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. 2 in Interference No. 106,127 to be accorded benefit of priority to U.S. provisional application No. 13/842,859, filed March 15, 2013, 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").

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."  Deferring its arguments against this motion to its Opposition, in this Responsive Motion CVC seeks 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 argues 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).  In the alternative, CVC in this motion asks to be accorded benefit of the filing date of U.S. Application No. 14/685,504, filed April 13, 2015 ("the '504 application") or U.S. Application No. 15/138,604, filed April 26, 2016 ("the '604 application"), all of which share a common specification with the '859 application "as a string of continuation applications and thus provide the same disclosure as the involved applications."

In addition to asserting the presumption that it is entitled to priority benefit to its earliest application having a specification identical to its involved applications, CVC sets forth its comparison evidence of what is disclosed in the specification of the '859 application with each element of the Count:

while at the same time reiterating its contention that it is entitled to priority benefit to its P1 (No. 61/652,086, filed May 25, 2012), P2 (No. 61/716,256, filed Oct. 19, 2012), and P3 provisional applications for providing a constructive reduction to practice of at least one embodiment falling within the scope of the Count.  This assertion is based on CVC's purported demonstration of eukaryotic CRISPR-Cas9 mediated genetic alterations in its E1 (fish cell), E2 (human cell), and E3 (fruit fly cell) embodiments (see "Berkeley Files Responsive Motion to Broad's Substantive Motion No. 2 in Interference").  CVC also relies on the Board's determination in the '115 Interference that CVC was entitled to priority benefit of the P3 provisional application (see "PTAB Decides Parties' Motions in CRISPR Interference").  CVC sets forth its evidence that the relevant disclosure in the P3 provisional, as well as in the '859 application in this interference, is the same, specifically with regard to the fish, human, and fruit fly cell embodiments.

The brief sets forth separately its arguments regarding the disclosure in Example 4 of the "common specification," which the brief describes as "an RNA-guided DNA endonuclease from a Type II CRISPR system" called CRISPR interference (CRISPRi)."  This system can suppress RNA transcription in human HEK293 cells, according to the brief, and that it meets all the elements of the Count in the '127 interference.  This example also avoids the criticism ToolGen aimed at CVC's Example 3 with regard to cell lysis being used to isolate CRISPR-modified DNA (which ToolGen asserts could result in artifactual, in vitro CRISPR cleavage outside the scope of the Count).  CVC argues in its brief that CRISPRi down-regulates transcription inside the cell without the need for cell lysis and thus ToolGen's criticism on this basis is inapposite.

The "common specification" also contains Example 5 according to the brief, which CVC argues discloses use of a "a fusion protein compr[i]sing a catalytically inactive Cas9 and an . . . activator domain or a repressor domain" that also modulates transcription within a eukaryotic cell. According to CVC the CRISPR system disclosed in Example 5 also comprises all the elements recited in the interference Count.

Finally CVC relies on disclosure in the common specification of Example 7, which discloses generating:

"[a] transgenic mouse expressing Cas9," isolating embryonic stem cells from the transgenic mouse, and using the Cas9-expressing embryonic stem cells to rapidly generate "new knock-out or knock-in cells (and therefore mice) . . . at any desired locus in the genome by introducing an appropriately designed DNA-targeting RNA that targets the Cas9 to a particular locus of choice."

As explained by CVC's expert cited in the brief, "gene knock-in" was known in the art, produced by other means, and the CRISPR system disclosed in Example 7 satisfied all the elements recited in the Count of the 106,127 Interference.

On these grounds CVC asked the Board to be accorded benefit of the '859 application's March 15, 2013 filing date in this interference.

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.

Relevant to CVC's motion is the portion of the Count identical to Claim 85 of ToolGen's priority application, U.S. provisional application No. 14/685,510:

An isolated mammalian cell comprising a Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas system for site specific, cleavage of a double-stranded target nucleic acid sequence in the isolated mammalian cell, wherein the CRISPR/Cas system comprises:
    a)    a nucleic acid encoding a Cas9 polypeptide, wherein the Cas9 polypeptide comprises a nuclear localization signal and wherein said nucleic acid is codon-optimized for expression in mammalian cells, and
    b)    a chimeric guide RNA comprising a CRISPR RNA (crRNA) portion and a transactivating crRNA (tracrRNA) portion,
    wherein the target nucleic acid sequence comprises a first strand having a region complementary to the crRNA portion of the chimeric guide RNA and a second strand having a trinucleotide protospacer adjacent motif (PAM), and
    wherein the Cas9 polypeptide and the chimeric guide RNA form a Cas9/RNA complex in the isolated mammalian cell and mediate double stranded cleavage at the target sequence.

