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.
In its Motion, Broad asserted that, should the Board grant its motion and deny Broad Substantive Motion No. 1 (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].
According to Broad, these five categories comprise claims drawn to "patentably distinct" inventions from the inventions within the scope of either Count 1 or Count 2. Broad argued that these distinctions are neither disclosed nor obvious in view of the Counts as they would be understood by those having ordinary skill in the art. Moreover, and consistent with Broad's arguments in this interference and in Interference No. 106,115, Broad contended that dual-molecule and single molecule guide RNA embodiments of CRISPR are also patentably distinct and claims not limited to single-molecule embodiments should be de-designated as not corresponding to Count 1. Broad's motion then set forth its arguments why claims from each of these categories do not correspond to the Count.
ToolGen's Opposition takes each of these categories and Broad's arguments in turn, after reminding the Board of the similarities between this Motion and Broad's Motion No. 3 in Interference 106,115 (which the Board denied). With regard to claims directed to use of vectors for RNA expression, ToolGen argues 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. ToolGen maintains in support of this assertion that "a POSA would have been motivated to use vectors in the eukaryotic CRISPR-Cas system of Count 1 or Proposed Count 2 with a reasonable expectation of success" because "as of the priority date, the use of vectors, e.g., plasmid vectors, was well known and widely employed for introducing DNA sequences encoding RNA molecules into eukaryotic cells." While acknowledging that, as Broad contends, "[d]elivery of RNA components of a CRISPR-Cas9 system can be accomplished in multiple ways," this argument does not refute that vectors are one known way to achieve intracellular sgRNA production because use of vectors for this purpose is "well-known and widely employed" for doing so according to ToolGen. ToolGen's brief cites the Federal Circuit (Genzyme Corp. v. Transkaryotic Therapies, 346 F.3d 1094, 1099–1100 (Fed Cir. 2003)) and treatises (J.F. SAMBROOK & D.W. RUSSELL, MOLECULAR CLONING: A LABORATORY MANUAL (3d ed. 2001)) to establish the conventionality (and hence reasonable expectation of success) of vector-based introduction methods, and distinguishes Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358 (Fed. 18 Cir. 2008) (cited by Broad), on the grounds that that case (unlike here) was related to a "factually distinct scenario" where there were not a small number of finite options that were available to a skilled artisan. Finally, ToolGen contends that Broad has not established any of the objective indicia of non-obviousness to support its arguments; this contention relies on ToolGen's argument that Broad failed to establish the required nexus between any of the asserted secondary considerations and the inventive feature of the claims Broad seeks to have de-designated (an argument getting increased traction before the Federal Circuit; see "The Federal Circuit Addresses Commercial Success").
Regarding Broad's challenge to claims reciting Staphylococcus aureus Cas9 protein (SaCas9), ToolGen argues 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. In addition, ToolGen argues 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." ToolGen challenges Broad's factual assertions that there were many Cas9 analogs known in the art at the priority date and that the skilled artisan would have had no basis for choosing to use SaCas9. ToolGen asserts that Broad was incorrect in arguing that SpCas9 was the predominant Cas9 species used in prokaryotes and that there was no reason for a POS to switch to SaCas9, nor that there were a plethora of smaller-sized Cas9 proteins to choose from as well as Broad's arguments with regard to amino acid sequence differences between SpCas9 and SaCas9. As with the vector claims, and for many of the same reasons, ToolGen argues that Broad has not established any of the asserted secondary considerations, particularly with regard to unexpected results.
Next, ToolGen's brief turns to claims reciting the use of chimeric Cas9 species, against which ToolGen first argues waiver, based on the paucity of the support ToolGen alleges Broad submitted regarding this argument, citing Oracle Am., Inc. v. Google Inc., 750 F.3d 1339, 1377 n.17 (Fed. Cir. 2014). Nevertheless, ToolGen walks through its argument 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." And again, ToolGen argues Broad failed to establish any of the objective indicia, particularly unexpected results, asserting that "a POSA would have expected a chimeric Cas9 protein to have altered results in areas such as specificity and the ability to target specific PAM sequences, which are the exact results Broad claims to be 'unexpected'" (emphasis in brief).
Further, with regard to Broad's arguments involving use of two nuclear localization signals (NLS) to target SaCas9 to the eukaryotic cell nucleus, ToolGen argues 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. Use of NLS sequences was routine in the art prior to the priority date ToolGen asserts, citing teachings in the art regarding "Type I and III CRISPR systems, and [with regard to] proteins of Zinc Finger Nucleases, TALENs, Rec A, Lac, and HaloTagTM proteins." Moreover, ToolGen maintains that before the priority date "several well-known and readily available commercial eukaryotic expression vectors attached two or more NLSs to proteins expressed from the vector." And again ToolGen argues Broad has not established the existence of any objective indicia of non-obvious.
ToolGen also sets 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. Again, ToolGen maintains that Broad had waived this argument by the paucity of evidence or argument Broad asserts in support thereof, 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 reiterates earlier arguments that "generating protein fusions had been used for decades before the priority date as a method of purifying proteins, and fusing green fluorescent protein (GFP) to proteins was also used as a method of detecting protein localization in prokaryotic and eukaryotic cells." And ToolGen again recited Broad's failure to establish any of the objective indicia of non-obviousness.
ToolGen then turns 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 is 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].
ToolGen also notes that their argument is consistent with the Board's determination in the '115 Interference, based on the principle that "where 'a patent applicant has elected to be a lexicographer by providing an explicit definition in the specification for a claim term, . . . the definition selected by the patent applicant controls,'" citing Renishaw PLC v. Marposs Societa' per Azioni, 158 F.3d 1243, 1249 (Fed. Cir. 1998). The specification provides an "explicit, clear, and unambiguous definition" that "makes it unnecessary to resort to weak inferences from cherry-picked claims" to rebut it, ToolGen asserts in response to Broad's attempted recourse (as in the '115 Interference) to claim differentiation arguments. ToolGen maintains that this equivalence in language in the specification is consistently used throughout Broad's patents-in-interference and cannot be disclaimed here in an attempt to distinguish the claims Broad argues the Board should de-designate as corresponding to either Count. ToolGen also maintains that the term "guide RNA" does not have a "plain and ordinary meaning" in the art (paradoxically illustrated ToolGen asserts by the references Broad cites in support of its arguments) and thus Broad's express definition should be conclusive as to the construction of the term given by the Board.
Finally, and particularly with regard to claims 15, 17–26, and 28–41 of the '713 patent and claims 1–24 of the '418 patent, ToolGen argues that the species recited in Count 1 anticipates these generic claims under 37 C.F.R. § 41.207(b)(2) (as the Board held in the '115 Interference) and In re Slayter, 276 F.2d 408, 411 23 (C.C.P.A. 1960).
For all these reasons ToolGen asks the Board to deny Broad's Substantive Preliminary Motion No. 3.
