March 23rd was the deadline for the parties in Interference No. 106,115 between Senior Party The Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad") and Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC"), to file their Reply Briefs to their opponents' Opposition to each parties Motions authorized by the PTAB last summer.  See "CRISPR Interference Parties Propose Motions" and "PTAB Redeclares CRISPR Interference and Grants Leave for Some (But Not All) of Parties' Proposed Motions".  CVC's Motion No. 2 was to be accorded the benefit of priority to three earlier-filed provisional applications contingent on the Patent Trial and Appeal Board granting the Broad's Motion No. 2 to Substitute the Count of the interference.

The Broad's proposed Count was as follows:

A method, in a eukaryotic cell, of cleaving or editing a target DNA molecule or modulating transcription of at least one gene encoded by the target DNA molecule, the method comprising:
    contacting, in a eukaryotic cell, a target DNA molecule having a target sequence with an engineered and/or non-naturally-occurring Type II Clustered Regularly lnterspaced Short Palindromic Repeats (CRISPR)-CRISPR associated Cas) (CRISPR-Cas) system comprising:
        a) a Cas9 protein, and
        b) RNA comprising
            i) a targeter-RNA that is capable of hybridizing with the target sequence of the DNA molecule or a first RNA comprising (A) a first sequence capable of hybridizing with the target sequence of the DNA molecule and (B) a second sequence; and
            ii) an activator-RNA that is capable of hybridizing to the targeter-RNA to form an RNA duplex in the eukaryotic cell or a second RNA comprising a tracr sequence that is capable of hybridizing to the second sequence to form an RNA duplex in the eukaryotic cell,
    wherein, in the eukaryotic cell, the targeter-RNA or the first sequence directs the Cas9 protein to the target sequence and the DNA molecule is cleaved or edited or at least one product of the DNA molecule is altered.

The distinction the Broad made in its Motion was between embodiments of CRISPR methods that are limited to "single-molecule guide RNA" (aka "fused" or "covalently linked" species), versus embodiments that encompass single-molecule and "dual molecule" species (wherein in the latter versions, the "targeter-RNA" and "activator-RNA" as recited in the proposed Count are not covalently linked).  The Broad argued that this Count should be adopted by the Board because it "properly describes the full scope of the interfering subject matter between the parties because both parties have involved claims that are generic, non-limited RNA claims."  The brief also argued that proposed Count 2 "sets the correct scope of admissible proofs [i.e., their own] for the breakthrough invention described by the generic claims at issue in these proceedings—the successful adaption of CRISPR-Cas9 systems for use in eukaryotic environments," which The Broad contended current Court 1 (in either alternative) does not.

In its Motion No. 2, CVC argued that it was entitled to priority to its earliest priority documents (USSN 61/652,086, filed May 25, 2012 (P1); USSN 61/716,256, filed October 19, 2012 (P2); USSN 61/757,640, filed January 28, 2013 (P3)) when this interference was declared, and filed this authorized contingent motion on October 14th to be accorded benefit.  As with CVC's Motion No.1 for priority under present Count 1, the significance for CVC should this motion be granted is that CVC and not the Broad would be Senior Party, with all the procedural advantages that status confers (the greatest of which being that CVC would be the presumptive first inventor).

The arguments in this Reply Brief are parallel to the arguments CVC made in its Reply to the Broad's Opposition to CVC's Motion No. 1 for priority discussed in an earlier post (see "CVC Reply No. 1 to Broad's Opposition No. 1 to CVC's Motion No. 1 to Be Accorded Benefit of Priority").  These include that CVC was entitled to priority because priority application P1 (and, in the alternative, P2 and P3) set forth in detail the disclosure for at least one embodiment falling within the scope of proposed Count 2.  Although P1 did not disclose actual reduction to practice of CRISPR-Cas9 in eukaryotic cells, CVC maintains that "[t]he CVC inventors immediately understood that the CRISPR-Cas9 DNA-cleavage complex could be used in a variety of different cellular and noncellular settings."  According to CVC:

P1 disclosed methods sufficient for a POSA to practice the method of [Proposed Count 2] without undue experimentation, and Broad has not proffered any credible evidence to the contrary.  While not required, CVC even provided post-filing date evidence confirming that materially the same methods disclosed in P1 for employing CRISPR-Cas9 in eukaryotes were successful.

As in Reply Brief No. 1, CVC argues that "Broad asserts arguments founded on legal and factual inaccuracies:

(i) Broad misconstrues blazemarks law by importing into the count elements that simply are not present, and Broad ignores P1's clear blazemarks;

(ii) Broad requires a working example for written description despite the clear legal precedent that neither examples nor actual reduction to practice is required;

(iii) Broad post-hoc fabricates reasons—with no credible evidence—that a POSA would have expected P1 to disclose "unique conditions" for using CRISPR-Cas9 in eukaryotes for adequate written description; and

(iv) Broad distorts the legal standard for constructive reduction to practice by conflating obviousness with written description and enablement, arguing that adequate written description and enablement must provide a POSA with a reasonable expectation of success."

