DETAILED ACTION
Status of the Application
Claims 1, 25, 54-59, 61-65, 67, 108, 113, 119, 161 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, 25, 54-57, 59, 61-65, 67, 113, 119, 161, cancellation of claims 60, 120 and amendments to the specification as submitted in a communication filed on 4/13/2026 is acknowledged.
Applicant elected with traverse Group III, claims 1, 25, 54-65, 67, 161, drawn in part to a genetically modified cell capable of producing 6-aminocaproic acid (6ACA), and further elected a genetic modification that decreases the activity of an oxidoreductase acting on an aldehyde or oxo moiety (A1), spermidine and octanol as a single combination of byproducts from Table 10 or Table 11, PA6 as the single combination of polymers, and the 6ACA production pathway from Figure 1 (steps A, B, C, D, N, O, P), in a communication filed on 7/28/2025.
Claims 108, 113, 119 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 7/28/2025.
Claims 1, 25, 54-59, 61-65, 67, 161 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Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Specification
The first paragraph of the specification was objected to because it did not provide the current status of related applications. In view of Applicant’s amendment, this objection is hereby withdrawn.
The title of the invention was objected as being non-descriptive. In view of Applicant’s amendments, this objection is hereby withdrawn.
Claim Objections
Claim 1 is objected to due to the recitation of “wherein said genetically modified cell comprises a genetic modification that provides an enzymatic activity that is one or both of 6-aminocaproate transaminase activity and 6-aminocaproate dehydrogenase activity”. The term should be amended to recite “wherein said genetically modified cell comprises a genetic modification that provides the cell with one or both of 6-aminocaproate transaminase activity and 6-aminocaproate dehydrogenase activity”. Appropriate correction is required.
Claim Rejections – Improper Markush Grouping
Claims 1, 25, 59-65, 161 and dependent claims 54-58, 67 were rejected on the basis that they contain an improper Markush grouping of alternatives. In view of the amendment of claims 1, 25, 59, 61-65, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
Claims 1, 25, 54-59, 61-65, 67, 161 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 25, 54-59, 61-65, 67, 161 dependent thereon) is indefinite in the recitation of “..genetic modification that decreases activity of an oxidoreductase acting on adipate semialdehyde, wherein said oxidoreductase comprises an enzyme catalyzing conversion of adipate semialdehyde to 6-hydroxyhexanoate and adipate; and (b) a genetic modification that decreases activity of an oxidoreductase catalyzing conversion of 5-carboxy-2-pentenoyl-CoA to 5-carboxy-2-pentenal..” for the following reasons. The term “decreases” is a relative term and the claim fails to provide the reference required to determine a decrease. If the intended limitation is “…a genetic modification to reduce the enzymatic activity of an endogenous oxidoreductase that catalyzes the conversion of adipate semialdehyde to 6-hydroxyhexanoate and adipate compared to the enzymatic activity of said endogenous oxidoreductase in the same cell lacking said genetic modification; (b) a genetic modification to reduce the enzymatic activity of an endogenous oxidoreductase that catalyzes the conversion of 5-carboxy-2-….to 5-carboxy-2-pentenal compared to the enzymatic activity of said endogenous oxidoreductase in the same cell lacking said genetic modification…”, the claim should be amended accordingly. Correction is required.
Claim 1 (claims 25, 54-59, 61-65, 67, 161 dependent thereon) is indefinite in the recitation of “..when compared to a corresponding cell lacking said one or more genetic modifications…” for the following reasons. The term “a corresponding cell” encompasses a genus of “corresponding cells” in view of the recitation of “a”. The claim does not require the comparison to be made with the same cell of the preamble (i.e., same genus/species) lacking the genetic modifications but rather allows for the comparison to be made with any cell lacking the genetic modifications. For example, as written, the comparison can be made between an E. coli strain X cell having the genetic modifications and a wild type E. coli strain Y cell lacking the genetic modifications. The basis for comparison is variable, thus making the determination as to what is encompassed and not encompassed by the claim impossible. For example, cell X may be encompassed by the claim if the comparison is made with cell Y but may not be encompassed by the claim if the comparison is made with cell Z. For examination purposes, it will be assumed that the claim reads “when compared to the same cell lacking the one or more genetic modifications”. Correction is required.
