DETAILED ACTION
Status of the Application
Claims 1, 4-6, 9-12, 15-20, 22-23 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, 4-6, 11-12, 16-19, addition of claims 22-23 and deletion of claim 21 as submitted in a communication filed on 4/21/2026 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/21/2026 has been entered.
Applicant elected with traverse Group I, claims 1-8, 11-14, drawn in part to a genetically modified microorganism that expresses a YeeX protein, in a communication filed on 6/23/2025.
New claims 22-23 are drawn to a non-elected invention. Claims 9-10, 15, 20, 22-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 6/23/2025.
Claims 1, 4-6, 11-12, 16-19 are at issue and are being examined herein.
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Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
Claims 1, 4-6, 11-12, 16-17, 19 remain 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.
Claim 1 (claims 4-6 dependent thereon) is indefinite in the recitation of “comprising a gene encoding a mutated protein in which the amino acid residue corresponding to position 84 in the amino acid sequence of SEQ ID NO: 1 or its variant originating from Escherichia is substituted from alanine to another amino acid…” for the following reasons. It is unclear as to which is the variant originating from Escherichia being referred to. Does the variant refer to a variant of the mutated protein? Does the variant refer to a variant of the polypeptide of SEQ ID NO: 1? It should also be noted that the term “originating from Escherichia” is unclear because one cannot determine if the variant originating from Escherichia is limited to a naturally occurring protein from Escherichia, or if it encompasses any Escherichia protein that has been modified in view of the fact that the term “originating” can encompass a protein that was first isolated from Escherichia and was later modified. Such protein originated from Escherichia. Moreover, even if the term refers to a naturally-occurring protein from Escherichia, it is unclear if the variant can be any naturally occurring protein from Escherichia, regardless of its function. Please note that one could have structural variants or functional variants of a protein. For examination purposes, no patentable weight will be given to the term “or its variant originating from Escherichia” and the claim will be interpreted as directed to a genetically modified Escherichia microorganism that comprises a gene encoding a variant of the polypeptide of SEQ ID NO: 1, wherein said variant has a substitution at the position corresponding to position 84 of the polypeptide of SEQ ID NO: 1. Correction is required.
Claim 1 (claims 4-6 dependent thereon) is indefinite in the recitation of “…wherein said genetically modified Escherichia microorganism further comprises a gene encoding an enzyme generating 3-oxoadipyl-CoA and coenzyme A from acetyl-CoA and succinyl-CoA….and/or an enzyme generating adipic acid from adipyl-CoA” for the following reasons. It is unclear as to what an enzyme generating compound X from compound Y means. While an enzyme can catalyze the conversion of compound Y into compound X, an enzyme does not generate a compound. For examination purposes, it will be assumed that the claim recites “…wherein said genetically modified Escherichia microorganism further comprises a gene encoding an enzyme that catalyzes the conversion of acetyl-CoA and succinyl-CoA to 3-oxoadipyl-CoA and coenzyme A ….and/or an enzyme that catalyzes the conversion of adipyl-CoA to adipic acid”. Correction is required.
Claim 5 is indefinite in the recitation of “…microorganism according to claim 4, which results from mutation of a gene capable of expressing the polypeptide of SEQ ID NO: 1 or its variant originating from Escherichia in the genome or replacement of the gene capable of expressing the polypeptide of SEQ ID NO: 1 or its variant originating from Escherichia with said gene capable of expressing the mutated protein” for the following reasons. It is unclear as to which is the variant originating from Escherichia being referred to. Does the variant refer to a variant of the mutated protein? Does the variant refer to a variant of the polypeptide of SEQ ID NO: 1? It should also be noted that the term “originating from Escherichia” is unclear because one cannot determine if the variant originating from Escherichia is limited to a naturally occurring protein from Escherichia, or if it encompasses any Escherichia protein that has been modified in view of the fact that the term “originating” can encompass a protein that was first isolated from Escherichia and was later modified. Such protein originated from Escherichia. Moreover, even if the term refers to a naturally-occurring protein from Escherichia, it is unclear if the variant can be any naturally occurring protein from Escherichia, regardless of its function. Please note that one could have structural variants or functional variants of a protein. For examination purposes, no patentable weight will be given to the term “or its variant originating from Escherichia”. Correction is required.
