By Kevin E. Noonan –

The alacrity with which the Patent Trial and Appeal Board (PTAB) came to the same conclusion in its latest priority determination in favor of the Senior Party in interference No. 106,115 that it had almost eleven months ago precluded an assessment of Broad’s Brief in Opposition to CVC’s Opening brief or both Parties’ Reply briefs,* but relevant portions of those submissions can be referenced for both Parties consistent with the arguments made throughout this interference and related Interference No. 106,048.
Broadly, the Broad’s position is consistent with its argument, expressed more directly in Interference No. 106,048, that the complexity of performing CRISPR in eukaryotic cells renders any conception incomplete unless and until there is a successful reduction to practice. That argument faded in the ‘048 interference (when application of the “two-way obviousness test” sufficed for Broad to prevail; see “PTAB Decides CRISPR Interference in Favor of Broad Institute – Their Reasoning“), and Broad did not explicitly rely on that concept (which gained traction during the heyday of obtaining patents in isolated gene-encoding nucleic acids) in the current interference (at least not by name). But it remains at the heart of Broad’s arguments, now couched in assertions that CVC’s conception was incomplete due to failure to reduce to practice prior to Broad’s success (the success of this misconception was at least part of the basis for the Federal Circuit to vacate and remand the PTAB’s earlier judgment in Broad’s favor). This argument runs through their submissions in both interferences, which is not surprising in view of the timeline of actual reduction to practice for the parties.
The Board’s decisions show that another Broad argument resonated as well, wherein in addition to having reduced eukaryotic CRISPR to practice a few months earlier Broad argued that the several labs that used the sgRNA component of CRISPR undisputedly conceived by CVC:

were of greater than ordinary skill in the art, and thus these labs achieving actual reduction to practice did not show that the person ordinary skill in the art would have been able to do so by being informed of this species in conjunction with the capacity to express RNA (e.g., using the U6 promoter) and Cas9 protein (using recombinant expression known in the art for over a generation) in eukaryotic cells. Broad was able to use the efforts by CVC and the time taken to achieve actual reduction to practice, as well as the litany of purported uncertainty by those CVC inventors gleaned by their improvident statements on the record, to convince the PTAB (once again) that Broad’s actual reduction to practice provided priority. This argument, negating CVC’s conception, also was once again used to overcome CVC’s derivation arguments, because if several components other than sgRNA were required then Dr. Marraffini’s disclosure to the Broad inventors could not be sufficient to support their derivation argument.
CVC for its part argued that the critical conception was the sgRNA, using the historical fact that until that species was known (from its disclosure) the art did not evince the capacity to achieve CRISPR in eukaryotic cells. The timing between Dr. Marraffini’s disclosure to Broad’s actual reduction to practice supported the conclusion that this species played some role in the achievement; this conclusion was also supported by labs other than Broad’s that used sgRNA acknowledging CVC’s contribution to their achievement. The PTAB did not, on the other hand, seem to give the same type of credence to evidence that Broad’s inventors were themselves having difficulties achieving eukaryotic CRISPR until the sgRNA species was disclosed to them (including multiple instances of Zhang himself and his students evincing sentiments of failure prior to obtaining their invention from Dr. Marraffini (“the results were ‘nonspecific’” (Zhang); “wondering whether “‘other factors need to be identified’ for a working CRISPR system” (Lin); “Zhang’s experiments ‘all failed’; ‘d[id] not work in human cells; and had ‘fail[ed] to induce genome modification’”; “‘it was really a pity’ that Zhang’s lab ‘did not work it out before seeing [CVC’s] paper.’” (Lin)). Also unavailing was the history (and Broad’s reliance on it, for example in its Supplemental Priority Statement filed under PTAB Order) that showed their construct for eukaryotic CRISPR:

(very different from CVC’s sgRNA) was not the species used to support actual reduction to practice more than six months after being submitted as part of an NIH grant proposal, where such actual reduction to practice using sgRNA took only a few weeks.
Unmentioned in all the briefing is the simple argument that, taking heed of Broad’s assertions in both the ‘048 and ‘115 interferences the complexities of eukaryotic cells made it just sufficiently less likely for a three component complex (Cas9, crRNA, and tracrRNA) to form in such cells than for a two component complex to do so (sgRNA and Cas9). The oligonucleotide linker joining the crRNA and tracrRNA species in CVC’s sgRNA would have this advantage over the more complicated construct disclosed in their January 2012 NIH grant proposal by Broad, wherein when expressed the tracrRNA and crRNA would need to coalesce independently with Cas9 to form an active CRISPRR complex.
The question before the Federal Circuit will be whether the PTAB heeded the earlier panel’s appreciation that the Board had not properly considered the role of earliest conception followed by diligence towards reduction to practice, or be convinced that the complexities of achieving eukaryotic CRISPR were sufficient that only actual reduction to practice will suffice. It might be fruitful for the Court to consider whether there is a “losing the forest for the trees” aspect of the PTAB’s analysis, unsurprising in view of the vigor with which Broad made its arguments asserting eukaryotic cell complexities, and whether the evidence is more consistent with sgRNA being the critical component of the CRISPR complex that permitted successful CRISPR cleavage in eukaryotic cells.
*Such analyses are forthcoming in perhaps more abbreviated form for completeness.






















