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 05/21/2025, applicants' response, arguments, amendments and a Terminal disclaimer filed on dated 11/18/2025 is acknowledged; in said response applicants’ have amended claims 295-296 and 298. Thus, amended claims 295-309 and 311-314 are pending and are now under consideration.
Examiner for the record reiterates that applicant’s elected Group I, claims 295-303 in part without traverse in the reply filed on 05/07/2025; said election was as follows: “to claim 295, which has been amended to recite that "the one or more amino acid substitutions include at least one substituted amino acid at the amino acid residues corresponding to position C17, S21, S54, E75, or K78, Applicant elects Option 2, without traverse, for substantive examination”.
Examiner also reiterates that the instant claims and instant amendments do not limit the claims to 90% sequence identity to SEQ ID NO: 6, as claim 295 encompasses many sequences, at least 61 (sixty one sequences) whose sequence identity ranges from 89.6% to 80.1% to SEQ ID NO: 6, for example SEQ ID NOs: SEQ ID NO: 136, SEQ ID NO: 288, …SEQ ID NO: 300…SEQ ID NO: 264…SEQ ID NO: 312 (see provided sequence alignments and new 35 U.S.C. 112(d) rejection below). Additionally, claim 295 encompasses 342 sequences other than the elected SEQ ID NO: 6, and thus examination of all sequences is a burden. Examiner clearly enunciated his position in the Examiner initiated interview summary dated 12/05/2025 and followed it up with another call on 12/29/2025 and no response is received to date from the applicants.
Thus, amended claims 295-309 and 311-314 are pending in this application; elected Group I, claims 295-303 in part is now under consideration for examination, and claims 304-309 and 311-314 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim.
The Terminal Disclaimer filed on 11/18/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of allowed patents: (i) US 11,060,119 B2 and (ii) US 11,866,758 B2 has been reviewed and accepted. The Terminal Disclaimer has been recorded.
Rejections and/or objections not reiterated from previous office action are hereby withdrawn.
Maintained-Priority
Applicants’ claim for the benefit of priority under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. This application is a CON of 17/341,813 filed on 06/08/2021 now US Patent 11,866,758, which is a CON of 16/503,092 filed on 07/03/2019 now US Patent 11,060,119 and applicants’ claim for the benefit of priority under 35 U.S.C. 119(e) to the Provisional Applications: 62/693,681 and 62/693,660 filed on 07/03/2018 is acknowledged; however note that priority date for the instant claims 295-303 in part, as it relates to amino acid changes corresponding to positions in SEQ ID NO: 6 now under consideration is only granted the priority date of the instant application/non-provisional 16/503,092 filed on 07/03/2019, as support for the elected/claimed subject-matter is only found in 16/503,092 filed on 07/03/2019.
Information disclosure statement
The information disclosure statement (IDS) submitted on 11/18/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS statement is considered and initialed by the examiner.
Withdrawn-Double patenting rejection
Previous rejection of claims 295-303 rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over: (i) claims 1-52 of reference patent US 11,060,119 B2 (Zanghellini et al.,); and (ii) claims 1-43 of reference patent US 11,866,758 B2 (Zanghellini et al.,), is being withdrawn due to submission of a Terminal Disclaimer.
Withdrawn-Claim Rejections: 35 USC § 112(b)
Previous rejection of claim 298 rejected under 35 U.S.C. 112(b), is being withdrawn due to claim amendments.
New-Claim Rejections: 35 USC § 112(d)
Necessitated by claim amendments
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 295 and claims 296-303 (depending therefrom) is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Examiner reiterates that the instant claims and instant amendments do not limit the claims to 90% sequence identity to SEQ ID NO: 6, as claim 295 encompasses many sequences, at least 61 (sixty one sequences) whose sequence identity ranges from 89.6% to 80.1% to SEQ ID NO: 6, for example SEQ ID NOs: SEQ ID NO: 136, SEQ ID NO: 288, …SEQ ID NO: 300…SEQ ID NO: 264…SEQ ID NO: 312 (see provided sequence alignments).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
The U.S. Court of Appeals for the Federal Circuit indicated that although the requirements of pre-AIA 35 U.S.C. 112, 4th paragraph, are related to matters of form, non-compliance with pre-AIA 35 U.S.C. 112, 4th paragraph, renders the claim unpatentable just as non-compliance with other paragraphs of 35 U.S.C. 112 would. See Pfizer, Inc. v. Ranbaxy Labs., Ltd., 457 F.3d 1284, 1291-92, 79 USPQ2d 1583, 1589-90 (Fed. Cir. 2006) (holding a dependent claim in a patent invalid for failure to comply with pre-AIA 35 U.S.C. 112, 4th paragraph). Therefore, if a dependent claim does not comply with the requirements of 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, the dependent claim should be rejected under pre-AIA 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as unpatentable rather than objecting to the claim. See also MPEP § 608.01(n),subsection III, “Infringement Test” for dependent claims.
