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 .
Application Status
In response to Non-Final Office Action mailed on 05/08/2026, applicants' response, arguments and amendments filed on dated 08/06/2026 is acknowledged; in said response applicants’ have amended claim 17 and canceled claims 21-22. Thus, amended claims 17-19 and 23-36 are pending in this application and is now under consideration for examination. Rejections and/or objections not reiterated from previous office action are hereby withdrawn.
Withdrawn-Claim Rejections: 35 USC § 102 (AIA )
Previous rejection of claims 17-19, 21, 23, 28-31 and 34-35 rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by De Waal et al., (US 2020/0024619 A1; priority 03/20/2018) and as evidenced by Kobayashi et al., (AMB Expr., 2018, Vol. 8:139, pages 1-11) disclose yeast comprises a transketolase encoding gene having 100% sequence identity to SEQ ID NO: 1 of the instant invention; see provided sequence alignment), is being withdrawn due to claim amendments.
Withdrawn-Claim Rejections: 35 USC § 103
Previous rejection of claims 17-19 and 21-36 rejected under 35 U.S.C. 103(a) as being unpatentable over De Waal et al., (US 2020/0024619 A1; priority 03/20/2018) as applied to claims 17-19, 21, 23, 28-31 and 34-35 (see 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) rejection above) and in view of Davidson R., (WO 2012/17092 A1; disclosing a transketolase having 100% sequence identities to SEQ ID NOs: 3-4 of the instant invention), Sun et al., (UniProtKB/TrEML database, Accession#G3AWW89; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 5 of the instant invention), Dujon et al., (UniProtKB/TrEML database, Accession#Q6BMN3; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 6 of the instant invention), De Schutter et al., (UniProtKB/TrEML database, Accession#C4QXK7; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 17 of the instant invention), Papapetridis et al., (US 10,689,670 B2), Pena-Moreno et al., (J. Indust. Miocrobiol. Biotechnol., 2019, Vol. 46: 209-220) and Petit et al., (US 2019/0292532 A1), is being withdrawn due to claim amendments.
Maintained-Claim Rejections: 35 USC § 112(a)
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—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 or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 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.
Maintained-Written Description
I. Claims 17-19 and 23-36 are rejected under 35 U.S.C. 112(a) or 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.
Claims 17-19 and 23-36 of the instant application as interpreted are directed to a process for production of ethanol, said process comprising a recombinant yeast cell Saccharomyces cerevisiae comprising a genus of polypeptides including mutants and variants of having the following activities: transketolase activity (EC 2.2.1.1), saccharolytic enzyme, ribulose-1,5-biphosphate carboxylase oxygenase (Rubisco) activity, chaperones, phosphoketolase activity, NAD+dependent acetylating acetaldehyde dehydrogenase activity, NADH-dependent nitrate reductase activity, and glucoamylase activity; wherein said transketolase comprising an amino sequence having 80% sequence identity to the amino acid sequences of SEQ ID NOs: 1, 3-6 and 17 (as in claims 17-19 and 23-36); wherein said recombinant yeast cell further comprising any promoter “a promoter having an anaerobic/aerobic expression ratio” including mutants and variants of undefined/unlimited structures (genus of promoters) driving the expression said genus of transketolases (as in claims 24-27).
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim.
MPEP § 2163 further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the biomolecule, it is "not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed biomolecule.”
“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.” MPEP 2163.
Furthermore, 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. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure ‘indicates that the patentee has invented species sufficient to constitute the gen[us].’ See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (‘[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.’). ‘A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.’ In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).” MPEP 2163.
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.
The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient. MPEP § 2163.
In the instant case, there is no structure associated with function with regard to the members a genus of polypeptides with the associated function and encoding polynucleotides and a genus of polynucleotides having promoter activity in the claimed process i.e., a process for production of ethanol, said process comprising a recombinant yeast cell Saccharomyces cerevisiae comprising a genus of polypeptides including mutants and variants of having the following activities: transketolase activity (EC 2.2.1.1), saccharolytic enzyme, ribulose-1,5-biphosphate carboxylase oxygenase (Rubisco) activity, chaperones, phosphoketolase activity, NAD+dependent acetylating acetaldehyde dehydrogenase activity, NADH-dependent nitrate reductase activity, and glucoamylase activity; wherein said transketolase comprising an amino sequence having 80% sequence identity to the amino acid sequences of SEQ ID NOs: 1, 3-6 and 17 (as in claims 17-19 and 23-36); wherein said recombinant yeast cell further comprising any promoter “a promoter having an anaerobic/aerobic expression ratio” including mutants and variants of undefined/unlimited structures (genus of promoters) driving the expression said genus of transketolases (as in claims 24-27).
No information, beyond the characterization of S. cerevisiae strain, isolated specific recombinant host/specific cellular context comprising specific structures encoding polypeptides with the following transketolase activity (EC 2.2.1.1), saccharolytic enzyme, ribulose-1,5-biphosphate carboxylase oxygenase (Rubisco) activity, chaperones, phosphoketolase activity, NAD+dependent acetylating acetaldehyde dehydrogenase activity, NADH-dependent nitrate reductase activity, and glucoamylase activity and said transketolase expression under the control of full-length intact promoters, specific heterologous promoter/ANB1 sequence (SEQ ID NO: 23) that are active under “anaerobic culturing condition” in prophetic Examples 1-10, (pages 124-134 of specification) and prophetic enzymes Table 1-14 of specification, has been provided by the applicants’, which would indicate that they had possession of the claimed genus of polypeptides with the associated function and encoding polynucleotides and a genus of polynucleotides having promoter activity in the claimed process i.e., a process for production of ethanol, said process comprising a recombinant yeast cell Saccharomyces cerevisiae comprising a genus of polypeptides including mutants and variants of having the following activities: transketolase activity (EC 2.2.1.1), saccharolytic enzyme, ribulose-1,5-biphosphate carboxylase oxygenase (Rubisco) activity, chaperones, phosphoketolase activity, NAD+dependent acetylating acetaldehyde dehydrogenase activity, NADH-dependent nitrate reductase activity, and glucoamylase activity; wherein said transketolase comprising an amino sequence having 80% sequence identity to the amino acid sequences of SEQ ID NOs: 1, 3-6 and 17 (as in claims 17-19 and 23-36); wherein said recombinant yeast cell further comprising any promoter “a promoter having an anaerobic/aerobic expression ratio” including mutants and variants of undefined/unlimited structures (genus of promoters) driving the expression said genus of transketolases (as in claims 24-27).