Claim 25 is indefinite in the recitation of “wherein said cell produces 6ACA comprising a reduced level of one or more byproducts selected from 6-hydroxyhexanoate and adipate” for the following reasons. Claim 1, from which claim 25 depends, requires the cell that produces 6ACA to produce a reduced amount of 6-hydroxyhexanoate and/or adipate. Therefore, since this limitation appears to be required by claim 1, it is unclear as to how claim 25 further limits claim 1. Correction is required.
Claim 54 is indefinite in the recitation of “wherein reducing the amount of said byproduct increases the yield of 6ACA” for the following reasons. As known in the art, reducing the production of a byproduct would inherently increase the yield of the desired product. Therefore, it is unclear as to how this limitation further limits the claimed cell. For examination purposes, claim 54 will be interpreted as a duplicate of claim 1. Correction is required.
Claim 55 is indefinite in the recitation of “wherein said byproduct decreases the yield of 6ACA” for the following reasons. As known in the art, the production of a byproduct would inherently decrease the yield of the desired product. Therefore, it is unclear as to how this limitation further limits the claimed cell. For examination purposes, claim 55 will be interpreted as a duplicate of claim 1. Correction is required.
Claim 56 is indefinite in the recitation of “wherein said byproduct increases the degradation of a polymer comprising 6ACA” for the following reasons. The term “increases” is a relative term and the claim fails to provide the reference to determine if an increase is present (i.e., increased compared to what?). In addition, the degradation of a polymer comprising 6ACA by the byproduct is a functional limitation associated with the byproduct and not of the cell. Please note that even if the argument is made that this functional limitation further limits the byproduct produced by the cell, the byproduct has been already defined in claim 1. For examination purposes, claim 56 will be interpreted as a duplicate of claim 1. Correction is required.
Claim 57 (claims 58-59 dependent thereon) is indefinite in the recitation of “wherein said byproduct inhibits polymerization of 6ACA to a polymer in a polymerization reaction” for the following reasons. It appears that this limitation intend to limit the byproduct to a specific compound. However, claim 1 already defines the byproduct to 6-hydroxyhexanoate and/or adipate. Therefore, it is unclear as to how claim 57 further limits claim 1. For examination purposes, claim 57 will be interpreted as a duplicate of claim 1. Correction is required.
Claims 61-63 are indefinite in the recitation of “greater than about” for the following reasons. The term “about” encompasses a range which includes values which are higher and lower than the recited reference value (e.g., 5 %, 99%). The term “greater than” implies that only values higher than the recited reference value are encompassed. Therefore, in the absence of a clear definition of what is encompassed by the term “about”, the term "greater than about" is unclear and confusing since the term refers to values which are higher than undefined values which are either higher or lower than the recited reference value. In essence, the term eliminates the relevance of the recited reference point because the reference value associated with “greater than” (e.g., 5 %, 99%) is variable and undefined. If the intended limitation is “greater than X%”, the claims should be amended accordingly. Correction is required.
Claim 61 is indefinite in the recitation of “cell produces 6ACA that comprises…..in fermentation broth” for the following reasons. Claim 61 is directed to a cell. The limitation regarding the amount of 6ACA in a fermentation broth can only be determined in a method that requires culturing a cell in a fermentation broth. Therefore, it is unclear as to how a limitation regarding the amount of a product in a fermentation broth can limit a cell. For examination purposes, claim 61 will be interpreted as a duplicate of claim 1. Correction is required.
Claims 62-63 are indefinite in the recitation of “…produces 6ACA that comprises….. 100%...6ACA by weight after processing or purification” for the following reasons. The claims require a particular purity after purification. While this limitation appears to limit the cell, it is noted that purification is a step of a process and cannot further limit the cell, which is a product. The same cell X that produces Y amount of 6ACA can be encompassed and not encompassed by the claims depending on whether one uses purification method A or purification method B. If purification method A yields a product which is 100% 6ACA and purification method B yields a product which is 50% 6ACA, when the raw material used prior to purification comes from the same cell X, it would be impossible to determine whether cell X is encompassed or not by the claims. For examination purposes, claims 62-63 will be interpreted as duplicates of claim 1. Correction is required.
