By Kevin E. Noonan —

On December 3rd, Junior Party the Broad Institute, Harvard University, and MIT (collectively, Broad) filed its Contingent Preliminary Motion No. 3 in Interference No. 106,133 (which names Sigma-Aldrich as Senior Party), asking the Patent Trial and Appeal Board to designate certain claims deemed in the Declaration as corresponding to the Interference Count as not having such correspondence, under 37 C.F.R. §§ 41.121(a)(1)(i) and 41.207(b)(2).  Senior Party Sigma-Aldrich filed its Opposition on March 16th and Broad filed its Reply on April 26th.

As argued by Broad, these claims fell into five discrete categories:

Category A:      Staphylococcus aureus Cas9 protein ("SaCas9");
Category B:      Cas9 chimeric CRISPR enzyme;
Category C:      Cas9 with two or more nuclear localization signals ("NLSs");
Category D:      Cas9 fused to specified protein domains; and
Category E:      Claims that are generic as to RNA and also do not specify integration of a donor polynucleotide sequence ("Donor Template Integration" claims), i.e., the only claims that should remain designated as corresponding to Count 1 are those that are either (i) limited to single molecule RNA ("sgRNA"), or (ii) require Donor Template Integration and are not otherwise separately patentable.

Broad made as a basis for its motion the distinction that the Broad portion of "McKelvey" Count 1 is directed to CRISPR-mediated cleavage in a eukaryotic cell (that "cover[s] many different inventions that are separately patentable from Count 1") while Sigma-Aldrich's portion of the Count recites CRISPR-mediated cleavage coupled with integration of a heterologous DNA molecule, termed "Donor Template Integration."

In its Opposition, Sigma-Aldrich argued that Broad failed to carry its burden to de-designate claims, inter alia, for failing to apply the "one-way obviousness" test or address the effect of prior art, including the Jinek 2012 paper, on obviousness of these claims.  Sigma-Aldrich further asserted that it "endeavored to review 461 of Broad's involved claims in all 16 of Broad's involved patents and applications" and, consistent with positions Senior Party has taken in Interference No 106,132 against CVC deign not to contest de-designation of the following claim types:

(a) claims reciting more than 1 targeting RNA (aka "multiplexing");
(b) claims reciting a Cas9 protein that includes a Protein Transduction Domain (PTD);
(c) claims reciting one or more mutation(s) in the Cas9 RuvC/HNH domain(s);
(d) claims a nickase for a creating a "nick" or a single stranded break in the target DNA; and
(e) claims reciting a chimeric Cas9 protein.

And for the claims Sigma-Aldrich did contest the Opposition set forth these tables:

In its Reply, Broad sets forth its own table of what it characterizes as Sigma-Aldrich's "concessions" for claims the Board should de-designate:

Regarding the remaining claims still in dispute, Broad argues that continuing the designation of any of the claims in Category E would be inequitable because, inter alia, the "one-way" obviousness test urged by Sigma-Aldrich as a standard is not a per se rule that must be applied when the outcome would be unfair to one party.  The unfairness, as Broad argued in its Motion, is that its proofs using dual-molecule RNA CRISPR embodiments without a donor template are excluded by Count 1 despite that Count encompassing such embodiments.  Broad asserts that it "should not be excluded from using its earliest dual-molecule proofs for Count 1 while simultaneously putting at risk claims with the same scope."  Citing Eli Lilly & Co. v. Board of Regents of University of Washington, 334 10 F. 3d 1264, 1268 (Fed. Cir. 2003), Broad argued that "the PTAB [has] the discretion to adopt a two-way test to prevent 'the proliferation of unnecessary, wasteful interference proceedings concluding that both parties are entitled to patents in situations in which the claimed inventions do not define the same patentable invention, but merely overlap in scope.'"  Broad further argues that Sigma-Aldrich did not address much less refute their arguments in Motion No. 3, nor that the term "guide RNA" encompasses both single- and dual-molecule RNA components of CRISPR-Cas9 embodiments encompassed by the Count.

