DETAILED ACTION
Status of the Application
Claims 1, 3-4, 7-10 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment of claims 1, 3-4, 7, addition of claims 9-10, cancellation of claims 2, 5, a declaration under 37 CFR § 1.132 by inventor Yuji Noguchi (hereinafter the Noguchi declaration) as submitted in a communication filed on 7/16/2026 is acknowledged.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/16/2026 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claim Objections
Claims 9 and 10 are objected to due to the recitation of “SEQID NO: 1”. The term should be amended to recite “SEQ ID NO: 1”. Appropriate correction is required.
Claim 9 is objected to due to the recitation of “wherein the Adk has at least 90% identity to SEQ ID NO: 1”. To enhance clarity and to be consistent with commonly used claim language, the claims should be amended to recite “wherein the Adk has at least 90% sequence identity to the polypeptide of SEQ ID NO: 1”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
Claims 1, 3-4, 7-8 remain rejected and new claims 9-10 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 pre-AIA the applicant regards as the invention. New grounds of rejection are necessitated by amendment.
Claims 1 and 4 (claims 3, 7-10 dependent thereon) are indefinite in the recitation of “wherein the ergothioneine biosynthetic gene is at least one combination of genes correspond to reference genes selected from…” for the following reasons. The term “the ergothioneine biosynthetic gene” implies a single gene. Therefore, it is unclear as to how a single gene can be a combination of genes. In addition, the term “genes corresponding to reference genes” is unclear because the specification states that a corresponding gene refers to a gene encoding a protein that has the same or similar function to a gene encoding a protein having a certain function. The term “similar” is a relative term and it is unclear in the absence of what is encompassed by “similar”. The metes and bounds of what is a similar function are completely undefined. For example, which genes are deemed similar to the M. smegmatis egtA gene? For examination purposes, it will be assumed that the claims require any ergothioneine biosynthetic gene. Correction is required.
Claim 1 (claims 3, 7-9 dependent thereon) is indefinite in the recitation of “..wherein the bacterium is a strain modified to increase ….overexpressing a gene encoding Adk, wherein Adk is a protein having adenosine kinase activity…relative to the same strain that does not overexpress the gene encoding Adk” for the following reasons. It is unclear as to how the term “wherein Adk is a protein having adenosine kinase activity” further limits the protein encoded by the gene if the term “Adk” has been defined in the claim as equivalent to adenosine kinase (e.g., adenosine kinase (Adk)). For examination purposes, it will be assumed that the claim recites “…wherein the bacterium has been transformed with a gene encoding an adenosine kinase”. Correction is required.
Claim 4 is indefinite in the recitation of “wherein the bacterium has an increased adenosine kinase activity….relative to the same strain that does not overexpress the gene encoding Adk” for the following reasons. The term “increased” is a relative term and the claim does not provide the reference to determine the increase (e.g., increased compared to what?). In addition, there is no antecedent basis for “the same strain”. For examination purposes, no patentable weight will be given to the term “wherein the bacterium has an increased adenosine kinase activity” and it will be assumed that the claim requires transformation of the bacterium to express a gene encoding an adenosine kinase. Correction is required.
Claim 10 is indefinite in the recitation of “the method of claim 4” for the following reasons. The subject matter of claim 4 is not a method. If the intended limitation is “the bacterium of claim 4”, the claim should be amended accordingly. Correction is required.
When amending the claims, applicant is advised to carefully review all examined claims and make the necessary changes to ensure proper antecedent basis and dependency.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
Claims 1, 3-4, 7-8 remain rejected and new claims 9-10 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection as it relates to claims 9-10 is necessitated by amendment.
Claims 1, 3-4, 7-8 remain rejected and new claims 9-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an E. coli cell transformed with the Schizosaccharomyces pombe egt1 gene, the Schizosaccharomyces pombe egt2 gene, and a polynucleotide that encodes the protein of SEQ ID NO: 1, and a method to produce ergothioneine by culturing said E. coli cell, does not reasonably provide enablement for any bacterium that has any ergothioneine biosynthetic gene or has been transformed with any gene associated with the synthesis of ergothioneine, wherein said bacterium has been transformed with any gene encoding an adenosine kinase. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/o use the invention commensurate in scope with these claims. This rejection as it relates to claims 7-8 is necessitated by amendment.
These rejections have been discussed at length in the prior Office action. They are maintained for the reasons of record and further applied to new claims 9-10 for the reasons set forth below.
