By Kevin E. Noonan —

On May 20th, Junior Party the University of California, Berkeley; the University of Vienna; and Emmanuelle Charpentier (collectively, "CVC") filed its Substantive Preliminary Motion No. 3 in Interference No. 106,127 (which names ToolGen as Senior Party), asking the Patent Trial and Appeal Board to add claims in ToolGen's U.S. Patent No. 10,851,380* to this interference, pursuant to 37 C.F.R. §§ 41.121(a)(1)(i) and 41.208(a)(2) and Standing Order ¶ 208.3.2.  On July 5th ToolGen filed its Opposition.  On August 27th, CVC filed its Reply.

In its Motion No. 3, CVC argued that the only difference between the language of the Count and the claims in the '380 patent is that those claims require the addition of two guanine residues ("GG") positioned before the crRNA portion of the sgRNA sequence.  CVC argued that these species of sgRNA (the fusion of crRNA and tracrRNA) recited in the '380 patent claims were solely a consequence of using the T7 phage RNA polymerase to produce sgRNA, and that in vitro RNA production using T7 RNAP promoters was well-known in the art ("for decades"; emphasis in brief) at the priority date of the '380 patent; these arguments are supported by testimony from CVC's expert, Dr. Scott Bailey and this method of producing sgRNA and relevant prior art disclosing the use of T7 RNAP and promoters recognized by the polymerase was set forth in the brief.

CVC argued that the distinction of including two guanine residues in crRNA and sgRNA comprised thereof is not enough to distinguish the claims of the '380 patent from the Count in this interference (to which CVC argues these claims correspond) because "including a 5'-GG would have been obvious over Count 1 in view of [CVC's] Jinek 2012" reference as illustrated above, which reliance is permitted under Desjardins v Wax, Interference No. 105,915, Paper 127, 17-20 (P.T.A.B. Jan. 21, 2014).  Regarding motivation to combine the teachings of the Jinek reference in this regard with the more general teachings of producing an sgRNA for eukaryotic CRISPR, CVC argued that such motivation is supported by the method's "low cost, efficiency, and accuracy," and because "Jinek 2012 had already used the method to generate RNAs that effectively cleave eukaryotic DNA sequences (e.g., GFP) in CRISPR-Cas9 systems (i.e., ToolGen knew the method would be successful in eukaryotic CRISPR).  This success also would have provided the requisite reasonable expectation of success to complete a prima facie case of obviousness and hence for the '380 claims to properly be determined to correspond to the Count in this interference.

ToolGen argued in its opposition that the claims of the '380 patent do not correspond to Count 1 of this interference and that CVC's motion did not comply with the requirements of 37 C.F.R. §§ 41.202 and 41.203.  With regard to the substantive question, ToolGen's brief focused on whether the Count would render those claims obvious (because the lack of the two guanine residues positioned before the crRNA portion of the sgRNA sequence in the Count precludes anticipation, i.e., each and every limitation in the claim is not found therein).  And, ToolGen contended, Count 1 alone cannot render the '380 patent claims obvious (and CVC did not so argue).  Thus, the issue was whether the combination of the language of the Count and the disclosure of the Jinek 2012 reference raises a prima facie obviousness case, which ToolGen maintained it does not.  ToolGen's reasoning was that, at the priority date of the '380 patent (October 23, 2012), "(1) a POSA would not have been motivated to combine Count 1 and Jinek; (2) a POSA would not have had an expectation of success in implementing the CRISPR/Cas9 system of independent claim 1 in eukaryotic cells; and (3) the claims of the '380 patent exhibit superior properties and advantages that a POSA would have found surprising or unexpected."  ToolGen's reasoning reiterated in part the argument raised in its opposition to CVC's Preliminary Motion No.2, that Jinek describes uses of prokaryotic CRISPR-Cas9 in a "non-cellular, experimental environment," citing the Board's decision in Interference No. 105,048 and the Federal Circuit's affirmance thereof.  Further, ToolGen argued that the Jinek 2012 reference does not describe any experiments using CRISPR in eukaryotic cells nor introduction of CRISPR complexes into such cells.  Finally, ToolGen cited the PTO's determination during prosecution of the '380 patent that Claim 1 of the '380 patent was non-obvious over the Jinek 2012 reference which is binding here they contended, citing Harris Corp. v. Fed. Exp. Corp., 502 F. App'x 957, 968 (Fed. Cir. 2013), and Glaxo Grp. Ltd. v. Apotex, Inc., 376 F.3d 1339, 1348 (Fed. Cir. 2004).