Claim 6 is indefinite in the recitation of “wherein said mutated protein has a mutation, which the amino acid residue corresponding to position 84 in the amino acid sequence of SEQ ID NO: 1 or its variant originating from Escherichia is substituted from alanine to valine….or methionine” for the following reasons. It is unclear as to how the term “which the amino acid residue corresponding to position 84 in the amino acid sequence of SEQ ID NO: 1” further limits the mutation. In addition, it is unclear as to which is the variant originating from Escherichia being referred to. Does the variant refer to a variant of the mutated protein? Does the variant refer to a variant of the polypeptide of SEQ ID NO: 1? It should also be noted that the term “originating from Escherichia” is unclear because one cannot determine if the variant originating from Escherichia is limited to a naturally occurring protein from Escherichia, or if it encompasses any Escherichia protein that has been modified in view of the fact that the term “originating” can encompass a protein that was first isolated from Escherichia and was later modified. Such protein originated from Escherichia. Moreover, even if the term refers to a naturally-occurring protein from Escherichia, it is unclear if the variant can be any naturally occurring protein from Escherichia, regardless of its function. Please note that one could have structural variants or functional variants of a protein. For examination purposes, no patentable weight will be given to the term “or its variant originating from Escherichia” and the claim will be interpreted as directed to the microorganism of claim 1, wherein the variant of the polypeptide of SEQ ID NO: 1 has a valine, leucine, phenylalanine, isoleucine or methionine at the position corresponding to position 84 of the polypeptide of SEQ ID NO: 1. Correction is required.
Claim 11 (claim 12 dependent thereon) is indefinite in the recitation of “belonging to the genus Escherichia, comprising a gene encoding a mutated protein in which the amino acid residue corresponding to position 84 in the amino acid sequence of SEQ ID NO: 1 or its variant originating from Escherichia is substituted from alanine to another amino acid, wherein said genetically modified Escherichia microorganism has the ability to produce endogenous organic acid(s)” for the following reasons. It is unclear as to which is the variant originating from Escherichia being referred to. Does the variant refer to a variant of the mutated protein? Does the variant refer to a variant of the polypeptide of SEQ ID NO: 1? It should also be noted that the term “originating from Escherichia” is unclear because one cannot determine if the variant originating from Escherichia is limited to a naturally occurring protein from Escherichia, or if it encompasses any Escherichia protein that has been modified in view of the fact that the term “originating” can encompass a protein that was first isolated from Escherichia and was later modified. Such protein originated from Escherichia. Moreover, even if the term refers to a naturally-occurring protein from Escherichia, it is unclear if the variant can be any naturally occurring protein from Escherichia, regardless of its function. Please note that one could have structural variants or functional variants of a protein. For examination purposes, no patentable weight will be given to the term “or its variant originating from Escherichia” and the claim will be interpreted as being directed to a genetically modified Escherichia microorganism that comprises a gene encoding a variant of the polypeptide of SEQ ID NO: 1, wherein said variant has a substitution at the position corresponding to position 84 of the polypeptide of SEQ ID NO: 1, wherein said genetically modified Escherichia microorganism is able to produce endogenous organic acids. Correction is required.
Claim 12 is indefinite in the recitation of “wherein said mutated protein has a mutation which the amino acid residue corresponding to position 84 in the amino acid sequence of SEQ ID NO: 1 or its variant originating from Escherichia is substituted from alanine to valine….or methionine” for the following reasons. It is unclear as to which is the variant originating from Escherichia being referred to. Does the variant refer to a variant of the mutated protein? Does the variant refer to a variant of the polypeptide of SEQ ID NO: 1? It should also be noted that the term “originating from Escherichia” is unclear because one cannot determine if the variant originating from Escherichia is limited to a naturally occurring protein from Escherichia, or if it encompasses any Escherichia protein that has been modified in view of the fact that the term “originating” can encompass a protein that was first isolated from Escherichia and was later modified. Such protein originated from Escherichia. Moreover, even if the term refers to a naturally-occurring protein from Escherichia, it is unclear if the variant can be any naturally occurring protein from Escherichia, regardless of its function. Please note that one could have structural variants or functional variants of a protein. For examination purposes, no patentable weight will be given to the term “or its variant originating from Escherichia” and the claim will be interpreted as directed to the microorganism of claim 11, wherein the variant of the polypeptide of SEQ ID NO: 1 has a valine, leucine, phenylalanine, isoleucine or methionine at the position corresponding to position 84 of the polypeptide of SEQ ID NO: 1. Correction is required.