The genus of polypeptides and the encoding polynucleotides required in the claimed process/invention is an extremely large structurally and functionally variable genus. While the argument can be made that the recited genus of polypeptides is adequately described by the disclosure of the structures as taught in the prior art with specific structures having the associated function/activity, since one could use structural homology to isolate those polypeptides and the encoding polynucleotides recited in the claims. The art clearly teaches the “Practical Limits of Function Prediction”: (a) Devos et al., (Proteins: Structure, Function and Genetics, 2000, Vol. 41: 98-107), teach that the results obtained by analyzing a significant number of true sequence similarities, derived directly from structural alignments, point to the complexity of function prediction. Different aspects of protein function, including (i) enzymatic function classification, (ii) functional annotations in the form of key words, (iii) classes of cellular function, and (iv) conservation of binding sites can only be reliably transferred between similar sequences to a modest degree. The reason for this difficulty is a combination of the unavoidable database inaccuracies and plasticity of proteins (Abstract, page 98) and the analysis poses interesting questions about the reliability of current function prediction exercises and the intrinsic limitation of protein function prediction (Column 1, paragraph 3, page 99) and conclude that “Despite widespread use of database searching techniques followed by function inference as standard procedures in Bioinformatics, the results presented here illustrate that transfer of function between similar sequences involves more difficulties than commonly believed. Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, page 105). Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, page 105). Applicants’ are respectfully directed to the problems associated EC Classification in the section “Transferring the EC Classification enzyme to Non-Enzyme Comparisons”; pages 101-102 and Fig. 2a)-b), highlighting the structural and functional heterogeneity based on EC Classification numbers; as the stereo-specificity, substrate-specificity and catalytic properties vary widely.
(b) Whisstock et al., (Quarterly Reviews of Biophysics 2003, Vol. 36 (3): 307-340,) also 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 (page 309, paragraph 4), 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 (page 312, paragraph 5), 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 (page 313, paragraph 4), 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 (page 323, paragraph 1).
(c) This finding is reinforced in the following scientific teachings for specific proteins in the art that suggest, even highly structurally homologous polynucleotides and encoded polypeptides do not necessarily share the same function. For example, Witkowski et al., (Biochemistry 38:11643-11650, 1999), teaches that one conservative amino acid substitution transforms a -ketoacyl synthase into a malonyl decarboxylase and completely eliminates -ketoacyl synthase activity. Seffernick et al., (J. Bacteriol. 183(8): 2405-2410, 2001), teaches that two naturally occurring Pseudomonas enzymes having 98% amino acid sequence identity catalyze two different reactions: deamination and dehalogenation, therefore having different function. Broun et al., (Science 282:1315-1317, 1998), teaches that as few as four amino acid substitutions can convert an oleate 12-desaturase into a hydrolase and as few as six amino acid substitutions can transform a hydrolase to a desaturase.
(d) Further, the art clearly teaches that a promoter has discrete spatial and temporal elements “cis-acting” elements that govern the activity of promoter, as said “cis-acting” elements are specific binding regions that are recognized by specific transcription factors and other accessory proteins known as “trans-acting” factors (cell specific) and any mutation or structural change in the “cis-acting” elements drastically affect the binding of said specific transcription factors and recruitment of other accessory proteins during gene transcription and consequently affects the control of gene expression. Even a single point mutation in a “cis-acting” element can affect/alter/abrogate the promoter activity: Applicants’ are referred to the following teaching in the art: Cohen et al., (Nuc. Acids Res., 2001, Vol. 29(3): 799-808; see Abstract; Fig. 1-6, Table 1, page 803; and entire document).
As stated above, no information beyond the characterization of S. cerevisiae strain, isolated specific recombinant host/specific cellular context comprising specific structures encoding polypeptides with the following transketolase activity (EC 2.2.1.1), saccharolytic enzyme, ribulose-1,5-biphosphate carboxylase oxygenase (Rubisco) activity, chaperones, phosphoketolase activity, NAD+dependent acetylating acetaldehyde dehydrogenase activity, NADH-dependent nitrate reductase activity, and glucoamylase activity and said transketolase expression under the control of full-length intact promoters, specific heterologous promoter/ANB1 sequence (SEQ ID NO: 23) that are active under “anaerobic culturing condition” in prophetic Examples 1-10, (pages 124-134 of specification) and prophetic enzymes Table 1-14 of specification, has been provided by the applicants’, which would indicate that they had possession of the claimed genus of polypeptides and the encoding polynucleotides and a genus of promoters. As the claimed genera of polypeptides and the encoding polynucleotides and a genus of promoters having widely variable structures and associated function, since minor changes in structure may result in changes affecting function and no additional information (species/variant/mutant) correlating structure with function has been provided. Furthermore, “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features” (See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895).
Therefore, one skilled in the art cannot reasonably conclude that applicant had possession of the claimed invention at the time the instant application was filed. Applicants are referred to the revised guidelines concerning compliance with the written description requirement of 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
Applicants have traversed the above written-description with the following arguments: (see pages 11-14 of Applicants’ REMARKS dated 08/06/2026).
Applicants argue: “…It is further noted that Devos, which was cited by the Office and by Whisstock (also cited by the Office), investigated protein structure/function relationship broadly, i.e., without focusing on specific proteins as the works of Witkowski, Seffernick, and Broun do. Devos Page 13 supports a finding that a person of skill in the art would in fact have expected that sequences with even lower identity than 80% would retain enzyme classification and function. In particular, Fig. 1b of Devos demonstrates that greater than approximately 85% of enzymatic function is expected to be conserved for sequences with percent identities as low as 55-65%...”
Reply: Applicants' arguments have been considered but are found to be non-persuasive for the following reasons. Examiner continues to maintain the rejection for reasons stated on record (dated 05/08/2026) and additionally for the following reasons.
