRISPR to work in human cells and that she knew that if she succeeded, CRISPER would be a profound discovery” (see opinion, p. 15).

UC argued that the selected quotations from the inventors are irrelevant because determination of “interference-in-fact” is from the viewpoint of a person of ordinary skill, not an inventor.  To this, the Board observed that “UC’s argument only tends to persuade us more because if the inventors themselves were uncertain, it seems that ordinarily skilled artisans would have been even more uncertain (opinion, p. 17).

Overall, the Board was not concerned that there were no explicit suggestions that CRISPER-Cas9 would not work for eukaryotic cells. What if found persuasive was the lack of any reasonable expectation that it would work.

Where Do UC and Broad go From Here:

For the moment, Broad is in the cat-bird seat but UC does have several options. The way things stand now, UC can appeal the Board’s decision to the Court of Appeals for the Federal Circuit (CAFC), or it can accept the reality of concurrent patents. Of course, the PTAB decision could be reversed on appeal, but the CAFC reviews legal conclusions of the PTAB de novo and factual findings of the PTAB for substantial evidence. To this observer, the Board did not apply the law in a particularly controversial fashion and its decision seems well-supported by the facts.

Some commentators have suggested that licenses will have to be obtained from both UC and Broad, in order to use CRISPER-Cas9 in practical applications. That is UC’s position. However, the ultimate value of the UC patent is far from clear. It still remains to be seen if the patent is invalid on the ground that the disclosure does not support generic claims and is therefore invalid for failure to satisfy the written description requirement of § 112 of the Patent Act.

Also, there is the question of claim construction. A court could reasonably find that, even apart from the question of validity, the claims cover only use in a prokaryotic environment.

Consider what will happen if, based on the Board’s decision, someone declines to take a license from UC for use with eukaryotic cells, but only from Broad. If UC decides to sue for infringement, which it may be compelled to do to maintain credibility as a licensor, the defendant is likely attack the validity of the patent and argue that it does not infringe for the reasons suggested above. If either of these defenses succeeds, UC’s patent will be essentially worthless.

There is even the horrible possibility (from UC’s standpoint) that the USPTO will reopen the prosecution of its application and reject its claims on the basis of the written description requirement. If that happens, UC may have to narrow its claims to a prokaryotic environment. That, too, could make its patent worthless.

Other commentators have suggested that the negative decision of the PTAB does not mean that Broad will get patents outside the U.S. under the prevailing first-to-file regimes. However, if Broad was able to convince the PTAB that its invention is novel and unobvious over UC’s invention, it’s not far-fetched to think that it can do so outside the U.S. as well. In that case, UC’s patent will not prevent Broad from also getting patents, and UC will be in the same position as it the U.S.

Finally, it has been suggested that UC’s most pragmatic option is to enter into some kind of settlement with Broad. That seems pretty sensible, except for the fact that, like the legal fees, the stakes are enormous. UC does have several licensees but there is no certainty that it will recoup its investment in legal fees alone. Indeed, in the worst case, UC could lose everything. Also, there is said to be such bad blood between UC and Broad, that settlement may not be possible.

Broad’s legal fees have also been enormous, but there is a good chance it got its money’s worth.  It has an exclusive licensee – Editas Medicine – for the field of human medical research and has granted non-exclusive licenses for agricultural applications.  It is also reportedly well-funded and can sustain a continuation of the conflict with UC. Thus, it, too, may not be motivated to settle.

UC is said to be reviewing its options. It will be interesting to see what it decides to do.

About the author: Larry Hoffman has a B.S. in Electrical Engineering and Comp. Sci. from Mass. Inst. of Technology and a J.D. from the George Washington University School of Law. He has been a lawyer since 1965 specializing in IP law and product liability defense. He is registered to practice before the USPTO, the U.S. Court of Appeals for the Federal Circuit and the state and federal courts in New York, Maryland, and the District of Columbia. His work includes preparation and prosecution of patents in countries throughout the world, and counseling on IP and product safety matters. He has been involved in the trial of close to 100 lawsuits of various kinds. You can reach him at Lawrence@ipatent.co.il.

 

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