Early last month, a group of scientists* filed an amici curiae brief in support of the appeal by Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") of the Patent Trial and Appeal Board's decision to award priority to Broad Institute, Harvard University, and MIT (collectively, "Broad") as Senior Party for claims reciting eukaryotic embodiments of CRISPR-Cas9 (see "PTAB Grants Priority for Eukaryotic CRISPR to Broad in Interference No. 106,115").
The scientists state in preface:
Science is not perfect. A perfectly designed experiment can fail for a host of reasons before subsequent experiments vindicate the underlying theories. Likewise, experiments may succeed (or appear to succeed) even when they are designed using incorrect or incomplete theories. Luck, human error, and unaccounted-for variables all play a role in determining the results of an experiment. It is impossible to control for all of these factors.
This reality has led to development of the scientific method, wherein "scientists have developed rigorous procedures for testing their initial results and moving past initial failures." And these failures are of two types, the scientists argue: one, mundane failures arising from biological variability, experimental imprecision, and the play of chance; and two, fundamental failures, where "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, suggesting the scientist has not actually made a discovery."
With these principles as backdrop, the scientists argue that the PTAB "fundamentally misunderstood how skepticism and failure operate within the scientific method." For inventions like CRISPR that "involve[] complex biological systems with many variables," the scientists maintain that "experimental failures are common and are not necessarily indicative of a problem in the underlying theories or experimental design." After all, the scientists note, "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." The PTAB's mistake was to take the CVC scientists' "ordinary skepticism" (that is a part of how experimental scientists evaluate their results and ensure they are reliable) with doubt regarding the experimental data (and hence whether the CVC inventors had conceived of operable embodiments for practicing CRISPR in a eukaryotic cell).
The scientists' brief then recites some of this skepticism (in their view) that the PTAB misinterpreted, from the evidence Broad asserted in arguing incomplete conception from statements by the CVC inventors. These statements, coupled with the five- to eight-month delay in getting eukaryotic embodiments of CRISPR to cleave target DNA effectively, convinced the Board that CVC's conception was incomplete. This was error, according to the scientists, because the Board "mistakes mundane failures—part of everyday lab work—for fundamental failures—which might suggest the inventive idea is inoperative or incomplete." Contrary to an admission of defeat, the scientists identify these statements to indicate that "the CVC inventors remained objective and open-minded in considering whether they needed to tweak their experimental design."
And of course, "despite initial setbacks, the inventors eventually reduced to practice their invention—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." This is evidence that "the CVC inventors never fundamentally doubted their invention; their expression of uncertainty was just ordinary scientific skepticism," according to the scientists. The brief hammers home the scientists' fundamental message that "scientific skepticism is not fundamental doubt" with regard to the PTAB's acceptance of Broad's expert witness, Dr Mirkin, on the potential reasons "why a person of ordinary skill in the art (i.e., a skeptical scientist) might have believed, prior to the successful implementation of CRISPR-Cas9 systems in eukaryotic cells, that routine laboratory techniques might not work due to theoretical obstacles such as RNA degradation in eukaryotic cells, differences in the environment of eukaryotic and prokaryotic cells, and toxic effects of prokaryotic RNAs on eukaryotic cells." The PTAB's error, the brief argues, was to misunderstand the scientists' skepticism regarding the absence of empirical data. This was just a scientist's prudent practice, CVC argues, that "[w]hen presented with a discovery (such as the use of CRISPR-Cas9 to cleave eukaryotic DNA in vitro, as disclosed in P1), responsible scientists will reserve judgment that the discovery works in other slightly different situations (such as eukaryotic cells) until experimental results demonstrate that it actually works." This just reflected the requirement for "tough, sustained scrutiny" that the scientific method requires, the scientists argue. While it is easy for the skilled worker to "come up with a list of any number of theoretical obstacles to reducing to practice an invention . . . that does not mean that clearing those obstacles requires additional disclosures or anything more than routine methods."
Turning to the putative consequences of the PTAB's decision in this interference, the scientists predict that if upheld the Board's decision will "discourage collaboration, slow scientific progress, and reward confirmation bias." In view of the collaborative nature in modern scientific labs, the scientists argue, the Board's decision to deny CVC's scientists with priority benefit to their invention will "discourage the free flow of communication between collaborators." Prudently, future scientists "may choose not to speculate openly with their colleagues about why an experiment failed or brainstorm next steps" and, should this closed mouth behavior extend to students, cripple scientific education. These concerns apply with at least equal risk to communication with the scientific community as a whole, the scientists argue. As they put it, "[s]cience is a conversation: an iterative process that allows for one idea to build and shape the next through refinement of the last. Sharing experimental results with the wider scientific community can launch a slew of new research." But the lesson from the PTAB's decision against CVC will encourage future scientists "to secret away their inventions until they can muster enough evidence to convince others that their inventions will work." Proposing the hypothetical, the scientists argue that the CVC inventors could have keep secret the discovery that CRISPR-Cas9 could be used to cleave DNA in vitro, waiting for the in vivo data to be later produced. This would have delayed the progress of CRISPR research with deleterious effects on progress.
The broader picture painted in the scientists' brief is that "the PTAB's decision will encourage bad science." This means that:
If the minor missteps and changes in strategy characteristic of routine bench work can later be used as evidence that an inventor lacked a definite and permanent idea of the invention, as the PTAB found here, scientists will avoid rigorously testing their own settled expectations. Instead, they will 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. Such confirmation bias is antithetical to the very core of the scientific method, which demands steadfast skepticism.
It is hard to say what the effects of this amicus brief will be. But what the scientists provide for the Court is context for the statements, e-mails, and other evidence Broad adduced during the interference that proved persuasive to the PTB in awarding priority to the Broad due to perceived failures of the CVC inventors to have had complete conception of eukaryotic CRISPR.
* The scientists on the brief are Thomas Cech (Nobel Prize winner, Chemistry, 1989), Titia de Lange, Michael Levine, David Jay Segal, and Jack Szostak (Nobel Prize Winner, Physiology/Medicine, 2009).
