By Kevin E. Noonan –

Two amici have filed briefs in support of the appeal by Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") of the decision by the Patent Trial and Appeal Board (PTAB) in favor of Senior Party the Broad Institute, Harvard University, and MIT (collectively, "Broad") sixteen months ago in the latest CRISPR interference No. 106,115.  The briefs provide arguments separately on the purported scientific (by several noted scientists*) and legal (by Regeneron Pharmaceuticals, Inc.) errors the Board made in arriving at its decision.

The scientists argue that the Board had a "fundamental misunderstanding" regarding the CVC scientists' expressions of healthy skepticism that scientists apply to their experiments and discoveries with lack of confidence and certainty regarding their invention.  What the Board observed was objectivity, the scientists argue, being expressions of "professional skepticism while confirming their discovery through the routine methods detailed in their patent application."  This skepticism is required by the scientific community as part of the proper exercise of the scientific method.  While the Board came to the wrong decision in this case, the scientists argue, the greater risk is that the decision will "harm science" for reasons elucidated expressly in the brief synopsized here.

The skepticism by the CVC inventors is a necessary part of the scientific method, these scientists argue, because "[s]cience is not perfect" and even a "perfectly designed experiment can fail for a host of reasons before subsequent experiments vindicate the underlying theories" (and the converse, that "experiments may succeed (or appear to succeed) even when they are designed using incorrect or incomplete theories").  Factors like "[l]uck, human error, and unaccounted-for variables all play a role in determining the results of an experiment," they argue and these cannot be controlled entirely.  In the face of these uncertainties, scientific discoveries verified by experiment are trusted because "scientists have developed rigorous procedures for testing their initial results and moving past initial failures."  These procedures include challenging their "observations, even their own expectations, with a 'tough, sustained scrutiny' beyond what is commonplace among lay persons" the scientists argue, citing Naomi Oreskes, Science Isn't Always Perfect—But We Should Still Trust It, TIME.COM (Oct. 24, 2019).  It is precisely this process of "confirming . . . discovery, collecting and weighing data to determine whether the idea will work" that "makes scientific progress possible."

This process involves failure, the brief asserts, of two types.  One type are the "mundane failures arising from biological variability, experimental imprecision, and the play of chance" that are "part of day-to-day life at the lab bench" but which can be overcome by "optimization and routine experimentation."  The other type are more fundamental and arise "when a well-designed and well-executed series of experiments fails to support a scientist's expectations despite efforts to optimize or improve the experimental design and execution."  Recognizing that either type of failure is possible, scientific skepticism is needed to avoid "one of the most pernicious problems in science: confirmation bias" they assert, citing Raymond S. Nickerson, Confirmation Bias: A Ubiquitous Phenomenon in Many Guises, 2 REV. GEN. PSYCH. 175, 175 (1998).

The PTAB's error, the scientists argue, was in not understanding "how skepticism and failure operate within the scientific method."  What the CVC scientists were attempting to confirm — their conception of how to achieve CRISPR-mediated DNA cleavage in eukaryotic cells — "involve[d] complex biological systems with many variables, and experimental failures are common and are not necessarily indicative of a problem in the underlying theories or experimental design."  These circumstances are illustrated in the brief by a comparison with the experiments the Board accepted as illustrating their reduction to practice, wherein "the Broad Institute reported only two positive results out of 265 sequencing reads in its first 'successful' use of the CRISPR-Cas9 system to cleave DNA in eukaryotic cells, a gene modification rate of less than one percent."  "Objective experimentalism is not fundamental doubt," they argue, and the Board erred in confusing one for the other.  This argument is illustrated by quotations from four of the e-mails the Board used to support its decision, and the Board's citation of the five to eight months it took for the CVC inventors to reduce their invention to practice.  The Board's decision based on this evidence was error the scientists argue because it "mistakes mundane failures—part of everyday lab work—for fundamental failures—which might suggest the inventive idea is inoperative or incomplete."  The time-consuming process of "eliminat[ing] variables one-by-one in a stepwise manner," which is "normal and natural for research at this level" demonstrate not uncertainty but that CVC's inventors "remained objective and open-minded" during the process and the problem-solving that it entailed.  To do otherwise, as the PTAB impliedly suggests CVC's inventors were remiss in not doing, "would have been evidence of an irresponsible departure from the scientific method"according to the brief.  Further, the scientists affirm CVC's contention that their eventual reduction to practice was achieved "in the form in which they had conceived of it . . . using only those routine materials and techniques known to persons of ordinary skill in the art."  The way the CVC inventors achieved their results, the scientists argue, was "evidence show[ing] the CVC inventors never fundamentally doubted their invention" and that "their expression of uncertainty was just ordinary scientific skepticism" (emphasis in brief).

The scientists also find error in the Board not acknowledging that CVC provided disclosure of eukaryotic CRISPR methods in their first provisional application (No. 61/652,086, filed May 12, 2012, "P1") that would have been recognized by one of ordinary skill in the art.  The brief specifically addresses the hypothetical obstacles enumerated by Broad's expert, Dr. Chad Mirkin, as another misunderstanding of "the ordinary skepticism the scientific community would have had in the absence of empirical data as a reason to deprive the CVC inventors of patent rights," saying that Dr. Mirkin's testimony merely illustrates that "it is easy to come up with a list of any number of theoretical obstacles to reducing to practice an invention—especially in a field as complex as CRISPR research."  That is not enough, scientifically, to "throw into question the inventor's patent rights when the patent application in fact describes all that is needed to practice the invention" they argue.

Finally, the scientists' brief addresses the consequences they envision should the Board's views prevail and the Federal Circuit affirm their decision.  Such an outcome would "discourage collaboration, slow scientific progress, and reward confirmation bias."  This is because science is no longer the province of "a brilliant individual toiling away in isolation" but instead relies on "the teamwork of scientists, each playing a role in the scientific process."  For such efforts to be successful the scientists must communicate with one another, but the Board's decision used such "internal communications among team members to strip the CVC scientists of their invention."  This can only "discourage the free flow of communication between collaborators" so as not to "jeopardizing future patent rights."  As a result, the scientists argue that "the PTAB's decisions have the potential to slow scientific progress and discourage the types of risk-taking critical to innovation."

These effects are not limited to collaborators, the scientists argue, but will spread to incentivize scientists from different laboratories to "feel pressure to secret away their inventions until they can muster enough evidence to convince others that their inventions will work" (the brief speculating that in this case "if after filing the P1 patent application the CVC inventors had chosen to conceal their discovery that the single-guide CRISPR-Cas9 system could cleave eukaryotic DNA in vitro (at least until publication of P1 18 months later), they might well have been the first to demonstrate use of the CRISPR-Cas9 system in eukaryotic cells and obtained the patents covering such use").  In addition such secrecy promoted by the Board's decision would have delayed the use by other labs of eukaryotic CRISPR.  At the extreme, upholding the Board's decision could lead scientists to "avoid rigorously testing their own settled expectations" and "be tempted to look for evidence that supports their view, building a case in favor of their invention for fear that proceeding objectively will result in denial of valuable intellectual property rights."