As it has in other Replies Broad argues that Sigma-Aldrich has improperly incorporated by reference arguments in its Opposition that were made in other Oppositions, thus achieving an expanded length of its arguments to avoid page limits, in violation of Standing Order ¶ 106.2.  Broad also argues that some of Sigma-Aldrich's arguments so incorporated from its Oppositions and ex parte prosecution are contradictory to arguments made in this Opposition.  The example most relevant to Broad's arguments here are Sigma-Aldrich's purported arguments elsewhere that "Donor Template Integration and other forms of cleavage and repair were separately patentable inventions, and that a POSA would not have reasonably expected success in integrating a donor template even if the art showed recognition of successful cleavage and repair in a eukaryotic cell."  In sum Broad asserts that "Sigma thus repeatedly argued that Donor Template Integration and other forms of cleavage and repair were separately patentable inventions in securing its claims.  Accordingly, Broad's claims that require neither sgRNA nor Donor Template Integration should be designated as not corresponding to Count 1."

For these reasons Broad asks the Board to grant its Contingent Motion No. 3 should the Board deny its Preliminary Motion No. 1.

By Kevin E. Noonan —

On December 3rd, Junior Party the Broad Institute, Harvard University, and MIT (collectively, Broad) filed its Contingent Preliminary Motion No. 2 in Interference No. 106,133 (which names Sigma-Aldrich as Senior Party), asking the Patent Trial and Appeal Board to add claims 52-54 of Broad Application No. 16/177,403 to the interference, pursuant to the provisions of 37 C.F.R. §§ 41.121(a)(1)(i) and 41.208 and Standing Order ¶ 203.2.  The motion was contingent on the Board granting Broad's Substantive Preliminary Motion No. 1 to substitute the Count.  On March 16th, Sigma-Aldrich filed its Opposition and on April 26th Broad filed its Reply.

The claims that were the subject of Broad's Motion recite a CRISPR method in eukaryotic cells that cleaves both strands and repairs the break by integration of a template polynucleotide.  Claim 52 is generic with regard to the guide RNA species, comprising dual-molecule and single-molecule (sgRNA) species:

52.  A method comprising: introducing into, or expressing in, a eukaryotic cell having a DNA molecule,
    (I) a Cas9 protein or one or more nucleotide sequences encoding the Cas9 protein,
    (II) an RNA or one or more nucleotide sequences encoding the RNA, the RNA comprising:
        (a) a first RNA comprising a first ribonucleotide sequence and a second ribonucleotide sequence, and
        (b) a second RNA, and
    (III) a template polynucleotide,
    wherein, the second RNA forms an RNA duplex with the second ribonucleotide sequence, and wherein, in the eukaryotic cell, the first ribonucleotide sequence directs the Cas9 protein to a target sequence of the DNA molecule, whereby the Cas9 cleaves both strands of the DNA molecule and the cleavage is repaired by integration of the template polynucleotide into  the DNA molecule in the eukaryotic cell.

Claim 53 (dual molecule RNA species) and claim 54 (single-molecule RNA species) recite the two alternative species.  Broad asserted that these claims were deemed allowable by the U.S. Patent and Trademark Office Examiner on November 15, 2021.

Sigma-Aldrich's Opposition noted that this motion will become moot should the Board deny Broad's Preliminary Motion No. 1 to change the Count.  Sigma-Aldrich also asserted that none of the claims in the '403 application have been allowed (or considered in condition for allowance) by the Examiner, prosecution of that application having been suspended with the Declaration of this Interference.  Should the Board reach the merits, Sigma-Aldrich contended that Broad has not applied the one-way obviousness test to address whether these claims 52-54 satisfy the written description requirement of 35 U.S.C. § 112(a).  Sigma-Aldrich also accused Broad of not satisfying the Board's requirements for leave to file Contingent Motion No. 2, characterizing Broad's position as being "misleading" and citing several assertions from the Contingent Motion that state or imply that the Examiner has made an allowability determination.  And on the merits Sigma-Aldrich asserted that under the one-way test for obviousness Claims 53 and 54 are not patentable over Proposed Count 3.

In its Reply, Broad first addresses Sigma-Aldrich's incorporation by reference of what Broad states is over 25 pages from its Opposition to Broad's Preliminary Motion No. 1, which besides being improper under Standing Order ¶ 106.2 was the only basis for several arguments.  Accordingly, Broad states that these arguments should be considered waived.  Broad also argues that Claim 52 "was and is allowable" because the Examiner sua sponte indicated these claims were allowable (and remained so upon entry of further amendments).  Allowability follows for dependent claims 53 and 54, which recite species of the RNA component of the claimed CRISPR-Cas9 complexes recited in Claim 52.  Broad further sets forth the basis for adequate written description of Claims 52-54 in the Zhang B1 priority document, because the disclosure in that document is identical in the specification of the '403 application (which incorporates the B1 application by reference, providing "an unbroken chain of identical disclosures supporting the subject matter of claims 52-54").