ToolGen also challenged CVC's contention that the skilled worker would have been motivated to combine the teachings of the Jinek 2012 reference with the subject matter of Count 1 in support of a prima facie obviousness case.  The basis for this argument was that "nothing in the prior art—cited by CVC or otherwise—'suggest[s] the desirability' of RNA transfection—a method necessitated by Jinek—as a method of introducing sgRNA (or 'guide RNA') into eukaryotic cells as of the priority date" (emphasis in brief), citing In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004), and Forest Labs., LLC v. Sigmapharm Labs., LLC, 918 F.3d 928, 22 934 (Fed. Cir. 2019).  This argument was based on the limitation recited in Count 1 to a method for "introducing into [a] eukaryotic cell" a CRISPR-Cas9 complex comprising an sgRNA.  Jinek's disclosure in limited to a method for preparing RNA by in vitro transcription (emphasis in brief) and this RNA would be understood by the skilled worker to be introduced into eukaryotic cells using RNA transfection techniques, ToolGen asserts, which were not routinely employed in the art.  And ToolGen argued the Jinek 2012 reference provided no disclosure (being "entirely silent" on the question) regarding RNA transfection that would overcome these limitations in the prior art (this argument being supported by copious citations to that art).

ToolGen also argued that the prior art, including the Jinek 2012 reference, did not disclose any reason to introduce two guanine residues before the crRNA portion of the sgRNA sequence, asserting that it was the '380 patent inventors who first discovered that doing so resulted in greater specificity.  Accordingly, ToolGen stated, "as of the priority date, a POSA would have understood the Jinek method as having inherent limitations, i.e., the requirement of one or more guanines at the 5' end, without any known benefit."  Indeed, ToolGen made the case that the state of the prior art would have preferred using eukaryotic promoters, such as the U6 promoter, as part of a DNA plasmid encoding sgRNA as the preferred method for producing (rather than introducing using RNA transfection methods fraught with known difficulties) sgRNA in a eukaryotic cell for achieving CRISPR in such a cell.  (After all, ToolGen noted that CVC's own application, filed three months after the '380 patent's priority date, utilized plasmids encoding sgRNA expressed using a eukaryotic promoter to produce RNA in a eukaryotic cell.)

ToolGen next turned to CVC's argument that the skilled worker would have had a reasonable expectation of success in combining the Jinek 2012 reference with the limitations of Count 1 to achieve CRISPR in a eukaryotic cell.  ToolGen bluntly asserts such a POSA would not have had such a reasonable expectation of success because it had been established by the Board, and affirmed by the Federal Circuit, "that as of 5 December 2012—two months after the priority date—a POSA 'would not have reasonably expected success' in implementing CRISPR/Cas9 in eukaryotic cells" by any means.  ToolGen refers to "a similar argument" made by CVC in Interference No. 106,115 (against Broad) and CVC's reliance on the Board distinguishing its decision in the '048 interference as meaning that "[e]xpectation of success in eukaryotes would not be in doubt" as of the priority date.  CVC is incorrect, ToolGen argued, because it ignored the distinctions regarding the limitations in Count 1 (which under 37 C.F.R §41.207(b) is considered prior art) and the "problematic nature of RNA transfection as of the priority date" arising in the context of this interference.  Under the prior art presumption regarding the Count, ToolGen argued, "to interpret §41.207(b) as providing for an assumption of a reasonable expectation of success—as CVC suggests—would be inconsistent with the plain language of the rule and Board precedent" and "such an interpretation would effectively nullify the requisite obviousness analysis of §41.207(b)."  Nor does the routine nature of producing RNA in vitro using T7 promoter and polymerase support a reasonable expectation of using such RNA to achieve CRISPR in eukaryotic cells as CVC argues in its Motion No. 3, ToolGen asserted.

