By Kevin E. Noonan —

On November 19th, Senior Party Sigma-Aldrich filed its Substantive Preliminary Motion No. 1 in CRISPR Interference No. 106,132, asking the Board to substitute the Count pursuant to 37 C.F.R. §§ 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.

In its Motion, Sigma-Aldrich sets forth its proposed 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, wherein the 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 patentably distinct inventions:  "(1) CRISPR-Cas9 in a eukaryotic cell to cleave a target DNA; and (2) CRISPR-Cas9 in a eukaryotic cell to cleave a target DNA and subsequently to integrate a donor DNA sequence 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 patentably distinct.  Citing 37 C.F.R. § 41.201, Sigma-Aldrich maintained that an interference count should not encompass two patentably distinct inventions, citing Ashurst v. Brugger, Int'f No. 105,482 (McK), 2008 Pat. App. LEXIS 5953, *51-52 (BPAI July 16, 2008), and Edelman v. Stomp, Int'f No. 105,261 (SGL), 2006 Pat. App. LEXIS 17, *18-19 (PTAB Apr. 14, 2006).  According to Sigma-Aldrich, 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 proofs of invention for the separately 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 considerably 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).  "CVC's evidence in CVC [U.S. Provisional Application No. 61/757,640, filed January 28, 2013] that CRISPR-Cas9 could cleave a DNA strand in a eukaryotic cell — full stop — should not entitle CVC to an invention that CVC did not demonstrate that it actually possessed, namely, preparing a donor polynucleotide, introducing that donor polynucleotide into the cell, and actually modifying the chromosomal sequence by integrating that donor polynucleotide into the cleaved DNA strand by HDR," Sigma-Aldrich argued.  CVC disclosure of potential uses of CRISPR for integrating DNA into a targeted site should not entitle CVC to claims for such embodiments that they did not possess (particularly under circumstances where Sigma-Aldrich achieved such inventive embodiments first, Sigma-Aldrich argued).  And the brief noted that there are three other interferences before the Board, none of which involve a priority dispute as to which party showed the "further technological advance of integrating a donor polynucleotide into the cleaved target DNA via HDR."

In its Opposition, CVC contends that Sigma-Aldrich fails to satisfy the requirements for substituting the Count because, inter alia, the Senior Party has not rebutted the presumption that the Count in the interference as declared is entitled to (there is a 'presumption that the initial count is limited to a single patentable invention" CVC contends, citing Lee v. Mcintyre, 55 U.S.P.Q.2d 1406 (B.P.A.I. 2000)).  Initially (albeit in a footnote), CVC disputes Sigma-Aldrich's dichotomy between its portion of the McKelvey Count as being limited to "cleavage only" CRISPR embodiments, contending that its half of Count 1 recites "'cleaving or editing or modulating transcription,' and it is inclusive of subsequent donor integration by HDR" (emphasis in brief).  CVC cites positions Sigma-Aldrich has taken during ex parte prosecution (which CVC contends 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").  According to CVC, Sigma-Aldrich refused to introduce a "cleavage only" claim into its application expressly to avoid an interference.  Citing 37 C.F.R. § 41.202(c) for a "disclaimer doctrine" CVC argues that "when the examiner suggests a claim to an applicant for purposes of a future interference, and the applicant refuses, such refusal operates as a 'concession' that the subject matter of the suggested claim was the prior invention of another," citing In re Ogiue, 517 F.2d 1382, 1391 (C.C.P.A. 1975).  Sigma-Aldrich's current Motion No. 1 is merely an attempt, CVC contends, by Sigma-Aldrich to "engineer a priority contest limited to donor integration by HDR."  CVC asserts that such a Count would preclude it from proffering its "best proofs," which could be avoided by a two-count interference that Sigma-Aldrich refused to provoke.  CVC maintains that only 10 of its claims-in-interference are directed to "cleavage plus integration" CRISPR species, and that CVC's generic CRISPR claims do not interfere with Sigma-Aldrich's proposed Count 2.  CVC characterizes this calculus (Sigma-Aldrich trying to bootstrap interference with 10 CVC claims to win priority over the other 176 of CVC's claims-in-interference) as "flagrant manipulation" (presumably of the interference rules) and argues that CVC is entitled to a judgment of priority on its own half of the original Count and its 176 generic CRISPR claims.

Following an explication of interference Rules and case law, and noting that double-stranded break (DSB) repair in eukaryotic cells utilizes "non-homologous end joining" (NHEJ) and "homologous recombination" (HDR) (and that these mechanisms are used in eukaryotic cells "independent of how the DSB occurred," emphasis in brief), CVC set forth its detailed arguments regarding its positions in Opposition to Sigma-Aldrich's Motion No. 1 as set forth above.  CVC asserts 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 [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 contends.

