Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Application Status
In response to Non-Final Office Action mailed on 10/07/2025, applicants' response, arguments and amendments filed on dated 12/16/2025 is acknowledged; in said response applicants’ have amended claims 1 and 6-8. Thus, amended claims 1-20, are pending and are now under consideration; elected Group I, amended claims 1-12 reading on the elected invention is now under consideration for examination; claims 13-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a non-elected invention, there being no allowable generic or linking claim. Rejections and/or objections not reiterated from previous office action are hereby withdrawn.
The Terminal Disclaimer filed on 12/16/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of over allowed patents: (i) US Patent 9,957,540; (ii) US Patent 10,612,066; and (iii) US Patent 11,530,431 has been reviewed and accepted. The Terminal Disclaimer has been recorded.
Withdrawn-Double Patenting rejection
Previous rejection of claims 1-12 rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over allowed patents: (i) claims 1-30 of US Patent 9,957,540; (ii) claims 1-24 of US Patent 10,612,066; and (iii) claims 1-19 of US Patent 11,530,431, is being withdrawn due to submission of a Terminal Disclaimer.
Maintained-Claim Rejections: 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(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.
Claims 1-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
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.
“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." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus.”). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
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.
The claims recite the following broadly claimed genera:
Claims 1-12 recite a genera of polypeptides, encoding polynucleotides in a recombinant cell i.e., “Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method (as in claims 1-5) or produced by a enzymatic method (as in claims 6-12); wherein the methods comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 65% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO:16; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 50% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; and (b) providing the whole cell or enzymatic method with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19-0-glucose,wherein the steviol glycoside is selected… Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method, wherein the method comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (b) providing the whole cell with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19- 0-glucose,wherein the steviol glycoside is selected… wherein the first 5'-UDP glycosyl transferase is capable of converting RebA to Rebaudioside D (RebD) at a rate that is at least 20 times faster than the rate at which a UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 is capable of converting RebA to RebD under corresponding reaction conditions; and/or wherein the first 5'-UDP glycosyl transferase polypeptide of (a)(i) is capable of converting higher amounts of RebA to RebD compared to the UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 under corresponding reaction condition.
The structural elements recited in claims 1-12 are not sufficient structure to form “(i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 65% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO:16; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 50% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO: 2” “a genera of polypeptides, encoding polynucleotides in a recombinant cell i.e., “Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method (as in claims 1-5) or produced by a enzymatic method (as in claims 6-12); wherein the methods comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 65% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO:16; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 50% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; and (b) providing the whole cell or enzymatic method with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19-0-glucose,wherein the steviol glycoside is selected… Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method, wherein the method comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (b) providing the whole cell with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19- 0-glucose,wherein the steviol glycoside is selected… wherein the first 5'-UDP glycosyl transferase is capable of converting RebA to Rebaudioside D (RebD) at a rate that is at least 20 times faster than the rate at which a UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 is capable of converting RebA to RebD under corresponding reaction conditions; and/or wherein the first 5'-UDP glycosyl transferase polypeptide of (a)(i) is capable of converting higher amounts of RebA to RebD compared to the UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 under corresponding reaction condition.
As such, claims 1-12 recite a genera of biomolecules described only by a functional characteristics i.e., being “(i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 65% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO:16; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 50% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO: 2”, 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.” Further, without any structural limitations for structural features that actually provide for “(i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 65% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO:16; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 50% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO: 2”, claims 1-12 have no defined outer bounds for the scope of polypeptides that fall within the scope of the claims. Due to the literal unlimited structural scope of the claims, it is not possible to provide for a representative number of species that adequately described are representative of the entire genus having no fixed structural outer boundaries. Further, such genera of altered enzymes as recited lack “a precise definition, such as by structure, formula, [or] chemical name, of the claimed subject matter sufficient to distinguish it from other materials” and without any required structure that is sufficient for providing the recited enzyme activity, the recited genera lack 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. The claims lack adequate written description in the as-filed specification for the reasons stated.