Regeneron's brief, on the other hand, addresses the legal errors occasioned by the Board's decision.  Citing Thomas Jefferson for the principle that "patent protection was meant as 'encouragement to men to pursue ideas, which may produce utility,'" the brief asserts (relevant to the underlying issues before the Court) that "'invention' thus 'is not the work of the hands, but of the brain,'" citing Edison v. Foote, 1871 C.D. 80, 81 (Comm'r Pat. 1871).  This is why patent law places emphasis on conception rather than production of a physical embodiment of an idea, amicus contends, and that "it is well settled that an invention may be patented before it is reduced to practice," citing Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 60 (1998), for both principles.  The brief also reminds the Court that it is equally well-settled that the first to conceive can properly be deemed the inventor even if she is the last to reduce the invention to practice, citing Price v. Symsek, 988 F.2d 1187, 1190 (Fed. Cir. 1993) (citing Lutzker v. Plet, 843 F.2d 1364, 1366 (Fed. Cir. 1988).  That is the case here, amicus contends, because the CVC inventors were the first to conceive the invention — the practice of CRISPR-Cas9 mediated DNA cleavage in all manner of eukaryotic cells.

The Board failed to protect this conception by rejecting CVC's argument that its inventors were the first to conceive.  Their "fundamental" errors the brief asserts are that "[i]n doing so, the Board conflated conception—a mental act that the patent system promotes and protects—with actual reduction to practice—a physical step" (emphasis in brief).  The brief recites two specific errors: first, that the Board required CVC's inventors to know that their invention would work to cleave eukaryotic DNA, which was error because "[a]n inventor's belief that his invention will work or his reasons for choosing a particular approach are irrelevant to conception," citing Burroughs Wellcome Co. v. Barr Lab'ys, Inc., 40 F.3d 1223, 1228 (Fed. Cir. 1994) (citing MacMillan v. Moffett, 432 F.2d 1237, 1239 (C.C.P.A. 1970)), and because reduction to practice, not conception, involves showing that an invention actually works, citing Applegate v. Scherer, 332 F.2d 571, 573 (C.C.P.A. 1964), and Oka v. Youssefyeh, 849 F.2d 581, 584 n. 1 (Fed. Cir. 1988).  The Board's second error identified in the brief was the Board's holding that the course of CVC's "post-conception" testing was evidence of incomplete conception, on the same basis: such a course of testing is relevant to reduction to practice and not conception.  The brief asserts in this regard that "post‑conception experimental failures cannot undo an earlier conception," citing In re Jolley, 308 F.3d 1317, 1325 (Fed. Cir. 2002).

The remedy recommended by amicus is that the Court "reinforce the fundamental distinction between conception and reduction to practice," citing Burroughs Wellcome for the former standard (conception arises when an inventor "had an idea that was definite and permanent enough that one skilled in the art could understand the invention") and Mahurkar v. C.R. Bard, Inc., 79 F.3d 1572, 1578 (Fed. Cir. 1996), Burroughs Wellcome and Oka for the latter (for a showing of reduction to practice, an "inventor must have (1) constructed an embodiment or performed a process that met all the claim limitations and (2) determined that the invention would work for its intended purpose," further citing Fox Grp., Inc. v. Cree, Inc., 700 F.3d 1300, 1305 (Fed. Cir. 2012), and quoting Teva Pharm. Indus. Ltd. v. AstraZeneca Pharms. LP, 661 F.3d 1378, 1383 (Fed. Cir. 2011).  This distinction is significant, amicus argues, because "[c]onception defines the legally operative moment of invention," citing Invitrogen Corp. v. Clontech Lab'ys, Inc., 429 F.3d 1052, 1063 (Fed. Cir. 2005), and they are "separate and distinct concepts and tests," citing Fox Grp.

This instance of the Board's error, amicus argues requires the Court's correction, because the Board's decision evinces that it misunderstood the distinction between conception and reduction to practice.  Echoing CVC's brief, amicus argues that while the Board recited the black letter law of Burroughs Wellcome regarding conception it then "did not practice what it preached" in reaching its erroneous conclusion, citing the Board's language that required CVC's inventors to know the invention as conceived would work for its intended purpose in order for its conception to be complete.  The brief mentions the necessity that conception cannot be retroactively established, citing Cooper v. Goldfarb, 154 F.3d 1321, 1331 (Fed. Cir. 1998), but that is not the same, amicus argues, as requiring an inventor to know the invention will work before operability (or patentability; Dow Chem. Co. v. Astro-Valcour, Inc., 267 F.3d 1334, 1341 (Fed. Cir. 2001)) is demonstrated by reduction to practice. In its misunderstanding the Board "mangle[d] an actual rule precluding nunc pro tunc conception into a non‑existent rule requiring knowledge that the invention will work."

Another principle the brief argues the Board mangled is that while conception involves "conceiving a way to make an idea operative," Dawson v. Dawson, 710 F.3d 1347, 1356 (Fed. Cir. 2013), this requirement is intended to distinguish having a "specific, settled idea [for] a particular solution to the problem at hand" (which is conception) with "a general goal or research plan" (which is not), citing Fiers v. Revel, 984 F.2d 1164, 1169 (Fed. Cir. 1993), and Amgen, Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1206 (Fed. Cir. 1991) (only the first of which was an interference case).

Amicus argues that the CVC inventors "easily satisfied the test," reciting the particulars of why that is so.  While the Board recognized that the evidence (notebooks, etc.) established CVC's conception the Board nevertheless erred in using the CVC inventors' purported uncertainty, evinced by the course of their reduction to practice, to determine conception was sufficiently uncertain to negate entitlement to priority of invention.

The brief further argues that the Board's application of these uncertainties was erroneous because they applied evidence related to reduction to practice to assess the sufficiency of CVC's conception; for example, that "in vivo verification is not required for a conception to be definite and permanent," Dana-Farber Cancer Inst., Inc. v. Ono Pharm. Co., 964 F.3d 1365, 1372 (Fed. Cir. 2020), and "[w]hether or not subsequent testing succeeded or failed, or even took place, does not determine whether conception was complete as of that date," In re Jolley.  Indeed, amicus argues, the inventor "may still need much patience and mechanical skill, and perhaps a long series of experiments, to give the conception birth in a useful, working form," citing Cameron & Everett v. Brick, 1871 C.D. 89, 90 (Comm'r Pat. 1871) (emphasis in brief) and Elizabeth v. Am. Nicholson Pavement Co., 97 U.S. 126, 137 (1877).  The Board's error was to "ignore[]" this precedent and cherrypick[]" a single sentence from Burroughs Wellcome regarding incomplete conception:

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.

The brief rebuts the Board's reliance on that sentence because it was limited to "the so-called doctrine of simultaneous conception and reduction to practice" which is limited to instances where "an inventor cannot envision a thing's composition . . . without first experimentally obtaining that that thing."  But in such cases a putative inventor cannot conceive an invention until it is reduced to practice, amicus reminds the Court, because "the event of reduction to practice in effect provides the only evidence to corroborate conception of the invention."  That was not the case here (although Broad raised the argument in its Priority Motion in this interference and later abandoned it).

The brief also relies on the fact that corroboration is required for date of conception, Burroughs Wellcome, and by definition post-conception testing related to reduction to practice occurs after conception.  While acknowledging that in some cases, such as Burroughs Wellcome reduction to practice was used to corroborate conception, such instances have involved those where reduction to practice provides the only evidence of such corroboration, and that "just because reduction to practice is sufficient evidence of completion, it does not follow that proof of reduction to practice is necessary in every case," citing Pfaff.

The brief concludes by advocating that the Federal Circuit correct the Board's two fundamental errors: first, by reinforcing the fundamental distinctions between conception and reduction to practice, that "the inventor's knowledge, understanding, or belief about the invention's workability is irrelevant to conception," and second that "post‑experimental failures cannot negate an earlier conception."