Finally, in this regard ToolGen contended that the invention claimed in Claim 1 of the '380 patent "exhibits superior properties and advantages that a POSA would have found surprising and unexpected as of the priority date."  Specifically, these include that having two guanine residues positioned before the crRNA portion of the sgRNA "discriminated off-target sites effectively," an improvement over a recognized drawback.  ToolGen relied on the non-obviousness of Claim 1 of the '380 patent in support of its contention that Claims 2-10 are also non-obvious when considered in view of the Jinek 2012 reference in combination with the limitations recited in Count 1 and thus the Board should deny CVC's motion to designate them as corresponding to the Count and including them in this interference.

In its Reply, CVC argues legal and evidentiary errors by ToolGen in reiterating the arguments made in CVC's Preliminary Motion No. 3. Ironically, CVC relies extensively on the Board's decision in the '115 Interference (Regents of the Univ. of Cal. v. The Broad Inst., Inc., Interference No. 106,115, 13 Paper 877, 66 (P.T.A.B. Sept. 10, 2020)) in support of its arguments that the '380 patent claims would have been obvious over the combination of the Jinek reference and Count 1.  Further, CVC argues that ToolGen improperly ignored (or at least did not rebut) its argument that direct methods for introducing CRISPR into eukaryotic cells (microinjection and RNA transfection) were known in the art and consistent with in vitro production of sgRNA by T7 RNA polymerase, which produces the added GG dinucleotides characteristic of ToolGen's methods claimed in the '380 patent.  CVC's arguments depend at their core on the legal fiction that the Count is in the prior art under Rule 207(b)2), because under those circumstances the issue is one CVC contends is no different from the factual predicate the Board applied in the '115 interference.  Under these circumstances CVC reiterates earlier arguments in its Motion that the combined teachings of Jinek and the Count would render obvious ToolGen's '380 patent claims because synthesizing sgRNA using T7 polymerase (and thus having the resulting sgRNA comprise the GG dinucleotide at its 5' end) and using microinjection or RNA transfection were known in the art and would have created a reasonable expectation of success.

CVC cites (undoubtedly with ironic satisfaction) the PTAB's refutation of similar arguments by Senior Party Broad in the '115 Interference that relied on the Board's decision in the '048 Interference:  "We are not persuaded by Broad's argument because the issue in the prior ['048] interference was whether a CRISPR-Cas9 system would have been expected to work in a eukaryotic cell. That issue is assumed under the framework of 37 C.F.R. § 41.207(b)(2), wherein Count 1 is presumed to be prior art to the Broad claims" (emphasis in brief).  And the fact that ToolGen overcame citation of the Jinek 2012 reference during ex parte prosecution is irrelevant, CVC argues, because those arguments did not concern obviousness in view of the recitations in Count 1 being considered part of the prior art.  Accordingly, CVC contends that "the PTAB should reject ToolGen's argument because it is fundamentally no different than Broad's failed argument in the '115 Interference."

CVC rebuts ToolGen's arguments regarding whether the skilled worker would have used plasmid-based methods for producing sgRNA in a eukaryotic cell by citing Apple Inc. v. Samsung 10 Electronics Co., Ltd., 816 F.3d 788, 801-802 (Fed. Cir. 2016), for the rubric that "a motivation to use the teachings of a particular prior art reference need not be supported by a finding that that feature be the 'preferred, or the most desirable.'"  CVC also argues that ToolGen's reference to which method of producing sgRNA and introducing CRISPR-Cas9 into a eukaryotic cell were more advantageous is also irrelevant in view of the teaching in the Jinek 2012 reference that "production and introduction of in vitro-transcribed RNA as described in Jinek 2012 was well-established, quick, cost-effective, and accurate."  Moreover, CVC cites expert testimony (from their own experts and, perhaps grudgingly, from ToolGen's expert) that introducing RNA into a eukaryotic cell by RNA transfection or microinjection were "routine" and "fairly standard" methods (supported, CVC notes, by "the pre-2012 availability of various commercial transfection reagents advertised as being appropriate for RNA transfection").

