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 .
Application Status
This action is written in response to applicant’s correspondence received 3/30/2026. Claim 2 is cancelled. Claims 1 and 3-11 are pending. Claims 7-11 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1 and 3-6 are examined herein. The restriction requirement mailed 5/22/2025 is still deemed proper. Applicant's elected Group I, claims 1-6, without traverse in the reply filed 7/3/2025.
Applicant elected with traverse species fabI (of claims 6 and 11), however, the argument was not found persuasive (see Non-Final OA, pages 2-3). With regard to the EOS of genes in claim 6, the Office is extending the search to the non-elected species of zwf. The gltA1, gltA2, and udhA genes in Claim 6 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/3/25.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Drawings - maintained
The drawings were received on 3/30/2026. These drawings are acceptable.
Specification - withdrawn
Objection to the specification is withdrawn in view of Applicant’s amendments to the specification to amend the abstract, to correct typographical errors, to remove hyperlinks, and to add copyright symbols.
Claim Objections - withdrawn
Objection to claim 1 is withdrawn in view of Applicant’s amendment to change “nuclease” to “gene”.
Claim Rejections - 35 USC § 112 - withdrawn
Rejection of claim 4 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of Applicant’s amendment to delete “activated”.
Claim Rejections - 35 USC § 102 - withdrawn
Rejection of claims 1, 3, and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tarasava et al. ("Combinatorial pathway engineering using type I-E CRISPR interference" BIOTECHNOLOGY AND BIOENGINEERING; published 3/30/2018); cited in IDS filed 7/11/2023) is withdrawn in view of Applicant’s amendment to incorporate the limitations of cancelled claim 2 into claim 1.
Claim Rejections - 35 USC § 103 – new necessitated by amendment
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.
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 1, 3 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Tarasava et al. ("Combinatorial pathway engineering using type I-E CRISPR interference" BIOTECHNOLOGY AND BIOENGINEERING; published 3/30/2018); cited in IDS filed 7/11/2023), in view of He et al. (Front. Cell. Infect. Microbiol., Sec Bacteria and Host; published 6/11/2018; cited in IDS filed 12/13/2022).
Tarasava’s disclosure is directed to an efficient method for generating expression diversity for complex metabolic networks on a combinatorial scale using CRISPR interference (entire document). Tarasava teaches the importance of optimizing metabolic flux by controlling the expression of multiple genes involved in metabolic networks in a combinatorial fashion to maximize production from bacterial strains (Introduction).
Regarding claim 1, Tarasava teaches a genetically modified native Escherichia coli Type I-E CRISPR-Cas system and an iterative cloning strategy for construction of guide RNA arrays (abstract). Tarasava teaches deleting the cas3 gene from an E. coli strain and inserting an arabinose-inducible pBAD promoter in front of a Cascade operon (generating BW25113Δcas3 strain) (p.1879, left column, para 1; and Figures 1 and 2). Tarasava teaches increased stability of the guide array in the genetically modified E. coli when compared to a microorganism lacking the cas3 nuclease deletion (p. 1879, left column, para 1) or conditional expression of a Cascade operon (Figure 2b).
However, Tarasava does not specifically teach that the cas1 gene is deleted or mutated.
He’s disclosure teaches cas1 and cas2 in Riemerella anatipestifer bacteria are required for spacer acquisition (entire document).
Regarding claim 1, He teaches that deletion of cas1 gene abrogated spacer acquisition and subsequently stabilized the exogenous plasmid, suggesting that both Cas1 and Cas2 are required for spacer acquisition of bacterial CRISPR-Cas system, consistent with the reported role of Cas1 and Cas2 in type I-E and II-A systems (abstract and p. 7).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Tarasava’s genetically modified cas3 knockout E. coli to further knock out cas1, as taught in He, to arrive at the claimed invention. Tarasava teaches increased stability of the guide array in cas3 knockout E. coli (p. 1879, left column, para 1) and teaches an iterative cloning strategy for construction of guide RNA arrays (abstract). He teaches that deleting cas1 increases stability of the exogenous plasmid (abstract and p. 7). One would have been motivated to create a cas3 cas1 knockout E. coli to further increase stability of the guide array. One would have had a reasonable expectation of success because both Tarasava and He teach deletion of cas genes of the CRISPR/Cas system in bacteria with an increase in stability of nucleic acids. Thus, the claimed invention as a whole is prima facie obvious.
Regarding claim 3, Tarasava teaches that Cascade operon of the BW25113Δcas3 strain is overexpressed under the arabinose-inducible pBAD promoter (Figure 2b).
Regarding claim 5, Tarasava teaches the genetically modified microorganism is Escherichia coli (entire document).
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Tarasava et al. ("Combinatorial pathway engineering using type I-E CRISPR interference" BIOTECHNOLOGY AND BIOENGINEERING; published 3/30/2018; cited in IDS filed 7/11/2023), in view of He et al. (Front. Cell. Infect. Microbiol., Sec Bacteria and Host; published 6/11/2018; cited in IDS filed 12/13/2022), as applied to claims 1, 3, and 5 above, and further in view of Stoudenmire et al. (An Iterative, Synthetic Approach To Engineer a High-Performance PhoB-Specific Reporter. Applied and Environmental Microbiology 84.14; published 7/2/2018).
The combined teachings of Tarasava and He are discussed in the 35 U.S.C. 103 rejection above.
