By Kevin E. Noonan —

Last December, Junior Party University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (hereinafter, "CVC") filed its Substantive Motion No. 3 under 37 C.F.R. § 41.121(a)(1) asking for judgment of unpatentability for all claims in interference under 35 U.S.C. § 102(f) or (if post-AIA) 35 U.S.C. § 115(a) for "failure to name all inventors of the alleged invention" against Senior Party The Broad Institute, Massachusetts Institute of Technology, and Harvard University (hereinafter, "Broad") in Interference No. 106,115.  In support of its motion, CVC argued that Broad deliberately misidentified the inventors on its involved patents and applications in the interference.  These allegations were based on differences between the named inventors in the patents- and applications-in-interference and the inventors named in a declaration by the Broad's patent attorney during a European opposition (EP 277146); it may be recalled that such irregularities involving a Rockefeller University inventor (Dr. Luciano Marraffini) not named in the European application were the basis for that patent to be invalidated (see "The CRISPR Chronicles — Broad Institute Wins One and Loses One").  Proper inventorship is important in the interference, inter alia, because the Board needs to know whose testimony can corroborate and whose needs to be corroborated under interference practice, where the uncorroborated testimony of an inventor is given no weight; see, Kolcraft Enters. v. Graco Children's Prods., Nos. 2018-1259, 2018-1260, 2019 U.S. App. LEXIS 19751 (Fed. Cir. July 2, 2019).

At the time, Broad filed a responsive motion asking for leave to correct inventorship, which CVC has opposed; this opposition will be the subject of a future post.  On March 26th Broad filed a motion in opposition to CVC's motion for judgment based on misjoinder of inventorship, which is discussed here.

Broad begins its opposition by asking the Board either to deny CVC's motion outright, or to grant the remedy requested in Broad's Contingent Responsive Motion No. 6 and permit correction of inventorship.  Rather than applying the proper test for inventorship, the Broad contends, CVC took "a shortcut" by arguing that a declaration by distinguished U.S. patent counsel Thomas Kowalski be considered dispositive on the issue of misjoinder.  This declaration set forth Mr. Kowalski's legal conclusions regarding inventorship of one of Broad's PCT applications, which was then submitted as evidence in an Opposition Proceeding against the counterpart granted European patent.  (Broad notes that "[t]he PCT applications that were the subject of that declaration are not involved in this interference.")  Broad then accused CVC of engaging in "a word search exercise, locating words in the PCT applications that match words in the involved claims" and asserting that the inventors of those claims are misjoined inventors of claims-in-interference here.  Broad argues that this effort is without support and should be denied on that basis.

The brief then accuses CVC of creating a fanciful narrative that Broad intentionally omitted inventors in patents-in-interference "so that it could keep in reserve a greater pool of corroborators for this Interference," starting in 2013.  This requires the Board to believe that the Broad's focus at that time was "eight years into the future to some imagined interference where Broad would want to rely on certain individuals for corroboration to help establish priority," a narrative Broad characterizes as "far-fetched".

Broad also objects to CVC's allegations that its prosecuting attorneys were guilty of inequitable conduct for participating in any such chicanery, terming this "rank speculation."  And Broad particularly objects to CVC's requested remedy, citing Federal Circuit precedent permitting 35 U.S.C § 256 and § 116 to be used as a "savings clause" for patents and applications, respectively, that name inventors incorrectly.

On the law, Broad argues that CVC has not carried its burden of establishing misjoinder, its motion being "almost wholly . . . attorney argument."  The declaration of Scott Bailey, proffered in support of CVC's motion, is impermissible expert testimony on a question of law, which is squarely and only within the Board's purview.  Accordingly, Broad argues it should be given no weight.  In addition, Broad argues that Mr. Bailey is a scientist not a lawyer, doubly damning his opinions as being irrelevant to the adverse inventorship determination requested from the Board.  And Broad sets forth another litany, in this case of all the deficiencies in Mr. Bailey's declaration regarding the inventorship question.

