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 granted Broad's Motion No. 4 for priority benefit to U.S. Provisional Application No. 61/736,527.  As a result, Broad will remain Senior Party during the Priority Phase of the interference.

Broad in its substantive Motion No. 4 argued that it had satisfied the standard for priority to USSN 61/736,527 to Zhang (termed "Zhang B1" in the motion).  The following diagram, showing the interrelatedness of the various Broad patents and applications in the interference, illustrates the basis of Broad's priority claim:

The Board in its Decision on Motions pursuant to 37 C.F.R. § 41.125(a) set forth a recapitulation of Broad's arguments, in sum that Zhang B1 "provides working examples and embodiments that meet each and every limitation of both halves of Count 1" and thus evinces to the skilled worker possession of an embodiment within the scope of the Count.  The Board in its Decision cited (and provided as an illustration) what it deemed to be successful practice of CRISPR-Cas9 in eukaryotic cells by reference to Figure 1D:

with the understanding that:

Figure 1D depicts a nuclease assay for SpCas9 mediated insertions and deletions wherein different combinations of four components of a CRISPR-Cas system are tested in each lane.  Bands indicating a 367 bp and a 317 bp product are present in the lanes that include Cas9, tracrRNA, and EXM1-target spacer, but not in the lanes that are missing either tracrRNA or EXM1-target spacer.

The Board also sets forth CVC's arguments in opposition, specifically that the priority document was non-enabling for the invention set forth in the interference Count because it relies exclusively on a 'chimeric guide RNA' that a [person of ordinary skill in the art or] POSA could not have made and used in a cell without undue experimentation."  This argument focuses (as the Broad did in its brief and the Board does in its Decision) on "Embodiment 17" (E17), wherein a chimeric guide RNA is expressed by a cell comprising both U and T bases:

In its Decision, the Board was convinced by Broad's evidence, particularly by expert testimony, that the skilled worker would have interpreted the "T's" in the sequence to be "U's."  Broad argued that describing Figure 2A as an RNA would have supported that interpretation (despite the contra designation as a "Chimeric guide RNA") and further states that Figures 12B and 8 would support this interpretation.  Further, the Board credited Broad's argument that the skilled worker would recognize that the disclosed vector would naturally produce the guide RNA having U's instead of T's:

The Board criticized CVC's arguments on several points.  For example, the Decision states that while CVC argued that the Examiner in related applications recognized the disparity regarding U's and T's comprising the chimeric guide RNA but noted that 'in the Examiner's requirement for correction CVC highlights, the Examiner only required Broad to include sequence identification numbers, not correction of the actual sequence and that "CVC does not direct us to any comment by the Examiner regarding the sequence in Figure 2A or to any rejection based on lack of enablement because of it."  And specifically with regard to this argument, the Board voiced its agreement with Broad's witness that the skilled worker would have understood that the illustrated T's would have been produced as U's in the RNA produced in a eukaryotic cell.  (Nor, the Board notes, has there been any correction of the corresponding scientific paper, Cong et al., 2013, "Multiplex Genome Engineering Using CRISPR/Cas Systems," Science 339: 819–23, in the record, supporting the view that the skilled worker's understanding would be consistent with Broad's argument and expert testimony.)

The Decision concludes on this issue that "[b]ecause Broad has persuaded us that Zhang B1 provides a constructive reduction to practice of an embodiment of Count 1, we are persuaded that Broad should be accorded its filing date."  Accordingly, the Board granted Broad Motion No 4.

As a consequence, Broad will remain the Senior Party in this interference.

The remainder of the Board's Decision with regard to CVC's motions will be discussed in future posts.

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.

By Kevin E. Noonan —

For those with long memories, last August the Patent Trial and Appeal Board received proposed motions from the parties (University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier, Junior Party, and The Broad Institute, Massachusetts Institute of Technology, and Harvard University, Senior Party) in Interference No. 106,115.  Thereafter, the Board authorized the parties to file some but not all of these motions; the Decision on these Motions was issued by the Board on September 10th (see "PTAB Decides Parties' Motions in CRISPR Interference").