* These include Nobel Laurates Thomas Cech (1989, Chemistry) and Jack Szostak (2009 Physiology or Medicine) and Titia de Lange (Rockefeller University), Michael Levine (Princeton University) and David Jay Segal (University of California, Davis).

By Kevin E. Noonan –

The decision by the Patent Trial and Appeal Board (PTAB) in favor of Senior Party the Broad Institute, Harvard University, and MIT (collectively, "Broad") and against Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") sixteen months ago in the latest CRISPR interference No. 106,115 is the subject of appeal from both parties.  CVC filed its brief on September 20, 2022; Broad (discussed herein) filed its (corrected) Responsive Brief (which included a Contingent Cross-Appeal in the event the Federal Circuit did not affirm the PTAB's decision below) on February 15, 2023.

Broad's brief is based on two arguments.  The first is one they have advanced since their earlier Interference against CVC (Interference No. 106,048), where the Board held (and the Federal Circuit affirmed) that there was no interference-in-fact between Broad's claims to methods of performing CRISPR-mediated DNA cleavage in eukaryotic cells and CVC's claims for CRISPR methods not limited to cell type.  The rationale in the '048 interference that was asserted in this interference is that being able to perform CRISPR in eukaryotic cells was so inherently unpredictable that only by actual reduction to practice could a party show complete conception.  (It may be remembered that during the Preliminary Motions phase of the '115 interference Broad advocated this reasoning as an instance of "simultaneous conception and reduction to practice," which they later did not pursue.)  Broad includes this list of the litany of inherent uncertainties recited throughout this and the earlier '048 Interference:

(1) delivery into the eukaryotic cell,
(2) expression of the components in the cell,
(3) surviving eukaryotic defense mechanisms,
(4) formation of the protein:RNA complex,
(5) toxicity to the cell,
(6) proper protein folding,
(7) localization in the nucleus,
(8) access to the desired DNA target in the chromatin, and
(9) cleavage of the DNA

based on (Broad argues) "a 1.5-billion-year evolutionary divergence," including:

• Eukaryotic cells have a nucleus protecting genomic DNA, organized into discrete structures, called chromosomes, composed of a protein/DNA complex called chromatin;

• Prokaryotic cells lack nearly all the structural organization found in eukaryotic cells, such as a nucleus and chromatin, that functions to organize and protect DNA;

• Eukaryotic cells employ different cellular machinery and mechanisms to express genes, relying on proteins and complexes not found in prokaryotic cells. Those proteins and complexes can be essential to the proper transcription and translation of genetic material;

• Prokaryotic and eukaryotic cells have different environments, including different intracellular temperatures, ion concentrations, and pH; [and]

• Prokaryotic systems expressed in eukaryotic cells are often destroyed by native eukaryotic defense mechanisms

(citations to the record omitted).

The second argument was directed to CVC's incomplete conception (as held by the PTAB), based on evidence that CVC's efforts to reduce eukaryotic CRISPR to practice involved "extensive research, experiment, and modification" based in part on the experimental record and in part on CVC's improvident e-mails and other documentary evidence that (Broad argues) illustrates this incomplete conception.  The brief focuses on the factual determinations made by the Board which, under In re Gartside, 203 F.3d 1305 (Fed. Cir. 2000), and Dickenson v.  Zurko, 119 S.Ct. 1816 (1999), are subject to deference before the Federal Circuit.

The brief provides a timeline illustrating Broad's comparison between its own conception and reduction to practice with CVC's in a revised diagram related to one advanced before the PTAB:

Broad primary legal argument regarding why the Federal Circuit should affirm the Board's decision is that the PTAB applied the standard enunciated in Burroughs Wellcome Co. v. Barr Labs., Inc., 40 F.3d 1223, 1228 (Fed. Cir. 1994), properly, that conception "is complete only when 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" and "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" (emphasis in brief).  The brief relies for its argument upon these three factual findings by the Board:

1.  That the CVC inventors and corroborators were of at least ordinary skill in the art and that they engaged in a "prolonged period of extensive research, experiment, and modification" which was contrary to the Burroughs standard of "the exercise of ordinary skill without extensive research and experimentation."

2.  That the CVC's inventors idea fell squarely within Burroughs standard of incomplete conception, saying:

[W]e are persuaded that the communications surrounding these experiments reflect "uncertainty that so undermines the specificity of the inventor's idea that it [was] not yet a definite and permanent reflection of the complete invention as it [would] be used in practice."

The brief Illustrates as follows this "veritable who's-who of eukaryotic-genome-editing experts—working with CVC inventors using cells from worms, yeast, mice, plants, medaka fish, zebrafish, and humans" who failed to reduced CVC's conception of eukaryotic CRISPR either entirely or not without extensive research, experiment, and modification:

Broad's illustration is in stark contrast to CVC's brief, which emphasizes the lack of ordinary skill in a graduate student that worked unsuccessfully throughout the summer of 2012 to reduce eukaryotic CRISPR to practice followed by success when these experiments were performed by a second graduate student (implied to be of greater skill in the art to explain her success).

Also in this regard the brief further addresses CVC's argument that the amount of time during which their inventors worked to reduce the invention to practice was "only four months," stating that the CVC researchers engaged in "extensive research, experiment, and modifications" during that time and that the inventors' own communications showed that they lacked a "settled plan" for reducing eukaryotic CRISPR to practice, conducted "ill-fated experiments" and did not have "a definite and permanent idea of how to address the obstacles they encountered."

3.  CVC offered no evidence of such a "definite and permanent idea" of an operative CRISPR system for cleaving eukaryotic DNA in vivo, Broad emphasizing the PTAB credibility determinations and "finding that the contemporary evidence contradicted CVC's present-day declaration testimony" regarding the routine nature of reducing sgRNA-comprising CRISPR to practice once the CVC inventors conceived of the sgRNA embodiments.  Broad also noted that the PTAB rejected CVC's attempts to use success by others as inuring to their benefit or showing they had conception.

As in the '048 Interference the underlying context of Broad's argument is the potential impediments in getting a prokaryotic system — CRISPR — to be functional in a eukaryotic cells and that CVC's failures to do so (in the context of contemporaneous evidence that CVC's inventors did not believe their attempts at reduction to practice were successful) was evidence of incomplete conception, as the PTAB held.

The Broad brief addresses CVC's arguments of PTAB legal error by arguing that CVC never raised the issue before the Board that their conception would be complete if no further invention was required, stating that CVC relied on Burroughs before the Board and is not asserting this standard now because the PTAB did not agree with them.  Further, Broad argues, regarding CVC's argument that the PTAB imposed a "need to know" requirement, such a requirement is not part of the PTAB's "23-page discussion" and indeed that the PTAB stated the opposite.  (In its brief CVC acknowledges that the Board stated that it did not "base [its] decision on a lack of reasonable expectation of success by the CVC inventors" but that the PTAB "contradicted that standard as quickly as it articulated it.")  Broad argues that "CVC ignored the functional eukaryotic system limitation [in the Count] in an effort to strip Count 1 down to simply sgRNA" (which is true, up to a point.)

