By Kevin E. Noonan —

On December 3rd, Junior Party the Broad Institute, Harvard University, and MIT (collectively, Broad) filed its Contingent Preliminary Motion No. 2 in Interference No. 106,133 (which names Sigma-Aldrich as Senior Party), asking the Patent Trial and Appeal Board to add claims 52-54 of Broad Application No. 16/177,403 to the interference, pursuant to the provisions of 37 C.F.R. §§ 41.121(a)(1)(i) and 41.208 and Standing Order ¶ 203.2.  The motion is contingent on the Board granting Broad's Substantive Preliminary Motion No. 1 to substitute the Count.

These claims recite a CRISPR method in eukaryotic cells that cleaves both strands and repairs the break by integration of a template polynucleotide.  Claim 52 is generic with regard to the guide RNA species, comprising dual-molecule and single-molecule (sgRNA) species:

52.  A method comprising: introducing into, or expressing in, a eukaryotic cell having a DNA molecule,
    (I) a Cas9 protein or one or more nucleotide sequences encoding the Cas9 protein,
    (II) an RNA or one or more nucleotide sequences encoding the RNA, the RNA comprising:
        (a) a first RNA comprising a first ribonucleotide sequence and a second ribonucleotide sequence, and
        (b) a second RNA, and
    (III) a template polynucleotide,
    wherein, the second RNA forms an RNA duplex with the second ribonucleotide sequence, and wherein, in the eukaryotic cell, the first ribonucleotide sequence directs the Cas9 protein to a target sequence of the DNA molecule, whereby the Cas9 cleaves both strands of the DNA molecule and the cleavage is repaired by integration of the template polynucleotide into  the DNA molecule in the eukaryotic cell.

Claim 53 (dual molecule RNA species) and claim 54 (single-molecule RNA species) recite the two alternative species.  These claims were deemed allowable by the U.S. Patent and Trademark Office Examiner on November 15, 2021.

The brief sets forth the four requirements for adding a claim to an interference:

(1) Identify the application or patent to be added;

(2) Certify that a complete copy of the application file for the application or patent has been served on all opponents except if it belongs to the opponent or if the Office has posted it electronically;

(3) Indicate which claims of the patent or application should be designated as corresponding to the count and show how the claims correspond to the count(s);

and

(4) Explain whether there are alternative remedies; if so, why alternative remedies are not adequate; and what attempts, if any, have been made to have the examiner recommend declaration of another interference.

Except for reiterating the grounds/bases for the Board to substitute the Count as declared for Proposed Substitute Count 3 (set forth more thoroughly in Broad's Substantive Preliminary Motion No. 1), the remainder of the brief sets out Broad's compliance with these four provisions of Rule 203.2.

By Kevin E. Noonan —

The Patent Trial and Appeal Board heard oral argument under 37 C.F.R. § 41.124(c) on February 4th in the Priority Phase of Interference No. 106,115 between the Broad Institute, Harvard University, and MIT (collectively, "Broad") as Senior Party and the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") as Junior Party.  The hearing was held by telephone and after a short delay for technical reasons transpired with each party having 20 minutes of argument.  CVC as Junior Party argued first, represented by Eldora Ellison who reserved five minutes for rebuttal.  Raymond Nimrod representing Broad followed, having reserved two minutes of his time for rebuttal.

