Almost three weeks ago, on October 31st, Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") filed its priority motion in Interference No. 106,115, setting forth for the first time its earliest conception date (March 1, 2012) and evidence of that conception for practicing CRISPR in eukaryotic cells:
In the remainder of its 50 page brief, CVC set out its arguments for serial events of conception (April 11, May 28, or June 28, 2012), when the invention encompassed by the Interference Court was serially reduced to practice (earliest date, August 9, 2012, and thereafter on October 31, November 1, 5, and 18, 2012), and its assertions that it pursued reduction to practice with the statutorily required diligence and never abandoned, suppressed, or concealed their invention.
That evidence is critical, because mere assertions or uncorroborated testimony by the inventors is entitled to no weight in an interference. Apator Miitors v. Kamstrup (Fed. Cir. 1996). However, consistent with PTAB rules the affidavits, copies of laboratory notebooks and other evidence that corroborate CVC's explication of these events is not yet available on the PTAB website; the brief, however, discloses this table:
Nevertheless, the story told in the brief in support of the priority motion is compelling. The brief sets forth the initial conception by inventors Jennifer Doudna, Emmanuelle Charpentier, Martin Jinek, and Krzysztof Chylinski as the date when the concept of introducing the CRISPR system comprising Cas9 protein and a single-molecule guide RNA (comprising truncated crRNA and tracrRNAs covalently linked via a short polynucleotide spacer) into eukaryotic cells first arose. The brief asserts that "only ordinary skill was needed to reduce [the invention] to practice." As CVC argued in the first interference (No. 105,048), "the inventors had multiple, straightforward actual reductions to practice (ARTP) within a few months" and (as they did not have the opportunity to argue in the '048 Interference) "before Broad's accorded benefit date" (emphasis in brief).
The brief mentions the in vitro work done prior to March 1, 2012, which one of CVC's experts hailed as the "gold standard" for understanding the necessary components of the CRISPR_Cas9 system. This work also presaged the use of first truncated and then single molecule guide RNA specifies for performing CRISPR. Turning to specifics and details, the brief tells the story of the months between their conception on March 1, 2012 and first actual reduction to practice on August 9, 2012. According to their recounting of this origin story for eukaryotic CRISPR, Dr. Doudna sent Mr. Jinek an e-mail the very next day to write up in his laboratory notebook (Exhibit 4381) how CRISPR could be adapted for use in eukaryotic cells, including getting the disclosure signed and witnessed (introduced as evidence herein at Ex. 4349, ¶34; Ex. 4381, 63-65). As for Jennifer Doudna, the brief explains that "Doudna so appreciated the significance of this invention that, for the first time in her career, she deliberately ensured it was promptly memorialized and witnessed" (Ex. 4350, ¶45). The elements of the count set forth in Jinek's notebook are illustrated in this version of the notebook page set forth above:
including embodiments where the crRNA and tracrRNA were fused and separated by a short look of intervening nucleotides. The brief illustrates that this conception was "definite and permanent" by comparing the original design from Jinek's notebook dated March 1, 2012 with the (more refined) embodiment of the same components in the Jinek 2012 Science paper and the drawing in U.S. Provisional Application No. 61/757,640 (designated "P3").
In further support for conception, the brief sets forth diagrams of the invention as disclosed in an Invention Disclosure Form (IDF) submitted on April 11, 2012 (Ex. 5105, 7, 9) containing this diagram:
which highlighted (in red) the NGG (PAM) sequence necessary for CRISPR alterations of specific DNA sequences as well as this diagram illustrating the components and their alignment needed for cleavage:
The brief also sets forth further conception for practicing CRISPR in eukaryotic cells using the gene for green fluorescence protein (on May 28, 2012), human CTLA gene ("[b]y April 28 and no later than May 28, 2012") and in June 28, 2012 arranged for a colleague to practice eukaryotic CRISPR in zebrafish as evidenced by an e-mail (Ex. 4799).