Broad's legal arguments revolve around their contentions that Broad achieved undisputed reduction to practice prior to CVC and thus were presumptively the first to invent, and that CVC's difficulties in reducing the invention to practice exhibited their incomplete conception. Broad's brief argues that the record provides substantial evidence supporting the PTAB's decision and thus deserves deference from the Federal Circuit.  While Broad argues the facts more than citing extensive interference precedent the brief expressly recites the following points regarding the Board's factual determinations:

1.  Persons of at least ordinary skill were unable to reduce the CVC inventors' ideas to practice without extensive experimentation

This argument focuses on factual determinations made by the PTAB and the support in the record for them, and in particular rebuts CVC's arguments of the incompetent graduate student (Cheng) with the "scores of emails between Doudna/Jinek and Cheng regarding the failed human cell experiments from April to October 2012" that Broad argues shows "near-constant communication with Cheng, directing him on exactly what experiments to perform and setting the parameters."  Moreover the brief names as "these skilled artisans" Drubin, Cheng, Doudna, Charpentier, Jinek, Chylinski, and Raible, all of whom failed to reduce to practice despite "extensive research, experiment, and modification," the brief stating that this is "powerful evidence" of incomplete conception.  The brief in particular cites to evidence regarding microinjection experiments with worms and "months of failure" (as shown in the expanded graphic above) and states that "a 2013 publication by Doudna and Meyer acknowledged that it was not until they obtained guidance from Broad's Cong 2013 article—and used Zhang's eukaryotic CRISPR-Cas9 system with the dual-molecule RNA configuration—that they achieved any success."

2.  CVC's inventors expressed uncertainty that so undermined the specificity of their idea that it was not a definite and permanent reflection of the complete invention

These arguments are based on Burroughs and its definition of incomplete conception as recited above, in addition to citing Bard Peripheral Vascular, Inc. v. W.L. Gore & Assocs., Inc., 776 F.3d 837, 845 (Fed. Cir. 2015); Univ. of Utah v. Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V., 734 F.3d 1315, 1323 (Fed. Cir. 2013); and Dawson v. Dawson, 710 F.3d 1347, 1352 (Fed. Cir. 2013), in support of its incomplete conception argument.

The brief states that "in the months following [CVC's] alleged conception [CVC inventors] expressed uncertainty, doubt, and confusion, and proposed ever-shifting plans to try to overcome their failures."  The brief also provides this table to illustrate the inventors' contemporary statements regarding the obstacles they were unable to overcome:

From this evidence Broad argues that "[t]hese were not minor problems or thoughts to optimize a definite and permanent idea—they are fundamental obstacles to achieving a functional eukaryotic system."

3.  CVC's inventors lacked a clear plan for overcoming the many obstacles to achieving a functional eukaryotic system

This argument is a repetition of Broad's earlier argument that instead of a defined plan CVC provided "a laundry-list of techniques that one might use in a research project attempting to deliver CRISPR-Cas9 to eukaryotic cells" (while characterizing the Jinek March 1, 2012 lab notebook page as "a cartoon").  The brief reminds the Court of the "multiple credibility determinations" made against CVC by PTAB which Broad says on appeal are "virtually unassailable," citing Charles G. Williams Const., Inc. v. White, 326 F.3d 1376, 1381 (Fed. Cir. 2003).  These include the familiar litany of improvident contemporaneous statements by Doudna and team regarding experimental difficulties encountered in trying to reduce to practice.

Addressing CVC arguments regarding other researchers success the brief asserts that PTAB properly disregarded these efforts as support for the completeness of CVC's conception because the work of independent labs did not establish CVC conception, especially Broad's own (for which the brief asserts that Broad's success was due to their successful dgRNA-comprising CRISPR embodiments and not CVC's sgRNA).  Broad also argues that their inventors had "already determined the technical features for creating a functional eukaryotic system" before being informed of sgRNA, and says Broad had demonstrated sgRNA is not necessary for eukaryotic CRISPR (albeit without citation to the record).  With regard to these other labs Broad argues that CVC provided no evidence that these labs were independent of Broad (indicating some were affiliated, for example the Church lab although the brief does not specifically make this identification) or whether these researchers were of extraordinary skill in the art, or that these labs may have encountered obstacles of their own that they overcame.  Broad's brief also addresses CVC's argument that the PTAB did not identify any differences between the system Broad used successfully that CVC did not, on the basis that the finding was "based on the eminently reasonable inference that the PTAB drew from Broad's success in contrast to CVC's many months of abject experimental failures" (raising the questions CVC's brief raised about the balance between inventive conception and the skilled mechanic).

Broad's brief rebuts CVC's reliance on Acromed Corp. v. Sofamor Danek Grp., Inc., 253 F.3d 1371 (Fed. Cir. 2001), on the grounds that this decision relied on Sewall for the same standard in Burroughs, and Barba v. Brizzolara, 104 F.2d 198, 202 (C.C.P.A. 1939), which Broad distinguished on its facts because in that case the inventors had worked together and the decision involved deciding who was entitled to inventorship.

Finally with regard to the question of incomplete conception the brief addresses these specific CVC allegations:

1.  CVC's criticism of the PTAB for finding the CVC inventors' failed eukaryotic experiments relevant to conception is legally incorrect, because CVC had asserted that their conception was complete because reduction to practice used routine and well-established techniques, which is contrary to their repeated failures and contemporary statements.

2.  CVC's arguments from their alleged conception to alleged reduction to practice is contrary to the PTAB's findings, which are all supported by substantial evidence, including that the PTAB found evidence of repeated failures and contemporary statements regarding different ways to reduce to practice.  These findings are due deference (again rebutting the "blame the graduate student" argument because of evidence of supervision by the named inventors).

3.  There is no basis for ignoring these contemporaneous communications that document the CVC inventors' lack of a plan to reduce their conception to practice; in this section Broad attacks amici for having "ties to Doudna" (because she was a postdoc in Tom Cech's lab and because Regeneron is "heavily invested in Doudna's CRISPR company), and further relies on PTAB statements in its decision that CVC did not rebut their inventors' contemporary statements in its Reply brief below.

Broad's arguments in rebuttal of CVC's originality argument is that sgRNA is not the whole invention, stating that "[t]he only element of Count 1 [that Broad inventor] Zhang learned from CVC's public disclosures in June 2012 was the sgRNA species—a configuration that is neither necessary nor sufficient for a functional eukaryotic system."

As for the APA violations asserted in CVC's brief, Broad reiterates its reliance on the extensiveness of the PTAB's decisions (180 pages, which must include all the Priority Motion decisions), the "hundreds of record citations," and "numerous credibility findings," and rebuts CVC's citation of their inventors winning the Nobel Prize by saying "the Nobel committee did not consider or reach any conclusion about invention of the eukaryotic subject matter of Count 1 under U.S. patent law."  The brief specifically addresses CVC arguments that PTAB's rejection of microinjection arguments was arbitrary and capricious because "the real-world failures using microinjection in worms and zebrafish demonstrate that microinjection did not overcome the hurdles to eukaryotic uses."  Broad further cites its own expert's testimony that microinjection had failed in attempts to get earlier prokaryotic-derived systems for DNA cleavage to work in eukaryotic cells.  "Rejecting CVC's argument[s] does not violate APA" provides a succinct synopsis of Broad's position in its brief.

Finally, Broad argues that substantial evidence supported PTAB's determination not to give CVC priority to P1 and P2 provisionals, stating that PTAB relied on the "highly unpredictable" state of the art, using the same arguments that were made in the '048 Interference.  These arguments include that there was no disclosure of working example (in the context of the later failures), citing:

Broad has persuaded us that absent results of a successful working example, the lack of discussion of PAM sequences, or sample target DNA sequences, the lack of special instructions or conditions necessary to accommodate the eukaryotic cellular environment, and the lack of a discussion of whether access to chromatin could hinder CRISPR-Cas activity would have indicated to those of ordinary skill in the art that the P1 applicants were not in possession of an embodiment of Count 1.

