By Kevin E. Noonan —

The latest installment in the cat-and-mouse game of deciding priority in Interference No 106,155 between Senior Party The Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad") and Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") is CVC's filing of its Miscellaneous Motion No. 2 to Exclude Evidence on April 2nd, and Broad's Opposition to this motion, filed on April 9th.

The interference rules (41 C.F.R. § 42 et seq.) provide that a party can object to an opponent's evidence including testimony.  Admissibility of evidence is governed by the Federal Rules of Evidence under 41 C.F.R. § 42.152; expert testimony is governed by the Federal Rules and Daubert v. Merrell Dow Pharmaceuticals, 509 U.S. 579, 593-94 (1993).  Here, CVC argues in its brief in support of Miscellaneous Motion No. 2 that four prior art references should not be considered by the Board because they were not cited in any of Broad's papers; declarations from several individuals, including some of Broad's inventors, are inadmissible as hearsay because these individuals had not been made available for deposition; and certain expert testimony fails the Supreme Court's Daubert test for expert testimony admissibility.

The brief deals summarily with the uncited references, relying on Fed. R. Evid. 403 and 41 C.F.R. § 42.152.2.1 as being irrelevant for being uncited.  Turning to hearsay under Fed. R. Evid. 804, the brief identifies two categories of such inadmissible evidence:  declarations from prior proceedings (significantly, prior Interference No 106,048) that should be excluded according to CVC because the declarants were not made available for cross-examination.  The other category comprises "two expert declarations that recite these hearsay declarations for the truth of the matters asserted therein, and serve as further conduits for presenting the inadmissible hearsay in these declarations."

With regard to the first category, CVC argues that Broad submitted declarations of three fact witnesses (Drs. Sanjana, Lambowitz, and Zhang) for "the truth of the matter asserted" (specifically, timing and success of experiments by Broad inventors) that were submitted to the U.S. Patent and Trademark Office during prosecution of involved Broad patents (Sanjana, Zhang) or was a third-party declaration (Lambowitz).  CVC maintains that it objected to these declarations and Broad did not make these declarants available for cross-examination and thus their declarations constituted inadmissible hearsay, citing specifically Rose v. Frazer, Inf. No. 104,733 Paper 73 at 4 (B.P.A.I. Mar. 29, 2002), and 37 C.F.R. § 42.51(c).  The brief also cites Praxair Distrib., Inc. v. INO Therapeutics LLC, IPR2015-00529, Paper 33 at 2 (PTAB Dec. 22, 2015, and Mexichem Amanco Holdings S.A. de C.V. v. Honeywell Int'l, Inc., Case IPR2013-00576, Paper 36 at 3 (PTAB Sept. 5, 2014), for the proposition that declaration evidence not subject to cross-examination (or an offer for cross-examination) should not be considered by the PTAB in contested cases.  The brief makes the appropriate representations that CVC requested these declarants be made available for deposition and Broad failed to make them available.  In addition, CVC suggests that the accuracy, if not the veracity, of Dr. Sanjana's declaration testimony was uncertain.

The second hearsay objection category involves expert testimony that CVC contends is merely a conduit for introducing (improperly) fact rather than opinion testimony.  CVC also argues that certain of the testimony (involving "state of mind" of inventors and others) violates "at least one of FRE 801, 802, and 804" as well as 41 C.F.R. § 42.152.2.1.  This type of testimony is particularly objectionable to CVC because it involved opinions on when Broad scientists possessed the invention and recognized that CRISPR could be performed using eukaryotic cells (certainly important if not dispositive factors involved in this interference).  Such testimony also violates Fed. R. Evid. 702 and 704 according to CVC's brief, which also cites In re Fosamax Prods. Liab. Litig., 645 F. Supp. 2d 164, 192 (S.D.N.Y. 2009); Lopez v. I-Flow Inc., No. CV 08-1063-PHX-SRB, 2011 WL 1897548 at *11 (E.D.N.Y. 2011); Fisher v. Halliburton, No. H-05-1731, 2009 WL 5216949 at *2 (S.D. Tex. Dec. 21, 2009); In re Heparin Prod. Liab. Litig., 803 F. Supp. 2d 712, at *8-9 (N.D. Ohio Mar. 21, 2011); and Hines v. Wyeth, No. 2:04-0690, 2011 WL 2680842 at *7 (S.D. W. Va. July 8, 2011).

