DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-8, along with the species a desaturase (claim 2), Cydia pomonella (claim 3), SEQ ID NO: 182 (claim 4), Drosophila virilis (claim 5),
∆
9 desaturase (claim 6), Helicoverpa armigera (claim 7), and SEQ ID NO: 83 (claim 8), in the reply filed on 02/04/2026 is acknowledged.
Priority
The instant application filed on 11/09/2023 is a 371 of PCT/EP2022/062641 filed on 05/10/2022 which claims priority to EP21173017.1 filed on 05/10/2021. EP21173017.1 finds support for the instantly claimed invention; therefore, the effective filing date of the instant application is 05/10/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/06/2024, 12/03/2024, and 03/18/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112(b), Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-8 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "the compound". There is insufficient antecedent basis for this limitation in the claim. No compound was previously recited.
Claims 5-6 recite the limitation “the desaturase”. There is insufficient antecedent basis for this limitation in the claim. No desaturase was previously recited.
Claims 7-8 recite the limitation “the FAR”. There is insufficient antecedent basis for this limitation in the claim. No FAR was previously recited.
Claims 2-4 are included in this rejection for depending on independent claim 1 and failing to rectify the noted deficiencies.
Claim Rejections - 35 USC § 103, Obviousness
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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Otte (WO 2017/2141433; Date of Publication: December 14, 2017 – cited in the IDS filed on 02/06/2024) in view of Zhu (Ncb5or is a novel soluble NAD(P)H reductase localized in the endoplasmic reticulum; 2004 – cited in the IDS filed on 12/03/2024) and Larade (Loss of Ncb5or Results in Impaired Fatty Acid Desaturation, Lipoatrophy, and Diabetes; 2008 – cited in the IDS filed on 02/06/2024).
Otte’s general disclosure relates to “methods of producing one or more fatty alcohols and/or one or more fatty aldehydes from one or more unsaturated lipid moieties by combining the obtainment or production of the one or more unsaturated lipid moieties from a biological source with conversion by non-biological means of the one or more unsaturated lipid moieties to one or more fatty alcohols and/or one or more fatty aldehydes. The present application also relates to recombinant microorganisms having a biosynthesis pathway for the production of one or more unsaturated lipid moieties” (see, e.g., Otte, abstract). Moreover, Otte discloses that the fatty alcohols, fatty aldehydes, and/or fatty acetates produced by the methods may be insect pheromones (see, e.g., Otte, abstract).
Regarding claims 1-2 pertaining to the first enzyme, Otte teaches fatty acyl-CoA desaturases (see, e.g., Otte, [0014]), wherein the fatty acyl-CoA desaturase converts fatty acyl-CoA to a desaturated fatty acyl-CoA (see, e.g., Otte, [0015]). Furthermore, Otte teaches that the fatty acyl-CoA desaturase can be expressed in a bacterial cell (see, e.g., Otte, [0013]).
Regarding claim 6 pertaining to the desaturase being a
∆
9 desaturase, Otte teaches that the fatty acyl desaturase is capable of generating a double bond at position C9 (see, e.g., Otte, [0015]), thereby making it a
∆
9 desaturase.
However, Otte does not teach: a heterologous NAD(P)H cytochrome b5 oxidoreductase (Ncb5or) (claim 1).
Zhu’s general disclosure relates to Ncb5or, wherein “NCB5OR is encountered in a broad range of vertebrates and invertebrates and is expressed in a variety of cells and tissues. Similar to the classical single domain cytochrome b5 and b5R counterparts, the cytochrome b5 domain in rat NCB5OR has a six-coordinate b-type heme (2), and the b5R domain binds flavin adenine dinucleotide (FAD) and NAD(P)H prosthetic groups as found in all members of the ferredoxin-NADP+ reductase superfamily (3). The classical cytochrome b5 and b5R proteins form a complex and reside on endoplasmic reticulum (ER) membranes with Δ9 stearoyl-CoA desaturase to catalyze fatty acid desaturation” (see, e.g., Zhu, Introduction, pg. 30316). Furthermore, Zhu discloses characterization of Ncb5or, wherein recombinant Nc5bor is soluble and “as stoichiometric amounts of heme and flavin adenine dinucleotide” (see, e.g., Zhu, abstract). Furthermore, Zhu discloses that “Kinetic measurements showed that full length and truncated NCB5OR reduce cytochrome c actively in vitro” (see, e.g., Zhu, abstract).