No information, beyond the characterization of specific structures and specific variants/mutants of a parental wild-type comprising the amino acid sequences of SEQ ID NO: 2 and the encoding polynucleotides, isolated specific strain of yeast Saccharomyces cerevisiae host cell comprising the encoding polynucleotides, method of making and method of use for producing Reb M (see Examples 1-16, pages 68-108 of specification), has been provided by the applicants’, which would indicate that they had possession of the claimed a genera of polypeptides, encoding polynucleotides in a recombinant cell i.e., “Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method (as in claims 1-5) or produced by a enzymatic method (as in claims 6-12); wherein the methods comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 65% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO:16; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 50% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; and (b) providing the whole cell or enzymatic method with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19-0-glucose,wherein the steviol glycoside is selected… Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method, wherein the method comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (b) providing the whole cell with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19- 0-glucose,wherein the steviol glycoside is selected… wherein the first 5'-UDP glycosyl transferase is capable of converting RebA to Rebaudioside D (RebD) at a rate that is at least 20 times faster than the rate at which a UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 is capable of converting RebA to RebD under corresponding reaction conditions; and/or wherein the first 5'-UDP glycosyl transferase polypeptide of (a)(i) is capable of converting higher amounts of RebA to RebD compared to the UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 under corresponding reaction condition.
The genus of polypeptides and encoding polynucleotides 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 is adequately described by the disclosure of the structures and the characterization of the variants/mutants of amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 16 and the encoding polynucleotides, 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, in IDS), 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).
(b) Whisstock et al., (Quarterly Reviews of Biophysics 2003, Vol. 36 (3): 307-340, in IDS) 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, in IDS), teaches that one conservative amino acid substitution transforms a b-ketoacyl synthase into a malonyl decarboxylase and completely eliminates b-ketoacyl synthase activity. Seffernick et al., (J. Bacteriol. 183(8): 2405-2410, 2001, in IDS), 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, in IDS), 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.
As stated above, no information beyond the characterization of specific structures and specific variants/mutants of a parental wild-type comprising the amino acid sequences of SEQ ID NO: 2 and the encoding polynucleotides, isolated specific strain of yeast Saccharomyces cerevisiae host cell comprising the encoding polynucleotides, method of making and method of use for producing Reb M (see Examples 1-16, pages 68-108 of specification), has been provided by the applicants’, which would indicate that they had possession of the a genera of polypeptides, encoding polynucleotides in a recombinant cell i.e., a genera of polypeptides, encoding polynucleotides in a recombinant cell i.e., “Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method (as in claims 1-5) or produced by a enzymatic method (as in claims 6-12); wherein the methods comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 65% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO:16; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 50% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; and (b) providing the whole cell or enzymatic method with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19-0-glucose,wherein the steviol glycoside is selected… Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method, wherein the method comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (b) providing the whole cell with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19- 0-glucose,wherein the steviol glycoside is selected… wherein the first 5'-UDP glycosyl transferase is capable of converting RebA to Rebaudioside D (RebD) at a rate that is at least 20 times faster than the rate at which a UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 is capable of converting RebA to RebD under corresponding reaction conditions; and/or wherein the first 5'-UDP glycosyl transferase polypeptide of (a)(i) is capable of converting higher amounts of RebA to RebD compared to the UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 under corresponding reaction condition.
As the claimed genera of polypeptides and encoding polynucleotides 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 (pre-AIA ), 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 17-21 of Applicants’ REMARKS dated 12/16/2025).
Applicants’ argue: “…In contrast to claim 2 of Example 9, claim 3 of Example 10, and claim 3 of Example 17 of the Training Materials, instant claims are directed to Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced in the whole cell in vitro method, wherein the whole cells are described both structurally and functionally, and the instant application discloses a sufficient correlation between the function and structure of the whole cells within the claimed genus.
