Senior Party Sigma-Aldrich Files Reply to Junior Party CVC’S Opposition to Its Substantive Preliminary Motion No. 1 to Change Count in Interference No. 106,132

By Kevin E. Noonan —

On November 19th, Senior Party Sigma-Aldrich filed its Substantive Preliminary Motion No. 1 in CRISPR Interference No. 1 106,132, asking the Board to substitute the Count pursuant to 37 CFR §§ 41.121(a)(1)(iii) and 41.208(a)(1). Junior Party the University of California, the University of Vienna, and Emmanuelle Charpentier (collectively “CVC”) filed its Opposition on February 18th. And on April 7th, Sigma-Aldrich filed its Reply.

In its Motion, Sigma-Aldrich set forth its Count 2 as, in the alternative, CVC Application No. 15/947,680, claim 164 or Sigma-Aldrich Application No. 15/456,204, claim 31 (the latter alternative Count based on Sigma-Aldrich’s claim remains the same as in the Count as the interference was declared). Claim 164 of CVC’s ‘680 patent recites (dependent on claims 156 and 157):

156. A method of cleaving or editing a target DNA molecule or modulating transcription of at least one gene encoded thereon, the method comprising:
contacting a target DNA molecule having a target sequence with 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 single molecule DNA-targeting RNA comprising
i) a targeter-RNA that hybridizes with the target sequence, and
ii) an activator-RNA that hybridizes with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment,
wherein the targeter-RNA and the activator-RNA are covalently linked to one another with intervening nucleotides; and
b) a Cas9 protein,
wherein the single molecule DNA-targeting RNA forms a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule,
whereby said target DNA molecule is cleaved or edited or transcription of at least on gene encoded by the target DNA molecule is modulated, and
wherein said contacting occurs in a eukaryotic cell.

157. The method of Claim 156, wherein, prior to the contacting step, the method comprises:
introducing into the eukaryotic cell containing the target DNA molecule:
1) the single molecule DNA-targeting RNA, or a DNA molecule comprising a nucleotide sequence that
(i) encodes the single molecule DNA-targeting RNA and
(ii) is operably linked to a regulatory element operable in said eukaryotic cell; and
2) the Cas9 protein, an RNA molecule comprising a nucleotide sequence encoding the Cas9 protein, or a DNA molecule comprising a nucleotide sequence that
(i) encodes the Cas9 protein and
(ii) is operably linked to a regulatory element operable in said eukaryotic cell.

164. The method of Claim 157, whereinthe method comprises creation of a double strand break in the target DNA molecule which is repaired by a homology-directed repair mechanism which incorporates a sequence of a donor polynucleotide into the target DNA molecule, thereby editing the target DNA molecule [emphasis in brief].

Sigma-Aldrich’s argument in favor of substituting the Count was that the so-called McKelvey count as declared encompasses two patently distinct inventions: “(1) CRISPR-Cas9 in a eukaryotic cell to cleave a target DNA; and (2) CRISPR-Cas9 in a eukaryotic cell to clear a target DNA and sequenced to integrate a donor DNA into the target DNA via homology-directed repair (“HDR)”(emphasis in brief). According to Sigma-Aldrich, this second, subsequent step is not obvious over merely cleaving a DNA target and thus claims to these embodiments are patently distinct. Sigma-Aldrich maintained that the “current Count 1 permits CVC to submit proofs of invention for cleavage alone [based on its claims encompassing “cleaving or editing the target DNA molecule or modulating transcription of at least one gene encoded by the target DNA molecule”]which do not constitute separately proofs of invention for the patentable cleavage plus integration invention.” Permitting CVC to prevail on this basis would be contrary to the “fundamental purposes of a first-to-invent patent interference” as well as being “manifestly unfair” to Sigma,” because it would deprive Sigma-Aldrich of patent protection for “its distinct and more technically challenging invention based on CVC’s proofs for a different and simpler invention.” In addition, Sigma-Aldrich asserted that none of CVC’s applications disclose embodiments for “cleavage plus integration” methods (even if their claims encompass such CRISPR methods in eukaryotic cells).

In its Opposition, CVC contended that Sigma-Aldrich failed to satisfy the requirements for substituting the Count because, inter alia, the Senior Party has not rebutted the presumption to which the Count in the interference as declared is entitled. CVC cited positions Sigma-Aldrich has taken during ex parte prosecution (which CVC contended were motivated by Sigma-Aldrich’s desire to “avoid an interference with CVC over the subject matter of CRISPR-Cas9 for cleaving or editing target DNA in a eukaryotic cell”) [that were] not limited to donor integration by HDR”). Citing 37 CFR § 41.202(c) for a “disclaimer doctrine” CVC argued that “when the examiner suggests a claim to an applicant for purposes of a future interference, and the refuse applicants, such refusal operates as a ‘concession’ that the subject matter of the suggested claim was the prior invention of another.” CVC further asserted that the Count Sigma-Aldrich proposed would preclude it from proffering its “best proofs,” which could be avoided by a two-count interference (that Sigma-Aldrich had refused to provoke). CVC argued that Sigma-Aldrich was trying to bootstrap an interference with 10 CVC claims to win priority over the other 176 of CVC’s claims-in-interference, calling this a” flagrant manipulation” (presumably of the interference rules) and argued that CVC is entitled to a judgment of priority on its own half of the original Count and its 176 generic CRISPR claims. CVC asserted that “Sigma has already failed, twice, to demonstrate that [cleavage and cleavage plus integration] are two separately patentable inventions,” “[f]irst, during prosecution of the application [in which this interference had been provoked, No. 15/456,204]” and second, upon initiation of this interference when the Board’s declaration contained Count 1 instead of Sigma-Aldrich’s preferred Count 2 (now recited in Sigma-Aldrich’s Proposed Count 2). These circumstances raised the presumption that the two species of eukaryotic CRISPR were patentably indistinct and Sigma-Aldrich has failed to rebut that presumption, CVC contended. to “cleavage + integration” embodiments.

