January 9th was a busy day at the Patent Trial and Appeal Board (PTAB). On that day no fewer than five substantive briefs were filed in Interference No. 106,115, two by Senior Party The Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad"), and three by Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC"). All five were oppositions to counterpart substantive motions by the opposing party; the Broad oppositions will be discussed first.
Broad Opposition No. 1 was filed in opposition to CVC's Responsive Motion No. 2, wherein CVC asked to be accorded benefit of the filing dates of three provisional applications with regard to Broad's proposed Count 2 (USSN 61/652,086, filed May 25, 2012 (P1); USSN 61/716,256, filed October 19, 2012 (P2): USSN 61/757,640, filed January 28, 2013 (P3)). To recap, Count 1 of the interference as declared is:
An engineered, programmable, non-naturally occurring Type II CRISPR-Cas system comprising a Cas9 protein and at least one guide RNA that targets and hybridizes to a target sequence of a DNA molecule in a eukaryotic cell, wherein the DNA molecule encodes and the eukaryotic cell expresses at least one gene product and the Cas9 protein cleaves the DNA molecules, whereby expression of the at least one gene product is altered; and, wherein the Cas9 protein and the guide RNA do not naturally occur together, wherein the guide RNAs comprise a guide sequence fused to a tracr sequence.
or
A eukaryotic cell comprising a target DNA molecule and an engineered and/or non-naturally occurring Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-— CRISPR associated (Cas) (CRISPR-Cas) system comprising
a) a Cas9 protein, or a nucleic acid comprising a nucleotide sequence encoding said Cas9 protein; and
b) a single molecule DNA-targeting RNA, or a nucleic acid comprising a nucleotide sequence encoding said single molecule DNA-targeting RNA; wherein the single molecule DNA-targeting RNA comprises:
i) a targeter-RNA that is capable of hybridizing with a target sequence in the target DNA molecule, and
ii) an activator-RNA that is capable of hybridizing with the targeter-RNA to form a double-stranded RNA duplex of a protein- binding segment,
wherein the activator-RNA and the targeter-RNA are covalently linked to one another with intervening nucleotides; and
wherein the single molecule DNA-targeting RNA is capable of forming a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule, whereby said system is capable of cleaving or editing the target DNA molecule or modulating transcription of at least one gene encoded by the target DNA molecule.
The Broad's proposed Count 2 is:
A method, in a eukaryotic cell, of cleaving or editing a target DNA molecule or modulating transcription of at least one gene encoded by the target DNA molecule, the method comprising:
contacting, in a eukaryotic cell, a target DNA molecule having a target sequence with an engineered and/or non-naturally-occurring Type II Clustered Regularly lnterspaced Short Palindromic Repeats (CRISPR)-CRISPR associated Cas) (CRISPR-Cas) system comprising:
a) a Cas9 protein, and
b) RNA comprising
i) a targeter-RNA that is capable of hybridizing with the target sequence of the DNA molecule or a first RNA comprising (A) a first sequence capable of hybridizing with the target sequence of the DNA molecule and (B) a second sequence; and
ii) an activator-RNA that is capable of hybridizing to the targeter-RNA to form an RNA duplex in the eukaryotic cell or a second RNA comprising a tracr sequence that is capable of hybridizing to the second sequence to form an RNA duplex in the eukaryotic cell,
wherein, in the eukaryotic cell, the targeter-RNA or the first sequence directs the Cas9 protein to the target sequence and the DNA molecule is cleaved or edited or at least one product of the DNA molecule is altered.
The distinction the Broad made in its Motion is between embodiments of CRISPR methods that are limited to "single-molecule guide RNA" (aka "fused" or "covalently linked" species), versus embodiments that encompass single-molecule and "dual molecule" species (wherein the in the latter versions the "targeter-RNA" and "activator-RNA" as recited in the proposed Count are not covalently linked). The Broad argued that the Board should adopt its Proposed Count 2 because it "properly describes the full scope of the interfering subject matter between the parties because both parties have involved claims that are generic, non-limited RNA claims." The brief also argued that Proposed Count 2 "sets the correct scope of admissible proofs [i.e., their own] for the breakthrough invention described by the generic claims at issue in these proceedings—the successful adaption of CRISPR-Cas9 systems for use in eukaryotic environments," which the Broad contended current Court 1 (in either alternative) does not.