Moreover, one skilled in the art would readily appreciate that the instant application discloses that Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM can be produced using whole cells that are fed raw materials that contain precursor molecules such as steviol and/or steviol glycosides, including mixtures of steviol glycosides derived from plant extracts (see e.g., [00229]). The specification further discloses that the host cells can contain one or multiple uridine diphosphate dependent glycosyltransferases (UGTs) catalyzing several glycosylation reactions on the steviol backbone, which leads to the production of various steviol glycosides. Some UGTs may be recombinant polypeptides (see e.g., [00230]). For example, the host cells can contain a polypeptide capable of beta 1,2 glycosylation of the C2’ of the 13-O-glucose, 19-O- glucose, or both 13-O-glucose and 19-O-glucose of the steviol glycoside and a polypeptide capable of beta 1,3 glycosylation of the C3’ of the 13-O-glucose, 19-O- glucose, or both 13-O-glucose and 19-O-glucose of the steviol glycoside such that when these polypeptides are expressed in the host cells, rubusoside, stevioside, Rebaudioside A, Rebaudioside E, or a combination thereof that are fed to the host cells are efficiently converted to Rebaudioside M. Example 2 describes characterization of reactions carried by the two polypeptides recited in the instant claim 1, as amended, to produce Rebaudioside M.
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 10/07/2025) and additionally for the following reasons.
Examiner continues to maintain the following: The claims encompass a large genus of proteins which are substantially unrelated or completely unrelated and includes random mutants of SEQ ID NO: 2. A polypeptide having 50% sequence identity with the polypeptide of SEQ ID NO: 2 allows for any combination of 229 amino acid modifications within SEQ ID NO: 2 (229 = 0.5x458; SEQ ID NO: 2 has 458 amino acids). The total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula N!x19a/(N-A)!/A!, where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. Thus, the total number of variants having at least X% sequence identity with the polypeptide of SEQ ID NO: X that result from amino acid substitutions is 458!x19229/(462-229)!/229! (SEQ ID NO: 2 has 458 amino acids) or 3.37x10442 variants, a very large number mutants or variants. A similar calculation for variants of the polypeptide of SEQ ID NO: 16 having 65% sequence identity with the polypeptide of SEQ ID NO: 16 also yields an extremely large number of variants or mutants.
Examiner’s position is supported by the following scientific evidence: Guo et al., (2004) 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, an amino acid sequence of 50% sequence identity to SEQ ID NO: 2 allows up to 229 random mutations within the 458 amino acid residues of SEQ ID NO: 2 and, thus, only (0.66)^229 X 100% or 4.73 x 10-40 % of random mutants having 50% sequence identity to of SEQ ID NO:2 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; an extremely low number of active mutants will be present among an enormously large number of inactive mutants and as such screening for these active mutants would be burdensome and undue experimentation when there is no guidance provided in the specification and there is no evidence of possession. 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 UDP-glycosyltransferases the following references teach the following: (i) Kubo et al., (Arch. Biochem. Biophys., 2004, Vol. 249: 198-203) provide evidence that a single point mutation alters the sugar donor specificities and catalytic activity of a glycosyltransferase ( see Abstract: Table 1, page 201; and entire document); and (ii) Bowles et al., (Annu. Rev. Plant Biol., 2006, Vol. 57: 67-97) provide evidence “In vitro studies have shown that a single gene product can glycosylate multiple substrates of diverse origins; multiple enzymes can also glycosylate the same substrate. These features suggest that in a cellular context, substrate availability is a determining factor in enzyme function, and redundancy depends on the extent of coordinate gene regulation” (see Abstract; Summary Points, pages 587-588; and entire document).
Contrary to applicants arguments, while methods to produce variants of a known sequence, such as site-specific mutagenesis, random mutagenesis, etc., are well known to the skilled artisan, producing variants capable of having the associated function/activity, i.e., any nucleic acid mutation in the encoding gene or amino acid mutation in the encoded polypeptide requires that one of ordinary skill in the art know or be provided with guidance for the selection of which, of the infinite number of variants, have the activity. Without such guidance, one of ordinary skill would be reduced to the necessity of producing and testing all of the virtually infinite possibilities. For the rejected claims, this would clearly constitute undue experimentation and lack of evidence of possession.
