By Kevin E. Noonan —

On May 20th, Junior Party the University of California, Berkeley; the University of Vienna; and Emmanuelle Charpentier (collectively, "CVC") filed its Substantive Preliminary Motion No. 1 in Interference No. 106,127 (which names ToolGen as Senior Party), asking the U.S. Patent and Trademark Office's Patent Trial and Appeal Board for benefit of priority to U.S. Provisional Application No. 61/652,086, filed May 25, 2012 ("P1"), U.S. Provisional Application No. 61/716,256, filed October 19, 2012, ("P2"), and U.S. Provisional Application No. 61/757,640, filed January 28, 2013 ("Provisional 3"), pursuant to 37 C.F.R. §§ 41.121(a)(1)(ii) and 41.208(a)(3) and Standing Order ¶ 208.4.1.  On July 15th, ToolGen filed its Opposition.  On August 27th, CVC filed its Reply.

The relationships between the patents and applications in the '127 interference are set forth in this chart (filed in CVC's earlier preliminary motion in the '115 Interference):

The significance of the Board granting this motion with regard to the P1 or P2 provisional applications would be that CVC would be Senior Party, with all the presumptions benefiting Senior Party status.

In its Preliminary Motion No. 1, CVC argued that its inventors invented eukaryotic cell CRISPR using a single-molecule guide RNA (sgRNA) that is described in each of the three provisional applications.  Once that breakthrough had been achieved, CVC argues that adapting CRISPR to the eukaryotic cell environment would have been "pretty straightforward" (quoting Dr. Luciano Marraffini, who informed the Broad inventors of the sgRNA embodiment in June, 2012 (see "CVC Files Motion in Opposition to Broad Priority Motion").  CVC supported this assertion with contemporaneous consistent statements from other scientists; by the existence of "platforms that had already been successfully used with the two incumbent systems: zinc-finger nucleases ("ZFNs") and transcription activator-like effector nucleases ("TALENs")"; and by the successful practice of CRISPR by several groups (including ToolGen) "[j]ust months after CVC presented this work" and the absence in the reports from any of these groups of "any 'special' adaptations or conditions needed to achieve CRISPR gene editing in eukaryotic cells."

CVC also addressed the PTAB's decision not to grant CVC's patents and applications in the '115 patent the benefit of priority to the P1 and P2 provisional applications sought here; the basis for that decision, according to CVC was that it was made "without the benefit of the now well-developed evidentiary record," specifically, that "[t]he prior decision credited assertions that have been seriously undermined by evidence presented during the priority phase of the '115 interference."  Part of that evidence is that the P1 provisional "contemplates and teaches that the sgRNA CRISPR-Cas9 system can be microinjected as a pre-assembled ribonucleoprotein ("RNP") complex into embryos, including fish cells ("E1"), which obviates the concerns alleged in the '115 interference" (emphasis in brief).  In view of this evidence, concerns raised by Broad regarding eukaryotic CRISPR embodiments ("RNA and protein expression, co-localization, and assembly") are avoided because the CRISPR-Cas9 complex is already formed in vitro prior to being microinjected into the embryo.

ToolGen based its opposition on three arguments.  First, ToolGen argued that (as a procedural matter) CVC failed to allege that either the P1 or P2 provisional application provide an enabling disclosure.  Second, ToolGen argued that the Board has already denied CVC benefit of priority to the P1 and P2 provisional applications in the '048 Interference (as part of its determination that there was no interference-in-fact) and the '115 Interference.  Third, ToolGen argued that CVC's arguments in support of its Preliminary Motion No. 1 do not cure the deficiencies of their arguments in earlier interferences and are just as unavailing.  Thus, ToolGen's first argument was procedural and its second and third argument went to the merits of CVC's disclosure (or lack of it) in these three provisional applications.