This argument is based on the scientific support from the teachings of Guo et al., (PNAS, 2004, Vol. 101 (25): 9205-9210), the findings teach that the percentage of random single-substitution mutations, which inactivate a protein, using a protein 3-methyladenine DNA glycosylase as a model, is 34% and that this number is consistent with other studies in other proteins (p 9206, paragraph 4). Guo et al., (supra) further show that the percentage of active mutants for multiple mutations appears to be exponentially related to this by the simple formula (0.66)^X X 100% where x is the number of mutations introduced (Table 1).
Applying this estimate to the protein recited in the instant application, for example, an amino acid sequence of 80% sequence identity to SEQ ID NOs: 3 and 4 allows up to 142 random mutations within the 707 amino acid residues of SEQ ID NOs: 3 and 4 and, thus, only (0.66)^142 X 100% or 2.4 x 10-24 % of random mutants having 80% sequence identity to of SEQ ID NOs: 3 and 4 would be active. While these calculations are only estimates of the actual situation, they are presented to provide a basis for understanding the examiner’s decision on which claim scope would require only routine experimentation and which would reach a level which is undue. The guidance in the instant case and current techniques in the art (i.e., high throughput mutagenesis and screening techniques) would allow for finding a reasonable number of active mutants within hundred thousand inactive mutants. Finding a few mutants within several trillions or more, would not be possible. While enablement is not precluded by the necessity for routine screening, if a large amount of screening is required, the specification must provide a reasonable amount of guidance with respect to the direction in which the experimentation should proceed (guided mutants). Such guidance has not been provided in the instant specification or in the prior art.
Specifically regarding transketolases Wikner et al., (Biochemistry, 1997, Vol. 36: 15643-15649) discloses mutations in transketolases severely impairs catalytic activity (see Abstract; Introduction, col. 1-2, page 15643; Table 2, page 15645; and entire document).
Furthermore, the art teaches the following regarding complexity of the structure/function relationship: The reference of Chica et al., (Curr. Opin. Biotechnol., 2005, Vol. 16: 378-384) teaches that the complexity of the structure/function relationship in enzymes has proven to be the factor limiting the general application of rational enzyme modification and design, where rational enzyme modification and design requires in-depth understanding of structure/function relationships. The reference of Sen et al., (Appl. Biochem. Biotechnol., 2007, Vol.143: 212-223), teaches in vitro recombination techniques such as DNA shuffling, staggered extension process (STEP), random chimera genesis on transient templates (RACHITT), iterative truncation for the creation of hybrid enzymes (ITCHY), recombined extension on truncated templates (RETT), and so on have been developed to mimic and accelerate nature's recombination strategy. However, such rational design and directed evolution techniques only provide guidance for searching and screening for the claimed polypeptide which is not guidance for making and/or using the claimed polypeptide.
Therefore, taking into consideration the extremely broad scope of the claims, the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between structure and the desired function, and the high degree of unpredictability of the prior art in regard to structural changes and their effect on function, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims in the claimed method and evidence of possession.
There are no examples provided to encompass the numerous characteristics of the whole genus claimed by the method. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals applicants’ hope the claimed invention achieves and the problems the invention will hopefully ameliorate”). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of structures with the associated function in the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention in the claimed method.
MPEP 2163.II.A.2. (a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”;
Examiner would like to reiterate
“The basic quid pro quo contemplated by the Constitution and the Congress for granting a patent monopoly is the benefit derived by the public from an invention with substantial utility”, [u]nless and until a process is refined and developed to this point-where specific benefit exists in currently available form-there is insufficient justification for permitting an applicant to engross what may prove to be a broad field”, and “a patent is not a hunting license”,[i]t is not a reward for the search, but compensation for its successful conclusion.”
Maintained-Enablement
II. Claims 17-19 and 23-36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, because the specification is enabling for the characterization of S. cerevisiae strain, isolated specific recombinant host/specific cellular context comprising specific structures encoding polypeptides with the following transketolase activity (EC 2.2.1.1), saccharolytic enzyme, ribulose-1,5-biphosphate carboxylase oxygenase (Rubisco) activity, chaperones, phosphoketolase activity, NAD+dependent acetylating acetaldehyde dehydrogenase activity, NADH-dependent nitrate reductase activity, and glucoamylase activity and said transketolase expression under the control of full-length intact promoters, specific heterologous promoter/ANB1 sequence (SEQ ID NO: 23) that are active under “anaerobic culturing condition” in prophetic Examples 1-10, (pages 124-134 of specification) and prophetic enzymes Table 1-14 of specification and a method of producing alcohol. However, specification does not reasonably provide enablement for a process for production of ethanol, said process comprising a recombinant yeast cell Saccharomyces cerevisiae comprising a genus of polypeptides including mutants and variants of having the following activities: transketolase activity (EC 2.2.1.1), saccharolytic enzyme, ribulose-1,5-biphosphate carboxylase oxygenase (Rubisco) activity, chaperones, phosphoketolase activity, NAD+dependent acetylating acetaldehyde dehydrogenase activity, NADH-dependent nitrate reductase activity, and glucoamylase activity; wherein said transketolase comprising an amino sequence having 80% sequence identity to the amino acid sequences of SEQ ID NOs: 1, 3-6 and 17 (as in claims 17-19 and 23-36); wherein said recombinant yeast cell further comprising any promoter “a promoter having an anaerobic/aerobic expression ratio” including mutants and variants of undefined/unlimited structures (genus of promoters) driving the expression said genus of transketolases (as in claims 24-27). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 8 USPQ 2nd 1400 (Fed. Cir. 1988)) as follows: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claim(s).