Maintained-Claim Rejections: 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 295-303 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim(s) 295-303 as a whole, do not recite something significantly different than a judicial exception. The rationale for this determination is explained below.
Claims 295-303 are directed to a naturally-occurring protein or compositions thereof, whether isolated, synthetic or recombinant or not, that are not patent-eligible pursuant to the Supreme Court decision in Association for Molecular Pathology v. Myriad Genetics, Inc., 106 USPQ2d 1972 (June 13, 2013) as they are not markedly different than the modified protein of SEQ ID NO: 6 as it occurs in nature.
Claims 295-303 of the instant application as interpreted are directed to genus of modified polypeptides including mutants and variants having 60% sequence identity to
While claims 295-303 recite a composition of the naturally occurring modified protein(s), the only recited ingredient(s) of the composition of said claims are the modified proteins itself and thus the composition is also not markedly different than the naturally occurring modified protein of SEQ ID NO: 6 as it occurs in nature. The mere aggregation of naturally occurring products together does not change the structure of either product (see the recent Office Guidance for Determining Subject Matter Eligibility of Claims Reciting or Involving Laws of Nature, Natural Phenomena, & Natural Products, available from http://www.uspto.gov/patents/law/exam/examguide.jsp).
Hence, claims 295-303 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Claim(s) 295-303 is/are directed to a natural phenomenon. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons stated below.
The “2014 Interim Guidance on Patent Subject Matter Eligibility” 79 FR 74618 (Dec. 16, 2014) directs that claims drawn to 1) a composition of matter, 2) a law of nature or a natural phenomenon and 3) lacking recitation of additional elements that make the claims directed to significantly more than a judicial exception are ineligible for patenting under 35 U.S.C. 101. See, 79 FR, page 74621 (flow chart). Nature-based compositions of matter are not directed to significantly more than a judicial exception when the claimed "naturally occurring products and some man-made products . . . are essentially no different from a naturally occurring product . . . that fall under the laws of nature or natural phenomena exception.” 79 FR, page 74623, left column. That is, a patent-eligible composition of matter must be "markedly different" in terms of the "product's structure, function, and/or other properties." 79 FR, page 74623, center column.
A “product that is purified or isolated, for example, will be eligible when there is a resultant change in characteristics sufficient to show a marked difference from the product’s naturally occurring counterpart. If the claim recites a nature-based product limitation that does not exhibit markedly different characteristics, the claim is directed to a ‘product of nature' exception.” 79 FR, page 74623, right column. A change in biological activity, chemical or physical properties, and structure and form are given as non-limiting examples of possible “markedly different characteristics.” 79 FR, page 74623, right column. Here, as stated, the claims encompass naturally-occurring variant/modified epimerases having the same structure, and therefore biological activity, chemical and physical properties, as a naturally-occurring product. As such, the claims appear to be directed towards nothing more than a judicial exception for the reasons stated.
SEQ ID NO: 6 with the recited amino acid substitutions and having the activity of converting fructose to tagatose through epimerization at the carbon-4 position of fructose.
As discussed above;
Coil et al., (Accession#B5YBD7, integrated into UniProtKB/TrEMBL database on 11/25/2008; see provided sequence alignment), disclose naturally occurring variant polypeptide having D-Tagatose-bisphosphate aldolase activity and having 87.4% sequence identity to SEQ ID NO: 6 and having the recited substitutions S21P, K78R, and said naturally-occurring reference polypeptide comprises H at position 85, D at position 121, H at position 247, D at position 250, and G at position 27 corresponding to the recited amino acid residue positions of SEQ ID NO: 6 of the instant invention and thus having all of the structural features of claims 295-303; examiner also notes that structure and function are inseparable.
