Last week, Junior Party The University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") filed its reply to Senior Party The Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad") motion in opposition (see "Broad Files Motion in Opposition to CVC Priority Motion") to CVC's motion for priority in Interference No. 106,115.

The Reply is (relatively) direct and to the point (motivated no doubt as much by the page limit in Reply briefs as to the rhetorical force of a short, pithy, to-the-point argument).  (Although to be fair the brief begins with a reminder that the CVC inventors "revolutionized the field of genome editing, giving the world a new system capable of cleaving and editing genes in eukaryotic cells," mixing the irrebuttable with the precise question the Board is asked with answering.)  The critical component of this achievement (no matter who did it) is the development of the combination of the tracr RNA and crRNA into a single guide RNA (sgRNA).  Asserting their multiple instances of earlier conception, CVC contends that these conceptions predated any conception by the Broad's inventors, accompanied by CVC's diligence in achieving reduction to practice.

The brief also counters Broad's long-running narrative, extending from the earlier interference between these parties (No. 106,048), that those skilled in the art would not have thought performing CRISPR in eukaryotic cells would be a routine extension of CVC's undoubted successes in performing prokaryotic CRISPR.  The brief asserts "new" testimony from its own witnesses (Barrangou and Sontheimer) as well as testimony adduced from Broad's collaborator Dr. Marraffini to the contrary.  The brief attempts to turn the Broad's inventors' achievements against Broad, as being actual corroboration of their assertions, by referencing Dr. Marraffini's testimony suggesting derivation of the sgRNA concept from a scientific talk by one of the CVC inventors, and then contending that the straightforward reduction to practice of this concept by Broad's inventors is actually evidence that doing so was straightforward and routine.

The brief sets out three reasons why CVC should prevail on the priority question:

• First, CVC argues earlier conception, coupled with "reasonable diligence" in actual reduction to practice.  And this "definite and permanent idea never changed," according to CVC, evidenced by its use in all later actual reduction-to-practice events.

• Second, CVC had conceived of a "preformed" CRISPR-Cas9 complex that they showed (on August 9, 2012) could achieve CRISPR-mediated genetic changes in eukaryotic cells by microinjection.  This method for achieving CRISPR in eukaryotic cells occasions none of the technical impediments Broad has asserted against eukaryotic CRISPR, and neither the Count nor the claims-in-interference are limited to specific methods of introducing CRISPR-Cas9 into eukaryotic cells.  In addition, CVC argues with regard to this reason that Broad has not provided any evidence that CVC's diligence was deficient (other than attacking the completeness of CVC's conception based on purported failure of actual reduction to practice attempts).

• Third, CVC finally gives full-throated voice to their allegation that the Broad inventors derived eukaryotic CRISPR from CVC's scientists.  The allegation is based on the testimony CVC adduced from Dr. Marraffini in his deposition, to the effect that Dr. Marraffini disclosed to the Broad inventors CVC's sgRNA embodiment after learning of it from review of a confidential manuscript and attending a scientific presentation.  This evidence is supported, according to CVC, by evidence from a graduate student working under Dr. Zhang that Broad's experiments relating to eukaryotic CRISPR had "all failed" prior to Dr. Marraffini's disclosure.

With regard to the first of these reasons, CVC reiterates the evidence it has proffered for conception as early as March 1, 2012.  (While a necessary part of their argument, the facts of CVC's conception(s) are not in dispute; rather, Broad has argued that the history of CVC's attempts to reduce the invention to practice, which is their view was protracted due to the non-routine nature of these experiments, should be held to mean that CVC's conception was not complete until actual reduction to practice, which occurred after Broad's June 26, 2012 conception date.)  CVC's brief in this regard focuses on elements of its conception with respect to various features of the CRISPR-Cas9 system (the presence of a nuclear localization sequence, NLS, for example), as well as the formation of a CRISPR-Cas9 RNP in vitro capable of being introduced into eukaryotic cells by microinjection.  Moreover, CVC argues that the embodiment it relies upon for priority is the same embodiment disclosed in Example 2 of its P3 application (USSN 61/757,640, filed January 28, 2013; see "PTAB Decides Parties' Motions in CRISPR Interference"), for which the Board had recognized its sufficiency as for at least constructive reduction to practice of eukaryotic CRISPR:

And regarding Broad's assertions that their inventors had "adapted" CRISPR for eukaryotic applications, CVC argues this embodiment had overcome any such impediments:

Because the Board rendered this decision with regard to their motion for priority benefit, CVC argues, constructive reduction to practice of this embodiment prior to Broad's earliest asserted conception date mandates the Board to grant its motion of priority of claims corresponding to the Count.

CVC also addressed Broad's various arguments regarding purported deficiencies in its conception, again with reference to this specific embodiment of eukaryotic CRISPR (and characterizing Broad's argument as "fabricat[ing] an illusion of doubt in the inventors' minds by cataloging snippets from 12 various CVC documents").  According to CVC, all Broad's "evidence" of CVC's deficiencies "simply reflect that the inventors understood and considered these routine implementation issues during the process and, at all stages, had a plan to address them," supported by inventor testimony.