With regard to its "conduit" theory, CVC cites Rule 703 for this principle, that "an expert is permitted to disclose hearsay for the limited purpose of explaining the basis for his expert opinion, but not as general proof of the truth of the underlying matter," citing Fox v. Taylor Diving & Salvage Co., 694 F. 2d 1349, 1356 (5th Cir. 1983), and United States v. Garcia, 793 F. 3d 1194, 1212 (10th Cir. 2015).  CVC specifically alleges that Drs. Seeger, Breaker, and Mirkin merely "[p]arrot[] extrajudicial information for the truth of the matter asserted" in certain portions of their declarations.  Moreover, CVC asserts that permitting Broad to introduce these factual assertions would permit Broad's scientists to enter "unchallengable statements" into the record, and "bootstrap untested evidence as proof of the underlying subject matter."

As it has in its Replies to Broad's Opposition to CVC's Motions No. 1 and No. 2 for benefit of priority, CVC takes particular issue with the testimony of Dr. Chad Mirkin.  As in those Replies, CVC argues that Dr. Mirkin is not an expert in genetic engineering (CVC asserts his expertise is in nanoparticles) and thus "his opinions are therefore irrelevant and unreliable" and the PTAB should discount his testimony under Daubert.  CVC states that it would be an abuse of discretion for the PTAB to permit Dr. Mirkin's testimony to be considered admissible in this interference, and that the status of an interference as being more in the nature of a bench trial instead of a jury trial does not change these considerations nor abrogate the Board's gatekeeping function.  CVC also contends that Dr. Mirkin's testimony is merely an "improper narrative based on no personal knowledge nor expertise" and hence inadmissible under FRE 602, 701-703, 801, and 802.  Nor should an expert be "an advocate or storyteller" without relevant expertise (which CVC argues Dr. Mirkin does not have), citing In re Rezulin Prods. Liab. Litig., 309 F. Supp. 2d 531, 551 (S.D.N.Y. 2004), and In re Prempro Prods. Liab. Litig., 554 F. Supp. 2d 871, 886 (E.D. Ark. 2008).  "In other words, an expert who merely reads or summarizes documents for the factfinder is not providing helpful testimony because the factfinder is capable of reading and reaching conclusions on its own," according to CVC's brief.  In this case and this witness, according to CVC, "Dr. Mirkin understands the relevant technology only well enough to serve as Broad's mouthpiece, and was unable to answer even the most basic questions about the technology or the evidence that was not part of his prepared statement."  For these reasons, CVC argues that the Board should rule the identified portions of Dr. Mirkin's testimony inadmissible.

Broad disagrees, and its brief in opposition makes two broad points.  First, Broad characterizes the evidence objected to as hearsay was submitted merely as a "proffer" to the Board that set forth Broad's arguments to be submitted during the Priority Phase, citing Byrn v. Aronhime, Patent Inf. 105,384 (McK), Paper 64 at 12:17-20 (PTAB Sept. 20, 2006).  Second, Broad asserts that CVC made similar proffers relying on purported hearsay during the '048 Interference; albeit not citing any precedent for such a "tit-for-tat" principle or evidentiary standard, but does use the argument to allege that CVC is being "disingenuous" (as well as being incorrect) for presumably trying to impose a stricter standard on Broad in this interference than was applied to CVC in the earlier '048 interference.

With regard to the availability vel non of Broad's declarants as a basis for considering their testimony to be hearsay, Broad in its turn dismisses these objection summarily by asserting that CVC never requested depositions of these witnesses.