But several of each parties' motions were deferred until the priority phase.  Last week, CVC requested and the Board granted leave to file one of them:  CVC's Motion 5, under 37 C.F.R. § 41.121(a)(1) that asks for judgment of unpatentability under 35 U.S.C. § 102(f) or (if post-AIA) 35 U.S.C. § 115(a) for "failure to name all inventors of the alleged invention."  In support of its request, CVC argued that it would "demonstrate that Broad deliberately misidentified the inventors on its involved patents and applications . . . ."  Proper inventorship is important in the interference, inter alia, because the Board needs to know whose testimony can corroborate and whose needs to be corroborated under interference practice, where the uncorroborated testimony of an inventor is given no weight; see, Kolcraft Enters. v. Graco Children's Prods., Nos. 2018-1259, 2018-1260, 2019 U.S. App. LEXIS 19751 (Fed. Cir. July 2, 2019).  The factual bases for this motion are differences between the named inventors in the patents- and applications-in-interference and the inventors named in a declaration by the Broad's patent attorney during a European opposition (EP 277146); it may be recalled that such irregularities involving a Rockefeller University inventor (Dr. Luciano Marraffini) not named in the EP application were the basis for that patent to be invalidated (see "The CRISPR Chronicles — Broad Institute Wins One and Loses One").

It will be appreciated that, as in Europe, a determination in CVC's favor would be dispositive for some if not all of Broad's claims.  The Board granted CVC leave to file its motion during Priority Phase No. 1, having a deadline of October 23rd (with Broad having the opportunity thereafter to oppose and CVC the opportunity to reply to any opposition).  It is somewhat ironic that CVC will now be in a position Broad sought in its Motion No. 1 regarding estoppel recently denied by the Board, to be able to get judgment in its favor without having to "prove up" priority (with all the attendant uncertainties and risk of that endeavor).

Posts on these efforts will appear shortly after the motion/opposition/reply are filed with the PTAB.

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. 2 to substitute the Count.

To recap, the Count in the '115 interference as declared recited in the alternative either claim 18 of the Broad's U.S. Patent No. 8,697,359 (dependent on claim 15), which taken together recites the following invention:

An engineered, programmable, non-naturally occurring Type II CRISPR-Cas system comprising a Cas9 protein and at least one guide RNA that targets and hybridizes to a target sequence of a DNA molecule in a eukaryotic cell, wherein the DNA molecule encodes and the eukaryotic cell expresses at least one gene product and the Cas9 protein cleaves the DNA molecules, whereby expression of the at least one gene product is altered; and, wherein the Cas9 protein and the guide RNA do not naturally occur together, wherein the guide RNAs comprise a guide sequence fused to a tracr sequence.

(where the underlined portion recites the relevant language from claim 18), or Claim 156 of Berkeley's U.S. Patent Application No. 15/981,807:

A eukaryotic cell comprising a target DNA molecule and 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 Cas9 protein, or a nucleic acid comprising a nucleotide sequence encoding said Cas9 protein; and
    b) a single molecule DNA-targeting RNA, or a nucleic acid comprising a nucleotide sequence encoding said single molecule DNA-targeting RNA; wherein the single molecule DNA-targeting RNA comprises:
        i) a targeter-RNA that is capable of hybridizing with a target sequence in the target DNA molecule, and
        ii) an activator-RNA that is capable of hybridizing with the targeter-RNA to form a double-stranded RNA duplex of a protein- binding segment,
    wherein the activator-RNA and the targeter-RNA are covalently linked to one another with intervening nucleotides; and
    wherein the single molecule DNA-targeting RNA is capable of forming a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule, whereby said system is capable of cleaving or editing the target DNA molecule or modulating transcription of at least one gene encoded by the target DNA molecule.