With regard to CVC's second reason it is entitled to priority judgment, the brief argues complete conception consistent with the elements of Count 1:

This evidence establishes that CVC's conception was "definite and permanent" according to the brief, again relying on assertions by the Board regarding Example 2 of CVC's P3 priority application.  The brief asserts for the significance of this embodiment as actual reduction to practice regarding Broad's arguments that CVC's conception was deficient:

There is no need for codon optimization, RNA or protein expression, concomitant folding, and co-localization of RNA and protein, because the complex is already formed before injection.  The use of pre-formed complexes also minimizes RNA and protein degradation, because the complex is protected from cellular factors, as it is in bacterial host cells [Testimony of Dr. Moens, CVC expert witness, italics in brief].

In addition, CVC's brief sets forth its evidence that "[m]ultiple lab groups used CVC's system with only ordinary skill and routine techniques," as well as testimony from several references regarding expectations of those skilled in the art, as further evidence of complete conception (as well as reiterating its argument that Broad's efficient reduction to practice is actually evidence supporting CVC's complete conception).  Specifically CVC argues:

The PTAB may not ignore the copious objective evidence showing that CVC and the rest of the field understood the alleged "problem" and knew how to solve it.  . . .  That neither CVC nor others encountered "perplexing intricate difficulties arising every step of the way" or "unduly extensive research or experimentation" when applying CVC's sgRNA CRISPR-Cas9 system in eukaryotic cells confirms the completeness of CVC's 22 conception [citations omitted].

And the existence of some failures in attempts to practice eukaryotic CRISPR is "irrelevant," according to CVC, because "[t]he law does not require a 100% success rate for attempts at reduction to practice" and "[i]n fact, the law of conception does not require any success rate for reductions to practice."

CVC also argues that, with regard to its priority motion granted by the Board regarding it P3 priority application, Broad had not argued a lack of diligence in "August, October, and November 2012, and through CVC's constructive reduction to practice in January 2013," but rather had focused these arguments on March and April 2012.  These dates are "outside the critical period" (i.e., between Broad's conception after CVC's asserted March 1, 2012 date of conception, through CVC's actual or constructive reduction to practice) and thus are unchallenged by Broad according to the brief.

CVC then turns to its legal argument that Broad was attempting to "rewrite conception law" to require a reasonable expectation of success; CVC argues it does not, citing Burroughs Wellcome Co. v. Barr 13 Labs., Inc., 40 F.3d 1223 (Fed. Cir. 1994), and Dana-Farber Cancer Inst., Inc. v. Ono Pharm. Co., 964 F.3d 16 1365, 1372 (Fed. Cir. 2020).  CVC also argues that Broad has mischaracterized Hitzeman v. Rutter, 243 F.3d 1345 (Fed. Cir. 2001), "as requiring both the inventors and a POSA to have a reasonable expectation of success for the inventors to have had a complete conception"; according to CVC, inventors are persons of extraordinary creativity and that the standard is whether here is complete conception in the mind of the inventor rather than a person having ordinary skill in the art.  In any event, CVC argues, its inventors having conceived of and actually reduced to practice the sgRNA CRISPR system "as a pre-formed RNP complex outside of a cell and had a way of delivering the complex into a eukaryotic cell via microinjection" settles the argument.  And if there is any dispute whether CVC's inventors expected CRISPR to be operable in eukaryotic cells, the brief cites contemporaneous statements from both Dr. Doudna and Dr. Charpentier asserting that they did.  The brief also counters Broad's arguments that persons of ordinary skill in the art doubted utility of CRISPR in eukaryotic cells by testimony from witnesses "Raible, Sontheimer, Barrangou, and Marraffini."  Finally, the brief asserts that the purported difficulties of eukaryotic CRISPR did not exist because those impediments would arise (if they did) for protein-mediated methods, whereas CRISPR was fundamentally an RNA-mediated protocol.

Finally regarding CVC's second basis for the Board to render a decision in its favor on priority, the brief notes its several corroborated instances of actual reduction to practice:  in zebrafish on August 9, 2012 and mammalian cells in October and November 2012.

As to the third reason for prevailing, derivation, CVC reiterates its evidence and argument that Broad's inventors derived eukaryotic CRISPR from CVC's inventors, specifically with regard to sgRNA embodiments.  The basis for this argument is the testimony by Dr. Marraffini in his deposition regarding his role as a confidential reviewer of a draft paper that eventually published as the Jinek reference; that Dr. Marraffini attended a scientific conference during which CVC's inventor disclosed this embodiment for use in eukaryotic CRISPR; that Dr. Marraffini appreciated its significance; and that he transmitted this information to the Broad inventors.  An important aspect of these allegations is that, according to CVC, Broad's inventor was unaware of the functional significance of the tracr RNA component of the CRISPR-Cas9 complex until Dr. Marraffini informed him of the sgRNA-containing embodiments.  This evidence compels the Board to grant judgment to CVC in this interference according to the brief.

In conclusion, CVC asserts:

The law rewards inventors, such has CVC, not those who merely derive and then reduce to practice using ordinary skill.  The CVC inventors, not Zhang, invented the subject matter of Count 1.  Whether applying priority of invention law or derivation law, the PTAB should recognize what the scientific community recognized in awarding the Nobel Prize to Charpentier and Doudna: it was their teamwork that made the tremendous scientific leap forward to allow the world to reap the benefits of a single-guide RNA CRISPR-Cas9 system for genome editing in eukaryotes.  The extensive corroborated evidence of record shows this to be the case, and the PTAB should award priority to CVC.