CVC began its argument by asserting that there was no priority contest for the Board to decide because a party, like Broad, that took the invention from another could not be an original inventor.  The theme developed focused almost entirely on the activities of Dr. Marraffini and his disclosure to the Broad inventors of the single molecule (sgRNA) RNA embodiments of CRISPR that formed the basis for both Broad's June 2012 (and subsequent) reductions to practice as well as CVC's slightly later successful experiments.  CVC supported its argument with reference to Dr. Marraffini's testimony on cross examination as well as copious citations to the record.  The important feature supplied therein was what Dr. Ellison termed "processed" crRNA and tracrRNA, and she characterized Broad's earlier attempts (prior to Marraffini's disclosure) as "fumbling around" with regard to attempting to use dual molecule CRISPR embodiments in eukaryotic cells.  Judge Katz interrupted with a question about prior conception by CVC and the derivation issue that seemed to question CVC's premise regarding the completeness of CVC's conception with allusions to Broad's simultaneous conception and reduction to practice (SCRP) arguments.  After Dr. Ellison's response, Judge Katz then questioned whether the long period of time (Dr. Ellison contradicting this characterization in the context of experimentation in the biological sciences) indicated defects in CVC's conception sufficient to preclude the required degree of conception for CVC to be entitled to priority.  Despite CVC's spirited rebuttal of Broad's SCRP contention, Judge Katz in her questioning focused on the "multiple failures" CVC experienced in reducing eukaryotic CRISPR to practice.  CVC argued that the time taken to achieve actual reduction to practice was "lightning fast" for a biological invention, relying on Example 2 of CVC's P3 provisional application (Provisional Application No. 61/757,640) and reminding the Board that there was no evidence that would support any failure of CVC's diligence.  Judge Katz continued to press Dr. Ellison on this issue, citing citations in the record of e-mails indicating uncertainty about whether successful eukaryotic CRISPR had been achieved and specifically questioning the zebrafish embodiment CVC asserted using an RNP for introducing the components of CRISPR into the fish embryo.  The Judge asked whether there was anything outside the declarations CVC submitted in the interference that showed contemporaneous recognition that successful eukaryotic CRISPR had been achieved and whether there was evidence that, once an experiment had been performed that the CVC inventors considered to be successful, it had been repeated.  No other members of the panel asked any questions.

Broad's advocate, Mr. Nimrod, for his part repeated familiar themes in this interference, first that eukaryotic CRISPR was sufficiently fraught with experimental uncertainty due to the complexity of eukaryotic cells in comparison to bacteria that only successful achievement could satisfy SCRP for determining priority.  Second, Broad emphasized CVC's inventors' uncertainty (evinced by e-mails and other statements) that Broad argued showed failure of conception, saying that all CVC had was "a hope and a wish" at the same time Broad had actually achieved success practicing CRISPR in eukaryotic cells.  Broad made frequent citations to the outcome and decisions, by the Board and Federal Circuit, in prior related Interference No. 106,048 regarding the overall degree of uncertainty in being able to practice CRISPR in eukaryotic cells.  Judge Katz asked for clarification on this point, whether there could be no conception without actual reduction to practice, which Mr. Nimrod deflected somewhat to a discussion of Broad's purported success in dual molecule CRISPR embodiments (which CVC contended were outside the scope of the Count in view of the limitation to sgRNA embodiments).  In Broad's view, CVC's derivation argument and purported earlier conception were irrelevant in view of the need for a showing of SCRP (which, in view of Broad's earlier actual reduction to practice would have the Board decide priority in Broad's favor).  Broad emphasized the many instances in the record where CVC's inventors seemed to question whether their attempts to reduce eukaryotic CRISPR to practice were successful.  Broad also referenced the many experts CVC collaborated with (having expertise in various different eukaryotic cell types) and their failure to achieve or recognize CRISPR cleavage during the relevant time period (June 2012-January 2013).  The panel raised an issue regarding some of Broad's corroborating witnesses who had been named as inventors in certain patents-in-interference, suggesting some weakness in Broad's proofs (the panel asked for a citation to support Broad's contention that such corroboration was proper).  Mr. Nimrod accentuated the "metadata" in Broad's documentary evidence as providing relevant corroboration and provided specific details regarding a July 27, 2012 picture of a gel showing CRISPR cleavage.  When the Dr. Marraffini question was finally reached in Broad's argument, they contended again that it is all irrelevant, here because sgRNA was not the invention.

In rebuttal CVC argued that the '048 decision was not dispositive and that the Federal Circuit had rejected Broad's SCRP arguments.  Dr. Ellison contended that the RNP microinjection embodiment was a complete conception that was later reduced to practice and rebutted Broad's characterization of any deficiencies in CVC's disclosure of vectors encoding Cas9 or sgRNA.  She characterized Broad's description of the activities of various expert collaborators as "misleading" and accused Broad of using a double standard with regard to the SCRP argument.  CVC returned to its allegations regarding Dr. Marraffini's disclosure and the role it played in Broad reducing eukaryotic CRISPR to practice.