Another deficiency Broad alleges in CVC's motion is that CVC did not perform any ("zero") inventorship analysis; Broad argues that "the appropriate legal test for inventorship barely makes a cameo appearance in CVC's motion—if you blink you'd miss it" before setting forth its objections to CVC's inventorship arguments with particularity.  These include not construing the claims and not providing factual support for why certain individuals were not named as inventors in a "claim-by-claim, element-by-element comparison."  Rather, CVC improperly relied on Mr. Kowalski's declaration in the European Opposition which was not directed at the issues CVC used it to support, according to the brief.  Broad uses Mr. Bailey's complaint that performing this analysis would have been a "mammoth task" to argue that the remedy CVC requests — invalidating all of the involved claims in all of the involved patents — requires performance of this task no matter how "mammoth' it may be in scope.  Of course, Broad further argues that such a proper analysis assessment would have found no error (thus providing a reason why CVC didn't make the argument).

The brief also notes that CVC "both relies upon and rejects Kowalski's inventorship analysis," calling this treatment "inconsistent" and providing specific examples.  The brief also argues that CVC does not provide support for its allegations that Mr. Kowalski's declaration should be considered conclusive, other than treating the declaration as a "judicial admission."  Which it is not, Broad argues, because it fails the definition that a judicial admission is a "formal statement[] of fact made in judicial proceedings that have the effect of deeming facts conclusively established, eliminating the need for proof," citing Barnes v. Owens-Corning Fiberglas Corp., 201 F.3d 815, 829 (6th Cir. 2000), as well as failing the definitional evidentiary tests used to establish a judicial admission.

As a consequence, Broad argues, CVC did not satisfy its burden of establishing misjoinder of inventorship and its motion should be denied.

Despite having addressed (and in their view rebutted) the substantive grounds of CVC's misjoinder arguments, Broad takes the time (and page numbers) to provide its rebuttal that it has intentionally omitted inventors for an improper purpose.  "CVC has not established and cannot establish,[ such an improper motive, and] CVC's attribution of an improper motive is unwarranted" according to the brief.

Broad completes its arguments in opposition by asking the Board to permit correction of inventorship as the proper remedy should the Board be swayed by CVC's argument that correction is required.  Broad's brief argues that Egenera, Inc. v Cisco Sys., Inc., 972 F.3d 1367 (Fed. Cir. 2020), Is controlling and permits correction under the appropriate statutory provisions.

By Kevin E. Noonan —

In its turn, Junior Party The University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") filed its motion in opposition to Senior Party The Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad") motion for priority in Interference No. 106,115.  CVC's motion challenges Broad's priority claim and the bases Broad set forth therein, rebutting Broad's legal arguments and mentioning more than once that Jennifer Doudna and Emmanuelle Charpentier received the 2020 Nobel Prize in Chemistry (and by implication that the Broad inventors had not).

CVC's motion is based on two principles.  First, as supported by deposition testimony of Dr. Luciano Marraffini (compelled by the Board's grant of CVC's motion to require compliance), CVC argues that Broad inventor Zhang derived the invention claimed in the patents-in-interference from disclosure of CVC's conception from Dr. Marraffini.  Dr. Marraffini was in possession of CVC's invention because he was a confidential reviewer of the manuscript later published in Science as Jinek et al. (2012, "A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity," Science 337: 816–21).  Dr. Marraffini also attended a CRISPR conference at Berkley on June 26, 2012 where the Doudna lab disclosed its CRISPR findings.  Indeed, the brief contains a comparison between what was disclosed at the meeting, what Dr. Marraffini disclosed to Dr. Zhang, and what Dr. Zhang communicated to his colleague Dr. Cong, first author on the paper published in the January 2013 issue of Science and containing Broad's disclosure of CRISPR practiced in eukaryotic cell:

CVC sets out testimony from Dr. Marraffini that he immediately communicated the key finding disclosed at that meeting by the Doudna/Charpentier group:  that CRISPR could be performed by single-guide RNA (sgRNA) comprising tracr and sequence-specific mature crRNA RNA fragments covalently linked in association with the Cas9 protein.  Prior to this discovery CVC relies on Dr. Marraffini's testimony that Dr. Zhang) understood that formation of functional CRISPR complexes required RNAse III cleavage of unprocessed tracr and crRNA.