In support of expert testimony that the invention could be reduced to practice by nothing more than the exercise of ordinary skill, the brief then sets forth details of actual reduction to practice. In the first successful experiment, the zebrafish rx3 gene was targeted; successful cleavage resulted in eyeless zebrafish that are otherwise normal. (Not reproduced here are pictures of the resulting zebrafish; see Exs. 4913-4915.) The brief sets forth in detail the course of these experiments from June 28th to August 9th, including toxicity testing of Cas9 protein in zebrafish and the use of alternative 20-nt target sequences and development of these RNA sequences for performing rx3-specific CRISPR in zebrafish:
The fact that these experiments were performed by researchers other than the named inventors does not negatively impact their status as the sole true inventors, because under Genentech, Inc. v. Chiron Corp., 220 F.3d 1345, 1354 (Fed. Cir. 2000), work of others can inure to the inventor's benefit.
Another example of actual reduction to practice occurred according to the brief on October 31, 2012 when (significantly) a first-year graduate student (whom the brief is certain to say was one of less than ordinary skill in the art having "with introductory lab skills") successfully performed CRISPR on the CLTA6 gene in human cells (Ex. 4353, ¶92; Ex. 4366, 31-33) using these RNA sequences:
(These experiments were disclosed in the P3 application.) This correspondence is important, because the PTAB has conferred priority to the P3 application in its decision on motions (see "PTAB Decides Parties' Motions in CRISPR Interference").
Finally, the brief describes successful performance of CRISPR in human U2OS cells on November 1, 2012 targeting the CTLA6 gene, and then achieving CRISPR on this gene in human HEK293T cells on November 5th and 18th.
The brief also uses scientific journal articles (including ones from the Broad inventors) to illustrate the routine nature of the experiments needed to practice CRISPR in eukaryotic cells using single-molecule RNA guide elements identical to the design set forth in Jinek's laboratory notebook.
In view of the relative speed and ease with which these experiments demonstrated actual reduction to practice of eukaryotic CRISPR, one can only imagine the frustration the CVC inventors must have felt regarding the basis for the outcome of the '048 Interference and their chagrin in how unfortunate comments were considered out of context by the PTAB and Federal Circuit.
At each step of this saga, the brief is careful to note that the invention disclosed in its evidence also corroborates the CVC inventors' conception and reduction to practice of all the limitations of Broad's half of the count. And of course all of the evidence and testimony was corroborated by witnesses other than the inventors themselves.
These recollections were interspersed with assertions regarding the pioneering nature of the inventors' work, their work is described as "groundbreaking," and of course the brief mentions the recent decision of the Nobel committee to award the Nobel Prize to Doudna and Charpentier alone. And the brief also sets forth evidence that the CVC inventors appreciated all the potential obstacles used to great effect in convincing the PTAB (and the Federal Circuit) in the '048 Interference that there was no interference in fact between CVC's applications and the Broad's eukaryotic CRISPR patent.
The brief also contains two statements from Broad scientists (or attributed to Broad scientists) meant to make it difficult for those scientists to argue prior conception and/or to support an argument that their conception was derived from CVC's invention. These include this portion of the brief:
According to Dr. Luciano Marraffini, who collaborated with Broad's Feng Zhang and co-filed Broad's first provisional application, the idea for sgRNA originated from the Jinek 2012 paper:
The Doudna–Charpentier paper is when we all learned about the single-guide RNA. That was online in June 2012 . . . . In the end, after seeing the paper, we recognized the value of the single guide RNA.
Dr. Shuailiang Lin, another collaborator of Zhang's and co-inventor on Broad's first provisional, independently confirmed this in a 2015 email he wrote to Dr. Doudna:
After seeing your in virto [sic] paper, Feng Zhang and Le Cong quickly jumped to the project . . . . We did not work it out before seeing your paper, it's really a pity.
The brief concludes with evidence and testimony of diligence from conception and actual reduction to practice of eukaryotic CRISPR, and that CVC did not abandon, suppress, or conceal the invention.
The Broad (whom as Senior Party is not obliged to do so) can file its Priority Motion on December 11th. Alternatively (or in addition) Broad can file an opposition on February 5, 2021.