On Friday, July 19, 2019, Sigma-Aldrich filed a self-described "extraordinary" petition to the Director of the U.S. Patent and Trademark Office (under 37 C.F.R. §§ 1.181-1.183) and the Chief Judge of the PTAB (under 37 C.F.R. § 41.3 and § 41.103), asking that the USPTO declare an interference between itself and the University of California, Berkeley "parallel" to the one recently declared between Berkeley and the Broad Institute and its companion institutions (see "CRISPR Battle Joined Again").
The petition is extraordinary because Sigma's claims are not in condition for allowance, which is a prerequisite for the Office declaring an interference. The basis for Sigma's prayer for extraordinary relief is that the Examiner reviewing its pending applications, U.S. Application Nos. 15/188,911, 15/188,924, and 15/456,204, has refused to find that two Berkeley provisional applications (U.S. Application Nos. 61/652,086 and 61/716,256) do not anticipate nor render obvious its claims to applications of CRISPR in eukaryotic cells, despite determinations to the contrary with regard to Broad et al. patents having later priority dates by the Patent Trial and Appeal Board (see "PTAB Decides CRISPR Interference -- No interference-in-fact" and "PTAB Decides CRISPR Interference in Favor of Broad Institute -- Their Reasoning") and Federal Circuit (see "Regents of the University of California v. Broad Institute, Inc. (Fed. Cir. 2018)"). The very similar claims in Sigma's three pending applications read as follows:
U.S. Application No. 15/188,911:
1. A method for integrating an exogenous sequence into a chromosomal sequence of a eukaryotic cell, the method comprising:
a) introducing into the eukaryotic cell (i) at least one RNA-guided endonuclease comprising at least one nuclear localization signal or codon-optimized nucleic acid encoding at least one RNA-guided endonuclease comprising at least one nuclear localization signal, wherein the at least one RNA-guided endonuclease is a clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR associated (Cas) (CRISPR-Cas) type II system protein and the CRISPR-Cas type II system protein is a Cas9 protein, (ii) at least one guide RNA or DNA encoding at least one guide RNA, and (iii) at least one donor polynucleotide comprising the exogenous sequence; and
b) culturing the eukaryotic cell such that the at least one guide RNA guides the at least one RNA-guided endonuclease to a target site in the chromosomal sequence where the RNA-guided endonuclease introduces a double-stranded break, the target site in the chromosomal sequence is immediately followed by a protospacer adjacent motif (PAM), and repair of the double-stranded break by a DNA repair process leads to integration of the exogenous sequence into the chromosomal sequence.
U.S. Application No. 15/188,924:
1. A method for modifying a chromosomal sequence in a eukaryotic cell, the method comprising:
a) introducing into the eukaryotic cell (i) at least one RNA-guided endonuclease comprising at least one nuclear localization signal or codon-optimized nucleic acid encoding at least one RNA-guided endonuclease comprising at least one nuclear localization signal, wherein the at least one RNA-guided endonuclease is a clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR associated (Cas) (CRISPR-Cas) type II system protein and the CRISPR-Cas type II system protein is a Cas9 protein, (ii) at least one guide RNA or DNA encoding at least one guide RNA, and, optionally, (iii) at least one donor polynucleotide; and
b) culturing the eukaryotic cell such that the at least one guide RNA guides the at least one RNA-guided endonuclease to a target site in the chromosomal sequence where the RNA-guided endonuclease introduces a double-stranded break, the target site in the chromosomal sequence is immediately followed by a protospacer adjacent motif (PAM), and repair of the double-stranded break by a DNA repair process leads to modification of the chromosomal sequence.
U.S. Application No. 15/456,204:
1. A method for modifying a chromosomal sequence in a eukaryotic cell by integrating a donor sequence, the method comprising introducing into the eukaryotic cell: (i) a Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas) (CRISPR-Cas) type II protein linked to at least one nuclear localization signal (NLS) or a nucleic acid encoding the CRISPR-Cas type II protein linked to at least one NLS, wherein the CRISPR-Cas type II protein is a Cas9 protein, and the nucleic acid encoding the CRISPR-Cas type II protein is codon optimized for expression in the eukaryotic cell; (ii) a guide RNA or DNA encoding the guide RNA, wherein the guide RNA comprises a first region that is complementary to a target site in the chromosomal sequence that is immediately followed by a protospacer adjacent motif, and a second region that interacts with the CRISPR-Cas type II protein; and (iii) a donor polynucleotide comprising the donor sequence;
wherein the guide RNA guides the CRISPR-Cas type II protein to the target site in the chromosomal sequence, the CRISPR-Cas type II protein introduces a double stranded break at the target site, and repair of the double-stranded break by a DNA repair process leads to integration or exchange of the donor sequence into the chromosomal sequence.