Second, CVC argues that once its seminal finding was made public, that CRISPR could be performed using sgRNA, no fewer than five labs ("Church (Harvard), Kim (ToolGen), Joung collaboration, and Chen (Sigma-Aldrich)"), including the Zhang lab, were able to perform eukaryotic CRISPR using routine, conventional laboratory methods, as evidenced by scientific papers from these labs published in Science in January 2013. Indeed, the brief argues that Dr. Zhang's alleged reduction to practice in June 2012, after receiving the information regarding sgRNA from Dr. Marraffini, is itself evidence of CVC's complete conception, because the information Dr. Marraffini communicated to Dr. Zhang came from Jennifer Doudna and Emmanuelle Charpentier.  The brief provides a convenient checklist of that disclosure:

CVC's derivation argument rests crucially on Dr. Marraffini's testimony.  As set forth in the brief, this deposition testimony established derivation of the Broad invention from CVC's inventors:

Before he attended the 2012 CRISPR Conference, Marraffini had already reviewed CVC's draft Jinek 2012 manuscript as one of the peer-review referees for Science.  CVC submitted the draft Jinek 2012 manuscript to Science by June 8, 2012, just before the conference.  The draft Jinek 2012 manuscript revealed to Marraffini that processed tracrRNA, mature crRNA, and Cas9 are the necessary and sufficient components of the catalytic CRISPR-Cas9 DNA-cleavage complex, the design and use of a functional sgRNA CRISPR-Cas9 system, and also expressly stated that the sgRNA CRISPR-Cas9 system could be used for "genome editing in cells of the three kingdoms of life for biotechnological, biomedical and gene therapeutic purposes."

Marraffini recalls that CVC's disclosure of tracrRNA as a necessary component in the catalytic DNA cleavage complex "as well [as] the development of the [sgRNA]" were "the most important findings that the team made" because, before CVC's breakthrough, no one knew that tracrRNA was an active component in the complex.  Before June 26, 2012, Zhang had no concept of a sgRNA CRISPR-Cas9 system of Count because he was unaware that tracrRNA was a necessary component of the catalytic CRISPR-Cas9 DNA-cleavage complex.  . . .  Prior to June 2012, the art taught that tracrRNA was merely an intermediate cofactor that RNase III and Cas9 needed for RNA processing to generate mature crRNA guides from long, unprocessed pre-crRNAs. Marraffini confirmed [this understanding in the art], testifying that tracrRNA was only "known . . . to be involved in the generation of guide RNAs."  Marraffini also testified that, before June 26, 2012, he and Zhang only discussed "the importance of tracr for what we knew at the time was generation of RNA guides," and that "the system, as we knew it, required RNase III to generate guides." [emphasis in brief]

Marraffini explained further that he remembered this discovery as "the most important findings that the team made, the fact that the tracrRNA is required for cleavage of DNA, which was not known at the time.  And I thought that was a very important finding."  Marraffini's review [of the Jinek manuscript] showed that he understood the CVC inventors intended to use their sgRNA CRISPR-Cas9 system in eukaryotic cells: Being guided by the crRNA sequence, the dsDNA nuclease activity of Cas9 could be re-programmed to target essentially any sequence in any genome with a very high specificity.  Perhaps in one of the most exciting experiments of this work, Jinek et al. show that Cas9 can be 'loaded' with synthetic crRNAs that direct any chosen sequence in a plasmid.  As the authors indicate, this provides a new, invaluable tool for genome editing.  Marraffini's [contemporaneous] reviewer comments comport with his deposition testimony that CVC's sgRNA was "a fundamental advance that we could use in our project."  After reading the published version of Jinek 2012 in Science, Zhang similarly stated in a June 30, 2012 email to Marraffini that Jinek 2012 was "a great paper" and made Zhang feel that CVC was "moving in [the] direction" of eukaryotes because the abstract refers to "genome editing" and the paper tested eukaryotic target gene (GFP) sequences.

