DETAILED ACTION
Status of the Application
Claims 1, 4, 8-9, 11, 14, 17, 19-20, 22-23, 25-26, 28-31 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, 8-9, 11, 19-20, 22-23, 25-26 and cancellation of claims 12-13, as submitted in a communication filed on 6/25/2026 is acknowledged.
Claims 28-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/22/2024.
Claims 1, 4, 8-9, 11, 14, 17, 19-20, 22-23, 25-26 are at issue and will be examined to the extent they encompass the elected invention.
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Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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, 11, 19, 20 are objected to due to the recitation of “SEQ ID NO. X”. To comply with sequence rules, a colon “:” should be placed next to “NO”. The term should be amended to recite “SEQ ID NO: X”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
Claims 1, 4, 8-9, 11, 14, 17, 19-20, 22, 23, 25-26 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, 8-9, 11, 14, 17, 19-20, 22, 23, 25-26 dependent thereon) is indefinite in the recitation of “…..malonyl-CoA compared to a corresponding Corynebacterium glutamicum cell lacking the following modifications, wherein the cell with the increased….comprises the following modifications…reduced or eliminated synthase functionality of a fatty acid synthase FasB of the Corynebacterium glutamicum bacteria cell, wherein said functionality thereof is the synthase of the fatty acids, which is reduced or eliminated compared to its synthase functionality in the corresponding Corynebacterium glutamicum cell lacking said modifications ” for the following reasons.
The term “a corresponding Corynebacterium glutamicum cell lacking the following..” implies that the comparison is made with a genus of Corynebacterium glutamicum cells lacking the recited modifications. The claim does not require the comparison to be made with the corresponding unmodified Corynebacterium glutamicum cell but rather allows for the comparison to be made with a genus of Corynebacterium glutamicum cells. For example, as written, the comparison can be made with the unmodified C. glutamicum strain A or with the unmodified C. glutamicum strain B. The basis for comparison is variable, thus making the determination as to what is included or excluded from the scope of the claims impossible. A C. glutamicum cell may or may not be within the scope of the claim depending on what is used as basis for comparison. For example, a modified C. glutamicum cell X may be encompassed by the claims if the comparison is made with unmodified C. glutamicum strain A but may not meet the limitations recited if the comparison is made with unmodified C. glutamicum strain B. If the intended comparison is with the corresponding C. glutamicum cell (same strain) lacking the modifications, the claim should be amended accordingly.
The term “corresponding Corynebacterium glutamicum cell lacking the following modifications, wherein…” is unclear because there are no modifications recited that follow the term “following modifications”. Therefore, it is unclear as to which are the modifications that should be lacking in the corresponding Corynebacterium glutamicum cell.
The term “reduced or eliminated synthase functionality of a fatty acid synthase FasB of the Corynebacterium glutamicum bacteria cell, wherein said functionality thereof is the synthase of fatty acids” is unclear because a synthase is an enzyme, thus fatty acids do not have a synthase. The term “synthase of fatty acids” is completely unclear. As such, one cannot determine which is the synthase functionality that should be reduced or eliminated. If the intended modification is a mutation, partial deletion or complete deletion of the endogenous C. glutamicum fasB gene to reduce or eliminate the synthase activity of the C. glutamicum FasB protein compared to the corresponding C. glutamicum cell lacking the mutation, partial deletion or complete deletion of the C. glutamicum fasB gene, the claim should be amended accordingly. Correction is required.
Claim 1 (claims 4, 8-9, 11, 14, 17, 19-20, 22, 23, 25-26 dependent thereon) is indefinite in the recitation of “reduced or eliminated functionality of the operator binding sites fasO for a Corynebacterium glutamicum bacterium regulator FasR in the promoter regions of the Corynebacterium glutamicum bacterium accBC and accD1 genes coding for acetyl-CoA carboxylase subunits compared to its functionality in the corresponding Corynebacterium glutamicum lacking said modification by mutation of the motif fasO in the binding site for the Corynebacterium glutamicum FasR transcriptional regulator in the Corynebacterium glutamicum accBC and accD1 genes, wherein said functionality is for encoding said acetyl-CoA carboxylase subunits; derepressed expression of the….accBC and accD1 genes coding for…compared with the expression in the corresponding…cell lacking said modification” for the following reasons. While the fasO motif is found in the binding site for the C. glutamicum FasR transcription regulator, wherein said binding site is within the promoter region of the C. glutamicum accD1 and accBC genes, the functionality of the fasO motif is not to encode the acetyl-CoA carboxylase subunits. If the intended modification is “a mutation in the endogenous accBC and accD1 genes that alters the structure of the fasO motif in the binding site for the C. glutamicum FasR transcriptional regulator present in the endogenous accBC and accD1 genes, wherein said mutation blocks the binding of the FasR transcriptional regulator to the accBC and accD1 genes”, the claim should be amended accordingly. Correction is required.