CVC argues 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 argues that these species of sgRNA (the fusion of crRNA and tracrRNA) recited in the '380 patent claims are 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.

This method of producing sgRNA and relevant prior art disclosing the use of T7 RNAP and promoters recognized by the polymerase are set forth in the brief as follows:

wherein the diagrams follow the source of the characteristic "extra" GG residues at the 5' end of crRNA and sgRNA produced thereby.  CVC also asserts a second reference, the Deltcheva reference, to illustrate the extent to which T7-catalyzed in vitro RNA production using a T7 promoter was well-known:

CVC argues 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 argues 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.

The brief sets forth in detail comparison between the Count and claims of the '380 patent to set forth CVC's argument that those claims would have been obvious over the Count (considered as part of the prior art for this analysis; see N.V. Nutricia v. Mass. Inst. of Tech., Interference No. 106,096, Paper 80, 4 (P.T.A.B. Mar. 29, 2019)) in combination, inter alia, the Jinek 2012 reference (or any other reference teaching the use of the T7 promoter/ T7 RNA polymerase system for producing RNA including sgRNA in vitro.  CVC characterizes its argument by stating that those claims "the predictable use of prior art elements according to their established functions," citing  KSR Intern. Co. v. Teleflex Inc., 127 S.Ct. 1727, 1731 (2007); these arguments are supported by a detailed claim chart set out as Appendix 3 to CVC's brief (providing the comparison with the portion of the Count taken from ToolGen's application).  (Appendix 4 contains a similar claim chart from the portion of the  Count taken from claim 156 of the CVC's U.S. Application No. 15/981,807.)

Turning to the basis for CVC's assertion of there being a reasonable expectation of success, CVC argues that:

Expectation of success in eukaryotes would not be in doubt because "whether a CRISPR-Cas9 system would have been expected to work in a eukaryotic cell . . . 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 . . . claims," citing The Univ. of Calif. v. The Broad Inst., Inc., Interference No. 106,115, Paper 877, 66 (P.T.A.B. Sept. 10, 2020); 37 C.F.R. 41.207(b)(2).

Having set forth the basis for the Board to find claim 1 obvious, the brief then sets forth CVC's obviousness analysis regarding claims 2-10 as having been obvious (and the brief is supplemented with Appendix showing those sites).

The brief completes its obviousness assessment by asserting that there was no objective indicia that would contradict the prima facia case of obviousness supported by the facts and argument set forth above.  These include specifically the absence of any evidence of unexpected results (which ToolGen argued during prosecution of the '380 patent) in view of (for the purposes of this interference) ToolGen's half of the Count, which differs from the '380 claims only by the addition of the GG residues at the 5' end of the sgRNA as a consequence of producing that RNA species in vitro using T7 RNA polymerase and its cognate promoter.  CVC arrives at this conclusion because the claim corresponding to ToolGen's half of the interference Count (claim 85 of ToolGen's involved '510 application) was prosecuted to allowance, inter alia, by ToolGen's argument for unexpected results; as CVC asserts "there can be no  unexpectedly superior results when the closest prior art (i.e., Count 1) has the same results as the claimed method," citing Millennium Pharmaceuticals, Inc. v. Sandoz, Inc., 862 F.3d 1356, 1368 (Fed. Cir. 2017) (emphasis in brief).  In addition, CVC argues that here the prima facie case is sufficiently strong so as not to be rebutted by unexpected results, citing Ohio Willow Wood Co. v. Alps South, LLC, 735 F.3d 1333, 1344 (Fed. Cir. 2013) ("[W]here a claimed invention represents no more than the predictable use of prior art elements according to established functions, as here, evidence of secondary indicia are frequently deemed inadequate to establish  nonobviousness.").  Finally, merely discovering the effect of adding the GG residues at the 5' end of the sgRNA is not sufficient to overcome a prima facie obviousness case, based on Federal Circuit precedent that a "'previously-unknown, yet inherent, food-effect property' did not make the claims patentable because 'merely discovering and claiming a new benefit of an old process cannot render the process again patentable,'" citing In re Huai-Hung Kao, 639 F.3d 1057 (Fed. Cir. 2011).