Like the other attendees at the June 21 CRISPR Conference, Marraffini knew that he and his collaborator Zhang were now in a race to be the first to apply CVC's sgRNA CRISPR-Cas9 system for gene editing in eukaryotic cells and publish the results.  After returning from the conference, Marraffini promptly emailed Zhang on June 26,[2012], requesting a phone call to discuss "a couple of 1 presentations" he saw at the conference that were "important" to their project.  Marraffini clarified on cross-exam that the important presentation he had in mind for "gene editing of human cells" was indeed "the presentation by . . . Jinek and Chylinski about the single-guide RNA."  Zhang quickly responded to Marraffini's email, and the two immediately set up a phone call to discuss the CVC presentation.  On that call, he and Zhang discussed CVC's sgRNA CRISPR-Cas9 system and how CVC's sgRNA was a "fundamental advance that we could use in our project."  In particular, Marraffini testified that he "must have" told Zhang about the role of tracrRNA in the catalytic DNA-cleavage complex.  (Marraffini testifying that prior to June 26, his conversations with Zhang were "only about the importance of tracr for what we knew at the time was  generation of RNA guides.")  Marraffini also communicated to Zhang the intended purpose of using CVC's sgRNA CRISPR-Cas9 system in eukaryotic cells:

Q:    So you . . . did you generally convey the view to Dr. Zhang that you thought the single-guide RNA would be an important tool for genome editing?

A:    Yeah.  Yes, I — that's why I sent him the information, yes.

When asked if he communicated to Zhang that CVC's sgRNA CRISPR-Cas9 system would be an important tool for genome editing in eukaryotes specifically, Marraffini stated unequivocally, "yes":

Q :    [W]hen you first conveyed to Dr. Zhang the single — single-guide RNA system described in Jinek 2012, did you convey to him that you thought it would be an important tool for genome editing in eukaryotes specifically?

A:    Yes.

Marraffini also disclosed to Zhang that there was no need to employ the cumbersome RNA-processing system with which Zhang had been unsuccessfully tinkering.  After their June 26 phone conversation, Marraffini sent a follow-up email to Zhang, stating that he "checked" the Jinek 2012 draft manuscript and "[CVC] provide pre-processed crRNAs to the in vitro reaction, so there is no need for RNAse III . . . ."  Marraffini testified that until that time, "the system, as [he and Zhang] knew it, required RNase III to generate guides."  Indeed, prior to June 26, all of Zhang's CRISPR experiments were failed attempts to mimic pre-crRNA processing, evident from his repeated use of unprocessed crRNAs, unprocessed tracrRNA, and RNase III in the experiments When asked on cross-exam whether he had ever used pre-processed (mature) crRNA or processed tracrRNA in his experiments before June 26, Zhang testified that "I don't have a clear recollection if I have done any experiments [with mature crRNA]" and "I don't remember if I had done experiment there, with that [processed tracrRNA]."

Zhang admits in his declaration that he obtained the sgRNA design from Marraffini, although he conspicuously omits the fact that the "chimeric RNA" Marraffini shared with him was CVC's sgRNA.  At deposition, however, Zhang conceded that the sgRNA structure indeed came from "the Doudna-Charpentier group."  Marraffini—who provides third party testimony that was unchallenged by Broad at deposition—testified that the sgRNA image in his June 26 email was a direct copy from the then-unpublished Jinek 2012 manuscript he had reviewed:

Q:    Where did you get that particular image from, Doctor?

A:    From the [Jinek 2012] manuscript.  But it was the same one that it was public from the conference.

The sgRNA structure Marraffini sent to Zhang in his June 26 email is identical to the "chimera A" sgRNA structure [set forth above herein] Jinek and Chylinski presented on June 21, which is also identical to the sgRNA Zhang claims he "designed" on June 27, 2012 [all references to exhibits omitted].