Claims 17-19 and 23-36 are so broad as to encompass: a process for production of ethanol, said process comprising a recombinant yeast cell Saccharomyces cerevisiae comprising a genus of polypeptides including mutants and variants of having the following activities: transketolase activity (EC 2.2.1.1), saccharolytic enzyme, ribulose-1,5-biphosphate carboxylase oxygenase (Rubisco) activity, chaperones, phosphoketolase activity, NAD+dependent acetylating acetaldehyde dehydrogenase activity, NADH-dependent nitrate reductase activity, and glucoamylase activity; wherein said transketolase comprising an amino sequence having 80% sequence identity to the amino acid sequences of SEQ ID NOs: 1, 3-6 and 17 (as in claims 17-19 and 23-36); wherein said recombinant yeast cell further comprising any promoter “a promoter having an anaerobic/aerobic expression ratio” including mutants and variants of undefined/unlimited structures (genus of promoters) driving the expression said genus of transketolases (as in claims 24-27). The scope of the claims is not commensurate with the enablement provided by the disclosure with regard to the extremely large number of polynucleotides of undefined structures having promoter activity broadly encompassed by the claims in the claimed process. Since the nucleic acid sequence of a promoter determines its structural and functional properties, predictability of which changes can be tolerated in a promoter nucleic acid sequence and obtain the desired activity requires knowledge and guidance with regard to which nucleic acid(s)/residue(s) in the promoter sequence, if any, are tolerant of modification and which are conserved (i.e., expectedly intolerant to modification), and detailed knowledge of the ways in which the encoded promoter’s structure relates to its function. In this case, the disclosure is limited to the characterization of S. cerevisiae strain, isolated specific recombinant host/specific cellular context comprising specific structures encoding polypeptides with the following activities (a) ribulose-1,5-phospahte carboxylase/oxygenase, (b) chaperones … and (c) … phosphoribulokinase; and said phosphoribulokinase expression under the control of full-length intact promoters, specific heterologous promoter sequences that are active under “anaerobic culturing condition” in Table 9 (page 43 of specification) and Table 10 (pages 45-46 of specification) and a method of producing alcohol. It would require undue experimentation of the skilled artisan to make and use the claimed polynucleotides having the associated function i.e., promoter activity. The specification provides no guidance with regard to the making of variants and mutants or with regard to other uses as claimed in the instant claims. In view of the great breadth of the claims, amount of experimentation required to make and use the claimed polynucleotides, the lack of guidance, working examples, and unpredictability of the art in predicting function, the claimed invention would require undue experimentation. As such, the specification fails to teach one of ordinary skill how to use the full scope of the polynucleotides and encoded polypeptides encompassed by the claims in the claimed process. The specification does not support the broad scope of the claims which encompass: a process for production of ethanol, said process comprising a recombinant yeast cell Saccharomyces cerevisiae comprising a genus of polypeptides including mutants and variants of having the following activities: transketolase activity (EC 2.2.1.1), saccharolytic enzyme, ribulose-1,5-biphosphate carboxylase oxygenase (Rubisco) activity, chaperones, phosphoketolase activity, NAD+dependent acetylating acetaldehyde dehydrogenase activity, NADH-dependent nitrate reductase activity, and glucoamylase activity; wherein said transketolase comprising an amino sequence having 80% sequence identity to the amino acid sequences of SEQ ID NOs: 1, 3-6 and 17 (as in claims 17-19 and 23-36); wherein said recombinant yeast cell further comprising any promoter “a promoter having an anaerobic/aerobic expression ratio” including mutants and variants of undefined/unlimited structures (genus of promoters) driving the expression said genus of transketolases (as in claims 24-27), because the specification does not establish (A) a rational and predictable scheme for modifying specific amino acid residues in any enzyme having no specific structural elements and an expectation of obtaining the desired biological/biochemical function; (B) defined core regions/motifs involved in the desired catalytic activity of encoded polypeptide; (C) the tertiary structure of the molecule and folding patterns that are essential for the desired activity and tolerance to modifications; and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful.
Thus, applicants’ have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claim broadly including polynucleotides and encoded polypeptides with an enormous number of modifications in the claimed process. The scope of the claim must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1975)). Without sufficient guidance, determination of polynucleotides having the desired biological characteristics in the claimed process is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Applicants have traversed the above enablement with the following arguments: (see pages 14-16 of Applicants’ REMARKS dated 08/06/2026).
Applicants argue: “…The specification as filed clearly describes the amino acid sequences, enzymes, promoters, and recombinant yeast cells presently claimed, including by way of incorporation by reference. For example, see sections "The yeast cell," "Native Transketolase," "Heterologous Transketolase," "TKL promoter," "Redox sink," "Rubisco," "Phosphoribulokinase," "Rubisco chaperones," "Phosphoketolase," etc. Each of these sections describes structural and functional elements of the polynucleotides, polypeptides, enzymes, promoters, and yeast cells, including the subject matter presently claimed. Furthermore, as described supra, a person of skill in the art having read Devos, Whisstock, and even Seffernick and Witkowski, would have considered sequences with 80% sequence identity to, e.g., the sequences recited in the pending claims, to have the same function…”.
Reply: Applicants' arguments have been considered but are found to be non-persuasive for the following reasons. Examiner continues to maintain the rejection for reasons stated on record (dated 05/08/2026) and additionally for the following reasons. Applicants’ arguments filed on 08/06/2026 for the traversal of enablement rejection are on similar lines to the arguments presented for traversing the written-description, said arguments have been fully considered but they are not persuasive. Examiner continues to maintain the rejection for reasons stated on record, supporting evidence and arguments presented above in maintaining the written-description rejection also applies to enablement rejection.
For the above cited reasons, examiner is maintaining the written-description and enablement rejection for claims 17-19 and 23-36.
New-Claim Rejections: 35 USC § 103
Necessitated by claim amendments
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
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(a) 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 17-19 and 23-36 are rejected under 35 U.S.C. 103(a) as being unpatentable over De Waal et al., (US 2020/0024619 A1; priority 03/20/2018) and as evidenced by Kobayashi et al., (AMB Expr., 2018, Vol. 8:139, pages 1-11) and further in view of Davidson R., (WO 2012/17092 A1; disclosing a transketolase having 100% sequence identities to SEQ ID NOs: 3-4 of the instant invention), Sun et al., (UniProtKB/TrEML database, Accession#G3AWW89; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 5 of the instant invention), Dujon et al., (UniProtKB/TrEML database, Accession#Q6BMN3; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 6 of the instant invention), De Schutter et al., (UniProtKB/TrEML database, Accession#C4QXK7; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 17 of the instant invention), Papapetridis et al., (US 10,689,670 B2), Pena-Moreno et al., (J. Indust. Miocrobiol. Biotechnol., 2019, Vol. 46: 209-220) and Petit et al., (US 2019/0292532 A1).