Broad asserts it proffer exception to the hearsay rule for the Sanjana, Lambowitz, and Zhang declarations, as well as the Cong 2013 reference.  Broad argues that CVC's hearsay objections "are, at best, premature."  The brief asserts instances in the '048 Interference where CVC made a proffer based on the type of evidence that CVC now objects to as hearsay.  Broad also makes "policy" arguments, citing the impracticality of subjecting to cross-examination "the authors of any exhibit used in a proffer, and even the lawyer explaining the import of those exhibits" which supposedly would be occasioned by CVC's interpretation of admissibility of this evidence.  More persuasively, Broad's brief notes that in the cases CVC cited in support of its objections the PTAB admitted the objected-to evidence but retained the ability to take those objections into consideration when deciding the weight to give to the evidence.  With regard to the Cong reference, Broad makes a related argument, that as a reference the Board is capable of considering it for what it says, citing Rozbicki v. Chiang, Inf. 105,898, Paper 154 at 25 (PTAB June 26, 2013) 10 (explaining that a document is always "admissible as proof of what it says"), as well as falling within the hearsay rule exception set forth in FRE 807 (which, as a reminder, is the "residuary" rule permitting evidence to be considered if (1) the statement is supported by sufficient guarantees of trustworthiness—after considering the totality of circumstances under which it was made and evidence, if any, corroborating the statement; and (2) it is more probative on the point for which it is offered than any other evidence that the proponent can obtain through reasonable efforts).

One drawback to the proffer argument, and its application to the Priority Phase, is that any such proffer is not being made in the Priority Phase but in the Motions Phase, and particularly with regard to Broad's Motions No. 2 (to substitute the Count), No. 3 (to designate certain claims as not corresponding to the Count), and No. 4 (for priority benefit of U.S. Provisional Application No. 61/736,527).

Regarding CVC's "conduit for hearsay" argument, Broad relies on its "non-hearsay" distinction based on its proffer argument, and buttresses this argument by the general proposition that an expert can rely on hearsay "[i]f experts in the particular field would reasonably rely on those kinds of facts or data in forming an opinion on the subject" under Fed. R. Evid. 703, citing In re Biogen '755 Patent Litig., No. CV102734CCCJBC, 2018 WL 3613162, at *10 (D.N.J. 6 July 26, 2018).  Regarding CVC's objection to one expert's testimony, Broad asserts that these "ring hollow" because CVC purportedly relied on "similar expert testimony" in the '048 Interference (calling this "a double standard").  The brief also cites as "baseless" CVC's "storyteller" objection, because according to Broad their expert simply relied on "evidence going to key issues."

Not surprisingly, Broad defends the competence of its expert Dr. Mirkin, noting that his expertise is relevant to eukaryotic applications of CRISPR technology, specifically having to do with technology for introducing proteins and nucleic acids into eukaryotic cells ("Dr. Mirkin is . . . one of the world's foremost experts in the chemistry and use of nanostructures for delivery of proteins and nucleic acids to eukaryotic cells") (although without establishing that such methods were methods used to introduce protein and nucleic acid components of CRISPR into eukaryotic cells).  And the brief reminds the Board of Dr. Mirkin's bona fides, including that "[h]e has published over 740 manuscripts, has been issued over 330 patents, and has been the recipient of over 100 national and international awards for his work in the above-mentioned areas" and that he "is one of very few scientists to be elected to all three US National Academies: the National Academy of Medicine, the National Academy of Sciences, and the National Academy of Engineering."  The brief then goes on to cite case law regarding the (relatively) permissive standards of expert testimony under FRE 702 ("a broad range of knowledge, skill, experience, training, and education [is sufficient] to qualify an expert as such), citing Pineda v. Ford Motor Co., 520 F.3d 237, 244 (3d Cir. 2008); Carnegie Mellon Univ. v. Marvell Tech. Grp., Ltd., 807 F.3d 1283, 1303 (Fed. Cir. 2015); and SEB S.A. v. Montgomery Ward & Co., 18 594 F.3d 1360, 1373 (Fed. Cir. 2010) ("Where an expert's testimony "establishe[s] an adequate relationship between his experience and the claimed invention," the expert will generally be qualified.).