Regarding claim 1 pertaining to a cell expressing a heterologous Ncb5or, Zhu teaches heterologous expression of Ncb5or, wherein “The full-length human and mouse NCB5OR, as well as truncated human NCB5OR, were prepared with a bacterial expression system (1). The coding sequence was cloned into NdeI and BamHI cloning sites of the pET19b vector (Novagen), and NCB5OR proteins were produced in BL21(DE3) host cells under isopropyl-β-D-thiogalactopyranoside induction at 8 °C to ensure proper folding” (see, e.g., Zhu, “Preparation of Recombinant NCB5OR”, pg. 30317). Furthermore, Zhu teaches that “Both full-length and truncated recombinant NCB5OR proteins have been generated in a bacterial system” (see, e.g., Zhu, Introduction, pg. 30317).
Larade’s general disclosure relates to targeted ablation of Ncb5or knockout results in progressive loss of β-cells and white adipose tissue over time, thereby confounding the effects of diabetes (see, e.g., Larade, abstract). Moreover, Larade discloses that levels of palmitoleic and oleic acids (Δ9 fatty acid desaturation) was decreased in the Ncb5or knockout mice relative to wildtype control (see, e.g., Larade, abstract). Furthermore, Larade discloses that Ncb5or acts as an alternative source of electrons for stearoyl CoA desaturase and Ncb5or deficiency results in impaired Δ9 desaturation (see, e.g., Larade, Introduction, pgs. 29285-29286 & Discussion, pgs. 29290-29291).
Regarding claim 1 pertaining to expressing a desaturase in combination with Ncb5or, Larade teaches that Ncb5or acts as an alternative source of electrons for stearoyl CoA desaturase and Ncb5or deficiency results in impaired Δ9 desaturation (see, e.g., Larade, Introduction, pgs. 29285-29286 & Discussion, pgs. 29290-29291). Furthermore, Larade teaches that the N- and C-domains of Ncb5or bear strong homology with classical cytochrome b5 and cytochrome b5 reductase, which supplies electrons to stearoyl CoA desaturase (see, e.g., Larade, Discussion, pg. 29290). Therefore, Ncb5or is important for fatty acid desaturation, and more specifically Δ9 desaturation (see, e.g., Larade, Discussion, pg. 29291).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a cell that expresses a fatty acyl-CoA desaturase, as taught by Otte, and a heterologous Ncb5or, as taught by Zhu. One would have been motivated to do so because Otte teaches the production of recombinant microorganisms manipulated for production of one or more unsaturated lipids through expression of one or more desaturases (see, e.g., Otte, [0014]). Additionally, Otte teaches that the desaturase can be a fatty acyl desaturase that can generate a double bond at position C9 (see, e.g., Otte, [0015]). Furthermore, Zhu teaches that Ncb5or is a soluble NAD(P)H reductase that preferentially reduces substrate(s) rather than transfer electrons to molecular oxygen (see, e.g., Zhu, abstract). Moreover, Zhu teaches that it is advantageous to express Ncb5or in E. coli because “NCB5OR expressed in Escherichia coli reduces a variety of artificial substrates in vitro, including cytochrome c, ferricyanide, methemoglobin, and molecular oxygen” (see, e.g., Zhu, Introduction, pg. 2). Larade teaches that Ncb5or is an alternative source of electrons for stearoyl CoA desaturase and Ncb5or deficiency results in impaired Δ9 desaturation (see, e.g., Larade, Introduction, pgs. 29285-29286 & Discussion, pgs. 29290-29291). Moreover, Larade discloses that levels of palmitoleic and oleic acids (Δ9 fatty acid desaturation) was decreased in the Ncb5or knockout mice relative to wildtype control (see, e.g., Larade, abstract). Therefore, Ncb5or is important for fatty acid desaturation, and more specifically Δ9 desaturation (see, e.g., Larade, Discussion, pg. 29291). Based on the teachings of Otte, Zhu, and Larade, it would have been obvious to produce a cell that expresses both a fatty acyl-CoA desaturase and Ncb5or because Ncb5or is an alternative source of electrons for the desaturase and is important in the activity of the fatty acid desaturation. One would have expected success because Otte, Zhu, and Larade all teach fatty acid desaturation.