In its Reply, Sigma-Aldrich begins its argument by reiterating its position that the Count in the Interference as declared “encompasses two patently distinct inventions: (1) CRISPR-Cas9-mediated cleavage only in a eukaryotic cell; and (2) CRISPR- Cas9-mediated cleavage plus integration of a donor polynucleotide via HDR (“cleavage plus integration”) in a eukaryotic cell” (wherein later in the brief Sigma-Aldrich characterizes these two processes as DNA destruction and DNA construction, and that the latter would not have been obvious over the former) (emphasis in brief). According to Sigma-Aldrich, its Motion No. 1 “sets forth a dozen reasons why in early December 2012 a POSITA would have had considerable uncertainty whether a double-stranded break (“DSB”) cleaved by CRISPR-Cas9 would be successfully repaired by donor integration via HDR in a eukaryotic cell.” In view of the understanding in the art in 2012, Sigma-Aldrich argues that at best “a POSITA could do very little but sit back and hope that HDR might work with this new prokaryotic-derived system [in eukaryotic cells]”(emphasis in brief). Sigma-Aldrich recites its continued contention that there were at least twelve reasons set forth in its Motion No. 1 why a POSITA would not have had a reasonable expectation of success in achieving HDR in a eukaryotic cell merely because eukaryotic CRISPR embodiments had been shown to produce DSBs in such cells. Indeed, Sigma-Aldrich contends that HDR was appreciated in the art in 2012 as being “the most challenging part of [CRISPR-mediated] genome engineering” because, inter alia, HDR was a “disfavored repair pathway” (setting forth scientific bases for this assertion). Sigma-Aldrich disparages CVC’s arguments based on HDR in yeast, which it contends “relied on different repair factors and is not representative of eukaryotes” and further contends that blunt-ended non-homologous end joining (NHEJ) would be preferred over HDR and could inhibit the HDR pathway. Sigma-Aldrich recites characteristics of eukaryotic cell biology (chromatin, off-target CRISPR cleavage, Cas9 remaining bound to CRISPR-cleaved ends in eukaryotic cells) as reasons the skilled worker could not have had any reasonable expectation of success in achieving HDR provoked by CRISPR cleavage in a eukaryotic cell and the further history in the field post-2012 (including expressions of skepticism in contemporary prior art documents). Moreover, Sigma-Aldrich contends that experience with other targeted nucleases (ZFP, TALENs) would not have overcome these reasonable obstacles to expectations for successful CRISPR-mediated HDR in eukaryotic cells.

Having made its principle argument in favor of the Board substituting the Count, Sigma-Aldrich then more briefly sets forth its further criticisms of CVC’s Opposition and its contentions in that Motion not disputed by CVC. These included the correspondence of all Sigma-Aldrich’s involved claims corresponding to proposed Count 2; “no substantive analysis” of the disputed correspondence of CVC’s involved claims to the substitute Count; and no substantive challenge to Sigma-Aldrich’s entitlement to benefit to its P1 priority document, US Provisional Application No. 61/734,256, filed December 6, 2012, under proposed Substitute Count 2. Sigma-Aldrich then challenges CVC’s contention that its P3 application, US Provisional Application No. 61/757,640, filed January 28, 2013, is entitled to priority benefit under Sigma-Aldrich’s Proposed Substitute Count 2, for failing to provide “any substantive evidence that the CVC inventors actually possessed the invention of Proposed Count 2″ (emphasis in brief). Instead, Sigma-Aldrich contends, “CVC relies on the basic textbook and boilerplate disclosures in CVC P3 regarding HDR, but fails to address the glaring omission of any discussion of a donor or integration of any kind in CVC’s experimental endeavors.” Sigma-Aldrich further criticizes CVC for failing to rebut its prima facie showing that its Proposed Count No. 2 is patentable. Sigma-Aldrich also contends that CVC’s argument regarding its best proofs for “cleavage only” eukaryotic CRISPR embodiments were “wholly irrelevant” when CVC “nowhere even suggests that its best proofs to the parties’ commonly claimed cleavage plus integration invention would counsel for an alternative formulation of Proposed Count 2.” Finally, Sigma -Aldrich argues CVC’s contentions regarding 37 CFR § 41.202(c) and that Sigma-Aldrich is seeking an interference directed to “generic cleavage” are either incorrect, nonse nsical, or both, that CVC’s proposal for a two-count interference ignores Sigma-Aldrich’s “rational” explanation that in such an interference Sigma-Aldrich would have no claims corresponding to the “cleavage-only” Count, and that the Board should disregard CVC’s proposal that the Board grant CVC judgment on Count 1 and grant Sigma-Aldrich’s Motion No. 1 to substitute the existing Count for its Proposed Count 2.

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