More specifically and relevant to the question of Dr. Mirkin's competency to testify as an expert in this interference, Broad argues that he was "exceedingly well-qualified" to speak to the question of the difficulties and challenges in adapting CRISPR to eukaryotic cells (a theme Broad developed successfully to convince the Board in the '048 Interference that there was no interference-in-fact).  Dr. Mirkin testified on this point expressly in his deposition, reproduced in the brief:

I think ultimately the basis of my expertise is the work that I do generally in the development of nucleic acid and protein-based medicines and an understanding,  perhaps a unique understanding, of the challenges associated with taking those types of constructs into cells and getting them to function properly.

(put more succinctly, testifying that his lab had developed over "decades" "a series of platforms . . . that are extremely good at moving nucleic acids and proteins into cells").  Because the ability to introduce the components of CRISPR-Cas 9 were "some of the greatest challenges with respect to [eukaryotic applications of] CRISPR" this expertise qualified him "to opine on whether a POSA would have understood CVC to have had possession in 2012 of a CRISPR-Cas9 system engineered to perform effectively in the complex environment of a eukaryotic cell."

Broad addressed directly the "storytelling" argument regarding Dr. Mirkin asserted by CVC in its brief, contending that his "application of his experience to an extensive review of the relevant scientific facts and data" was permissible for expert testimony.  And as for the specific deficiencies CVC asserts Dr. Mirkin demonstrated on particular questions relating to CRISPR technology in his deposition, Broad argues that this is a mischaracterization of his testimony and/or takes his testimony out of context (issues the Board will be able to determine for itself).

On balance, Broad set forth a robust defense of the qualifications of its expert witness, and it seems unlikely that the Board will rule his testimony inadmissible.  What remains unclear is the extent to which CVC's disparagements of Dr. Mirkin's general competence in CRISPR technology and deficiencies on specific points will cause the Board to diminish the weight it gives to his testimony.

By Kevin E. Noonan —

March 23rd was the deadline for the parties in Interference No. 106,115 between Senior Party The Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad") and Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC"), to file their Reply Briefs to their opponents' Opposition to each parties Motions authorized by the PTAB last summer.  See "CRISPR Interference Parties Propose Motions" and "PTAB Redeclares CRISPR Interference and Grants Leave for Some (But Not All) of Parties' Proposed Motions".  CVC's Motion No. 2 was to be accorded the benefit of priority to three earlier-filed provisional applications contingent on the Patent Trial and Appeal Board granting the Broad's Motion No. 2 to Substitute the Count of the interference.

The Broad's proposed Count was as follows:

A method, in a eukaryotic cell, of cleaving or editing a target DNA molecule or modulating transcription of at least one gene encoded by the target DNA molecule, the method comprising:
    contacting, in a eukaryotic cell, a target DNA molecule having a target sequence with an engineered and/or non-naturally-occurring Type II Clustered Regularly lnterspaced Short Palindromic Repeats (CRISPR)-CRISPR associated Cas) (CRISPR-Cas) system comprising:
        a) a Cas9 protein, and
        b) RNA comprising
            i) a targeter-RNA that is capable of hybridizing with the target sequence of the DNA molecule or a first RNA comprising (A) a first sequence capable of hybridizing with the target sequence of the DNA molecule and (B) a second sequence; and
            ii) an activator-RNA that is capable of hybridizing to the targeter-RNA to form an RNA duplex in the eukaryotic cell or a second RNA comprising a tracr sequence that is capable of hybridizing to the second sequence to form an RNA duplex in the eukaryotic cell,
    wherein, in the eukaryotic cell, the targeter-RNA or the first sequence directs the Cas9 protein to the target sequence and the DNA molecule is cleaved or edited or at least one product of the DNA molecule is altered.