Broad in its rebuttal refuted CVC's "fumbling around" description of the Broad inventors' work, referencing the dual molecule experiments, and cited Broad's October 5th manuscript that expert reviewers had accepted as showing successful eukaryotic CRISPR.  Mr. Nimrod returned to the litany of CVC's failures during the critical period and cited contemporaneous evidence of CVC attempting to reduce eukaryotic CRISPR that Broad cast as failures.

Oral argument distilled each Party's narratives supporting their position.  For CVC's part Broad derived the invention from Dr. Marraffini's questionable (if not somewhat illicit) disclosure of sgRNA CRISPR embodiments that was the key to achieving CRISPR cleavage in eukaryotic cells.  Broad denied the relevance of any such disclosure and focused on the relatively longer amount of time it took CVC to achieve actual reduction to practice as evidence of a failure of conception.  To the extent that these are factual questions any decision by the Board will be entitled to substantial deference in the inevitable appeal to the Federal Circuit.  And lurking in the background are CVC's motion for a finding of disjoinder of inventorship and inequitable conduct by Broad.  As Judge Katz put it at the end of oral argument the interference is now closed; what is certainly the case is that it is also far from over.

By Kevin E. Noonan —

On December 3rd, Junior Party the Broad Institute, Harvard University, and MIT (collectively, Broad) filed its Substantive Preliminary Motion No. 1 in Interference No. 106,133 (which names Sigma-Aldrich as Senior Party), asking the Patent Trial and Appeal Board to substitute the interference Count, pursuant to the provisions of 37 C.F.R. §§ 41.121(a)(1)(i) and 41.208(a)(2).  Broad's Proposed Substitute Count takes the "McKelvey" format (comprising in the alternative a claim from one of each Party's applications in interference); the proposed change is in the portion of the Count reciting Broad's claims:

Proposed Count No. 3 (numbered presumably for consistency with other pending CRISPR-related interferences):

Sigma-Aldrich Application No. 15/456,204 (as declared)

or

Claim 2 of Broad Application No. 16/177,403:

52.  A method comprising: introducing into, or expressing in, a eukaryotic cell having a DNA molecule,
    (I) a Cas9 protein or one or more nucleotide sequences encoding the Cas9 protein;
    (II) an RNA or one or more nucleotide sequences encoding the RNA, the RNA comprising: (a) a first RNA comprising a first ribonucleotide sequence and a second ribonucleotide sequence, and (b) a second RNA;
and
    (III) a template polynucleotide;
wherein, the second RNA forms an RNA duplex with the second ribonucleotide sequence, and wherein, in the eukaryotic cell, the first ribonucleotide sequence directs the Cas9 protein to a target sequence of the DNA molecule, whereby the Cas9 cleaves both strands of the DNA  molecule and the cleavage is repaired by integration of the template polynucleotide into the DNA molecule in the eukaryotic cell.

In proposing this Substitute Count, Broad emphasizes Sigma-Aldrich's contentions during prosecution that its invention comprised "cleave + insertion" CRISPR methods in eukaryotic cells which were patentably distinct from embodiments comprising "cleavage only" followed by non-homologous end joining of the cleaved DNA target.  In making this Motion, Broad clearly intends to cabin Broad's claims at risk in the interference to a small subset of its claims.

In support of its Motion, Broad relies heavily on Sigma-Aldrich's arguments taking substantially the same position in Interference No. 106,132 against Junior Party the University of California, Berkeley; the University of Vienna; and Emmanuelle Charpentier (collectively, "CVC") (see "Sigma-Aldrich Files Substantive Preliminary Motion 1 to Change the Count in Interference No. 106,133"), including arguments Sigma-Aldrich has made regarding the propriety of its claims not being part of other interferences having interfering subject matter limited to "cleavage only" eukaryotic CRISPR methods:

Sigma is properly not a party to those pending 'cleavage only' interferences because all of Sigma's involved claims are directed solely to the patentably distinct 'cleavage plus integration' technological advance in the art.

