DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group II (claims 29-35) in the reply filed on 06/16/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1 and 36-43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/16/2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
STATUS OF CLAIMS
Claims 1 and 29-43 are pending.
Claims 2-28 and 44-45 are cancelled.
Claims 1 and 36-43 are withdrawn.
Claims 29-35 are under examination on the merits.
Priority
This application is a continuation of U.S. Application No. 16/333,134, filed March 13, 2019, which is a national stage filing under 35 U.S.C. § 371 of international application number PCT/US2017/051409, filed September 13, 2017, which was published under PCT Article 21(2) in English and claims the benefit of U.S. Provisional Application No. 62/393,944, filed on September 13, 2016, U.S. Provisional Application No. 62/485,210, filed on April 13, 2017, and U.S. Provisional Application No. 62/535,113, filed on July 20, 2017.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 29-35 are supported by the specification of prior-filed U.S. Provisional Application No. 62/393,944, filed on September 13, 2016.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/01/2023 and 06/16/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 29-35 are rejected under 35 U.S.C. 103 as being unpatentable over Xu X. et al., (Cell Discov 2, 16009, published May 03, 2016, provided in IDS) in view of Wang Y. et al., (FEBS J.; 280(16):3755-3767, published June 24, 2013) and Konermann S et al., (Nature, 517(7536):583-8, published Jan. 29, 2015).
Regarding claims 29-32 and 34-35, Xu teaches a method for targeted DNA demethylation in a mammalian cell (e.g., SH-SY5Y and HeLa cell lines) employing single guide RNAs (sgRNAs) modified with two copies of bacteriophage MS2 RNA elements to facilitate recruitment of TET1 tethered to either dCas9 or MS2 coat proteins to targeted gene loci, and that upon delivery of the demethylation protein conjugate via transfection into mammalian cells result in demethylation of a target nucleic acid, see abstract, introduction, and materials and methods. Further regarding claim 34, Xu further teaches the method comprises a first polynucleotide encoding dCas9 (fused to the TET1 catalytic domain, Tet1-CD), a second polynucleotide encoding sgRNA with MS2 RNA elements inserted at the tetraloop and stem-loop, and a third polynucleotide encoding MS2 coat protein gene fused with Tet1-CD.
Xu does not teach employing sgRNA modified with one or more PUF binding sites (PBSs), a demethylation domain fused to the PUF domain C-terminus, or a three-vector system.
Wang teaches “engineering protein factors with a PUF domain as the RNA-binding scaffold” by “fusing a target recognition module” (i.e., “modified PUF domains with re-designed RNA binding specificity”) “with a functional module” (i.e., “protein domains with desired activities”) see introduction 1st paragraph, expanding the modular binding code for cytosine, and engineered factors with PUF as RNA-binding scaffold. Wang further teaches that the “PUF scaffold, whose specificity, itself simple and modular, is determined by a combination of functional base recognition repeats,” and that “this unique RNA-binding mode allows one to reprogram the specificity of the PUF scaffold with a small number of mutations,” introduction 1st paragraph.
Wang teaches versatility of PUF proteins/fusions as RNA probes, regulatory factors for gene expression, RNA endonucleases, base editors, and factors to control RNA localization, RNA stability and RNA splicing. Of particular note, Wang teaches replacing one or more of the adenosine deaminase acting on RNA (ADAR) dsRNA-binding domains (dsRBDs) with modified PUF domains to engineer a base editor enzyme that can “specifically recognize an RNA target by sequence and deaminate a nearby adenosine,” see engineering RNA editing enzymes.
Konnerman teaches appending a minimal hairpin aptamer, which selectively binds dimerized MS2 bacteriophage coat proteins in mammalian cells, and to sgRNA tetraloop and stem-loop, and then tested whether MS2-mediated recruitment of VP64 to the tetraloop and stem-loop 2 could mediated transcriptional up-regulation more efficiently than a dCas9-VP64 fusion. Konnermann reports that aptamer-mediated recruitment of MS2-VP64 to either tetraloop or stem-loop mediated 3- and 5-fold higher levels of Neorog2 up-regulation than a dCas9-VP64 fusion, and that recruiting to both loops resulted in a 12-fold increase the fusion and non-aptamer augmented gRNA. Konermann further reports that combining the aptamer augmented sgRNA with the dCas9-VP64 fusion instead of dCas9 alone provided and additional 1.3-fold increase in Neurog2 upregulation. See Figure 1 and Structure-guided design of Cas9 complex 1st and 2nd paragraphs.
Konermann further teaches Neuro-2a cells and A375 melanoma cells were transfected using Lipofectamine 2000, and further teaches the cells were transfected with a 1:1:1: mass ration of a first, a second, and a third polynucleotide vector: 1) sgRNA plasmid with gene-specific targeting sequence or pUC19 control plasmid, 2) MS2-effector plasmid of pUC19, and 3) dCas9 plasmid, dCas9-effector plasmid or pUC19. See Methods, transient transfection experiments, 1st and 2nd paragraphs, and Extended Data Figure 7a.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) to modify the CRISPR-mediated targeted DNA demethylation system of Xu by replacing the MS2/MS2 coat protein RNA recruitment system with an engineered PUF/PBS RNA recruitment system as taught by Wang, wherein the TET1 demethylation domain is operably linked to a PUF domain and recruited to a guide RNA comprising one or more PUF binding site sequences, and to implement the resulting system using the vector configurations and transfection methods taught by Xu and Konermann. It would have further been obvious to employ a three-vector system with each vector encoding one of the polynucleotides.
A PHOSTA would have been motivated to make this modification in order to provide an alternative modular RNA-guided recruitment platform capable of directing the demethylation effector to the target locus while maintaining the advantages of scaffold-mediated effector recruitment, including modularity, programmability, and efficient localized recruitment of catalytic domains. Such a substitution replaces one known RNA-binding recruitment system with another known programmable RNA-binding recruitment system to perform the same function within the CRISPR targeting architecture. A PHOSITA would have has a reasonable expectation of success because the individual components of the modified system were each known to perform their intended functions, including single guide RNA scaffold-mediated recruitment of effector proteins, programmable RNA recognition by engineered PUF fusion domains, and targeted demethylation through localized recruitment of a demethylase domain via modified sgRNA comprising binding sites for an RNA binding protein fused to the effector domain. Accordingly, incorporating a programmable PUF/PBS recruiting module into an otherwise working CRISPR scaffold-recruitment system, in either a two-or three-vector system, represents the predictable use of prior art elements according to their established functions.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 29-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 22 of U.S. Patent No. US 11,780,895 B2 in view of Konermann S et al., (Nature, 517(7536):583-8, published Jan. 29, 2015). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 22 of US 11,780,895 B2 broadly recites a method of modulating the methylation state of a nucleic acid in a mammalian cell by delivering a composition comprising a guide RNA having a PUF binding site, a nuclease-deficient DNA endonuclease, and a PUF domain linked to a demethylation domain. Konermann teaches delivering CRISPR system components as separate expression vectors by transfection, including separate vectors encoding the guide RNA, effector fusion protein, and nuclease deficient Cas component. It would have been obvious to a person having ordinary skill in the art to implement the method of claim 22 using the routine vector configurations and transfection methods taught by Konermann, thereby arriving at the presently claimed method.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to COREY LANE BRETZ whose telephone number is (571)272-7299. The examiner can normally be reached M-F 7:30am - 6:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/COREY LANE BRETZ/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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