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 .
DETAILED ACTION
Application status
Claims 1-22 and 24-25 are pending in this application.
Priority
The instant application is the 371 national stage entry of PCT/EP2021/084194, filed on 12/03/2021.
Acknowledgment is made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to a foreign patent application United Kingdom GB2019175.5 filed on 12/04/2020.
Election
Applicant's election without traverse of Group I, Claims 1-11, 20 and 25 in the response filed on 03/26/2026, is acknowledged.
Claims 12-19, 21-22 and 24 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b) as being drawn to a non-elected invention.
For the reasons provided above, this restriction requirement is deemed proper, and therefore, it is made final.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/01/2023, 09/09/2025 and 11/24/2025 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Objections to the Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code, i.e., “https://” on page 67, line 3. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code. See MPEP § 608.01.
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825; Applicants’ attention is directed to the final rulemaking notice published at 55 FR 18230 (May 1, 1990), and 1114 OG 29 (May 15, 1990). To be in compliance, Applicants should identify nucleotide sequences of at least 10 nucleotides and amino acid sequences of at least 4 amino acids in the specification by a proper sequence identifier, i.e., “SEQ ID NO:” (see MPEP 2422.01). If these sequences have not been listed in the computer readable form and paper copy of the sequence listing, applicant must provide an initial computer readable form (CRF) copy of the “Sequence Listing”, an initial paper copy of the “Sequence Listing”, as well as an amendment directing its entry into the specification, and a statement that the content of the paper and CRF copies are the same and, where applicable, include no new matter as required by 37 C.F.R. 1.821(e) or 1.821(f) or 1.821(g) or 1.821(b) or 1.825(d). See particularly Figures 2C of the specification containing nucleic acid sequences, and therefore, those sequences should be represented by proper sequence identifier numbers.
If the noted sequences are not in a sequence listing as filed, Applicants must provide (1) an updated copy of the sequence listing containing the requisite sequences in computer readable form (CRF), (2) an amendment directing its entry into the specification, (3) a statement that no new matter has been added and (4) an amendment to the specification to identify each of the identified sequences by SEQ ID NO:, and (5) an incorporation by reference statement with the date of creation, sequence file name and size in bytes. – See also MPEP 2422.
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 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.
Claim 2 is rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 2 recites the phrase “increases the yield…, or increases the productivity” which is unclear. The noted phrase is unclear because there is no recitation of what the reference point is from which said “increases” are measured. The Examiner suggests amending the claim as shown below:
“Claim 2. The method of claim 1, wherein the method increases the yield or titer of the product produced by the bacterial cell compared to the bacterial cell without inactivated origin of replication, or increases the productivity of the bacterial cell compared to the bacterial cell without inactivated origin of replication.” (italicized for added emphasis)
In the interest of advancing prosecution, claim 2 has been interpreted as suggested by the Examiner above.
Claim Rejections - 35 USC § 102
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, 6-8, 10, 11, 20 and 25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rudolph et al. (Avoiding chromosome pathology when replication forks collide, Nature, Vol. 500, pgs. 608-611, 08/29/2013) in view of an evidentiary reference of Datsenko et al. (One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc. Natl Acad. Sci. USA 97, 6640–6645 (2000)).
The instant claims are drawn to a method of producing a product by a bacterial cell, the method comprising a step of irreversibly inactivating an origin of replication in the bacterial cell.
Rudolph et al. teach a method of irreversibly inactivating an origin of replication (also known as oriC) thereby slowing growth of E. coli cells using the one-step gene replacement method (see page 608, right column, 1st para; Supplementary Figs 1 and 3) developed by Datsenko et al. (see evidentiary reference), thereby anticipating claims 1, 6-8, 10, 11, 20 and 25.
It is noted by the Examiner that claim 10 is included in this rejection because the Office does not have the facilities for examining and comparing the bacterial cells taught by Rudolph et al. and Applicants’ in order to determine if the bacterial cells taught by Rudolph et al. were in the exponential growth phase or not when the Rudolph et al. inactivated the oriC. The Examiner assumed that at least some of the bacterial cells taught by Rudolph et al. were in the exponential growth phase. Therefore, the burden is on the applicants to show a novel or unobvious difference between the claimed method and the method of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
For the reasons stated herein, teachings of Rudolph et al. anticipate claims 1, 6-8, 10, 11, 20 and 25.
Claim Rejections - 35 USC § 103
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.
Claims 1-11, 20 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Rudolph et al. (Avoiding chromosome pathology when replication forks collide, Nature, Vol. 500, pgs. 608-611, 08/29/2013 including Supplemental Information) in view of Burg et al. (Large-scale bioprocess competitiveness: the potential of dynamic metabolic control in two-stage fermentations, Current Opinion in Chemical Engineering 2016, 14:121–136, see IDS), Li et al. (Enhanced protein and biochemical production using CRISPRi-based growth switches, Metabolic Engineering 38 (2016) 274–284, see IDS) and an evidentiary reference of Datsenko et al. (One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc. Natl Acad. Sci. USA 97, 6640–6645 (2000), see IDS).
The instant claims are drawn to a method of producing a product by a bacterial cell, the method comprising a step of irreversibly inactivating an origin of replication in the bacterial cell.
Teachings of Rudolph et al. are as described above.
Rudolph et al. do not teach a method of producing a product by a bacterial cell.
Burg et al. teach advantages of two-stage fermentation for decoupling growth (which requires replication) from product production, such that how arresting growth of a cell can lead to increased yield/titer/production of a product of interest (see page 124).
Li et al. teach that “[p]roduction of proteins and biochemicals in microbial cell factories is often limited by carbon and energy spent on excess biomass formation“. Li et al further teach developing a method of using CRISPRi-based “growth switches” in E. coli that specifically target dnaA and oriC, thereby arresting cell growth while preserving metabolic activity for enhanced protein/biochemical production, i.e., 2.2 fold increase in GFP protein production (a heterologous product) or 41% increase in mevalonate production (a homologous or endogenous product) (see abstract).
It would have been obvious to a person of ordinary skill in the art (POSITA) prior to the effective filing date of the instant application to practice methods of producing a product as taught by Rudolph et al., Burg et al. and Li et al. A POSITA would have been motivated to practice such methods because “[p]roduction of proteins and biochemicals in microbial cell factories is often limited by carbon and energy spent on excess biomass formation“ (see abstract of Li et al.), and that inactivating oriC as taught by Rudolph et al. would be an obvious solution to slow down growth of E. coli as discussed in above. A POSITA would have had a reasonable expectation of success to practice such methods because all of the required biochemical reagents and techniques were readily available and rampantly used as evidenced by Rudolph et al., Burg et al., Li et al. and Datsenko et al. prior to the filing of the instant application.
It is noted by the Examiner that claim 9 is included in this rejection because the Office does not have the facilities for examining and comparing the bacterial cells taught by the prior art references of Li et al., Rudolph et al. and Applicants’ in order to determine if the inactivation of oriC and the induction of product formation occurred simultaneously or sequentially within the bacterial cells taught by the prior art references The Examiner assumed that the inactivation of oriC and the induction of product formation would have occurred simultaneously and/or sequentially in at least some of the bacterial cells taught by the prior art references. Therefore, the burden is on the applicants to show a novel or unobvious difference between the claimed method and the method of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Conclusion
Claims 1-11, 20 and 25 are rejected for the reasons as stated above. Applicants must respond to the objections/rejections in this Office action to be fully responsive in prosecution.
The instant Office action is non-final.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAE W LEE whose telephone number is (571)272-9949. The examiner can normally be reached on M-F between 9:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571)272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAE W LEE/
Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
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