Regarding claims 1-2 recitation of “whereby the cell is capable of producing the compound with a higher titer and/or purity compared to a cell expressing the first group of enzymes but no heterologous Ncb5or when cultivated in the same conditions”, this is considered inherent. The combined prior art of Otte and Zhu teaches the instantly claimed invention of a cell that expresses a fatty acyl-CoA desaturase and a heterologous Nc5bor, which would inherently lead to the desired outcome of producing a compound with a higher titer and/or purity compared to a cell that just expresses a fatty acyl-CoA desaturase and no heterologous Ncb5or (see, e.g., MPEP 2112.01(I)).
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Otte, Zhu, and Larade as applied to claims 1-2 and 6 above, and further in view of Houot (Gene Regulation and Species-Specific Evolution of Free Flight Odor Tracking in Drosophila; 2018).
The teachings of Otte, Zhu, and Larade, herein referred to as modified-Otte-Zhu-Larade, are discussed above as it pertains to a cell that expresses a fatty acyl-CoA desaturase and a heterologous Ncb5or.
However, modified-Otte-Zhu-Larade does not teach: wherein the desaturase is native to Drosophila virilis (claim 5).
Houot’s general disclosure relates to investigating the natural and molecular evolution of free flight odor tracking in Drosophila (see, e.g., Houot, abstract). Moreover, Houot discloses that the desaturase1 enzyme (desat1) is involved in the production and perception of pheromones (see, e.g., Houot, Introduction, pg. 3), and desat1 expression and regulation is involved in distinct flight features (see, e.g., Houot, abstract). Furthermore, Houot discloses that “the dissection of the putative desat1 regulatory regions (PRRs) revealed that the pheromone production depends on desat1 expression in abdominal cells (oenocytes) whereas the pheromone perception relies on desat1 expression in antennal olfactory sensillae projecting into the “olfactory brain”” (see, e.g., Houot, Introduction, pgs. 3-4).
Regarding claim 5 pertaining to a desaturase from Drosophila virilis, Houot teaches that desat1 is expressed by Drosophila virilis (see, e.g., Houot, “Interspecific Molecular Conservation and Intraspecific Transcriptomic Variation of desat1”, pg. 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Otte-Zhu-Larade’s cell expressing a desaturase and a heterologous Ncb5or, wherein the desaturase is desat1 from Drosophila virilis, as taught by Houot. One would have been motivated to do so because Houot teaches that the desaturase1 enzyme (desat1) is involved in the production and perception of pheromones (see, e.g., Houot, Introduction, pg. 3), and desat1 expression and regulation is involved in distinct flight features (see, e.g., Houot, abstract). Furthermore, Houot discloses that “the dissection of the putative desat1 regulatory regions (PRRs) revealed that the pheromone production depends on desat1 expression in abdominal cells (oenocytes) whereas the pheromone perception relies on desat1 expression in antennal olfactory sensillae projecting into the “olfactory brain”” (see, e.g., Houot, Introduction, pgs. 3-4). Moreover, modified-Otte-Zhu-Larade teaches desaturation of lipids in order to produce unsaturated lipid moieties used for production of insect pheromones (see, e.g., Otte, [0037]). Additionally, modified-Otte-Zhu-Larade teaches that Ncb5or is an alternative source of electrons for stearoyl CoA desaturase and Ncb5or deficiency results in impaired Δ9 desaturation (see, e.g., Larade, Introduction, pgs. 29285-29286 & Discussion, pgs. 29290-29291). Moreover, Larade discloses that levels of palmitoleic and oleic acids (Δ9 fatty acid desaturation) was decreased in the Ncb5or knockout mice relative to wildtype control (see, e.g., Larade, abstract). Therefore, Ncb5or is important for fatty acid desaturation, and more specifically Δ9 desaturation (see, e.g., Larade, Discussion, pg. 29291).. Therefore, based on the teachings of modified-Otte-Zhu-Larade and Houot, it would have been obvious to have the desaturase be desat1 from Drosophila virilis because this enzyme is involved in the production and perception of pheromones and Ncb5or is important for desaturation activity. One would have expected success because modified-Otte-Zhu-Larade and Houot both teach production of insect pheromones via expression of desaturases.
