By Kevin E. Noonan —
Inventorship determinations have been called, in some of their incarnations, "one of the muddiest concepts in the muddy metaphysics of patent law." Mueller Brass Co. v. Reading Indus., 352 F. Supp. 1357, 1372 (E.D. Pa. 1972), aff'd, 487 F.3d 1395 (3d Cir. 1983); see In re VerHoef, 888 F.3d 1362, 1365 (Fed. Cir. 2018) (quoting Mueller Brass Co., 352 F. Supp. at 1372). Whatever complications may arise in "simple" inventorship determinations are amplified in interferences. These determinations are further burdened by over a century of case law, both in the U.S. Patent and Trademark Office and the courts, which can be charitably characterized as arcane. And these considerations are evident in the decision last week giving priority to CRISPR technology in eukaryotic cells to inventors at The Broad Institute, Harvard University, and MIT (collectively, "Broad") over inventors at the University of California, Berkeley, the University of Vienna, and one of the inventors herself, Emmanuelle Charpentier (collectively, "CVC"); see "PTAB Grants Priority for Eukaryotic CRISPR to Broad in Interference No. 106,115").
The basis for Board's decision was that CVC failed to provide sufficient, persuasive evidence of an earlier reduction to practice or conception, as they are legally defined, of each and every element of Count 1 before Broad's evidence of actual reduction to practice. The Board cited its legal grounds for this determination: "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," citing Cooper v. Goldfarb, 154 F.3d 1321, 1327 (Fed. Cir. 1998). Further, the Board opined "[a]n actual reduction to practice requires proving that the inventors constructed an embodiment of the count, meeting all its limitations, and that they determined the invention would work for its intended purpose," citing Cooper, 154 F.3d at 1327.
In applying these rubrics to the facts adduced by the parties, the Board cited with particularity testimony and contemporaneous statements regarding an August 9, 2012 zebrafish experiment performed by collaborator Florian Raible, Ph.D., to wit: "In his supporting testimony, Dr. Raible's indicates that one of the 30 embryos he injected with one concentration of the test solution showed the characteristic eyeless morphological phenotype expected for the homozygous rx3/chokh/chk mutant fish. (See Raible Decl., Ex. 4294, ¶¶ 54– 18 55.)" Specifically quoted in the Board's opinion was this excerpt from in Dr. Raible's declaration:
[Dr. Raible testified that he] prepared [an animal with the homozygous rx3/chokh/chk phenotype] on August 8, 2012, on behalf of the CVC inventors by injecting into the animal a preformed complex of the Cas9 protein and two single-guide RNAs that included crRNA and tracrRNA sequences where the crRNA sequence targeted the rx3/chokh/chk locus. This fish indicated to me that there was successful site-specific DNA cleavage in a zygote injected with the inventors' CRISPR-Cas9 system. The inventor's CRISPR-Cas9 system thus worked as predicted in zebrafish using previously known methods for delivery and analysis.
Unfortunately for CVC, the Board found that "CVC does not direct us to contemporaneous evidence showing that Dr. Raible considered the results of the 9 August 2012 experiment to have been successful." In addition to this absence of evidence (which would not otherwise be evidence of absence), the opinion quotes what it considered to be contrary contemporaneous evidence, including an e-mail from Dr. Chylinski (Dr. Raible's collaborator) to Inventor Charpentier, which states:
Potentially good news about fish. We tested the NLS-tagged Cas9 that we just got from Martin as the normal protein was not giving anything conclusive. It looks like GFP expression in medaka is much lower in the embryo although there are still problems with toxicity and so on, so it will require some more optimization from their site. Anyway, there is a hint it might work but we shouldn't be overexcited now [italics added].
This e-mail was sufficient for the Board to conclude that "by itself, neither Dr. Chylinski's e-mail of 9 August, nor Dr. Charpentier's response demonstrates that either recognized and appreciated Dr. Raible's August 2012 experiment was an actual reduction to practice of an embodiment of Count 1" (emphasis added).
