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 .
Claim Status
Claims 1-11 are pending. Claims 7-11 are withdrawn. Claims 1-6 are currently under examination.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-6, drawn to a genetically modified microorganism, in the reply filed on 7/3/2025 is acknowledged.
Claims 7-11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 7/3/2025.
Applicant's election with traverse of species fabI (of claims 6 and 11) in the reply filed on 7/3/2025 is acknowledged. The traversal is on the grounds that claims 6 and 11 provide a practical example of regulation of more than one of the genes usable together as directed in generic claims 1 and 7 by synthetic metabolic valves and is wholly supported in the specification. Applicant argues that use of regulation of the fabI gene should not exclude, as now required by the species election, regulation of fabI and gltA1 together- because gltA1 is considered nonelected. Applicant argues that since the species further are usable together, the required election is overly restrictive and claims 6 and 11 represent a rather small, limited, and fully defined group of search terms. This is not found persuasive because each species would require a different field of search by searching different classes/subclasses or electronic resources, or employing different search queries. Also see MPEP 2434 “…, polynucleotide inventions will be considered for restriction, rejoinder and examination practice in accordance with the standards set forth in MPEP Chapter 800. Claims to polynucleotide molecules will be considered for independence, relatedness, distinction and burden in the same manner as claims to any other type of molecule.”.
The requirement is still deemed proper and is therefore made FINAL.
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The gltA1, gltA2, and udhA genes in Claim 6 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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.
Drawings
The drawings are objected to for the following reasons:
37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.”
In the current case, the view numbers for the partial views for “Figures 1B, 2, 4, and 5” that appear on several sheets are followed by "CON’T" instead of a new capital letter, such as FIG. 1A, FIG. 1B, etc., or number such as FIG. 1Bi, FIG. 1Bii, etc..
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The abstract of the disclosure is objected to because it contains grammatical and typographical errors, where in line 1, “various application form” should read “various applications from” as it appears in paragraph 0005 of the specification. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because of the following informalities:
The drawings contain figures not specifically referred to and described in the brief description of the drawings on page 2 of the specification. See MPEP 608.01(f) which states: “If the drawings show Figures 1A, 1B, and 1C and the brief description of the drawings refers only to Figure 1, the examiner should object to the brief description, and require applicant to provide a brief description of Figures 1A, 1B, and 1C.”
In accordance with MPEP 608.01(f), Applicant is required to provide a brief description of Figures 1B, 2, 4, and 5. Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in paragraphs 0014 and 0042. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term E. CLONI® on page 12, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Examiner believes the term contains a clerical or typographical error and should read “an endogenous cas3 gene is deleted or mutated” to match the claim language of claim 2. Claim 1 is objected to because of the following informalities: claim 1 recites the term “an endogenous cas3 nuclease is deleted or mutated”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 4 is rejected 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.
Claim 4 recites the limitation “wherein the tightly repressed inducible promoter is PhoB activated”. It is unclear whether the promoter is an activated PhoB or whether the promoter is a promoter that is activated by PhoB. For the purposes of compact prosecution, the Office is interpreting this recitation to mean an activated PhoB promoter.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
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).
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).
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).
Tarasava teaches each and every limitation of claims 1, 3, and 5, therefore, Tarasava anticipates claims 1, 3, and 5.
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.
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.
Claim 2 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) as applied to claims 1, 3, and 5 above, and further 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).
The teachings of Tarasava are discussed in the 35 U.S.C. 102 rejection above.
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 2, 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.
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) 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 teachings of Tarasava are discussed in the 35 U.S.C. 102 rejection above.
However, Tarasava does 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’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 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) 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 teachings of Tarasava are discussed in the 35 U.S.C. 102 rejection above. Tarasava further teaches that fabI is an essential gene involved in fatty acid biosynthesis and that the fabI gene has been identified as an important target for increasing malonyl-CoA flux (p. 1779, left column, last paragraph). Tarasava further teaches a 6-gRNA array targeting acid fermentation genes (ldhA, ackA/pta, adhE, pflB, poxB) and fabI for gene repression by CRISPRi (p. 1879 – entire page).
However, Tarasava does not specifically teach 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 the Tarasava’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 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.
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