Broad broadens the scope of what Sigma-Aldrich asserts it is entitled to, excluding "no cleavage, cleavage only, altering gene expression, or other forms of cleavage and repair" reciting claims.  Broad also alludes to what can be characterized as a "quasi-estoppel" argument, that Sigma-Aldrich was able to get their claims allowed based on these arguments distinguishing "cleavage only" and "cleavage + integration" eukaryotic CRISPR embodiments and so should not be permitted to ignore these limitations now.

In its argument, Broad agrees with Sigma-Aldrich that the Count should be changed based on the arguments Sigma-Aldrich made in the '132 interference, raising a possible later argument that Sigma-Aldrich should not be heard in Opposition to substituting the Count (in contrast for example on an Opposition based on how the Count should be substituted).  In making this argument, Broad asserts that Sigma-Aldrich should not be permitted to seek the "anomalous possibility" of being permitted to seek priority over Broad's "cleavage only" claims-in-interference based on the Count of the Interference as declared (and thus, presumably, should not be permitted to oppose Broad's motion on the merits):

Count 1 allows Sigma just that opportunity, to try to claim priority to the entirety of Count 1—which it has represented to the Office covers two separate species inventions—based only on proofs that it allegedly made one of those species—Donor Template Integration.  This is not "consonant with [the] fundamental purpose [of an interference] to determine priority separately as to each common, patentably distinct invention."  Zymogenetics, Inc., [(6,528,050), Junior Party, v. Ludwig Instit. for Cancer Res. and Licentia LTD. (09/852,209), Senior Party, Int'f No. 105,433] 2006 WL 6630888 [(Bd. Pat. App. & Interf. Sept. 26, 2006)].

Broad further argues that maintaining the Count as declared would deny Broad the benefit of its "best proofs," which Broad contends relate to embodiments of eukaryotic CRISPR that (1) do not include a "donor polynucleotide template" (i.e., exogenous DNA to be inserted at the CRISPR cleavage site) and (2) are limited to single molecule sgRNA (rather than the dual-molecule, crRNA and tracrRNA, embodiments, Broad contends its inventors had reduced to practice much earlier than either CVC's sgRNA-limited CRISPR experiments or their own (the latter being subject to CVC's allegations in Interference No. 106,115 that Broad derived from their disclosure; see "CVC Files Reply to Broad's Opposition to CVC's Priority Motion").  For Broad, the Count as declared represents a "Catch-22" wherein it cannot satisfy the Sigma-Aldrich portion of the McKelvey Count because it lacks best proofs of "cleavage + integration" embodiments and cannot satisfy its own portion of the Count because it is limited to sgRNA embodiments.

As to what Broad proposes should happen regarding its claims-in-interference, Junior Party again references Sigma-Aldrich's motions in the '132 Interference and specifically addresses these issues here, specifying "claim 30 of U.S. Patent No. 8,906,616 ("616 patent") . . . , claim 14 of U.S. Patent No. 9,840,713 ("713 patent") . . . , claims 14-16 of U.S. Patent Application Nos. 14/704,551 ("551 application") . . . , and claims 52-54 of the 403 application . . ." as Broad claims corresponding to Proposed Substitute Count 3.

Broad argues and presents evidence in the Appendices to its brief that all of Sigma-Aldrich's involved claims are limited to "cleavage + integration" embodiments of eukaryotic CRISPR while Broad's claims to such embodiments are much more limited, and the remaining Broad claims are not limited in ways that fall within the scope of Proposed Count 3.

Broad then sets forth an extensive explication of Sigma-Aldrich's prosecution history to support its contention that the Count should be substituted consistent with these representations that claims to "cleavage only" and "cleavage + integration" eukaryotic CRISPR embodiments were directed to patentably distinct inventions.

Similarly, Broad sets forth a synopsis of Sigma-Aldrich's arguments in the '132 Interference (having CVC as Junior Party) in support of substituting the Count analogously to what Broad is proposing in its Motion No. 1.

After explicating these factual issues, Broad provides its legal argument in support of substituting the Count based on these arguments:

• "First, as Sigma acknowledged in the '132 Interference, a Count that includes Non-Template activity—such as current Count 1 here—does not reflect the scope of the common interfering subject matter claimed by the parties.

