Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
This application is a 371 of PCT/KR2021/095036
The response filed on October 21, 2025 has been entered.
Election/Restrictions
Applicant’s election of Group I with a species election of (1) SEQ ID NO:1 as the parent ATP-phosphoribosyltransferase and (2) R250H, T252A/L/G/V/I, E271K, and S288P as the amino acid modifications made in said parent in the reply filed on October 21, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 5-7 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on October 21, 2025.
Status of Claims
Claims 1-7 are pending.
Claims 5-7 are withdrawn.
Claims 1-4 are under examination.
Claim for Foreign Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 16, 2024 and June 26, 2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 USC § 112
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 following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1 and claims 2-4 depending therefrom are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation “in an ATP-phosphoribosyltransferase consisting of the amino acid sequence of SEQ ID NO:1”. The metes and bounds of this limitation in the context of the above claims are not clear. It is unclear if (1) the ATP-phosphoribosyltransferase variant is a variant of SEQ ID NO:1, (2) the ATP-phosphoribosyltransferase variant consists of the amino acid sequence of SEQ ID NO:1, or (3) if the ATP-phosphoribosyltransferase variant has a substitution of lysine for glutamic acid at the position corresponding to 250 of SEQ ID NO:1. If (1), it is unclear how a polypeptide can consist of the amino acid sequence of SEQ ID NO:1 and have amino acid substitutions. A polypeptide either has the amino acid sequence of a given sequence identifier or it does not. Clarification is requested.
Claim 2 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites the limitation “wherein the ATP-phosphoribosyltransferase is expressed from E. coli hisG gene”. The metes and bounds of this limitation in the context of the above claims are not clear. It is unclear (1) if “the ATP-phosphoribosyltransferase” refers to the ATP-phosphoribosyltransferase consisting of the amino acid sequence of SEQ ID NO:1 or (2) if the ATP-phosphoribosyltransferase refers to the variant ATP-phosphoribosyltransferase. If (2), since “E. coli hisG gene” denotes wild-type E. coli hisG gene, it is unclear how an ATP-phosphoribosyltransferase variant is expressed from wild-type E. coli hisG gene. Clarification is requested.
Claim 3 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 recites the limitation “wherein the variant is reduced feedback inhibition of the variant by histidine”. The metes and bounds of this limitation in the context of the above claims are not clear. It is unclear as to how a variant “is reduced feedback inhibition of the variant by histidine”. Further, the reference ATP-phosphoribosyltransferase is not recited. Therefore, it is unclear how much feedback inhibition is considered as “reduced”. Clarification is requested.
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.
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 1-4 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.
MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow.'' 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 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 arginine, alanine/leucine/glycine/valine/isoleucine for threonine, lysine for glutamic acid, and proline for serine at the positions corresponding to 250, 252, 271, and 288, respectively, of SEQ ID NO:1 and any other amino acid modifications and the variant has ATP-phosphoribosyltransferase activity and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1. Therefore, the claims are drawn to a genus of ATP-phosphoribosyltransferase variants having unknown structure except having lysine and proline at the positions corresponding to SEQ ID NO:1 but having ATP-phosphoribosyltransferase activity and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1.
MPEP 2163 I. states that to “satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
MPEP 2163. II.A.3.(a) sates that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
According to MPEP 2163.II.A.3.(a).ii), “Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For 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…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
The recitation of “ATP-phosphoribosyltransferase” and “reduced feedback inhibition” fails to provide a sufficient description of the genus of polypeptides as it merely describes the functional features of the genus without providing any definition of the structural features of the species within the genus. The specification does not specifically define any of the species that fall within the genus. The specification does not define any structural features commonly possessed by members of the genus that distinguish them from others. One skilled in the art therefore cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus.
E. coli ATP-phosphoribosyltransferase having the amino acid sequence of SEQ ID NO:1 was known in the art. Wen (US 2019/0338282 – form PTO-892) discloses E. coli ATP-phosphoribosyltransferase (HIsG) having the amino acid sequence of SEQ ID NO:54, which is identical to the E. coli ATP-phosphoribosyltransferase of SEQ ID NO:1 of the instant application ([1198] and see the sequence alignment below). Wen also discloses an ATP-phosphoribosyltransferase variant (HisG*) having the amino acid sequence of SEQ ID NO:53, which is a variant of SEQ ID NO:54 wherein glutamic acid is replaced with lysine (E271K amino acid substitution) and the variant has reduced feedback inhibition by histidine ([1198] and see the sequence alignment below). However, the prior art does not disclose variants of any ATP-phosphoribosyltransferase or SEQ ID NO:1, wherein the variants have g unknown structure but has ATP-phosphoribosyltransferase and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1
Fransceus (J Ind Microbiol Biotechnol. 2017 May;44(4-5):687-695. – form PTO-892) 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, Volume 18, 2020, Pages 1968-1979. – form PTO-892) 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 R250H and one or more T232K, T252A/L/G/V/I, E271K, and S288P amino acid substitutions 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 variants 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 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 1-4.