Claim 16 (claim 17 dependent thereon) is indefinite in the recitation of “..comprising a gene encoding a mutated protein in which the amino acid residue at position 87 in the amino acid sequence of SEQ ID NO: 2 is substituted from alanine to another amino acid…wherein said genetically modified…further comprises a gene encoding an enzyme generating 3-oxoadipyl-CoA and coenzyme A from acetyl-CoA and succinyl-CoA…and/or an enzyme generating adipic acid from adipyl-CoA” for the following reasons. While an enzyme can catalyze the conversion of compound Y into compound X, an enzyme does not generate a compound. For examination purposes, it will be assumed that the claim is directed to a genetically modified Serratia microorganism that comprises a gene encoding a variant of the polypeptide of SEQ ID NO: 2, wherein said variant comprises a substitution at the position corresponding to position 87 of the polypeptide of SEQ ID NO: 2, wherein said genetically modified Escherichia microorganism further comprises a gene encoding an enzyme that catalyzes the conversion of acetyl-CoA and succinyl-CoA to 3-oxoadipyl-CoA and coenzyme A ….and/or an enzyme that catalyzes the conversion of adipyl-CoA to adipic acid. Correction is required.
Claim 17 is indefinite in the recitation of “wherein said mutated protein thereof has a mutation, which the amino acid residue at position 87 in the amino acid sequence of SEQ ID NO: 2 is substituted from alanine to valine…or methionine” for the following reasons. The term “mutated protein thereof” is unclear because one cannot determine what is associated with the phrase “thereof”. Also, it is unclear as to how the term “which the amino acid residue corresponding to position 87 in the amino acid sequence of SEQ ID NO: 2” further limits the mutation. For examination purposes, it will be assumed that claim 17 is directed to the microorganism of claim 16, wherein the variant of the polypeptide of SEQ ID NO: 2 comprises a valine, leucine, phenylalanine, isoleucine, or methionine at the position corresponding to position 87 of the polypeptide of SEQ ID NO: 2. Correction is required.
Claim 19 is indefinite in the recitation of “wherein said mutated protein thereof has a mutation, which the amino acid residue at position 87 in the amino acid sequence of SEQ ID NO: 2 is substituted from alanine to valine…or methionine” for the following reasons. The term “mutated protein thereof” is unclear because one cannot determine what is associated with the phrase “thereof”. Also, it is unclear as to how the term “which the amino acid residue corresponding to position 87 in the amino acid sequence of SEQ ID NO: 2” further limits the mutation. For examination purposes, it will be assumed that claim 19 is directed to the microorganism of claim 18, wherein the variant of the polypeptide of SEQ ID NO: 2 comprises a valine, leucine, phenylalanine, isoleucine, or methionine at the position corresponding to position 87 of the polypeptide of SEQ ID NO: 2. 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, 4-6, 11-12, 16-19 remain 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.
Claims 1, 4-6, 11-12, 16-19 remain 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 a microorganism that comprises a nucleic acid encoding a protein that (i) comprises SEQ ID NO: 44, or (ii) comprises SEQ ID NO: 12, wherein said microorganism has been transformed with the P. putida pcaF gene of SEQ ID NO: 13, the S. marcescens gene encoding a 3-oxoadipyl-CoA reductase of SEQ ID NO: 14, the P. putida paaF gene of SEQ ID NO: 15, the A. baylyi dcaA gene of SEQ ID NO: 16, the P. putida pcaI gene of SEQ ID NO: 17 and the P. putida pcaJ gene of SEQ ID NO: 18, does not reasonably provide enablement for a microorganism that comprises (i) a nucleic acid encoding any variant of the polypeptide of SEQ ID NO: 1 having any structure and function, wherein said variant has a substitution at the position corresponding to position 84 of the polypeptide of SEQ ID NO: 1, or (ii) a nucleic acid encoding a variant of the polypeptide of SEQ ID NO: 2 having any structure and function, wherein said variant comprises a substitution at the position corresponding to position 87 of the polypeptide of SEQ ID NO: 2, wherein said microorganism (a) comprises a gene encoding any enzyme that can catalyze the conversion of acetyl-CoA and succinyl-CoA to 3-oxoadipyl-CoA, a gene encoding any enzyme that can catalyze the conversion of 3-oxoadipyl-CoA to 3-hydroxyadipyl-CoA, a gene encoding any enzyme that can catalyze the conversion of 3-hydroxyadipyl-CoA to 2,3-dehydroadipyl-CoA, a gene encoding any enzyme that can catalyze the conversion of 2,3-dehydroadipyl-CoA to adipyl-CoA, a gene encoding any enzyme that can catalyze the conversion of 3-hydroxyadipyl-CoA to 3-hydroxyadipic acid, a gene encoding any enzyme that can catalyze the conversion of 2,3-dehydroadipyl-CoA to α-hydromuconic acid, and/or a gene encoding any enzyme that catalyzes the conversion of adipyl-CoA to adipic acid, or (b) produces endogenous organic acids.