• "Second, 'a showing that an original count encompasses patentably distinct species is a proper basis for redefining the count to limit the interference subject matter to a single patentable invention and thereby exclude from its scope a second patentably distinct invention,' citing Zymogenetics, 2006 WL 6630888 (citing [Lee v. ]McIntyre, 55 USPQ2d [1137, 1142, BPAI 2000)].

• "Third, Count 1 would unfairly exclude Broad's best proofs to the generic eukaryotic subject matter. Broad's best and earliest proofs—like many of its designated claims—are dualRNA and not directed to Donor Template Integration."

Proposed Substitute Count 3 cures these deficiencies, Broad argued.

In addition to asking the Board to substitute the Count, Broad also asks that it be given priority to U.S. provisional application No. 61/736,527 having a filing date of December 12, 2012 (which would not result in Broad becoming Senior Party in view of Sigma-Aldrich's December 6, 2012 priority date).  Broad sets forth its argument for having the benefit of priority to its December 12, 2012 filing date, again based not only on the merits but on Sigma-Aldrich's reliance on the PTO Examiner allowing its '204 claims-in-interference based on Sigma-Aldrich's representation that Broad's '527 priority document satisfied the "relevant limitations," i.e., integrating donor DNA.  Broad further argues that it has properly maintained continuity of its priority claim from its December 12, 2012 priority date through the intermediate applications wherein "cleavage + integration" eukaryotic CRISPR embodiments were expressly disclosed.

Broad contends that Proposed Substitute Count 3 is patentable over the prior art, relying in part on Regents of Univ. of Cali. v. Broad Instit., Inc., 903 F.3d 1286, 1293 (Fed. Cir. 2018).

Finally, Broad sets forth its arguments for claim correspondence of its claims in interference and those claims that do not correspond, and that all Sigma-Aldrich's claims in interference correspond to Proposed Substitute Count 3.

By Kevin E. Noonan —

Pursuant to the Patent Trial and Appeal Board Order issued November 29, 2021, Junior Party the University of California, Berkeley; the University of Vienna; and Emmanuelle Charpentier (collectively, "CVC") on December 17, 2021 filed its Responsive Preliminary Motion No. 1 in Interference No. 106,132 (which names Sigma-Aldrich as Senior Party), asking the Board for benefit of priority to U.S. Provisional Application No. 61/652,086, filed May 25, 2012 ("P1"), or in the alternative either U.S. Provisional Application No. 61/716,256, filed October 19, 2012 ("P2"); U.S. Provisional Application No. 61/757,640, filed January 28, 2013 ("P3"); U.S. Application No. 13/842,859, filed March 15, 2013; U.S. Application No. 14/685,504, filed April 13, 2015; or U.S. Application No. 15/138,604, filed April 26, 2016, pursuant to 37 C.F.R. §§ 41.121(a)(1)(ii) and 41.208(a)(3) and Standing Order ¶ 208.4.1, contingent on the Board granting Sigma-Aldrich's Substantive Preliminary Motion No. 1 to Substitute the Count.

The relationships between the patents and applications in the '132 interference are set forth in this chart (filed in CVC's earlier preliminary motion in Interference No. 106,115):

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 benefits of Senior Party status.

CVC has filed similar motions in earlier Interferences (in the '115 Interference and in Interference No. 106,127) without (at least complete) success (as to the '115 Interference; the Board has not yet ruled on the corresponding motion in the '127 Interference) and in this Interference with regard to the Count as declared.  Unlike in each of these cases, however, CVC seeks priority benefit to the earliest of its priority documents which focuses the argument to what was disclosed therein.  Specifically, the brief references the disclosure for using sgRNA in a pre-assembled ribonucleoprotein complex with Cas9 microinjected into fish embryos, human cells, and fruit fly cells and produce double-stranded breaks at specific target sequences followed by homology-directed repair using endogenous cellular machinery.  Because these functions comprise the elements of CRISPR as recited in the Substitute Count, CVC argues they are entitled to P1's May 26, 2012 priority date (or in the alternative the filing dates of the P2, P3, or other utility applications set forth in the brief).