Regarding claims 17-19, 23, 28-31 and 34-35, De Waal et al., (US 2020/0024619 A1; priority 03/20/2018), discloses functionally expressing: [¶ 0009] a yeast cell comprising: [¶ 0010] one or more genes coding for an enzyme having glycerol dehydrogenase activity; [¶ 0011] one or more genes coding dihydroxyacetone kinase (E.C. 2.7.1.28 and/or E.C. 2.7.1.29); [¶ 0012] one or more genes coding for an enzyme in an acetyl-CoA-production pathway; and [¶ 0013] one or more genes coding for an enzyme having at least NAD+dependent acetylating acetaldehyde dehydrogenase activity (EC 1.2.1.10 or EC 1.1.1.2); and [¶ 0014] one or more genes coding for a glycerol transporter;
[¶ 0123] the recombinant cell overexpresses the one or more endogenous or heterologous genes encoding enzyme activities in the non-oxidative pentose phosphate pathway under control of a constitutive promoter; said enzymatic activities are at least transketolase (EC 2.2.1.1, encoded in S. cerevisiae by TKL1 and TKL2; as evidenced by Kobayashi et al., (AMB Expr., 2018, Vol. 8:139, pages 1-11) disclose yeast comprises a transketolase encoding gene having 100% sequence identity to SEQ ID NO: 1 of the instant invention; see provided sequence alignment;
[¶ 0135] to increase the likelihood that enzyme activity is expressed at sufficient levels and in active form in the recombinant cell, the nucleotide sequence encoding these enzymes, as well as the Rubisco enzyme;
[¶ 0074] said recombinant cell comprises one or more genes coding for an enzyme in an acetyl-CoA-production pathway, the one or more genes coding for an enzyme in an acetyl-CoA-production pathway comprises: [¶ 0075] one or more genes coding for an enzyme having phosphoketolase (PKL) activity (EC 4.1.2.9 or EC 4.1.2.22); and/or [¶ 0076] one or more genes coding for an enzyme having phosphotransacetylase (PTA) activity (EC 2.3.1.8); and or [¶ 0077] one or more genes coding for an enzyme having acetate kinase (ACK) activity (EC 2.7.2.12);
[¶ 0078] said recombinant cell may comprise one or more (heterologous) genes coding for an enzyme having phosphoketolase activity; as used herein, a phosphoketolase catalyzes at least the conversion of D-xylulose 5-phosphate to D-glyceraldehyde 3-phosphate and acetyl phosphate;
[¶ 0108] in an embodiment the one or more genes encoding an enzyme having at least NAD+dependent acetylating acetaldehyde dehydrogenase activity.
Regarding claim 18, De Waal et al., discloses, [¶ 0162] strains are semi-aerobically propagated in a Mineral Medium supplemented with 20 g/L glucose into main fermentation medium; fermentation experiments are performed in an Alcoholic Fermentation Monitor containing. 60 g/L glucose.
Regarding claim 19, De Waal et al., discloses, said recombinant yeast cell/Saccharomyces cerevisiae for improved glycerol free ethanol production; said reference recombinant yeast cell recombinant yeast cell/Saccharomyces cerevisiae under Micro-/Anaerobic Cultivations and said process is carried out in the presence of saccharolytic enzyme glucoamylase; [¶ 0161] 0.16 g/kg glucoamylase (Spirizyme, Novozymes) is added at the start of fermentation.
Regarding claim 34, De Waal et al., discloses, [¶ 0101] said recombinant cell either lacks enzymatic activity needed for NADH-dependent glycerol synthesis or has reduced enzymatic activity needed for NADH-dependent glycerol synthesis compared to its corresponding wild type (yeast) cell; alternatively, strains that are defective in glycerol production may be obtained by random mutagenesis followed by selection of strains with reduced or absent activity of GPD and/or GPP.
The disclosure of De Waal et al., (US 2020/0024619 A1; priority 03/20/2018) is described in the rejection above. However, De Waal et al., is silent regarding; wherein said heterologous transketolase comprising the amino acid sequences of SEQ ID NOs: 3-5 and 17 (as in claim 17); wherein the expression of the nucleic acid sequence encoding the heterologous protein having transketolase activity is under control of a promoter having an anaerobic/aerobic expression ratio for the transketolase of 2 or more and said a promoter of ANB1 or DAN1 (as in claims 24-27); wherein the recombinant yeast cell functionally expresses a nucleic acid sequence encoding an enzyme having NADH-dependent nitrate reductase activity and/or a nucleic acid sequence encoding an enzyme having NADH-dependent nitrite reductase activity (as in claim 32); wherein the recombinant yeast cell further functionally expresses a nucleic acid sequence encoding an enzyme having nitrate and/or nitrite transporter activity (as in claim 33); and wherein the recombinant yeast cell further functionally expresses a nucleic acid sequence encoding a protein having glucoamylase activity (EC 3.2.1.20 or 3.2.1.3) (as in claim 36).
Regarding claim 17, the following references advantageously provide the structural and functional elements of the instant invention: Davidson R., (WO 2012/17092 A1; disclosing a transketolase having 100% sequence identities to SEQ ID NOs: 3-4 of the instant invention), Sun et al., (UniProtKB/TrEML database, Accession#G3AWW89; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 5 of the instant invention), Dujon et al., (UniProtKB/TrEML database, Accession#Q6BMN3; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 6 of the instant invention), De Schutter et al., (UniProtKB/TrEML database, Accession#C4QXK7; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 17 of the instant invention).
Regarding claims 24-27, Papapetridis et al., (US 10,689,670 B2) provide teaching, suggestion and motivation for a recombinant yeast cell functionally expressing one or more heterologous nucleic acid sequences under control of a promoter ABN1 or DAN1 (the “PRK promoter”), expression ratio anaerobic/aerobic of 2 or more that enables higher expression under anaerobic conditions than under aerobic conditions and production of ethanol (see Abstract; col. 2, lines 46-62; col. 7, lines 30-42; col. 8, lines 34-55; and entire document); said reference recombinant yeast cells comprise genes encoding for ribulose-1,5-phosphate carboxylase/oxygenase (EC4.1.1.39; Rubisco), one or more molecular chaperones for Rubisco, and one or more phosphoribulokinase (EC2.7.1.19; PRK), and phosphoribulokinase is (Abstract; and entire document); said reference also discloses one or more genes of the non-oxidative branch of the pentose phosphate pathway of the recombinant yeast of the invention are overexpressed, and/or a glycerol-3-phosphate dehydrogenase (GPD) gene is deleted or disrupted; embodiment a glycerol-3-phosphate dehydrogenase (GPD) gene is deleted or disrupted; the one or more genes of the pentose phosphate pathway that is overexpressed encodes for an enzyme selected from the list of a transaldolase (EC 2.2.1.2), a transketolase (EC 2.2.1.1), a ribose-5-phosphate isomerase (EC 5.3.1.6) and a D-ribulose-5-phosphate 3-epimerase (EC 5.1.3.1); the one or more genes of the pentose phosphate pathway that is overexpressed is selected from the list of TAL1, TAL2, NQM1, TKL1, TKL2, RPE1 and RKI1 (col. 33, lines 15-40).