The brief argues that PTAB applied the correct written description standard (another question of fact) in the context of "the nature of the subject matter and the art—highly unpredictable," wherein the PTAB cited Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1357-58 (Fed. Cir. 2010) (en banc).  And Broad cited these three categories of substantial evidence that support PTAB's findings:

1.  Evidence that a person of ordinary skill in the art would have been aware of the many reasons why prokaryotic CRISPR-Cas might not work in eukaryotic cells, reciting the familiar litany of such reasons;

2.  Evidence of prior art failures to adapt other prokaryotic-derived DNA cleavage systems to eukaryotic cells, including TALENS, ZNF, and Group II introns in particular; and

3.  Contemporaneous statements of CVC's inventors "indicating doubt that a CRISPR-Cas9 system would work in eukaryotic cells"

After completing its arguments countering CVC's opening brief, Broad provides its affirmative arguments in support of its appeal (contingent on the Federal Circuit reversing or vacating the PTAB's decision below).  The gist of these argument is that the PTAB erred in limiting "guide RNA" to sgRNA based on claim construction properly performed using the plain and ordinary meaning of the term.  The legal bases for this argument include that "claim terms [in an interference should] receive their broadest reasonable interpretation," citing Dionex Softron GmbH v. Agilent Technologies, Inc., 56 F.4th 1353, 1358 (Fed. Cir. 2023); that "[t]he patentee may deviate from plain meaning only by including 'expressions of manifest exclusion or restriction, representing a clear disavowal of claim scope,'" citing Thorner v. Sony Computer Entertainment Amer. LLC, 669 F.3d 1362, 1366 (Fed. Cir. 2012); and "[a]bsent a clear disavowal or contrary definition in the specification or the prosecution history, the patentee is entitled to the full scope of its claim language," citing Home Diagnostics, Inc. v. LifeScan, Inc., 381 F.3d 1352, 1358 (Fed. Cir. 2004).  The brief (with some irony) cites the Jinek 2012 reference as providing the ordinary and customary meaning of guide RNA to include dgRNA and sgRNA and that the Broad specification is consistent in this definition.

Broad requests the Federal Circuit vacate the PTAB's denials of their Preliminary Motion 2 and Motion 3, and remand for consideration that would shield Broad from losing priority to its claims to dgRNA-comprising eukaryotic CRISPR embodiments.

By Kevin E. Noonan –

The decision by the Patent Trial and Appeal Board (PTAB) in favor of Senior Party the Broad Institute, Harvard University, and MIT (collectively, "Broad") and against Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") sixteen months ago in the latest CRISPR interference No. 106,115 is the subject of appeal from both parties.  CVC filed its Opening Brief (discussed herein) on September 20, 2022; the remaining briefs will be the subject of later posts.

To recap, the Board was convinced by Broad's arguments that CVC's attempts to reduce eukaryotic CRISPR to practice were unavailing until after Broad's reduction to practice as evidenced by a manuscript submitted on October 5, 2012.  Operating on the legal principle that "priority of invention goes to the first party to reduce an invention to practice unless the other party can show that it was the first to conceive of the invention and that it exercised reasonable diligence in later reducing that invention to practice," Cooper v. Goldfarb, 154 F.3d 1321, 1327 (Fed. Cir. 1998), the Board was unconvinced that CVC's March 1, 2012 conception satisfied the requirements of "complete" conception.  Using much of the same argument (albeit for different purposes) as it had to prevail in Interference No. 106,048 (see "PTAB Decides CRISPR Interference in Favor of Broad Institute — Their Reasoning"), the Broad persuasively argued that the evidence of CVC's attempts to reduce eukaryotic CRISPR to practice showed sufficient uncertainty and failures for the Board to conclude that CVC did not satisfy the requirements for conception.  On this evidence the Board was unpersuaded that all that had been needed was the application of routine experimentation using the sgRNA detailed in CVC's March 1st priority statement.  Nor was the Board convinced that Broad derived the embodiments of eukaryotic CRISPR that they reduced to practice embodying sgRNA only after Dr. Marraffini obtained it from CVC and disclosed it to the Broad inventors (see "CVC Files Reply to Broad's Opposition to CVC's Priority Motion").  In addition to the decision on priority, the Board denied CVC's motion for improper inventorship under 35 U.S.C. § 102(f) (see "CVC Files Substantive Motion No. 3 (for Improper Inventorship) and Broad Opposes") for evidentiary deficiencies, and in their discretion refused to consider CVC's allegations of inequitable conduct against the Broad (see "Inequitable Conduct by Senior Party Broad Alleged in Interference No. 106,115 (and PTAB May Finally Hear Evidence About It)").

CVC's brief begins with a reminder that Drs. Doudna and Charpentier had received the Nobel Prize for CRISPR (as every paper filed in the '115 Interference has done since the award).  The brief also sets forth the timeline of CVC's conception and reduction to practice, containing several relevant considerations for the Federal Circuit to ponder when assessing whether the Board erred in reaching its decision.  These include (first and foremost) that Broad and colleagues derived their invention totally from CVC's public disclosure of sgRNA species; according to CVC everything else was just routine applications of introducing exogenous molecules into eukaryotic cells using methods well known in the art.  Evidence (according to CVC) of the routine nature of these methods was that five other groups "quickly" performed CRISPR cleavage of eukaryotic DNA, as illustrated by this table:

(where methods using prior art systems, such as ZFNs and TALENS are shown in orange and those using CRISPR are shown in purple).  In this regard CVC argues that its own efforts, which formed the basis for the Board's determination that their conception was incomplete, took only four months of diligent effort.

The recitation of the factual background recites that it was the CVC inventors who recognized the role the tracrRNA played in the CRISPR complex (in work showing DNA cleavage in vitro) and, most importantly, that the tracrRNA and target site-specific CRISPR RNA (crRNA) could be linked by an oligonucleotide linker to form sgRNA.  Others, specifically the Broad group in CVCs retelling had been investigating whether there were "other factors" that needed to be included, such as RNase III, in so-called "preprocessing steps."  CRISPR as conceived by CVC is illustrated in the brief by this graphic:

and the laboratory notebook from March 1, 2012 showing conception of sgRNA (termed "chimera A") is also provided:

Chimera A was later disclosed in CVC's scientific publication, A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity ("Jinek et al., 2012"):

According to the brief, when used in their in vitro DNA cleavage system, embodiments of CRISPR comprising chimera A "cleaved the [DNA] target each time."  This disclosure was included in CVC's P1 provisional application (No. 61/652,086, filed May 12, 2012), along with prophetic examples for producing or introducing sgRNA-containing CRISPR complexes into eukaryotic cells (including "fruit fly," "fish, amphibian, reptile, bird, mammal," and "human" cells) using prior art-recognized, "routine" techniques "(e.g., microinjection, electroporation, transfection, etc.)," according to CVC.  Later-filed provisional applications (P2, filed October 19, 2012 and P3, filed January 28, 2013, the latter being the earliest priority date awarded to CVC by the Board) contained more details of their invention, the brief asserts.

