By Kevin E. Noonan --
In the Patent Trial and Appeal Board's decision on motions issued September 10th in Interference No. 106,115 (see "PTAB Decides Parties' Motions in CRISPR Interference") between Senior Party The Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad") and Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC"), the Board denied Broad's Motion No. 3 to De-designate Claims as Not Corresponding to Count No. 1.
Broad's brief parsed its claims into three categories of claims that it argued do not correspond to the Count, depending on how the Board rules on Substantive Motions Nos. 1 and 2:
• USP 8,865,406 – Claims 1-30 (all); 8,871,445 – Claims 1-30 (all); USP 8,889,356 – Claims 1-30 (all); USP 8,932,814 – Claims 1-30 (all); USP 8,945,839 – Claims 1-28 (all); USP 8,993,233 – Claims 1-43 (all); USP 8,999,641 – Claims 1-28 (all); USP 8,697,359 – Claims 1-3, 5-10, 12-17, and 19-20; USP 8,771,945 – Claims 1-4 and 6-29; USP 8,895,308 – Claims 1-9 and 11-28; USP 8,906,616 – Claims 1, 3-4, 6-30; USP 9,840,713 – Claims 1-7, 10-15, 17-26, and 28-41; and U.S. Patent Application No. 14/704,551: in the event that the Board denies both Motions No. 1 and 2.
• USP 8,865,406 – Claims 1-30 (all) and USP 8,895,308 – Claims 1-30 (all): in any event, claims reciting Ca9 from Staphylococcus aureus (the SaCas9 claims).
• USP 8,871,445 – Claims 1-30 (all); USP 8,932,814 – Claims 1-30 (all); USP 8,993,233 – Claim 7; USSN 14/704,551 – Claims 9-11: clams reciting two or more nuclear localization signal (the NLS claims).
As set forth by the Board in its Decision on Motions pursuant to 37 C.F.R. § 41.125(a), the Board refutes Broad's assertion that denial of their Motions Nos. 1 and 2 was equivalent to a determination that "claims to a single-molecule RNA CRISPR-Cas9 system are separately patentable from non-limited guide RNA claims." "Rather," said the Board, "our denials of Broad Motions 1 and 2 are based on a failure of Broad to meet its burdens." (Indeed, the Decision expressly disclaims any determination on patentability with regard to RNA molecule configuration.)
On the merits, the Decision states that the standard it has applied is whether each involved claim in Broad's patents-in-interference would have been anticipated or rendered obvious by the subject matter of Count 1. The Board notes that "[m]any of Broad's supporting reasons are similar to those put forth in Motion 2," setting forth examples. The Board being specific in its language interprets some of Broad's arguments to be limited to its claims wherein reciting "fused" or "chimeric" RNA species should be construed to recite single RNA molecule CRISPR species. The Board expressly rejects Broad's assertion that "all but 43 of Broad's 387 involved claims" should be designated as not corresponding to Count 1 on this rationale, which the Decision states is based on Broad's argument (rejected by the Board in its denial of Broad Motion No. 2) involving the claim term "guide RNA."
The Board recognizes the Broad makes a different argument with regard to Claims 15 and 26 of the '713 patent:
Claim 15:
A CRISPR-Cas complex-mediated method for the production of a multicellular genetically modified non-human animal or multicellular genetically modified plant, the method comprising delivery to one or more target sequences in a cell of the multicellular non-human animal or plant of:
a Cas9 protein;
a guide sequence linked to a tracr mate sequence; and
a tracr sequence;
wherein the guide sequence directs sequence-specific binding of a CRISPR complex to the target sequence in the cell, whereby the multicellular genetically modified non-human animal or multicellular genetically modified plant is produced, and displays a phenotype or carries DNA to display a phenotype of the genetic modification.
This claim, according to the Board, does not recite any linking, fusing, or other language to describe the relationship between the guide and tracr RNA molecules.
Claim 26:
A CRISPR-Cas complex-mediated method for the production of a multicellular genetically modified non-human animal or multicellular genetically modified plant, the method comprising delivery to a cell of the multicellular non-human animal or plant having one or more target sequences of a Cas9 protein, or a nucleic acid molecule encoding the Cas9 protein; and a guide sequence linked to a tracr mate sequence; and a tracr sequence, or one or more nucleic acid molecules encoding the guide sequence linked to the tracr mate sequence and the tracr sequence,
wherein the guide sequence directs sequence-specific binding of a CRISPR complex to the target sequence in the cell, whereby the multicellular genetically modified non-human animal or multicellular genetically modified plant is produced, and displays a phenotype or carries DNA to display a phenotype of the genetic modification.
This claim, according to the Board, recites a method for delivering nucleic acids comprising Cas9, a guide RNA and trace RNA separately, or nucleic acids "encoding the guide sequence linked to the tracr mate sequence and the tracr sequence."
CVC had argued that claim 15 was limited to single RNA molecule CRISPR embodiments by the language of claim 26; the Board was not persuaded by this argument. Under the broadest reasonable interpretation of claim 15 as found by the Board these species encompassed any physical relationship between the guide and tracr RNAs. Likewise, claim 26 recites that the guide and tracr RNAs could be encoded by separate nucleic acid molecules. Accepting this construction, the Board recites again the requirement for a claim to correspond to the Count, including the rule that "[a] count directed to a species, if prior in time, would typically anticipate a generic claim" under Rule 41.207(b)(2). To the Broad's argument that this Rule merely recites "a presumption" (Board: "which apparently does not apply to Broad in this case") the Board states that it is not persuaded by Broad's argument (citing comment 186 in the Final Rulemaking) and that the cited comment was rather directed to Rule 41.207(b)(1), which specifies a "rebuttable presumption that all claims designated as corresponding to a count stand or fall together."
