DETAILED ACTION
Status of the Application
Claims 1, 5, 7-11, 17 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, 5, 9-11, 17 and cancellation of claims 2-3, 14-16, 18-19 as submitted in a communication filed on 3/17/2026 is acknowledged.
The present application is being examined under the pre-AIA first to invent provisions. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/17/2026 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Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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
Claim 10 is objected to due to the recitation of “converting the cysteine produced in b) into cysteine derivatives, wherein the cysteine derivative is at least one selected from the group consisting of….”. To provide clarity and consistency, the term should be amended to recite “converting the cysteine produced in b) into a cysteine derivative, wherein the cysteine derivative is selected from the group consisting of….”, or in the alternative, “converting the cysteine produced in b) into cysteine derivatives, wherein the cysteine derivatives are selected from the group consisting of….”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
Claims 1, 5, 7-11, 17 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.
Claim 1 (claims 5, 7-11 dependent thereon) are indefinite in the recitation of “mdtH protein” for the reasons of record. The term as written, appears to be generic and not limited to a specific organism. It is noted that the claims requires an mdtH protein having an amino acid sequence at least 99% sequence identical to SEQ ID NO: 1 as well as replacing the promoter of a gene encoding an mdtH protein in any Escherichia cell. As such, the claims are not limited to the E. coli mdtH protein of SEQ ID NO: 1. While the gene/protein nomenclature used may be appropriate for E. coli genes/proteins, the use of this nomenclature for proteins of identical function from other organisms may not be accurate. As known in the art, genes encoding proteins of identical function in two different organisms may use different designations. For example, the ARO4 gene of Candida albicans encodes a DAHP synthase whereas the E. coli counterpart is the aroF gene. See the abstract of Sousa et al. (Microbiology 148(Pt5):1291-1303, 2002; previously cited). As such, the use of gene/protein terminology which is applicable to some organisms and not to others as used herein is confusing since one cannot determine if by using this nomenclature, the claims are limiting the organism from which these proteins derive to those that use the same gene/protein nomenclature. For examination purposes, the term “mdtH protein” will be interpreted as a transporter protein. Correction is required.
Claim 1 (claims 5, 7-11, 17 dependent thereon) is indefinite in the recitation of “..in which the O-phosphoserine exporting activity of….is increased relative to that of a wild-type or a non-modified E. coli microorganism by transformation of a polynucleotide encoding…or replacing a promoter for a polynucleotide …on the chromosome with a stronger promoter, and in which enzymatic activity of phosphoserine phosphatase….is reduced relative to that of a wild-type or a non-modified E. coli” for the following reasons. The term “a wild-type or a non-modified E. coli microorganism” encompasses a genus of E. coli cells. The basis for comparison is variable, making the determination as to what is encompassed or excluded from the claim impossible. A cell can be excluded or included depending on which wild type or non-modified E. coli is used as basis for comparison. For example, an Escherichia cell X can be included if the basis for comparison is an E. coli Y cell but at the same time excluded if the basis for comparison is an E. coli Z cell. The term “by transformation of a polynucleotide” is unclear because the claim fails to indicate what is the polynucleotide transformed into. If the intended limitation is “by transformation with a polynucleotide”, the claim should be amended accordingly. The term “in which enzymatic activity of phosphoserine phosphatase is reduced…” is unclear because one cannot determine if the intended enzymatic activity is that of an endogenous phosphoserine phosphatase. If the intended limitation is “in which the enzymatic activity of an endogenous phosphoserine phosphatase is ....”, the claim should be amended accordingly. For examination purposes, it will be assumed that claim 1 is directed in part to a recombinant Escherichia cell that produces O-phosphoserine, wherein said cell comprises a polynucleotide that encodes the protein of SEQ ID NO: 1 or a protein having O-phosphoserine transport activity at least 99% sequence identical to the polypeptide of SEQ ID NO: 1, wherein said cell has been modified to have reduced phosphoserine phosphatase activity compared to the corresponding Escherichia cell lacking the modification. Correction is required.
