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
Amendments filed 06/27/2025 are entered. Claims 1-9 are pending and under consideration.
Priority
The application is a 371 application, filed 06/27/2025, of PCT application PCT/KR2023/021784, filed 12/28/2023, which claims priority benefits from Foreign Application No. KR10-2022-0187717, filed 12/28/2022.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
However, no English translation is provided for Foreign Application No. KR10-2022-0187717. Therefore, priority benefit cannot be determined from this document.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 06/12/2026 and 06/27/2025 is/are being considered by the examiner.
Claim Rejections - 35 USC § 112(b)
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.
Claims 2 and 4 are 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. The list structure of claim 2 renders its boundaries indefinite. Claim 2 recites the protein “comprises any one or more amino acid sequences selected from SEQ ID NOS: 1, 3, and 5, or an amino acid sequence having 87.5% or more identity thereto”, which includes the option for the protein to comprise of more than one of the following sequences in the subsequent list. Is the option “or an amino acid sequence having 87.5% or more identity thereto” modifying only the individual sequences, SEQ ID NOS: 1, 3, or 5, or is it modifying the “any one or more amino acid sequences selected from SEQ ID NOS: 1, 3, and 5”, meaning the protein can have 87.5% or more sequence identity to a udhA protein comprising of both SEQ ID NO: 1 and SEQ ID NO: 3?
Claim 4 recites the Corynebacterium comprising the exogenous udhA protein has an increased L-tryptophan producing ability compared to “a wild-type microorganism of the genus Corynebacterium”. Is this wild-type Corynebacterium microorganism the counterpart to the claimed Corynebacterium comprising the exogenous udhA protein, or is does this wild-type Corynebacterium microorganism include any other wild-type Corynebacterium microorganism (i.e. it could be a different species than the Corynebacterium that comprises the exogenous udhA protein, which could be a wild-type Corynebacterium that does not have any L-tryptophan producing ability). This must be understood to provide the minimum baseline for the relative term “increased”.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1-4, 6-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
There are three Written Description issues:
Claim 1-4, 6-9 lack written description for the entire genus of Corynebacterium having an L-tryptophan producing ability.
Claim 2 further lacks written description for the exogenous udhA protein comprising an amino acid sequence having 87.5% or more identity to SEQ ID NO: 1, SEQ ID NO: 3, and/or SEQ ID NO: 5 (not including 100% identity, which would be the exact sequence of SEQ ID NO: 1, 3, and 5).
Claim 4 further lacks written description for the entire genus of Corynebacterium microorganism having an L-tryptophan producing ability, comprising an exogenous udhA protein or a polynucleotide encoding the protein is introduced, wherein the Corynebacterium microorganism has an increased L-tryptophan producing ability compared to a wild-type microorganism of the genus Corynebacterium.
CLAIMED INVENTION
The claimed invention in claims 1-4, 6-9 is directed to a microorganism of the genus Corynebacterium having an L-tryptophan producing ability that comprises of an exogenous udhA protein or a polynucleotide encoding the protein. Possession of this invention, first, requires knowing the Corynebacterium species that have an L-tryptophan or knowing enough species that are appropriately representative of the variability of the entire genus.
The claimed invention in claim 2, dependent on claim 1, is further directed to the genus of udhA protein sequences comprising an amino acid sequence having 87.5% or more identity to SEQ ID NO: 1, SEQ ID NO: 3, and/or SEQ ID NO: 5. Possession of this invention, therefore, requires knowing enough species that are appropriately representative of the variability of the entire genus and/or some structure-function correlation between the sequences and the udhA protein function.
The claimed invention in claim 4, dependent on claim 1, is further directed to the genus of exogenous udhA proteins that when introduced into Corynebacterium will yield a Corynebacterium that has increased L-tryptophan producing ability compared to a wild-type microorganism of the genus Corynebacterium. Possession of this invention, therefore, requires knowing enough species that are appropriately representative of the variability of the entire genus and/or some structure-function correlation between the Corynebacterium with the exogenous udhA protein or udhA gene and having the claimed function.