Claim 64 is indefinite in the recitation of “…produces 6ACA that comprises less than ….1 ppm of one or more byproducts selected from 6-hydroxyhexanoate and adipate” for the following reasons. The term “ppm” or parts per million is a concentration unit. In the absence of a statement indicating which is the volume being used to determine such concentration (e.g., intracellular), it would be impossible to determine whether a cell is encompassed by the claim. For examination purposes, it will be assumed that claim 64 is a duplicate of claim 1.
Claim 67 is indefinite in the recitation of “….or 100% compared to a corresponding cell lacking said genetic modification” for the following reasons. The term “a corresponding cell” encompasses a genus of “corresponding cells” in view of the recitation of “a”. The claim does not require the comparison to be made with the same cell of the preamble (i.e., same genus/species) lacking the genetic modifications but rather allows for the comparison to be made with any cell lacking the genetic modifications. For example, as written, the comparison can be made between an E. coli strain X cell having the genetic modifications and a wild type E. coli strain Y cell lacking the genetic modifications. The basis for comparison is variable, thus making the determination as to what is encompassed and not encompassed by the claim impossible. For example, cell X may be encompassed by the claim if the comparison is made with cell Y but may not be encompassed by the claim if the comparison is made with cell Z. For examination purposes, it will be assumed that the claim reads “when compared to the same cell lacking the one or more genetic modifications”. Correction is required.
Claim 161 is indefinite in the recitation of “wherein said cell comprises a 6ACA target product pathway comprising at least one exogenous nucleic acid encoding a 6ACA target product pathway enzyme expressed in a sufficient amount to produce 6ACA, wherein said 6ACA target product pathway comprises a pathway as described in Figure 1” for the following reasons. It is unclear as to what the meaning of the term “6ACA target product pathway” is or what a “6ACA target product” is. Is 6ACA the target product or is the target product a compound that reacts with 6ACA? Is the pathway enzyme an enzyme associated with the synthesis of 6ACA or the synthesis of a compound that reacts with 6ACA?
In addition, the term “as described in Figure 1” is unclear because one could interpret the term “as described” as exemplary language (e.g., like in Figure 1). Therefore, it is unclear if the pathway is a pathway specifically disclosed in Figure 1. Furthermore, it is noted that Figure 1 has more than one pathway to produce 6ACA. As such, it is unclear as to which is the pathway being referred to. Moreover, as set forth in MPEP 2173.05(S), claims are to be complete in themselves and incorporation by reference to a specific figure or table is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. In the instant case, the pathways shown in Figure 1 are defined by the reactions encompassed by these pathways and can be incorporated in the claims by reciting the conversions encompassed by the pathways (e.g., levulinic acid pathway comprises the conversion of succinyl-CoA and acetyl-CoA to 3-oxoadipyl-CoA, the conversion of 3-oxoadipyl-CoA to 3-oxoadipate, and the conversion of 3-oxoadipate to levulinic acid). For examination purposes, claim 161 will be interpreted as a duplicate of claim 1. 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, 25, 54-59, 61-65, 67, 161 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection is necessitated due to the introduction of new matter.
As set forth in MPEP 2163 (I)(B), new or amended claims which introduce elements or limitations that are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971) (subgenus range was not supported by generic disclosure and specific example within the subgenus range); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (an adequate description of a genus may not support claims to a subgenus or species within the genus). The claims have been amended to now require a genetic modification to decrease the activity of an oxidoreductase that catalyzes the conversion of adipate semialdehyde to 6-hydroxyhexanoate and adipate. While the Examiner has found support for an enzyme that catalyzes the conversion of adipate semialdehyde to 6-hydroxyhexanoate (adipate semialdehyde reductase; Figure 4, reaction F and Figure 5, reaction B), the Examiner has found no support for (a) an oxidoreductase that catalyzes the conversion of adipate semialdehyde to 6-hydroxyhexenaote and adipate, or (b) a genetic modification to reduce the activity of an oxidoreductase that catalyzes the conversion of adipate semialdehyde to 6-hydroxhexanoate and adipate. Thus, there is no indication that a genetically modified cell that comprises a genetic modification to decrease the activity of an oxidoreductase that catalyzes the conversion of adipate semialdehyde to 6-hydroxyhexanoate and adipate was within the scope of the invention as conceived by Applicant at the time of the invention. Accordingly, Applicant is required to cancel the new matter in the response to this Office Action.