The Board also addressed Broad's resort to fairness (that has been a theme throughout its briefing), stating that "Broad cites to no authority that holds unfairness or any other condition, such as facts beyond the relationship of the subject matter of the claims and the count, can be used to determine claim correspondence differently."
And turning to specific citations to case law, the Board finds Broad's reliance on Eli Lilly & Co. v. Bd. of Regents of Univ. of Washington, 334 F.3d 1264 (Fed. Cir. 2003), to be "misplaced" because that case was about determination of whether there was an interference-in-fact using the two-way test rather than, as here, claim correspondence under the one-way test. Nor did the Lilly court state that "a genus invented before a species is separately patentable," which the Board believes was Broad's argument. In the Board's view, Broad must prove that the genus and species are separately patentable inventions. In like manner, the Decisions states that none of Godtfredsen v. Banner, 598 F.2d 589, 590 (CCPA 1979); Theeuwes v. Bogentoft, 2 U.S.P.Q.2d 1378 (B.P.A.I. 1987); nor Ex Parte Hardman, 142 U.S.P.Q. 329 (CCPA 1964), stand for the proposition that claim correspondence can be determined by anything other than the test enunciated in Rule 207(b)(2). And somewhat ironically in view of Broad's Motion No 1, the Board finds that comments to Final Rulemaking support their view that estoppel is determined by correspondence to the Count:
[37 C.F.R. § 41.207(b)] simply formalizes the effect of estoppel arising out of cases like In re Deckler, 977 F.2d 1449, 1452 . . . (Fed. Cir. 1992), in which a party could not subsequently seek claims that were patentably indistinct from the subject matter of the count lost in the interference. As discussed earlier, no one "wins" a count because surviving a priority contest for one count does not mean that one is thereby entitled to a claim. [Application of] Kyrides [159 F.2d 1019 (CCPA 1947)].
There is no unfairness in proper application of the principles set forth in Deckler, the Board asserts. Thus, if Broad's generic claims are found anticipated or rendered obvious by Count 1 the estoppel will apply to these claims. Here, the Board finds that "Broad fails to meet the burden of persuading us that either its claims do not correspond to Count 1 or that we should add a separate count." And the only Broad argument the Board appreciates as being directed to anticipation or obviousness is "a general reference to CVC's arguments that claims to CRISPR/Cas9 systems with single-molecule RNA configurations are separately patentable from claims to systems with generic RNA configurations." In the Board's view, this argument is contradicted by Broad's argument in Motion No. 2 that "CVC's single-molecule RNA claims are not patentable over a generic count, such as proposed Count 2." In this regard, the Decision states that "it is not clear that Broad could argue that a count reciting a single-molecule RNA configuration CRISPR-Cas9 system would not at least render obvious a claim reciting a generic RNA configuration." The result is the Board's determination that Broad failed to set forth a sufficiently clear argument to support that claims 15 and 26 do not correspond to Count 1.
Turning the SaCas9 claims, after reciting the positions and evidence adduced by the parties, the Board states that it was persuaded by one of the cited references to Sapranauskas et al. (2011, "The Streptococcus thermophilus CRISPR/Cas system provides immunity in Escherichia coli," Nucleic Acids Research, 39: 9275–82) that "S. aureus was considered to be a model CRISPR/Cas system in 2011." This reference also persuaded the Board that Broad's arguments regarding lack of sequence homology or domain regions were insufficient to support Broad's arguments that the use of a different Cas9 source was sufficient for these claims not to correspond to the Count. And the requisite motivation to try argued by CVC to exist in the art was supported by one of Broad's experts based on its advantageously smaller size compared with other Cas9 species. Finally, the Decision states that the Board was not persuaded by Broad's expert that the skilled worker would not have had a reasonable expectation of success using CRISPR with SaCas9 nor that it would have been unexpected. Accordingly, the Board states that "Broad fails to persuaded us that a CRISPR-Cas9 system using SaCas9 would not have been obvious over Count 1," citing the standard set forth in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
Finally, the Board similarly did not find persuasive Broad's argument that CRISPR embodiments comprising multiple nuclear localization sequences (the NLS claims) would not have been obvious over Count 1. Broad provided its expert to support these assertions, comparing bacterial proteins acting in the bacterial milieu compared to how they act in a eukaryotic cell and testifying that the presence of these NLS sequences would have unpredictably influenced Cas9 activity. The Board did not find convincing Broad's argument on this point, either. In the Board's view, the efficacy of the use of one or more NLSs attached to a protein such as Cas9 would be a matter of no more than routine experimentation, relying on Fieck et al. (1992, "Modifications of the E. coli Lac repressor for expression in eukaryotic cells: effects of nuclear signal sequences on protein activity and nuclear accumulation," Nucl. Acids. Res. 20: 1785–91). In addition, CVC asserted and the Board credited that it was known in the art that Cas9 could be functional when expressed as a chimeric protein, citing Jinek 2012, testimony of its expert witness, and U.S. Patent Application Publication No. 2010/0076057. Broad's reliance on the outcome and reasoning of the prior interference between the parties, No. 105,048 was also unavailing because the question here is "whether adding two or more NLSs to the functional eukaryotic system of Count 1 would have been obvious" and Broad, in the Board's view, did not supply any such evidence. And while Broad argues that modifying Cas9 with two or more NLSs "significantly improved localization and unexpectedly improved efficiency", the Board found no evidence that such improvements would have been unexpected, nor did Broad provide any evidence of secondary considerations to rebut the obviousness of these claims in view of Count 1 of the interference.
"In summary," the Decision concludes on this issue, "Broad fails to persuade us that any of its claims should be designated as not corresponding to Count 1" and this Broad Motion No 3 was denied.
The remainder of the Board's Decision will be discussed in future posts.
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