By Kevin E. Noonan —

On May 20th, Senior Party ToolGen filed its Substantive Motion No. 1 for benefit of priority to U.S. Provisional Application No. 61/837,481, filed June 20, 2013 ("P3" or "ToolGen 5 P3"), or alternatively, International Application No. PCT/KR2013/009488, filed October 23, 2013 ("PCT").  Junior Party the Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad") filed its Opposition to this motion, and on September 24th ToolGen filed its Reply.

As set forth in ToolGen's motion, the Board had granted ToolGen the benefit of its U.S. Provisional Application No. 61/717,324, filed October 23, 2012 ("P1"), resulting in ToolGen having an earlier priority date than Broad.  ToolGen submitted this motion to be accorded benefit of priority to two later-filed, related applications:  U.S. Provisional Application No. 61/837,481, filed June 20, 2013 ("P3" or "ToolGen 5 P3"), or alternatively, International Application No. PCT/KR2013/009488, filed October 23, 2013 ("PCT").  In its motion, ToolGen explains that it is submitting this motion contingent on the Board granting CVC's Substantive Motion No. 2, which attacks ToolGen's entitlement to priority to the P1 priority document in Interference No. 106,127.  The brief sets out graphically the relationship of these priority documents:

The brief then set out the basis for ToolGen's claim of priority, specifically its arguments for satisfaction of the written description and enablement requirements under 35 U.S.C. § 112(a) regarding two embodiments falling within the scope of the Interference Count.

In its Opposition, Broad asked the Board to defer consideration of ToolGen's Motion, properly pointing out that Broad (unlike CVC in the '127 Interference) has not challenged ToolGen's benefit of priority to its P1 provisional application.  Accordingly, Broad asserted that ToolGen's motion is premature and "completely irrelevant" at this time.  Broad further asserted that this motion may "potentially" become relevant "only if multiple contingencies in this and other proceedings—that may or may not ever come to pass—do actually arise."  These include that:

1) the PTAB finds ToolGen is not entitled to the benefit of its P1 application in the co-pending 127 Interference,

2) Broad requests and is granted permission to file a motion here challenging ToolGen's benefit to P1 based on estoppel from that determination in the 127 Interference, and

3) the PTAB grants Broad's motion, depriving ToolGen here of benefit of its P1.

Broad's justification included that the Board considering this motion under these circumstances would be "waste of judicial resources" as well as improperly constituting an advisory opinion.  The interference rules provide that the Board has discretion to defer consideration of motions under 37 C.F.R. § 41.125 as applied in Berman v. Housey, 291 F.3d 1345, 1352 (Fed. Cir. 2002).  Broad urged the Board to exercise that discretion regarding ToolGen's Preliminary Motion No. 1.  Broad's brief explicated in further detail the contingent nature of the circumstances needing to arise for ToolGen's motion to be timely, in support of its opposition and request for the Board to defer consideration thereof.

Broad argued that priority to either of ToolGen's U.S. Provisional Application No. 61/837,481, filed June 20, 2013 ("P3" or "ToolGen P3"), or alternatively, International Application No. PCT/KR2013/009488, filed October 23, 2013 ("PCT"), would never be relevant because "ToolGen will be unable to beat Broad's dates of [conception and reduction to practice]" if Broad is granted priority in the '115 Interference.  This argument also sounds in representations made by ToolGen during prosecution regarding what was needed to provide a skilled worker with a reasonable expectation of success:

Rather, the only thing that would have alleviated the unpredictability in the art and allayed the concerns of one of ordinary skill at this time would have been the actual demonstration of a Type II Cas9 system successfully introducing site-specific double-stranded breaks in a target nucleic acid sequence within a eukaryotic, e.g., mammalian, cell . . . [emphasis in brief].

Here, Broad resurrects an argument made in Interference No. 106,115, that eukaryotic CRISPR is an invention for which conception can only be shown by successful reduction to practice (under a theory of "simultaneous conception and reduction to practice" first enunciated thirty years ago regarding conception of a nucleic acid encoding a particular protein; see Amgen v. Chugai, Fed. Cir. 1990).

In its Reply, ToolGen boldly asks the Board to dismiss rather than defer its Preliminary Motion No. 1 should the Board deny CVC's Preliminary Motion No. 1 in co-pending Interference No. 106,126 to deny ToolGen priority benefit to its U.S. Provisional Application No. 61/717,324, filed October 23, 2012 ("P1").  In addition, ToolGen raises the procedural requirement that decisions on Motions must be decided prior to initiation of the Priority Phase.  And finally, ToolGen argues that should the contingency arise and the Board grant CVC's motion and deny ToolGen priority benefit to its P1 provisional application the Board should grant its Preliminary Motion No. 1 because Broad's opposition was procedural in nature and not on the merits.

Regarding the many contingencies Broad identifies in its Opposition, ToolGen argues that Broad has not brought a motion or advanced an argument to deny ToolGen the benefit of priority to its P1 application.  And at this point Broad should not be permitted to benefit from the Board deferring the priority benefit issue until after the priority phase has begun because that would be procedurally improper according to ToolGen, relying on 37 C.F.R. § 41.121(a)(1), the Standing Order at 6:22-24 and Hum. Genome Scis., Inc. v. Genentech, Inc., 589 F. Supp. 2d 512, 514 (D. Del. 2008), dismissed 368 F. App'x 116 (Fed. Cir. 2009).  And to the extent any contingency resulting in ToolGen's loss of priority benefit to the P1 application should arise, ToolGen argues, its Preliminary Motion No. 1 was not addressed on the merits in Broad's Opposition and thus its Motion No. 1 is unopposed.

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.