WHAT THE SPECIFICATION TEACHES and THE STATE OF THE ART REGARDING THE ELECTED INVENTION
The specification reduces to practice a Corynebacterium glutamicum comprising of the exogenous udhA protein. The specification teaches the microorganisms may be other species in the Corynebacterium genus, providing a nonlimiting list (p. 16, para. 4).
The state of the art teaches amino acid producing Corynebacterium species, Corynebacterium glutamicum, Corynebacterium efficiens, and Corynebacterium callunae cluster together phylogenetically (p. 339, col. 1, para. 2). The state of the art teaches that Corynebacterium glutamicum is an industrial amino acid producer and Corynebacterium efficiens is a potential amino acid producer (Eggeling, published 2021; p. 343, Table 27.1), wherein the amino acid includes tryptophan, as evidenced by having the tryptophan synthesis genes, thereby having an L-tryptophan producing ability (p. 344, Table 27.2). However, Corynebacterium callunae is only reported to produce glutamic acid (Persicke, published 2015; Abstract). The state of the art is silent on other Corynebacterium species that have amino acid-producing abilities, let alone L-tryptophan producing abilities. Further, although the state of the art teaches the genes involved in tryptophan production for Corynebacterium glutamicum (Brune, published 2007; Abstract and para. 2) the art is silent on whether there are homologues in other Corynebacterium species and or if there are other tryptophan-producing genes in the Corynebacterium genus.
The specification teaches udhA proteins comprising the amino acid sequences of SEQ ID NO: 1, 3, and 5, and others, all from different genus of bacteria, introduced into Corynebacterium glutamicum (e.g. p. 24-25, Table 1) and their tryptophan yield (p. 34, Table 4). The state of art also teaches the udhA gene is also present in E. coli (Sauer, published 2004; Abstract) and its divergent functions in NADPH metabolism from another transhydrogenase in E. coli, PntAB (Sauer, published 2004; Abstract), wherein this PntAB has been shown to improve amino acid production when introduced into Corynebacterium glutamicum (Kabus, published 2007; Abstract). Therefore, this protein has associated functions and effects. However, the specification and the art does not disclose what parts of the udhA sequences are critical to the function of this udhA protein. Therefore, one would not know what amino acids to keep or can be mutated to achieve at least 87.5% and less than 100% sequence identity to SEQ ID NO: 1, 3, and 5 while still retaining its function.
The specification teaches that some Corynebacterium glutamicum introduced with an exogenous udhA protein or udhA gene do not yield an increase in tryptophan production compared to the tryptophan-producing strain of Corynebacterium glutamicum without the udhA protein or udhA gene (p. 34, Table 4). For example, the specification discloses a udhA protein comprising of SEQ ID NO: 11, which has an 87.7% query match to the SEQ ID NO: 1, but leads to a Corynebacterium glutamicum with a lower tryptophan production than the Corynebacterium glutamicum without any exogenous udhA protein, which is the opposite of the Corynebacterium glutamicum with the udhA protein comprising of SEQ ID NO: 1. There is no disclosed nor art recognized structure-function correlation between the claimed increased tryptophan-production and the Corynebacterium glutamicum introduced with an exogenous udhA protein or udhA gene. In other words, knowing the function (i.e. increased tryptophan-production compared to Corynebacterium glutamicum without an exogenous udhA protein or udhA gene) does not give one skilled in the art possession of the complete structure of the Corynebacterium glutamicum introduced with an exogenous udhA protein or udhA gene that possesses this function. Further, due the apparent variability in affects between Corynebacterium glutamicum introduced with an exogenous udhA protein or udhA gene, even knowing one species of this genus of Corynebacterium glutamicum introduced with an exogenous udhA protein or udhA gene that has an increased tryptophan production does not give one possession of another species of this genus. In other words, there is high variability in the genus and each species is not representative of the entire genus nor does it allow one to predict other species in the genus.
WHAT WRITTEN DESCRIPTION IS MET BY THE ELECTED INVENTION
Written description is met for the microorganism of the genus Corynebacterium being Corynebacterium glutamicum from the disclosure and the art and Corynebacterium efficiens from the art.