Claim 5 is indefinite in the recitation of “in which an enzymatic activity of any one of phosphoglycerate dehydrogenase.., phosphoserine aminotransferase…, or a combination thereof is further increased relative to that of a wild-type or a non-modified E. coli microorganism” for the following reasons. The term “a wild-type or a non-modified E. coli microorganism” encompasses a genus of E. coli cells. The basis for comparison is variable, making the determination as to what is encompassed or excluded from the claim impossible. A cell can be excluded or included depending on which wild type or non-modified E. coli is used as basis for comparison. For example, an Escherichia cell X can be included if the basis for comparison is an E. coli Y cell but at the same time excluded if the basis for comparison is an E. coli Z cell. In addition, the term “an enzymatic activity” implies more than one enzymatic activity. Therefore, it is unclear if the intended limitation is increasing phosphoglycerate dehydrogenase activity and/or phosphoserine aminotransferase activity in said Escherichia microorganism. For examination purposes, the claim will be interpreted as requiring any modification to increase phosphoglycerate dehydrogenase activity and/or a phosphoserine aminotransferase activity compared to the corresponding Escherichia microorganism lacking the modification. 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(d) or Fourth Paragraph (pre-AIA )
Claim 10 was rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. In view of Applicant’s amendment of claim 10, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
Claims 1, 5, 7-11 and 17 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. This rejection as it relates to new claims 14-19 is necessitated by amendment.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that the claims have been amended to render the instant rejection moot.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the rejection of claims 1, 5, 7-11 and 17. The Examiner acknowledges the amendments made to the claims. However, the Examiner disagrees with Applicant’s contention that the entire scope of the claims is adequately described.
As interpreted, the claims still require a genus of modifications to decrease phosphoserine phosphatase activity in any Escherichia cell. In addition, the claims also require a genus of modifications to increase phosphoglycerate dehydrogenase activity and/or phosphoserine aminotransferase activity in any Escherichia cell. This would encompass transformation of the Escherichia cell with a genus of nucleic acids encoding phosphoglycerate dehydrogenases and/or phosphoserine amino transferases having any structure, as well as unknown genetic modifications to endogenous genes encoding phosphoglycerate dehydrogenase and/or phosphoserine aminotransferase, such as unknown structural modifications to genes in any Escherichia cell that encode these enzymes to increase its expression or to increase their enzymatic activity, and the expression of unknown inducers of expression of said genes. The specification only discloses the expression of nucleic acids encoding an E. coli phosphoglycerate dehydrogenase and an E. coli phosphoserine aminotransferase as modifications to increase enzymatic activity. Moreover, claims 9-11 require a genus of O-phosphoserine sulfhydrylases having any structure. While the specification and the prior art disclose an E. coli phosphoglycerate dehydrogenase, phosphoserine phosphatase, and a phosphoserine aminotransferase, and the art discloses a limited number of O-phosphoserine sulfhydrylases, neither the specification nor the prior art disclose the structural features required in any of these enzymes, or a structure/function correlation that would allow one of skill in the art to determine which proteins have these enzymatic activities.
While the claims require a genus of unknown modifications to reduce the enzymatic activity of a phosphoserine phosphatase, such as unknown structural modifications to the coding region of a polynucleotide that encodes a phosphoserine phosphatase to reduce its enzymatic activity, unknown structural modifications to the region upstream from the coding region of a polynucleotide that encodes a phosphoserine phosphatase to reduce its enzymatic activity, antisense oligonucleotides having any structure that can block the expression of any Escherichia gene encoding a phosphoserine phosphatase, or the expression of unknown repressors of the expression of a gene encoding a phosphoserine phosphatase, the specification only discloses disruption of an endogenous gene encoding a phosphoserine phosphatase..
The claims encompass an immense number of proteins of unknown structure as well as an immense number of unknown modifications to reduce the enzymatic activity of an endogenous Escherichia protein and increase the enzymatic activity of endogenous and exogenous enzymes. Therefore, contrary to Applicant’s assertions, in view of the fact that the specification only discloses a limited number of species of the genus of proteins required by the claimed microorganisms and methods, a limited number of methods to achieve the desired increase/decrease in activity, and the lack of description of any additional species by any relevant, identifying characteristics or properties, one of skill in the art cannot reasonably conclude that the entire scope of the claims is adequately described by the teachings of the specification and/or the prior art.
Claims 1, 5, 7-11 and 17 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 recombinant E. coli cell transformed with a nucleic acid encoding the protein of SEQ ID NO: 1, wherein said recombinant E. coli cell has a disruption in the endogenous serB gene, and has been transformed with the E. coli serA and serB genes, and a method for producing O-phosphoserine by culturing said recombinant E. coli cell, does not reasonably provide enablement for (i) a method to produce cysteine or a cysteine derivative using an O-phosphoserine sulfhydrylase having any structure, (ii) any Escherichia microorganism that expresses a variant of the polypeptide of SEQ ID NO: 1 or the polypeptide of SEQ ID NO: 1, wherein said Escherichia microorganism has been modified by any means to (a) reduce phosphoserine phosphatase activity in said microorganism, and (b) increase phosphoglycerate dehydrogenase activity and/or phosphoserine aminotransferase activity in said microorganism, (iii) a method to produce O-phosphoserine by culturing the microorganism of (ii), or (iv) a method to produce cysteine or a cysteine derivative using the microorganism of (ii) and an O-phosphoserine sulfhydrylase having any structure. 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/or use the invention commensurate in scope with these claims.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant states that independent claim 1 has been amended to recite that the Escherichia cell expresses an mtdH protein comprising SEQ ID NO: 1 or an amino acid sequence having at least 99% identity to SEQ ID NO: 1, thus rendering this rejection moot.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the rejection of claims 1, 5, 7-11 and 17. The Examiner acknowledges the amendments made to the claims. However, the Examiner disagrees with Applicant’s contention that the entire scope of the claims is fully enabled.