Claim 1 (claims 4, 8-9, 11, 14, 17, 19-20, 22, 23, 25-26 dependent thereon) is indefinite in the recitation of “reduced functionality of a promoter operably linked to the ….gltA gene thereby reducing expression of the gltA gene…compared to tis expression in the corresponding ….cell lacking the modification by mutation to the endogenous promoter of the …gltA gene to reduce the expression of said gene…wherein said functionality is for synthesis of the citrate synthase CS” for the following reasons. While a promoter is a regulatory DNA region placed upstream of a coding nucleic acid which recruits transcription factors and an RNA polymerase to start transcription, a promoter does not synthesize the protein encoded by the coding nucleic acid. If the intended limitation is “a mutation to the endogenous promoter of the C. glutamicum gltA gene to reduce or eliminate the expression of the endogenous C. glutamicum gltA gene, compared to the expression of the endogenous gltA gene in the corresponding C. glutamicum cell lacking the mutation”, the claim should be amended accordingly. Correction is required.
Claim 8 is indefinite in the recitation of “fatty acid synthase FasB whose functionality….wherein the FasB amino acid sequence with reduced or turned off functionality has at least …” for the following reasons. It is unclear as to which is the functionality being referred to as it relates to the fatty acid synthase FasB since a protein can have more than one function. In addition, there is no antecedent basis for the FasB amino acid sequence. Furthermore, as known in the art, an amino acid sequence is the graphical representation of the order in which amino acids are arranged in a protein. Therefore, an amino acid sequence cannot have functionality. It is noted that the proteins of SEQ ID NO: 2, 4, 6 and 8 appear to be full length proteins while the protein of SEQ ID NO: 10 appears to a variant of the polypeptide of SEQ ID NO: 2 that results from the deletion of amino acids 9-2981 of the polypeptide of SEQ ID NO: 2. For examination purposes, it will be assumed that claim 8 is a duplicate of claim 1. Correction is required.
Claim 9 is indefinite in the recitation of “..coding for a fatty acid synthase FasB from C. glutamicum bacteria selected from the group consisting of: a. a nucleic acid sequence….at least 95% identity to the nucleic acid sequence selected from the group consisting of SEQ ID NO: 1…and 9, b. a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1…and 9, and c. a nucleic acid sequence coding for a …FasB according to SEQ ID NO: 2…or 10” for the following reasons. As written, it is unclear if the recited nucleic acid sequences for the polynucleotide that encodes the FasB are the nucleic acid sequences of the polynucleotide that encodes the FasB before or after the modification. As indicated in claim 1, the FasB endogenous enzymatic activity is reduced or eliminated by mutation or partial/complete deletion of the fasB gene. Therefore, it is unclear if the recited nucleic acid sequences are those of the fasB gene after the modification or prior the modification. Also, the term “according to SEQ ID NO: 2…” is unclear because one cannot determine if the term is intended to be equivalent to “FasB comprising SEQ ID NO: 2..”, or if the term “according to SEQ ID NO: 2…” is merely exemplary (i.e.., like SEQ ID NO: 2…). For examination purposes, claim 9 will be interpreted as a duplicate of claim 1. Correction is required.
Claim 11 is indefinite in the recitation of “…wherein the cell has the modifications a. the reduced or eliminated functionality of a …fatty acid synthase FasB compared with its functionality in the corresponding…cell lacking the modification, wherein the FasB amino acid sequence with reduced or eliminated functionality has at least 95% identity to an amino acid sequence selected from….b. the mutation or partial or complete deletion of the…fasB, wherein the fasB nucleic acid sequence has at least 95% identity to the nucleic acid sequence selected from the group consisting of…c. the reduced functionality of the promoter operably linked to the citrate synthase gltA gene….compared with its functionality in the corresponding…cell lacking the modification, wherein the promoter nucleic acid sequence comprises SEQ ID NO: 11; and d. the reduced or eliminated functionality of the operator binding sites fasO for the regulators FasR in the promoter regions of the accBC and accD1 genes from….compared with their functionality in the corresponding …glutamicum cell lacking the modification, wherein the nucleic acid sequences of the accBC and accD1 promoter regions comprise SEQ ID NO: 13…” for the following reasons.
