March 23rd was a busy day at the Patent Trial and Appeal Board (PTAB) regarding 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"), where the parties filed 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. 1 was to be accorded the benefit of priority to three earlier-filed provisional applications.

To recap, Count 1 of the interference as declared is:

An engineered, programmable, non-naturally occurring Type II CRISPR-Cas system comprising a Cas9 protein and at least one guide RNA that targets and hybridizes to a target sequence of a DNA molecule in a eukaryotic cell, wherein the DNA molecule encodes and the eukaryotic cell expresses at least one gene product and the Cas9 protein cleaves the DNA molecules, whereby expression of the at least one gene product is altered; and, wherein the Cas9 protein and the guide RNA do not naturally occur together, wherein the guide RNAs comprise a guide sequence fused to a tracr sequence.

or

A eukaryotic cell comprising a target DNA molecule and an engineered and/or non-naturally occurring Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-— CRISPR associated (Cas) (CRISPR-Cas) system comprising
    a) a Cas9 protein, or a nucleic acid comprising a nucleotide sequence encoding said Cas9 protein; and
    b) a single molecule DNA-targeting RNA, or a nucleic acid comprising a nucleotide sequence encoding said single molecule DNA-targeting RNA; wherein the single molecule DNA-targeting RNA comprises:
        i) a targeter-RNA that is capable of hybridizing with a target sequence in the target DNA molecule, and
        ii) an activator-RNA that is capable of hybridizing with the targeter-RNA to form a double-stranded RNA duplex of a protein- binding segment,
    wherein the activator-RNA and the targeter-RNA are covalently linked to one another with intervening nucleotides; and
    wherein the single molecule DNA-targeting RNA is capable of forming a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule, whereby said system is capable of cleaving or editing the target DNA molecule or modulating transcription of at least one gene encoded by the target DNA molecule.

CVC was not granted 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 motion on October 14th to be accorded benefit.  The significance, of course, 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).

CVC's Substantive Motion No. 1 argued that it was entitled to priority to its earliest provisional filings, because these applications set forth in detail the disclosure for at least one embodiment falling within the scope of Count 1.  CVC further argued that these priority documents "disclosed, for the first time, that complexes of Cas9 and a double- or single-molecule DNA-targeting RNA . . . are useful for targeted DNA cleavage and described numerous applications of this gene-editing technology, including modifying target DNA in eukaryotic cells" and 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."  The brief recited (prophetic) Example 1 in the P1 specification, asserting that the failure of the P1 specification to show actual reduction to practice is not required to satisfy the requirement for entitlement benefit.  According to CVC:

[A person of ordinary skill in the art] reading P1 in light of the state of the art at the time of filing would have understood that the application describes and enables at least one embodiment within the scope of Count 1.  Moreover, post-filing-date publications report successfully practicing CVC's claimed invention in eukaryotes using the very methods and components that P1 describes.  The Board should therefore accord CVC the benefit of P1's May 25, 2012 filing date with respect to Count 1.

CVC's brief in support of Substantive Motion No. 1 to be accorded priority benefit to these provisional applications tracked (in large part) its arguments regarding priority to these provisional application if the Board granted the Broad's motion to substitute its Proposed Count No. 2, the Broad's Opposition brief tracked the same arguments made in its Opposition to CVC's Motion to be accorded benefit to these priority documents for Proposed Count 2 here with regard to Count 1 in the interference as declared.  Broadly stated, these arguments were: "(1) the PTAB's fact findings in the [earlier] 048 interference" (which the Broad argues are binding in this interference) and "(2) an independent assessment of the evidence of record."

In its Reply, 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 Count 1:  a fish cell (E1), a human cell (E2), and a fruit fly cell (E3).  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 Count 1, and that this was sufficient for CVC to be entitled to the benefit of priority to the invention set forth in Count 1, 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 Count 1" after the P1 priority date, which CVC states "confirm[s] enablement."

The Reply Brief also takes to task Broad's expert witness, Dr. Mirkin, who "is woefully unqualified to provide expert testimony on gene-editing systems from the viewpoint of a POSA in 2012," according to CVC.  At least one basis for this allegation of professional incompetence cited by CVC is that "Dr. Mirkin's research focus is nanoparticles—not CRISPR or any other type of gene editing."  Further, CVC was able to elicit under cross-examination that "Dr. Mirkin admitted he had not published any gene editing papers before May 2012, has never personally performed any CRISPR laboratory research, and none of his numerous scientific publications concerns CRISPR."  CVC also alleges 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.").

Turning to specific testimony, CVC asserts that Dr. Mirkin's consideration of certain portions of P1 was "myopic," and cites 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."

Citing his deposition testimony, CVC asserts that "Dr. Mirkin could not dispute the following facts:

• P1 discloses that the RNAs used in Example 1's CRISPR-Cas9 systems are "DNA-targeting RNAs" and that Example 1's SpCas9 protein is a "site-directed modifying polypeptide" . . . ;

• P1 discloses that the "subject methods" of the application involve "contacting a target DNA with a complex" comprising "a DNA-targeting RNA and a site-directed modifying polypeptide" . . . ;

• P1 discloses that "the subject methods may be employed to induce DNA cleavage and DNA modification in mitotic or post-mitotic cells" which include a "eukaryotic cell," and P1 explicitly identifies a "fish," "human," and "fruit fly" cell – all of which are indisputably eukaryotic cells . . . ; and

• P1 expressly claims using CRISPR-Cas systems in a vertebrate cell (claim 67), a mammalian cell (claim 68), and a human cell (claim 69) . . . ."

The Reply brief 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.