These rejections have been discussed at length in the prior Office action. They are maintained for the reasons of record and those set forth below.
Applicant argues that the claims have been amended to clarify that the genetically modified microorganisms are limited to the genus of Escherichia or Serratia. Applicant also argues that claims 1 and 16 have been amended to further comprise genes encoding enzymes of the adipic acid biosynthetic pathway. Applicant states that the claims have been amended such that the mutated protein is defined structurally by reference to SEQ ID NO: 1 or SEQ ID NO: 2, or variants originating from Escherichia or Serratia, wherein a particular residue corresponding to position 84 or 87 of SEQ ID NO: 1 or SEQ ID NO: 2, respectively, has been substituted. Applicant is of the opinion that the claims recite a specific and well defined structural modification within the disclosed protein sequences, rather than relying on functional or nomenclature based definitions. Applicant states that the claims are directed to a structurally defined set of protein variants. Applicant submits that in view of the limitations present, the claims do not encompass an unrestricted or undefined genus of proteins or organisms.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejections. The Examiner acknowledges the amendments made to the claims. However, the Examiner disagrees with Applicant’s contention that the claims as amended comply with the written description and enablement requirements.
The claims as amended now require Escherichia or Serratia microorganisms that comprise a genus of nucleic acids encoding variants of the polypeptide of SEQ ID NO: 1 or the polypeptide of SEQ ID NO: 2 having any structure and function, wherein the variants comprise a substitution at the position corresponding to position 84 of the polypeptide of SEQ ID NO: 1, or position 87 of the polypeptide of SEQ ID NO: 2. As written, the variant encoded by the recited gene is not required to have any structural feature found in the polypeptide of SEQ ID NO: 1 or the polypeptide of SEQ ID NO: 2. All that is required is a variant of the polypeptide of SEQ ID NO: 1 that lacks an alanine at the position corresponding to position 84 of the polypeptide of SEQ ID NO: 1, or a variant of the polypeptide of SEQ ID NO: 2 that lacks an alanine at the position corresponding to position 87 of the polypeptide of SEQ ID NO: 2. In addition, claims 1, 4-6, 16-17 require a genus of genes encoding enzymes having any structure and the ability to catalyze specific reactions. It is noted that more than one type of enzyme can catalyze the same reaction. Therefore, the genes required by the claims are not limited to a single type of enzyme for each of the conversion recited. For example, the conversion of X to Y can be catalyze by enzyme A as well as enzyme B, wherein enzyme A and enzyme B are not necessarily enzymes having the same enzymatic activity or belong to the same EC number. As such, for each of the conversions recited, the claims require a genus of genes encoding enzymes having any structure and function. See also Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
While the specification in the instant application discloses the structure of a limited number of species of the genus of proteins that could enhance the production of a limited number of organic acids, such as the proteins of SEQ ID NO: 1 and SEQ ID NO: 2, as well as a variant of the protein of SEQ ID NO: 1 that comprises all of SEQ ID NO: 1 except for a valine at the position corresponding to position 84 of the polypeptide of SEQ ID NO: 1 (SEQ ID NO: 44), and a variant of the protein of SEQ ID NO: 2 that comprises all of SEQ ID NO: 2 except for a valine at the position corresponding to position 87 of the polypeptide of SEQ ID NO: 2 (SEQ ID NO: 12), the specification and the prior art are completely silent as to the structural elements required in any protein having the same biological activity as that of the polypeptides of SEQ ID NO: 1 or SEQ ID NO: 2, nor does it teach which structural elements within the polypeptide of SEQ ID NO: 1 or the polypeptide of SEQ ID NO: 2 are required in any variant having the ability to increase the production of any endogenous organic acid, or the production of succinic acid, acetic acid, 3-hydroxyadipic acid, α-hydromuconic acid, and/or adipic acid in a Escherichia or Serratia cell. It should be noted that the only endogenous organic acids whose production was increased by expression of the proteins of SEQ ID NO: 12 or 44 are succinic acid and acetic acid. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which proteins encoded by the recited genus of nucleic acids have the ability to increase the production of any endogenous organic acid in any Escherichia or Serratia cell, or the production of succinic acid, acetic acid, 3-hydroxyadipic acid, α-hydromuconic acid, and/or adipic acid. While the claims require genes encoding proteins having any structure and function, it is noted that the only use disclosed for the recited genes is to encode a protein that can enhance the production of organic acids. No use has been provided for genes encoding proteins which are structural variants of the polypeptide of SEQ ID NO: 1 or SEQ ID NO: 2 that have the recited substitution and do not promote an increase in the production of organic acids.
While the specification discloses a single gene encoding an enzyme that can catalyze the conversion of acetyl-CoA and succinyl-CoA to 3-oxoadipyl-CoA, a single gene encoding an enzyme that can catalyze the conversion of 3-oxoadipyl-CoA to 3-hydroxyadipyl-CoA, a single gene encoding an enzyme that can catalyze the conversion of 3-hydroxyadipyl-CoA to 2,3-dehydroadipyl-CoA, a single gene encoding an enzyme that can catalyze the conversion of 2,3-dehydroadipyl-CoA to adipyl-CoA, a single gene encoding an enzyme that can catalyze the conversion of 3-hydroxyadipyl-CoA to 3-hydroxyadipic acid, a single gene encoding an enzyme that can catalyze the conversion of 2,3-dehydroadipyl-CoA to α-hydromuconic acid, and a single gene encoding an enzyme that catalyzes the conversion of adipyl-CoA to adipic acid, the specification is silent with regard to additional species of the genus of genes required or the structural features required in any gene that encodes an enzyme that can catalyze the recited conversions. No structure/function correlation has been provided such that one of skill in the art can envision the structure of any gene encoding an enzyme able to catalyze the desired conversions.
While the argument can be made that the structure/identity of those enzymes and proteins and their corresponding genes required by the claims can be obtained by structural homology, the art clearly teaches that (i) there is a high level of unpredictability associated with accurate functional annotation of proteins based solely on structural homology, and (ii) modification of a protein’s amino acid sequence to obtain the desired activity without any guidance/knowledge as to which amino acids in a protein are tolerant of modification and which ones are conserved is highly unpredictable. See teachings of Singh et al., Sadowski et al., Witkowski et al., Seffernick et al. and Tang et al. previously discussed.
While methods of generating or isolating variants of a polynucleotide or polypeptide were known in the art, and enzymatic assays were also known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of proteins and polynucleotides to (a) find those that can increase the production of any endogenous organic acid, or the production of succinic acid, acetic acid, 3-hydroxyadipic acid, α-hydromuconic acid, and/or adipic acid by an Escherichia or Serratia microorganism that expresses them, (b) find genes encoding enzymes that can catalyze the recited conversions in any Escherichia or Serratia microorganism, and (c) find a use for those Escherichia or Serratia microorganisms that express a gene encoding any variant of the polypeptide of SEQ ID NO: 1 or 2 that has the recited substitution but lacks the ability to enhance the production of an organic acid. In the absence of (i) a rational and predictable scheme for selecting those nucleic acids encoding proteins most likely to have the desired functional features, (ii) a rational and predicable scheme for determining a potential use for those microorganisms that express variants of the polypeptide of SEQ ID NO: 1 or SEQ ID NO: 2 having the recited substitution and do not enhance the synthesis of any organic acid, and/or (iii) a correlation between structure and the desired activity, one of skill in the art would have to test any number of nucleic acids, and proteins to enable the entire scope of the claims.
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.
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
April 30, 2026
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