Claim 1 requires a mutation or a partial deletion of the fasB gene in the C. glutamicum cell to obtain the reduction or elimination of the functionality of the FasB. Claim 11 appears to require two modifications a. and b., namely any modification to reduce/eliminate the functionality of the FasB protein as well as a mutation/deletion of the fasB gene. Therefore, the scope of claim 11 is broader than the scope of claim 1. Similarly, while item c. requires any modification to reduce the functionality of the gltA gene, claim 1 requires mutation of the promoter of the gltA gene to reduce the functionality of the gltA gene. Therefore, the scope of claim 11 is broader than the scope of claim 1. Moreover, while item d. requires any modification to reduce the functionality of the fasO motif, claim 1 requires a mutation of the fasO motif to reduce its functionality. Therefore, the scope of claim 11 is broader than the scope of claim 1.
The term “FasB amino acid sequence with reduced or eliminated functionality has…” is unclear because an amino acid sequence is the graphical representation of the order in which amino acids are arranged in a protein, thus it does not have any functionality. Furthermore, as written, it is unclear if (i) the sequence identity requirement in item b. is that of the fasB gene before or after the modification, (ii) the sequence limitation of the promoter of the gltA gene is that of the promoter of the gltA gene before or after the modification, and (iii) the sequence limitation of the promoter regions of the accBC and accD1 genes is that of the accBC and accD1 genes before or after the modification. For examination purposes, it will be assumed that claim 11 is a duplicate of claim 1. Correction is required.
Claim 14 is indefinite in the recitation of “The Coryneform glutamicum bacteria cell according to claim 1, wherein the cell is …ATCC 13032” for the following reasons. As written, it is unclear if the ATCC 13032 strain is the corresponding unmodified Coryneform glutamicum or if the Coryneform glutamicum ATCC 13032 strain is the modified Coryneform glutamicum cell of the preamble of claim 1. For examination purposes, claim 14 will be interpreted as a duplicate of claim 1. Correction is required.
Claim 17 is indefinite in the recitation of “wherein the cell comprises E. coli genes coding for a…synthase (aroH) and for a Flavobacterium….lyase (tal)” for the following reasons. The term appears to indicate that the genes encoding the 3-deoxy-D-arabinoheptulosonate-7-phosphate synthase and tyrosine ammonium lyase are E. coli genes, thus it is unclear as to how the gene encoding the tyrosine ammonium lyase can be from F. johnsoniae. For examination purposes, it will be assumed that the cell of claim 17 requires an E. coli gene encoding a feedback-resistant 3-deoxy- D-arabinoheptulosonate-7-phosphate synthase and a F. johnsoniae gene encoding a tyrosine ammonium lyase. Correction is required.
Claim 19 is indefinite in the recitation of “wherein the cell comprises a protein of a 4-coumarate CoA ligase; wherein the amino acid sequence of the protein has….to the amino acid sequence according to SEQ ID NO: 22” for the following reasons. A ligase is a protein. Therefore, it is unclear as to what “a protein of a ligase” is. In addition, even if one assumes that the claim requires a cell that comprises a 4-coumarate CoA ligase having the recited % sequence identity to the protein of SEQ ID NO: 22, it is unclear if the claim is limiting the P. crispum 4cl gene of claim 1 to one that encodes a 4-coumarate CoA ligase having the recited % sequence identity to the protein of SEQ ID NO: 22, or if the claim further requires a protein having the recited % sequence identity which is unrelated to the protein encoded by the P. crispum 4cl gene of claim 1. The term “according to SEQ ID NO: 22” is unclear because one cannot determine if the term is intended to be equivalent to “amino acid sequence of SEQ ID NO: 22”, or if the term “according to SEQ ID NO: 22” is merely exemplary (i.e.., like SEQ ID NO: 22). For examination purposes, it will be assumed that the P. crispum 4cl gene encodes a 4-coumarate CoA ligase that has at least 95% sequence identity to the polypeptide of SEQ ID NO: 22. Correction is required.