Further, CVC argues that Sigma-Aldrich is incorrect in arguing in its Motion that "[w]hen an interference is declared with a single count directed to two patentably distinct inventions, a motion to substitute the count is appropriate."  On the contrary, CVC contends, the remedy is a two-count interference, but here Sigma-Aldrich is precluded from that remedy because it refused to add a claim to generic cleavage methods earlier.  The authority Sigma-Aldrich relies upon in its motion is inapposite, CVC contends because 37 C.F.R. § 41.201 applies only in multiple count interferences and M.P.E.P. § 2309.01 and the examples therein Sigma-Aldrich relies upon instructs that a party should move to add a Count rather than substitute one.  CVC also distinguishes the case law relied upon in Sigma-Aldrich's motion, arguing that Godtfredsen v. Banner, 598 F.2d 589, 592 (C.C.P.A. 1979), relates to the purpose of an interference to resolve inventorship issues for each of the inventions at issue, and Ashurst v. Stampf, 2008 WL 2781979 (B.P.A.I. 2008), and Edelman v. Stomp, 83 U.S.P.Q.2d 1200 (B.P.A.I. 2006) each "involved situations where the movant sought to remove from the interference subject matter that it alone claimed" (emphasis in brief), as opposed to the circumstances here where (CVC contends) the subject matter sought to be removed from the Count is solely their own.

The consequence of the history of this interference, in CVC's view, is that "Sigma has thus created a situation in which it is ineligible for the only relief supported by the rules—i.e., a two-count interference" and noting preemptively that "Sigma cannot request such relief for the first time in its reply," citing 37 C.F.R. § 41.208(b).  And no doubt to Sigma-Aldrich's chagrin and CVC's satisfaction the Opposition brief contends that under circumstances where a party (Sigma-Aldrich) has refused to include claims to a putatively separately patentable invention in an interference, that party (Sigma-Aldrich) has conceded priority to that invention under 37 C.F.R. § 41.202(c), citing In re Ogiue, 517 F.2d 1382, 1391 (C.C.P.A. 1975); In re Williams, 62 F.2d 86, 88 (C.C.P.A. 1932); In re McKellin, 529 F.2d 1324, 1328 (C.C.P.A. 1976); Ethyl Gasoline Corp. v. Coe, 139 4 F.2d 372, 373 (D.C. Cir. 1943); M.P.E.P. § 2304.04, and Fed. Reg. Vol. 69, No. 155, 8 49992 (Aug. 12, 2004), in support of this legal interpretation.  Having ensnared itself in this procedural quagmire, CVC contends that Sigma-Aldrich is entitled neither to have the Board substitute the Count nor to a two-count interference.

CVC further asserts as a basis for the Board to deny Sigma-Aldrich's motion that the Senior Party has asserted than only 10 of CVC's claims recite "cleavage plus integration" species of eukaryotic CRISPR but nevertheless contends that all 186 CVC claims in this interference correspond to Proposed Count 2, which CVC calls "a complete perversion of the reasoned claim correspondence analysis that Sigma was obligated to perform," citing Grose v. Plank, 15 U.S.P.Q.2d 1338 (B.P.A.I. 1990).  And in addition, CVC contends, Sigma-Aldrich has "failed to make out a prima facie case" regarding "why any of CVC's 176 non-interfering claims correspond to Proposed Count 2" (despite Sigma-Aldrich's expert testifying to the contrary).

CVC's Opposition then turns to the "best proofs" question, citing Grose v. Plank, 15 U.S.P.Q.2d 1338 (B.P.A.I. 1990), and Univ. of S. California v. DePuy Spine, Inc., 473 F. App'x 893, 895 (Fed. Cir. 2012), as authority.  For this portion of their argument, CVC cites (perhaps improvidently, in retrospect) its priority briefs in Interference No. 106,115, which showed CVC's conception and reduction to practice of "cleavage" CRISPR species first and "cleavage plus integration" species thereafter.  These constitute CVC's best proofs, which they contend Proposed Count 2 would exclude, even though claims (176 of them) encompassing cleavage species of eukaryotic CRISPR would fall within the scope of Proposed Count 2.

In this portion of its Opposition, CVC also contends Sigma-Aldrich has failed to establish patentability of the invention recited in Proposed Count 2 over the prior art under 37 C.F.R. § 41.208(c)(2) and Louis v. Okada, 59 U.S.P.Q.2d 1073 (B.P.A.I. 2001), and the declaration of this interference was predicated on the "hypertechnicality" that permitted Sigma-Aldrich to swear behind references by ToolGen.  These circumstances do not prevent CVC from asserting that the Board can require Sigma-Aldrich to distinguish these references in this interference when deciding whether to grant the requested relief (which, should the Board require CVC contends Sigma-Aldrich will not be able to do).