CVC also contradicts ToolGen's arguments regarding unexpected results on the basis that "there can be no unexpectedly superior results for a claimed species when a previously-disclosed genus to which the species 1belong demonstrates those same results," citing AbbVie, Inc. v. Mathilda and Terence Kennedy Inst. of Rheumatology Trust, 764 F.3d 1366, 1380 (Fed. Cir. 2014).

Finally, CVC argues that its Motion was procedurally proper under 37 C.F.R. §§ 41.202 and 41.203 and that ToolGen's arguments to the contrary improperly apply the law with regard to having a new interference declared rather than having a claim of another patent designated as corresponding to the Interference Count (citing several Board decisions in other interferences having that effect).  But just in case the Board agrees with ToolGen's argument that CVC's priority showing was deficient, CVC asks the Board to use its discretion under Rule 41.104(b) in this case to waive any such requirement based on the priority case CVC has asserted in its other pleading which apply in this instance as well.

* '830 Patent Claims CVC Asserts Correspond to the Count in the '127 Interference

1.  A method of introducing a site-specific, double-stranded break at a target nucleic acid sequence in a eukaryotic cell, the method comprising introducing into the eukaryotic cell a Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas system, wherein the CRISPR/Cas system comprises: a) a nucleic acid encoding a Cas9 polypeptide comprising a nuclear localization signal, wherein the nucleic acid is codon-optimized for expression in eukaryotic cells, and b) a guide RNA that hybridizes to the target nucleic acid, wherein the guide RNA is a chimeric guide RNA comprising a CRISPR RNA (crRNA) portion fused to a trans activating crRNA (tracrRNA) portion, wherein the guide RNA comprises two guanines at its 5' end, and there are no additional nucleic acid residues between the two guanines at the 5' end and the crRNA portion of the guide RNA; whereby a site-specific, double stranded break at the target nucleic acid sequence is introduced.

2.  The method of claim 1, wherein the nuclear localization signal is located at the C terminus of the Cas9 polypeptide.

3.  The method of claim 1, wherein the eukaryotic cell is a mammalian cell.

4.  The method of claim 3, wherein the mammalian cell is a human cell.

5.  The method of claim 1, wherein the nucleic acid encoding the Cas 9 polypeptide is codon-optimized for expression in mammalian cells.

6.  The method of claim 1, wherein the target nucleic acid sequence is a genomic sequence located at its endogenous site in the genome of the eukaryotic cell.

7.  The method of claim 1, wherein the nucleic acid encoding the Cas9 polypeptide is a vector.

8.  The method of claim 1, wherein the Cas9 polypeptide is a Streptococcus pyogenesCas9 polypeptide.

9.  The method of claim 1, wherein the nucleic acid encoding the Cas9 polypeptide is introduced into the eukaryotic cell before introducing the guide RNA into the eukaryotic cell.

10.  The method of claim 1, wherein the Cas9 polypeptide is a StreptococcusCas9 polypeptide.

By Kevin E. Noonan —

On June 11th, Junior Party the University of California, Berkeley; the University of Vienna; and Emmanuelle Charpentier (collectively, "CVC") filed its Responsive Preliminary Motion No. 1 in Interference No. 106,127 to be accorded benefit of priority to U.S. Patent Application No. 13/842,859, filed March 15, 2013, or in the alternative U.S. Patent Application No. 14/685,504, filed April 7, 2015, or U.S. Patent Application No. 15/138,604, filed April 26, 2016, pursuant to 37 C.F.R. §§ 41.121(a)(2) and 41.208(a)(3) and Standing Order ¶ 208.4.1.  CVC filed this motion contingent on the Board granting Senior Party ToolGen's Substantive Preliminary Motion No. 2 to deny CVC priority benefit to U.S. Provisional Application No. 16/757,640, filed January 28, 2013 ("P3").  On July 15th, Toolgen filed its Opposition, and on August 27th CVC filed its Reply.