Further quoting Dr. Chylinski's testimony, the opinion contains this excerpt:
We believed that these effects were the result of our sgRNA CRISPR-Cas9 system's activity in the fish, though we had not confirmed an effect on the targeted regions by sequencing. Ex. 4916. While my fish experiment result summary noted that the effects of possible incomplete GFP loss in the medaka might be the result of "heterozygotes" or "unspecific" effects, the zebrafish eyeless phenotype indicated that we had successfully used our sgRNA CRISPR-Cas9 system to target and cleave target DNA within the zebrafish. Ex. 4916. The reference to repeating experiments indicated that a journal publication would require multiple experiments and a second molecular detection assay [emphasis added].
But, to the contrary in the Board's view, is a contemporaneous slide presentation which states:
Fish experiment results
• Pretty high toxicity observed (death or misdevelopment)
• Small amount of putative mutants (1 in 30-50) seen in some of the experiments
• "Less green" embryos for Medaka [a zebrafish relative], no eyes or misdeveloped eyes for Zebrafish – might be heterozygotes, might be unspecific
• Mutants tested for the mutations in the gene by PCR amplification of the targeted regions (repair of dsDNA breaks is usually connected with trimming of the DNA) – no effect visible
• Experiments are still being repeated [emphasis added]
The Board concluded that "[w]e agree with Broad and find that, contrary to CVC's argument, Exhibit 4916 does not indicate an acknowledgement of positive results by Dr. Chylinski." And contemporaneous statements by Dr. Charpentier that she was "convinced" the zebrafish experiments would work are not supported by any reference to any actual zebrafish experiments, the Board stated. The Board's conclusions are summarized in the opinion thusly:
In general, we find that CVC over-emphasizes isolated words by its inventors to argue that they recognized and appreciated Dr. Raible's results. We are further persuaded that CVC over-interprets the inventors' recognition and appreciation of Dr. Raible's results because neither Dr. Doudna nor Dr. Jinek remembers learning of them at the time . . . . We note, too, that no zebrafish experiments were included in CVC's provisional applications filed 19 October 2012 and 28 January 2013 . . . . The lack of communication by Drs. Chylinski and Charpentier regarding Dr. Raible's 9 August 2012 zebrafish experiment and lack of reference to it later indicates to us that the CVC inventors did not consider it to be a success or a reduction to practice of Count 1 because Dr. Raible did not communicate any success to them.
Additional evidence persuasive to the Board that Dr. Raible did not appreciate that the experiments were a success was that no scientific research paper was forthcoming; Dr. Raible testified that:
While I was happy to have helped the inventors validate their sgRNA CRSIRPCas9 system in zebrafish, I did not believe that merely showing successful cleavage in a eukaryote using only routine techniques, with no special parameters to introduce a nuclease into eukaryotic cells, would be a publication-worthy discovery. That was a trivial and expected result. I felt that to justify expending additional resources on these experiments, I needed results suggesting that the efficiency of CRISPR-Cas9 in vivo could compete with ZFNs and TALENs. I believed that other labs with more resources would likely generate such data before I would be able to, for instance by being able to perform massive parallel sequencing on targeted gene loci, bypassing the need to rely on the presence of length variants identified by PCR.
Which would be fine as it goes, but the Board was able to contrast this testimony with Dr. Raible's contemporary statements (before the experiments had been performed) to the contrary (in their view):
Given the massive interest in simple methods for genome editing, we would expect that the establishment of a CRISPR/CAS-based genome editing system in any fish system would be of broad interest, and therefore a short article in a high-impact journal would not be unlikely as a result (provided the results match the expectations based on the in vivo data).
The Board concluded that this contrast indicated that Dr. Raible's 2012 behavior was more consistent with abandoning the zebrafish CRISPR project because he did not think it had worked rather than, as he maintains today, being consistent with an appreciation of success. And for the Board, while CVC provided evidence that Dr. Raible's results had been communicated to Drs. Chylinski and Charpentier, there was no evidence that this information had been communicated to the other two CVC inventors, Dr. Doudna or Dr. Jinek.
The Board eschewed reliance on a "battle of the zebrafish experts" because "'there is no conception or reduction to practice where there has been no recognition or appreciation of the existence of' new subject matter," citing Silvestri v. Grant, 496 F.2d 18 593, 597 (CCPA 1973), and "what matters is appreciation of the results by the inventors" (italics in opinion). Accord, Invitrogen Corp. v. Clontech Lab'ys, Inc., 429 F.3d 1052, 1065 (Fed. Cir. 2005).