CVC's Responsive Motion No. 2 argued that it was equally entitled to priority to its earliest provisional filings as the Broad was entitled to its provisional applications, by setting forth in detail the disclosure in its earlier priority applications for at least one embodiment falling within the scope of Proposed Count 2. In addition, and addressing the Broad's argument that CVC's disclosure (and this interference) were directed to single-molecule embodiments of CRISPR, CVC argued that on the contrary this priority document "disclosed, for the first time, that complexes of Cas9 and a double- or single-molecule DNA-targeting RNA . . . are useful for targeted DNA cleavage and described numerous applications of this gene-editing technology, including modifying target DNA in eukaryotic cells" and that "[t]he CVC inventors immediately understood that the CRISPR-Cas9 DNA-cleavage complex could be used in a variety of different cellular and noncellular settings." The brief recited (prophetic) Example 1 in the P1 specification, asserting that the failure of the P1 specification to show actual reduction to practice is not required to satisfy the requirement for entitlement benefit. CVC also cautioned the Board against any attempt by the Broad to "erroneously to link the issues in this motion to the PTAB's termination of Interference No. 106,048 due to no interference-in-fact," stating that "the legal and factual issues raised here are fundamentally different from those decided in the prior '048 proceeding" based on the PTAB's own prior statements of the grounds for its no interference-in-fact determination. Rather, according to CVC:
[A person of ordinary skill in the art] reading P1 in light of the state of the art at the time of filing would have understood that the application describes and enables at least one embodiment within the scope of Proposed Count 2. Moreover, post-filing-date publications report successfully practicing CVC's claimed invention in eukaryotes using the very methods and components that P1 describes. The Board should therefore accord CVC the benefit of P1's May 25, 2012 filing date with respect to Proposed Count 2.
In its opposition the Broad makes at least some of the arguments CVC anticipated, specifically that "[a] person of ordinary skill in the art . . . in 2012 could not have reasonably concluded from reading P1 or P2 – which disclose no more than in vitro experiments and laundry lists of routine techniques known in the at generally – that the [CVC] applicants possessed an embodiment that falls within the scope of Proposed Count 2." The Broad's brief sets forth two "separate and independent grounds" for this result: "(1) the PTAB's fact findings in the [earlier ']048 interference" (which the Broad argues are binding in this interference) and "(2)separate and independent de novo assessment of the evidence of record."
With regard to its first argument, the Broad asserts that the PTAB's fact-findings in the '048 interference preclude CVC from establishing benefit to P1 and P2, based on a 2012 reference to Jinek et al. (2012, A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity, Science 337: 816-21) and the finding that a person of ordinary skill in the art would not have had a reasonable expectation of success in performing CRISPR in eukaryotic cells. This argument is one of lack of an adequate written description and illustrates another aspect of a familiar conundrum: a specification cannot provide an adequate written description if one of ordinary skill in the art would not have had a reasonable expectation of success in achieving the invention (which was the basis for the PTAB's decision in the '048 interference that there was no interference-in-fact). The Broad's brief further argues that the skilled artisan would have expected bacterial CRISPR would need "its own set of unique conditions" to be adapted to practice in eukaryotic cells, which P1 and P2 did not disclose. Finally regarding this argument, the Broad asserts that neither of CVC's P1 or P2 do priority documents disclosed anything not found in the Jinek reference, except for well-known techniques in the art, and PTAB found that the combination of Jinek plus these known prior art techniques did not render eukaryotic CRISPR obvious.
The Broad's second argument is that the Board should arrive at this same conclusion if the evidence is assessed de novo. The Broad asserts that neither the P1 nor P2 priority documents provide a constructive reduction to practice of eukaryotic embodiments of CRISPR because none of the "fictitious" embodiments relied upon by CVC's expert were disclosed in P1 or P2, calling them "post-hoc creations of CVC's expert, manufactured by stitching together disparate disclosures from P1 and P2, using Proposed Count 2 as a roadmap." The brief alleges that P1 and P2 provide no "blazemarks" for practicing eukaryotic CRISPR, and even if the Board finds there were blazemarks there were no eukaryotic experiments or specific instructions needed to satisfy the written description or enablement requirements of 35 U.S.C. § 112. Finally, in this portion of the argument the brief asserts that the third priority document contained in CVC's request for priority benefit is irrelevant because it was filed after publication of scientific references disclosing eukaryotic CRISPR by Broad and Harvard scientists and named inventors.
