Broad Files Opposition to CVC's Motion No. 1 for Priority Benefit

By Kevin E. Noonan --

One of the briefs filed on January 9th 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") was the Broad's Opposition to CVC's Motion No. 1 to be accorded benefit to three priority applications for Count No. 1 in the interference as declared by the U.S. PTO.

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.

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.  CVC also cautioned the Board against any attempt by the Broad to "erroneously to link the issues in this motion to the PTAB's termination of Interference No. 106,048 due to no interference-in-fact," stating that "the legal and factual issues raised here are fundamentally different from those decided in the prior '048 proceeding" based on the PTAB's own prior statements of the grounds for its no interference-in-fact determination.  Rather, 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.

Just as 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 tracks 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.  (Indeed, discerning readers will appreciate that much of our description of the Broad's arguments in this brief are the same set forth in our description of the Broad's Opposition to CVC Responsive Motion No. 2.)  Broadly stated, these arguments are: "(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."

With regard to its first argument, the Broad asserts that the PTAB's fact-findings in the '048 interference preclude CVC from establishing benefit to P1 and P2, based on a 2012 reference to Jinek et al. (2012, A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity, Science 337: 816-21) and the finding that a person of ordinary skill in the art would not have had a reasonable expectation of success in performing CRISPR in eukaryotic cells.  This argument is one of lack of an adequate written description and illustrates another aspect of a familiar conundrum:  a specification cannot provide an adequate written description if one of ordinary skill in the art would not have had a reasonable expectation of success in achieving the invention (which was the basis for the PTAB's decision in the '048 interference that there was no interference-in-fact).  The Broad's brief further argues that the skilled artisan would have expected bacterial CRISPR would need "its own set of unique conditions" to be adapted to practice in eukaryotic cells, which P1 and P2 did not disclose.  Finally regarding this argument, the Broad asserts that neither of CVC's P1 or P2 do priority documents disclosed anything not found in the Jinek reference, except for well-known techniques in the art, and PTAB found that the combination of Jinek plus these known prior art techniques did not render eukaryotic CRISPR obvious.

The Broad's second argument is that the Board should arrive at this same conclusion if the evidence is assessed de novo.  The Broad asserts that neither the P1 nor P2 priority documents provide a constructive reduction to practice of eukaryotic embodiments of CRISPR because none of the "fictitious" embodiments relied upon by CVC's expert were disclosed in P1 or P2, calling them "post-hoc creations of CVC's expert, manufactured by stitching together disparate disclosures from P1 and P2, using Proposed Count 2 as a roadmap."  The brief alleges that P1 and P2 provide no "blazemarks" for practicing eukaryotic CRISPR, and even if the Board finds there were blazemarks there were no eukaryotic experiments or specific instructions needed to satisfy the written description or enablement requirements of 35 U.S.C. § 112.  Finally, in this portion of the argument the brief asserts that the third priority document contained in CVC's request for priority benefit is irrelevant because it was filed after publication of scientific references disclosing eukaryotic CRISPR by Broad and Harvard scientists and named inventors.

The brief provides a synopsis of the "State of the CRISPR Art by 2012" in the Broad's view, relying on PTAB findings from the '048 Interference.  The brief cites the generic disclosure in P1 regarding methods for introducing nucleic acids into cells, a characterization acknowledged by CVC's expert in this interference.  According to the Broad, the P1 and P2 references were limited to in vitro examples and routine methods known in the art.  The brief further argues that there was "continuing uncertainty" regarding the ability to practice eukaryotic embodiments of CRISPR until the Broad's Zhang and colleagues demonstrated that CRISPR could be adapted to eukaryotic cells.  This uncertainty is supported (as it was in the '048 interference) by quotations from CVC's published scientific journal articles and interviews.  Also, as before, the Broad notes that CVC's expert in the '048 interference had published a paper contemporaneously that cast doubt on whether CRISPR could be used in eukaryotic cells.  And of course the brief notes that the Broad inventors were able to achieve eukaryotic CRISPR as set forth in the Broad's earliest priority date, December 12, 2012.  (In this regard the brief makes the argument that the P3 priority document shows achievement of eukaryotic CRISPR only after getting assistance from Broad inventors, specifically George Church.)