Zhou et al. (Accession#A0A7V3ZJ27, integrated into UniProtKB/TrEMBL database on 06/02/2021; see provided sequence alignment), disclose naturally occurring variant polypeptide having D-Tagatose-bisphosphate aldolase activity and having 87.6% sequence identity to SEQ ID NO: 6 and having the recited substitutions S21P, K78R, and said naturally-occurring reference polypeptide comprises H at position 85, D at position 121, H at position 247, D at position 250, and G at position 27 corresponding to the recited amino acid residue positions of SEQ ID NO: 6 of the instant invention and thus having all of the structural features of claims 295-303; examiner also notes that structure and function are inseparable.
Applicants’ have traversed the above written-description and enablement with the following arguments: (see page 6 of Applicants’ REMARKS dated 11/18/2025).
Applicants’ argue: “…Applicant's claimed invention is directed to patent eligible subject matter, at least in view of the amendments to the independent claim. The Office Action asserts the claimed invention is directed to "a naturally-occurring protein or compositions thereof, whether isolated, synthetic or recombinant or not, that are not patent eligible as they are not markedly different than the modified protein of SEQ ID NO: 6 as it occurs in nature." (See Office Action, p. 5.) To this end, the Office Action asserts that the naturally-occurring tagatose 6 phosphate kinases disclosed in Coil et al. 1 ("Coil") and Zhou et al. 2 have ~85% identity to SEQ ID NO: 6 and include one or more of the claimed substitutions. (See Office Action, p. 6.) However, in addition to being unmodified, naturally-occurring polypeptides, the cited tagatose 6 phosphate kinases are additionally not encompassed by independent claim 295 because independent claim 295, as amended, recites a modified polypeptide comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOS: 6, 46-320, and 374-444.”
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 05/21/2025) and additionally for the following reasons. Contrary to applicants’ arguments, claims as amended has broadened the scope of claims; examiner reiterates that the instant claims and instant amendments do not limit the claims to 90% sequence identity to SEQ ID NO: 6, as claim 295 encompasses many sequences, at least 61 (sixty one sequences) whose sequence identity ranges from 89.6% to 80.1% to SEQ ID NO: 6, for example SEQ ID NOs: SEQ ID NO: 136, SEQ ID NO: 288, …SEQ ID NO: 300…SEQ ID NO: 264…SEQ ID NO: 312 (see provided sequence alignments).
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.
Written Description
I. Claims 295-303 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 295-303 of the instant application as interpreted are directed to a genus of modified polypeptides including mutants and variants of undefined/unlimited structures and a method of producing tagatose, comprising: contacting fructose with a modified polypeptide comprising one or more modifications as compared to the unmodified polypeptide being SEQ ID: 6, wherein the modified polypeptide converts the fructose to the tagatose through epimerization at the carbon-4 position of the fructose, and the modified polypeptide comprises at least 90% identity to SEQ ID NO: 6… .
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., 119, F.3d 1559, 1568, 43 USPQ2d 1398, 1405 (Fed. Cir. 1997).
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/activity and having the activity of converting fructose to tagatose through epimerization at the carbon-4 of fructose with regard to the members of genus of modified polypeptides including mutants and variants of undefined/unlimited structures in the claimed method i.e., a genus of modified polypeptides including mutants and variants of undefined/unlimited structures and a method of producing tagatose, comprising: contacting fructose with a modified polypeptide comprising one or more modifications as compared to the unmodified polypeptide being SEQ ID: 6, wherein the modified polypeptide converts the fructose to the tagatose through epimerization at the carbon-4 position of the fructose, and the modified polypeptide comprises at least 90% identity to SEQ ID NO: 6… .
