DETAILED ACTION
The Examiner assigned to the instant Application at the USPTO has changed. Please direct all further correspondence to Art Unit 1656 and to the Examiner signed below.
Status of Application
The amendments and response to the previous Office action are acknowledged and have been considered in their entireties. Claim 3 is canceled and claims 1-3 and 5-6 are pending and subject to examination on the merits.
This Office action introduces additional rejections not previously applied, as such, this is a non-final Office action.
Priority
The instant application is a 371 of PCT/KR2021/005268 filed 26 April 2-21 which claims benefit of foreign priority document KE10-2020-0184660 filed 28 December 2020 is acknowledged. Said document has been received.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08 May 2026 has been considered by the examiner. See initialed and signed PTO/SB/08.
Withdrawal of Previous Objections/Rejections
The provisional non-statutory double patenting rejections of co-pending applications: 18269683, 18269689, 18269694 and 18269666 are all withdrawn in view of the amendments made in each of the co-pending applications to remove substitution of H232K/T as a specific substitution in the claims.
New Rejections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The claim 3 is drawn to variant ATP-PRT of SEQ ID NO: 1 having substitutions at position(s): H232K/T, with the option of having additional substitutions at R250H, T252A/L/G/V/I, E271L or S288P, wherein the variant has reduced feedbach inhibition by histidine. However, any asserted reduction in/for anything needs a comparative. That is, reduced feedback inhibition compared to what? Furthermore, to be an accurate comparative, it would necessarily have to be a like for like comparison; e.g. as compared to ATP-PRT SEQ ID NO: 1 not having the claimed substitutions.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph 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.
Claims 1-3 and 5-6 are rejected under 35 U.S.C. 112(a) 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 at the time the application was filed, had possession of the claimed invention.
The MPEP in section 2163(I) states that the purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made/filed, of the specific subject matter claimed:
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonable conclude the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. However, a showing of possession alone does not cure the lack of a written description. Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 969-70, 63 USPQ2d 1609, 1617 (Fed. Cir. 2002). For example, it is now well accepted that a satisfactory description may be found in originally-filed claims or any other portion of the originally-filed specification. See In re Koller, 613 F.2d 819, 204 USPQ 702 (CCPA 1980); In re Gardner, 475 F.2d 1389, 177 USPQ 396 (CCPA 1973); In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). However, that does not mean that all originally-filed claims have adequate written support. The specification must still be examined to assess whether an originally-filed claim has adequate support in the written disclosure and/or the drawings.
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An applicant shows that the inventor was in possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997)"
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"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 (Fed. Circ. 1997).
MPEP 2111.03. I. states that “t]he transitional term “comprising”, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps”. In the instant case, the examiner has broadly but reasonably interpreted the claims to encompass any variant of any ATP-phosphoribosyltransferase or any variant of the ATP-phosphoribosyltransferase of SEQ ID NO:1, wherein the variant comprises substitutions of a histidine for lysine or threonine at position 232 (H232T/K); which may further include substitutions at positions R250H, T252A/L/G/V/I, E271L or S288P. Claim 3 recites the variant has reduced feedback inhibition by histidine. Therefore, the claims are drawn to a large and variable genus of ATP-phosphoribosyltransferase variants having unknown structure except having H232T/K); which may further include substitutions at positions R250H, T252A/L/G/V/I, E271L or S288P of SEQ ID NO:1 but having any activity or not, and further having reduced feedback inhibition by histidine (presumably compared to any the ATP-phosphoribosyltransferase of SEQ ID NO:1 – see 35 USC 112(b) above).
Fransceus (J Ind Microbiol Biotechnol. 2017 – cited in IDS 05/08/2026) reviews protein engineering techniques, such as random mutagenesis and recombination, directed evolution and iterative or combinatory saturation “hotspots”. Fransceus states that “a recurring problem, however, is choosing which amino acid positions should be targeted. Answering this question is not an easy feat and requires substantial insight in the relationship between an enzyme’s sequence or structure and its properties.” Sanavia (Computational and Structural Biotechnology Journal, 2020 - cited in IDS 05/08/2026) discloses challenges in the prediction of protein stability in the occurrence of multiple mutations. “Multiple-point mutations are common variations of the protein sequence that may be needed in protein engineering when a single-point mutation is not enough to yield the desired stability change. Dealing with multiple-site variations adds another level of complexity beyond the prediction of the effect of a single variant on protein stability, since it requires the learning of many types of combinatorial effects”.