Claims 1, 25, 54-59, 61-65, 67, 161 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 are directed to a defined 6-aminocaproic acid production pathway and an associated metabolic control strategy involving modification of enzyme activity at specific pathway intermediates and reduction of defined byproducts. Applicant states that the limitations of claim 1 define a particularized pathway-based system rather than an open-ended functional genus. Applicant states that the specification provides explicit description of the 6ACA pathway as shown in Figure 1 including the conversion of adipate semialdehyde to 6ACA via transaminase and dehydrogenase activity. Applicant states that the specification provides enzymes acting at specific nodes and the ability to modulate pathway flux through genetic modification of enzymes acting on the intermediates. Applicant states that the specification provides specific compounds as byproducts associated with the disclosed pathway.
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 and the teachings of the specification. However, the Examiner disagrees with Applicant’s contention that the full scope of the claims is adequately described.
The claims as amended require a genetically modified cell that has been modified by any means to produce 6-aminocaproic acid (6ACA), including providing by any means the activity of any 6-aminocaproate transaminase and/or a 6-aminocaproate dehydrogenase, wherein said cell has been further modified by any means to decrease the activity of a genus of enzymes having any structure, wherein said enzymes catalyze the conversion of adipate semialdehyde to 6-hydroxyhexanoate and adipate, and/or catalyze the conversion of 5-carboxy-2-pentenoyl-CoA to 5-carboxy-2-pentenal, and wherein said cell produces a reduced level of 6-hydroxyhexanoate and/or adipate, compared to the level of 6-hydroxyhexanoate and/or adipate produced in a cell of the same genus and species lacking the genetic modifications. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
With regard to the argument that the limitations of claim 1 define a particularized pathway-based system rather than an open-ended functional genus, it is noted that the claims still require a genus of cells of any species modified by any means to produce 6ACA. The specification fails to provide a structure/function correlation that would allow one of skill in the art to recognize those genes that encode the enzymes required by the claimed cells to produce 6ACA and the genetic modifications required in any cell to obtain the levels of byproducts recited. The requirement to provide the activity of any 6-aminocaproate transaminase and/or a 6-aminocaproate dehydrogenase does not by itself impart any cell of any species with the ability to produce 6ACA because it is unclear if any cell can endogenously produce the required precursors, including adipate semialdehyde. In addition, the claims are not limited to the expression of nucleic acids encoding a 6-aminocaproate transaminase and/or a 6-aminocaproate dehydrogenase as the means by which 6-aminocaproate transaminase activity and/or a 6-aminocaproate dehydrogenase activity are provided to the cell. Instead, the claims encompass any genetic modification that would provide said enzymatic activities, such as the expression of any unknown protein that would enhance the expression of endogenous 6-aminocaproate transaminases and/or 6-aminocaproate dehydrogenases, or the expression of inhibitors of repressors of the synthesis of endogenous 6-aminocaproate transaminases and/or 6-aminocaproate dehydrogenases. In the instant case, the specification is silent as to which are the structural characteristics required in any endogenous 6-aminocaproate transaminase and/or a 6-aminocaproate dehydrogenase found in any cell, or the genetic modifications that could be made to provide 6-aminocaproate transaminase activity and/or a 6-aminocaproate dehydrogenase activity to any cell.
With regard to the argument that the specification provides enzymes acting at specific nodes and the ability to modulate pathway flux through genetic modification of enzymes acting on the intermediates, as well as specific compounds as byproducts associated with the disclosed pathway, it is noted that the specification is silent with regard to (a) an endogenous oxidoreductase that can catalyze the conversion of adipate semialdehyde to 6-hydroxyhexanoate and adipate in any cell, let alone the structural features required in any endogenous enzyme that is capable of catalyzing the conversion of adipate semialdehyde to 6-hydroxyhexanoate and adipate, and (b) the structural features required in any endogenous enzyme that is capable of catalyzing the conversion of 5-carboxy-2-pentenoyl-CoA to 5-carboxy-2-pentenal in any cell. Furthermore, even if the argument is made that at least one species of each of these oxidoreductases has been provided, it is noted that the claims require a genus of genetic modifications to reduce the activity of these enzymes. The claims are not limited to the disruption of endogenous genes encoding these oxidoreductases but rather encompass any modification to obtain such reduction, like structural changes to the promoter region of genes encoding these oxidoreductases, the expression of antisense oligonucleotides having any structure that would block the expression of genes encoding these oxidoreductases, or the synthesis of unknowns repressors of the expression of genes encoding these oxidoreductases. 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 by the teachings of the specification and/or the prior art.