No information, beyond the characterization of a few species: isolated specific modified polypeptide(s), wherein said modified polypeptide(s) consists of at least one amino acid residue substitution(s) at position(s) selected from C17, S21, S54, E75, or K78 and unchanged remaining amino acid residues relative to the amino acid sequence of the wild-type C-4 epimerase of SEQ ID NO: 6, wherein said modified polypeptide has the activity of converting fructose to tagatose through epimerization at the carbon-4 of fructose and the method of use (for details see Table 1-2, pages 60-93 of specification), has been provided by the applicants’, which would indicate that they had possession of the claimed genus of modified polypeptides including mutants and variants of undefined/unlimited structures in the claimed method, and a method of producing tagatose, comprising: contacting fructose with a modified polypeptide comprising one or more modifications as compared to the unmodified polypeptide being SEQ ID: 6, wherein the modified polypeptide converts the fructose to the tagatose through epimerization at the carbon-4 position of the fructose, and the modified polypeptide comprises at least 60% identity to SEQ ID NO: 6… .
The genus of polypeptides and the 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 of SEQ ID NO: 6 with specific structures and specific amino acid residue substitution/modifications 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, 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). 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 -ketoacyl synthase into a malonyl decarboxylase and completely eliminates -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.
(d) Specifically, regarding carbon 4-epimerization enzyme activity of D-fructose to D-tagatose is normally repressed and modification of certain amino acid residues in the wild-type enzyme affects the catalytic/enzymic activity; for details see Abstract; a triple-mutant of wild-type epimerase completely abolished the activity, paragraphs 2-4, page 3; para 3, page 4 and Table 1; and entire document of Lee et al., (Nature, Scientific Reports, 2017, Vol. 7:1934, page 1-9, in IDS).
As stated above, no information beyond the characterization of a few species: isolated specific modified polypeptide(s), wherein said modified polypeptide(s) consists of at least one amino acid residue substitution(s) at position(s) selected from C17, S21, S54, E75, or K78 and unchanged remaining amino acid residues relative to the amino acid sequence of the wild-type C-4 epimerase of SEQ ID NO: 6, wherein said modified polypeptide has the activity of converting fructose to tagatose through epimerization at the carbon-4 of fructose and the method of use (for details see Table 1-2, pages 60-93 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 in a genus of host cells in the claimed method. As the claimed genera of polypeptides 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 and enablement with the following arguments: (see pages 7-8 of Applicants’ REMARKS dated 11/18/2025).
Applicants’ argue: “…Applicants identified the residues required for functional activity by mutating those residues and establishing loss of catalytic activity when those residues are mutated. (See, e.g., Example 12-1 and paras. [00156]-[00159].) In Example 12-1, active site residues 28, 52, 64, 95, 96, 130, 132, 178, 263, 265, 268, 289, 361 of SEQ ID NO: 2, which correspond to residues 17, 41, 53, 84, 85, 119, 121, 167, 245, 247, 250, 271, 340 of SEQ ID NO: 6, were mutated to related amino acids to determine the catalytic impact of each residue (SEQ ID NOS: 24-45), as also presented in Table 1. The following mutations all caused a complete loss of activity (SEQ ID NO: 6 numbering): H85A (SEQ ID NO: 31), D121A (SEQ ID NO: 33), D121N (SEQ ID NO: 34), H247A (SEQ ID NO: 39), D250A (SEQ ID NO: 40), G271A (SEQ ID NO: 42), and G271D (SEQ ID NO: 43). To this end, FIG. 16 shows that pA07217 (G271A; SEQ ID NO: 42) lost its catalytic activity to convert fructose to tagatose. These data confirm that H85, D121, H247, D250 and G271 are residues that support catalytic activity.”
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 05/21/2025) and additionally for the following reasons.
Contrary to applicants’ arguments claims as amended has broadened the scope of claims; the claims are not limited to polypeptides having 90% sequence identity to SEQ ID NO: 6 and comprising H85, D121, H247, D250 and G271 amino acid residues. Examiner reiterates that the instant claims and instant amendments do not limit the claims to 90% sequence identity to SEQ ID NO: 6, as claim 295 encompasses many sequences, at least 61 (sixty one sequences) whose sequence identity ranges from 89.6% to 80.1% to SEQ ID NO: 6, for example SEQ ID NOs: SEQ ID NO: 136, SEQ ID NO: 288, …SEQ ID NO: 300…SEQ ID NO: 264…SEQ ID NO: 312 (see provided sequence alignments and new 35 U.S.C. 112(d) rejection above).
