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 .
DETAILED ACTION
Application Status
This application is a DIV of US patent application 16/496,411, filed on 09/13/2021.
Claims 142, 144-161 are currently pending in this patent application.
The preliminary amendment filed on 02/12/2026, amending claims 152-155, canceling claims 1-141 and 143 is acknowledged.
Election/Restriction
Applicant's election without traverse of Group IV, Claims 1, 9-10, 12, 16, 18 and 27, which are equivalent to new claims 142, 143, 144-160, and 161 (in part), drawn to a method of making succinate comprising: (a) contacting a Cl carbon with a genetically-modified microorganism that, comprises a heterologous fumarate hydratase and/or a heterologous fumarate reductase, or any combination thereof; and (b) growing the genetically-modified microorganism to produce succinate, wherein the genetically-modified microorganism comprises an isocitrate dehydrogenase (icdA), and SEQ ID NO: 51 as species in the response filed on 02/12/2026 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Claims 142, 144-160 and 161 are present for examination.
Priority
Acknowledgement is made of applicants claim for priority of US patent applications 17/447,568, filed on 09/13/2021, now US patent 12018310; 16/496,411, filed on 09/13/2021, now US patent 11155837 and US Provisional application 62/470,953, filed on 03/14/2017.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 05/10/2024 and 04/27/2026 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is considered by the examiner. The signed copies of 1449s are enclosed herewith.
Drawings
Drawings submitted on 05/10/2024 are accepted by the Examiner.
Claim Objections
Claim 145 is objected to in the recitation “1,4-BDO”; as abbreviations should not be used without at least once fully setting forth what they are used for. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
A. Written Description
Claims 142, 144-146, 151-151, 156-160 and 161 are rejected under 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
Claim 142 as interpreted under Broadest Reasonable Interpretation (BRI), directed to a method of making succinate comprising: (a) contacting a Cl carbon with a genetically-modified microorganism that, comprises a heterologous fumarate hydratase and/or a heterologous fumarate reductase, and (b) growing the genetically-modified microorganism to produce succinate.
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials”. As indicated in MPEP § 2163, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Claims are directed to a method of making succinate comprising: (a) contacting a Cl carbon (one carbon gas or compound) with any genetically-modified microorganism that, comprises a heterologous any fumarate hydratase derived from any unknown sources having no structural feature, and/or any heterologous fumarate reductase derived from any unknown sources having no structural feature, and (b) growing the genetically-modified microorganism to produce succinate, i.e. No Structure-Function Correlation for the genetically modified microorganism, fumarate hydratase enzyme, and fumarate reductase enzyme, which are required for fulfilling the Written Description (WD) requirement.
As discussed in the written description guidelines the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A representative number of species means that the species, which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, Claims are drawn to a method of making succinate comprising: (a) contacting a Cl carbon (one carbon gas or compound) with any genetically-modified microorganism that, comprises a heterologous any fumarate hydratase derived from any unknown sources having no structural feature, and/or any heterologous fumarate reductase derived from any unknown sources having no structural feature, and (b) growing the genetically-modified microorganism to produce succinate, i.e. No Structure-Function Correlation for the genetically modified microorganism, fumarate hydratase enzyme, and fumarate reductase enzyme, whose structures are not fully described in the specification. No information, beyond the characterization of few microorganisms, few genes encoding polypeptides of fumarate hydratase and/or fumarate reductase has been provided, which would indicate that applicants had possession of the claimed genus.