Finally, CVC's brief concludes with its argument that there is an interference-in-fact between CVC's involved claims in this interference and the '380 patent claims (illustrating the principle that once bitten is twice shy).  CVC argues here that the "two-way" test for interfering subject matter is met between at least one claim of the '380 patent and at least one of CVC's involved claims.  Specifically, the brief calls out claim 1 of the '380 patent and claim 156 of CVC's involved application No. 15/981,807:

156.    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.

CVC identifies as "the only relevant differences" between this claim and claim 1 of ToolGen's '380 patent:

• codon optimization of the Cas9 polynucleotide,
• the NLS-tag on Cas9, and
• including a 5'-GG on the guide RNA.

Noting that claim 185 of CVC's '807 application recites use of the NLS tag, CVC argues that the skilled worker would have had a reasoned basis for including all of these features into a CRISPR-Cas9 system, under the rubric that a "combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results," citing KSR Intern. Co. v. Teleflex Inc., 127 S.Ct. 1727, 1731 (2007).  And, CVC maintains, the skilled worker would have had a reasonable expectation of success in achieving operative embodiments of CRISPR thereby, satisfying one prong of the two-way test.

With regard to the other prong, CVC argues that claim 1 of ToolGen's '380 patent teaches all the elements of CVC's claim 156 in the order in which it is claimed, which is enough to satisfy the test for anticipation.

Accordingly, CVC concludes, the Board should designate the claims of the '380 to correspond to Count 1, adding that "[t]here are no adequate alternative remedies because leaving the '380 patent out of this proceeding risks the inefficiency and expense of another interference proceeding involving CVC and ToolGen."

* '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 pyogenes Cas9 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 Streptococcus Cas9 polypeptide.

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. 2 in Interference No. 106,127 (which names ToolGen as Senior Party), asking the Patent Trial and Appeal Board to deny ToolGen benefit of priority to U.S. provisional application No. 16/717,324, filed October 23, 2012, pursuant to 37 C.F.R. §§ 41.121(a)(1)(ii) and 41.208(a)(3) and Standing Order ¶ 208.4.1.  The significance of the Board granting this motion would be that CVC would be Senior Party, with all the presumptions benefiting from Senior Party status.

CVC argues that the Board should deny ToolGen priority benefit to the '324 application based on party admissions because this provisional application does not disclose an operative embodiment falling within the scope of the interference Count.  Specifically, CVC argues that ToolGen in the prosecution of the '324 patent application leading to allowance (and declaration of this interference) had argued to the Patent Examiner (and PTAB) that "a codon-optimized Cas9 nucleic acid is required for CRISPR-Cas9 to function in eukaryotic cells" and that "a skilled artisan would have no idea what the outcome may be if one were to codon optimize a Cas9 nucleic acid."  This position was consistent with the prokaryotic source of Cas9, and the Board and Examiner relied upon these arguments to find allowable claims in the '324 application (now claims designated as corresponding to the Count in this interference), CVC asserts.  All such claims require use of a Cas9-encoding nucleic acid that is codon-optimized for expression in eukaryotic cells, and ToolGen added this limitation to the claims to overcome anticipation and obviousness rejections based on the prior art.  But ToolGen's '324 application does not disclose a codon-optimized Cas9 nucleic acid, according to CVC, nor by ToolGen's own argument would the skilled worker be able to discern such a nucleic acid with any reasonable basis for expecting such an embodiment could be produced using the disclosure in the '324 application.  Accordingly, CVC argues in its motion, ToolGen cannot in this interference renounce these arguments and rely on the priority date of the '324 patent to constitute a constructive reduction to practice for eukaryotic CRISPR-Cas9 embodiments falling within the scope of the interference Count.  Thus, according to CVC, the Board should deny ToolGen priority benefit to the '324 application (and redeclare the interference naming CVC as Senior Party).

