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
Claim status
Claims 1-5, 7-13, 15-16 are currently pending. Claim 1 has been amended currently. Claims 6, 14 are canceled. There are no new claims. Claims 1-5, 7-8 will be examined on the merits.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, certified English copies have not been filed. For the sake of searching the art, the effective date is March 31, 2022.
Information Disclosure Statement (IDS)
The IDS submission is in compliance with the provisions of 37 CFR 1.97. However, the IDS filed 12/15/2023 has no application number and the foreign references, are mostly in non-English language. Thus, these references have not been considered by the examiner.
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Election/Restrictions
Applicant’s election with traverse of Group I (claims 1-5, 7-8) in reply filed on April 22, 2026 is acknowledged.
Applicant’s arguments in reply filed on April 22, 2026 have been considered but are not persuasive.
Ma teaches 3 upstream gene variant indel mutations (deletions and insertions) and a SNP mutation; 292G>A (N.T); Gly98Arg in the cg0809 gene (also known as NCgl0775 and cg0923), which encodes a VKOR protein in Corynebacterium glutamicum.
Therefore, there is no special technical features and the restriction is maintained. Claims 1-5, 7-8 will be examined on the merits in this office action.
Priority
Acknowledgement is made of applicant’s claim for foreign priority based on application KR10-2021-0085738 filed in Republic of Korea on June 30, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
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 8 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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 8 recites the limitation of “OdhA protein is further inactivated” in “a microorganism of Corynebacterium glutamicum in which vitamin K epoxide reductase family protein (VKOR protein) is inactivated” (claim 1). See Specifications; pages 25-26; Example 3. Page 32; Example 5.
There is insufficient antecedent basis for this limitation in the claim.
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 1-5 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Ma et al. (Published 2018; hereafter Ma; PTO-892).
As claims 1-5, 7, Ma teaches “Corynebacterium glutamicum is an excellent platform for the production of amino acids, and is widely used in the fermentation industry. Most industrial strains are traditionally obtained by repeated processes of random mutation and selection, but the genotype of these strains is often unclear owing to the absence of genomic information. As such, it is difficult to improve the growth and amino acid production of these strains via metabolic engineering.
Ma teaches that “wild-type strains, the synthesis of BCAAs is strictly subjected to feedback regulation systems, and some mutagenized strains already have desired phenotypes that make their genotypes of high research value”.
Ma teaches “In order to establish the relationship between genotypes and physiological characteristics, a comparative genomic analysis was performed to explore the core genome, structural variations, and gene mutations referring to an industrial L-leucine-producing strain, C. glutamicum CP, and the widely used C. glutamicum ATCC 13032”. See abstract.
Ma teaches comparative genomic analyses, SNP and Indel identification between L-Valine-producing strain and C. glutamicum ATCC 13032, mutation, genomic position, gene, influence, N.T. change and A.A change. Ma also teaches that cgl0809 gene (also known as cg0923 and NCgl0775) has a SNP mutation; Genome position 850708, missense variant: C (13032 strain) to T (C. glutamicum XV strain); 292G>A (N.T); Gly98Arg. See Supplementary Table 8. Page 135. Also, cgl0809 gene has the 3 indel upstream gene variant mutations. Genome position 855518, 855860 and 855936; upstream gene variant: -4525delA, -4865delA and -4938_4935insG. See Supplementary Table 8. Page 223. See below, alignment results for SEQ ID NOs: 1, 2 (99% homology with cgl0809).
The cgl0809 gene encodes a VKOR protein, which is 99% identical to SEQ ID NO:1. The SEQ ID NO: 2 is also 99% identical to cgl0809 gene. It is noted that SEQ ID NO: 2 has 100% match with C624_044960 gene (ID: AGN18577.1) in the genome of C. glutamicum SCg1 strain and the gene product has been annotated as “Predicted membrane protein”. See Figures below.
Regarding the limitation in claim 7 "an increased L-glutamic acid producing ability compared to a parent strain or wild-type strain”, the claim teaches all structural features from the claim, so it is presumed to be capable of the claimed intended use. See MPEP 2112.01: "Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433." See also MPEP 2111.02: "To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997)".
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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.
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.
Claim 8 are under 35 U.S.C. 103 as being unpatentable over by Ma et al. (Published 2018; hereafter Ma; PTO-892) as applied to claims 1-5, 7 in view of Nakamura et al. (Published 2007; hereafter Asakura; PTO-892) as evidenced by Goodstadt et al (Published 2004; hereafter Goodstat; PTO-892).
Ma teaches the limitations of claims 1-5, 7 as fully discussed above and incorporated herein.
However, Ma does not teach OdhA protein is further inactivated as claim 7.