Therefore, the scope of the instant claims are broad despite the guidance of the art and specification, the claims remain not commensurate with evidence of possession or in scope with the enabled invention. An important consideration is that structure is not necessarily a reliable indicator of function, as the art clearly teaches: i) 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 (Devos et al., and Whisstock et al., supra) and in the instant application there is no disclosed correlation between structure and function for any mutant or any modified isomaltase or maltase polypeptides having 50%-65% sequence identity (mutants/variants of SEQ ID NO: 2 or 16, as conservation of certain motifs with remainder of the structure undefined, is not necessarily a surrogate for conservation of function.
Given this scenario, a skilled artisan needs to be provided with the specific structure associated with the function. The specification does not provide support for the full scope and breadth of the claims, thus examiner continues to hold the position the experimentation left to those skilled in the art is unnecessarily, and improperly extensive and undue.
Examiner in the body of rejction above has cited references/scientific findings that support examiner’s position, for the following reason; mutations affect the inter or intra molecular interactions of the encoded enzymes and said interactions determine the folding, 3-D configurations that are required for the activity and examiner would like to reiterate, that the instant invention is limited to the characterization of an of a full-length intact wild-type polypeptide sequences of SEQ ID NO: 2 or SEQ ID NO: 65 and specific variants of SEQ ID NO: 2 and there is no additional information regarding variants, mutants i.e., structure correlated to function. Therefore, the scope of the instant claims are broad despite the guidance of the art and specification, the claims remain not commensurate with evidence of possession or in scope with the enabled invention.
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.
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
Claims 1-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification is enabling for the characterization of specific structures and specific variants/mutants of a parental wild-type comprising the amino acid sequences of SEQ ID NO: 2 and the encoding polynucleotides, isolated specific strain of yeast Saccharomyces cerevisiae host cell comprising the encoding polynucleotides, method of making and method of use for producing Reb M (see Examples 1-16, pages 68-108 of specification). However, specification does not reasonably provide enablement for a genera of polypeptides, encoding polynucleotides in a recombinant cell i.e., “Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method (as in claims 1-5) or produced by a enzymatic method (as in claims 6-12); wherein the methods comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 65% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO:16; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 50% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; and (b) providing the whole cell or enzymatic method with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19-0-glucose,wherein the steviol glycoside is selected… Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method, wherein the method comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (b) providing the whole cell with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19- 0-glucose,wherein the steviol glycoside is selected… wherein the first 5'-UDP glycosyl transferase is capable of converting RebA to Rebaudioside D (RebD) at a rate that is at least 20 times faster than the rate at which a UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 is capable of converting RebA to RebD under corresponding reaction conditions; and/or wherein the first 5'-UDP glycosyl transferase polypeptide of (a)(i) is capable of converting higher amounts of RebA to RebD compared to the UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 under corresponding reaction condition. 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 1-12 are so broad as to encompass: a genera of polypeptides, encoding polynucleotides in a recombinant cell i.e., “Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method (as in claims 1-5) or produced by a enzymatic method (as in claims 6-12); wherein the methods comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 65% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO:16; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 50% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; and (b) providing the whole cell or enzymatic method with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19-0-glucose,wherein the steviol glycoside is selected… Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method, wherein the method comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (b) providing the whole cell with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19- 0-glucose,wherein the steviol glycoside is selected… wherein the first 5'-UDP glycosyl transferase is capable of converting RebA to Rebaudioside D (RebD) at a rate that is at least 20 times faster than the rate at which a UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 is capable of converting RebA to RebD under corresponding reaction conditions; and/or wherein the first 5'-UDP glycosyl transferase polypeptide of (a)(i) is capable of converting higher amounts of RebA to RebD compared to the UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 under corresponding reaction condition. The scope of the claim is not commensurate with the enablement provided by the disclosure with regard to the extremely large number of polynucleotides and encoded polypeptides broadly encompassed by the claims. Since the amino acid sequence of a protein encoded by a polynucleotide determines its structural and functional properties, predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which amino acids in the protein's sequence and the respective codons in its polynucleotide, 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 proteins' structure relates to its function. However, in this case the disclosure is limited to the characterization