Regarding claims 32-33, Pena-Moreno et al., (J. Indust. Miocrobiol. Biotechnol., 2019, Vol. 46: 209-220) provide teaching, suggestion and motivation for a recombinant yeast cell further expressing an enzyme having NADH-dependent nitrate reductase activity; an enzyme having NADH-dependent nitrite reductase activity; and an enzyme having nitrate and/or nitrite transporter activity. Pena-Moreno et al., provide evidence and information on the physiology of yeast growing in the presence of nitrogen source and under anerobic (complete absence of oxygen; see Abstract; Table 1, page 212; Fig. 2, page 214 and entire document); provide evidence that said genes in nitrogen assimilation are an enzyme having NADH-dependent nitrate reductase activity; an enzyme having NADH-dependent nitrite reductase activity; and an enzyme having nitrate and/or nitrite transporter activity “The first cluster was related to nitrate assimilation composed by YNT1, YNR1 and YNI1, that ultimately converts nitrate into ammonium, and by GDH1 that uses this ammonium to produce glutamate (Fig. 2)” (see Fig. 2, page 214; col. 1-2, & Fig. 6, page 218).
Regarding claim 36, analogous art Petit et al., (US 2019/0292532 A1) provide teaching, suggestion and motivation for a recombinant yeast cell further expressing an enzyme having glucoamylase activity. Petit et al., disclose improved Saccharomyces cerevisiae yeast strains that co-express a gene encoding a glucoamylase to produce bioethanol. Applicants’ are directed to the following sections in Petit et al., (US 2019/0292532 A1): Abstract; [¶ 0002]; [0008-0021]; claims 1-12; and entire document.
Therefore, it would have been obvious to a person of ordinary skill in the art to combine and modify the teachings of De Waal et al., and employ the DAN1/ANB1 promoters of Papapetridis et al., that teach structural and functional elements involved in the enhanced production of organic compounds/ethanol under anaerobic culturing conditions to generate a genetically modified recombinant microbial/host cell comprising recombinant proteins involved in the biochemical pathway of organic compounds/ethanol under anaerobic culturing conditions; said genetic modification in said recombinant host cell involving enhancing the activities of enzymes/proteins/functional elements and controlling their expression depending on the experimental need, that are involved in the synthesis of precursors/intermediate products and the enhanced production of final product organic compounds/ethanol under anaerobic culturing conditions i.e., an enzyme having NADH-dependent nitrate reductase activity; an enzyme having NADH-dependent nitrite reductase activity; an enzyme having nitrate and/or nitrite transporter activity and an enzyme having glucoamylase activity, as suggested in the teachings of Pena-Moreno et al., and Petit et al. Motivation to generate such a modified microorganism derives from the fact that organic compounds/ethanol is a commercial product of importance and useful in the preparation of fine chemicals, agrochemicals, pharmaceuticals, food, oil and plastic industry (De Waal et al., Papapetridis et al., Pena-Moreno et al., and Petit et al.,). The expectation of success is high, because the combined teachings of De Waal et al., Papapetridis et al., Pena-Moreno et al., and Petit et al., teach genetically modified recombinant microbial/host cells comprising recombinant enzymes/proteins/functional promoter elements and the entire pathway for the enhanced production of organic compounds/ethanol under anaerobic culturing conditions and said references also provide the structural and functional elements of the instant invention (Teaching, Suggestion and Motivation).
Given this extensive teaching in prior art ((De Waal et al., Papapetridis et al., Pena-Moreno et al., and Petit et al.,) a process for production of ethanol, said process comprising a recombinant yeast cell Saccharomyces cerevisiae comprising a genus of polypeptides including mutants and variants of having the following activities: transketolase activity (EC 2.2.1.1), saccharolytic enzyme, ribulose-1,5-biphosphate carboxylase oxygenase (Rubisco) activity, chaperones, phosphoketolase activity, NAD+dependent acetylating acetaldehyde dehydrogenase activity, NADH-dependent nitrate reductase activity, and glucoamylase activity; wherein said transketolase comprising an amino sequence having 80% sequence identity to the amino acid sequences of SEQ ID NOs: 1, 3-6 and 17; wherein said recombinant yeast cell further comprising any promoter “a promoter having an anaerobic/aerobic expression ratio” including mutants and variants of undefined/unlimited structures (genus of promoters) driving the expression said genus of transketolases, as taught by the instant invention and as claimed in claims 17-19 and 23-36 is not of innovation but of ordinary skill in the art and the expectation of success is extremely high i.e., “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.”KSR, 550 U.S. at, 82 USPQ2d at 1397”.
The cited references render claims 17-19 and 23-36 prima facie obvious to one of ordinary skill in the art when one applies the Teaching, Suggestion and Motivation (TSM) test under the rationale for arriving at a conclusion of obviousness as suggested by the KSR ruling. The rationale applied for this rejection is as follows:
(1) Combining prior art elements according to known method to yield predictable results.
(2) Simple substitution of one known element for another to obtain predictable results.
(3) "Obvious to try"- choosing from a finite number of identified, predictable solution, with a reasonable expectation of success.