Claim 20 is indefinite in the recitation of “…a. a nucleic acid sequence …according to SEQ ID NO: 19….b. a nucleic acid sequence according to SEQ ID NO: 19, or c. a nucleic acid sequence …corresponding to each of the nucleic acids in accordance with a)-b) which is adapted to the codon usage of coryneform bacteria; and d. a nucleic acid sequence coding….according to SEQ ID NO: 20” for the following reasons. As written, it is unclear if the claim requires (i) all of a., b., c., and d., (ii) one of a., b., c., or d., (iii) a., b., or, the combination of c. and d. together. In addition, the term “according to SEQ ID NO: X” is unclear because one cannot determine if the term is intended to be equivalent to “nucleic acid sequence of SEQ ID NO: X” or “nucleic acid sequence comprising SEQ ID NO: X”, or if the term “according to SEQ ID NO: X” is merely exemplary (i.e.., like SEQ ID NO: X). For examination purposes, claim 20 will be interpreted as requiring only one of a., b., c., or d., and the term “according to SEQ ID NO: X” will be interpreted as “nucleic acid sequence comprising SEQ ID NO: X” or “nucleic acid sequence of SEQ ID NO: X”. Correction is required.
Claim 23 is indefinite in the recitation of “…gene according to SEQ ID NO: 21” for the following reasons. The term “according to SEQ ID NO: 21” is unclear because one cannot determine if the term is intended to be equivalent to “gene comprising SEQ ID NO: 21”, or if the term “according to SEQ ID NO: 21” is merely exemplary (i.e.., like SEQ ID NO: 21). For examination purposes, it will be assumed that the claim reads “…gene comprising SEQ ID NO: 21”. Correction is required.
Claim 25 is indefinite in the recitation of “…gene according to SEQ ID NO: 21…sts gene according to SEQ ID NO: 23, …..chs gene according to SEQ ID NO: 25 and…chi gene according to SEQ ID NO: 27…a pcsshort gene according to SEQ ID NO: 19” for the following reasons. The term “according to SEQ ID NO: X” is unclear because one cannot determine if the term is intended to be equivalent to “gene of SEQ ID NO: X” or “gene comprising SEQ ID NO: X”, or if the term “according to SEQ ID NO: X” is merely exemplary (i.e.., like SEQ ID NO: X). In addition, it is unclear if the C. glutamicum bacteria cell of claim 25 is required to comprise two pcs genes, an A. arborescens pcs gene as well as a pcsshort gene that comprises SEQ ID NO: 19, or if the A. arborescens pcs gene of claim 1 is the pcsshort gene required to comprise SEQ ID NO: 19. If the intended limitation is a C. glutamicum cell that comprises a pcs gene that comprises SEQ ID NO: 19 and not two pcs genes, claims 1 and 25 should be amended accordingly, making sure that the proper antecedent basis is provided. For examination purposes, it will be assumed that the claim reads “…gene comprising SEQ ID NO: 21 and an A. hypogea sts gene comprising SEQ ID NO: 23,…..chs gene comprising SEQ ID NO: 25 and a Petunia x hybrida chi gene comprising SEQ ID NO: 27…and a gene comprising SEQ ID NO: 19”. Correction is required.