Applicant argues that the specific origin or structure of each EGT biosynthetic gene is not the feature relied upon for the technical effect of the invention. Applicant states that the key point is that in a bacterium having EGT biosynthetic capability and increased Adk activity, one could observe an increase in the biosynthesis of ergothioneine or its related forms. Applicant states that Adk is not itself an enzyme that directly forms the EGT biosynthetic route. Applicant states that one of skill in the art would be able to select suitable EGT biosynthetic genes based on the disclosure of the specification, including the reference genes and the definition of “corresponding gene”. Applicant states that the enzyme function, EC numbers and ordinary public annotations explain the meaning of “gene corresponding to a reference gene”. Applicant states that EC numbers identify the type of enzymatic reaction. Applicant states that the “gene corresponding to a reference gene” should not be treated as an undefined gene or a gene with a similar name. Applicant states that the same arguments apply to adenosine kinase. Applicant states that Adk is not an arbitrary kinase and that one of skill in the art can identify genes encoding Adk based on the specification, known adenosine kinase activity, EC number information and public databases.
Applicant refers to the working examples as supporting the technical concept, namely an increase in ergothioneine synthesis when Adk activity is increased. Applicant refers to the Noguchi declaration as providing additional experimental data regarding Streptomyces where it is allegedly shown that in a Streptomyces strain having the EGT biosynthetic pathway, overexpression of the gene encoding Adk increases EGT production compared with a control strain that does not overexpress Adk. Applicant states that the Noguchi declaration provides results with Streptomyces lividans showing that EGT production increased when Adk was overexpressed compared to the control strain.
Applicant’s arguments and the Noguchi declaration have been fully considered but not deemed persuasive to overcome the instant rejections or avoid the rejection of new claims 9-10. The Examiner acknowledges the teachings of the specification, the amendments made to the claims and the Noguchi declaration. However, the Examiner disagrees with applicants contention that the claims meet the written description and enablement requirements.
The claims as currently presented and interpreted require (i) a genus of bacterial cells that endogenously have an ergothioneine biosynthetic pathway or have been transformed with a genus of genes encoding proteins having any structure and function which are associated with the synthesis of ergothioneine, wherein said bacterial cells have been modified to express a genus of adenosine kinases having any structure, or an adenosine kinase having at least 90% sequence identity to the polypeptide of SEQ ID NO: 1, and (ii) a method to produce ergothioneine by culturing said genus of microorganisms. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation. There is no limitation with regard to the members of the genus of bacterial cells that endogenously produce ergothioneine, the genus of genes that can be introduced to any bacterial cell such that the bacterial cell can produce ergothioneine, and the genus of adenosine kinases that can be expressed by the recited bacterial cells.
With regard to the arguments that (i) the specific origin or structure of each EGT biosynthetic gene is not the feature relied upon for the technical effect of the invention and the key point is that in a bacterium having EGT biosynthetic capability and increased Adk activity, one could observe an increase in the biosynthesis of ergothioneine or its related forms, and (ii) Adk is not itself an enzyme that directly forms the EGT biosynthetic route, it is noted that while it is agreed that Adk is not an enzyme that directly forms the EGT biosynthetic route, the structure of the genes associated with ergothioneine synthesis and the structure of the gene encoding an adenosine kinase is essential to the claimed invention because the recited bacterium could not function as claimed without transformation of said bacterium with said genes. Knowledge of the structure of the recited genes is required to obtain the bacterium of the claims and to practice the method of the claims. As previously indicated, not all microorganisms endogenously produce ergothioneine, as evidenced by page 2 and Table 1 disclosed by Sato et al. (Applied Microbiology and Biotechnology 109:93, pages 1-14, 2025). Please note that even if all the claims were to require an adenosine kinase having at least 90% sequence identity to the adenosine kinase of SEQ ID NO: 1, the claims still require a genus of genes associated with the synthesis of ergothioneine having any structure.
With regard to the arguments that (i) one of skill in the art would be able to select suitable EGT biosynthetic genes based on the disclosure of the specification, (ii) “gene corresponding to a reference gene” should not be treated as an undefined gene or a gene with a similar name, and (iii) the enzyme function, EC numbers and ordinary public annotations explain the meaning of “gene corresponding to a reference gene”, it is noted that while it is agreed that one could use the specific combinations of genes disclosed in the specification, namely the Mycobacterium smegmatis egtA, egtB, egtC, egtD, and egtE genes; the Schizosaccharomyces pombe egtl and egt2 genes; the Neurospora crassa egt1 and egt2 genes; or the Chlorobium limicola eanA and eanB genes, the claims are not limited to these combinations of genes. Instead, the claims require any gene associated with the synthesis of ergothioneine, known and unknown. In addition, while the term “corresponding gene” has been defined in the specification as a gene encoding a protein that has the same or similar function to a gene encoding a protein having a certain function, the term “similar” is unclear in the absence of a definition of what is encompassed or excluded from “similar”. For example, if the reference gene encodes a protein hydrolase, would a gene encoding a lipase (lipid hydrolase) be considered “similar” by virtue of both enzymes being hydrolases? Contrary to Applicant’s assertions, enzyme function, EC numbers and ordinary public annotations do not explain the meaning of “gene corresponding to a reference gene” because neither the claims nor the specification disclose or define (i) which is the enzyme function that is considered similar to the enzymatic activity of the proteins encoded by the reference genes, and (ii) which EC numbers are considered similar or intended for the proteins encoded by the corresponding genes.