Broad's Motion No. 2 requested that the Board substitute proposed Count 2:

A method, in a eukaryotic cell, of cleaving or editing a target DNA molecule or modulating transcription of at least one gene encoded by the target DNA molecule, the method comprising:
    contacting, in a eukaryotic cell, a target DNA molecule having a target sequence with an engineered and/or non-naturally-occurring Type II Clustered Regularly lnterspaced Short Palindromic Repeats (CRISPR)-CRISPR associated Cas) (CRISPR-Cas) system comprising:
        a) a Cas9 protein, and
        b) RNA comprising
            i) a targeter-RNA that is capable of hybridizing with the target sequence of the DNA molecule or a first RNA comprising (A) a first sequence capable of hybridizing with the target sequence of the DNA molecule and (B) a second sequence; and
            ii) an activator-RNA that is capable of hybridizing to the targeter-RNA to form an RNA duplex in the eukaryotic cell or a second RNA comprising a tracr sequence that is capable of hybridizing to the second sequence to form an RNA duplex in the eukaryotic cell,
    wherein, in the eukaryotic cell, the targeter-RNA or the first sequence directs the Cas9 protein to the target sequence and the DNA molecule is cleaved or edited or at least one product of the DNA molecule is altered.

The distinction Broad made was between embodiments of CRISPR methods that are limited to "single-molecule guide RNA" (aka "fused" or "covalently linked" species), versus embodiments that encompass single-molecule and "dual molecule" species (wherein in the latter versions, the "targeter-RNA" and "activator-RNA" as recited in the proposed Count are not covalently linked).  Broad argued that its Proposed Count 2 should be adopted by the Board because it "properly describes the full scope of the interfering subject matter between the parties because both parties have involved claims that are generic, non-limited RNA claims."  The brief also argued that Proposed Count 2 "sets the correct scope of admissible proofs [i.e., their own] for the breakthrough invention described by the generic claims at issue in these proceedings—the successful adaption of CRISPR-Cas9 systems for use in eukaryotic environments," which Broad contended current Court 1 (in either alternative) does not.

The Board denied this motion for the simple reason that, in its opinion, "Broad fails to provide a sufficient reason why the count should be changed."  Citing Louis v. Okada, 59 U.S.P.Q.2d 1073, 1076 (BPAI 2001) (relied upon in opposition by CVC), the Board notes that it will only change the Count when reasons for doing so are "compelling."  Broad's motion argued that their claims (and CVC's) were directed to eukaryotic embodiments of CRISPR that were not limited to either single- or dual-molecule RNA species, but that the phrase "guide RNA" was generic.  Based on the claim construction, the Board rejected this construction, limiting the claims to single-molecule RNA embodiments.

The Decision also states that "Broad's argument for broadening the scope of the count to be generic as to RNA configuration is unpersuasive."  According to the Decision, CVC convinced the Board that there were other differences between Count 1 (as declared in the interference) and Broad's proposed Count 2.  These include that Count 2 is directed to a method whereas Count 1 recites system or eukaryotic cell.  This is enough, the Board states, for the PTAB to deny Broad's Motion No. 2 simply on these grounds.  The Board also was persuaded by CVC's argument that all of the Broad's claims are directed to "guide RNA" or "chimeric RNA" and thus to single-RNA molecule eukaryotic CRISPR embodiments.  Further, the Board faulted the Broad for not specifically identifying all the claims it contends recite generic eukaryotic CRISPR embodiments with regard to its RNA components.  Continuing, the Decision asserts that Broad also failed to convince the Board that the few claims that expressly recited "fused" RNA embodiments were sufficient under the doctrine of claim differentiation to construe the independent claims as encompassing both single- and dual-RNA molecule eukaryotic CRISPR embodiments.