Claims 1, 25, 54-59, 61-65, 67, 161 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 an E. coli cell transformed with a nucleic acid encoding (i) a 3-oxoadipyl-CoA thiolase to catalyze the conversion of succinyl-CoA and acetyl-CoA to 3-oxoadipyl-CoA, (ii) a 3-oxoadipyl-CoA reductase to catalyze the conversion of 3-oxoadipyl-CoA to 3-hydroxyadipyl-CoA, (iii) a 3-hydroxyadipyl-CoA dehydratase to catalyze the conversion of 3-hydroxyadipyl-CoA to 5-carboxy-2-pentenoyl-CoA, (iv) a 5-carboxy-2-pentenoyl-CoA reductase to catalyze the conversion of 5-carboxy-2-pentenoyl-CoA to adipyl-CoA, (v) an adipyl-CoA reductase (aldehyde forming) to catalyze the conversion of adipyl-CoA to adipate semialdehyde, and (vi) a 6-aminocaproate transaminase and a 6-aminocaproate dehydrogenase to catalyze the conversion of adipate semialdehyde to 6ACA, wherein said E. coli cell has been further modified to disrupt the endogenous yqhD or adhE genes, does not reasonably provide enablement for any genetically modified cell that has been modified by any means to produce 6-aminocaproic acid (6ACA), including providing by any means the activity of any 6-aminocaproate transaminase and/or a 6-aminocaproate dehydrogenase, wherein said cell has been further modified by any means to decrease the activity of oxidoreductases having any structure, wherein said oxidoreductases catalyze the conversion of adipate semialdehyde to 6-hydroxyhexanoate and adipate, and/or catalyze the conversion of 5-carboxy-2-pentenoyl-CoA to 5-carboxy-2-pentenal, and wherein said cell produces a reduced level of 6-hydroxyhexanoate and/or adipate, compared to the level of 6-hydroxyhexanoate and/or adipate produced in a cell of the same genus and species lacking the genetic modifications. 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 argues that the claims are directed to a defined 6ACA production pathway and associated metabolic control strategy. Therefore, Applicant concludes that the present claims as amended are not directed to modification of any enzyme or any oxidoreductase in the abstract but to modification of enzyme activity within a defined biosynthetic pathway at identified metabolic nodes. Applicant asserts that the specification provides a defined 6ACA pathway, identification of specific enzymatic activities, description of enzymatic transformations at relevant intermediates, and identification of pathway associated byproducts. Applicant states that the specification provides representative enzymes and guidance on pathway implementation and control of intermediates. Applicant states that the specification provides sufficient guidance to allow one of skill in the art to make and use the claimed subject matter. Applicant states that the specification provides relevant pathways, intermediates and enzymatic activities. Applicant states that the claimed subject matter does not require screening all possible enzymes or cell types. Applicant submits that reduction of byproducts follows from modification of pathway flux at the specified intermediates. Applicant states that the Examiner’s position is based on a different scope.
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 and the teachings of the specification. However, the Examiner disagrees with Applicant’s contention that the full scope of the claims is enabled by the teachings of the specification and/or the prior art, or that the Examiner’s position is based on a different scope.