Furthermore, the genus of microorganism, genes and encoded polypeptides and functional homologs or variants required in the claimed invention is an extremely large structurally and functionally variable genus. While the argument can be made that the recited genus of polypeptides and encoding polynucleotides are adequately described by the disclosure of the structures of prior art, i.e., genes associated with the production of succinate from C1 compounds, since one could use structural homology to isolate those polypeptides and the encoding polynucleotide recited in the claims. However, the art clearly teaches the “Practical Limits of Function Prediction”: Whisstock et al., (2003, see IDS) highlight the difficulties associated with “Prediction of protein function from protein sequence and structure”; “To reason from sequence and structure to function is to step onto much shakier ground”, closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function, in such cases, assignment of function on the basis of homology, in the absence of direct experimental evidence, will give the wrong answer, it is difficult to state criteria for successful prediction of function, since function is in principle a fuzzy concept. Given three sequences, it is possible to decide which of the three possible pairs is most closely related. Given three structures, methods are also available to measure and compare similarity of the pairs. However, in many cases, given three protein functions, it would be more difficult to choose the pair with most similar function, although it is possible to define metrics for quantitative comparisons of different protein sequences and structures, this is more difficult for proteins of different functions, in families of closely related proteins, mutations usually conserve function but modulate specificity i.e., mutations tend to leave the backbone conformation of the pocket unchanged but to affect the shape and charge of its lining, altering specificity, although the hope is that highly similar proteins will share similar functions, substitutions of a single, critically placed amino acid in an active-site residue may be sufficient to alter a protein’s role fundamentally (see, whole document). This finding is reinforced in the following scientific teachings for specific proteins in the art that suggest, even highly structurally homologous polypeptides do not necessarily share the same function and many functionally similar proteins will have little or no structural homology to disclosed proteins. For example, proteins having similar structure have different activities (structure does not always correlate to function); Witkowski et al., (1999, see IDS) teaches that one conservative amino acid substitution transforms a -ketoacyl synthase into a malonyl decarboxylase and completely eliminates -ketoacyl synthase activity. Similarly, the art also teaches that functionally similar molecules have different structures; Kisselev L., (2002, see IDS) teach that polypeptide release factors in prokaryotes and eukaryotes have same function but different structures.
As stated, no information, beyond the characterization of few microorganisms including Methylococcus capsulatus, few genes encoding polypeptides of fumarate hydratase and fumarate reductase has been provided, which would indicate that applicants had possession of the claimed genus. The specification does not contain sufficient disclosure of the structure with function of all the fumarate hydratase and fumarate reductase within the scope of the claimed genus. The genus of polypeptides claimed is a large variable genus including many fumarate hydratase and fumarate reductase polypeptides with many mutants, variants and fragments thereof, which can have wide variety of structures. Therefore, many structurally unrelated fumarate hydratase and fumarate reductase polypeptides are encompassed within the scope of these claims. The specification teaches the structure of only few representative species of such proteins. Moreover, the specification fails to describe any other representative species by any identifying characteristics or properties other than the functionality of the encoding the polypeptide having ability of producing succinate in said genetically modified. Given this lack of description of representative species encompassed by the genus of polypeptides of the claim, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the claimed invention.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
Claim Rejections – AIA 35 U.S.C. § 103
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.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
According to MPEP 2143:
“Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield
predictable results;
(B) Simple substitution of one known element for another to obtain predictable
results;
(C) Use of known technique to improve similar devices (methods, or products)
in the same way;
(D) Applying a known technique to a known device (method, or product) ready
for improvement to yield predictable results;
(E) “ Obvious to try ” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in
either the same field or a different one based on design incentives or other market
forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art
reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.”
Claims 142, 144-146, 151, 156-157 and 158-159 are rejected under 35 U.S.C. 103 before the effective filing date as being unpatentable over Lee et al. (Novel gene encoding fumarate hydratase C and method for preparing succinic acid using the same. US 2007/0042477A1, 02/22/2007), in view of Lee et al. (Metabolic engineering of methanotrophs and its application for the production of chemicals and biofuels from methane. BioFuels, Bioprod. Bioref. (2016); 10(6): p848-863 (Epub 08/08/2016), Miura et al. (A Soluble NADH-Dependent Fumarate Reductase in the Reductive Tricarboxylic Acid Cycle of Hydrogenobacter thermophilus TK-6., J. Bacteriol (2008):190(21): 7170-7177), and Choi et al. (Bestowing Inducibility on the Cloned Methanol Dehydrogenase Promoter (PmxaF)of Methylobacterium extorquens by Applying Regulatory Elements of Pseudomonas putida F1. Appl and Environ Microbiol (2006), 72(12): 7723-7729).
