By Kevin E. Noonan —

On January 9th, Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") filed a Motion in Opposition to Senior Party The Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad") Substantive Motion No. 3 in support of the Patent Trial and Appeal Board ("Board") de-designating certain claims as not corresponding to Count 1 in Interference No. 106,155 as declared.

To recap, in its Motion No. 3, the Broad reiterated the arguments made in Motion No. 2, that there are two embodiments of CRISPR, one involving single-molecule RNA guide RNA that corresponds to Count 1 (which the Broad argues here is not recited in the claims it wants the Board to designate as not corresponding to the Count) and further that certain of the Broad's claims directed to "SaCas9" systems that require two or more nuclear localization signals (NLSs) do not correspond to the Count.  The Broad parsed the Broad's claims into three categories of claims that 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

• 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

And what would remain, should the Board grant this motion:

• U.S. Patent No. 8,697,359, claims 4, 11, and 18; U.S. Patent No. 8,795,965, claims 1-30 (all); U.S. Patent No. 8,771,945, claim 5; U.S. Patent No. 8,906,616, claims 2 and 5; and U.S. Patent No. 9,840,713, claims 8-9, 16, and 27

The Broad argued with regard to the first category of these claims (comprising the majority of the claims the Broad wants to have de-designated) that the Count of the interference as declared is directed to "single-molecule guide RNA molecule" embodiments of CRISPR that do not encompass these single-molecule guide RNA embodiments and thus do not corresponding to the Count.  The brief sets forth the Broad's understanding that, should the Board deny the Broad's Substantive Motions Nos. 1 and 2, then the interference will involve priority to such single-molecule guide RNA embodiments as a separate, patentable invention over claims that encompass both single-molecule and dual molecule embodiments (termed "generic guide" embodiments in the brief).  The Broad argues that its claims limited to dual-molecule embodiments do not correspond to the Count and the Board should so designate.

The Broad asserts as reasons/justifications for de-designating certain (most) of its claims:

• Count 1 is limited to the single-molecule invention, and would not be determining priority to generic, non-limited RNA embodiments of CRISPR, "violating" the "'primary purpose of an interference'" to make a priority determination of "each of the common [patentably distinct] inventions claimed by the parties,'" citing Godtfredsen v. Banner, 598 F. 2d 589, 592 (C.C.P.A. 1979).  The brief takes the opportunity to reiterate the unfairness of this outcome in view of the nature of their invention, e.g., a "breakthrough invention that revolutionized gene editing was the successful engineering of CRISPR-Cas9 systems for use in eukaryotic cells."

• There can be no interfering subject matter between the single-molecule RNA "invention" and generic, non-limited RNA CRISPR embodiments.  Under these circumstances, the brief argues a two-count interference should be declared with each invention to reiterate its allegation that CVC had made a strategic decision not to present claims to eukaryotic embodiments of CRISPR in the earlier, '048 interference.

• It would be unfair to put all the Broad's claims at risk under these circumstances because it would "t[ie] its hand to its best generic RNA proofs," which the brief characterizes as being "particularly egregious given that Broad could have relied on its best proofs during the 048 Interference, when the Count properly reflected the scope of the parties' claims."

The Broad also argued that its claims to SaCas9 embodiments and to claims requiring two or more nuclear localization sequences (NLS's) do not correspond to Count 1.  The Broad argues that these embodiments were not disclosed in the prior art and "provide[] a surprising combination of benefits not taught or suggested by the art" for both types of embodiments.

CVC's argument centers on proper application of Rule 207(b)(2):

A claim corresponds to a count if the subject matter of the count, treated as prior art to the claim, would have anticipated or rendered obvious the subject matter of the claim.  37 C.F.R. §41.207(b)(2).