CVC argues in its Reply that it disclosed three "example embodiments" in P1 that fell within the scope of Proposed Count 2:  a fish cell (E4), a human cell (E5), and a fruit fly cell (E6).  CVC argues that P1 provides a written description for each embodiment, and that this description in conjunction with the general knowledge in the art would have enabled a person having ordinary skill in the art (POSA) in 2012 to make and use each embodiment without undue experimentation, that each embodiment meets all the limitations of Proposed Count 2, and that this was sufficient for CVC to be entitled to the benefit of priority to the invention set forth in Proposed Count 2, citing Falkner v. Inglis, 448 F.3d 1357, 1362 (Fed. Cir. 2006); Storer v. Clark, 860 F.3d 1340, 1345 (Fed. Cir. 2017); 37 C.F.R. § 41.201.

CVC argues that the Broad's arguments regarding putative insufficiencies in it P1 priority application conflate the requirements for obviousness, particularly the "reasonable expectation of success" under which the Broad prevailed in the earlier interference between these parties (Interference No. 106,048) and the enablement requirement under 35 U.S.C. § 112(a) and In re Wands, 858 F.2d 731, 739 (Fed. Cir. 1988), that the disclosure be sufficient that the invention can be practiced by one having ordinary skill in the art without undue experimentation.  CVC argues that the Broad's arguments are legally deficient:

Blazemarks cases deal with situations where the applicant made specific selections from multiple long lists to arrive at a specific, narrowly claimed invention, such as a specific compound, plasma concentration, or specific mutation.  In re Ruschig, 379 F.2d 990, 993 (CCPA 1967); Purdue Pharma v. Faulding Inc., 230 F.3d 1320, 1327 (Fed. Cir. 2000); and Novozymes v. DuPont Nutrition Biosci., 723 F.3d 1336, 1348 (Fed. Cir. 2013).  These cases demonstrate that blazemarks are merely a tool to assess written description support for a claim.  This tool provides a backstop of objective proof that a POSA would recognize in the specification the claimed subject matter, and prevents hindsight selection of narrow subject matter to demonstrate that the Applicants possessed the invention.  The tool is inapt where, as here, (1) the features are not an element of the count, and (2) Broad has not presented evidence that alternative features (e.g. alternative eukaryotic cells, target sequences, or delivery methods) are inoperable.  See Novozymes, 723 F.3d at 1350.

CVC further argues that the POSA at the time the P1 priority document was filed would have understood, from the P1 disclosure, that the CRISPR-Cas9 systems described therein could be performed in vitro, in a prokaryotic cell, and in a eukaryotic cell, by explicit disclosures thereof.  The Reply brief cites expressly in support of this argument the disclosure of CRISPR-Cas9 systems in Example 1, which include "a fish cell, human cell, and fruit fly cell."  CVC also cites the disclosure of claim 67 of P1, which recites a method of using the CRISPR-Cas system in a vertebrate cell, and notes that there are "only five types of vertebrate cells [as disclosed] in paragraph [00165]:  "a cell from a vertebrate animal (e.g., fish, amphibian, reptile, bird, mammal)."  As for disclosure of practice of CRISPR in human cells, the Reply brief cites Claim 69 of P1, which is directed to a method of using the CRISPR-Cas system in a human cell.  Finally, CVC cites the "[n]umerous researchers [who] used materially the same components and methods disclosed in P1 to make embodiments of [Proposed Count 2]" after the P1 priority date, which CVC states "confirm[s] enablement."

And as in CVC's Reply No 1, its Reply No. 2 take to task the Broad's expert declarant, for personal lack of competence with regard to CRISPR technology ("Dr. Mirkin's research focus is nanoparticles—not CRISPR or any other type of gene editing") and that "Dr. Mirkin's testimony is fraught with conclusory statements and speculation, contravening 37 C.F.R. § 41.158(a) ("[e]xpert testimony that does not disclose the underling facts or data on which the opinion is based is entitled to little or no weight.").  CVC's arguments and examples regarding specific deficiencies tracked its arguments in its Reply No. 1, that Dr. Mirkin's review was "myopic" based on testimony where the expert "admitted" that he only reviewed "a select four paragraphs of Example 1 in P1," and stated that his testimony was "based on my review paragraphs [00248]-[00251] [that] do not disclose) any . . . 'blazemarks'" for performing CRISPR in eukaryotic cells.  According to CVC, "Dr. Mirkin ignored other disclosures in P1 that clearly describe using the CRISPR-Cas9 systems in eukaryotic cells."

This Reply brief also concludes with CVC refutation of the Broad's arguments as merely being an attempt to apply its (and the Board's) obviousness determination in the '048 Interference to the current interference, which is error due to the different evidentiary showings between the two Interferences, and misreads the holding on In re Wright, 866 F.2d 422 (Fed. Cir. 1989), regarding the evidentiary standards for establishing enablement.