ToolGen's Substantive Preliminary Motion No. 2 challenged CVC's entitlement to priority benefit to the P3 provisional in this interference on the grounds that it did not disclose "successful cleavage of DNA within eukaryotic cells, nor does it otherwise show a constructive reduction to practice of an embodiment within Count 1."  In its Responsive Motion, CVC sought to establish its entitlement to later-filed applications, to retain its best priority position against ToolGen (CVC itself has filed its Preliminary Motion No. 2 to deny ToolGen of the priority benefit to its earliest application, U.S. Provisional Application No. 16/717,324, filed October 23, 2012).  In its Responsive Motion, CVC argued entitlement to the '859 application as a matter of law because it is the earliest application having an identical specification to CVC's applications-in-interference and CVC argues that it therefore is entitled to a presumption that this application provides a constructive reduction to practice thereby, citing Transco Prod. Inc. v. Performance Contracting, Inc., 38 F.3d 551, 556–57 (Fed. Cir. 1994).  CVC's alternative priority claims were based on the common specification shared by all these applications, comprising "a string of continuation applications [that] thus provide[s] the same disclosure as the involved applications."  CVC provided the following table of comparison evidence of what is disclosed in the specification of the '859 application with each element of the Count:

Specifically, CVC argued that Examples 4, 5, and 7 set forth a constructive reduction to practice of an embodiment falling within the scope of the Interference Count.

ToolGen disagreed, arguing in its Opposition that CVC failed to carry its burden of showing the constructive reduction to practice it alleged.  As an initial matter, ToolGen cited CVC's argument that the disclosure in the three non-provisional applications here has been continuously disclosed in earlier provisional applications (U.S. Provisional Application No. 61/652,086, filed May 25, 2012 ("P1"), U.S. Provisional Application No. 61/716,256, filed October 19, 2012, ("P2"), and U.S. Provisional Application No. 61/757,640, filed January 28, 2013 ("P3"), priority to which CVC asked the Board to accord benefit in its Substantive Preliminary Motion No. 1 (opposed by ToolGen separately).  ToolGen understandably repeated (in brief) its principal argument in that Opposition, that CVC had not shown that CRISPR-mediated DNA cleavage in eukaryotic cells would have been a matter of routine and predictable experimentation, based inter alia on the Board's decisions in Interference No 105,048 (and Federal Circuit affirmance thereof; Regents of Univ. of California v. Broad Inst., Inc., 903 F.3d 1286, 1291–92 (Fed. Cir. 2018)) and Interference No. 106,115 to the contrary.  And ToolGen, as it has done in its own Preliminary Motion No. 2 to deny priority benefit, argued that the Board erred in granted CVC priority benefit to its P3 provisional application (U.S. Provisional Application No. 61/757,640, filed January 28, 2013) in the '115 Interference because it did not consider ToolGen's arguments that CVC had not satisfied the constructive reduction to practice requirement for this provisional (again, briefly recounting their earlier arguments here).  ToolGen thus made its first argument on the backs of its earlier arguments with regard to the P1, P2, and P3 priority documents, because if CVC was not entitled to priority to them then the Board should not grant CVC priority benefit to the three non-provisional applications at issue here in the face of CVC's representations that the disclosure in Examples 4, 5, and 7 was the same in these non-provisional applications and the earlier-filed provisional applications.  ToolGen supported these arguments by applying them to each of these Examples to illustrate what it considered to be their flaws that precluded CVC from entitlement to priority benefit.