This is the standard, and CVC argues first that on this basis the Board should deny the Broad's motion, and moreover that the Broad had not satisfied its burden that it is entitled to the relief requested under 37 C.F.R. §§ 41.121(b) and 41.208(b).  And the Broad will not be able to meet this burden, CVC argues, because a claim to a species (single-molecule guide RNA CRISPR embodiments) anticipates a claim to a genus (generic-guide RNA CRISPR embodiments), citing In re Gostelli, 872 F.2d 1008 (Fed. Cir. 1989).

CVC further parses the language of the Rule to distinguish that this section does not set forth a (rebuttable) presumption despite the title of this rule being "Presumptions."  CVC draws a parallel with Rule 207(a), wherein subsection (1) sets forth the presumptions and subsection (2) sets forth the standard (for priority in subsection (a) and for claim correspondence in subsection (b)); the brief recited several citations to case law to support this interpretation, including Yorkey v. Diab, 601 F.3d 1279, 1286-87 (Fed. Cir. 2010), citing Bosies v. Benedict, 27 F.3d 539, 541 (Fed. Cir. 1994); and Brown v. Barbacid, 276 F.3d 1327, 1333 (Fed. Cir. 2002).  In addition, the brief asserts that a plain text reading of Rule 207(b)(2) is enough and controlling with regard to the Board's decision, citing Octane Fitness LLC v. ICOM Health & Fitness, Inc., 572 U.S. 545, 553 (2014), and the Standing Order Para. 208.3.2.  The brief also counters the Broad's arguments regarding comments made during rulemaking, that such comments cannot override the text of the rule, citing two Executive Orders from the Trump Administration (E.O. 13891, Promoting the Rule of Law through Improved Agency Guidance Documents, 84 Fed. Ref. 55235 (Oct. 15, 2019) and 13892, Promoting the Rule of Law through Transparency and Fairness in Civil Administrative Enforcement and Adjudication, 84 Fed. Reg. 55239 (Oct. 15, 2019)).

CVC counters the Broad's arguments that the Board should grant its Motion No. 3 because Count 1 does not correspond to its "best proofs" because, inter alia, the Broad hasn't offered any evidence that it has better proofs that it would be able to offer under Count 1.  CVC also asserts that the Broad assumes, without proving or even arguing, that the generic-guide claims are patentably distinct over single-molecule guide embodiments of CRISPR.  In addition, CVC argues that the Broad's assertion of this argument is inconsistent with the Broad's argument in its Substantive Motion No. 2 that claims to single-molecule guide embodiments of CRISPR are not patentably distinct over generic-guide embodiments.  "Broad cannot have it both ways," says CVC with regards to these allegedly inconsistent arguments.  Further, with regard to the Broad's "best proofs" argument, CVC contends that it is fair to have all the Broad's claims stand or fall in this interference because the Broad has not established its "best proofs" argument and it has the burden to do so to be entitled to the relief of de-designating the claims.

Turning to the Broad's expert testimony, CVC asserts that the Board cannot, and should not rely on the Broad's experts because these experts did not review documentary evidence supporting the Broad's assertions that the Broad inventors practiced generic-guide RNA CRISPR in 2011 (prior to CVC's earliest priority date), as the Broad alleges in its motion.  There are also contradictions, according to CVC, between what the expert testified is disclosed in an NIH grant proposal in this interference and what the Broad declared before the USPTO during ex parte prosecution of USSN 14/704,551 regarding this document.  The declarations submitted during prosecution were the basis for the Examiner to determine that the Broad could antedate CVC's earlier single-molecule guide RNA disclosures and thus were patentable over them.  And CVC contends that the Board should consider these declarations in ex parte prosecutions to be admissions.  The brief also argues that judicial estoppel precludes the Broad from relying on the purportedly contradictory expert testimony, citing Zedner v. U.S. and setting forth how circumstances in this interference satisfy the Supreme Court's Zedner test.  Specifically, estoppel should lie when a party's legal position is "clearly inconsistent with" a prior position; the party prevailed based on its prior position; and the opposing party (here, CVC) would be clearly disadvantaged, imposing an unfair detriment against them, by permitting a party to take a position in this proceeding contrary to its position in the earlier proceeding.  All those factors align in CVC's favor, according to their brief, under circumstances regarding the position the Broad has taken with regard to this brief in this interference and the contrary position taken by Senior Party during ex parte prosecution.