The brief then sets forth a further synopsis of the '048 interference and its outcome, which does not bear repeating here (see "PTAB Decides CRISPR Interference in Favor of Broad Institute -- Their Reasoning" and "Regents of the University of California v. Broad Institute, Inc. (Fed. Cir. 2018): Federal Circuit Affirms PTAB in Appeal of CRISPR Interference").

Finally, the Broad sets forth its legal arguments based on the fact finding by the PTAB in the '048 interference, to the effect that neither P1 nor P2 satisfy the requirements of § 112 sufficient to establish constructive reduction to practice of eukaryotic embodiments of CRISPR.  These arguments are based, as the Broad's arguments have been based throughout this interference, on the issue preclusive effects of 37 C.F.R. § 41.127(a)(1) and corresponding Standing Order Rule 127(a)(1).  Further, the Broad argues that the PTAB's decision in the '048 interference is law of the case and controlling here, under MPEP 706.07(h)(XI)(A).  The Broad also argues that CVC has used this "law of the case" doctrine during ex parte prosecution to overcome prior art-based rejections over the Broad's extensive eukaryotic CRISPR portfolio of granted patents.

The brief next asserts that CVC's arguments for being accorded priority benefit to P1 and P2 are contrary to the PTAB's findings in the '048 interference.  Specifically, the brief cites CVC's current expert's assertions that P1 or P2 plus the ordinary skill in the art showed possession of eukaryotic CRISPR, which the Broad argues is contrary to the PTAB's decision that the skilled person would have had no reasonable expectation of success.  The brief sets forth express portions of the PTAB's earlier decision in support of this argument with regard to reasonable expectation of success, the need for a unique set of conditions for practicing CRISPR in eukaryotic cells, and that the practice of CRISPR in vitro combined with well-known techniques for expressing heterologous genes in eukaryotic cells did not render eukaryotic CRISPR obvious.  These circumstances preclude CVC from being accorded priority benefit to P1 and P2 as a matter of law, the Broad argues, based on lack of enablement, including the utility requirement embodied in that statute.

The brief concludes by providing the Broad's point-by-point rebuttal of CVC's arguments concerning why the prior PTAB decision are not preclusive, and further argues that de novo review of the record does not support CVC's position.  These arguments are based on:  1) failure of P1 or P2 to disclose embodiment E4, E5, or E6 cited in CVC's motion; 2) there being no "blazemarks" in P1 or P2 regarding how to create these undisclosed ("fictitious") embodiments (with extensive rebuttal of CVC's expert's testimony); 3) that the P1 and P2 disclosures fail to anticipate or render obvious Proposed Count 2 as required under 37 C.F.R. § 41.201; 4) that the fictitious embodiments are incomplete for failure to disclose "a specific target sequence or delivery method to the [eukaryotic] cell"; and 5) there is no support in the P1 or P2 disclosures for anything but in vitro embodiments of CRISPR, and thus no possession in view of recognized uncertainty in the art (and set forth in detail in the brief).  As a final argument, the brief sets forth in detail how, in the Broad's view, the P1 and P2 priority documents no not provide an enabling disclosure under the factors set forth in In re Wands.

Comments

[Paul F. Morgan]

Whatever the outcomes, claims in this interference will be getting inter partes and extensive APJ 112 scrutiny no ex parte examiner could have the time and resources for. [No longer possible for newer applications no longer subject to interferences under the AIA.]

[Skeptical]

Mr. Morgan, your point as to time spent in contested reviews (post grant) applies to each and every patent ever granted.

Combine these two things and what is the take-away?