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Otte and Zhu as applied to claims 1-2 and 6 above, and further in view of Borodina (US 2018/0162916; Date of Publication: June 14, 2018).
The teachings of Otte and Zhu, herein referred to as modified-Otte-Zhu, are discussed above as it pertains to a cell that expresses a fatty acyl-CoA desaturase and a heterologous Ncb5or.
However, modified-Otte-Zhu does not teach: wherein the FAR is native to Helicoverpa armigera (claim 7); or wherein the FAR is a FAR set forth in SEQ ID NO: 83 (claim 8).
Borodina’s general disclosure relates to “methods for production of (Z)-11-hexadecen-1-ol in a yeast cell using desaturases and fatty acyl-CoA reductase” (see, e.g., Borodina, abstract). Moreover, Borodina discloses biological processes for production of insect pheromones, wherein production costs are lower, and fermentation processes are less hazardous and environmentally friendly than chemical synthesis (see, e.g., Borodina, [0008]).
Regarding claims 7-8 pertaining to the FAR, Borodina teaches SEQ ID NO: 8, which is a FAR from Helicoverpa armigera, and has 100% sequence similarity to instant SEQ ID NO: 83 (see, e.g., Borodina, [0101] & Office Action Appendix).
It would have been obvious to one of ordinary skill in the art to produce modified-Otte-Zhu’s cell, wherein the cell expresses FAR from Helicoverpa armigera, as taught by Borodina. One would have been motivated to do so because Borodina teaches expression of alcohol-forming fatty acyl-CoA reductase (FAR) in yeast cells in order to convert (Z)11-hexadecenoyl-CoA to (Z)-11-hexadecenol (see, e.g., Borodina, [0013], [0018]), wherein (Z)-11-hexadecenol can be used in compositions comprising pheromones for monitoring the presence of pests and/or disrupting the mating of pests (see, e.g., Borodina, [0033]-[0034]). Additionally, Borodina teaches a Δ11-desaturase that “is capable of converting at least part of said hexadecanoyl-CoA to (Z)11-hexadecenoyl-CoA; and said FAR is capable of converting at least part of said (Z)11-hexadecenoyl-CoA to (Z)-11-hexadecenol” (see, e.g., Borodina, [0016]-[0018]). Moreover, modified-Otte-Zhu teaches desaturation of lipids in order to produce unsaturated lipid moieties used for production of insect pheromones (see, e.g., Otte, [0037]). Therefore, based on the teachings of modified-Otte-Zhu and Borodina, it would have been obvious to produce a cell expressing FAR from Helicoverpa armigera because this allows for conversion of fatty acyl-CoA products to fatty alcohol(s), wherein the fatty alcohol(s) can be used in compositions comprising insect pheromones. One would have expected success because modified-Otte-Zhu and Borodina both teach enzymes for production of insect pheromones.
Conclusion
Claims 1-8 are rejected.
No claims are allowed. However, claims 3-4 appear free from the art. Prior to the effective filing date of the claimed invention, the prior art does not teach Ncb5or from Cydia pomonella, nor does the art teach SEQ ID NO: 182, which encodes for Ncb5or from Cydia pomonella.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE IANNUZO whose telephone number is (703)756-5559. The examiner can normally be reached Mon - Fri: 8:30-6:00 EST.
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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