of specific structures and specific variants/mutants of a parental wild-type comprising the amino acid sequences of SEQ ID NO: 2 and the encoding polynucleotides, isolated specific strain of yeast Saccharomyces cerevisiae host cell comprising the encoding polynucleotides, method of making and method of use for producing Reb M (see Examples 1-16, pages 68-108 of specification). It would require undue experimentation of the skilled artisan to make and use the claimed polypeptides i.e., a genera of polypeptides, encoding polynucleotides in a recombinant cell i.e., “Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method (as in claims 1-5) or produced by a enzymatic method (as in claims 6-12); wherein the methods comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 65% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO:16; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 50% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; and (b) providing the whole cell or enzymatic method with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19-0-glucose,wherein the steviol glycoside is selected… Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method, wherein the method comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (b) providing the whole cell with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19- 0-glucose,wherein the steviol glycoside is selected… wherein the first 5'-UDP glycosyl transferase is capable of converting RebA to Rebaudioside D (RebD) at a rate that is at least 20 times faster than the rate at which a UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 is capable of converting RebA to RebD under corresponding reaction conditions; and/or wherein the first 5'-UDP glycosyl transferase polypeptide of (a)(i) is capable of converting higher amounts of RebA to RebD compared to the UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 under corresponding reaction condition. The specification but provides no guidance with regard to the making of variants and mutants or with regard to other uses. In view of the great breadth of the claims, amount of experimentation required to make and use the claimed polypeptides, the lack of guidance, working examples, and unpredictability of the art in predicting function from a polypeptide primary structure (for example, see Whisstock et al., Prediction of protein function from protein sequence and structure. Q Rev Biophys. 2003, Aug. 36 (3): 307-340. Review, in IDS), the claimed invention would require undue experimentation. As such, the specification fails to teach one of ordinary skill how to make and use the full scope of the polypeptides and encoding polynucleotides encompassed by the claims. However, claims reading on significant numbers of inoperative embodiments would render claims non-enabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative.” Atlas Powder Co. v. E.I. duPont de Nemours & Co., 750 F.2d 1569, 1577, 224 USPQ 409, 414 (Fed. Cir. 1984); In re Cook, 439 F.2d 730, 735, 169 USPQ 298, 302 (CCPA 1971); MPEP 2164.08(b). Here, the claims read on a significant number of inoperative embodiments.
While enzyme isolation techniques, recombinant and mutagenesis techniques are known, and it is not routine in the art to screen for multiple substitutions or multiple modifications as encompassed by the instant claims, the specific amino acid positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions.
The specification does not support the broad scope of the claims which encompass: a genera of polypeptides, encoding polynucleotides in a recombinant cell i.e., “Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method (as in claims 1-5) or produced by a enzymatic method (as in claims 6-12); wherein the methods comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 65% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO:16; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside and having 50% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; and (b) providing the whole cell or enzymatic method with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19-0-glucose,wherein the steviol glycoside is selected… Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method, wherein the method comprises:(a) providing a whole cell comprising: (i) a first uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (ii) a uridine 5'-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, the 19-0-glucose, or both the 13-0-glucose and the 19-0-glucose of the steviol glycoside; and (b) providing the whole cell with: (i) composition comprising a steviol glycoside having a 13-0-glucose, a 19-0-glucose, or both a 13-0-glucose and a 19- 0-glucose,wherein the steviol glycoside is selected… wherein the first 5'-UDP glycosyl transferase is capable of converting RebA to Rebaudioside D (RebD) at a rate that is at least 20 times faster than the rate at which a UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 is capable of converting RebA to RebD under corresponding reaction conditions; and/or wherein the first 5'-UDP glycosyl transferase polypeptide of (a)(i) is capable of converting higher amounts of RebA to RebD compared to the UDP glycosyl transferase polypeptide having the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 86 under corresponding reaction condition; and wherein the a genera of modified polypeptides capable of beta 1,3 glycosylation of the C3' of the 13-0-glucose, 19-0-glucose, or both 13-0-glucose and 19-0-glucose of the steviol glycoside comprises a polypeptide having 50% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO: 2, because the specification does not establish: (A) a rational and predictable scheme for modifying specific amino acid residues in any “glycosyltransferase“ having no specific structural elements and an expectation of obtaining the desired biological/biochemical function; (B) a rational and predictable scheme for modifying any amino acid residue with an expectation of obtaining the desired biological/biochemical function; (C) defined core regions/motifs involved in the desired catalytic activity of encoded polypeptide; (D) the tertiary structure of the molecule and folding patterns that are essential for the desired activity and tolerance to modifications; and (E) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful.