As is its wont, the Board identified formal deficiencies in some Broad arguments that were sufficient to deny the relief requested under the rubric set forth in 37 C.F.R. § 41.121(b) that "the party filing the motion has the burden of proof to establish that it is entitled to the requested relief."  These include instances where the Broad's brief cited a footnote that does not stand for the cited proposition, and hence that "CVC did not have notice of arguments regarding claim 15 or of any other claim Broad asserts is directed to a generic RNA configuration without using the term 'guide RNA'".  Accordingly, the Board concluded that "[b]ecause Broad did not provide arguments about the interpretation of specific claims in its Motion 2 we are not persuaded by its argument that the scope of the 'vast majority' of its claims requires a broader count."

The Board's Decision also turns on its head the Broad's argument (recited throughout its briefing) that this interference is unfair to Broad due to "CVC's strategic decisions" in earlier Interference No. 105,048 between the parties.  The Board notes that the outcome in that interference, that there was no interference-in-fact, "achiev[ed] Broad's desired remedy–ending the interference."  "Had Broad wished to remain in a priority contest with CVC under the count in that interference, it could have chosen not to file the motion for no interference-in-fact," according to the decision, and thus the Board saw "no unfairness in Broad not having had a chance to present its best proofs in a priority contest with CVC in the '048 interference under these circumstances."

This portion of the decision concludes by denying Broad's alternative remedy of redeclaring the interference with both Counts, the Board stating its reasoning that "Broad fails to explain why this would be an appropriate remedy, given that we are not persuaded that a majority, or even a significant number, of its claims are drawn to a generic RNA configuration."

The remainder of the Board's Decision will be discussed in future posts.

By Kevin E. Noonan —

Judge Giles Sutherland Rich's most famous aphorism in patent law is "the name of the game is the claim."* This rubric is important to keep in mind when considering 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 focus of the claim construction issue was the meaning of the term "guide RNA," specifically whether it was a generic term encompassing dual-species or single-species ("fused") RNA components of the CRISPR-Cas9 complex, as illustrated in the Decision (taken from the Jinek 2012 reference; Jinek et al., 2012, "A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity," Science 337: 816–21):

 

 

 

 

 

In its Motions Nos. 2 and 3, Broad asserted this distinction, relying on portions of the specifications of several of its patents-in-interference.  While the term "crRNA" is recited in these Broad specifications, the involved claims recite "guide RNA," "chimeric RNA," and "guide sequence," and as the Decision states, the parties disputed the meaning of this term.  Broad noted that "the majority" of their involved claims recite "guide RNA" and that term was not limited to single- or dual-(RNA) molecule embodiments.  CVC, for its part, argued that the term should be limited to single-(RNA) molecule species for all Broad's claims-in-interference.

The Board used the "broadest reasonable interpretation" test (that standard was not changed when the Patent and Trademark Office adopted the Phillips test for post-grant review proceedings; see "PTAB Adopts Litigation Standards for Claim Construction in AIA Proceedings"), noting that in applying that standard "the Board's construction cannot be divorced from the specification and the record evidence, and must be consistent with the one that those skilled in the art would reach," citing Microsoft Corp. v. Proxycom, Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015).

Broad's argument in favor of construing "guide RNA" as a generic term encompassing both single- and dual-molecule embodiments was based on claims that distinguished between "guide RNA" and "fused guide RNA." Under the principle of claim differentiation, Broad argued that a claim reciting "fused guide RNA" that was dependent on a claim reciting "guide RNA" indicates that the latter term is broader than "fused" guide RNA (citing claim 18, dependent on claim 15, of Broad's Patent No. 8,697,359 in support of this argument).  Similarly, Broad cited claim 3 of its Patent No. 8,993,233 that recites a limitation wherein the guide RNA comprises a tracrRNA sequence on a different vector than the nucleic acid encoding the Cas9 protein.

CVC in opposition countered that claim differentiation is not "a rigid rule" and the segregation of guide RNA and Cas9-encoding RNA in the '233 patent did not mandate either guide RNA configuration.