The brief sets forth the legal requirements for priority benefit (i.e., describing one embodiment falling within the scope of the Count; Falkner v. Inglis, 448 F.3d 1357, 1362 (Fed. Cir. 2006)) as understood by one of ordinary skill in the art (setting forth the characteristics of this entity).  As part of the latter standard, the brief sets forth the level of skill in the art at the priority date, specifically with regard to ZFN- and TALEN-mediated methods for site-specific DNA cleavage in eukaryotic cells, as models for CRISPR-Cas9 mediated cleavage (noting that Sigma-Aldrich's '204 application in interference makes this comparison expressly).  And in addition, the brief notes that those in the field pursuing eukaryotic CRISPR embodiments themselves adapted existing ZFN and TALEN protocols for performing sgRNA comprising CRISPR systems.

In making these arguments, CVC disparages (gently) the Board's decision in the '115 Interference granting their Preliminary Motion No. 1 only in part (i.e., to confer priority benefit to their P3 provisional application only).

The brief then turns to Sigma-Aldrich's Proposed Substitute Count No. 2:

Claim 156:       

[1] A method of cleaving or editing a target DNA molecule or modulating transcription of  at least one gene encoded thereon, the method comprising:
    contacting [in a eukaryotic cell] … a target DNA molecule … with an engineered and/or non-naturally-occurring Type II [CRISPR] system comprising:
    [2] a) a single molecule DNA-targeting RNA comprising
        [3] i) a targeter-RNA …
        [4] ii) an activator-RNA …
        [5] wherein the targeter-RNA and the activator-RNA are covalently linked to one another with intervening nucleotides; and
    [6] b) a Cas9 protein,
    [7] wherein the single molecule DNA-targeting 1 RNA forms a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule,
[8] whereby said target DNA molecule is cleaved or edited or transcription of at least one gene encoded by the target DNA molecule is modulated, and wherein said contacting occurs in a eukaryotic cell.

Claim 157:

[9] The method of [Elements [1]-[8]], wherein, prior to the contacting step, the method comprises: introducing [the sgRNA and the Cas9] into the eukaryotic cell containing the target DNA molecule …

Claim 164:

[10] The method of [Element [9]], wherein the method comprises creation of a double strand break in the target DNA molecule which is repaired by a homology-directed repair mechanism which incorporates a sequence of a donor polynucleotide into the target DNA molecule, thereby editing the target DNA molecule.

wherein the bold and bracketed numbers represent the elements in the Proposed Substitute Count that CVC will use to compare its claims to the Count for establishing correspondence therewith.  The brief then sets forth a table of this correspondence between the disclosure and the recited limitations in Sigma-Aldrich's Proposed Substitute Count:

stating "[i]n light of general knowledge in the art and the POSA's high degree of skill, P1 conveys possession of at least one embodiment within the scope of PC2 and all the detail needed to practice it."  The brief then sets forth the details of this correspondence for each of these embodiments as disclosed in the P1 specification (following the same template for this argument regarding the P1 disclosure that CVC had used in similar Motions in other Interferences, for both written description and enablement).  In particular, the brief follows the rubrics of In re Wands to establish enablement, and as CVC has done in earlier interferences the brief sets out post-filing evidence by "independent researchers" showing that the disclosed methods achieved and were adopted for performing CRISPR in eukaryotic cells.  Finally, in this regard (and again reprising earlier arguments) CVC sets forth and rebuts purported "concerns" in the art showing them to have been "unfounded."

The brief then argues that, in the alternative, its P2 and P3 applications are constructive reductions to practice of CRISPR embodiments falling within the scope of Sigma-Aldrich's Proposed Substitute Count ("The same disclosures in P1 are carried forward in P2 and P3"), and further that its '859, '504' and '604 applications provide constructive reductions to practice of CRISPR embodiments falling within the scope of Sigma-Aldrich's Proposed Substitute Count.

The brief concludes with a brief argument that "although not required, those in the field, including the inventors, expected CRISPR-Cas9 to work in eukaryotes" (including "[t]estimony from Luciano Marraffini, Erik Sontheimer, Rodolphe Barrangou, Dana Carroll, Samuel Sternberg, and Jennifer Doudna) and that there is a continuous chain of CVC's involved applications as set forth in the drawing above.