With regard to the argument that the present claims as amended are not directed to modification of any enzyme or any oxidoreductase in the abstract but to modification of enzyme activity within a defined biosynthetic pathway at identified metabolic nodes, it is reiterated herein that the claims as amended require a genetically modified cell that has been modified by any means to produce 6-aminocaproic acid (6ACA), including providing by any means the activity of any 6-aminocaproate transaminase and/or a 6-aminocaproate dehydrogenase, wherein said cell has been further modified by any means to decrease the activity of a genus of oxidoreductases having any structure, wherein said oxidoreductases catalyze the conversion of adipate semialdehyde to 6-hydroxyhexanoate and adipate, and/or catalyze the conversion of 5-carboxy-2-pentenoyl-CoA to 5-carboxy-2-pentenal, and wherein said cell produces a reduced level of 6-hydroxyhexanoate and/or adipate, compared to the level of 6-hydroxyhexanoate and/or adipate produced in a cell of the same genus and species lacking the genetic modifications. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation. Therefore, contrary to Applicant’s assertions, the claims as currently presented encompass a cell that has been genetically modified to produce any enzyme associated with the synthesis of 6ACA, as well as any means to provide an enzymatic activity or decrease the activity of an enzyme.
With regard to the argument that the specification provides a defined 6ACA pathway, identification of specific enzymatic activities, description of enzymatic transformations at relevant intermediates, and identification of pathway associated byproducts, description of representative enzymes and guidance on pathway implementation and control of intermediates, it is noted that the claims still require a genus of cells of any species modified by any means to produce 6ACA. The specification fails to provide a structure/function correlation that would allow one of skill in the art to recognize those genes that encode the enzymes required by the claimed cells to produce 6ACA and the genetic modifications required in any cell to obtain the levels of byproducts recited. While it is agreed that the specification discloses the conversion of adipate semialdehyde to 6ACA as one step to produce 6ACA and discloses two enzymes as catalysts for this conversion, it is noted that providing the activity of any 6-aminocaproate transaminase and/or a 6-aminocaproate dehydrogenase does not by itself impart any cell of any species with the ability to produce 6ACA because it is unclear if any cell is able to produce the precursors required, including adipate semialdehyde. Furthermore, the claims are not limited to the expression of nucleic acids encoding a 6-aminocaproate transaminase and/or a 6-aminocaproate dehydrogenase as the means by which 6-aminocaproate transaminase activity and/or a 6-aminocaproate dehydrogenase activity are increased in any cell. Instead, the claims encompass any genetic modification that would provide said enzymatic activities, such as the expression of any unknown protein that would enhance the expression of endogenous 6-minocaproate transaminases and/or 6-aminocaproate dehydrogenases, and the expression of inhibitors of repressors of the synthesis of 6-aminocaproate transaminases and/or 6-aminocaproate dehydrogenases. In the instant case, the specification is silent as to which are the structural characteristics required in any endogenous 6-aminocaproate transaminase and/or a 6-aminocaproate dehydrogenase found in any cell, or the genetic modifications that could be made to enhance the endogenous 6-aminocaproate transaminase activity and/or a 6-aminocaproate dehydrogenase activity in any cell.
With regard to the argument that the specification provides the identification of pathway associated byproducts and that the reduction of byproducts follows from modification of pathway flux at the specified intermediates, it is reiterated herein that the specification is silent with regard to (a) an endogenous oxidoreductase that can catalyze the conversion of adipate semialdehyde to 6-hydroxyhexanoate and adipate in any cell, or the structural features required in any endogenous enzyme that is capable of catalyzing the conversion of adipate semialdehyde to 6-hydroxyhexanoate and adipate, and (b) the structural features required in any endogenous enzyme that is capable of catalyzing the conversion of 5-carboxy-2-pentenoyl-CoA to 5-carboxy-2-pentenal in any cell. As indicated above, even if the argument is made that at least one species of each of these oxidoreductases has been provided, the claims as amended require any genetic modification to reduce the activity of these enzymes. The claims are not limited to the disruption of endogenous genes encoding these oxidoreductases but rather encompass any modification to obtain such reduction. This includes, for example, structural changes to the promoter region of genes encoding these oxidoreductases, the expression of antisense oligonucleotides having any structure that would block the expression of genes encoding these oxidoreductases, or the synthesis of unknowns repressors of the expression of genes encoding these oxidoreductases.
With regard to the argument that the specification provides relevant pathways, intermediates and enzymatic activities and that the claimed subject matter does not require screening all possible enzymes or cell types, it is noted that while it is agreed that the specification provides a limited number of pathways, and enzymes that can catalyze the reactions required in these pathways, the claims as explained above are not limited to cells transformed with nucleic acids encoding the enzymes required to synthesize 6ACA and require any genetic modification to provide a particular enzymatic activity or decrease the activity of enzymes that are either disclosed or unknown.