The Board stated that while it agrees with Broad that some of its claims suggest that the term "guide RNA" is generic, in other instances the claims are amenable to a contrary construction of the term.  Accordingly, the Decision went on to consider other evidence to see if it rebutted the presumption that these claims had raised.

That evidence included support for Broad's argument that there is no "clear disavowal of scope" not to include both species of guide RNAs in the claims.  Broad contended that the phrase is a "term of art" having a plain meaning that encompasses both single- and dual-RNA species.  Broad relied on the Jinek reference for support, citing this figure:

accompanied by the caption "In this ternary complex, the dual tracrRNA:crRNA structure acts as guide RNA that directs the endonuclease Cas9 to the cognate target DNA" (emphasis in opinion).  Broad further supported this argument with expert testimony (consistent with Broad's interpretation of the figure) that:

The "ternary complex" refers to the three part complex that consists of (1) Cas9, (2) a mature crRNA molecule and (3) a tracrRNA molecule.  This is significant because "the dual tracrRNA:crRNA structure" makes up two parts of the three part complex.  Otherwise, Jinek 2012 would not have referred to the Cas9:RNA complex as a "ternary complex," but as a binary complex.  Thus, the "guide RNA" in that sentence references the dual-guide RNA consisting of separate strands of tracrRNA and crRNA.

The Board found other evidence from the Broad to be "less persuasive."  This included expert testimony evaluating CVC's specification in U.S. Serial No. 15/947,680 as reciting "[t]he term 'DNA-targeting RNA' or 'gRNA' is inclusive, referring both to double-molecule DNA-targeting RNAs and to single-molecule DNA-targeting RNAs (i.e., sgRNAs)," which the Board professed was not conclusive with regard to an interpretation that the meaning of "gRNA" meant "guide RNA."  Similarly, Broad's expert testified that CVC inventors used the term "guide RNA" inclusively to mean "all crRNA:tracrRNA complexes, whether present as a single or a double-molecule" in a scientific paper (Sternberg et al., 2014, "DNA interrogation by the CRISPR RNA-guided endonuclease Cas9," Nature 507: 62), but the Board stated that "without an explanation of how these specific instances of the terms would have been understood by those in the art at the time, we are not certain they demonstrate uses of 'guide RNA' as a generic term."  The same expert also cited CVC witness testimony from earlier Interference No. 105,048 that "guide DNA targeting RNA" includes either single- or dual-guide species, but the Board noted that this term is not the same as the "guide RNA" term as used in Broad's motions in this interference.  And the Board rejected out of hand similar statements by CVC counsel in the '048 interference, because counsel "is not one of skill in the art and we are not persuaded that his use of technical terms indicates anything about how they would have been understood by those in the art at the time."

The Board then turned to Broad's assertion of extrinsic evidence, including several contemporaneous scientific journal articles and references, all of which (being published prior to 2011) the Board found irrelevant.  In summary the Board states that:

We are not persuaded from the extrinsic evidence cited by Broad that the term "guide RNA" was well known in the art to mean either a single or a dual RNA molecule configuration.  In some publications cited by Broad, such as Jinek 2012, the term "guide RNA" is used to refer to a dual molecule RNA configuration.  But in other examples, such as CVC's '680 application and Drs. Geider and Carroll's declarations in the prior '048 interference, the specific term "guide RNA" was not actually used.  In yet other references, such as Bhaya, Horvath, Rand, and Tolia, the term is used, but not for a complex of the crRNA and tracrRNA.  This evidence does not persuade us that the term "guide RNA" had a plain meaning in the art, which "indisputably" included both single- and dual- molecule RNA configurations, as Broad argues.