Therefore, claims 17-19 and 23-36 are rejected under 35 U.S.C. 103(a) as being unpatentable over De Waal et al., (US 2020/0024619 A1; priority 03/20/2018) and as evidenced by Kobayashi et al., (AMB Expr., 2018, Vol. 8:139, pages 1-11) and further in view of Davidson R., (WO 2012/17092 A1; disclosing a transketolase having 100% sequence identities to SEQ ID NOs: 3-4 of the instant invention), Sun et al., (UniProtKB/TrEML database, Accession#G3AWW89; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 5 of the instant invention), Dujon et al., (UniProtKB/TrEML database, Accession#Q6BMN3; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 6 of the instant invention), De Schutter et al., (UniProtKB/TrEML database, Accession#C4QXK7; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 17 of the instant invention), Papapetridis et al., (US 10,689,670 B2), Pena-Moreno et al., (J. Indust. Miocrobiol. Biotechnol., 2019, Vol. 46: 209-220) and Petit et al., (US 2019/0292532 A1).
Applicants’ have traversed the above 35 U.S.C. 103(a) rejection following claim amendments and said arguments are relevant to the new rejection (see pages 17-20 of Applicants’ REMARKS dated 08/06/2026).
Applicants’ argue (A): “…Cited references Sun, Dujon, De Schutter, and Davidson relied upon for allegedly teaching SEQ ID NOs: 3-6 and 17, recited by presently pending claim 17, merely disclose the existence of particular transketolase sequences. The fact that a sequence appears in a patent publication or protein database does not provide motivation to select that sequence for incorporation into a recombinant Saccharomyces cerevisiae host engineered for ethanol production. The Office has not identified any disclosure suggesting that these particular heterologous transketolases would be preferred, advantageous, or even suitable for use in the teachings of De Waal. Furthermore, Davidson, which is cited for allegedly teaching polypeptides having 100% sequence identify to SEQ ID NOs: 3 and 4 (see, SEQ ID NOs: 4 and 5 of Davidson), actually teaches the deletion of such transketolase enzymes in yeast. See, for example, Examples 2-5 as well as claims 1, 4, 5, and 12-15 of Davidson, which teach deletion of Das 1p (SEQ ID NO: 4 of Davidson) and/or Das2p (SEQ ID NO: 5 of Davidson). Therefore, a person of ordinary skill in the art would not have been motivated to combine the teachings of Davidson with those of De Waal because Davidson teaches away from expressing a transketolase in yeast. Nor has the Office established a reasonable expectation of success…”
Reply: Applicants' arguments have been considered but are found to be non-persuasive for the following reasons. Examiner continues to maintain the rejection for reasons stated on record (dated 05/08/2026) and additionally for the following reasons. Furthermore, applicants' arguments appear to be self-contradictory, i.e., applicants’ are arguing in the alternative “having it both ways”, on one hand to overcome the written-description and enablement rejections based on the broadest interpretation of claims, applicants’ have presented the following argument: “…Therefore, a person of skill in the art having read Devos and Whisstock (and even Witkowski and Seffernick), would have considered sequences with 80% sequence identity to, e.g., the sequences recited in the pending claims, to have the same function. A person of skill in the art having read Devos and appreciated the broad approach and analysis undertaken in the article would also likely have viewed Witkowski, Seffernick, and Broun as describing unique instances of deviations from the norm. Thus, a person of skill in the art would have reasonably concluded that the Applicant was in possession of the claimed invention at the time of filing based not only on the disclosure of specification but also on the existing literature, including such literature cited by the Office…” (pages 13-14 of Applicants’ REMARKS dated 08/06/2026); and on the other hand to overcome the 35 U.S.C. 103(a)obviousness rejection applicants’ are presenting the following argument in the alternative: “… The cited transketolase references merely identify protein sequences. They do not teach expression of the instantly claimed transketolases in recombinant yeast cells, and, in the case of Davidson, even teach the deletion of such claimed transketolases in yeast cells gives rise to a benefit. They do not teach or suggest the claimed combination of native and heterologous transketolases. They do not teach or suggest the particular engineered metabolic framework recited in the claims. Nor do they provide any teaching that would lead a skilled artisan to combine the references in the manner asserted by the Office....” (pages 18-19 of Applicants’ REMARKS dated 08/06/2026). Therefore, examiner takes the position that applicants’ own argument presented in pages 13-14 of Applicants’ REMARKS dated 08/06/2026 supports examiner’s position.
Contrary to applicants arguments, the combination of references cited above in 35 U.S.C. 103(a) provide teaching, suggestion and motivation and the structural and functional elements of the instant invention (for details see the rejection above).
Hence, examiner continues to take the following position:
I. The applicant’s arguments are directed against the references individually. However, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
II. The cited references are in congruence with the obviousness rejection and teach all limitations of the instant claims i. e., meet all the criteria and parameters (Teaching, Suggestion and Motivation) as defined by Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966) and the rationale for TSM test (Teaching, Suggestion and Motivation) according to the KSR ruling.
III. a) The objectives of the cited references need not be the same as the instant invention to be used in an obviousness rejection; and b) obviousness does not require an absolute certainty of success but merely a reasonable expectation thereof, so long as the motivation or suggestion to combine the teaching of the cited references is known or disclosed in the prior art and is obvious to one skilled in the art and this is sufficient to establish a prima facie case of obviousness.
Therefore, examiner has provided ample evidence regarding structural and functional elements having the associated function (for details see 35 U.S.C. 103 rejection above) and continues to take the position that each and every element of the instant invention is taught in the combination of cited references and that the combined teachings in the cited prior art provides a reasonable expectation of success and predictability for the claimed method herein and the claimed benefits are very much expected and predictable.
Maintained-Double Patenting rejection
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 17-19 and 23-36 are provisionally rejected on the ground of nonstatutory double patenting over: (i) amended claims 15-23 and 25-31 (dated 07/29/2026) of co-pending Application No. 18/578,581 (US 2025/0277205 A1); (ii) amended claims 15-30 (dated 04/16/2026) of co-pending Application No. 18/578,587 (US 2025/0320529 A1); (iii) amended claims 15-31 (dated 04/16/2026) of co-pending Application No. 18/578,589 (US 2024/0401088 A1); and (iv) amended claims 15-31 (dated 08/16/2026) of co-pending Application No. 18/578,592 (US 2025/0333768 A1). This is a provisional double patenting rejection because the patentably indistinct claims have not in fact been patented.