However, Tarasava and He do not specifically teach that the tightly repressed inducible promoter is PhoB activated.
Stoudenmire’s disclosure is directed to synthesizing a high performance PhoB-specific reporter with broad utility and screening GFP constructs in V. fischeri, E. coli, and other bacteria (entire document).
Regarding claim 4, Stoudenmire teaches that PhoB is the response regulator portion of a two-component regulatory system that activates the expression of several genes under low-phosphate conditions in various bacteria (p. 2, paragraph 4). Stoudenmire teaches that E. coli PhoBR system is activated upon sensing low levels of environmental phosphate (p. 10, last paragraph). Stoudenmire teaches a PhoB activated promoter in a reporter construct that induces expression in E. coli and other bacteria at low phosphate concentrations (p. 6 – entire page).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the pBAD promoter of Tarasava and He’s genetically modified cas3 knockout E. coli with the PhoB promoter, as described by Stoudenmire because it would have amounted to a simple substitution of one know promoter for another to obtain predictable results. Tarasava teaches the importance of optimizing metabolic flux by controlling the expression of multiple genes involved in metabolic networks in a combinatorial fashion to maximize production from bacterial strains and further teaches a cas3 knockout strain with a pBAD promoter (Introduction). Stoudenmire teaches that the PhoB induces expression at low phosphate concentrations (p. 6 – entire page). One of ordinary skill would have recognized the benefits of having a PhoB promoter and would have been motivated to more tightly regulate gene expression under different environments, adding an additional layer of control. One would have had a reasonable expectation of success because Tarasava, He, and Stoudenmire teach improving tightly controlled gene expression constructs in E. coli. Thus, the claimed invention as a whole is prima facie obvious.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Tarasava et al. ("Combinatorial pathway engineering using type I-E CRISPR interference" BIOTECHNOLOGY AND BIOENGINEERING; published 3/30/2018; cited in IDS filed 7/11/2023), in view of He et al. (Front. Cell. Infect. Microbiol., Sec Bacteria and Host; published 6/11/2018; cited in IDS filed 12/13/2022), as applied to claims 1, 3, and 5 above, and further in view of Wu et al. (Enhancing flavonoid production by systematically tuning the central metabolic pathways based on a CRISPR interference system in Escherichia coli. Scientific reports 5.1 (2015): 13477; published 9/1/2015).
The combined teachings of Tarasava and He are discussed in the 35 U.S.C. 103 rejection above.
However, Tarasava and He do not specifically significantly reduced expression of the fabI gene.
Wu’s disclosure is directed to systematically tuning the central metabolic pathways with CRISPR interference in E. coli to enhance flavonoid production (entire document).
Regarding claim 6, Wu teaches the targeting of fabI and zwf for reduced expression (p. 2, paragraphs 5-7; Figures 2-4; and Table 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Tarasava and He’s gRNA array targeting ldhA, ackA/pta, adhE, pflB, poxB and fabI with Wu’s CRISPRi system for reducing expression of fabI and zwf because it would have amounted to a simple substitution of one known gRNA for another to obtain predictable results. Tarasava teaches gRNA array with the successful targeting of several metabolic genes and Wu teaches the successful repression of fabI with gRNAs in a CRISPRi system. One would have had a reasonable expectation of success because Tarasava, He, and Wu are directed to controlling gene expression with guide arrays by CRISPRi. Thus, the claimed invention as a whole is prima facie obvious.
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
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 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 7, 10-12, 15, and 17 of U.S. Patent No. 11746362B2 in view of He et al. (Front. Cell. Infect. Microbiol., Sec Bacteria and Host; published 6/11/2018; cited in IDS filed 12/13/2022) and Stoudenmire et al. (An Iterative, Synthetic Approach To Engineer a High-Performance PhoB-Specific Reporter. Applied and Environmental Microbiology 84.14; published 7/2/2018).
Claims 1 and 3 of the ‘362 patent encompasses a genetically modified microorganism comprising a chromosomal a deletion or disruption of a cas3 (claim 1). Claims 1, 5, and 7 of the ‘362 patent encompasses a genetically modified microorganism comprising at least one silencing synthetic metabolic valve characterized by CRISPR interference of gene expression of a gene that is a fabI, gltA, lpd, zwf, or udhA gene and expression of a CASCADE plasmid comprising an array of guide RNA genes (claims 1, 3, and 6). Claims 10-12, 15, and 17 of the ‘362 patent encompass E. coli genetically modified microorganisms (claim 5).
Claims 1, 3, 5, 7, 10-12, 15, and 17 of the ‘362 patent do not specially teach that endogenous cas1 gene is deleted or mutated (claim 2) or that the tightly repressed inducible promoter is PhoB (claim 4).
However, the teachings of He and Stoudenmire are discussed above. In particular, the teachings of He regarding deleting cas1 gene and the teachings of Stoudenmire regarding using a PhoB promoter are discussed above.
It would have been obvious to one or ordinary skill in the art to have modified the genetically modified microorganism of the ‘362 patent to create cas1 knockout E. coli strains as taught by He and further to create strains using the PhoB promoter as taught by Stoudenmire because He and Stoudenmire teach improving tightly controlled gene expression constructs in E. coli.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHALEDA B HASAN whose telephone number is (571)272-0239. The examiner can normally be reached IFP, Monday - Friday 7:30am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KHALEDA B HASAN/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
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