Written description is met for the udhA proteins comprising the amino acid sequences of SEQ ID NO: 1, 3, and 5.
Written description is met for the Corynebacterium glutamicum having an L-tryptophan producing ability into which an exogenous udhA protein or a polynucleotide encoding the udhA protein is introduced, wherein the protein comprises any one or more amino acid sequences selected from SEQ ID NO:1, SEQ ID NO: 3, and SEQ ID NO: 5.
WHY THE INVENTION LACKS WRITTEN
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.” The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. In this case, there is high variation amongst the species of the genus of Corynebacterium microorganisms as some species have tryptophan-producing function and some have no reported ability. It is unclear if these that are not reported to have the ability truly have or do not have the function. There is only one disclosed species and one species supported by the art without any predictability of tryptophan function in other species. Therefore, the Applicant lacks possession of the entire genus encompassed by the claims. The state of the art is silent on what Corynebacterium species have L-tryptophan producing abilities besides Corynebacterium glutamicum and Corynebacterium efficiens. Further, even having the ability to produce one amino acid does not allow one to predict the ability to produce other amino acids, such as the case for Corynebacterium callunae. Therefore, absent any explicit teaching from the disclosure or the art, one skilled in the art, could not use the fact that the disclosed Corynebacterium glutamicum can produce L-tryptophan to arrive at the full claimed genus of Corynebacterium microorganisms that also meet this limitation. The disclosure therefore does not show possession of this entire genus.
Absent disclosed or art-recognized correlation between structure and function, or specific teachings on regions to conserve or mutate in SEQ ID NO: 1, 3, and 5 to retain udhA protein function, one skilled in the art could not envision the entire claimed scope of the genus of sequences that preserve udhA protein function.
MPEP 2163(I)(A) states:
“An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function.”
In this case, the structure (i.e. Corynebacterium glutamicum having an L-tryptophan producing ability into which an exogenous udhA protein or a polynucleotide encoding the udhA protein is introduced) is described solely by its function (i.e. increased L-tryptophan producing ability compared to a wild-type microorganism of the genus Corynebacterium) and there is no described or art-recognized correlation between the disclosed increased tryptophan function and the structure(s) responsible for the function to show that Applicant has possession of the full genus of claimed microorganism from the species disclosed. In other words, one would not be able to predict from a structure of another potential species in the genus (e.g. another Corynebacterium glutamicum comprising an exogenous udhA protein) whether or it will have the claimed increased L-tryptophan production.
Closest Prior Art
Kabus et al, Expression of the Escherichia coli pntAB genes encoding a membrane-bound transhydrogenase in Corynebacterium glutamicum improves L-lysine formation, published 2007.
Kabus teaches introducing an exogenous pntAb gene encoding transhydrogenase (membrane-integral nicotinamide nucleotide transhydrogenase PntAB) in Corynebacterium glutamicum improves L-lysine formation. Kabus teaches the role of pntAB in NADPH production and teaches that sufficient supply of NADPH is critical for production of L-lysine with Corynebacterium glutamicum (Abstract). However, Kabus teaches that pntAB expression had a negative effect on growth and glutamate production (Abstract).
Kabus does not explicitly teach an exogenous udhA protein and tryptophan production.
Lui et al, Metabolic Engineering and Fermentation Process Strategies for L-Tryptophan Production by Escherichia coli, published 2019.
Lui teaches that NADPH is a critical cofactor involved in L-tryptophan biosynthesis in E. coli (p. 8).
Lui does not explicitly teach the udhA protein or gene.
Chang et al, KR102284730B1, Novel soluble pyridine nucleotide transhydrogenase variant and a method for producing L-tryptophan using the same; published 08/02/2021.
Chang teaches a soluble pyridine nucleotide transhydrogenase protein variant introduced into an E. coli and a method of increasing L-tryptophan from this E. coli compared to an E. coli without this variant transhydrogenase.
Chang does not teach introducing this transhydrogenase into Corynebacterium.
Boonstra et al, The udhA gene of Escherichia coli encodes a soluble pyridine nucleotide transhydrogenase, published 1999.