The specification discloses an E. coli genetically modified to express nucleic acids encoding (i) a 3-oxoadipyl-CoA thiolase to catalyze the conversion of succinyl-CoA and acetyl-CoA to 3-oxoadipyl-CoA, (ii) a 3-oxoadipyl-CoA reductase to catalyze the conversion of 3-oxoadipyl-CoA to 3-hydroxyadipyl-CoA, (iii) a 3-hydroxyadipyl-CoA dehydratase to catalyze the conversion of 3-hydroxyadipyl-CoA to 5-carboxy-2-pentenoyl-CoA, (iv) a 5-carboxy-2-pentenoyl-CoA reductase to catalyze the conversion of 5-carboxy-2-pentenoyl-CoA to adipyl-CoA, (v) an adipyl-CoA reductase (aldehyde forming) to catalyze the conversion of adipyl-CoA to adipate semialdehyde, and (vi) a 6-aminocaproate transaminase and a 6-aminocaproate dehydrogenase to catalyze the conversion of adipate semialdehyde to 6ACA. The specification also discloses disruption of the endogenous yqhD and/or adhE genes which encode oxidoreductases that act on an aldehyde to reduce the production of specific byproducts. However, the specification fails to disclose (i) other genetic modifications to produce 6ACA, (ii) the structure and/or identity of additional genes which encode enzymes that can be used for the synthesis of 6ACA, (iii) the structure of oxidoreductases that catalyze the conversion of adipate semialdehyde to 6-hydroxyhexanoate and adipate, or oxidoreductases that catalyze the conversion of 5-carboxy-2-pentenoyl-CoA to 5-carboxy-2-pentenal, (iv) other genetic modifications to provide the recited enzymatic activities and decrease enzymatic activity, or (v) other modifications to decrease the level of byproducts recited beyond the disruption of genes encoding enzymes associated with the synthesis of those byproducts. No structure/function correlation has been provided that would allow one of skill in the art to determine those genes that encode the recited enzymes, or the structural modifications that can be made to any cell that would result in the desired byproduct levels.
In the absence of (a) a rational and predictable scheme for identifying which proteins and their genes are more likely to have the desired activity, (b) a correlation between structure and activity, (c) a rational and predictable scheme for identifying those genetic modifications most likely to result in an increase or decrease in activity, or reduction of byproduct formation, and (d) some knowledge or guidance as to which genetic modifications can result in decreased/increased enzymatic activity in any cell, one of skill in the art would have to test an essentially infinite number of proteins, nucleic acids, and modifications to determine which genetic modifications would lead to the desired outcome, and which proteins have the desired activity. This is not deemed routine experimentation. Therefore, for the reasons of record and those set forth above, one cannot reasonably conclude that the entire scope of the claims is adequately described by the teachings of the specification and/or the prior art.
Claim Rejections - 35 USC § 102 (AIA )
Claims 1, 25, 54-65, 67, 161 were rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Lau et al. (US Publication No. 2013/0288320, publication date 10/31/2013; cited in the IDS).
Claim 1 has been amended to now require a genetic modification to increase the enzymatic activity of a 6-aminocaproate transaminase and/or a 6-aminocaproate dehydrogenase. While Lau et al. teach a genetically modified organism that produces 6-amino caproic acid (6ACA; paragraph [0024], [0071]) by transforming the organism with at least one polynucleotide encoding an enzyme involved in the engineered metabolic pathway (paragraph [0032]), Lau et al. do not specifically teach a genetic modification to increase the enzymatic activity of a 6-aminocaproate transaminase and/or a 6-aminocaproate dehydrogenase. Therefore, this rejection is hereby withdrawn.
Claims 1, 25, 54-59, 61-65, 67, 161 remain rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Burk et al. (U.S. Patent No. 8,377,680, issued 2/19/2013; cited in the IDS).
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 Burk et al. do not teach the limitations currently recited in claim 1, either individually or in combination. Applicant states that Burk et al. do not teach decreasing the activity of an oxidoreductase at the adipate node to suppress formation of 6-hydroxyhexanoate or adipate, or decreasing the activity of an oxidoreductase catalyzing the conversion of 5-carboxy-2-pentenoyl-CoA to 5-carboxy-2-pentenal. Applicant states that Burk et al. do not teach reducing the specific byproducts recited in the claims. Applicant further submits that Burk et al. do not disclose the claimed combination of limitations arranged as required.