CVC's Reply focuses on having the Board grant priority to the '859 application even if its claims for priority benefit to all the earlier applications have been denied.  The basis for this claim is that the '859 application contains disclosures regarding eukaryotic CRISPR embodiments that appear in all the other, later-filed applications in this interference and thus CVC is entitled to priority benefit under 35 U.S.C. § 120 and precedent, citing Transco Prods. 6 Inc. v. Performance Contracting, Inc., 38 F.3d 551, 556 (Fed. Cir. 1994).  CVC bootstraps ToolGen's failure to challenge specification support in later-filed applications (inter alia, its involved Application No. 15/981,807) as an admission that the disclosure in the '859 application is similarly sufficient, based on its assertion that the disclosures (at least with respect to Examples 4, 5, and 7) are the same, citing Dreyfus v. Lilienfeld, 49 F.2d 1062, 1064 (C.C.P.A. 1931), and Renz v. Jacob, 326 F.2d 792, 799 (C.C.P.A. 1964).

On the merits, CVC sets forth its case regarding what is disclosed in the '859 application as the basis for its priority claim.  In doing so, CVC distinguishes the Board's basis for denying priority to earlier applications (specifically in the '048 and '115 Interferences) because it asserts that "the evidence supporting this motion involves additional disclosures, including at least the '859 application's Examples 4, 5, and 7, which were not at issue in the '048 or '115 interferences, as well as different expert testimony and a later state of the art, March 15, 2013—by which time numerous peer-reviewed publications had reported using sgRNA CRISPR-Cas9 in eukaryotic cells."  CVC characterizes ToolGen's arguments are requiring actual (as opposed to constructive) reduction to practice, which is generally not required, citing Falkner v. Inglis, 448 F.3d 1357, 1362 (Fed. Cir. 2006).  Regardless, CVC argues that ToolGen is wrong in asserting any deficiencies in its disclosure of eukaryotic CRISPR falling within the scope of Count 1, which errors it then explicates in its brief.

Specifically, CVC argues that ToolGen is wrong at least with regard the human cell experiments set forth in Example 4 (and alleging that ToolGen's expert Dr. Tuchi agreed), enumerating the eight specific elements of the Count and where in the Example they were satisfied.  CVC's brief faults ToolGen for applying an incorrect legal theory, specifically that the '859 application would need to provide "definitive evidence that CRISPR-Cas9 modulates transcription of at least one gene encoded by the target DNA molecule in eukaryotic cells" (emphasis in brief).  CVC cites Faulkner and In re Borkowski, 422 F.2d 904, 908 (C.C.P.A. 1970), for the principle that there is no need to show specific working examples to satisfy constructive reduction to practice.  CVC's brief faults ToolGen's expert witness for a variety of blunders in his analyses and consideration of the prior art (including positions CVC contends are contradicted by the '859 application), and accordingly urges that his testimony be given no weight.  And CVC argues that reassertion of arguments regarding its P1-P3 provisional applications here against the '859 application are mere illustrations of the consistency of ToolGen's errors it makes in supporting its Opposition.

The focus of the parties' arguments is at the nexus of where a constructive reduction to practice in an unpredictable art meets the requirement that a skilled artisan would recognize by that disclosure that an inventor has possession of the disclosed invention, described in such a way that a person of ordinary skill in the art would be able to practice a claim throughout its full scope without undue experimentation.  In an interference context these principles apply to an application receiving priority benefit adequately discloses at least one embodiment of an invention falling within the scope of the interference Count, which ultimately is what the Board will need to decide in determining the priority question regarding the '859 application.

By Kevin E. Noonan —

On May 20th, Junior Party the University of California, Berkeley; the University of Vienna; and Emmanuelle Charpentier (collectively, "CVC") filed its Substantive Preliminary Motion No. 1 in Interference No. 106,127 (which names ToolGen as Senior Party), asking the U.S. Patent and Trademark Office's Patent Trial and Appeal Board for benefit of priority to U.S. Provisional Application No. 61/652,086, filed May 25, 2012 ("P1"), U.S. Provisional Application No. 61/716,256, filed October 19, 2012, ("P2"), and U.S. Provisional Application No. 61/757,640, filed January 28, 2013 ("Provisional 3"), pursuant to 37 C.F.R. §§ 41.121(a)(1)(ii) and 41.208(a)(3) and Standing Order ¶ 208.4.1.  On July 15th, ToolGen filed its Opposition.  On August 27th, CVC filed its Reply.