These circumstances also seem to put the Broad's experts in a bad position because they were not given access to information that might have reduced or eliminated their ability to make the representations they did in their testimony in this interference, including ones showing that Broad inventors had not been able to practice CRISPR in eukaryotic cells in the June 2012 timeframe.

CVC notes (in a "sauce for the goose" manner) that should the Board determine that the Broad's generic-guide claims be de-designated, then CVC's generic guide claims should be de-designated as well, requiring the Board to provide another interference count or declare another interference.  However, the presumption is that the PTAB properly designated the claims corresponding to the count and the burden is on a party requesting de-designation relief to establish they are entitled to such relief.  Much of these issues depend on claim construction, and according to CVC the term "guide RNA" did not have a plain and ordinary meaning but was dependent on definitions in the Broad's specification(s) that don't support Broad's construction.  Furthermore, the Broad's arguments in this regard should fail, according to CVC's brief, because all the claims recite "chimeric" RNA which comprise single-molecule embodiments, citing definitions in the specifications of the Broad's patents and applications in interference.

With regard to the Broad's arguments concerning S. aureus Cas9 claims and claims reciting multiple nuclear localization signal (NLS), that the Broad argues should be de-designated as not corresponding to Count 1, CVC makes its case that these proteins were known in the art and their smaller size and capacity to be introduced using adeno-associated virus (AAV) vectors would have motivated a person of ordinary skill in the art (POSA) to use them for eukaryotic CRISPR and further that there would be a reasonable expectation of success in doing so.  CVC also makes a detailed case with regard to why the Sa Cas9 species are not patentably distinct, and makes similar arguments regarding CRISPR embodiments comprising multiple NLS species.

Finally, throughout the brief CVC reiterates the theme that the Broad's motions are all attempts to avoid having the Board determine priority of eukaryotic cell embodiments of CRISPR.

By Kevin E. Noonan —

Continuing explication of the motions submitted on January 9th to the U.S. Patent and Trademark Office Patent Trial and Appeal Board in Interference No. 106155 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") is CVC's Motion No. 2 in Opposition to the Broad's Substantive Motion No. 2 to Substitute the Count.

To recap, the Broad's Substantive Motion No. 2 seeks to have the Board substitute the Count in the interference.  Count 1 of the interference as declared is:

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.

or

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.

The Broad's proposed Count 2 is:

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 the Broad makes is 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).  The Broad argues that this Count 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 argues 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 The Broad contends current Court 1 (in either alternative) does not.

The brief also requests that the Broad be accorded benefit to its provisional application U.S. Serial No. 61/736,527, and that CVC not be accorded benefit to any of its earlier applications (which just maintains the status quo requiring CVC to move to be accorded benefit), because CVC's applications-in-interference were not accorded benefit when this interference was declared.

The Broad's argument in support of its motion is that Count 1 is too narrow for encompassing just a subset of the parties' involved claims.  In particular, the brief asserts that most of the Broad's involved clams encompass "non-limited" RNA systems and methods.  Similarly, the brief argues that CVC itself has many claims directed to non-limited RNA systems and methods and has entire applications that do not recite claims to non-limited RNA systems and methods.  The Broad asserts that Count 1 does not permit the Broad to rely on its earliest and best proofs of invention, which the brief states is "plainly unfair."  This unfairness would preclude the Broad from establishing what the brief terms "the fundamental breakthrough – the invention of use of CRISPR in eukaryotic cells" (emphasis in brief).  Failing to substitute the Count would instead improperly focus the priority question on who invented the single molecule modification.  Colorfully, the brief declares that "[a]llowing the interference to proceed with Count 1 would permit the (single molecule RNA) tail to wag the (breakthrough use of CRISPR in eukaryotic cells) dog."