Enablement
II. Claims 295-303 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 a few species: isolated specific modified polypeptide(s), wherein said modified polypeptide(s) consists of at least one amino acid residue substitution(s) at position(s) selected from C17, S21, S54, E75, or K78 and unchanged remaining amino acid residues relative to the amino acid sequence of the wild-type C-4 epimerase of SEQ ID NO: 6, wherein said modified polypeptide has the activity of converting fructose to tagatose through epimerization at the carbon-4 of fructose and the method of use (for details see Table 1-2, pages 60-93 of specification). However, specification does not reasonably provide enablement for a genus of modified polypeptides including mutants and variants of undefined/unlimited structures and a method of producing tagatose, comprising: contacting fructose with a modified polypeptide comprising one or more modifications as compared to the unmodified polypeptide being SEQ ID: 6, wherein the modified polypeptide converts the fructose to the tagatose through epimerization at the carbon-4 position of the fructose, and the modified polypeptide comprises at least 90% identity to SEQ ID NO: 6… . 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 295-303 are so broad as to encompass: a genus of modified polypeptides including mutants and variants of undefined/unlimited structures and a method of producing tagatose, comprising: contacting fructose with a modified polypeptide comprising one or more modifications as compared to the unmodified polypeptide being SEQ ID: 6, wherein the modified polypeptide converts the fructose to the tagatose through epimerization at the carbon-4 position of the fructose, and the modified polypeptide comprises at least 90% identity to SEQ ID NO: 6… . The scope of the claims is not commensurate with the enablement provided by the disclosure with regard to the extremely large number of polypeptides and encoding polynucleotides broadly encompassed by the claims in a genus of recombinant host cells. 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 a few species: isolated specific modified polypeptide(s), wherein said modified polypeptide(s) consists of at least one amino acid residue substitution(s) at position(s) selected from C17, S21, S54, E75, or K78 and unchanged remaining amino acid residues relative to the amino acid sequence of the wild-type C-4 epimerase of SEQ ID NO: 6, wherein said modified polypeptide has the activity of converting fructose to tagatose through epimerization at the carbon-4 of fructose and the method of use (for details see Table 1-2, pages 60-93 of specification). It would require undue experimentation of the skilled artisan to make and use the claimed polypeptides and the encoding polynucleotides i.e., a genus of modified polypeptides including mutants and variants of undefined/unlimited structures and a method of producing tagatose, comprising: contacting fructose with a modified polypeptide comprising one or more modifications as compared to the unmodified polypeptide being SEQ ID: 6, wherein the modified polypeptide converts the fructose to the tagatose through epimerization at the carbon-4 position of the fructose, and the modified polypeptide comprises at least 90% identity to SEQ ID NO: 6… . 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 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, in IDS), 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 polypeptides and the encoding polynucleotides encompassed by these claims in a genus of host cells in the claimed method.
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 genus of modified polypeptides including mutants and variants of undefined/unlimited structures and a method of producing tagatose, comprising: contacting fructose with a modified polypeptide comprising one or more modifications as compared to the unmodified polypeptide being SEQ ID: 6, wherein the modified polypeptide converts the fructose to the tagatose through epimerization at the carbon-4 position of the fructose, and the modified polypeptide comprises at least 90% identity to SEQ ID NO: 6…, because the specification does not establish: (A) a rational and predictable scheme for identifying an enzyme exhibiting associated function/activity and comprising an amino acid sequence mutants and variants of undefined/unlimited structures having 60% sequence identity to SEQ ID NO: 6 and with an expectation of obtaining the desired biological function; (B) defined core regions/motifs involved in the desired catalytic activity of encoded polypeptides; (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 claims broadly including polypeptides and encoding polynucleotides with an enormous number of modifications in a genus of host cells. 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 having the desired biological characteristics in a genus of host cells 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 page 9 of Applicants’ REMARKS dated 11/18/2025).
Applicants’ argue: “…Further, because claim 295 recites catalytic residues, the sequences within the scope of the claim will have catalytic activity. Testing sequences that contain those, which are 90% identical to SEQ ID NOS: 6, 46-320, and 374-444, and are mutated at the recited positions, is routine in the art in view of the specification's disclosure. Claim 295 and claims depending therefrom are, therefore, enabled. Applicant respectfully requests that the rejections of claims 295-303 under 35 U.S.C. § 112(a) as lacking enablement be withdrawn.”