The distinction the Broad made in its Motion was between embodiments of CRISPR methods that are limited to "single-molecule guide RNA" (aka "fused" or "covalently linked" species), versus embodiments that encompass single-molecule and "dual molecule" species (wherein in the latter versions, the "targeter-RNA" and "activator-RNA" as recited in the proposed Count are not covalently linked).  The Broad argued that this Count should be adopted by the Board because it "properly describes the full scope of the interfering subject matter between the parties because both parties have involved claims that are generic, non-limited RNA claims."  The brief also argued that proposed Count 2 "sets the correct scope of admissible proofs [i.e., their own] for the breakthrough invention described by the generic claims at issue in these proceedings—the successful adaption of CRISPR-Cas9 systems for use in eukaryotic environments," which The Broad contended current Court 1 (in either alternative) does not.

In its Motion No. 2, CVC argued that it was entitled to priority to its earliest priority documents (USSN 61/652,086, filed May 25, 2012 (P1); USSN 61/716,256, filed October 19, 2012 (P2); USSN 61/757,640, filed January 28, 2013 (P3)) when this interference was declared, and filed this authorized contingent motion on October 14th to be accorded benefit.  As with CVC's Motion No.1 for priority under present Count 1, the significance for CVC should this motion be granted is that CVC and not the Broad would be Senior Party, with all the procedural advantages that status confers (the greatest of which being that CVC would be the presumptive first inventor).

The arguments in this Reply Brief are parallel to the arguments CVC made in its Reply to the Broad's Opposition to CVC's Motion No. 1 for priority discussed in an earlier post (see "CVC Reply No. 1 to Broad's Opposition No. 1 to CVC's Motion No. 1 to Be Accorded Benefit of Priority").  These include that CVC was entitled to priority because priority application P1 (and, in the alternative, P2 and P3) set forth in detail the disclosure for at least one embodiment falling within the scope of proposed Count 2.  Although P1 did not disclose actual reduction to practice of CRISPR-Cas9 in eukaryotic cells, CVC maintains that "[t]he CVC inventors immediately understood that the CRISPR-Cas9 DNA-cleavage complex could be used in a variety of different cellular and noncellular settings."  According to CVC:

P1 disclosed methods sufficient for a POSA to practice the method of [Proposed Count 2] without undue experimentation, and Broad has not proffered any credible evidence to the contrary.  While not required, CVC even provided post-filing date evidence confirming that materially the same methods disclosed in P1 for employing CRISPR-Cas9 in eukaryotes were successful.

As in Reply Brief No. 1, CVC argues that "Broad asserts arguments founded on legal and factual inaccuracies:

(i) Broad misconstrues blazemarks law by importing into the count elements that simply are not present, and Broad ignores P1's clear blazemarks;

(ii) Broad requires a working example for written description despite the clear legal precedent that neither examples nor actual reduction to practice is required;

(iii) Broad post-hoc fabricates reasons—with no credible evidence—that a POSA would have expected P1 to disclose "unique conditions" for using CRISPR-Cas9 in eukaryotes for adequate written description; and

(iv) Broad distorts the legal standard for constructive reduction to practice by conflating obviousness with written description and enablement, arguing that adequate written description and enablement must provide a POSA with a reasonable expectation of success."

CVC argues in its Reply that it disclosed three "example embodiments" in P1 that fell within the scope of Proposed Count 2:  a fish cell (E4), a human cell (E5), and a fruit fly cell (E6).  CVC argues that P1 provides a written description for each embodiment, and that this description in conjunction with the general knowledge in the art would have enabled a person having ordinary skill in the art (POSA) in 2012 to make and use each embodiment without undue experimentation, that each embodiment meets all the limitations of Proposed Count 2, and that this was sufficient for CVC to be entitled to the benefit of priority to the invention set forth in Proposed Count 2, citing Falkner v. Inglis, 448 F.3d 1357, 1362 (Fed. Cir. 2006); Storer v. Clark, 860 F.3d 1340, 1345 (Fed. Cir. 2017); 37 C.F.R. § 41.201.