The relationships between the patents and applications in the '127 interference are set forth in this chart (filed in CVC's earlier preliminary motion in the '115 Interference):

The significance of the Board granting this motion with regard to the P1 or P2 provisional applications would be that CVC would be Senior Party, with all the presumptions benefiting Senior Party status.

In its Preliminary Motion No. 1, CVC argued that its inventors invented eukaryotic cell CRISPR using a single-molecule guide RNA (sgRNA) that is described in each of the three provisional applications.  Once that breakthrough had been achieved, CVC argues that adapting CRISPR to the eukaryotic cell environment would have been "pretty straightforward" (quoting Dr. Luciano Marraffini, who informed the Broad inventors of the sgRNA embodiment in June, 2012 (see "CVC Files Motion in Opposition to Broad Priority Motion").  CVC supported this assertion with contemporaneous consistent statements from other scientists; by the existence of "platforms that had already been successfully used with the two incumbent systems: zinc-finger nucleases ("ZFNs") and transcription activator-like effector nucleases ("TALENs")"; and by the successful practice of CRISPR by several groups (including ToolGen) "[j]ust months after CVC presented this work" and the absence in the reports from any of these groups of "any 'special' adaptations or conditions needed to achieve CRISPR gene editing in eukaryotic cells."

CVC also addressed the PTAB's decision not to grant CVC's patents and applications in the '115 patent the benefit of priority to the P1 and P2 provisional applications sought here; the basis for that decision, according to CVC was that it was made "without the benefit of the now well-developed evidentiary record," specifically, that "[t]he prior decision credited assertions that have been seriously undermined by evidence presented during the priority phase of the '115 interference."  Part of that evidence is that the P1 provisional "contemplates and teaches that the sgRNA CRISPR-Cas9 system can be microinjected as a pre-assembled ribonucleoprotein ("RNP") complex into embryos, including fish cells ("E1"), which obviates the concerns alleged in the '115 interference" (emphasis in brief).  In view of this evidence, concerns raised by Broad regarding eukaryotic CRISPR embodiments ("RNA and protein expression, co-localization, and assembly") are avoided because the CRISPR-Cas9 complex is already formed in vitro prior to being microinjected into the embryo.

ToolGen based its opposition on three arguments.  First, ToolGen argued that (as a procedural matter) CVC failed to allege that either the P1 or P2 provisional application provide an enabling disclosure.  Second, ToolGen argued that the Board has already denied CVC benefit of priority to the P1 and P2 provisional applications in the '048 Interference (as part of its determination that there was no interference-in-fact) and the '115 Interference.  Third, ToolGen argued that CVC's arguments in support of its Preliminary Motion No. 1 do not cure the deficiencies of their arguments in earlier interferences and are just as unavailing.  Thus, ToolGen's first argument was procedural and its second and third argument went to the merits of CVC's disclosure (or lack of it) in these three provisional applications.

In its Reply, CVC begins by asserting that there is no estoppel based on the Board's decisions in the '048 and '115 Interferences because 1) the issues were different in the '048 interference (no interference-on-fact based on non-obviousness), and 2) there has not been a final decision in the '115 interference.  According to CVC, "[t]he record supporting this motion is different, contains new evidence, and must be considered as a whole" and "[g]ranting this motion would not require overturning or contradicting any prior findings."  Moreover, "[i]t would violate the law and basic principles of equity and fairness to give preclusive effect here based on the record in the '048 proceeding" CVC asserts, citing Smith v. Bayer Corp., 564 U.S. 299, 312 n.9 (2011); and Fears v. Wilkie, 843 F. App'x 256, 261 (Fed. Cir. 2021) (quoting and applying Smith).  And finally, CVC quotes passages from the Federal Circuit's opinion emphasizing its express dependence on the record before the Court (which of course is not the record here).  With regard to the Board's decision in the '115 Interference, CVC emphasizes the provisional nature of the Board's decision as well as the great difference between priority benefit and priority of invention determinations, while noting that application of a preclusive effect of these decisions is discretionary.  CVC contends that the differing circumstances and addition evidence presented in this interference (specific to ToolGen) should turn the Board's discretion against applying preclusion against CVC here.

