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.