The Broadest Reasonable Interpretation (BRI) of claim 142, which is drawn to a method of making succinate comprising:(a) contacting a C1 carbon with a genetically-modified microorganism that comprises a heterologous fumarate hydratase and/or a heterologous fumarate reductase; and (b) growing the genetically-modified microorganism to produce succinate.
Regarding claims 142, 144, 145 and 146, Lee et al. (2007) teach an isolated fumC gene encoding a fumarate hydratase C derived from Mannheimia succiniciproducens MBEL55E having an amino acid sequence of SEQ ID NO: 4, which has a DNA sequence of SEQ ID NO: 3, and a recombinant E. coli shuttle vector containing the fumC gene encoding a fumarate hydratase C, wherein the recombinant vector is pMEfumC, and a recombinant microorganism obtained by introducing the fumC gene encoding a fumarate hydratase C into a host cell selected from the group consisting of bacteria, yeast and mold, wherein the host cell is a succinic acid-producing microorganism , wherein the succinic acid-producing microorganism is from the genus Mannheimia, and species M. succiniciproducens LPK7, wherein M. succiniciproducens LPK7, is an engineered bacterial strain derived from M. succiniciproducens MBEL55E, optimized via metabolic engineering for the industrial-scale production of succinic acid, wherein the FumC gene is derived from M. succiniciproducens MBEL55E can be introduced into other microorganism including bacteria, yeast and mold as heterologous, and wherein the succinic acid-producing microorganism has one or more pathways, selected from the group consisting of an acetate-producing pathway, a lactate-producing pathway, a formate-producing pathway, an ethanol-producing pathway and an oxaloacetate-producing pathways are blocked, and a method for preparing succinic acid, wherein the method comprising the steps of: culturing the recombinant microorganism for 25 to 50 hrs, and recovering succinic acid from the culture broth of the recombinant microorganism (see, abstract, para 14, 18, 29, 33-35, 37, Example 2, Table 3, claims 1-11).
Lee (2007) et al. do not teach expression of heterologous fumC gene in other bacterium, or yeast as heterologous expression, but indeed teach exogenous expression of fumC gene derived from Mannheimia genus, and introduced into Mannheimia succiniciproducens MBEL55E. However, it is obvious to a skilled artisan to introduce fumC gene in other microorganisms such as bacteria or yeast cell as Lee et al. teach that said fumC gene can be introduced in other bacteria and yeast cell as heterologous with an expectation of success for producing succinate.
Lee (2007) et al. do not teach culturing recombinant cells for 96 hrs. However, it is obvious to a skilled artisan culturing recombinant cells as ferment for 96 hrs instead of 25 to 50 hrs, which is nothing but optimization, to produce enhance amount of succinate with an expectation of success.
Lee (2007) et al. do not teach converting succinate into 1,4-BDO (for claim 145) by said recombinant bacterial strain.
However, Lee (2016) et al. teach metabolic engineering of methanotrophs and its application for the production of chemicals and biofuels including succinate from methane and methanol, and further teach metabolic engineering in methanotrophic bacteria including Methylococcus capsulatus, and major route for producing succinate and 1,4-BDO in a fermentation process using methanotrophic bacteria including Methylococcus capsulatus through utilizing enzymes including Co-A-dependent succinate semialdehyde dehydrogenase, 4-hydroxybutyrate dehydrogenase and alcohol dehydrogenase , and the recombinant methylotroph accumulated 11 mM of 1,4-BDO (see, Fig. 4).
