Amici Support Reversal of PTAB Decision in CRISPR Interference

McDonnell Boehnen Hulbert & Berghoff LLP

McDonnell Boehnen Hulbert & Berghoff LLP

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).

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