It is reiterated herein that as interpreted, the claims still require any number of modifications to decrease phosphoserine phosphatase activity in any Escherichia cell. In addition, the claims still require any number of modifications to increase phosphoglycerate dehydrogenase activity and/or phosphoserine aminotransferase activity in any Escherichia cell. As indicated above, this encompasses transformation of the Escherichia cell with a genus of nucleic acids encoding phosphoglycerate dehydrogenases and/or phosphoserine amino transferases having any structure, as well as unknown genetic modifications to endogenous genes encoding phosphoglycerate dehydrogenase and/or phosphoserine aminotransferase, such as unknown structural modifications to genes in any Escherichia cell that encode these enzymes to increase its expression or to increase their enzymatic activity, and the expression of unknown inducers of expression of said genes. The specification only disclose the expression of nucleic acids encoding an E. coli phosphoglycerate dehydrogenase and an E. coli phosphoserine aminotransferase as modifications to increase enzymatic activity. Moreover, claims 9-11 require O-phosphoserine sulfhydrylases having any structure. While the specification and the prior art disclose an E. coli phosphoglycerate dehydrogenase, phosphoserine phosphatase, and a phosphoserine aminotransferase, and the art discloses a limited number of O-phosphoserine sulfhydrylases, neither the specification nor the prior art disclose the structural features required in any of these enzymes, or a structure/function correlation that would allow one of skill in the art to determine which proteins have these enzymatic activities.
As previously discussed, while the claims require any number of unknown modifications to reduce the enzymatic activity of a phosphoserine phosphatase, such as unknown structural modifications to the coding region of a polynucleotide that encodes a phosphoserine phosphatase to reduce its enzymatic activity, unknown structural modifications to the region upstream from the coding region of a polynucleotide that encodes a phosphoserine phosphatase to reduce its enzymatic activity, antisense oligonucleotides having any structure that can block the expression of any Escherichia gene encoding a phosphoserine phosphatase, or the expression of unknown repressors of the expression of a gene encoding a phosphoserine phosphatase, the specification only discloses disruption of an endogenous gene encoding a phosphoserine phosphatase.
The claims encompass an immense number of proteins of unknown structure as well as an immense number of unknown modifications to reduce the enzymatic activity of an endogenous Escherichia protein and increase the enzymatic activity of endogenous and exogenous enzymes.
While methods of generating or isolating variants of a polypeptide as well as enzymatic/functional assays were 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 to find those having the desired activity. Similarly, while methods of altering the structure of a nucleic acid or a polypeptide, and detecting changes in expression were 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 all possible structural modifications to a polypeptide, a polynucleotide, and oligonucleotides to determine which ones would yield in the desired enhancement/decrease. This is not deemed routine experimentation. Therefore, contrary to Applicant’s assertions, neither the specification nor the prior art enable the entire scope of the claimed invention.
Claim Rejections - 35 USC § 102 (AIA )
Claims 1, 5, 7-11 and 17 remain rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Kim et al. (EP 3181685 published 6/21/2017; cited in the IDS) as evidenced by Blattner et al. (GenBank accession No. AAC74149 9/24/2018).
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that claim 1 has been amended and that Kim et al. do not teach a protein comprising SEQ ID NO: 1 or a protein that comprises an amino acid sequence at least 99% identical to SEQ ID NO: 1. Applicant states that the YhhS protein of Kim et al. has only 27% sequence identity to the polypeptide of SEQ ID NO: 1.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the amendments made to the claims. However, contrary to Applicant’s assertions, the cell of Kim et al. comprises a polynucleotide that encodes the polypeptide of SEQ ID NO: 1. As previously stated, Kim et al. teach an E. coli cell that has been genetically modified to have a modification in the endogenous serB gene to reduce the production of endogenous phosphoserine phosphatase (page 5, paragraphs [0034]-[0036]); page 8, Example 1, paragraph [0068]; CA07-0012). As evidenced by Blattner et al., E. coli has a nucleic acid that encodes a protein that comprises SEQ ID NO: 1. See alignment provided with the previous Office action. Therefore, the E. coli cell of Kim et al. comprises a polynucleotide encoding the polypeptide of SEQ ID NO: 1.