Claim 26 is indefinite in the recitation of “…an Aloe arborescens derived gene pcsshort according to SEQ ID NO: 19 coding for a protein with an increased …synthase activity for the synthesis of polyketides compared to the presence of a pcs gene..” for the following reasons. The term “according to SEQ ID NO: 19” is unclear because one cannot determine if the term is intended to be equivalent to “gene comprising SEQ ID NO: 19”, or if the term “according to SEQ ID NO: 19” is merely exemplary (i.e.., like SEQ ID NO: 19). In addition, the term “compared to the presence of a pcs gene” is unclear because one cannot determine how one could compared synthase activity for the synthesis of polyketides with the presence of a gene. Moreover, the term “a pcs gene” implies that the comparison is made with a genus of genes. The claim does not require the comparison to be made with a single pcs gene but rather allows for the comparison to be made with a genus of pcs genes. For example, as written, the comparison can be made with a pcs gene that comprises SEQ ID NO: X or with a pcs gene that comprises SEQ ID NO: Y. The basis for comparison is variable, thus making the determination as to what is included or excluded from the scope of the claims impossible. A C. glutamicum cell may or may not be within the scope of the claim depending on what is used as basis for comparison. Furthermore, since claim 1 requires an A. arborescens pcs gene, it is unclear if the C. glutamicum bacteria cell of claim 26 requires two pcs genes, a wild type A. arborescens pcs gene as well as a pcs gene that comprises SEQ ID NO: 19. If the intended limitation is a C. glutamicum cell that comprises a pcs gene that comprises SEQ ID NO: 19 and not two pcs genes, claims 1 and 26 should be amended accordingly, making sure that the proper antecedent basis is provided. For examination purposes, it will be assumed that claim 26 requires a gene that comprises SEQ ID NO: 19, a C. glutamicum aroF1 gene and a C. glutamicum tal gene. 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, 8-9, 11, 14, 17, 19-20, 22, 23, 25-26 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 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 as amended clearly comply with the written description requirement insofar as (a) claim 1 has been amended to refer to specific genes instead of “enzymes derived from plants or genes encoding them for polyphenol or polyketide synthesis, (b) claims 19-20 now recite functions for the proteins of the recited amino acid sequences and (c) claim 1 as amended set forth the functionalities of the recited genes, operator binding sites, promoters and proteins which are modified.
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, even if we set aside the issues of indefiniteness set forth above, and assume that the C. glutamicum cell is required to (a) have (i) a mutation in the endogenous fasB gene to reduce/eliminate the synthase activity of the endogenous FasB protein, (ii) a mutation in the promoter of the endogenous gltA gene to reduce/eliminate the expression of the endogenous gltA gene, and (iii) a mutation in the endogenous accBC and accD1 genes that alters the structure of the fasO motif in the binding site for the C. glutamicum FasR transcriptional regulator present in the endogenous accBC and accD1 genes, wherein said mutation blocks the binding of the FasR transcriptional regulator to the accBC and accD1 genes, (b) comprise one or more genes selected from the group consisting of a P. crispum 4cl gene that encodes a 4-coumarate-CoA ligase, an A. hyposea sts gene that encodes a stilbene synthase, a Petunia x hybrida chi gene encoding a chalcone isomerase, a Petunia x hybrida chs gene encoding a chalcone synthase, and an Aloe arborescens gene encoding a 5,7-dihydroxy-2-methylchromone synthase, and (c) comprise deletions in the endogenous C. glutamicum phdBCDE operon, endogenous cat gene, endogenous ben gene, endogenous pca gene, endogenous pobA gene and endogenous qsuB gene, the claims still require a genus of modifications to derepress the expression of the endogenous C. glutamicum accBC and accD1 genes. Please note that claim 1 does not state that the modification made to the fasO motif results in derepressed expression of the C. glutamicum accBC and accD1 gene. Thus, claim 1 and dependent claims require the mutation of the fasO motif as well as any modification to obtain the recited derepressed expression. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