The relationship between patents and applications owned by Berkeley, the Broad, and Sigma are set forth in Figure 1 of the petition graphically as follows:
The Examiner (who is the same Examiner responsible for allowing Berkeley's patents), according to the petition, has provided no legal justification for refusing to acknowledge what Sigma contends is the precedential value of the decisions in the earlier interference. Sigma's position is that if the Doudna et al. provisional applications did not provide sufficient support to find the Broad's claims obvious (in an interference context) they cannot support a determination of obviousness in ex parte patent prosecution involving Sigma's applications. Sigma further alleges that the evidence adduced in its ex parte examination of the three identified pending applications is "even more extensive" than the record in the earlier Berkeley/Broad interference; here, Sigma asserts that it has provided "multiple declarations from prominent experts explaining in even greater detail why (a) UC's disclosure of CRISPR-Cas9 in a prokaryotic environment does not render obvious Sigma-Aldrich's CRISPR-Cas9 eukaryotic claims, and (b) UC's provisional applications (UC P1 and UC P2) do not enable or adequately describe use of CRISPR-Cas9 in eukaryotic cells."
According to the petition, the Examiner merely responds that their evidence is "unpersuasive" in refusing to recognize the allowability of their pending claims (in the latest Office Action, in the '911 application, Sigma asserts that this phrase or its equivalent was repeated "over 70 times"). (It is only fair to the Examiner to note that there was an in-person interview between Sigma's representatives and "the Examiner, her Supervisory Patent Examiner, two Interference Practice Specialists, and the Group Art Unit Director" that did not resolve the issue in Sigma's favor.) Sigma-Aldrich argues that "[f]or the effective administration of justice, efficiencies of the USPTO and the parties, conservation of considerable valuable resources, and the public interest" the new interference should be declared (between Berkeley and Sigma in their petition; it is difficult to see the USPTO not including the Broad et al. patents in any such interference). The alternative, according to the petition, would be appeal to the PTAB over the obviousness rejection and, if need be, further appeal to the Federal Circuit.
Confident of its position, Sigma contends that this would be contrary to the Director's recent pronouncements (albeit in a different context) regarding there being a "level playing field" for all applicants and other parties; this portion of the petition waxes wroth regarding the "palpable" unfairness to Sigma and that "[i]n today's highly charged political environment, certainly the Director and CAPJ are sensitive to criticism leveled at the Agency regarding issues of fairness and equity." In addition, Sigma notes that it would be "grossly inefficient" for the USPTO to conduct the current interference between Berkeley and the Broad and then have to conduct a further interference between Sigma and either or both of the other parties. Finally, the petition notes the public interest in resolving the priority and ownership disputes between the several parties to prevent inhibiting development of the technology due to uncertainties regarding licensing and freedom to operate issues.
Should the Director and/or Chief Judge grant Sigma its requested relief, it is likely that the current interference will be redeclared naming all three parties, the patents and applications currently in interference, and the Sigma-Aldrich applications (with their attendant priority claims). The interfering subject matter has been set forth in alternate counts, corresponding either as claim 18 of the Broad's U.S. Patent No. 8,697,359 (dependent on claim 15), which taken together recites the following invention:
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.
(where the underlined portion recites the relevant language from claim 18) and claim 156 of Berkeley's U.S. Patent Application No. 15/981,807:
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.
There is no time frame for the petition to be considered much less granted, but as Sigma notes, the latest Berkeley-Broad interference is in the earliest stage; the parties must submit their proposed motions to the Board by July 30th and a teleconference between the Board and the parties is scheduled for August 5th. None of these dates is written in stone, of course, and the Director or the Board could postpone progress in the pending interference to consider Sigma's request. That would be the logical course; whether it is the Office's course remains to be seen.