According to the brief, the Broad group "had attempted—unsuccessfully—to use incomplete CRISPR-Cas9 systems to edit eukaryotic genes " because they did not understand "that mature tracrRNA was a necessary third component of the final DNA-cleavage complex" (emphasis in brief).  Consequently, Broad "struggled with experiments using unprocessed RNAs and other extraneous elements, wondering what 'other factors need to be identified.'"  Importantly, the brief asserts that it was only when Dr. Marraffini informed the Broad group of the CVC inventors' disclosure of the sgRNA species that Broad was able to reduce eukaryotic CRISPR to practice.  Indeed, the brief identifies the Broad's asserted conception date (June 26, 2012) to be the very day Dr. Marraffini disclosed sgRNA to them, illustrated by a copy of an e-mail:

The brief also notes that "[d]espite years of litigation, including an earlier appeal to this Court [in Interference No. 106,048], Broad withheld that communication until discovery halfway through the proceedings below" (emphasis in brief).  The brief goes on to describe the steps taken by Broad in reducing eukaryotic CRISPR to practice using the same chimera A sgRNA disclosed by CVC and communicated to Broad by Dr. Marraffini:

The brief asserts that the CVC inventors had "conceived of and described every element of the invention before Broad's first alleged conception."  The brief asserts further than the PTAB "never identified any inventive contribution Broad made" and awarded priority to Broad solely on the purported basis of first reduction to practice (emphasis in brief).

With regard to their efforts to reduce to practice sgRNA-comprising CRISPR in eukaryotic cells, the brief sets forth those attempts in ways that contradict or at least minimize the Board's basis for finding CVC's conception to be incomplete.  For example, the brief emphasizes that the vectors used to produce sgRNA and Cas 9 protein were designed in May 2012 and ordered by June 2012.  The brief also describes the efforts of a colleague to introduce preformed sgRNA-comprising CRISPR complexes into eukaryotic cells by microinjection into zebrafish.  As for those experiments using vectors to produce both sgRNA and Cas 9 protein in eukaryotic cells, the brief emphasizes that these experiments were initially performed by a graduate student (who CVC argues was not a person of ordinary skill in the art) who, after some preliminary positive results in CRISPR-mediated cleavage of eukaryotic DNA in vivo was unable to demonstrate homology-directed DNA repair in the cells (which embodiments were outside the scope of the interference count).  It was only after about three months of failure that the project was given to another graduate student who the brief asserts was able to reduce CRISPR-mediated cleavage to practice in eukaryotic cells "just weeks after joining Doudna's lab and only four months after CVC's first human-cell experiments."  For the microinjection experiments, while positive results were obtained they did not demonstrate CRISPR cleavage with the efficiency obtained from in vitro experiments, and thus these results were never published (something the brief notes the PTAB interpreted as indicating a lack of success, despite this frequency, 1 in 30, being better than the frequency obtained in the Broad's initial experiments in mouse cells, 2 in 275).

The brief asserts several grounds of error by the PTAB.  The first error is in refusing to apply an "objective" standard for conception, i.e., "whether CVC's invention was sufficiently complete that it was ready for skilled artisans to reduce it to practice without further invention."  Instead, CVC argues that the PTAB required that the CVC inventors knew the invention would work, "disregard[ing] copious unrebutted evidence that artisans understood exactly how to reduce CVC's invention to practice using routine techniques," as illustrated by the evidence provided by synopsis in the table above.  This was due to assertions by Broad that paralleled those made in the earlier '048 Interference with regard to the "theoretical hurdles to introducing the CRISPR-Cas9 complex into eukaryotic cells using expression vectors—RNA degradation, potential need for nuclear localization signals and codon optimization, and chromatin access," without the Board ever identifying which of those hurdles would prevent a skilled artisan from achieving CRISPR-mediated DNA cleavage in a eukaryotic cell according to the brief.  The brief also asserts that the PTAB did not recognize or acknowledge that CVC "never changed its invention in any material way" nor determined whether the microinjection experiments represented an actual reduction to practice.  Second, CVC argues that the PTAB did not identify "a single limitation of the count" that was independently provided by Broad.  Third, CVC argues with regard to the PTAB's denial of their priority claim to their P1 and P2 provisional application that the Board used the wrong standard for written description:  "[r]ather than assess whether CVC's patent disclosures were sufficient to allow skilled artisans to identify the invention, the PTAB demanded more:  It required CVC's disclosures to persuade skeptical artisans the invention would overcome various imagined hurdles to reduction to practice in eukaryotic cells."  Finally, CVC argued that the Board violated the Administrative Procedures Act because it "failed to engage in . . . reasoned decisionmaking" and its priority determination was thus arbitrary and capricious.

The brief supports these assertions of error with interference practice precedent.  Regarding conception the brief argues that "CVC conceived of every limitation in the count before Broad's first alleged conception date of June 26, 2012."  The Board's decision to the contrary, the brief argues, is based on "twin legal errors."  The first is that it is hornbook law for over a century that "'conception' occurs once 'the inventor is ready to instruct the mechanic in relation to putting [the invention] in working form,'" citing Cameron & Everett v. Brick, 1871 C.D. 89, 90 (Comm'r Pat.), and that an idea is "sufficiently 'definite and permanent' if the inventors had 'both the idea of the invention's structure and possession of an operative method of making it,'" citing Amgen, Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1206 (Fed. Cir. 1991).  Particularly relevant to the facts in this case, CVC argues that "[c]onception thus is complete when "[a]ll that remains to be accomplished . . . belongs to the department of construction, not invention," citing Mergenthaler v. Scudder, 11 App. D.C. 264, 276 (1897), that is, "when one of ordinary skill in the art could construct the apparatus without unduly extensive research or experimentation," citing Sewall v. Walters, 21 F.3d 411, 415 (Fed. Cir. 1994).  Contrary to the standard in Sewall, that conception must provide the skilled artisan with a sufficient description that the invention could be reduced to practice, the brief argues that the Board ignored the evidence that five other laboratory groups, including Broad, achieved sgRNA-comprising CRISPR-mediated DNA cleavage in eukaryotic cells using CVC's disclosed invention.  CVC argues that whatever challenges or delays were occasioned in their own efforts to reduce their invention to practice are "irrelevant" "when the evidence shows the invention is sufficiently firm, definite, and developed that skilled mechanics can do so," which CVC asserts the evidence shows was the case (emphasis in brief).  The brief relies on Cameron for the principle that "[c]onception can be complete even if 'much patience and mechanical skill, and perhaps a long series of experiments,' are required to reduce the invention to practice."  The brief then sets forth examples of instances where a patent was granted to the first to conceive even though an inventor did not, or could not, actually reduce the invention to practice.  These cases include Dolbear v. American Bell Telephone Co., 126 U.S. 1 (1888)(Bell's invention of the telephone); the Wright Brothers invention of the airplane "nearly a year before their first successful flight and—despite an intervening series of discouraging tests—the patent was granted"; and the use of AZT to treat AIDS, which was conceived before demonstrating that the drug "actually worked," citing Burroughs Wellcome Co. v. Barr Labs., Inc., 40 F.3d 1223, 1228 (Fed. Cir. 1994).

The reason the PTAB "reached the wrong result" with regard to priority was because, CVC asserts, the Board "asked the wrong question," specifically by "insisting that inventors must know their invention would work for conception to be complete" because "[c]onception does not require even an 'expectation' the invention will work, much less knowledge it will," citing Burroughs Wellcome Co. and Univ. of Pittsburgh of Commonwealth Sys. of Higher Educ. v. Hedrick, 573 F.3d 1290, 1299 (Fed. Cir. 2009).  The brief characterizes as "overwhelming" evidence that "CVC's invention was ready to be handed off to skilled artisans," as illustrated by the table from the brief set forth above. CVC argues that "[i]t is hard to imagine more powerful, objective, real-world evidence that conception was 'complete' . . . than the fact that so many actually did, so quickly after learning of CVC's invention."  The brief also argues that the Board ignored the widespread recognition in the art, beginning with public disclosure of sgRNA-comprising CRISPR embodiments, that CRISPR was expected to be capable of cleaving DNA in eukaryotic cells (this evidence bolstered CVC argues by Broad reducing their invention to practice "within weeks" of receiving CVC's disclosure of chimera A).