As previously indicated, the derepression of the accBC and accD1 genes encompasses, for example, the expression of antisense molecules of unknown structure that would block the expression of a repressor of these genes, the addition of chemicals that would block repressors of the expression of the recited genes, or the expression of proteins that can block the repressors of the expression of these C. glutamicum genes. The specification and the prior art are silent regarding these repressors, chemical compounds, or antisense molecules. Therefore, contrary to Applicant’s assertions, 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 1-2, 4, 8-9, 11-23, 25-26 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 C. glutamicum cell that comprises (i) a disruption in the endogenous fasB gene and/or the endogenous gltA gene, (ii) a disruption in the endogenous phdBCDE operon, endogenous cat gene, endogenous ben gene, endogenous pca gene, endogenous pobA gene, and endogenous qsuB gene, (iii) a mutation that alters the structure of the fasO motif in the promoter region of the C. glutamicum accBC and accD1 genes, wherein said mutation blocks the binding of the C. glutamicum FasR transcriptional regulator to the C. glutamicum accBC and accD1 genes, (iv) an E. coli gene encoding a feedback resistant DAHP synthase and a Flavobacterium johnsoniae gene encoding a tyrosine ammonium lyase, (v) a nucleic acid encoding the P. crispum 4-coumarate-CoA ligase of SEQ ID NO: 22, and a nucleic acid encoding the A. hypogea stilbene synthase of SEQ ID NO: 24, (vi) nucleic acids encoding the P. hybrida chalcone synthase of SEQ ID NO: 26, and the P. hybrida chalcone isomerase of SEQ ID NO: 28, and (vii) a nucleic acid encoding the 5,7-dihydroxy-2-methylchromone synthase of SEQ ID NO: 20, does not reasonably provide enablement for a C. glutamicum cell that has been modified by any means to (a) reduce the synthase activity of the endogenous C. glutamicum FasB protein, including any genetic modification to reduce the expression of the endogenous C. glutamicum fasB gene, (b) reduce the expression of the endogenous C. glutamicum gltA gene, (c) derepress the endogenous C. glutamicum accBC and accD1 genes, or (d) alter the ability of the endogenous promoter of the C. glutamicum gltA gene to initiate expression of said gene, wherein said C. glutamicum cell further expresses a P. crispum 4cl gene that encodes a 4-coumarate-CoA ligase, an A. hyposea sts gene that encodes a stilbene synthase, a Petunia x hybrida chs gene encoding a chalcone synthase, a Petunia x hybrida chi gene encoding a chalcone isomerase, and an Aloe arborescens gene encoding a 5,7-dihydroxy-2-methylchromone synthase. 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 in view of the amendments discussed above with regard to the written description rejection, the pending claims as amended are fully enabled.
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, as explained above, even if we assume that the C. glutamicum cell is required to (a) have (i) a mutation in the endogenous fasB gene to reduce/eliminate the synthase activity of the endogenous FasB protein, (ii) a mutation in the promoter of the endogenous gltA gene to reduce/eliminate the expression of the endogenous gltA gene, and (iii) a mutation in the endogenous accBC and accD1 genes that alters the structure of the fasO motif in the binding site for the C. glutamicum FasR transcriptional regulator present in the endogenous accBC and accD1 genes, wherein said mutation blocks the binding of the FasR transcriptional regulator to the accBC and accD1 genes, (b) comprise one or more genes selected from the group consisting of a P. crispum 4cl gene that encodes a 4-coumarate-CoA ligase, an A. hyposea sts gene that encodes a stilbene synthase, a Petunia x hybrida chi gene encoding a chalcone isomerase, a Petunia x hybrida chs gene encoding a chalcone synthase, and an Aloe arborescens gene encoding a 5,7-dihydroxy-2-methylchromone synthase, and (c) comprise deletions in the endogenous C. glutamicum phdBCDE operon, endogenous cat gene, endogenous ben gene, endogenous pca gene, endogenous pobA gene and endogenous qsuB gene, the claims still require any number of modifications to derepress the expression of the endogenous C. glutamicum accBC and accD1 genes. It is reiterated herein that claim 1 does not state that the modification made to the fasO motif results in derepressed expression of the C. glutamicum accBC and accD1 gene. Thus, claim 1 and dependent claims require the mutation of the fasO motif as well as any modification to obtain the recited derepressed expression. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
As previously indicated, the derepression of the accBC and accD1 genes encompasses, for example, the expression of antisense molecules of unknown structure that would block the expression of a repressor of these genes, the addition of chemicals that would block repressors of the expression of the recited genes, or the expression of proteins that can block the repressors of the expression of these C. glutamicum genes. The specification and the prior art are silent regarding these repressors, chemical compounds, or antisense molecules. In the absence of a rational and predictable scheme for selecting those genetic modifications, chemicals, proteins or nucleic acids that would result in the derepressed expression of the desired genes, one of skill in the art would have to test an essentially infinite number of genes, proteins, genetic modifications and compounds to enable the entire scope of the claimed invention. Therefore, contrary to Applicant’s assertions, the entire scope of the claims is not fully enabled by the teachings of the specification and/or the prior art.