Boonstra teaches the udhA gene of E. coli and the soluble pyridine nucleotide transhydrogenase protein it encodes, its function, and its presence in other bacteria of different genera (Abstract and Figure 4).
Boonstra does not teach introducing this gene into Corynebacterium.
Zhan et al, Metabolic engineering of Corynebacterium glutamicum for improved
L‑arginine synthesis by enhancing NADPH supply, published 2019.
Zhan teaches that in C. glutamicum, NADPH is mainly generated through the pentose phosphate pathway and that NADPH availability in vivo could generally be enhanced by redirecting the metabolic fluxes from glycolysis toward the pentose phosphate pathway (p. 46, col. 1, para. 1).
Sauer et al, The Soluble and Membrane-bound Transhydrogenases UdhA and PntAB Have Divergent Functions in NADPH Metabolism of Escherichia coli*, published 2004.
Sauer teaches transhydrogenases UdhA and PntAb have divergent functions in NADPH metabolism (Figure 1). UdhA oxidizes NADPH (i.e. converts NADPH) whereas PntAB reduces NADP+ with NADH to produce NADPH (Abstract). Sauer teaches NADPH production and consumption after combinatorial knockouts of udhA and pntAB (Figure 5), however, this is in E. coli, which has both transhydrogenases, unlike Corynebacterium.
Sauer teaches that in metabolic conditions that lead to excess NADPH formation, UdhA was essential for growth, and such conditions included growth on acetate, phosphoglucose isomerase (pgi) mutants or glucose-limited chemostat cultures (p. 6618, col. 2, para. 3), which are not apparently relevant to the claimed invention, according to the media disclosure (instant Specification, p. 33, Seed Medium and Production Medium).
In light of the teachings of the previously presented art that pntAB in Corynebacterium glutamicum leads to increased NADPH production, it is not evident from Sauer why one skilled in the art would introduce of an exogenous UdhA to Corynebacterium, which already has its own NADPH metabolism mechanism, and further, reasonably expect an increase in tryptophan production if udhA has the opposite function as pntAB.
Li et al, Engineering Escherichia coli to improve tryptophan production via genetic
manipulation of precursor and cofactor pathways, published 2020.
Li teaches transhydrogenase SthA is another name of transhydrogenase UdhA. Li teaches that glutamine is an important precursor for tryptophan synthesis (p. 203, col. 1, section: Engineering the glutamine synthesis pathway, para. 1 and p. 202, Figure 1), and the precursor pathways, i.e. glutamine production, relevant to tryptophan synthesis require both NADH and NADPH (p. 201, col. 1, para. 3 and p. 202, Figure 1). Specifically, the glutamine production pathway first consumes NADP+ to NADPH and then NADPH to NADP+ (p. 202, Figure 1). Li teaches that that since SthA preferentially transforms NADPH under metabolic conditions with excess NADPH, they hypothesize that tryptophan production could be further improved if the expression of sthA was further enhanced (p. 204, col. 2, section: The metabolic regulation of NADH and NADPH, para. 2). Li teaches that when they optimized Li teaches increased sthA gene expression indeed improved tryptophan production rate, even though bacterial cell growth decreased (p. 204, col. 2, section: The metabolic regulation of NADH and NADPH, para. 2).
However, the Li does not explicitly teach how this would impact tryptophan production in Corynebacterium, which does not have the same pntAB transhydrogenase as E. coli, since the rate of production will depend on the redox balance of NADH and NADPH.
Allowable Subject Matter
Claim 5 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Further, within the broad genus presently claimed, subject matter that has written support, as indicated in the Written Description rejection is allowable subject matter within the rejected claims, i.e. the microorganism Corynebacterium glutamicum having an L-tryptophan producing ability, comprising an exogenous udhA protein or a polynucleotide encoding the protein, wherein the protein comprises any one or more amino acid sequences selected from SEQ ID NOS: 1, 3, and 5.
Conclusion
No claims are allowed.
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/BONIRATH CHHAY/Examiner, Art Unit 1645 August 3, 2026
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 August 4, 2026
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