On March 23rd Senior Party The Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad") filed its Reply to Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") Motion No. 2 in Opposition to Broad's Substantive Motion No. 2 to Substitute the Count.

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 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 proceedingsthe successful adaption of CRISPR-Cas9 systems for use in eukaryotic environments," which Broad contended current Court 1 (in either alternative) does not.

Broad's argument in support of its motion was that Count 1 is too narrow for encompassing just a subset of the parties' involved claims. In particular, the brief asserted that most of Broad's involved clams encompass "non-limited" RNA systems and methods. Similarly, the brief argued 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. Broad asserted that Count 1 does not permit Broad to rely on its earliest and best proofs of invention, which the brief stated is "plainly unfair." This unfairness would preclude Broad from establishing what the brief termed "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 declared 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."

CVC in its Opposition argued that 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" according to CVC.

CVC further argued 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.

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 "productof 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 'ora nucleic acid comprising a nucleotide sequence comprising . . . .'"

CVC further asserts that the Broad has not shown that Proposed Count 2 is patentable over the prior art.

In its Reply, Broad asserts that CVC did not dispute that the "major advance" at issue is which party invented successful CRISPR in eukaryotic cells, and that this "breakthrough" was not limited to single RNA embodiments of the technology. The brief asserts that current Count 1 "precludes reliance on dual-molecule proofs" (unfairly to Broad) but at the same time this Count "puts at risk all of Broad's claims," which might be considered paradoxical until it is realized that Broad submitted other Motions asking that many if not most of Broad's claims would not correspond to Proposed Count 2.

The brief characterizes CVC's arguments as "nitpick[ing]" and alleges that in CVC's interpretation CRISPR as recited in Count 1 is "so broad it no longer requires a targeting complex 12 that includes crRNA, tracrRNA, and Cas9" (an interpretation that CVC's expert allegedly does not share, which would be curious at least). But even though Broad characterizes these nitpicks as "immaterial" it states that "addressing them would require only small adjustments that could easily be adopted sua sponte by the PTAB." With regard to CVC's purported attempt to limit the scope of the interference to single-molecule embodiments, Broad also asserts that CVC's argued that Broad's 2011 experiments were limited to such embodiments, again arguing that CVC's expert testified to the contrary and characterizing CVC's assertions as being "only attorney argument." The basis for CVC's incorrect arguments in this regard Broad asserts to be an incorrect interpretation of the term "guide RNA" as being limited to single-molecule RNA species.

Broad's synopsis of its reasons for its Motion No. 2 should be granted is:

Broad requests the PTAB to adopt Proposed Count 2 to ensure that, should this interference go forward, claims directed to the broad invention of use of CRISPR-Cas9 in eukaryotic cells, as at issue here, are awarded to the party that first invented use of CRISPR-Cas9 in eukaryotic cells. CVC seeks an interference where claims to use of CRISPR-Cas9 in eukaryotic cells (regardless of type of RNA used) are awarded not to the first inventor of that subject matter, but rather to the party that first created one specific embodiment for which CVC believes it has the best proofs (a single-molecule RNA embodiment). Failing to substitute a generic count for Count 1 would be unjust to Broad and antithetical to the purpose of the Interference, to determine "which of the competing parties was the first to invent the duplicative subject matter." Eli Lilly & Co. v. Bd. of 15 Regents of Univ. of Wash., 334 F. 3d 1264, 1267 (Fed. Cir. 2003) [all emphasis in brief].

Turning to specific arguments against particular features of CVC's brief with which Broad takes issue, the brief (as it must) cites these particular arguments chapter and verse (or more accurately, page and line). The first is that all Broad's claims are directed towards single-molecule embodiments, supported according to Broad solely by attorney argument. Broad argues that both parties have involved claim "indisputably directed to generic RNA guides" (i.e., both single- and dual-molecule guide RNA embodiments). Broad asserts that CVC's misinterpretation of "guide RNA" ignores the plain meaning and "misreads the intrinsic evidence," despite (according to Broad) the use of the term in the Jinik 2012 reference (which Broad states was "perhaps the most important CRISPR publication up to that point and widely read by skilled artisans") as referring to the naturally occurring guide RNA. Broad also asserts that CVC misinterpreted disclosure in its involved patent, which disclosure "does not rise to an 'expression of manifest exclusion or restriction, representing a clear disavowal of claim scope,'" citing Thorner v. Sony Computer Entertainment America LLC, 669 F.3d 1362, 1366 (Fed. Cir. 2012).

The brief also broadly characterizes CVC's criticisms of Proposed Count 2 as "baseless" regarding the four "alleged" differences that "have nothing to do with the single-molecule format of the RNA." Broad says in response that its Proposed Count 2 is "materially the same" as current Count 1 with regard to these four aspects, enumerating the its differences with CVC's interpretation for each:

First, that Proposed Count 2 requires contacting a DNA target with all three components of the CRISPR system (Cas9, crRNA, and tracrRNA) (citing "specific language" of Proposed Count 2 in support);

Second, that Proposed Count 2 requires the occurrence of effects at the target DNA ("cleaving or editing or modulating transcription of DNA") (again relying heavily on CVC's expert's testimony purportedly contrary to CVC's arguments);

Third, that the change from "cell" or "system" in Count 1 to "method" is "immaterial":

Fourth, that eliminating language in Count 1 from Proposed Count 2, recited in the alternative, "a nucleic acid comprising a nucleotide sequence" does not narrow the Count.

Broad also argues that CVC's allegation that Proposed Count 2 is broader than the claims in interference is "based on its erroneous interpretation" of the Proposed Count, which is that the Count does not require tracr RNA (which Broad asserts it does).

With regard to Broad's burden in being granted the relief requested by the PTAB, Broad argues that CVC's challenge regarding Broad's "best proofs" corresponding better to Proposed Count 2 than the current Count are "legally and factually incorrect." Broad supports this allegation by returning to its earlier argument that CVC was wrong in asserting that Broad's earliest eukaryotic application of CRISPR technology was performed with single-molecule guide RNA (calling it "meritless"). The brief sets forth a portion of Inventor Zhang's declaration to illustrate the point:

As Broad argues, this diagram shows three components of CRISPR: Cas9, and separate tracr and crRNAs.

The brief also challenges CVC's argument that Broad had not shown its best proofs are outside the scope of Count 1 (as it is required to so to obtain the requested relief) and that CVC is wrong to assert that Broad was obligated to prove its dual-molecule guide RNA experiments before its single-molecule guide RNA experiments.

The brief specifically addresses CVC's citation of Louis v. Okada, 59 U.S.P.Q.2d 1073 (B.P.A.I. 2001), by asserting that Louis explicitly was not adopted as part of the Board Rules despite a proposal to do so and even if CVC was correct Broad's proffer was sufficient under the rules the PTAB actually adopted.

Finally, Broad argues that CVC did not establish that Broad had failed to show Proposed Count 2 to be patentable; that CVC had not even contested that Broad is not entitled to the benefit of the Zhang B1 reference (its earliest provisional application); and that contrary to CVC's argument a single-molecule Count would not be patentably distinct from a non-limited count.

Follow this link:
Broad Reply No. 2 to CVC's Opposition No. 2 to Broad's Motion No 2 to Substitute the Count - JD Supra

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