By Kevin E. Noonan —
On May 28th, Junior Party the Broad Institute, Harvard University, and MIT (collectively, "Broad") filed its Substantive Preliminary Motion No. 3 in CRISPR Interference No. 106,126 (where ToolGen is the Senior Party). This motion, pursuant to 37 C.F.R. §§ 41.121(a)(1)(iii) and 41.208(a)(1) requested that the Board de-designate Broad claims in these five categories as not corresponding to either Count 1 or proposed Count 2 (A-E) or Count 1 (F):
• Category A: use of vectors for RNA expression;
• Category B: Staphylococcus aureusCas9 protein ("SaCas9");
• Category C: Cas9 chimeric CRISPR enzyme;
• Category D: Cas9 with two or more nuclear localization signals ("NLSs");
• Category E: Cas9 fused to specified protein domains; and
• Category F: Claims not limited to single-molecule RNA.
On August 6th ToolGen filed its Opposition and on September 24th Broad filed its Reply.
In its Motion, Broad asserted that, should the Board grant its motion and deny Broad Substantive Motion No. 1 to Substitute the Count (see "Broad Files Substantive Preliminary Motion No. 1 in CRISPR Interference"), these of the Broad claims would correspond to Count 1:
[C]laim 18 of U.S. Patent No. 8,697,359, claims 26-30 of U.S. Patent No. 8,795,965, claims 2 and 5 of U.S. Patent No. 8,906,616, and claim 16 and 27 of U.S. Patent No. 9,840,713 [exhibit references omitted].
On the other hand, should the Board grant both Broad's Motion No. 3 and Broad's Motion No. 1, these of Broad's claims would remain in the interference as corresponding to Proposed Count 2:
[C]laims 15-20 of the '359 patent, claims 26-29 of U.S. Patent No. 8,771,945, claims 26-30 of the '965 patent, claims 24-30 of U.S. Patent No. 8,889,356, all claims of the '616 patent, claims 21-28 of U.S. Patent No. 8,945,839, and claims 15-17, 20-24, 26-28, 31-35, and 38-39 of the '713 patent, as well as allowable claims 1, 40, and 41 of Application 15/160,710 and allowable claims 74, 94, and 95 of Application 15/430,260 should the Board also grant Broad's Contingent Substantive Motion No. 2 [see "Broad Files Contingent Preliminary Motion No. 2 in CRISPR Interference"; exhibit references omitted].
ToolGen's Opposition took each of these categories and Broad's arguments in turn:
• With regard to claims directed to use of vectors for RNA expression, ToolGen argued that Broad failed to satisfy the relevant standard under 37 C.F.R. § 41.207(b)(2) that either Count 1 as declared or Count 2 as proposed by Broad (see "Broad Files Substantive Preliminary Motion No. 1 in CRISPR Interference") would not have anticipated nor rendered obvious the "vector claims" Broad now asks the Board to de-designate.
• Regarding Broad's challenge to claims reciting Staphylococcus aureus Cas9 protein (SaCas9), ToolGen argued that the skilled worker would have been motivated to use it in the eukaryotic CRISPR-Cas system recited in either alterative Count due to its small size (the advantages of CRISPR embodiments using this Cas9 species being recognized in the prior art according to ToolGen) and that the nucleotide sequence encoding it was known in the art.
• ToolGen also argued that the skilled worker would have been motivated to use SaCas9 in adeno-associated virus (AAV) vectors due to their being "available and commonly used in the art—particularly for 'human therapeutics'" due to their lack of pathology to humans and their capacity for "long-term gene expression."
• For claims reciting the use of chimeric Cas9 species, ToolGen first argued waiver, based on the paucity of the support ToolGen alleges Broad submitted regarding this argument.
• ToolGen also argued that a POSA would have been motivated to use chimeric SaCas9 proteins, due to the "vast array of prior-art references disclosing the use and numerous benefits of chimeric proteins."
• With regard to Broad's arguments involving use of two nuclear localization signals (NLS) to target SaCas9 to the eukaryotic cell nucleus, ToolGen argued the skilled worker would have been motivated to use two or more NLSs with Cas9 to make CRISPR-Cas9 complexes in eukaryotic cells, with a reasonable expectation of success, inter alia because use of NLS sequences was routine in the art prior to the priority date.