The claims include such generic species that encompass both single-molecule and dual molecule embodiments, according to the brief, but the breakthrough invention was adapting CRISPR-Cas9 to be used in eukaryotic cells, an argument the Broad has used consistently here and in the earlier '048 interference to distinguish its claims from CVC's.  The brief notes that the first disclosure of this use was in a scientific journal article by some of the Broad's named inventors that "has become by far the most frequently cited CRISPR publication" as evidence of the groundbreaking nature of the invention.  Also cited (as a reminder to the Board of its earlier decision, the basis thereof and the Federal Circuit's affirmance of it) is the Board's earlier decision that there was no reasonable expectation of adapting CRISPR for use in eukaryotic cells as further evidence of the breakthrough nature of (as asserted herein) the Broad's invention.

CVC's brief begins by characterizing the Broad's argument that Count 1 of the interference as declared "potentially' exclude Broad's best proofs relating to dual-guide (i.e., dual-molecule) experiments" is a "pretext," because, inter alia, Proposed Count 2  "goes far beyond converting Count 1 into a generic-guide count."  Instead, according to CVC, "it transforms Count 1 into a method so broad that it no longer requires formation of the DNA-targeting complex that includes crRNA, tracrRNA, and Cas9."  In addition, according to CVC, Proposed Count 2 does not require that the CRISPR-Cas9 complex even have an effect on the target DNA; rather, it recites that "'a product of the DNA' is altered in some unspecified way" (emphasis in brief), which could include (according to CVC) "alterations to RNA or protein caused by processes that are unrelated to the activity of CRISPR-Cas9" including contamination.  And the changes the Broad has effected in Proposed Count 2 "have nothing to do with whether the RNA limitation is single-molecule or generic, Broad's only purported reason for needing a new count."

CVC further argues that the Broad's motion is contrary to the provisions of  precedential Board decision, Louis v. Okada, 59 U.S.P.Q.2d 1073 (B.P.A.I. 2001).  Under Louis, a party must satisfy a three-prong test:  "'(1) should make a proffer of the party's best proofs, (2) show that such best proofs indeed lie outside of the scope of the current count, and (3) further show that the proposed new count is not excessively broad with respect to what the party needs for its best proofs.'"  CVC's position (explicated in the brief) is that the Broad failed to provide what Louis required for the "significant alterations" made to Count 1 resulting in Count 2.  In addition, CVC argues that the Broad has not shown that Count 1 excludes their best proofs, equivocating in using characterizations like its best proofs only potentially fall outside the scope of Count 1.  And CVC alleges that the Broad's representations to the Board regarding its best proofs including dual-guide experiments are contradictory to ("flatly contradicts") positions the Broad has taken in ex parte prosecution.  And CVC characterizes these prior statements as admissions that preclude the Broad from advancing these arguments in this interference.

In arguing the specifics of what CVC alleges are the Broad's deficiencies in satisfying the Louis standards, CVC quotes the case to the effect that there must be "'a genuine need to change the count, and not simply cause a change for change's sake'" that cannot be supplied outside the brief supporting the motion under 37 C.F.R. § 41.121(b) and 37 C.F.R. § 41.208(b).  The changes in Proposed Count 2 "significantly alter the scope of Count 1 in ways that go far beyond encompassing dual-molecule CRISPR-Cas9."  The brief provides a table:

The brief summarizes these unnecessary changes as"

• "first, Broad has inexplicably eliminated structural and functional limitations that specify the formation of the three-component DNA-targeting complex that includes crRNA, tracrRNA, and Cas9."

• "Second, Broad has inexplicably eliminated the requirement that this complex have activity with effects at the DNA level (e.g., cleaving or editing or modulating transcription of DNA).  Rather, Proposed Count 2 encompasses merely altering a "product of the DNA molecule" in unspecified ways. Problematically, this breadth includes alterations to downstream products of DNA, such as RNA and protein, that have nothing to do with the activity of the CRISPR-Cas9 system."