The brief provides a synopsis of the "State of the CRISPR Art by 2012" in the Broad's view, relying on PTAB findings from the '048 Interference. The brief cites the generic disclosure in P1 regarding methods for introducing nucleic acids into cells (e.g., "infection, lipofection, electroporation, calcium phosphate precipitation," and others), a characterization acknowledged by CVC's expert in this interference. According to the Broad, the P1 and P2 references were limited to in vitro examples and routine methods known in the art. The brief further argues that there was "continuing uncertainty" regarding the ability to practice eukaryotic embodiments of CRISPR until the Broad's Zhang and colleagues demonstrated that CRISPR could be adapted to eukaryotic cells. This uncertainty is supported (as it was in the '048 interference) by quotations from CVC's published scientific journal articles and interviews. Also, as before, the Broad notes that CVC's expert in the '048 interference had published a paper contemporaneously that cast doubt on whether CRISPR could be used in eukaryotic cells. And of course the brief notes that the Broad inventors were able to achieve eukaryotic CRISPR as set forth in the Broad's earliest priority date, December 12, 2012. (In this regard the brief makes the argument that the P3 priority document shows achievement of eukaryotic CRISPR only after getting assistance from Broad inventors, specifically George Church.)
The brief then sets forth a further synopsis of the '048 interference and its outcome, which does not bear repeating here (see "PTAB Decides CRISPR Interference in Favor of Broad Institute -- Their Reasoning" and "Regents of the University of California v. Broad Institute, Inc. (Fed. Cir. 2018): Federal Circuit Affirms PTAB in Appeal of CRISPR Interference").
Finally, the Broad sets forth its legal arguments based on the fact finding by the PTAB in the '048 interference, to the effect that neither P1 nor P2 satisfy the requirements of §112 sufficient to establish constructive reduction to practice of eukaryotic embodiments of CRISPR. These arguments are based, as the Broad's arguments have been based throughout this interference, on the issue preclusive effects of 37 C.F.R. § 41.127(a)(1) and corresponding Standing Order Rule 127(a)(1). Further, the Broad argues that the PTAB's decision in the '048 interference is law of the case and controlling here, under MPEP 706.07(h)(XI)(A). The Broad also argues that CVC has used this "law of the case" doctrine during ex parte prosecution to overcome prior art-based rejections over the Broad's extensive eukaryotic CRISPR portfolio of granted patents.
The brief next asserts that CVC's arguments for being accorded priority benefit to P1 and P2 are contrary to the PTAB's findings in the '048 interference. Specifically, the brief cites CVC's current expert's assertions that P1 or P2 plus the ordinary skill in the art showed possession of eukaryotic CRISPR, which the Broad argues is contrary to the PTAB's decision that the skilled person would have had no reasonable expectation of success. The brief sets forth express portions of the PTAB's earlier decision in support of this argument with regard to reasonable expectation of success, the need for a unique set of conditions for practicing CRISPR in eukaryotic cells, and that the practice of CRISPR in vitro combined with well-known techniques for expressing heterologous genes in eukaryotic cells did not render eukaryotic CRISPR obvious. These circumstances preclude CVC from being accorded priority benefit to P1 and P2 as a matter of law, the Broad argues, based on lack of enablement, including the utility requirement embodied in that statute.
The brief concludes by providing the Broad's point-by-point rebuttal of CVC's arguments concerning why the prior PTAB decision are not preclusive, and further argues that de novo review of the record does not support CVC's position. These arguments are based on: 1) failure of P1 or P2 to disclose embodiment E4, E5, or E6 cited in CVC's motion; 2) there being no "blazemarks" in P1 or P2 regarding how to create these undisclosed ("fictitious") embodiments (with extensive rebuttal of CVC's expert's testimony); 3) that the P1 and P2 disclosures fail to anticipate or render obvious Proposed Count 2 as required under 37 C.F.R. § 41.201; 4) that the fictitious embodiments are incomplete for failure to disclose "a specific target sequence or delivery method to the [eukaryotic] cell"; and 5) there is no support in the P1 or P2 disclosures for anything but in vitro embodiments of CRISPR, and thus no possession in view of recognized uncertainty in the art (and set forth in detail in the brief). As a final argument, the brief sets forth in detail how, in the Broad's view, the P1 and P2 priority documents no not provide an enabling disclosure under the factors set forth in In re Wands.
The Broad's other brief filed January 9th will be the subject of another post.