From this determination that the term "guide RNA" was not understood to be generic at the time of Broad's filings, the Board states that it is not convinced that "the specification must provide a clear intent to exclude a dual-molecule RNA configuration from the term," citing Trs. of Columbia Univ. v. Symantec Corp., 811 F.3d 1359, 1363 (Fed. Cir. 2016), for an explication of the requirements under Phillips v. AWH Corp., 415 F.3d 1303, 1320 (Fed. Cir. 2005 (en banc), in this regard.  Broad cited a portion of its specification in support of its argument:

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.  The term "guide sequence" refers to the about 20 bp sequence within the guide RNA that specifies the target site and may be used interchangeably with the terms "guide" or "spacer".  The term "tracr mate sequence" may also be used interchangeably with the term "direct repeat(s)".  An exemplary CRISPR-Cas system is illustrated in FIG. 1.

Broad argued this portion of the specification referenced some (but not all) aspects of the invention to encompass single RNA guide RNA species.  Broad also argued that "used interchangeably" does not mean that the listed terms are themselves the same molecules.  CVC disputed these characterizations, arguing that "the specification specifically states that the terms 'guide RNA,' 'chimeric RNA,' 'chimeric guide RNA,' and 'single guide RNA' all 'refer to the polynucleotide sequence comprising the guide sequence, the tracr sequence and the tracr mate sequence.'"  And CVC further argued that "this portion of the specification defines "guide RNA" as a singular polynucleotide sequence comprising a guide sequence, a tracr sequence, and a tracr mate sequence and corresponding to the fused crRNA and the tracrRNA."

These arguments were persuasive to the Board, which stated that "this paragraph of the Broad specification indicates that 'chimeric RNA,' 'chimeric guide RNA,' 'single guide RNA,' as well as 'guide RNA' include these three components."

The Decision further explicated other portions of the various Broad specifications, to the same effect:  the Board is persuaded by CVC's arguments (or not persuaded by Broad's arguments) regarding the status of the term "guide RNA" as a generic term encompassing both single- and dual-RNA species.

The Board offers this conclusion regarding its construction of this sole term:

Our review of the parties' arguments leads us to the conclusion that Broad's use of the term "guide RNA" in its involved claims is not a generic term, but is limited to a single-molecule RNA configuration of the guide sequence and tracrmate, which together make the crRNA, and the tracrRNA sequences.  Although some dependent claims, such as claim 18 of the '359 patent, might indicate by claim differentiation that the term "guide RNA" is generic, that presumption is overcome by Broad's specification.  The specification of Broad's involved patents, specifically the sentence providing that "guide RNA" and other terms "refer to the polynucleotide sequence comprising the guide sequence, the tracr sequence and the tracr mate sequence" ('359 patent, Ex. 3011, 12:6–10), limits the interpretation of the term.  Broad fails to direct us to other uses of the term "guide RNA" in the specification that indicate a dual-molecule RNA configuration and we are not persuaded that the term was so clearly understood  the art to be a generic term that only a clear disavowal in the specification would define it to mean a single-molecule RNA configuration.  Thus, we are persuaded that the broadest reasonable interpretation of Broad claim term "guide RNA" encompasses only a single-molecule RNA configuration.

The consequences of this claim construction will be the subject of future posts.

*And then there is this ditty sung to the tune of "Camelot":

A law was made 200 years ago here
Grant patents, help promote inventive thought
Today the system's thriving and our credo
Is claim-a-lot

We push the envelope,
Expand the boundaries
Create a circle from a tiny dot
Our product's forged with words
and not in foundries
We claim a lot

Claim-a-lot (claim-a-lot)
I know it sounds a bit bizarre
Lord, we claim-a-lot (oh yes, we claim-a-lot)
Stretch out those claims so far

Though prior art may set some limitations
Restricts our flights of fancy, clever thought
Our efforts, not for naught
Results, so boldly wrought
Construct our patent juggernauts
By claiming quite a lot.

Kramer, Levin, Naftalis & Frankel LLP, Claim-a-Lot, in Pamphlet for N.Y. Intellectual Property Law Association 78th Annual Dinner (Mar. 24, 2000).