CVC sets forth an extensive discussion regarding why Sigma-Aldrich has not overcome the presumption that Count 1 recites but one invention.  According to CVC, what is required by Sigma-Aldrich is a showing that the subject matter in Proposed Count 2 is patentably distinct from the CVC portion of Count 1 as declared, citing Hester v. Allgeier, 21 687 F.2d 464, 466 (C.C.P.A. 1982), and M.P.E.P. § 2309.01(A) (wherein the subject matter of Count 1 is considered to be prior art to Proposed Count 2).  Sigma-Aldrich has not and cannot do so, CVC contends for at least these reasons:

• HDR was known in the art by the use of several "targeted" nucleases (including zinc finger nucleases and transcription activator–like effector nucleases) to repair double-stranded breaks (DSB) in "a variety of eukaryotic cells and organisms, including nematodes, Xenopus laevis oocytes, fruit flies (Drosophila melanogaster), plants, stem cells, and mammalian cell types in culture (e.g., HEK293, HEK293T, mouse), and that these intrinsic mechanisms could be expected to operate in the CRISPR context;

• There were express suggestions in the art to "introduce CRISPR-Cas9 and a donor sequence for integration by HDR and thereby perform precise genome editing in a eukaryotic cells," citing examples;

• The CVC portion of Count 1 being considered prior art, the difference with Sigma-Aldrich's Proposed Count 2 is "a homology-directed repair mechanism which incorporates a sequence of a donor polynucleotide into the target DNA molecule, thereby editing the target DNA molecule," something that "occurs naturally in the cell in response to a DSB when there is a donor sequence present.

Under these circumstances, CVC argues that any "alleged uncertainty" regarding the function of CRISPR in eukaryotic cells generally as alleged by Sigma-Aldrich is "irrelevant and misleading because Count 1 assumes the successful application of sgRNA CRISPR Cas9 in eukaryotic cells."  This conclusion is supported, CVC argues, by Sigma-Aldrich's expert's concession that the skilled artisan, taking the prior art (including ZFN, TALENs and CRISPR) would be confident that HDR could be achieved in eukaryotic cells.  Under these circumstances CVC argues that the skilled artisan would have been motivated to combine CVC's portion of Count 1 with what was known in the prior art regarding HDR, and would have had a reasonable expectation of success in achieving CRISPR-mediated HDR in eukaryotic cells.  In the absence of Sigma-Aldrich making any assertion of secondary considerations, CVC contends that the Sigma-Aldrich portion of Proposed Count 2 would have been obvious (and hence not patentably distinct) over the Count in this interference as declared, and Sigma-Aldrich has not (and cannot) make the required showing of patentable distinction for substituting the Count.  And, CVC contends, the "hypothetical concerns" (12 of them) Sigma-Aldrich raises in this regard in its Motion are "fundamentally flawed" and are "post-hoc litigation positions," setting forth its reasoning supporting this conclusion for each of these concerns.  But generally, CVC argues, "Sigma's alleged concerns, while itemized, amount to a generalized requirement that a skilled artisan have certainty.  But the law does not require "absolute certainty," citing Par Pharm.,  Inc. v. TWi Pharms., Inc., 773 F.3d 1186, 1198 (Fed. Cir. 2014), and Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007).  Accordingly, CVC contends, Sigma-Aldrich's arguments do not support their contention that Proposed Count 2 is patentably distinct from Count 1 in the interference as declared.

CVC also argues that Sigma-Aldrich's arguments set forth in its Motion No. 1 amount to a concession that the Senior Party is not entitled to priority to Count 1 under Rule § 41.202(c) (vide supra) and thus if the Board were to deny Sigma-Aldrich's Motion the Board should grant priority to CVC.  In the alternative, should the Board grant Sigma-Aldrich's Motion then the Board should award priority to the cleavage-only portion of the Count (based on CVC's claims) as well as the generic cleavage claims, calling this "the only logical consequence" of Sigma-Aldrich's concessions.  And CVC further contends that "in any event, CVC's 176 noninterfering claims to generic cleavage should not be designated as corresponding to Proposed Count 2, for the reasons detailed above."  Moreover, CVC argues, should the Board grant Sigma-Aldrich's Motion the Board should deny priority to the Senior Party's U.S. Provisional Application No. 61/736,527, filed December 12, 2012 (because Sigma-Aldrich failed to submit an affidavit required by 37 C.F.R. § 41.158(b)), whereas the Board should recognize CVC to be entitled to priority to its U.S. Provisional Application No. 61/757,640, filed January 28, 2013, asserting that Sigma-Aldrich's basis for their contention that CVC is not entitled to this priority amounts to a requirement for an actual reduction to practice or a working example" which is not required under Ariad Pharms., Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1352 (Fed. Cir. 22 2010) (en banc), and Dana-Farber Cancer Inst., Inc. v. Ono Pharm. Co., Ltd., 964 F.3d 1365, 23 1372 (Fed. Cir. 2020) (this assertion perhaps being undermined by the Board's recent decision against CVC in Interference No. 106,115; see "PTAB Holds for Broad in CRISPR Interference: The Reasoning").  The significance of the Board resolving these  priority questions is that CVC would then be entitled to Senior Party status in this interference.