The specification is limited to specific variants of the ATP-phosphoribosyltransferase of SEQ ID NO:1, wherein the variants consist of an E271K and one or more T232K, R250H, T252A/L/G/V/I, and S288P and wherein the variant has reduced feedback inhibition by histidine compared to SEQ ID NO:1. While MPEP 2163 acknowledges that in certain situations “one species adequately supports a genus,” it also acknowledges that “[f]or inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.” In view of the widely variant species encompassed by the genus, the above example described above is not enough and does not constitute a representative number of species to describe the whole genus. Therefore, the specification fails to describe a representative species of the claimed genus.
Further, one of skill in the art could identify avariants of an ATP-phosphoribosyltransferase or variants of the ATP-phosphoribosyltransferase of SEQ IDNO:1. However, there is no teaching regarding which amino acids can vary from an ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1 and result in polypeptide having ATP-phosphoribosyltransferase activity and further reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1. An important consideration is that structure is not necessarily a reliable indicator of function. In the instant case, there is no disclosure relating similarity of structure to conservation of function. Conservation of structure is not necessarily a surrogate for conservation of function. Since the claimed invention is that of an enzyme, and there is no disclosure of the domains responsible for having ATP-phosphoribosyltransferase activity and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1, the absence of information may be persuasive that those of skill in the art would not take the disclosure as generic.
Given this lack of description of the representative species encompassed by the genus of the claims, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the inventions of claims 1-3 and 5-6.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-3 and 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Lohkamp et al. (JMB, 2004 - cited herein) in view of Mittelstadt et al. (Protein Science, 2016 - cited herein) and Zhang et al. (Biochimie, 2012 - cited on IDS of 12/20/2024).
Lohkamp et al. teach E. coli ATP-phosphoribosyltransferase (ATP-PRT) having 100% sequence identity to instant SEQ ID NO: 1 (See Supplemental Content, 20250902_143000_us-18-269-647-1.rup file, Result #1, Duplicates thereof) and expressed in E. coli from a modified HisG gene, wherein said expressed ATP-phosphoribosyltransferase protein is then purified, and crystallized and the 3-D structure determined therefrom. It is stated (See p. 139, 2nd col, 2nd paragraph and p. 141, 1st col., 3rd paragraph):
The M.tuberculosis ATP-PRT His þ AMP complex structure clearly shows that this intersubunit pocket is the binding site for histidine, and that binding induces a conformational change in the domain, forming a closed structure.14 The side chain hydroxyl group of Thr252 (Thr238 M. tuberculosis numbering) binds the amino group of the histidine residue, while a more variable residue at position 232* ( *denotes trimer-related monomer) of an adjacent C-terminal domain (Asp218p in M. tuberculosis) coordinates the amino group. The remainder of the contacts to histidine involve main-chain interactions, the carboxylate hydrogen bonds to a loop Gly247-Arg250 (Gly233 Ser236 in M. tuberculosis) with conserved proline residues at 246 and 251 probably stabilizing the structure. This region is poorly ordered in the E. coli structure reported here and residue 235 is not resolved in the M. tuberculosis apo structure. Surprisingly, the histidine R-group forms only a single hydrogen bond to the carbonyl group of Ser288p (Ala273p in M. tuberculosis); despite this, the site has been shown to be highly specific for histidine.17
The binding of histidine and AMP to ATP-PRT has been shown structurally to result in a large conformational change in enzyme.14 In this hexameric form of the enzyme the active site is effectively closed off and we propose that key residues involved in PRPP binding are also disrupted, making catalysis impossible. The binding of AMP to ATP-PRT reduces significantly the dissociation constant for histidine.10 Comparison of the M.tuberculosis His-AMP structure with the E. coli AMP structure and M.tuberculosis apo enzyme clearly shows that the binding of AMP to the enzyme alone forms a stable hexamer10 and orientates residues in the C-terminal domain favourably for histidine binding. Equally, the presence of a 50 mM concentration of histidine results in a fourfold reduction in the dissociation constant for AMP in the S. typhimurium enzyme.17 Therefore, it is reasonable to assume that the enzyme inhibited by low concentrations of histidine alone is at equilibrium between fully closed and more open forms of the enzyme. These open forms of the enzyme are in a conformation in which AMP is bound readily, probably by a favourable conformation between domains 1 and 2 of the enzyme. In this way, the enzyme is extremely sensitive to both histidine and low energy levels.
Thus, effectively, Lohkamp et al. teach that E. coli His232, while it can vary from His to Asn to Asp at position 232 (See Figure 2), details nonetheless it has binding interaction with the histidine inhibiting substrate; as does Thr252 which is an absolute conserved residue.