Reply: Applicants' arguments have been considered but are found to be non-persuasive for the following reasons. Applicants’ arguments filed on 11/18/2025 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 295-303.
Maintained-Claim Rejections: 35 USC § 103
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 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.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
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.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claims 295-303 are rejected under 35 U.S.C. 103(a) as being unpatentable over Yang et al., (WO 2018/182345, priority date 03/31/2017 in IDS; see provided English translation and English equivalent CA 3058589 A1 (in IDS) in the parent application 17/341,813; disclosing a polypeptide having 100% sequence identity to SEQ ID NO: 6 and homologs of the instant invention) and in view of Coil et al., (Acc.#B5YBD7, UniProtKB/TrEMBL database, 11/25/2008; disclosing a polypeptide having 87.4% sequence identity to SEQ ID NO: 6 and variant of the instant invention) and Datta et al., (3 Biotech, 2013, Vol. 3: 1-9, in IDS).
Regarding claims 295-299 analogous art Yang et al., (WO 2018/182345, priority date 03/31/2017; see provided English Machine translation and English equivalent CA 3058589 A1) disclosing a polypeptide having 100% sequence identity to SEQ ID NO: 6 of the instant invention and homologs having tagatose-6-phopshate kinase/fructose-6-phopshate 4-epimerase activity (Abstract; page 3; and entire document of CA 3058589 A1); said reference teaches variants/homologs of reference polypeptide having tagatose-6-phopshate kinase/fructose-6-phopshate 4-epimerase having at least 80% sequence identity (pages 7-8; see Fig. 2-5); said reference also teaches transformed host cells producing the reference tagatose-6-phopshate kinase/fructose-6-phopshate 4-epimerase and a method of converting fructose to tagatose, wherein said method comprises at least 1% by weight fructose in the reaction (page 43); and purification of produced tagatose by chromatography, fractional crystallization and ion purification (page 36).
However, Yang et al., is silent regarding wherein said herein the one or more amino acid substitutions of SEQ ID NO: 6 are selected from the group consisting of K67, C17, S21, S54, E75, or K78 (as in claims 295-297); and wherein said modified polypeptide is immobilized to a carrier or a support… (as in claims 300-303).
Regarding claims 296-298, Coil et al., (Acc.#B5YBD7, UniProtKB/TrEMBL database, 11/25/2008; disclose a polypeptide having D-Tagatose-bisphosphate aldolase activity and having 87.4% sequence identity to SEQ ID NO: 6 and having the recited substitutions S21P, K78R, and said reference polypeptide comprises H at position 85, D at position 121, H at position 247, D at position 250, and G at position 27 corresponding to the recited amino acid residue positions of SEQ ID NO: 6 of the instant invention and thus having all of the structural features of claims 295-298; examiner also notes that structure and function are inseparable.
Regarding claims 300-303, the following reference teach the structural and functional elements of the instant invention: Datta et al., (3 Biotech, 2013, Vol. 3: 1-9) teach methods for enzyme immobilization including different techniques, materials used for fabrication of immobilization supports such as alginate … zeolite (see Abstract; pages 2-6; and Conclusion).
Therefore, it would have been obvious to a person of ordinary skill in the art to combine and modify the teachings of Yang et al., and employ the tagatose 6 phosphate kinase of Coil et al., a variant of the instant invention; comprising the following amino acid substitutions S21P, K78R, and said naturally-occurring reference polypeptide comprises H at position 85, D at position 121, H at position 247, D at position 250, and G at position 27 corresponding to the recited amino acid residue positions of SEQ ID NO: 6 that teach structural and functional elements involved in the enhanced production of tagatose from fructose and employ enzyme immobilization method taught in the reference of Datta et al., as said reference highlights enzyme immobilization provides advantages for large-scale and economic formulation of enzymes employed in various industries (see Abstract; and entire document). Motivation to generate such a method for the production of tagatose derives from the fact that tagatose is a commercial product of importance and useful in the preparation of fine chemicals, agrochemicals, pharmaceuticals, food, oil and plastic industry (Yang et al.,). The expectation of success is high, because the combined teachings of Yang et al., Coil et al., and Datta et al., teach genetically modified recombinant microbial/host cells comprising recombinant enzymes/proteins/functional elements and the entire pathway for the enhanced production of tagatose from fructose 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 (Yang et al., Coil et al., and Datta et al.,) a method of producing tagatose, comprising: contacting fructose with a modified polypeptide comprising one or more modifications as compared to the unmodified polypeptide being SEQ ID: 6, wherein the modified polypeptide converts the fructose to the tagatose through epimerization at the carbon-4 position of the fructose, and the modified polypeptide comprises at least 60% identity to SEQ ID NO: 6…, as taught by the instant invention and as claimed in claims 295-303 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”.
