The CRISPR Chronicles: Enter Toolgen

By Kevin E. Noonan --

The U.S. Patent and Trademark Office Patent Trial and Appeal Board has declared interferences individually between Toolgen as Senior Party and as Junior Party the parties in the pending interference, Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad") and The University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") (see "Separate Interferences Declared between Toolgen and Broad and CVC over CRISPR Priority Question)".  This raises questions about the strength and priority position of Toolgen's claims, which suggests a review of the prosecution might reap benefits in relevant comprehension.

Toolgen filed its earliest priority applications as U.S. Provisional Application Nos. 61/717,324, filed October 23, 2012; 61/803,599, filed March 20, 2013; 61/837,481, filed June 20, 2013; and International Application No. PCT/KR2013/009488, filed in the Korean Patent Office on October 23, 2013.  Thus, its earliest priority date, October 23, 2012, is two months prior to Broad's earliest priority date of December 12, 2012 for U.S. Provisional Application No. 61/736,527 (see "PTAB Decides Parties' Motions in CRISPR Interference").  Upon entering U.S. national phase as a continuation, U.S. Application No. 14/685,510, on April 13, 2015, Applicant Toolgen filed a preliminary amendment, having claims directed to provoking an interference with Broad and its colleagues and CVC.

Seven months later, on November 17, 2015, the USPTO issued an Office Action from Primary Examiner Catherine S. Hibbert, rejecting the claims under 35 U.S.C. §§ 101, 103, and 112.  The §§ 101 and 112 rejections were quickly dispatched by amendment, but rejections under § 103 persisted until the Patent Trial and Appeal Board reversed the Examiner in a decision handed down June 22, 2020.  The basis for the obviousness rejection was, as a primary reference, the first Doudna et al. U.S. Application Publication No. US2014/0068797, claiming priority to provisional applications filed in May and September 2012, combined with references teaching nuclear localization signal modifications to target the Cas9 protein to the eukaryotic nucleus, and a reference for codon optimization for enhanced expression in human cells) or the Jinek 2012 Science paper (Jinek et al., 2012, "A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity," Science 337: 816-21) combined with these secondary references.  Toolgen responded by asserting that the skilled artisan would not have had a reasonable expectation to expect that CRISPR exemplified in bacterial cells would be operable in eukaryotic cells (a very similar argument to the one The Broad and colleagues used to prevail in the first Broad/CVC interference (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").

This argument did not persuade the Examiner, who maintained the rejection substantially unfazed through a Final Rejection, a Non-Final Rejection after Toolgen filed a Request for Continued Examination, followed by another Final Rejection, this last in the face of expert testimony from Dr. Bryan R. Cullen, and through several Examiner interviews.  These later rejections were maintained even after the PTAB's decision in the earlier Broad/CVC interference, on the rationale that "the fact pattern for each of the application records for the Broad/UC Interference were different than the fact pattern for the instant application and the Board's decision in the Broad/US Interference was not precedential" (perhaps and certainly true, respectively, but frustratingly missing the point).  Further, the same rationale was proffered by the Office when Toolgen argued that "the fact that different patent applications include difference fact patterns and evidence does not give the Patent Office latitude to characterize the same prior art disclosure completely differently across different patent applications," Toolgen arguing that doing so is "arbitrary and capricious."  The Office took a similar stance in rejecting Toolgen's arguments for unexpected results by citing the Doudna and Jinek prior art as teaching that CRISPR cleavage was not unexpected because those references taught such cleavage.  Of course, this rationale ignored the argument Toolgen was making that the achievement of CRISPR cleavage in a eukaryotic cell was surprising and unexpected for all the reasons previously persuasive to the Board and Federal Circuit in the first Broad/CVC interference.

Finally, Toolgen appealed (successfully) but in the interim the PTAB declared Interference No. 106,115 (see "New CRISPR Interference: The Details"), and like Sigma-Aldrich had done previously (see "Sigma-Aldrich Wants Its Piece of CRISPR Pie"), petitioned the Director under 37 C.F.R. §§ 1.181 and 1.1.83 and the Chief Administrative Patent Judge under 37 C.F.R. §§ 41.3 and 41.103 on September 29, 2019 to declare an interference.  (This petition was dismissed on procedural grounds on April 6, 2020.)