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 assertion that Burk et al. do not teach the claimed invention.
Claims 1, 25, 54-59, 61-65, 67, 161 as amended are directed in part to a cell that produces 6ACA, wherein said cell has been genetically modified to express at least one exogenous nucleic acid encoding an enzyme having 6-aminocaproate dehydrogenase activity or an enzyme having 6-aminocaproate transaminase activity, wherein said cell comprises (i) a disruption in an endogenous gene encoding an oxidoreductase that catalyzes the conversion of adipate semialdehyde to 6-hydroxyhexanoate and adipate, and/or (ii) a disruption in an endogenous gene encoding an oxidoreductase that catalyzes the conversion of 5-carboxy-2-pentenoyl-CoA to 5-carboxy-2-pentenal, wherein said cell produces a reduced amount of a byproduct, wherein said byproduct is selected from 6-hydroxyhexanoate and adipate, compared to the same cell which has not been genetically modified. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
As previously indicated, Burk et al. teach a genetically modified organism that produces 6-amino caproic acid (6ACA; Abstract). Burk et al. teach E. coli as one of the genetically modified organisms (column 6, lines 55-64). Burk et al. teach a 6ACA biosynthetic pathway that requires the enzymes 3-oxoadipyl-CoA thiolase, 3-oxoadipyl-CoA reductase, 3-hydroxyadipyl-CoA dehydratase, 5-carboxy-2-pentenoyl-CoA reductase, adipyl-CoA reductase (aldehyde forming), 6-aminocaproate transaminase, and 6-aminocaproate dehydrogenase (Figure 10, column 2, lines 51-64). According to Figure 10 of Burk et al. reactions O and P are catalyzed by 6-aminocaproate transaminase, and 6-aminocaproate dehydrogenase, respectively. Burk et al. teach enzymes that have 6-aminocaproate transaminase activity (column 123, second table, lines 17-57), including those encoded by the E. coli gdhA gene or the T. maritima gdh gene. Burk et al. teach enzymes that have 6-aminocaproate dehydrogenase activity (column 125, second table, lines 17-40) including the protein encoded by the E. coli gabT gene or the E. coli puuE gene. Burk et al. teach transforming a microbial organism with exogenous nucleic acids encoding the enzymes of the 6ACA pathway (column 15, line 25-50; column 137, Example XV). Therefore, the genetically modified cell of Burk et al. comprises a genetic modification to provide an 6-aminocaproate transaminase activity and a 6-aminocaproate dehydrogenase activity by virtue of expressing nucleic acids encoding said enzymes.
Burk et al. teach gene disruptions to reduce the production of byproducts, including disruptions in the adhE, gene (Table 12, ADHEr; Table 14). As indicated in the specification, the E. coli adhE gene encodes an oxidoreductase that uses 5-carboxy-2-pentenoy-CoA (5c2pcoa) as a substrate (Table 3, Enzyme A4) to produce the corresponding aldehyde. Also, as indicated in the specification, the byproduct 6-hydroxyhexanoate (By 15) is produced from the conversion of 5-carboxy-2-pentenoy-CoA to 5-carboxy-2-pentenal (column 27, Table 10, By 15). Therefore, since the specification teaches that E. coli adhE catalyzes the conversion of 5-carboxy-2-pentenoy-CoA to 5-carboxy-2-pentenal and that the byproduct 6-hydroxyhexanoate is produced by the conversion of 5-carboxy-2-pentenoy-CoA to 5-carboxy-2-pentenal, it follows that the E. coli cell of Burk et al. also has a genetic modification (disruption) that reduces the activity of an oxidoreductase (encoded by adhE) that catalyzes the conversion of 5-carboxy-2-pentenoy-CoA to 5-carboxy-2-pentenal, thus reducing the production of the byproduct 6-hydroxyhexanoate. Therefore, contrary to Applicant’s assertion, the teachings of Burk et al. anticipate the instant claims as written/interpreted.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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
July 3, 2026
Prosecution Insights