As in other Replies, Broad sets forth the basis for the Board to find claims 52-54 to be patentable over Sigma-Aldrich's earliest priority disclosure and why the '403 application is entitled to the benefit of pre-AIA status.  Regarding the latter argument, Broad argues that AIA §§ 3(n)(1) and 3(n)(2) (the statutory basis for Sigma-Aldrich's argument) do not apply to priority claims to a provisional application under 35 U.S.C. § 119(e) (although a fair reading of the statute would appreciate that the basis for the distinctions under the AIA relate to the claims in a pre-AIA priority application and provisional applications have no claims, at least not formally).  And Broad reminds the Board that Sigma-Aldrich attempted to broach this issue in its own Preliminary Motion but the Board denied that request.  On the merits, Broad also contends that any differences between what is disclosed in the '403 application and the priority applications, including the Zhang application, do not satisfy the standard to qualify as new matter and hence prohibit pre-AIA status.

For all these reasons, Broad asks the Board to grant this Motion if it grants Broad's Preliminary Motion No. 2.

By Kevin E. Noonan —

On December 3rd, Junior Party the Broad Institute, Harvard University, and MIT (collectively, Broad) filed its Substantive Preliminary Motion No. 1 in Interference No. 106,133 (which names Sigma-Aldrich as Senior Party), asking the Patent Trial and Appeal Board (PTAB) to substitute the interference Count, pursuant to the provisions of 37 C.F.R. §§ 41.121(a)(1)(i) and 41.208(a)(2).  On March 16th Senior Party Sigma-Aldrich filed its Opposition to Broad's Motion and on April 26th Broad filed its Reply.

As a reminder, Broad's Proposed Substitute Count takes the "McKelvey" format (comprising in the alternative a claim from one of each Party's applications in interference); the proposed change is in the portion of the Count reciting Broad's claims:

Proposed Count No. 3 (numbered presumably for consistency with other pending CRISPR-related interferences):

Sigma-Aldrich Application No. 15/456,204 (as declared)

or

Claim 2 of Broad Application No. 16/177,403:

52.  A method comprising: introducing into, or expressing in, a eukaryotic cell having a DNA molecule,
    (I) a Cas9 protein or one or more nucleotide sequences encoding the Cas9 protein;
    (II) an RNA or one or more nucleotide sequences encoding the RNA, the RNA comprising: (a) a first RNA comprising a first ribonucleotide sequence and a second ribonucleotide sequence, and (b) a second RNA;
and
    (III) a template polynucleotide;
    wherein, the second RNA forms an RNA duplex with the second ribonucleotide sequence, and
    wherein, in the eukaryotic cell, the first ribonucleotide sequence directs the Cas9 protein to a target sequence of the DNA molecule, whereby the Cas9 cleaves both strands of the DNA  molecule and the cleavage is repaired by integration of the template polynucleotide into the DNA molecule in the eukaryotic cell.

In proposing this Substitute Count, Broad emphasized Sigma-Aldrich's contentions during prosecution that its invention comprised "cleave + insertion" CRISPR methods in eukaryotic cells which were patentably distinct from embodiments comprising "cleavage only" followed by non-homologous end joining of the cleaved DNA target.  In making this Motion, Broad clearly intended to cabin Broad's claims at risk in the interference to a small subset of those claims.

In support of its Motion, Broad relied heavily on Sigma-Aldrich's arguments taking substantially the same position in Interference No. 106,132 against Junior Party the University of California, Berkeley; the University of Vienna; and Emmanuelle Charpentier (collectively, "CVC") (see "Sigma-Aldrich Files Substantive Preliminary Motion 1 to Change the Count in Interference No. 106,132"), including arguments Sigma-Aldrich has made regarding the propriety of its claims not being part of other interferences having interfering subject matter limited to "cleavage only" eukaryotic CRISPR methods:

Sigma is properly not a party to those pending 'cleavage only' interferences because all of Sigma's involved claims are directed solely to the patentably distinct 'cleavage plus integration' technological advance in the art.