Lohkamp et al., however, does not teach a variant E. coli ATP-ART comprising SEQ ID NO: 1 containing (i) a substitution of lysine or threonine for histidine at position 232 in an ATP- phosphoribosyltransferase consisting of the amino acid sequence of SEQ ID NO:1; or (ii) a substitution of lysine or threonine for histidine at position 232 and at least one of the following amino acid substitutions in the amino acid sequence of SEQ ID NO: 1: (a) a substitution of histidine for arginine at position 250; (b) a substitution of alanine, leucine, glycine, valine or isoleucine for threonine at position 252: (c) a substitution of lysine for glutamic acid at position 271; and (d) a substitution of proline for serine at position 288; nor methods of producing histidine by culturing a transformed strain expressing the variant ATP-PRT as in claim 1.
Mittelstadt et al. teach the crystal structure of ATP-PRT from Camplyobacter jejuni in both open and closed structures with histidine bound, wherein it is taught (See p. 1502, 1st col., 2nd full paragraph):
His binding in both structures occurs at the interface between two adjacent domains III in their trimeric arrangement, similar to the His-bound MtuATP-PRT structure.15 Consequently one His is bound per chain, but each chain provides two different faces for the interaction with His. The His carboxyl and amino groups are coordinated via hydrogen bonding interactions with the backbone and Thr252 side chain of the highly conserved binding loop between a9 and b13 of one ACT domain (consensus sequence: PGXXXPT, CjeATP-PRT residues Pro246-Thr252; Supporting Information Fig. S8), whereas the imidazole side chain is inserted into a small cavity created by the side chains on the b-sheet of the other ACT domain, involving interactions with His232’, Ser288’, Leu290’, and a conserved water molecule [Fig. 7(C)].
AND (See p. 1504, 1st col., 2nd paragraph):
Many of the observed conformational and interface changes between His-bound and non His-bound CjeATP-PRT hexamer are also strikingly similar in the reported structures of MtuATP-PRT and EcoATP-PRT.11,15 This suggests a common allosteric mechanism for all long form ATP-PRT enzymes.
It is noted, the sequence of Camplyobacter jejuni ATP-PRT has the exact same sequence numbering as E. coli ATP-PRT – See Lohkamp et al., Figure 2 (third sequence of the alignment, HIS1-CAMJE).
Zhang et al. teach that four residues are highly conserved among ATP-phosphoribosyltransferase, including C. glutamicum and E. coli ATP-phosphoribosyltransferase (4th full paragraph at page 835 and Fig. 5 at page 834). Zhang teaches that these residues include H232, A248, and T252 of E. coli ATP-phosphoribosyltransferase, which is equivalent to N215, L231, and T235, respectively, of C. glutamicum ATP-phosphoribosyltransferase (4th full paragraph at page 835). Zhang discloses C. glutamicum ATP-phosphoribosyltransferase variant having an N215K results in histidine feedback inhibition (See Table 2). In addition, the triple substitution of N215K/L231F/T235A, wherein the variant is resistant (i.e. has reduced) to feedback inhibition by histidine (abstract and Table 2). Zhang also discloses that S288 of E. coli ATP-phosphoribosyltransferase also binds to histidine (4th full paragraph at page 835). Zhang also discloses that the mutation of N215K (i.e. H232K) does not have any impact in the enzymes catalytic activity (See p. 836, 1st col., last line of 1st paragraph and see Table 2, kcat values).
Therefore, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to modify the E. coli ATP-phosphoribosyltransferase variant of Lohkamp et al. by introducing either a N232K single mutation which has decreased feedback inhibition for histidine but does not impact the catalytic activity of the enzyme or a H232K/A248F/T252A amino acid substitutions substitution into the E. coli ATP-phosphoribosyltransferase of Lohkamp et al. having the most reduced rate of histidine feedback inhibition (See Table 2 of Zhang et al.) because this would then increase the enzyme capabilities to produce histidine in the first place (e.g. by increasing the condensation of ATP and PRPP as the first step in histidine biosynthesis – See Zhang Abstract). This would be motivation in and of itself to one having ordinary skill in the art would. One having ordinary skill in the art would have has a reasonable expectation of success in making these particular substitutions as taught by Zhang and as applied to the enzyme of Lohkamp because Lohkamp, Mittelstadt and Zhang disclose that H232, T252, S288 are located in the histidine binding site of E. coli ATP-phosphoribosyltransferase, and Zhang discloses that substitution of these residues reduces feedback inhibition by histidine. One of ordinary skill in the art would have been the knowledge and skill to provide such an enhancement to E. coli ATP-PRT of Lohkamp (ATP-phosphoribosyltransferase variant of Wen) because Lohkamp, Mittelstadt and Zhang demonstrate the conserved structure/sequences are the same across multiple species which render similar substitutions of Zhang and applied to other species such as E. coli ATP-PRT comprising SEQ ID NO: 1 as a predictable outcome.
Therefore, the combined references render claims 1-3 and 5-6 prima facie obvious.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUZANNE M NOAKES whose telephone number is (571)272-2924. The examiner can normally be reached M-F (7-4).
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/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656 11 September 2026
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