Shortly thereafter the PTAB reversed the § 103 rejection.  In its opinion, the Board wrote:

Although the Examiner extensively discussed the disclosures of the Doudna '086 provisional and the Doudna '256 provisional and explained why she determined they disclosed the claimed subject matter, the Examiner did not establish that Doudna, which incorporates these provisionals by reference . . . is prior art.  The Examiner never compared any claim of Doudna to the disclosures of the Doudna '086 provisional or the Doudna '256 provisional.  . . .  It was the Examiner's initial burden to do so but, even were it not, it became the Examiner's obligation to do so once Appellant argued that Doudna was not prior art . . . .

The Board also noted that it was persuaded by Toolgen's argument that the cited art did not support a skilled worker having had a reasonable expectation of success in practicing CRISPR in a eukaryotic cell, at least in part due to Dr. Cullen's expert testimony as well as evidence of record of Dr. Doudna's contemporary statements regarding her uncertainty about the unpredictability of eukaryotic cell embodiments of CRISPR (some of the same evidence The Broad successfully asserted in the first Broad/CVC Interference).  The Board summarized its decision as follows:

To conclude, on the present record, the Examiner has not demonstrated that all references in the cited combination qualify as prior art.  However, even had the Examiner done so, we determine that the Examiner has not established a prima facie case of obviousness.  Although the Examiner accounted for each claim element in the cited prior art combination, "[o]bviousness requires more than a mere showing that the prior art includes separate references covering each separate limitation in a claim under examination."  UnigeneLabs.,Inc. v. Apotex, Inc., 655 F.3d 1352, 1360 (Fed. Cir. 2011).  Proof of obviousness requires a showing of at least a reasonable expectation of success from the perspective of a person of ordinary skill in the art.  In re Vaeck, 947 F.2d488, 493 (Fed. Cir. 1991) . . . .  Here the balance of evidence of record supports that the relevant field was highly unpredictable, which diminishes any reasonable expectation of success in achieving the claimed invention.  Considering the evidence of record, on balance it supports Appellant's positions. We therefore reverse the Examiner's rejection over Doudna, Gustafsson, and Chen.

And the Board came to a similar conclusion regarding the obviousness rejection asserted using Jinek as the primary reference.

This prosecution history presages Toolgen's likely arguments in each of the current interferences.  Like Broad, Toolgen will likely argue that CVC's earlier priority dates were inoperable in eukaryotic cells and thus its October 2012 date (and any earlier dates of conception followed by actual reduction to practice) should entitle it to priority.  The path forward against Broad is less clear, however, particularly in view of the evidence presented in Broad's priority motion (see "Broad Files Priority Motion in CRISPR Interference*"), including this timeline:

Toolgen has no priority application filed earlier than Broad's asserted July 20, 2012 date of actual reduction to practice, and should the Board (and Federal Circuit) be persuaded by Broad's "simultaneous conception and reduction to practice" standard for awarding priority, Toolgen may be no more successful than CVC in having priority awarded to its patent application (depending, of course, on its first successful demonstration of practicing CRISPR in eukaryotic cells).

But that remains in the future.  Both sets of interference parties have proposed Preliminary Motions, which the Board will consider tomorrow.  These motions, and the Board's decision on which motions it will entertain, will be the subject of future posts.

Comments

[Crspr]

It seems as though Kevin Noonan holds a chunk of Editas stock(or Beam Therapeutics). It is hilarious that Feng Zhang's experiment notes count. Currently, Toolgen has a clear edge over Broad and CVC, for sure. Sorry Dude.

[Broad]

There is a chance that Broad's experiment notes were manipulated.(No offense, don't sue me) Why did they submit their notes in 2020 if they really had it?

[Crspr]

I sincerely apologize for offending Mr. Kevin Noonan earlier. I didn't read the very last paragraph. My word about the stock was very inappropriate. You're right. The Board will consider today. I just did not agree with his statement that there is no chance for Toolgen for the patent.
Have a good day.