In its Reply, CVC begins by asserting that there is no estoppel based on the Board's decisions in the '048 and '115 Interferences because 1) the issues were different in the '048 interference (no interference-on-fact based on non-obviousness), and 2) there has not been a final decision in the '115 interference.  According to CVC, "[t]he record supporting this motion is different, contains new evidence, and must be considered as a whole" and "[g]ranting this motion would not require overturning or contradicting any prior findings."  Moreover, "[i]t would violate the law and basic principles of equity and fairness to give preclusive effect here based on the record in the '048 proceeding" CVC asserts, citing Smith v. Bayer Corp., 564 U.S. 299, 312 n.9 (2011); and Fears v. Wilkie, 843 F. App'x 256, 261 (Fed. Cir. 2021) (quoting and applying Smith).  And finally, CVC quotes passages from the Federal Circuit's opinion emphasizing its express dependence on the record before the Court (which of course is not the record here).  With regard to the Board's decision in the '115 Interference, CVC emphasizes the provisional nature of the Board's decision as well as the great difference between priority benefit and priority of invention determinations, while noting that application of a preclusive effect of these decisions is discretionary.  CVC contends that the differing circumstances and addition evidence presented in this interference (specific to ToolGen) should turn the Board's discretion against applying preclusion against CVC here.

On the substantive merits, CVC argues that the disclosure of P1, which is contained in P2 and P3, is sufficient to satisfy the requirements for reduction to practice of at least one embodiment falling within the scope of the Interference Count, in view of the high level of skill in the art, as evidenced by how quickly CVC's inventors and other groups (including Broad, ToolGen, and others) achieved CRISPR-mediated DNA cleavage in eukaryotic cells when sgRNA was disclosed (albeit the provisionals not having been disclosed).

CVC repeats its argument that ToolGen errs in maintaining that "a constructive reduction to practice requires experiments, working examples, and optimization of the invention," which CVC properly argues (at least regarding the standard) it does not.  CVC also contends that ToolGen would require CVC's P1 application to "instruct a POSA how to overcome or rule out every hypothetical concern that ToolGen conjures up, as well as convey certainty of success," also (CVC contends, erroneously) it does not.  As CVC argues, its P1 application "describes how to make pre-assembled ribonucleoprotein complexes (RNPs) that function in vitro," as well as the well-known technique of microinjection, which would result in successful CRISPR gene editing activity in a eukaryotic cell (CVC dismissing the obstacles to successful eukaryotic CRISPR other than mere introduction into a eukaryotic cell that its opponents have urged).  Relying on what it now known (including "new evidence obtained during the priority phase of the '115 interference") CVC argues that these purported obstacles would not have precluded eukaryotic CRISPR (which while likely true does not address the issue of what the skilled worker would have understood the P1, P2, or P3 applications to have described and enabled with what was known at the time they were filed).  "[T]here is overwhelming contemporaneous evidence showing that a POSA would have expected sgRNA CRISPR-Cas9 to have activity in eukaryotes," CVC argues, and thus any discussion of "expectation of success" is inapposite.

Specifically, CVC asserts that its P1 provisional application disclosed three eukaryotic CRISPR embodiments falling within the scope of the Interference Count: (i) as pre-assembled RNP complexes; (ii) as expression vectors encoding the system; or (iii) as RNA molecules encoding the system (citations omitted) in a fish cell (E1), a human cell(E2), and a fruit fly cell (E3).  The skill in the art was such, according to CVC, that this disclosure, founded on the use of sgRNA and associated specifics (like PAM sequences, preassembly of RNPs in vitro, the conventionality of microinjection techniques), was sufficient to satisfy the requirements of written description and enablement needed to establish the priority right.  (And CVC makes the argument that these teachings were "continuous and logically arranged" to rebut ToolGen's argument that they appeared "hundreds of paragraphs apart" in the P1 specification.)

Finally, CVC addressed ToolGen's argument that the P1 (and P2 and P3) disclosures would not provide the skilled artisan with a reasonable expectation of success (which is not required according to their brief) by citing "contemporaneous evidence [that] overwhelmingly shows that those in the field expected sgRNA CRISPR-as9 to function in a eukaryotic cell environment.  This argument was based on evidence from other labs contemporaneous with the disclosure of the P1, P2, and P3 provisional applications and comparisons with zinc-finger nucleases (ZFNs) and TALEN sequences, catalytic RNA species such as Group II introns, ribozymes, and riboswitches (as well as T7 polymerase) and distinguishing CRISPR from each of them.

In weighing the evidence and argument the parties set forth related to CVC's Substantive Preliminary Motion No. 1, the issue for the Board may be quite simple:  is CVC's development of the single molecule guide RNA (sgRNA) embodiment of CRISPR enough to support reduction to practice of eukaryotic CRISPR, or are the obstacles (asserted by Broad successfully in the '048 Interference and again in the '115 Interference and here by ToolGen) enough to deny CVC priority benefit to any priority document that does not expressly exemplify that CRISPR is capable of DNA cleavage in eukaryotic cells.