Berkeley Files Opening Brief in CRISPR Appeal

By Kevin E. Noonan --

The University of California/Berkeley filed its opening brief to the Federal Circuit last week, asking that Court to overturn the Patent Trial and Appeal Board's decision that there was no interference-in-fact between Berkeley's application and several U.S. patents and applications assigned to The Broad Institute.  That decision is entitled to review under the substantial evidence standard for the Board's factual determinations, but de novo review for the PTAB's legal determination that Broad's claims-in-interference would not have been obvious in view of the claimed invention in Berkeley's earlier-filed patent application.

To recap, the Board found that there was no interference-in-fact based on these requirements:

In this proceeding, to prevail on its argument that there is no interference, Broad must show that the parties' claims do not meet at least one of the following two conditions:

1) 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

2) that, if considered to be prior art to Broad's claims, UC's involved claims would not anticipate or render obvious Broad's claims.

Broad will prevail and a determination of no interference-in-fact will be made if a preponderance of the evidence indicates one of these conditions is not met.

In considering the evidence before it, the PTAB gave great weight to contemporaneous, cautious statements in the art in view of Professor Doudna's disclosure of in vitro CRISPR activity regarding whether the system would work in eukaryotic cells.  Specifically, these statements convinced the Board that while the results "suggested the 'exciting possibility'" that CRISPR-Cas9 could be operative in eukaryotic cells, "it was not known whether such a bacterial system would function in eukaryotic cells."  And, "[i]n another report, Doudna was quoted as stating that she had experienced 'many frustrations' getting CRISPR to work in human cells and that she knew that if she succeeded, CRISPR would be 'a profound discovery.'"  UC's assertion of other statements by their inventors that could be interpreted more positively did not convince the Board that there was a reasonable expectation of success in the art for getting the CRISPR-Cas9 system to work in eukaryotic cells, the Board stating that:

Although the statements express an eagerness to learn the results of experiments in eukaryotic cells and the importance of such results, none of them express an expectation that such results would be successful.

The Board swept aside Berkeley's arguments that this reasoning was flawed because the standard is not the inventor's expectations but those of the worker of ordinary skill by stating that "if the inventors themselves were uncertain, it seems that ordinarily skilled artisans would have been even more uncertain."  The Board also quoted Berkeley's expert as having said (contemporaneously with Professor Doudna's report of in vitro CRISPR activity):

There is no guarantee that Cas9 will work effectively on a chromatin target or that the required DNA-RNA hybrid can be stabilized in that context.

The Board concluded that "[w]e fail to see how 'no  guarantee' indicates an expectation of success."

Nor was the Board convinced based on the history of the development of CRISPR technology, which showed that many laboratories independent of the Doudna group quickly applied the new technology to manipulate eukaryotic cell genomic DNA:

Regardless of how many groups achieved success in eukaryotic cells, we are not persuaded that such success indicates there was an expectation of success before the results from these experiments were known.  The unpublished results of research groups are not necessarily an indication of whether ordinarily skilled artisans would have expected the results achieved.  Instead of viewing such work as evidence of an expectation of success, we consider the number of groups who attempted to use CRISPR-Cas9 in eukaryotic cells to be evidence of the motivation to do so, an issue that is not in dispute.  We agree with Broad's argument that a large reward might motivate persons to try an experiment even if the likelihood of success is very low.

On balance, the Board found that this evidence further supported their decision that there was insufficient evidence of a reasonable expectation of success to support Berkeley's allegation that their earlier work and publications would have rendered Broad's invention obvious.  This evidence was that "differences in gene expression, protein folding, cellular compartmentalization, chromatin structure, cellular nucleases, intracellular temperature, intracellular ion concentrations, intracellular pH, and the types of molecules in prokaryotic versus eukaryotic cells, would contribute to this unpredictability [regarding whether the CRISPR-Cas9 system would be operative in eukaryotic cells]."  In response to Berkeley's allegations that these considerations turned out not to be an impediment to CRISPR's activity in eukaryotic cells, the Board said "[t]he relevant question before us is whether those of skill in the art would have expected there to be problems before the experiments were done," not whether it turned out that the experiments were successful once they were tried.

Finally, the Board rejected Berkeley's citation of other prokaryotic genetic modification systems found to work in eukaryotes, generally on the grounds that there was no "commonality" in these methods that would have refuted Broad's evidence that the skilled worker would not have had any reasonable expectation of success.

In its brief, Berkeley found fault with both the Board's factual determinations and its legal conclusions (although wisely focusing the majority of their 64-page brief on their legal arguments).  These arguments begin with Berkeley's allegation that the PTAB applied an incorrect legal standard for obviousness that cannot be reconciled with the Supreme Court's KSR v. Teleflex Int'l precedent as has been further explicated by the Federal Circuit (most notably in In re Kubin).  Specifically, Berkeley's brief characterizes the Board's analysis as requiring "specific instructions" in the prior art regarding adapting CRIPSR as demonstrated in bacterial systems to use in eukaryotic cells.  This application of the obviousness analysis constitutes a standard "even more rigid" than the Federal Circuit's "teaching-suggestion-motivation test" that the Court "rejected" (albeit not entirely) in KSR.  Citing Kubin and In re O'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988), Berkeley contends that:

This Court has explained how KSR applies in the context of an "unpredictable art" such as biotechnology.  Kubin, 561 F.3d at 1359-60.  In such fields, the obviousness inquiry should not focus exclusively on the degree of ex ante predictive confidence that a potential solution will succeed, because "for many inventions that seem quite obvious, there is no absolute predictability of success until the invention is reduced to practice" through experimentation.  In re O'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988).  Rather, the focus should be on the extent of the guidance provided by the prior art—and therefore the extent to which a skilled artisan must innovate beyond that guidance to achieve the solution.  Kubin, 561 F.3d at 1359-60 (the question is whether the claimed advance reflects innovation beyond "the predictable use of prior art elements according to their established functions") (quoting KSR, 550 U.S. at 417).

The "key insight" provided by KSR, according to the brief, is that "when the prior art contains sufficient guidance to enable one skilled in the art to draw on well-known conventional techniques to achieve an advance without any genuine innovation, mere ex ante uncertainty about whether such routine efforts will succeed does not elevate a 'product . . . of ordinary skill and common sense' to the status of a patentable invention," citing KSR.  This is a theme that runs throughout the body of the arguments in the brief.  And, according to Berkeley, applying this "more rigid" standard was legal error by the PTAB.

The brief also asserts as another major theme that the Board erred for not considering contemporaneous evidence of "simultaneous invention," providing a tabulation of the scientific publications that appeared in the art just before and just after Broad's first-filed provisional application:

The presence of this art "can be compelling evidence" of obviousness (the inverse of long-felt need and failure of others) as a secondary consideration, and Berkeley argues that the Board committed legal error in failing to properly consider this evidence.  The Board did consider this evidence, of course, but only to support its appreciation that there was express motivation in the art to apply CRISPR to eukaryotic systems, not to support Berkeley's contention that the skilled worker would have had a reasonable expectation of success.

With regard to the question of expectation of success, the brief argues that this evidence of contemporaneous "invention" by several other groups, and the conventionality of the methods used by these groups (and Broad) in using CRISPR in eukaryotes is strong evidence that this accomplishment required no "innovation" and no "invention" independent of Professors Doudna and Charpentier's disclosure of CRISPR in prokaryotes (in the Jinek 2012 paper published prior to Broad's earliest provisional filing date).

The brief asserts that the Board misinterpreted the scientifically cautious statements by Professor Doudna and other Berkeley experts regarding whether CRISPR was "expected" to be operative in eukaryotic cells.  The "fundamental error" in the Board's consideration of these statements was that they were "imbue[d] . . . with significance divorced from the context in which they were made," which was not as an opinion regarding whether there was a reasonable expectation of success that CRISPR would be operative in eukaryotic cells according to the brief.  Taken as a whole, according to the brief, the prior art establishes that the skilled worker would have had a reasonable expectation of success in using CRISPR in eukaryotes.

The brief also faults the Board for not considering a provisional application by Kim (U.S. Provisional Application No. 61/717,324, filed October 23, 2012, and later published as U.S. Application No. 14/685,568) as prior art under 35 U.S.C. §102(e).  (In many ways this is the brief's strongest argument, because this reference is clearly prior art to the earliest-filed Broad provisional, and Berkeley has a strong argument that the Board not considering it was legal error.)

Finally, Berkeley argues that Broad had not shown that it was entitled to the December 12, 2012 filing date of its earlier provisional.  According to the brief, the Board should have considered October 15, 2013 as the relevant "end date" for considering prior art; if it had done so, many of the references not considered by the Board (set forth in the table above) would have made it impossible for Broad to satisfy its burden of proof that its claims were not obvious.  Instead, the brief contends that the Board "assume without analysis" that Broad was entitled to its December 12, 2012 first provisional filing date for its "hundreds of involved claims," a conclusion Berkeley contends was error.

Broad will have the opportunity to make its arguments in favor of the Board's decision in the coming months; oral argument should be scheduled for some time before the end of the year.

Comments

[Larry]

Hi Kevin,
Can you please post a link to the brief? Thanks.

[Don Champagne]

I have not studied these arguments in detail, but it strikes me that Professor Doudna's comments make it clear that SHE was far from certain that CRISPR-Cas9 could be made to work in eukaryotes. I've heard her lecture and believe she is THE lead inventor in this science. So, if something wasn't obvious to her, I find ii hard to believe that it was obvious to anyone else.

[Kevin E. Noonan]

Dear Don:

Substantially the PTAB's basis for their decision.

Thanks for the comment

[SHAKLAIN KHURSHID]

This is an interesting case and will teach us during further progress of the case specially on reasonable expectation of success.

Say for example if a plasmid construct is being claimed in a patent for expression of the gene of interest in a bacterial system can also work well within the eukaryotic system may be with minor changes or modification well known in the art. Hence no one can claim a separate patent for the same.

However this technology i.e. a CRISPR-Cas9 system is a combination of protein and ribonucleic acid (“RNA”) that can alter the genetic sequence of an organism is very new. So this will be come clear in near future whether this can work well within the eukaryotic system without any undue experiments or not. I mean reasonable expectation of success in the Berkeley application would be answered.