CVC argues that the Broad's arguments regarding putative insufficiencies in it P1 priority application conflate the requirements for obviousness, particularly the "reasonable expectation of success" under which the Broad prevailed in the earlier interference between these parties (Interference No. 106,048) and the enablement requirement under 35 U.S.C. § 112(a) and In re Wands, 858 F.2d 731, 739 (Fed. Cir. 1988), that the disclosure be sufficient that the invention can be practiced by one having ordinary skill in the art without undue experimentation.  CVC argues that the Broad's arguments are legally deficient:

Blazemarks cases deal with situations where the applicant made specific selections from multiple long lists to arrive at a specific, narrowly claimed invention, such as a specific compound, plasma concentration, or specific mutation.  In re Ruschig, 379 F.2d 990, 993 (CCPA 1967); Purdue Pharma v. Faulding Inc., 230 F.3d 1320, 1327 (Fed. Cir. 2000); and Novozymes v. DuPont Nutrition Biosci., 723 F.3d 1336, 1348 (Fed. Cir. 2013).  These cases demonstrate that blazemarks are merely a tool to assess written description support for a claim.  This tool provides a backstop of objective proof that a POSA would recognize in the specification the claimed subject matter, and prevents hindsight selection of narrow subject matter to demonstrate that the Applicants possessed the invention.  The tool is inapt where, as here, (1) the features are not an element of the count, and (2) Broad has not presented evidence that alternative features (e.g. alternative eukaryotic cells, target sequences, or delivery methods) are inoperable.  See Novozymes, 723 F.3d at 1350.

CVC further argues that the POSA at the time the P1 priority document was filed would have understood, from the P1 disclosure, that the CRISPR-Cas9 systems described therein could be performed in vitro, in a prokaryotic cell, and in a eukaryotic cell, by explicit disclosures thereof.  The Reply brief cites expressly in support of this argument the disclosure of CRISPR-Cas9 systems in Example 1, which include "a fish cell, human cell, and fruit fly cell."  CVC also cites the disclosure of claim 67 of P1, which recites a method of using the CRISPR-Cas system in a vertebrate cell, and notes that there are "only five types of vertebrate cells [as disclosed] in paragraph [00165]:  "a cell from a vertebrate animal (e.g., fish, amphibian, reptile, bird, mammal)."  As for disclosure of practice of CRISPR in human cells, the Reply brief cites Claim 69 of P1, which is directed to a method of using the CRISPR-Cas system in a human cell.  Finally, CVC cites the "[n]umerous researchers [who] used materially the same components and methods disclosed in P1 to make embodiments of [Proposed Count 2]" after the P1 priority date, which CVC states "confirm[s] enablement."

And as in CVC's Reply No 1, its Reply No. 2 take to task the Broad's expert declarant, for personal lack of competence with regard to CRISPR technology ("Dr. Mirkin's research focus is nanoparticles—not CRISPR or any other type of gene editing") and that "Dr. Mirkin's testimony is fraught with conclusory statements and speculation, contravening 37 C.F.R. § 41.158(a) ("[e]xpert testimony that does not disclose the underling facts or data on which the opinion is based is entitled to little or no weight.").  CVC's arguments and examples regarding specific deficiencies tracked its arguments in its Reply No. 1, that Dr. Mirkin's review was "myopic" based on testimony where the expert "admitted" that he only reviewed "a select four paragraphs of Example 1 in P1," and stated that his testimony was "based on my review paragraphs [00248]-[00251] [that] do not disclose) any . . . 'blazemarks'" for performing CRISPR in eukaryotic cells.  According to CVC, "Dr. Mirkin ignored other disclosures in P1 that clearly describe using the CRISPR-Cas9 systems in eukaryotic cells."

This Reply brief also concludes with CVC refutation of the Broad's arguments as merely being an attempt to apply its (and the Board's) obviousness determination in the '048 Interference to the current interference, which is error due to the different evidentiary showings between the two Interferences, and misreads the holding on In re Wright, 866 F.2d 422 (Fed. Cir. 1989), regarding the evidentiary standards for establishing enablement.