Turning to CVC's arguments regarding contemporaneous reduction to practice by other research groups (including Broad), the Board rejected them because all evidence regarding reducing eukaryotic CRISPR to practice by CVC had dates — "31 October 2012, 1 November 2012, 5 November 2012, and 18 November 2012" — later than the 5 October 2012 date when Broad submitted its manuscript to Science (that the Board relied upon as evidence of actual reduction to practice).
With regard to any question of diligence, the Board recognized that CVC could have prevailed if it showed conception prior to Broad and reduction to practice with the "exercise of reasonable diligence." Importantly, the opinion reminds that "[an] inventor need not know that the invention will work for conception to be complete because determining it works is part of reduction to practice," citing Burroughs Wellcome Co. v. Barr Lab., Inc., 40 F.3d 1223, 1228 (Fed. Cir. 1994). The standard the Board applied for incomplete conception is taken from Alpert v. Slatin, 305 F.2d 891, 894 (CCPA 1962) ("where results at each step do not follow as anticipated, but are achieved empirically by what amounts to trial and error" there has not been a complete conception), and Burroughs Wellcome ("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 "a conception may not be 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 issue, according to the Board, is whether there is "factual uncertainty" about whether the inventor had a complete conception, rather than uncertainty in a field of endeavor. The Board cites Hitzeman v. Rutter, 243 F.3d 1345, 1357 (Fed. Cir. 2001), for the analogous factual predicate that there, "statements made by the inventor during prosecution and subsequent publications . . . revealed he had not conceived of the complete subject matter of the count and considered it not to have been reasonably expected by one of ordinary skill in the art." The Board supported its finding of the requisite degree of uncertainty to indicate incomplete conception by CVC inventor Doudna's statements in an e-mail exchange with Inventor Jinek:
I'm very excited about the Csn-1/Cas9-based genome targeting ideas we discussed yesterday, this will be fabulous if it works [emphasis added].
[I]t would be good to demonstrate that the single-RNA guide works to direct DNA cleavage by Csn1/Cas9 in vitro ASAP, . . . and then proceed with the experiments necessary to show that this strategy will actually work in mammalian cells [emphasis added].
CVC argues that conception was "definite and permanent" on March 1, 2012, because "it did not change between conception and subsequent reduction to practice" and that this "blueprint" was expected to work using conventional methods. (The opinion reproduces pages from Jinek's laboratory notebook memorializing the plans for these experiments; pp. 29-31 of the opinion). But according to the Board:
The IDF [Invention Disclosure Form] demonstrates that the CVC inventors planned to use their sgRNA CRISPR-Cas9 system in eukaryotic cells but does not provide many details of how the inventors envisioned such a system would be operable. Instead, the IDF and Dr. Jinek's testimony indicates that as of 1 March 2012 the inventors assumed that what was known about other genome editing systems such as TALENs and zinc fingers would be applicable to a CRISPR-Cas9 system.
Specifically, CVC set out evidence of experimental designs targeting genes in human cells and that they had produced sgRNAs for the purpose by May 28, 2012 and a plan to inject zebrafish embryos by June 28, 2012. Broad asserted purported evidence of failures, including an e-mail from August 16, 2012 of "unfortunate results" in failure to achieve CRISPR cleavage of CTLA gene in human cells and a response from Dr. Doudna of "Shucks! I guess it would have been too easy of it worked the first time . . . I'll think on this and get back to you – my quick take is maybe try again with improved Cas9 expression?" Also asserted by Broad was an e-mail from September 14, 2012 entitled "no good news" that said, "[u]nfortunately no cleavage for any RNA chimeras despite using the codon-optimized Cas9 constructs this time." This e-mail also contained what the Board characterized as "generalized suggestions about repeating the experiment with increased amount of plasmid" and included the quotation:
Since there are so many variables in these experiments I think we have to try to move forward in a stepwise fashion as much as possible.