Claim Rejections - 35 USC § 103 (AIA )
Claims 1, 4, 8-9, 11-14, 17, 19, 22, 25 remain rejected under 35 U.S.C. 103 as being unpatentable over Kallscheuer et al. (Metabolic engineering 38:47-55, 2016; cited in the IDS) in view of Radmacher et al. (Microbiology 151:2421-2427, 2005; cited in the IDS), van Ooyen et al. (Journal of Biotechnology 154:140-148, 2011), Eikmanns et al. (Microbiology 140:1817-1828, 1994), Nickel et al. (Molecular Microbiology 78(1):253-265, 2010), and Yoon et al. (Biotechnology and Bioengineering 115:2067-2074, August 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 states that for the reasons stated in the response of 5/2/2025, none of the references previously cited, either alone or in combination, disclose or suggest the features of independent claim 1. Applicant states that none of the references disclose or suggest a C. glutamicum bacteria cell with the recited modifications and an increased provision of malonyl-CoA compared to a corresponding C. glutamicum cell lacking the recited modifications. Applicant submits that the position that the cited references disclose or suggest a cell with increased provision of malonyl-CoA compared to wildtype appears to be built upon speculation unsupported by evidence. According to Applicant, none of the cited references disclose that any of the modifications recited in claim 1 lead to an increased intracellular amount of malonyl-CoA. Applicant states that the Office makes a number of assumptions to arrive to the desired conclusion. Applicant states that the Office is attempting to take official notice of an alleged fact, i.e., increasing levels of acetyl-CoA will lead to an increase in malonyl-CoA levels. Applicant also submits that the Office is attempting to take official notice of the alleged fact that malonyl-CoA level will increase by reduction or elimination of FasB activity. Applicant refers to the teachings of Radmacher et al. in support of the argument that this reference does not teach that reduction of FasB activity will increase malonyl-CoA levels. Applicant states that should the Office continue to maintain these assertions, Applicant requests an affidavit of the appropriate employee’s of the USPTO sufficient to document this element of the rejection and supply the required evidentiary support. Applicant states that for the same reasons, there has been no showing that a person of ordinary skill in the art would have had a reasonable expectation that a Corynebacterium glutamicum bacteria cell with the modifications recited in claim 1 as amended would have an increased intracellular amount of malonyl-CoA.
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, the Examiner disagrees with Applicant’s contention that the claimed invention is not obvious over the cited prior art.
With regard to the argument that none of the cited references disclose that any of the modifications recited in claim 1 lead to an increased intracellular amount of malonyl-CoA and that the Office makes a number of assumptions to arrive to the desired conclusion, it is noted that contrary to Applicant’s assertions, the cited references clearly suggest that a C. glutamicum cell with the recited modifications could produce higher levels of malonyl-CoA compared to the corresponding C. glutamicum cell lacking the recited modifications. Kallscheuer et al. teach that future optimization efforts for the production of polyphenols should focus on increasing the intracellular malonyl-CoA pool, by, for example, increasing the expression of genes encoding the dimeric acetyl-CoA carboxylase (AccBC-AccD1) in C. glutamicum since this strategy has been found successful for the production of stilbene and (2S) flavone in E. coli and S. cerevisiae (page 54 second full paragraph). Nickel et al. teach that mutations in the promoter region of the accD1 and accBC genes that would inhibit the binding of the negative regulator FasR would allow the deregulated expression of the genes encoding acetyl-CoA carboxylase. Therefore, contrary to Applicant’s assertions, the prior art teaches that the mutation to the fasO motif in the genes encoding acetyl-CoA carboxylase would increase the expression (deregulate the expression) of the genes encoding acetyl-CoA carboxylase (accBC and accD1), which is an action that would result in an increase in acetyl-CoA levels according to Kallscheuer et al. As such, the combination of the teachings of Kallscheuer et al. and Nickel et al. would result in the accumulation of acetyl-CoA based on the teachings of Kallscheuer et al. regarding the effect of increasing the expression of the accD1 and accBC genes in malonyl-CoA levels.