Claims 1, 5, and 17 as interpreted, are directed in part to a microorganism of the genus Escherichia that expresses a nucleic acid encoding a transporter, wherein said transporter comprises SEQ ID NO: 1, wherein said microorganism has a genetic modification to reduce the endogenous phosphoserine phosphatase activity compared to the corresponding microorganism of the genus Escherichia lacking said modification, wherein the Escherichia microorganism expresses a phosphoglycerate dehydrogenase and a phosphoserine aminotransferase. Claims 7-8 are directed in part to a method for producing O-phosphoserine, wherein said method comprises culturing a microorganism of the genus Escherichia that expresses a nucleic acid encoding a transporter, wherein said transporter comprises SEQ ID NO: 1, wherein said microorganism has a genetic modification to reduce the endogenous phosphoserine phosphatase activity compared to the corresponding microorganism of the genus Escherichia lacking said modification, and recovering O-phosphoserine, and claims 9-11 are directed in part to a method for producing cysteine or a cysteine derivative, wherein said method comprises culturing a microorganism of the genus Escherichia that expresses a nucleic acid encoding a transporter, wherein said transporter comprises SEQ ID NO: 1, wherein said microorganism has a genetic modification to reduce the endogenous phosphoserine phosphatase activity compared to the corresponding microorganism of the genus Escherichia lacking said modification, reacting O-phosphoserine produced by said microorganism with a sulfide in the presence of O-phosphoserine sulfhydrylase to produce cysteine, wherein said sulfide is Na2S, NaSH, (NH4)2S, H2S, or Na2S2O3, and wherein said cysteine derivative is N-acetylcysteine (NAC), S-carboxymethylcysteine (SCMC), Boc-Cys(Me)-OH, (R)-S-(2-amino-2-carboxyethyl)-L-homocysteine, (R)-2-amino-3-sulfopropionic acid, D-2-amino-4-(ethylthio)butyric acid, 3-sulfino-L-alanine, Fmoc-Cys(Boc-methyl)-OH, seleno-L-cysteine, S-(2-thiazolyl)-L-cysteine, S-(2-thienyl)-L-cysteine, or S-(4-tolyl)-L-cysteine. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
As previously stated, Kim et al. teach that the strain CA07-0012 has been transformed with vectors comprising the E. coli yhhS and mdtD (yegB) genes which encode transporters (page 10, Example 3) and the increase in the production of O-phosphoserine as a result of expressing the E. coli yhhS and mdtD genes (Table 3; 2.1 g/L and 1/8 g/L). Kim et al. also teach transforming E. coli cells with plasmids comprising the E. coli serA and serC genes, as well as the E. coli yhhS or E. coli mdtD genes (page 6, paragraphs [0044]-[0046]; page 11, Example 3-2 and Example 3-3; Table 4; pages 11-12, Table 5). Kim et al. teach a method for producing cysteine by reacting the O-phosphoserine produced with the recombinant E. coli cells with a sulfide in the presence of an O-phosphoserine sulfhydrylase (page 7, paragraphs [0057]-[0060]). Kim et al. teach a method for producing the cysteine derivatives N-acetylcysteine (NAC), S-carboxymethylcysteine (SCMC), Boc-Cys(Me)-OH, (R)-S-(2-amino-2-carboxyethyl)-L-homocysteine, (R)-2-amino-3-sulfopropionic acid, D-2-amino-4-(ethylthio)butyric acid, 3-sulfino-L-alanine, Fmoc-Cys(Boc-methyl)-OH, seleno-L-cysteine, S-(2-thiazolyl)-L-cysteine, S-(2-thienyl)-L-cysteine, and S-(4-tolyl)-L-cysteine (page 8, paragraph [0065]). Kim et al. teach that the sulfide can be Na2S, NaSH, (NH4)2S, H2S, or Na2S2O3 (page 8, paragraph [0061]). Kim et al. teach a method for the production of O-phosphoserine by culturing the recombinant microorganism that expresses the transporter and the purification of said O-phosphoserine (page 7, paragraph [0052]). Therefore, the teachings of Kim et al. anticipate the instant claims as written/interpreted.
Conclusion
No claim is in condition for allowance.
Applicant is advised that any Internet email communication by the Examiner has to be authorized by Applicant in written form. See MPEP § 502.03 (II). Without a written authorization by Applicant in place, the USPTO will not respond via Internet email to any Internet correspondence which contains information subject to the confidentiality requirement as set forth in 35 U.S.C. 122. Sample written authorization language can be found in MPEP § 502.03 (II). An Authorization for Internet Communications in a Patent Application or Request to Withdraw Authorization for Internet Communications form (SB/439) can be found at https://www.uspto.gov/patent/forms/ forms-patent-applications-filed-or-after-september-16-2012, which can be electronically filed.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
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 17, 2026
Prosecution Insights