As for RNA localization I think we're hoping that the Cas9 protein binds the RNA such that the RNP is transported into the nucleus I wonder if having a too-efficient NLS on Cas9 is actually counterproductive if it means that Cas9 is transported before it has a chance to find and bind the guide RNA . . . . Thoughts?
A colloquy of further e-mails beginning on October 11, 2012 between Dr. Doudna and Inventor Jinek regarding the CTLA cleavage experiments (after the date Broad submitted its paper) are also reproduced in the opinion:
Hi Alex and Aaron – thanks for sending your results although it's disappointing not to see Cas9-mediated cleavage in these experiments. Aaron I'm wondering if you think there is anything different about the way you did the experiment back in August when it appeared that there was some cleavage with the CLTA6 guide? Or could that result have been due to a contamination, say with the ZFN sample -? And it will be interesting to see the result from the RNA transfection experiment. Is it worth trying the transfections again with the codon-optimized Cas9? As we have discussed I still think the problem may be with the assembly and localization of the Cas9 RNP – either due to degradation of the guide RNA failure to assemble with Cas9 or failure of the RNP nuclear localization. I will think on this on my way back to SF tonight and we can meet soon to discuss [emphasis added].
And on the same day in an e-mail from Dr. Jinek to Dr. Doudna:
Re mammalian cells – Based on the latest set of results, I suspect we have a problem with our RNA design. Either we are not targeting the right piece of DNA (due to chromatin structure etc.), or the problem lies with the RNA design per se. Given that the ZFN has no problems cleaving the same region (+/- 30 bp), the former is probably the lesser concern at this point. On the other hand, there could be a number or reasons for the latter including:
-RNA is not made at sufficient levels
-RNA is expressed strongly but turns over too fast to associate with Cas9 possibly due to degradation by exonucleases
-RNA is stable but does not associate with Cas9 at the right place and at the right time.
For the next set of experiments I think we should switch to CMV vectors cloning today and explore alternatives to our first-generation RNA design – e.g. modify the hairpin length introduce extensions at the 5' and 3' termini. Or possibly block potential degradation from either end by introducing hairpins etc. [emphasis added].
To which Dr. Doudna responded:
As for Cas9 in mammalian cells I completely agree with your analysis and suspect that one or more aspects of the RNA expression/stability/Cas9 assembly/localization are problematic.
It would be great to test some alternate designs of the guide RNA in vitro – perhaps this is something Alex could do using target plasmids you already have available? Maybe we could also try this in cell extracts? We can discuss further tomorrow – 10 am OK? [emphasis added]
Followed by a further response by Dr. Jinek:
I agree that we should explore various alternate RNA designs for targeting in cells. As for the in vitro experiments – I thought that this was what Steve Lin was going to do. Maybe it would be good to bring him on board for this as well at this stage. Then things could be parallelized and Alex could focus more on the mammalian cell work. When Enbo gets back he could then help out with IPs and Northerns because we will need to check whether the RNAs are associating with Cas9 in vivo. Anyway, let's talk tomorrow [emphasis added].
Broad argued, and the Board agreed, that these e-mails indicated that "instead of having a definite and permanent idea of an embodiment of Count 1, the CVC inventors were engaged in 'guesswork' and 'returned to the drawing board'" and that "the CVC inventors had to redesign their components and strategy beyond what would have been routine techniques for one of ordinary skill in the art and did not have a definite and permanent idea of the invention by 1 March 2012." The Board rejected CVC's contentions that Broad had fabricated an "illusion of doubt" in the CVC inventors based on the language and content of inter alia the cited testimony and contemporary documentary evidence, and also noted the apparent disparities between their testimony in this interference and confidence that CRISPR cleavage would be achieved in eukaryotic cells merely by the exercise of conventional methods and the difficulties encountered in attempting to reduce eukaryotic CRISPR to practice:
We find the facts related to the CVC's inventors' asserted conception on 1 March 2012 and the further evidence of 11 April 2012, 28 May 2012, and 28 June 2012 to be different from the facts of inventorship presented in Burroughs. In that case, the confirmatory testing was "brief" and followed the "normal course of clinical trials." Burroughs, 40 F.3d at 1230. In contrast, CVC argues its inventors had the materials for an actual reduction to practice in human cells on 28 May 2012, but allegedly completed it, after diligent work, on 31 October 2012 – over five months later – after encountering many problems and trying many times. Contrary to CVC's argument, we find that the CVC inventors engaged in a "prolonged period of extensive research, experiment, and modification" following the alleged conception on 1 March 2012. Burroughs, 40 F.3d at 1230. The evidence shows that, at best, the CVC inventors encountered one unrecognized positive result and several failures with zebrafish embryos and several months of failed experiments and doubt with human cells. Given that the scientists performing these experiments were of at least ordinary skill, we 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." Id. at 1229. [citations to the record omitted]