With regard to the argument that the Office is attempting to take official notice of an alleged fact, i.e., increasing levels of acetyl-CoA will lead to an increase in malonyl-CoA levels, it is noted that the Examiner has not indicated that it is a fact that the increase in acetyl-CoA results in an increase in malonyl-CoA. Instead, the Examiner has shown that it is a fact, based on the teachings of Yoon et al., that acetyl-CoA is a precursor of malonyl-CoA, acetyl-CoA carboxylase catalyzes the conversion of acetyl-CoA to malonyl-CoA, and that acetyl-CoA is also a substrate for the production of citrate. Please note that Eikmanns et al. teach that citrate synthase (encoded by the gltA gene) uses acetyl-CoA as s substrate for the synthesis of citrate. The Examiner has previously indicated that those mutations that would reduce or eliminate the expression of genes encoding enzymes that catalyze the conversion of acetyl-CoA into other metabolites, such as the C. glutamicum gltA gene, would be highly desirable because an enzyme that consumes acetyl-CoA, which is a precursor of malonyl-CoA, as a substrate is no longer able to consume it. The Examiner has simply provided a reasoned statement as to why one of skill in the art would have been motivated to inactivate the expression of the gltA gene, which is a gene that encodes an enzyme that uses acetyl-CoA to produce a metabolite (citrate) which is not malonyl-CoA. As stated in MPEP § 2143(G), the courts have made clear that the teaching, suggestion, or motivation test is flexible and an explicit suggestion to combine the prior art is not necessary. The motivation to combine may be implicit and may be found in the knowledge of one of ordinary skill in the art, or, in some cases, from the nature of the problem to be solved. While one could argue that there is no absolute certainty that inactivation of the expression of the gltA gene would result in the accumulation of malonyl-CoA, the obviousness analysis does not require absolute certainty but rather a reasonable expectation of success. The Examiner has merely provided a motivation to combine the references and arrive to the claimed invention and has also provided reasons as to why there is a reasonable expectation of success to arrive to the claimed invention. Therefore, contrary to Applicant’s assertions, the Office is not attempting to take official notice of an alleged fact.
With regard to the argument that the Office is attempting to take official notice of the alleged fact that malonyl-CoA level will increase by reduction or elimination of FasB activity, and that Radmacher et al. do not teach that reduction of FasB activity will increase malonyl-CoA levels, it is noted that (i) the Examiner has not indicated that it is a fact that malonyl-CoA levels will increase by reduction or elimination of FasB activity, and (ii) the Examiner has previously acknowledged that Radmacher et al. do not specifically state that reduction of FasB activity will increase malonyl-CoA levels. The Examiner previously provided a reasoned statement as to why one of skill in the art would have been motivated to inactivate FasB and why one of skill in the art would have reasonably concluded that the inactivation of the fasB gene could lead to an increase in malonyl-CoA. As known in the art and also taught by Radmacher et al., FAS-I enzymes such as FasB use malonyl-CoA as a substrate (page 2426, right column, last three lines). While it is agreed that Radmacher et al. do not specifically teach the effect of the fasB deletion on malonyl-CoA levels, one of skill in the art would reasonably expect that the level of malonyl-CoA would increase because an enzyme that uses malonyl-CoA (FasB) is no longer active to consume it. As previously indicated, there is no evidence to suggest that the level of biosynthesis of fatty acids from malonyl-CoA with only FasA present is absolutely unchanged, such that the consumption of malonyl-CoA is exactly the same as if FasB were to be present. Since Kallscheuer et al. teach that blocking the biosynthesis of fatty acids from malonyl-CoA allows for an increase in the intracellular malonyl-CoA pool, inactivating mutations in genes encoding fatty acid synthases is desirable. As previously indicated, one of skill in the art would have been highly motivated to delete the fasB gene because by doing so, an enzyme that consumes the desired precursor, malonyl-CoA, is no longer active, and growth is not affected. Please note that the fact that growth is not affected by a deletion in the fasB gene is an advantage. It is reiterated herein that the courts have made clear that the teaching, suggestion, or motivation test is flexible and an explicit suggestion to combine the prior art is not necessary. The motivation to combine may be implicit and may be found in the knowledge of one of ordinary skill in the art, or, in some cases, from the nature of the problem to be solved. Furthermore, while one could argue that there is no absolute certainty that inactivation of the expression of the fasB gene would result in the accumulation of malonyl-CoA, the obviousness analysis does not require absolute certainty but rather a reasonable expectation of success. The Examiner has simply provided a motivation to combine the cited references to arrive to the claimed invention and a reasoned statement as to why there is a reasonable expectation of success. As such, contrary to Applicant’s assertions, the Office is not attempting to take official notice of an alleged fact.
Therefore, for the reasons of record and those set forth above, one of skill in the art would conclude that the claimed invention is obvious over the cited prior art.
Conclusion
No claim is in condition for allowance.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a). A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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.
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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
September 14, 2026
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