Moreover, even if the argument is made that the corresponding genes have to encode proteins having the same enzymatic activity as that of the reference genes, knowing the EC number and the reaction that they catalyze does not provide the structure of those genes. Public annotations, unless experimentally validated, are merely predictions of what the protein could be. As previously indicated, the prior art teaches that function determination based solely on structural similarity is highly unpredictable even in cases where the structural similarity is high. See the teachings of Witkowski et al., Seffernick et al., Tang et al., Singh et al. and Sadowski et al. previously discussed. Therefore, one of skill in the art cannot reasonably conclude that the few enzymes associated with the synthesis of ergothioneine disclosed would allow one of skill in the art to envision the structure of any enzyme/protein associated with ergothioneine biosynthesis as required by the claims.
With regard to the argument that Adk is not an arbitrary kinase and that one of skill in the art can identify genes encoding Adk based on the specification, known adenosine kinase activity, EC number information and public databases, it is noted that while a limited number of adenosine kinases are known in the art, and the enzymatic activity of an adenosine kinase as well as its EC number are known in the art, the claims are not limited to known adenosine kinases but it also encompasses unknown adenosine kinases. The structure of the adenosine kinase is essential for the claimed invention because one of skill in the art would have to know the structure of the polynucleotide encoding the adenosine kinase to transform the bacterial cell and use the cell in the claimed method. Neither the specification nor the prior art discloses the structural features required in any adenosine kinase or the structural features required in any adenosine kinase that is a variant of the polypeptide of SEQ ID NO: 1 such that the variant would also have adenosine kinase activity. No structure/function correlation has been provided to envision the structure of any adenosine kinase. As explained above, the teachings of Witkowski et al., Seffernick et al., Tang et al., Singh et al. and Sadowski et al. previously discussed are evidence to show that function determination based solely on structural similarity is highly unpredictable even in cases where the structural similarity is high. Therefore, it is unclear if the disclosure of a limited number of adenosine kinases in the art would allow one of skill in the art to determine which proteins are most likely to be adenosine kinases or which variants of the polypeptide of SEQ ID NO: 1 are adenosine kinases.
With regard to the working examples provided and the additional data provided in the Noguchi declaration, it is noted that the Examiner is not in disagreement with the findings regarding the increase of ergothioneine if there is an increase in adenosine kinase activity. The issue in the instant case is whether or not the specification and/or the prior art provide adequate description and enablement for the entire genus of genes required by the claims to practice the claimed invention. The specification is silent with regard to those bacterial cells that naturally produce ergothioneine, the structure of any gene that can be introduced into any bacterial cell such that said bacterial cell can produce ergothioneine, and the structure of any gene that encodes an adenosine kinase. No correlation between structure and function has been presented that would allow one of skill in the art to recognize which genes are associated with the biosynthesis of ergothioneine, and which genes encode an adenosine kinase. It is reiterated herein that the claims are not structurally and/or functionally limited with regard to the genus of genes required. As previously indicated, the structure of the genes recited is essential to practice the claimed invention since without knowing the structure of the genes, one of skill in the art cannot transform the recited bacterial cells and practice the claimed method. It was not routine in the art to screen by a trial and error process for an essentially infinite number of genes to find those that can be used in the bacterial cells required by the claims. In the absence of (a) a rational and predictable scheme for selecting those polynucleotides most like to encode the desired proteins, (b) a rational and predictable scheme for selecting those bacterial cells that naturally produce ergothioneine, (c) and/or a correlation between structure and the desired activity, one of skill in the art would have to test any number of genes, enzymes and bacterial cells to determine which ones have the desired functional characteristics and effects. This is not deemed routine experimentation. Therefore, for the reasons of record and those set forth above, one cannot reasonably conclude that the entire scope of the claims is adequately described or enabled by the teachings of the specification and/or the prior art.
Art of Interest
Kanai et al. (Appl. Microbiol. Biotechnol. 101:1351-1357, 2017) discloses a method to accumulate S-adenosylmethionine (SAM) in yeast wherein the ado1 gene in S. cerevisiae was deleted (page 1354, right column ADO1 (adenosine kinase)). SAM is a precursor of ergothioneine as evidenced by Figure 1 of Tanaka et al. (Scientific Reports 9:1895, pages 1-10, published 2/13/2019).
Conclusion
No claim is in condition for allowance.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
August 7, 2026
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