The Board rejected CVC's argument that, in the end they were correct that the invention conceived on March 1, 2012 was reduced to practice using "only routine materials and techniques," because "we look to what the CVC inventors understood as evidence of their conception, not what others might have understood later" (applying cases involving nunc pro tunc invention which may not be completely relevant in this situation). And by focusing on the limitation in Count 1 that CRISPR cleavage must be achieved to satisfy the requirements of the Count the Board included the requirement for conception that CVC's inventors "must have had a definite and permanent idea of an operative invention, that is of a system they knew would produce the effects on genes in a eukaryotic cell recited in Count 1." (It will be appreciated that this standard comes very close to the "simultaneous conception and reduction to practice" requirement Broad earlier argued was the proper basis for determining priority.)
Turning to Broad's evidence for priority, while the opinion sets forth evidence Broad proffered for its activities from 2011 through the fall 2012, it was the manuscript Broad submitted to Science (for which favorable reviews supported the Board's decision) on October 5, 2012 that established Broad's date of actual reduction to practice. As set forth above, because this date was earlier than CVC's activities that the Board might have considered to be an actual reduction to practice the Board required no other evidence to grant priority to Broad.
The opinion also addressed (and rejected) CVC's argument that Broad derived its (successful) sgRNA eukaryotic CRISPR embodiments from CVC via communications from Dr. Marraffini. In doing so, the Board applied the rubrics of derivation, which required CVC to "establish prior conception of the claimed subject matter and communication of the conception to the adverse claimant," citing Price v. Symsek, 988 F.2d 1187, 1190 (Fed. Cir. 1993) (which standard immediately doomed CVC's argument in view of the Board's determination that their March 1, 2012 conception was incomplete). The Board makes abundantly clear that CVC must fail based on their priority determination, saying "[t]hus, to prove derivation, CVC must first establish that its inventors conceived of the claimed subject matter before the Broad inventors." But "CVC does not direct us to evidence that overcomes our determination, discussed above" [of the Board purported evidence of] "multiple experimental failures" and did not address them in its Opposition asserting derivation. To CVC's attempt to establish conception based on Broad's rapid achievement of actual reduction to practice close on Dr. Marraffini's disclosure of CVC's sgRNA embodiment, the Board states that "[r]egardless of any success by the Broad inventors, the preponderance of the evidence presented by the parties demonstrates that the CVC inventors' experimental failures reveal uncertainty undermining a definite and permanent idea of an sgRNA CRISPR-Cas9 system that edits or cleaves DNA in a eukaryotic cell" and accuses CVC of "attempt[ing] to shift our focus to the activities of other, competing inventors, rather than on the activities of its own inventors," which attempt was unavailing. Broad's activities, whatever they were, "do not inure to CVC" according to the Board because to do so would require CVC to have "submitted" something to Broad for testing, citing Genentech, Inc. v. Chiro Corp., 220 F.3d 1345, 1353 (Fed. Cir. 2000) (which citation appears inapposite under the scenario underlying CVC's allegations). And the Board concludes that "there must have been [technical] differences" between Broad's activities to reduce eukaryotic CRISPR to practice and CVC's, based on CVC's failures prior to Broad's success on October 5, 2012 (emphasis added). These technical features, which are not recited in the Count, were necessary according to the opinion in order to satisfy the Count limitation for "a functional fused or covalently linked RNA CRISPR-Cas9 system in eukaryotic cells that alters the expression of at least one gene product, cleaves or edits a target DNA molecule, or modulates transcription of a one gene encoded by the target DNA molecule (emphasis in opinion). And the same "failures" relied upon by the Board in negating CVC's conception on the priority issue doomed CVC's arguments on derivation, because the Board similarly was "not persuaded that the CVC inventors could have divulged the complete subject matter of Count 1 to the Broad inventors."