• "Third, Broad has inexplicably converted Count 1 from a 'cell' or 'system' to a 'method.'"

• "Fourth, Broad has inexplicably eliminated the alternative language in CVC's part of Count 1 reciting 'or a nucleic acid comprising a nucleotide sequence comprising . . . .'"

CC's brief characterizes as "thread-bare" the Broad's justifications related to its best proofs including use of dual-molecule guide RNA for practicing CRISPR in eukaryotic cells, and argues that the Broad's experts "turned a blind eye" the these differences between Count 1 and Proposed Count 2, "testifying that the only difference they considered was with respect to the single-molecule or generic format of the RNA."  According to CVC's brief, the Broad could have achieves its purported "best proofs" goal by proposing a McKelvey Count reciting Claim 15 of the '359 patent:

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.

CVC also argues that Proposed Count 2 "does not specify that the DNA-targeting complex contains: (a) the first RNA and the second RNA; or (b) the targeter-RNA and the activator-RNA" (emphasis in brief), instead requiring only that "the targeter-RNA or the first sequence directs the Cas9 protein to the target sequence," an interpretation that CVC demonstrates Broad's experts did not dispute despite the reality that all three components are necessary for the DNA targeting complex.  And CVC points out that Proposed Count 2 is consistent with the understanding in the art prior to publication of the Jinek 2012 reference that corresponds to disclosure of CVC's earliest priority document (A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity, Science 337: 816-21).

CVC reiterates its argument that Proposed Count 2 does not require CRISPR-Cas9 to exhibit DBA-altering effects due to its excessive breadth, again affirmed (or at least not effectively rebutted" by the Broad's experts.  Moreover Proposed Count 2 changes the count from being directed to a eukaryotic cell or a CRISPR system to a method, which CVC characterizes as "change for change's sake" and that "without justification" Count 2 deletes limitations related to "a) Cas9 protein, or a nucleic acid comprising a nucleotide sequence encoding the Cas9 protein," [CVC-2], and "b) a single molecule DNA-targeting RNA, or a nucleic acid comprising a nucleotide sequence encoding said single molecule DNA targeting RNA," [CVC-3].  Citing Louis, CVC argues that the Broad has not shown a "compelling reason" for the proposed changes making Proposed Count 2 broader than Count, and that the proposed Count is "broader than the parties' common invention," citing Conservolite, Inc. v. Widmayer, 21 F.3d 1098, 1104 (Fed. Cir. 1994).

Finally, CVC argues that the Broad's claims in interference all recite "single-molecule RNA" embodiments of CRISPR, which defines the "common interfering subject matter" and thus rebut the Broad's arguments regarding its best proofs for dual-molecule RNA embodiments.  The brief accuses the Broad of equivocating regarding its best proofs, also contrary to the requirements in Louis and that the Broad's "alleged best proofs" do not justify substitution of Count 1 with Proposed Count 2 and deficiencies in the Broad's expert testimony supporting its position.  These deficiencies include characterization of the prior art that contradict statements and positions taken by the Broad (according to CVC) during ex parte prosecution which CVC asserts are admissions that prevent the Broad from making these assertions in support of its motion to substitute the Count.

CVC further asserts that the Broad has not shown that Proposed Count 2 is patentable over the prior art, as set forth in another table:

From this CVC concludes "[b]ecause these numerous unexplained broadening alterations raise "a serious question" with respect to the patentability of Proposed Count 2, Broad has not satisfied its burden to address patentability over the art," citing Louis.

As an alternative, CVC argues that, if the Board adopts what the brief calls "a generic-guide count," Count 1 should remain in the interference because it is patentably distinct from Proposed Count 2, supported by the differences in limitations as set forth in the remainder of the brief.