Therefore, claims 295-303 are rejected under 35 U.S.C. 103(a) as being unpatentable over Yang et al., (WO 2018/182345, priority date 03/31/2017 in IDS; see provided English translation and English equivalent CA 3058589 A1 (in IDS) in the parent application 17/341,813; disclosing a polypeptide having 100% sequence identity to SEQ ID NO: 6 and homologs of the instant invention) and in view of Coil et al., (Acc.#B5YBD7, UniProtKB/TrEMBL database, 11/25/2008; disclosing a polypeptide having 87.4% sequence identity to SEQ ID NO: 6 and variant of the instant invention) and Datta et al., (3 Biotech, 2013, Vol. 3: 1-9, in IDS).
Applicants’ have traversed the above 35 USC § 103 rejection with the following arguments: (see pages 9-10 of Applicants’ REMARKS dated 11/18/2025).
Applicants’ argue: “…Claim 295 recites a modified polypeptide comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOS: 6, 46-320 and 374-444. The modified polypeptide directly converts fructose to tagatose through epimerization at the carbon-4 position of fructose, comprises one or more amino acid substitutions as compared to SEQ ID NO: 6, and comprises H at position 85, D at position 121, H at position 247, D at position 250, and G at position 271. The one or more amino acid substitutions include at least one substituted amino acid at the amino acid residues corresponding to position C17, S21, S54, E75, or K78. None of Yang, Coil, or Datta, either alone or in combination, teaches or suggests such a modified polypeptide…”.
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 05/21/2025) and additionally for the following reasons.
Contrary to applicants’ arguments claims as amended has broadened the scope of claims; the claims are not limited to polypeptides having 90% sequence identity to SEQ ID NO: 6 and comprising H85, D121, H247, D250 and G271 amino acid residues. Examiner reiterates that the instant claims and instant amendments do not limit the claims to 90% sequence identity to SEQ ID NO: 6, as claim 295 encompasses many sequences, at least 61 (sixty one sequences) whose sequence identity ranges from 89.6% to 80.1% to SEQ ID NO: 6, for example SEQ ID NOs: SEQ ID NO: 136, SEQ ID NO: 288, …SEQ ID NO: 300…SEQ ID NO: 264…SEQ ID NO: 312 (see provided sequence alignments and new 35 U.S.C. 112(d) rejection above).
Summary of Pending Issues
The following is a summary of issues pending in the instant application.
Claim 295 and claims 296-303 (depending therefrom) is rejected under 35 U.S.C. 112(d).
Claims 295-303 are rejected under 35 U.S.C. 101.
Claims 295-303 are rejected under 35 U.S.C. 112(a) for written-description and enablement.
Claims 295-303 are rejected under 35 U.S.C. 103(a) as being unpatentable over Yang et al., (WO 2018/182345, priority date 03/31/2017 in IDS; see provided English translation and English equivalent CA 3058589 A1 (in IDS) in the parent application 17/341,813; disclosing a polypeptide having 100% sequence identity to SEQ ID NO: 6 and homologs of the instant invention) and in view of Coil et al., (Acc.#B5YBD7, UniProtKB/TrEMBL database, 11/25/2008; disclosing a polypeptide having 87.4% sequence identity to SEQ ID NO: 6 and variant of the instant invention) and Datta et al., (3 Biotech, 2013, Vol. 3: 1-9, in IDS).
Claims 304-309 and 311-314 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions.
Conclusion
None of the claims are allowable. Claims 295-303 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