The subject matter claimed in the instant application is fully disclosed in the referenced co-pending applications and would be covered by any patent granted on that co-pending applications, since the referenced co-pending applications and the instant application are claiming common subject matter, as follows: “a process for production of ethanol, said process comprising recombinant yeast cell comprising a genus of polypeptides having the following activities: transketolase activity (EC 2.2.1.1), saccharolytic enzyme, ribulose-1,5-biphosphate carboxylase oxygenase (Rubisco) activity, chaperones, phosphoketolase activity, NAD+dependent acetylating acetaldehyde dehydrogenase activity, NADH-dependent nitrate reductase activity, and glucoamylase activity; wherein said transketolase comprising an amino sequence having 80% sequence identity to the amino acid sequences of SEQ ID NOs: 1, 3-6 and 17; wherein said recombinant yeast cell further comprising “a promoter having an anaerobic/aerobic expression ratio” driving the expression said genus of transketolases”. The recited (i) amended claims 15-23 and 25-31 (dated 07/29/2026) of co-pending Application No. 18/578,581 (US 2025/0277205 A1); (ii) amended claims 15-30 (dated 04/16/2026) of co-pending Application No. 18/578,587 (US 2025/0320529 A1); (iii) amended claims 15-31 (dated 04/16/2026) of co-pending Application No. 18/578,589 (US 2024/0401088 A1); and (iv) amended claims 15-31 (dated 08/16/2026) of co-pending Application No. 18/578,592 (US 2025/0333768 A1) also encompass, “a process for production of ethanol, said process comprising recombinant yeast cell (genus of yeasts) comprising a genus of polypeptides having the following activities: transketolase activity (EC 2.2.1.1), saccharolytic enzyme, ribulose-1,5-biphosphate carboxylase oxygenase (Rubisco) activity, chaperones, phosphoketolase activity, NAD+dependent acetylating acetaldehyde dehydrogenase activity, NADH-dependent nitrate reductase activity, and glucoamylase activity; wherein said transketolase comprising an amino sequence having 80% sequence identity to the amino acid sequences; wherein said recombinant yeast cell (genus of yeasts) further comprising “a promoter having an anaerobic/aerobic expression ratio” driving the expression said genus of transketolases”; said references also disclose polypeptide sequences having 100% sequence identity to SEQ ID NOs: 1, 3-6 and 17 of the instant invention (see provided sequence alignments). This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Applicants have traversed the above double patenting with the following arguments: (see page 20 of Applicants’ REMARKS dated 08/06/2026).
Applicants argue: “…Without acquiescing and for the sole purpose of expediting prosecution, Applicant submitted a terminal disclaimer and the terminal disclaimer fee on August 6, 2026 via the U.S. Patent and Trademark Office Patent Center system.”
Reply: Applicants' arguments have been considered but are found to be non-persuasive for the following reasons. Examiner continues to maintain the rejection for reasons stated on record (dated 05/08/2026) and additionally for the following reasons. Contrary to applicants arguments, no Terminal-Disclaimed of record has been filed along with the response dated 08/06/2026.
Summary of Pending Issues
The following is a summary of issues pending in the instant application.
Claims 17-19 and 23-36 are rejected under 35 U.S.C. 112(a) for written-description and enablement.
Claims 17-19 and 23-36 are rejected under 35 U.S.C. 103(a) as being unpatentable over De Waal et al., (US 2020/0024619 A1; priority 03/20/2018) and as evidenced by Kobayashi et al., (AMB Expr., 2018, Vol. 8:139, pages 1-11) and further in view of Davidson R., (WO 2012/17092 A1; disclosing a transketolase having 100% sequence identities to SEQ ID NOs: 3-4 of the instant invention), Sun et al., (UniProtKB/TrEML database, Accession#G3AWW89; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 5 of the instant invention), Dujon et al., (UniProtKB/TrEML database, Accession#Q6BMN3; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 6 of the instant invention), De Schutter et al., (UniProtKB/TrEML database, Accession#C4QXK7; disclosing a transketolase having 100% sequence identities to SEQ ID NO: 17 of the instant invention), Papapetridis et al., (US 10,689,670 B2), Pena-Moreno et al., (J. Indust. Miocrobiol. Biotechnol., 2019, Vol. 46: 209-220) and Petit et al., (US 2019/0292532 A1).
Claims 17-19 and 23-36 are provisionally rejected on the ground of nonstatutory double patenting over: (i) amended claims 15-23 and 25-31 (dated 07/29/2026) of co-pending Application No. 18/578,581 (US 2025/0277205 A1); (ii) amended claims 15-30 (dated 04/16/2026) of co-pending Application No. 18/578,587 (US 2025/0320529 A1); (iii) amended claims 15-31 (dated 04/16/2026) of co-pending Application No. 18/578,589 (US 2024/0401088 A1); and (iv) amended claims 15-31 (dated 08/16/2026) of co-pending Application No. 18/578,592 (US 2025/0333768 A1).
Conclusion
None of the claims are allowable. Claims 17-19 and 23-36 are rejected for the reasons identified in the Rejections and Summary sections of this Office Action. Applicants must respond to the rejections in each of the sections in this Office Action to be fully responsive for prosecution.
THIS ACTION IS MADE FINAL. Applicants are 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 mailing date of this final action.
Regarding filing an After Final amendment, Applicants are directed to MPEP 714.13, which states:
II. ENTRY NOT A MATTER OF RIGHT
It should be kept in mind that applicant cannot, as a matter of right, amend any finally rejected claims, add new claims after a final rejection (see 37 CFR 1.116) or reinstate previously canceled claims. Except where an amendment merely cancels claims, adopts examiner suggestions, removes issues for appeal, or in some other way requires ONLY A CURSORY REVIEW by the examiner (e.g., typographical errors), compliance with the requirement of a showing under 37 CFR 1.116(b)(3) is expected in all amendments after final rejection. An affidavit or other evidence filed after a final rejection, but before or on the same date of filing an appeal, may be entered upon a showing of good and sufficient reasons why the affidavit or other evidence is necessary and was not earlier presented in compliance with 37 CFR 1.116(e). See 37 CFR 41.33 and MPEP § 1206 for information on affidavit or other evidence filed after appeal. (Examiner's emphasis) If more than a cursory review is required, Applicants are referred to CFR §1.114.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GANAPATHIRAMA RAGHU whose telephone number is (571)272-4533. The examiner can normally be reached on M-F 8:30am-5pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on 408-918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/GANAPATHIRAMA RAGHU/ Primary Examiner, Art Unit 1652
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