Instead, CVC maintains, the Board was "doubly wrong" in focusing on purported subjective "uncertainty" by CVC inventors regarding their own attempts to reduce their invention to practice.  First, the brief argues that "the 'existence of research or experimentation'—even 'a long series of experiments'—does not itself prove conception incomplete," citing Sewall and Cameron. What is determinative, CVC argues, is whether any experimentation required the exercise of "more than routine skill," citing Rey-Bellet v. Engelhardt, 493 F.2d 1380, 1387 (C.C.P.A. 1974), something CVC argues the Board never did.  And the Board also never explained why the purported "months of failed experiments" were "too long" in view of their being performed by graduate students who were not persons of ordinary skill, CVC argues.  Prior interference decisions (Dolbear, Hedrick) awarded priority based on evidence such as laboratory notebooks that "sufficiently described to those skilled in the art how to proceed."  These rubrics were supported in CVC's brief by citation of other  precedent, including Barba v. Brizzolara, 104 F.2d 198, 202 (C.C.P.A. 1939); Field v. Knowles, 183 F.2d 593, 603 (C.C.P.A. 1950); In re Tansel, 253 F.2d 241, 243-44 (C.C.P.A. 1958); Acromed Corp. v. Sofamor Danek Group, Inc., 253 F.3d 1371, 1380 (Fed. Cir. 2001); and Sewall.  CVC's brief distinguishes the case, Alpert v. Slatin, 305 F.2d 891 (C.C.P.A. 1962), relied upon by the Board for incomplete conception being evidenced by failures in actual reduction to practice on the grounds that in that case the only evidence was the inventor's failure, whereas here multiple other groups including Broad were able to reduce to practice sgRNA comprising CRISPR-mediated DNA cleavage in eukaryotic cells from CVC's disclosure of their invention.

CVC also contends that the Board was wrong in characterizing their reliance on the successful work of others to demonstrate their own complete conception as an attempt at nunc pro tunc conception, or that CVC was improperly attempting to use Broad's success to inure to their benefit, because there was nothing defective in their conception (which was used without revision or modification by Broad and others) and CVC did not fail to recognize its invention, as was the case in Hitzeman v. Rutter, 243 F.3d 1345, 1358 (Fed. Cir. 2001).

The Board, CVC argues, further erred in applying a "subjective expectation of success" standard, that "the inventors kn[e]w their invention would work" (emphasis in brief).  This standard "defies" precedent, the brief maintains, citing City of Elizabeth v. Nicholson Pavement, 97 U.S. 126 (1877) (where the inventor was "not sure" the invention would work); Applegate v. Scherer, 332 F.2d 571, 573 (C.C.P.A. 1964); Dana-Farber Cancer Inst., Inc. v. Ono Pharm. Co., 964 F.3d 1365, 1372 (Fed. Cir. 2020); Hedrick; and Burroughs (although the Board stated that it did not "base [its] decision on a lack of reasonable expectation of success by the CVC inventors" the PTAB "contradicted that standard as quickly as it articulated it" according to the brief).  And the brief in a footnote anticipates assertion of the "simultaneous conception and reduction to practice" standard of conception, which was earlier raised by Broad in some of their preliminary motions, by stating that PTAB's "failure to rely on it—and explain why it would apply—precludes its assertion on appeal" under In re Lee, 277 F.3d 1338, 1344-45 (Fed. Cir. 2002).

The brief then turns to what in some ways is the heart of the matter, regarding the question (the basis of all interferences) of who invented the invention of Count 1.  According to CVC, the PTAB awarded priority to Broad based on first reduction to practice while identifying nothing the Broad inventors "actually invented," including no "adaptation" or "technical element" lacking in CVC's disclosure or that the skilled worker would have lacked.  "Any test that awards inventorship to a party without identifying the inventive element he contributed cannot be right," CVC argues, because "[p]atent law rewards 'innovation,' not "'the work of a mechanic'" in reducing others' inventions to practice," citing Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 330 (1945).  The brief argues that the PTAB concluded that "there must have been differences" between Broad's actual reduction to practice and CVC's based on the differences in when each party achieved actual reduction to practice.  Because this is an "ipse dixit [that] is unexplained and inexplicable" the brief argues the Board never provided any reason or rationale that these "assumed" differences "reflected different inventive approaches, or [were] simply mechanical skill or luck."  Nor did the Board acknowledge that Broad reduced the invention to practice using the same techniques [including chimera A] first disclosed by CVC.  The brief answers its own rhetorical question — why not? — by asserting that the reason is that Broad derived its invention in toto from CVC, as evidenced by the activities of Dr. Marraffini (once again mentioning that these activities were kept undisclosed by Broad until "after a decade of patent prosecution and litigation").  CVC argues that "patents [are to] be awarded to an 'original inventor'—not a 'borrower or a copyist,'" citing 1 W. Robinson, The Law of Patents for Useful Inventions § 58 (1890) as well as the Constitution, and that someone who merely confirms another's conception using ordinary skill is not an "original" inventor, citing Applegate.  CVC further argues that the PTAB "almost conceded" that, had CVC hired the Broad to reduce its invention to practice CVC and not Broad would be entitled to priority and states that the "result should not be different simply because [Broad], instead of being hired by CVC, took chimera A from CVC's still-unpublished manuscript and proved the invention works."  "Patent rights to the invention of the century should not be awarded based on a footrace to implement it using routine techniques" according to CVC's brief.

CVC also argues that the Board contravened the standards and statutory requirements of the Administrative Procedures Act in arriving at its incorrect priority determination under the "reasoned decisionmaking" requirement and is thus arbitrary and capricious.  Support for these allegations include the PTAB's failure to provide evidentiary support for its "must be differences" theory of CVC's alleged incomplete conception (the brief calls this "res ipsa reasoning") and the failure to identify the technical features purportedly lacking in CVC's attempts at actual reduction to practice.  Citing Morall v. DEA, 412 F.3d 165, 178 (D.C. Cir. 2005), CVC argues that "[a]gency decisions must be grounded in evidence" and that the PTAB's priority determination lacked any such evidence, asserting:

Here, the PTAB did not identify any relevant difference between CVC's conception and Zhang's reduction to practice—because the record would not support any.  Zhang used the same tools CVC had selected by June 2012 to reduce the invention to practice: expression vectors; standard promoters, including the U6 promoter; NLSs; and codon optimization.  . . .  The PTAB, moreover, did not explain how any of those techniques could make a difference: Broad conceded that none required more than ordinary skill.  . . .  Broad touted the "combination" as inventive, but never meaningfully disputed that CVC identified the same combination first [emphasis in brief].

Moreover, CVC argues that "[c]ourts cannot 'uphold agency action if' the agency decision 'fails to consider "significant and viable and obvious alternatives,"'" citing Dist. Hosp. Partners, L.P. v. Burwell, 786 F.3d 46, 59 (D.C. Cir. 2015), which "precisely describes the PTAB's decision here" according to CVC.  After all, Broad's purported success rate (0.75%) at sgRNA-comprising CRISPR-mediated DNA cleavage in mammalian cells was not demonstrably better than success rates by CVC scientists that they deemed inconclusive (e.g., one transformed zebrafish embryo in 30, or ~3%) CVC argues.  In addition, CVC argues that "the line between CVC's supposed failures and its successes was not drawn by a change in techniques.  It followed a change in graduate students and could be the result of "random chance . . . human error, equipment quality, and measurement failures."  And many of the first graduate student's "failures" were the result of attempts to reduce to practice CRISPR embodiments (HDR) that were outside the scope of the count (which was limited to CRISPR-mediated DNA cleavage).