While as discussed above, the specification provides guidance with regard to the characterization of specific structures and specific variants/mutants of a parental wild-type comprising the amino acid sequences of SEQ ID NO: 2 and the encoding polynucleotides, isolated specific strain of yeast Saccharomyces cerevisiae host cell comprising the encoding polynucleotides, method of making and method of use for producing Reb M (see Examples 1-16, pages 68-108 of specification), however, the scope of claims 1-12 is so broad and the lack of guidance either in the specification or in the prior art, the claims remains not commensurate in scope with the enabled invention and therefore for the rejected claims, this would clearly constitute undue experimentation. 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. The art also teaches the following regarding complexity of the structure/function relationship: The reference of Chica et al., (Curr. Opin. Biotechnol., 2005, Vol. 16: 378-384, in IDS) 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. Additionally, knowledge is not extant in the art to assay all possible enzymatic activities, how to express all possible enzymes or how predictably assay for such activities. For example, the reference of Banerjee et al., (Bioenerg. Res. 2010, Vol. 3: 82-92), on page 84, right column, second paragraph, describe that “enzymes have critical properties besides specific activity and thermal tolerance that must be considered but which can be difficult to assay in vitro. For example, besides catalyzing a particular chemical reaction, enzymes must be efficiently translated and secreted, able to resist proteases, act cooperatively with other enzymes, and have low product and feedback inhibition. One can easily imagine that an “improved” enzyme, based on assay in isolation on a model substrate, might perform poorly in a real-world situation”.
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 claims broadly including polynucleotides and encoded polypeptides with an enormous number of modifications. 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 polypeptides/enzymes having the desired biological characteristics 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 rejection with the following arguments: (see pages 21-23 of Applicants’ REMARKS dated 12/16/2025).
Applicants’ argue: “…All that is necessary and sufficient to enable the instant claims, as amended, is that one of ordinary skill in the art be able to produce Rebaudioside M (RebM) or a steviol glycoside composition comprising RebM produced by a whole cell in vitro method using a whole cell comprising: (i) a first uridine 5’-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,2 glycosylation of a C2’ of the 13-O-glucose, the 19-O-glucose, or both the 13-O-glucose and the 19-O-glucose of the steviol glycoside and having 65% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO:16; and (ii) a uridine 5’-diphospho (UDP) glycosyl transferase polypeptide capable of beta 1,3 glycosylation of the C3’ of the 13-O-glucose, the 19-O-glucose, or both the 13-O-glucose and the 19-O-glucose of the steviol glycoside and having 50% or greater sequence identity to the amino acid sequence set forth in SEQ ID NO:2; and wherein the whole cell is provided with (i) composition comprising a steviol glycoside having a 13-O-glucose, a 19-O-glucose, or both a 13-O-glucose and a 19-O-glucose, wherein the steviol glycoside is selected from the group consisting of rubusoside, stevioside, Rebaudioside A (RebA), and isomers thereof; and (ii) UDP-sugars…”.
Reply: Applicants' arguments have been considered but are found to be non-persuasive for the following reasons. Applicants’ arguments filed on 12/16/2025 for the traversal of enablement rejection is 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 1-12.
Summary of Pending Issues
The following is a summary of issues pending in the instant application.
Claims 1-12 are rejected under 35 U.S.C. 112(a) for written-description and enablement.
Claims 13-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a non-elected invention.
Conclusion
None of the claims are allowable. Claims 1-12 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. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the 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