Based on this testimony, CVC argues that the evidence shows that Broad's inventors, and specifically Dr. Zhang, derived their claimed invention from the CVC inventors through Dr. Marraffini.  The brief further characterizes (turnabout being fair play) their own litany of purported "failures" by the Zhang lab, particularly with regard to the "fallback position" set forth in Broad's priority brief, that work performed prior to CVC's March 2012 conception date should be considered by the Board in making its priority determination.  This work, on alternative systems for gene editing (e.g., TALEN and ZFN), is not CRISPR, CVC argues, and without knowledge of CVC's sgRNA discovery the Broad inventors were pursuing (fruitlessly) more complicated versions of CRISPR that required, inter alia, RNAse III and unprocessed tracr and crRNA fragments.  Indeed, CVC argues that until Dr. Marraffini's disclosure of its invention to Dr. Zhang there was no recognition by the Broad inventors of the role and importance of tracr RNA.

CVC sets out its own summary timeline of events by the parties, modifying the timeline presented in Broad's priority motion according to CVC's version of events as supported by the evidence set forth in this brief:

With regard to their purported incomplete conception argued by Broad, CVC argues that it had recognized and addressed each and every one of these putative deficiencies.  In addition, CVC argues that each of these "adaptations" required to practice CRISPR in eukaryotic cells "is not an invention, is not in the count, and is not required for reduction to practice," providing a mantra repeated for each of the various adaptations asserted by Broad:

(Missing, of course because it belongs properly in CVC's reply to Broad's opposition to their priority motion, is an explanation of the litany of CVC's failures recited in Broad's opposition.)

Turning to Broad's evidence of actual reduction to practice, CVC makes the argument that the evidence is uncorroborated, because three of the witnesses (Sanjana, Cong, and Cox) set forth in this table are named as inventors, citing Chen v. Bouchard, 347 F.3d 1299, 1309 (Fed. Cir. 2003):

And the fourth, Kosuri, does not corroborate Dr. Zhang's testimony regarding ARTP, relying on vague ("this system") contemporaneous representations from Dr. Zhang and not having firsthand knowledge.

The brief further alleges failure of proof, no contemporaneous inventor recognition, and failure of corroboration, for each of Broad's purported actual reductions to practice of eukaryotic CRISPR on July 20, July 28, July 31, and August, 2012, and further argues that because Broad did not establish the actual August date for this last instance of ARTP, the Board should consider it to be August 31, which is after CVC's August 9, 2012 asserted ARTP date.

Broad's Reply brief to this opposition is due April 6, 2021.

By Kevin E. Noonan —

Senior Party The Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad") filed its motion in opposition to Junior Party The University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") motion for priority in Interference No. 106,115.  Although Broad argued in its own priority motion that the invention as defined by the Count was one that could only be conceived once it was reduced to practice (a standard originally applied to since-invalidated claims to isolated DNA) and, not coincidentally that Broad's  earliest actual reduction to practice (ARTP) antedated CVC's ARTP, in its opposition to CVC's priority motion, Broad takes a more conservative albeit more strongly supported tack.

In its most recent motion, Broad argues that CVC did not have conception of the invention defined by the '115 Interference Count because the person of ordinary skill in the art could not have any reasonable expectation of success in ARTP from the evidence CVC uses in support of its motion, citing Hitzeman v. Rutter, 243 F.3d 1345, 1357-58 (Fed. Cir. 2001).  As a reminder, conception is "the formation in the mind of the inventor, of a definite and permanent idea of the complete and operative invention, as it is hereafter to be applied in practice."  Hybritech Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1376, 231 U.S.P.Q. 81, 87 (Fed. Cir. 1986), citing  Coleman v. Dines, 754 F.2d 353, 359, 224 USPQ 857, 862 (Fed. Cir. 1985).  Since conception occurs in the mind of the inventor, there must be "corroborating evidence of a contemporaneous disclosure that would enable one of ordinary skill to make the invention."  Burroughs Wellcome, Id. at 1919, citing Coleman v. Dines, 754 F.2d 353, 359, 224 USPQ 857, 862 (Fed. Cir. 1985).  However, conception of a method does not require knowledge that the invention will work for its intended purpose.  Burroughs Wellcome Co. v. Barr Labs, Inc., 40 F.3d 1223, 32 USPQ 2d 1915 (Fed. Cir. 1994).  Relevant to Broad's arguments in their motion, in Burroughs Wellcome, the claims of the patents-in-suit were directed to methods for using AZT for treating AIDS, and the issue was whether the AZT inventors had conceived of the claimed methods before obtaining evidence that AZT could indeed provide an effective treatment for HIV infection.  Id. at 1225.  The Burroughs Wellcome defendants argued that for an invention in an "uncertain or experimental discipline, where the inventor cannot reasonably believe an idea will be operable until some result supports that conclusion," conception occurs only when there is experimental confirmation that the invention works for its intended purpose.  Id. at 1228.  The Federal Circuit was clear, stating:  "[b]ut this is not the law.  An inventor's belief that his invention will work or his reasons for choosing a particular approach are irrelevant to conception."  Id., citing MacMillan v. Moffett, 432 F.2d 1237, 1239, 167 U.S.P.Q. 550, 552 (CCPA 1970).  This is sufficient for conception, unless there is evidence of subsequent experimental failure (the argument Broad relies upon in their argument against CVC): "[a] conception is not complete if the subsequent course of experimentation, especially experimental failures, reveals uncertainty that so undermines the specificity of the inventor's idea that it is not yet a definite and permanent reflection of the complete invention as it will be used in practice."  Id. at 1229, citing Rey-Bellet v. Engelhardt, 493 F.2d 1380, 1387, 181 U.S.P.Q. 453, 457-58 (CCPA 1974).