The Board also denied CVC's Motion No. 3 that Broad's involved patents and applications are invalid under 35 U.S.C. § 102(f). The Board's basis for this decision was that "[a] determination of inventorship requires two steps performed as a claim-by-claim analysis: first a construction of each asserted claim to determine the subject matter encompassed and then a comparison of the alleged contributions of each asserted co-inventor with the subject matter of the properly construed claim to determine whether the correct inventors were named, citing Trovan, Ltd. v. Sokymat SA, Irori, 6 299 F.3d 1292, 1302 (Fed. Cir. 2002). On this basis the Board held CVC's evidence was insufficient to support its argument. This evidence, appreciated by the Board to be limited to a declaration by Broad's former patent counsel submitted in a European Patent Office Opposition, "does not provide an analysis of individual claims and does not list or discuss Broad's currently involved patents or applications." The disparities alleged by CVC arose solely in a comparison between the testimony in the declaration to the EPO and CVC's list of individuals that it contends "should have been named" as inventors. CVC's argument that these patents and involved applications all "originate from a common source" (i.e., the same original provisional application) was ("completely") unpersuasive before the Board because "[c]laiming benefit to the same provisional application says nothing about what is claimed in later applications . . . [w]ithout an actual analysis of Broad's involved claims and the alleged contributions of each asserted co-inventor." The opinion sets forth several instances of uncertainty or lack of specificity in the declaration regarding inventive contributions of various individuals, which motivated the Board to "decline to adopt the CVC attorney's assumptions" as to misjoinder of inventorship. Because CVC bore the burden of proving improper inventorship under 37 C.F.R. § 41.208(b), the Board denied the Motion.
Except for dismissing motions to exclude evidence from both parties, the remaining decision contained in the opinion was that the Board exercised its discretion not to consider CVC's assertion of inequitable conduct. The Board's grounds were that CVC's allegations in this regard "are not directly related to the issue of priority for the subject matter of the current count" and that it was within the sound exercise of the Board's discretion to refuse to consider CVC's motion.
While the Board's citation to the record provides sufficient evidence to satisfy the substantial evidence standard for review before the Federal Circuit, the implication of the outcome produces a certain level of disquiet. If in fact the use of the sgRNA embodiment was the basis for successful practice of CRISPR in eukaryotic cells (despite Broad's evidence for successful dual molecule CRISPR embodiments that were not considered in this interference because the Count was limited to single-molecule versions thereof), then the apparent basis for the Board's decision is that Broad's inventors were more technically proficient than CVC's at achieving successful reduction to practice more quickly. Under circumstances where both inventors reduced eukaryotic CRISPR to practice within 4-5 months of the Marraffini disclosure (and less than 8 months from CVC's asserted March 1, 2012 conception date, a timeframe CVC's counsel Dr. Ellison characterized at the Oral Hearing as "lightening quick") no issue of diligence arose. The Board speculated that certain differences between Broad's experimental setup and CVC's (e.g., using a U6 promoter or Broad's sgRNA species having an oligonucleotide linker length 2 nucleotides longer than CVC's) were responsible, with the only apparent basis for its speculation the logical fallacy of post hoc ergo propter hoc ("there must have been [technical] differences" to explain why Broad achieved actual reduction to practice before CVC). But none of these putative differences are required to satisfy the Count.
Whether CVC can mount a legal challenge to the Board's reasoning supporting what it can be anticipated to be an assertion of fundamental injustice in the Board's decision will likely be dispositive of the question of who controls eukaryotic CRISPR technology. And while the opinion states that "[t]here is no dispute in this proceeding over the patentability of those claims [that are not limited to cell type] or that the CVC inventors were the first to invent a CRISPR-Cas9 system with a single guide RNA to cleave DNA in a generic environment," this may provide cold comfort to CVC if, as can be anticipated, CVC will not be able to assert those patents against Broad's (or others') licensees over the practice of eukaryotic embodiments of CRISPR in view of the Board's priority determination in this Interference.
Patent Docs 