Nakamura teaches Corynebacterium glutamicum is a biotin auxotroph that secretes L-glutamic acid in response to biotin limitation; this process is employed in industrial L-glutamic acid production. Fatty acid ester surfactants and penicillin also induce L-glutamic acid secretion, even in the presence of biotin.
Nakamura teaches ODHC is located at the branch point between the tricarboxylic acid (TCA) cycle and l-glutamate biosynthesis, a decrease in ODHC activity could switch the metabolic flow from the TCA cycle to l-glutamate synthesis. The ODHC generally comprises three enzymes: 2-oxoglutarate dehydrogenase (E1o), dihydrolipoamide S-succinyltransferase (E2o), and dihydrolipoamide dehydrogenase (E3).
Nakamurta teaches disruption of odhA, encoding a subunit (E1) of the 2-oxoglutarate dehydrogenase complex, resulted in L-glutamic acid secretion without induction. In this study, we analyzed odhA disruptants and found that those which exhibited constitutive L-glutamic acid secretion carried additional mutations in the NCgl1221 gene, which encodes a mechanosensitive channel homolog.
Nakamura teaches the NCgl1221 genes of other odhA disruptants of C. glutamicum that produce large amounts of l-glutamate.
Nakamura teaches that disruption of odhA, which encodes the E1o subunit, results in l-glutamate secretion without induction. Metabolic linkage between acetyl-CoA carboxylase and 2-oxoglutarate dehydrogenase complex (ODHC) might trigger l-glutamate secretion, since a dtsR1 disruptant produced a significant amount of l-glutamate and exhibited reduced ODHC activity. ODHC activity was strongly inhibited by the nonphosphorylated form of the OdhI protein, which is phosphorylated by the serine/threonine protein kinase PknG.
Nakamura teaches that treatments that induce l-glutamate production also cause a decrease in ODHC activity, resulting in an increase in the intracellular l-glutamate concentration, potentially mediated by the OdhI-PknG system.
Goodstadt teaches that Vitamin K epoxide reductase (VKOR) recycles reduced vitamin K, which is used subsequently as a co-factor in the gamma-carboxylation of glutamic acid residues in blood coagulation enzymes. VKORC1, a subunit of the VKOR complex, has recently been shown to possess this activity. NCgl0775 (cgl0809) shares 70% of VKORC1 [a subunit of the Vitamin K epoxide reductase (VKOR) complex] homologues, including a bacterial thiol–disulfide interchange proteins dsbA and two Corynebacterium efficiens, CE0880 and CE3P019. See Figure 1.
Goodstadt also teaches that the human VKORC1 amino acid sequence as query, revealed significant sequence similarity (E=5x10-4) to a hypothetical protein from the bacterium Corynebacterium efficiens.
Goodstadt teaches that the enzymatic activity of VKOR has been shown to depend on thiol reagents. These have been proposed to initiate the substrate reaction by reducing an active-site disulfide to two sulfhydryl groups. The thioredoxin-like (Trx) oxidoreductases, such as protein disulfide isomerase (PDI), thiol–disulfide inter change protein (dsbA), or Trx itself, might initiate the reduction cascade. These molecules contain active site CxxC motifs that reduce disulfide bonds or oxidize sulfhydryls. VKORC1 homologues in plants and prokaryotes identifies four cysteine and one Ser/Thr candidate active-site residues.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Ma and Nakamura by making genetically modifications to inactivate the genes encoding VKOR protein (cgl0809) and OdhA, thereby arriving at the invention of claim 8. Since the genomic information provided by Ma teaches the mutations related to VKOR protein (cg0809), including the L-glutamate producer strain, C. glutamicum ATCC13032, and as evidenced by Goodstadt, the VKOR1 of NCgl0775 (cgl0809) has homology with a bacterial thiol–disulfide interchange proteins dsbA, it would be beneficial to add the odhA disruptions of Nakamura to a C. glulamicum strain to improve production of L-glutamate in C. glutamicum, it would have been obvious to substitute these known equivalents; see MPEP 2144.06.
See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.
Reasonable expectation of success would be expected because Ma teaches VKOR protein (cg0809) inactivation in the genome of a L-glutamate high producer strain, C. glutamicum ATCC13032 and Nakamura teaches disruptions of odhA gene aiming to increase the production of L-glutamate in Corynebacterium glutamicum strain, ATCC 13869 and neither Ma nor Nakamura specify which parent strain should not be used to genetically modify the target genes in order to increase the production of L-glutamate.
Also, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the simple substitution of one known element for another to obtain predictable results is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results".
Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
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Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PRICILA HAUK TEODORO whose telephone number is (571)272-2784. The examiner can normally be reached 6:15AM-3:00PM.
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/PRICILA NMN HAUK TEODORO/Examiner, Art Unit 1645
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684
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