• ToolGen also set forth its arguments in contradiction to Broad's arguments that "Cas9 fused to specified protein domains or including heterologous domains" correspond to either of the alternative Counts, on the basis that Broad had waived this argument and, more substantively, that the skilled worker would have understood Cas9 species joined with one or more NLS to be "fused" (and thus known in the art).
ToolGen then turned to Broad's arguments that certain of its claims having been designating as corresponding to Count 1 do not recite single-guide RNA (sgRNA) with regard to "three sets of claims":
(1) those "that do not require an RNA component at all";
(2) those "that are generic as to the RNA component and do not use the term 'guide RNA'"; and
(3) those "that are generic as to the RNA component and that use the term 'guide RNA.'"
ToolGen's argument was that by their own specifications Broad's patents-in-interference rebut this argument, citing in particular U.S. Patent No. 8,697,359 for the teachings that:
In aspects of the invention the terms "chimeric RNA", "chimeric guide RNA", "guide RNA", "single guide RNA" and "synthetic guide RNA" are used interchangeably and refer to the polynucleotide sequence comprising the guide sequence, the tracr sequence and the tracr mate sequence [emphasis on brief].
Particularly with regard to claims 15, 17–26, and 28–41 of the '713 patent and claims 1–24 of the '418 patent, ToolGen argued that the species recited in Count 1 anticipates these generic claims under 37 C.F.R. § 41.207(b)(2).
In its Reply, Broad argues that the methods it set forth in its earliest priority document (the NIH grant proposal) constitute conception of CRISPR species for eukaryotic applications that do not correspond to the Count and should be excluded. According to Broad's Reply, "ToolGen also does not dispute that Broad could lose its generic RNA claims even if Broad was the first to conceive and reduce to practice the generic RNA invention." Broad further asserts:
The response is that, while Broad proffered proof that it was the first to invent the generic RNA invention in connection with Motion 1, it was not necessary to prove that its dual-molecule RNA proofs came before its experiments with single-molecule RNA as in Count 1 at this time. Unless Motion 1 is granted, if ToolGen successfully attacks Broad's single-molecule RNA proofs, Broad would lose its generic RNA claims even if Broad's dual-molecule RNA experiments were successful and came before ToolGen's single-molecule RNA work [emphasis added].
Which is of course true. Notably, however, nowhere in its Reply does Broad does say that it is the case that they had reduced to practice dual-molecule guide RNA CRISPR embodiments in eukaryotic cells prior to the priority dates asserted by ToolGen and granted by the Board in the Interference Declaration herein. While conception and a description of such embodiments in some instances might be sufficient (i.e., it is not the case that a party in an interference must show actual reduction to practice), Broad itself has argued, extensively, that the complicated nature of performing CRISPR successfully in eukaryotic cells makes this a case for a "simultaneous conception and reduction to practice" standard (at least as applied to CVC or ToolGen; see "Broad Files Priority Motion in CRISPR Interference" and "Broad Files Opposition to ToolGen Substantive Preliminary Motion No. 1"). The Cong et al. reference discloses such successes, and as Broad has previously argued the submission date of this paper antedates ToolGen's earliest priority date in this interference. That may be enough for the Board to conclude that Broad had an earlier invention date for the dual-molecule guide RNA CRISPR species in eukaryotic cells; the question then would be whether the Board will excise claims to eukaryotic CRISPR generic for guide RNA configuration but that would effectively leave Broad in a position to preclude ToolGen (or CVC) from practicing sgRNA-comprising eukaryotic CRISPR embodiments. This outcome would be analogous to the outcome of Interference No. 105,048, where CVC was deemed entitled to claims generic as to cell type while Broad was entitled to eukaryotic CRISPR embodiments (see "Regents of the University of California v. Broad Institute, Inc. (Fed. Cir. 2018)").
Briefing on the parties' Preliminary Motions being completed, the Board will hold a final hearing sometime within the next several months.
Patent Docs 