Although stated differently (and in a way that is supported by the Board's decision in prior Interference No. 106,048 as affirmed by the Federal Circuit), Broad's argument is that CVC's conception was flawed as evidenced by repeated failures to reduce the invention to practice.  Broad also supports this assertion by contemporaneous statements by CVC's named inventors as well as statements by experts CVC recruited in its efforts to achieve ARTP from the time of its asserted conception (March 1, 2012) to the priority date accorded by the Board in this interference, the filing date of U.S. Provisional Application No. 61/757,640, January 28, 2013.

Broad references its own priority motion for the comparator of having achieved ARTP "no later than July 31, 2012, followed by further ARTP in its October 5, 2012."  This is Broad's line in the sand, establishing that CVC be required to show conception prior to the July 31, 2012 date followed by diligence until actual or constructive reduction to practice.  This, of course, Broad argues CVC cannot do.

Broad's brief argues three grounds for its assertion that CVC's conception failed.  First, Broad argues that CVC lacked a reasonable expectation of successfully targeting and cleaving DNA in a eukaryotic cell.  Second, Broad argues CVC lacked a definite and permanent idea of the operative invention as of their alleged conception date.  Third, Broad argues that CVC did not have possession of a system that could target and cleave eukaryotic DNA as required by the Count.  Broad further argues that CVC's asserted ARTP (when finally achieved) failed for proof that DNA was cleaved in zebrafish cells on August 9, 2012, and further failed to show DNA cleavage in human cells on October 31, November 1, 5 and 18, 2012.

The brief characterizes CVC's priority evidence as "no more than an ill-defined research plan" constituting "a laundry list of possible techniques enlisting at least six different highly-skilled research labs" that failed.  Indeed, the brief alleges that only one of the six research lab collaborations were revived and that one only after Zhang published Broad's results in the Cong et al. Science article, nicely turning back on CVC its allegations that Broad derived their invention from information disclosed publicly by the Doudna/Charpentier group.  These efforts amounted to "failure after failure" according to the brief, due to the obstacles of "RNA degradation, misfolding, complexation, localization, and chromatin access," just the obstacles Broad has maintained prevented the person of ordinary skill in the art from having a reasonable expectation of successfully adapting CRISPR to a eukaryotic cell context, here and in the prior '048 Interference.  The brief relies on the earlier PTAB determinations as affirmed by the Federal Circuit but here prudently also asserts evidence that neither CVC's conception nor ARTP had succeeded in time to be entitled to priority over Broad's invention.  The Broad contends that CVC's arguments here are the same as in the previous interference, and the outcome here is the same based on CVC's priority evidence which was not assessed in the earlier interference.  As it has in other contexts, Broad puts forth statements by the inventors (including by Jennifer Doudna in her book, A Crack In Creation: Gene Editing and the Unthinkable Power to Control Evolution and Walter Issacson's book, The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race) which the brief characterizes as admissions, including:

• "this will be fabulous if it works" (Ex. 4406)
• "test whether the strategy can be used to induce DSBs in mammalian cells" (Ex. 4381 at 65)
• "there is a hint it [CRISPR-Cas9] might work but we shouldn't be overexcited now" (Ex. 4911)
• "aspects of the RNA expression/stability/Cas9/assembly/ localization are problematic" (Ex. 5041)
• "I wonder if having a too-efficient NLS on Cas9 is actually counterproductive" (Ex. 4988)

In addition, the brief contains reference to statements by several other scientists supporting Broad's assertions that complete conception of eukaryotic CRISPR required actual reduction to practice (including Dr. Luciano Marraffini, perhaps anticipating his deposition or at least providing Broad with a basis for cross-examining any testimony he provides that support CVC's allegations set forth in their granted motion for leave from the Board to depose him).

With regard to the Jinek laboratory notebook evidence CVC proffered to show its earliest conception date, March 1, 2012, the brief calls it a "cartoon" without any accompanying disclosure regarding how adaptation of CRISPR to the eukaryotic cell context would be achieved.  The brief then goes through the evidence provided by CVC regarding these efforts (including the Board's prior determination that CVC was not entitled to priority to its earliest provisional applications (USSN 61/652,086, filed May 25, 2012 (P1) and USSN 61/716,256, filed October 19, 2012 (P2)) for failing to provide sufficient disclosure of eukaryotic embodiments of CRISPR.  The brief sets forth with specificity the identities and efforts (failed according to Broad) by third parties to achieve ARTP of eukaryotic embodiments of CRISPR technology encompassed by the Count, specifically:

• Worms – Dr. Meyer, Howard Hughes Medical Institute Investigator and Professor of Cell and Developmental Biology at University of California and her student Te-Wen Lo
• Yeast – Dr. Jamie Cate, Professor of Biochemistry, Biophysics and Structural 1 Biology in Microbiology Professor of Cell and Developmental Biology at University of California
• Mice – Dr. Dirk Hockemeyer, Assistant Professor Department of Molecular & Cell Biology at University of California
• Plants – Drs. Chris and Shauna Somerville, Professors, Plant & Microbial Biology, at University of California
• Medaka fish – Dr. Kristin Teßmar-Raible, Professor and Group Leader Max Perutz Labs, at University of Vienna
• Zebrafish – Dr. Florian Raible, Professor and Group Leader Max Perutz Labs, at University of Vienna, and his post-doctoral researcher Dr. Stephanie Bannister
• Human – Dr. David Drubin, Department Co-Chair and Ernette Comby Chair in Microbiology Professor of Cell and Developmental Biology at University of California

The status of these efforts as failures is important to Broad's argument, because complete conception sufficient to support a claim to priority of invention in an interference requires that "the idea is so clearly defined in the inventor's mind that only ordinary skill would be necessary to reduce the invention to practice, without extensive research or experimentation," citing Dawson v. Dawson, 710 F.3d 1347, 1352 (Fed. 1 Cir. 2013), and "[t]he failures of these experts provide real-world evidence that the inventors' ideas were not 'so clearly defined' but rather required extensive research and experimentation."  In addition to the inventors' own comments showing at best skepticism regarding ARTP of CRISPR in eukaryotic cells, the brief sets forth a litany of "confirmation of failure of CRISPR-Cas9 system" by contemporary statements of others:

In addition to these arguments, Broad contends that CVC cannot show possession of the invention defined by the Count because CVC's evidence does not show CRISPR-mediated DNA cleavage (i.e., functional CRISPR activity) in eukaryotic cells, as recited as an affirmative limitation in Count 1 of the Interference, citing Coleman v. Dines, 754 F.2d 353, 359 (Fed. Cir. 1985), for the requirement that "in establishing conception a party must show possession of every 1 feature recited in the count."