The first argument in Sigma-Aldrich's Opposition asking the Board to deny Broad's Motion No. 1 was procedural, that Claim 52 of U.S. Application No. 16/177,403 (the '403 application) had not been determined to be allowable when Broad filed its motion (complete with a timeline produced from the '403 application's prosecution history).  In addition, Sigma-Aldrich contended "Broad's Claim 52 is exceedingly broad for at least eight reasons" (as well as being properly subject to the first-inventor-to-file requirements under the Leahy-Smith America Invents Act (AIA) and thus ineligible for consideration in an interference).  Sigma-Aldrich also contended that "Broad never even asserts, let alone demonstrates, that 'cleavage plus altering gene expression' is patentably distinct from 'cleavage plus integration by [Homology-Dependent Recombination] HDR'" (in a footnote providing a tally that "[o]f Broad's 461 involved patent claims, 340 claims are directed to 'cleavage plus altering gene expression' (or an analogous recital), 42 claims are directed to insertion of a 'template,' and 8 dependent claims are directed to 'cleavage plus integration by HDR'").  Finally, Sigma-Aldrich asserted that Broad has neglected to "explain how Claim 52 is patentable over Sigma P1."  Citing Louis v. Okada, 2011 Pat. App. 21 LEXIS 24048, at *10 (BPAI May 25, 2011), Sigma-Aldrich contended that a party in an interference must show that there is a genuine need to change the Count and not make a "change for change's sake."

In its Reply, Broad tells the Board that Sigma-Aldrich's Opposition must fail because the Senior Party did not "meaningfully dispute" any of Broad's three reasons for moving to substitute the Count, particularly with regard to the issue that the Count as declared encompasses two distinct inventions (i.e, "cleavage + altering gene expression" and "cleavage + integration" of heterologous DNA).  Broad defines this scope (of the "commonly-claimed interfering subject matter") as "use of a CRISPR-Cas9 system in a eukaryotic cell to target and cleave both strands of a DNA molecule, with the cleavage being repaired by integrating a donor polynucleotide sequence ("Donor Template Integration")(an interpretation that would liberate most (340) of Broad's claims corresponding to Count 1 of the interference as declared).  Broad's arguments are directed to some degree to the nature of the McKelvey Count itself, wherein distinct aspects of patentably indistinct inventions are combined (the latter characterization forming the core of Broad's dispute).  Broad also argues regarding the similarity between Sigma Claim 31 and claim 18 from an involved CDC patent in the '115 interference (in which Broad mentions in passing it the Board granted them priority).  The Count as declared "[will] work a tremendous injustice" upon Broad should the Board deny its Motion No. 1 and Sigma-Aldrich be deemed entitled to priority on the half of the Count Broad contends it is entitled, the Reply asserts.  Broad also argues that Sigma-Aldrich has not "explain[ed] away" its statements agreeing with the patentable distinction Broad argues exists between the two portions of the McKelvey Count as declared in this interference.  And Broad reiterates its argument that the position Sigma-Aldrich takes in its Opposition is contrary to positions it has taken during ex parte prosecution of its applications-in-interference (including U.S. Application  15/456,204) and in Interference No. 106,132.  Finally, Broad argues that both its dual-molecule and single-molecule proofs will be excluded if the Board maintains Count 1 as declared, the latter set of proofs having been the basis for Broad prevailing in the '115 Interference and hence (according to Broad) be unjust.

Sigma-Aldrich's procedural arguments are relegated to a shorter portion of the Reply, regarding whether Claim 52 was in condition for allowance and whether the '403 application is entitled to the provisions of the 1952 Patent Act and thus properly within the purview of an interference.  Broad dissects the former argument allegation-by-allegation with regard to what Claim 52 recites.  And regarding the '403 application's status as a pre-AIA application, Broad argues that AIA §§ 3(n)(1) and 3(n)(2) (the statutory basis for Sigma-Aldrich's argument) do not apply to priority claims to a provisional application under 35 U.S.C. § 119(e)(although a fair reading of the statute would appreciate that the basis for the distinctions under the AIA relate to the claims in a pre-AIA priority application and provisional applications have no claims, at least not formally).  And Broad reminds the Board that Sigma-Aldrich attempted to broach this issue in its own Preliminary Motion but the Board denied that request.  On the merits, Broad also contends that any differences between what is disclosed in the '403 application and the priority applications, including the Zhang application, do not satisfy the standard to qualify as new matter and hence prohibit pre-AIA status.  Broad also rejects Sigma-Aldrich's attempts to incorporate arguments by reference from its Oppositions to other Broad Preliminary Motions, understanding these efforts to be a way for Sigma-Aldrich's arguments to exceed the page limit for its Opposition here.  Finally, Broad argues that its Claim 52 is patentable to Broad over Sigma's earliest priority application, U.S. Application No. 61/734,256.

For all these reasons Broad asks the Board to grant its Preliminary Motion No. 1.