CVC also argued that the Board "ignored rafts of evidence contrary to its position" (or conclusions).  The brief cites Princeton Vanguard, LLC v. Frito-Lay N. Am., Inc., 786 F.3d 960, 970 (Fed. Cir. 2015), for the proposition that under the APA "the PTAB must address the evidence for and against the results it reached," and then recites 4 species of such evidence they argue the Board did not consider.  These included contemporary opinion by "CRISPR luminaries" regarding how "straightforward" application of CRISPR-mediated DNA cleavage would be in eukaryotic cells; that five other labs were able to reduce to practice CRISPR cleavage methods within the scope of the interference count "shortly" after CVC announced its conception of sgRNA-comprising CRISPR embodiments; that CVC (and everyone else) ultimately achieved actual reduction to practice of the invention CVC had conceived with no changes; and that CVC was in fact subjectively confident that its invention "would work in eukaryotic cells," contrary to the meme of doubt successfully argued to the Board by Broad.  In this regard CVC brought up the (relatively) short time (four months) between conception and undisputed actual reduction to practice and that the Board "never explained why a four-month [delay in] reduction to practice amounts to 'perplexing' difficulties 'every step of the way,'" contrasting this time with difficulties encountered by the Wright Brothers and Bell for reducing their inventions to practice.  "Nowhere did the PTAB explain why the inventors awarded the Nobel Prize for probably the most stunning advance of the century should be disqualified because their graduate students initially stumbled but ultimately succeeded in just four months.  That lack of reasoned explanation is arbitrary and unsustainable," CVC argued.  And the Board's treatment of the microinjection experiments "fares worse still, CVC argues because "the PTAB simply refused to engage with evidence that there is 'something different about microinjection' that 'negates' the purported hurdles that (according to the PTAB) might prevent implementing the count with vectors, and this failure is a violation of the APA, citing Provisur Techs., Inc. v. Weber, Inc., — F.4th —, 2022 WL 4474941, at *4-5 (Fed. Cir. Sept. 27, 2022).  CVC characterizes the Board's analysis of these experiments as comprising "bare assertion without 'substantial evidence,' or any evidence, behind it" because it did not dispute that "microinjecting a pre-formed complex into rapidly dividing cells like zebrafish embryos obviates most, if not all, of" the purported obstacles in using vectors to express functional sgRNA and Cas9 in eukaryotic cells.  The Board's decision with regard to CVC's reduction to practice without considering these differences was thus arbitrary and capricious, according to CVC.  And the brief raises similar objections to the Board's application of the written description requirement to the microinjection experiments based on purported obstacles arising from the vector-mediated experiments (because microinjection of preformed sgRNA-comprising CRISPR complexes obviated such obstacles).

The brief concludes with CVC's arguments regarding the Board's application of the written description requirement to the question of whether CVC was entitled to the priority dates of its P1 or P2 provisional applications (which if granted would have make CVC the Senior Party, with the advantages regarding burdens of proofs and presumptions attendant thereto).  Citing Alcon Rsch. Ltd. v. Barr Labs., Inc., 745 F.3d 1180, 1190 (Fed. Cir. 2014), Crown Packaging Tech., Inc. v. Ball Metal Beverage Container Corp., 635 F.3d 1373, 1380-81 (Fed. Cir. 2011), and Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc), CVC argues that the Board used an incorrect standard; in an interference the proper standard entails providing a description of even "one embodiment within the scope of the court" to be  enough to constitute a constructive reduction practice, citing Falkner v. Inglis, 448 F.3d 1357, 1362 (Fed. Cir. 2006).  CVC argues that its P1 provisional provides such a description of expressing sgRNA-comprising CRISPR-mediate DNA cleavage on a eukaryotic cell, i.e., how to make and use the invention.  The PTAB's error was in requiring that P1 do more than this, needing to "convince skilled artisans that the invention would work" according to CVC.  (While enunciating the extent of the disclosure relating to sgRNA-comprising CRISPR-mediated DNA cleavage in eukaryotic cells in P1 what remains unmentioned in the brief is that this disclosure is prophetic with regard to in vivo embodiments.)  The brief cites Evans v. Eaton, 20 U.S. (7 Wheat.) 356, 434 (1822), for the principle that P1 discloses what CVC claims as its invention, and Crown Packaging to support CVC's conception of this invention.  The brief argues that P1 discloses the "scientific principles underlying [the] invention" and discloses how to use CRISPR-Cas9 in eukaryotic cells using the same "well-known techniques" used in prior art TALENS and ZFN methods, including microinjection and use of expression vectors as well as including nuclear location sequences and codon optimization for Cas9 protein components.  In the face of this disclosure CVC argues that the Board erred by "improperly engraft[ing] a burden-to-convince requirement onto written description."  The proper standard is disclosure sufficient for the skilled worker to "recognize that what was claimed corresponds to what was described" and "not about whether the patentee has proven to the skilled reader that the invention works," citing Alcon.  The Board erred, according to CVC, because it required evidence in the P1 disclosure that what was described "worked," i.e., a disclosure of actual rather than constructive reduction to practice. CVC argues that the law does not require such a showing (Alcon) nor disclosure of "examples," "data" or "prior experimental work" (Ariad).  And delay by an inventor in achieving actual reduction to practice does not negate a showing of possession of an adequately disclosed invention the brief states, citing BASF Plant Sci., LP v. Commonwealth Sci. & Indus. Rsch. Org., 28 F.4th 1247, 1267 (Fed. Cir. 2022).  CVC's brief enumerates the evidence the Board improperly required, including "data from eukaryotic experiments"; how "all possible difficulties" were to be overcome; disclosure of "specific instructions or conditions necessary for CRISPR-Cas9 activity in a eukaryotic cell"; and "[c]onvincing skeptics they should not 'doubt' the in vitro experiment results."  Precedent holds that a lack of adequate written description involves a failure to disclose not a failure to persuade, CVC argues, citing Ariad and Biogen Int'l GMBH v. Mylan Pharms. Inc., 18 F.4th 1333, 1343-44 (Fed. Cir. 2021), and the Board's requirement for persuasion in the P1 priority document was thus error.  And the nature and root of this error is illustrated, according to CVC, by the Board's acknowledgement thereof by awarding priority to the P3 provisional application, which differed from P1 and P2 only because it included a working example of sgRNA-comprising CRISPR-mediated DNA cleavage in a eukaryotic cell.  CVC summarizes this argument by stating:

No inventor can anticipate and preempt with instructions every single litigation-inspired hypothetical problem that can be conjured.  Lawyers can always imagine 1,001 reasons an invention might not work.  Paid experts can invent still more.  "'[W]hen the question is whether a thing can be done or not, it is always easy to find persons ready to show how not to do it.'"  Dolbear, 126 U.S. at 536.  For groundbreaking inventions like this, it is easier still to hypothesize why they might fail.  But written description is description of the invention, not proof it works.  "Possession" means possession of the idea, not construction of a working example.  The patent system does not punish inventors of breathtaking innovations by saddling them with the burden of convincing putative skeptics their invention will work.

The brief concludes by asking the Federal Circuit to vacate the PTAB's judgment and findings and to reverse or remand, presumably for consideration under the proper interpretation of the law as set forth in CVC's brief.