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Lee (2016) et al. also teach producing succinate in M. capsulate expressing malate dehydrogenase (MDH) and culturing for 100 hrs, and a process for producing 1,4-BDO from methane by methanotrophic bacteria including Methylococcus capsulatus (see, Abstract, pg 8, left Col, para 2-3, Fig. 1-2, 3 and 4, and Table 1, 3).
Lee (2016) et al. do not teach using fumarate reductase (frdABCD) and frdm (mitochodrial) genes derived from a bacteria (for claim 151).
However, Miura et al. teach a Soluble NADH-Dependent Fumarate Reductase in the Reductive Tricarboxylic Acid Cycle from Hydrogenobacter thermophilus TK-6, a bacterium, and further teach Fumarate reductase (FRD) is an enzyme that reduces fumarate to succinate, in many organisms, it is bound to the membrane and uses electron donors such as quinol, and further teach that an FRD from a thermophilic chemolithoautotrophic bacterium, Hydrogenobacter thermophilus TK-6, was purified and characterized. FRD activity using NADH as an electron donor was not detected in the membrane fraction but was found in the soluble fraction, and the purified enzyme was demonstrated to be a novel type of FRD, consisting of five subunits, wherein one subunit showed high sequence identity to the catalytic subunits of known FRDs. Although the genes of typical FRDs are assembled in a cluster, the five genes encoding the H. thermophilus FRD were distant from each other in the genome. Furthermore, phylogenetic analysis showed that the H. thermophilus FRD was located in a distinct position from those of known soluble FRDs. This is the first report of a soluble NADH-dependent FRD in Bacteria and of the purification of a FRD that operates in the reductive tricarboxylic acid cycle (see, abstract and Title).
Miura et al. do not teach using promoters pMxaF, J23111 and J23100 to express fumarate reductase gene (for claim 159).
However, Choi et al. teach bestowing Inducibility on the Cloned Methanol Dehydrogenase Promoter (PmxaF) of Methylobacterium extorquens by Applying Regulatory Elements of Pseudomonas putida F1 (see, Title, and abstract).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to combine the teachings of Lee (2007) et al. Le (2016) et al. Miura et al. and Choi et al. to convert succinate into 1,4-BDO by said recombinant bacterial strain as taught by Lee et al. (2016) and utilizing genetically modified or engineered fumarate reductase (frdABCD) and frdm (mitochodrial) genes derived from a bacteria as taught by Miura et al. and using promoter pMxaF to express fumarate reductase gene as taught by Choi et al. and modify Lee et al. (2007) to produce 1,4-butanediol (1,4-BDO) from succinate using genetically modified or engineered Methylococcus capsulatus, and for producing succinate and 1,4-BDO to arrive the claimed invention.
One of ordinary skilled in the would have been motivated to produce 1,4-butanediol (1,4-BDO), which is a raw material for producing plastic, elastic fiber and films, which is commercially, industrially and financially beneficial.
One of ordinarily skilled artisan would have had a reasonable expectation of success because Lee et al. (2007) and Lee et al. (2016) could successfully generate genetically modified or engineered methanotrophs microorganism Methylococcus capsulatus for producing succinate and 1,4-BDO.
Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of claimed invention.
Conclusion
Status of the claims:
Claims 142, 144-146, 151-151, 156-160 and 161 are rejected.
Claims 147-150, 152-155 are objected to depend on rejected base claim 142.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IQBAL H CHOWDHURY whose telephone number is (571)272-8137. The examiner can normally be reached on M-F, from 9:00-5:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao, can be reached on 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Iqbal H. Chowdhury, Primary Examiner
Art Unit 1656 (Recombinant Enzymes and Protein Crystallography)
US Patent and Trademark Office
Office Rm. REM 5A49 and Mailbox-REM3C70
Ph. (571)-272-8137 and Fax (571)-273-8137
/IQBAL H CHOWDHURY/
Primary Examiner, Art Unit 1656
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