Turning to actual reduction to practice (ARTP), the brief then specifically sets out a timeframe for CVC's purported continued failure to achieve ARTP of CRISPR in eukaryotic cells, in support of Broad's argument that CVC's conception was flawed and incomplete (and thus that CVC does not deserve its March 1, 2012 conception date):

Of course, it inures to Broad's benefit that many of these statements concern and highlight precisely the impediments and obstacles Broad has argued here and in the '048 Interference would be relevant to adapting CRISPR to the eukaryotic context.  In particular, Broad's brief asserts that CVC has not established CRISPR-mediated DNA cleavage in the zebrafish experiments performed August 9, 2012 nor in the human cell experiments performed on October 31 and November 1, 5, and 18, 2012.  (Indeed, the brief characterizes some of CVC's evidence as "a litigation-inspired resurrection of a failed experiment that never saw the light of day in 2012 or any other time before this Interference," which insofar as it is true is due at least in part to Broad's success in obtaining a judgment of no interference-in-fact in the '048 Interference).  The brief goes into great detail regarding these purported failures, again using contemporary statements in CVC's evidence to support its argument that the CVC inventors themselves did not recognize these experiments as having successfully demonstrated successful eukaryotic cell CRISPR.  And to the extent there is evidence of DNA cleavage in the human cell experiments, Broad contends that by changing the cell lysis conditions CRISPR cleavage occurred in the lysate rather than in the cells themselves.  The Broad also spends a good portion of its brief regarding the uncertainties in achieving successful practice of ZFN or TALEN systems or RNA-based genetic methods (including Group II introns, ribozymes and riboswitches) in eukaryotic cells as evidence of the expectations of the skilled worker regarding adapting CRISPR to the eukaryotic cell milieu.  Interspersed with these arguments are references to Board decisions denying CVC's motions to be awarded priority benefit and decisions in the earlier '048 Interference.

The brief also asserts an experimental distinction between the methods CVC has asserted in its priority papers and the methods used by Broad inventor Zhang that, according to Broad, resulted in successful CRISPR-mediated DNA cleavage in eukaryotic cells no later than July 31, 2012:

The chimera A design showcased by CVC and disclosed in Jinek 2012—a design with a 26 nucleotide tracr sequence—is not what results when expressed from a U6 promoter driven plasmid in eukaryotic cells. MF133; see Ex. 3424 ¶¶ 128, 181; Breaker 3rd Dec. ¶¶ 238-241.  This is a key distinction.  As Zhang explains in his declaration, when he saw the 26 nucleotide design, he immediately appreciated that this minimal tracrRNA "eliminated the two larger natural stem-loop structures from the tracrRNA segment" which he understood were important in a complex environment, like a eukaryotic cell, to "achieve sufficient loading onto Cas9 in a cell, particularly because the secondary structures (in the form of stem-loops) could be important for loading the RNA duplex onto Cas9, and important for forming an RNA-protein complex with Cas9."  Ex. 3424, Zhang Dec. ¶¶17-18.  Thus, Zhang deliberately chose a system "using a vector [with a U6 promoter] that would express chimeric RNA with a truncated tracrRNA segment of 30 nucleotides—four nucleotides longer than the chimeric RNA" in Jinek 2012.  Id. ¶19.  That is because Zhang understood that "[t]he addition of those four nucleotides could assist in protecting the nucleotides on the 3' end of the tracrRNA [which are important for loading/complexing] from RNA degradation by endogenous RNases present in the cell."  Id.  A point seemingly lost on the CVC inventors.  Ex. 6207 at 192:9-201:6, 199:0-201:6.

Almost as an afterthought, the brief contends that CVC has not shown diligence from its earliest claimed conception date to ARTP, citing "gaps and a hodgepodge of efforts" in these efforts; this argument is blunted somewhat by the brief's efforts to show CVC's continued but failed efforts to reduced eukaryotic CRISPR to practice.

Science, particularly cutting-edge science, can be messy as it is being performed, and Broad takes advantage of this messiness to make its case that CVC had not satisfied the requirement for conception that CVC's inventors had a "definite and permanent idea of the complete and operative invention" at the claimed conception date.  CVC will have its chance to reply to this motion.  However, Broad has amassed an impressive array of documentary and contemporaneous witness statements in support of its arguments in this brief for CVC to rebut.  CVC's reply brief is due on April 6, 2021.