On the substantive merits, CVC argues that the disclosure of P1, which is contained in P2 and P3, is sufficient to satisfy the requirements for reduction to practice of at least one embodiment falling within the scope of the Interference Count, in view of the high level of skill in the art, as evidenced by how quickly CVC's inventors and other groups (including Broad, ToolGen, and others) achieved CRISPR-mediated DNA cleavage in eukaryotic cells when sgRNA was disclosed (albeit the provisionals not having been disclosed).

CVC repeats its argument that ToolGen errs in maintaining that "a constructive reduction to practice requires experiments, working examples, and optimization of the invention," which CVC properly argues (at least regarding the standard) it does not.  CVC also contends that ToolGen would require CVC's P1 application to "instruct a POSA how to overcome or rule out every hypothetical concern that ToolGen conjures up, as well as convey certainty of success," also (CVC contends, erroneously) it does not.  As CVC argues, its P1 application "describes how to make pre-assembled ribonucleoprotein complexes (RNPs) that function in vitro," as well as the well-known technique of microinjection, which would result in successful CRISPR gene editing activity in a eukaryotic cell (CVC dismissing the obstacles to successful eukaryotic CRISPR other than mere introduction into a eukaryotic cell that its opponents have urged).  Relying on what it now known (including "new evidence obtained during the priority phase of the '115 interference") CVC argues that these purported obstacles would not have precluded eukaryotic CRISPR (which while likely true does not address the issue of what the skilled worker would have understood the P1, P2, or P3 applications to have described and enabled with what was known at the time they were filed).  "[T]here is overwhelming contemporaneous evidence showing that a POSA would have expected sgRNA CRISPR-Cas9 to have activity in eukaryotes," CVC argues, and thus any discussion of "expectation of success" is inapposite.

Specifically, CVC asserts that its P1 provisional application disclosed three eukaryotic CRISPR embodiments falling within the scope of the Interference Count: (i) as pre-assembled RNP complexes; (ii) as expression vectors encoding the system; or (iii) as RNA molecules encoding the system (citations omitted) in a fish cell (E1), a human cell(E2), and a fruit fly cell (E3).  The skill in the art was such, according to CVC, that this disclosure, founded on the use of sgRNA and associated specifics (like PAM sequences, preassembly of RNPs in vitro, the conventionality of microinjection techniques), was sufficient to satisfy the requirements of written description and enablement needed to establish the priority right.  (And CVC makes the argument that these teachings were "continuous and logically arranged" to rebut ToolGen's argument that they appeared "hundreds of paragraphs apart" in the P1 specification.)

Finally, CVC addressed ToolGen's argument that the P1 (and P2 and P3) disclosures would not provide the skilled artisan with a reasonable expectation of success (which is not required according to their brief) by citing "contemporaneous evidence [that] overwhelmingly shows that those in the field expected sgRNA CRISPR-as9 to function in a eukaryotic cell environment.  This argument was based on evidence from other labs contemporaneous with the disclosure of the P1, P2, and P3 provisional applications and comparisons with zinc-finger nucleases (ZFNs) and TALEN sequences, catalytic RNA species such as Group II introns, ribozymes, and riboswitches (as well as T7 polymerase) and distinguishing CRISPR from each of them.

In weighing the evidence and argument the parties set forth related to CVC's Substantive Preliminary Motion No. 1, the issue for the Board may be quite simple:  is CVC's development of the single molecule guide RNA (sgRNA) embodiment of CRISPR enough to support reduction to practice of eukaryotic CRISPR, or are the obstacles (asserted by Broad successfully in the '048 Interference and again in the '115 Interference and here by ToolGen) enough to deny CVC priority benefit to any priority document that does not expressly exemplify that CRISPR is capable of DNA cleavage in eukaryotic cells.