The brief is replete with examples from the '324 prosecution history (CVC characterizing these statements as "unambiguous" and "unequivocal"), including this colloquy from oral argument before the Board in an appeal during that prosecution:

*  *  *
and

ToolGen even went so far as to represent to the Office that CRISPR-Cas9 would not function in eukaryotic cells without codon optimization, CVC argues.  In summary, CVC asserts ToolGen took the position:

ToolGen's position during prosecution is clear and unmistakable: its invention required a codon-optimized Cas9 nucleic acid, codon-optimizing the Cas9 nucleic acid was unpredictable, and one would have "no idea" of the outcome of codon optimizing [emphasis in brief].

and should not now be permitted to disavow it.  (And the fact that the Board instituted this interference having a Count comprising in the alternative a CVC claim that does not require a codon-optimized nucleic acid encoding Cas9 does not change the argument, CVC asserts.)

CVC concedes that, in fact, codon optimization was known in the art as of the '324 application's filing date.  But ToolGen's admissions should preclude this fact from overcoming the estoppel-creating admissions, CVC tells the Board in their brief.  The legal basis for CVC's argument is based on judicial estoppel (citing Zedner v. United States, 547 U.S. 489 (2006)), and the effect of party admissions on positions taken in a later proceeding before the Board.  Citing Springs Window Fashions LP v. Novo Industries, L.P., 323 F.3d 989, 995 (Fed. Cir. 2003), CVC argues that "[t]he public notice function of a patent and its prosecution history requires that a patentee be held to what he declares during the prosecution of his patent" (emphasis in brief); accord, Louis v. Okada, 59 U.S.P.Q.2d 1073, 1075 (B.P.A.I. 2001) (precedential), wherein the Board denied a motion to amend the Count to "better align with [a party's] best proofs" because the party had relied on the element in question to overcome a prior art-based rejection.  In addition to Zedner, CVC cites New Hampshire v. Maine, 532 U.S. 742, 742 (2001), in support of the application of the "equitable doctrine of judicial estoppel" here, and Wilson v. Martin, 789 Fed. Appx. 861, 872 (Fed. Cir. 2019), for the Board having the authority to apply the doctrine.  CVC bases its argument on the inconsistency of a finding that there is any basis of support in the '324 for providing a constructive reduction to practice in this interference in the absence of disclosure of codon-optimized CAS9-encoding nucleic acid with ToolGen's consistent position to the contrary during prosecution (as evidenced by citations to the prosecution history throughout the brief).  And ToolGen would receive an unfair advantage should the Board rule to the contrary, CVC asserts (that advantage including ToolGen being Senior Party instead of CVC in this interference).

One factual basis for CVC's argument is that while ToolGen's asserted codon optimization was necessary to produce a Cas9 protein functional in a eukaryotic cell, and the undisputed fact that codon optimization was known in the art at the '324 application's filing date, which embodiment of a codon-optimized nucleic acid encoding Cas9 was not disclosed therein, and not only did the '324 not provide any nucleic acid encoding Cas9 from any species other than its native one (S. pyogenes), the application did not even disclose a codon-optimization table (for a feature ToolGen argued was necessary to achieve operative eukaryotic CRISPR embodiments).  CVC also proffered expert testimony regarding the significance of these deficiencies, including the existence at the priority date of several codon-usage tables in the art having different frequencies for 12 of the 20 naturally occurring amino acids (and thus there being no consensus in the art as to which codons would be optimal for eukaryotic cell expression of Cas9).

And the fact that ToolGen's specification purportedly shows successful reduction to practice of CRISPR-Cas9 mediated gene editing in eukaryotic cells does not cure the lack of written description of a codon-optimized Cas9 according to CVC, citing In re Alonso, 545 F.3d 1015, 1021 (Fed. Cir. 2008), for the principle that "[p]roof of a reduction to practice, absent an adequate description in the specification of what is reduced to practice, does not serve to describe or identify the invention for purposes of the written description requirement" (emphasis added).

CVC is careful to argue that "of course" ToolGen's deficiencies in no way can be attributed to CVC, because CVC never argued the absolute need for codon optimization for nucleic acids encoding Cas9 for operable eukaryotic embodiments of CRISPR, nor did CVC argue that codon optimization was either essential nor unpredictable (indeed, CVC asserts its consistent argument that by May 2012 codon optimization was "a routine technique such that skilled artisans would have expected to express a functional Cas9 protein from a codon-optimized nucleic acid in eukaryotic cells").

CVC asserts that these arguments are sufficient for the Board to deny priority benefit to ToolGen of the '324 application.