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).

By Kevin E. Noonan —

On September 10th, the Patent Trial and Appeal Board rendered its decision on the parties' Motions in Interference No. 106,115 (see "PTAB Decides Parties' Motions in CRISPR Interference").  Perhaps the decision of most immediate significance was the Board's decision denying the Senior Party's (The Broad Institute, Harvard University, and the Massachusetts Institute of Technology, collectively, "Broad") Substantive Motion No. 1, that Junior Party Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") should be estopped in this interference by the PTAB's decision in the earlier 105,048 interference between these parties.  What follows is a description and analysis of the Board's reasoning.

The Board is direct in denying Broad's Motion No. 1, saying they have not been persuaded by Broad's arguments.  Because the Board dissolved the '048 interference because there was no interference-in-fact, that judgment "neither cancel[ed] nor finally refuse[d] either parties' claims," citing its Judgment.  Accordingly, in the Board's view, "the resolution at the end of the '048 interference was that interference between the claims presented at that time did not deprive either party of its claims."  Broad's estoppel arguments are based on CVC losing rights to claims directed to eukaryotic embodiments of CRISPR; in the Board's view, the basis for its decision in the '048 Interference is contrary to Broad's characterization.

Turning to specifics, the Board addressed Broad's contention that Rule 127(a)(1) mandated its request relief.  The Board disagreed, noting that "[t]he prior CVC claims did not interfere with Broad's claims, whereas Broad does not contest that the currently involved CVC claims do."  Accordingly, "it is not clear that the subject matter of the interference is the same, even if the subject matter of Broad's claims is the same."  Evidentiarily, the Board's decision states that "Broad fails to provide a sufficient comparison of the subject matter of the two interferences to persuade us that the current interference is, or will be, the same subject matter of the '048 interference and will raise the same issues."  Specifically, the Board notes that "Broad fails to compare the count in the current interference, or Broad's proposed counts, with either parties' claims in the prior interference" and that "the current count in the current interference recites a limitation on the RNA configuration that is not recited in the count of the '048 interference."  The Board finds further fault with the Broad's arguments in support of its motion in that "whether the prior count and the current count are drawn to the same subject matter is a disputed issue, which is not sufficiently addressed in Broad's Motion 1."

Turning to Broad's argument that CVC is estopped under Rule 127(a)(1) because Junior Party did not request authorization to file a motion to add eukaryotic CRISPR embodiment claims in the '048 Interference, the Board agreed with CVC's argument that the first sentence of Rule 127(a)(1) does not mention estoppel, and that sentence is limited to decisions "disposing all issues of the proceeding."  A holding of no interference-in-fact, according to the Board, disposes of no issues other than whether there is an interference-in-fact and thus Rule 127(a)(1) does not apply.  Indeed, such a finding precludes the Board from deciding any other issue, states the opinion, citing Berman v. Housey, 291 F.3d 1345, 1352 (Fed. Cir. 2002).  Similarly unpersuasive was Broad's citation of PTO comments during the Notice-and-Comment period related to adoption of the current interference rules, because those comments were directed to interferences directed to the same subject matter and "Broad fails to persuade us that the current interference is for the same subject matter as the prior '048 interference."  And while not expressly agreeing with CVC, the Board cites the MPEP consistent with CVC's argument that "there is no losing party" resulting from a determination of no interference-in-fact.

Interference estoppel by judgment, according to the Board's opinion, "rests on the principle that a 'judgment in an action precludes relitigation of claims or issues that were . . . raised in [the earlier] proceeding,'" citing  In re Deckler, 977 F.2d 1449, 1452 (Fed. Cir. 1992).  Stating the Board's basis for its decision most distinctly, the opinion states that "Broad has failed to persuade us that under 37 C.F.R. § 41.127(a)(1) CVC is estopped because Broad fails to persuade us that the subject matter of the current interference is the same as the subject matter of the prior '048 Interference."

The opinion further asserts that the Board's application of its rules here are consistent with its responsibility under 37 C.F.R. § 41.1 "to secure the just, speedy, and inexpensive resolution of every proceeding before the Board."

And with regard to CVC's putative obligation or responsibility to move to file a motion adding claims to eukaryotic CRISPR embodiments in the '048 Interference, the Board noted that CVC had no claims in condition for allowance during that interference.  "Because the patentability of such claims to CVC was not certain at the time of the '048 Interference, we agree with CVC that allowing ex parte examination to conclude was preferable" according to the Board, noting that Broad itself had "expressed this view" in response to CVC's request to file a preliminary motion to add a claim and substitute a count in the '048 interference.  "Under the facts and circumstances of this interference, where UC believes all of its current claims interfere with all of Broad's claims, there is no reason why UC should need to add a new claim.  If UC's claims in other applications are ultimately found to be allowable, UC may suggest additional interferences to the examiner" (emphasis in opinion).

Under this reasoning the Board denied Broad's Motion No. 1 and then turned to the other motions filed by the parties, which will be discussed in future posts.