Claims 1-4 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for specific variants of the ATP-phosphoribosyltransferase of SEQ ID NO:1, wherein the variants consist of R250H and one or more T232K, T252A/L/G/V/I, E271K, and S288P amino acid substitutions and wherein the variant has reduced feedback inhibition by histidine compared to SEQ ID NO:1, does not reasonably provide enablement any ATP-phosphoribosyltransferase variant having unknown structure except having lysine and proline at the positions corresponding to SEQ ID NO:1 but 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 specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and 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 USPQ2nd 1400 (Fed. Cir, 1988). They include (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 claims.
The breadth of the claims.
MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow.'' 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 interpreted the claims to encompass any variant of any ATP-phosphoribosyltransferase any or any variant of the ATP-phosphoribosyltransferase of SEQ ID NO:1, wherein the variant comprises substitutions of a histidine for arginine, alanine/leucine/glycine/valine/isoleucine for threonine, lysine for glutamic acid, and proline for serine at the positions corresponding to 250, 252, 271, and 288, respectively, of SEQ ID NO:1 and any other amino acid modifications and the variant has ATP-phosphoribosyltransferase activity and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1. Therefore, the claims are drawn to any ATP-phosphoribosyltransferase variant having unknown structure except having lysine and proline at the positions corresponding to SEQ ID NO:1 but 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 claims are not commensurate with the enablement provided by the disclosure with regard to the extremely large number of polypeptides having ATP-phosphoribosyltransferase activity and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1. In the instant case, the specification is limited to specific variants of the ATP-phosphoribosyltransferase of SEQ ID NO:1, wherein the variants consist of R250H and one or more T232K, T252A/L/G/V/I, E271K, and S288P amino acid substitutions and wherein the variant has reduced feedback inhibition by histidine compared to SEQ ID NO:1.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification.
While enzyme isolation techniques, recombinant and mutagenesis techniques were known in the art at the time of the invention, e.g. mutagenesis, and it is routine in the art to screen for variants comprising multiple substitutions or multiple modifications as encompassed by the instant claims, the specific amino acid positions within the 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.
In the absence of: (a) rational and predictable scheme for making any variant of any ATP-phosphoribosyltransferase or SEQ ID NO:1 and having ATP-phosphoribosyltransferase activity and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1, and (b) a correlation between structure and the function of 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 specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful. One of skill in the art would have to test these infinite possible polypeptides to determine which polypeptides have ATP-phosphoribosyltransferase activity and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1. While enablement is not precluded by the necessity for routine screening, if a large amount of screening is required, as is the case herein, the specification must provide a reasonable amount of guidance which respect to the direction in which the experimentation should proceed so that a reasonable number of species can be selected for testing. In view of the fact that such guidance has not been provided in the instant specification, it would require undue experimentation to enable the full scope of the claims.
The state of prior art, the relative skill of those in the art, and predictability or unpredictability of the art.
Since the amino acid sequence of the mutant 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, 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 proteins' structure relates to its function. In the instant case, neither the specification or the art provide a correlation between structure and activity such that one of skill in the art can envision the structure of any polypeptides having galactose oxidase activity or predict said function of a polypeptide from its primary structure. In addition, the art does not provide any teaching or guidance as to (1) which amino acids within the polypeptide of SEQ ID NO:1 or any ATP-phosphoribosyltransferase (other than the amino acid positions corresponding to 271, 232, 250, 252, and 288 of SEQ ID NO:1) that can be modified and which ones are conserved such that one of skill in the art can make the recited polypeptides having ATP-phosphoribosyltransferase activity and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1, (2) which segments of the polypeptide of SEQ ID NO:1 or any ATP-phosphoribosyltransferase that are essential for polypeptides having ATP-phosphoribosyltransferase activity and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1, and (3) the general tolerance of the polypeptide of SEQ ID NO:1 or any ATP-phosphoribosyltransferase to structural modifications and the extent of such tolerance. The art clearly teaches that changes in a protein's amino acid sequence to obtain the desired activity without any guidance/knowledge as to which amino acids in a protein are required for that activity is highly unpredictable. At the time of the invention there was a high level of unpredictability associated with altering a polypeptide sequence with an expectation that the polypeptide will maintain the desired activity. For example, Studer (Residue mutations and their impact on protein structure and function: detecting beneficial and pathogenic changes. Biochem. J. (2013) 449, 581–594. – form PTO-892) teach that (1) protein engineers are frequently surprised by the range of effects caused by single mutations that they hoped would change only one specific and simple property in enzymes, (2) the often surprising results obtained by experiments where single mutations are made reveal how little is known about the rules of protein stability, and (3) the difficulties in designing de novo stable proteins with specific functions.
E. coli ATP-phosphoribosyltransferase having the amino acid sequence of SEQ ID NO:1 was known in the art. Wen (US 2019/0338282 –form PTO-892) discloses E. coli ATP-phosphoribosyltransferase (HIsG) having the amino acid sequence of SEQ ID NO:54, which is identical to the E. coli ATP-phosphoribosyltransferase of SEQ ID NO:1 of the instant application ([1198] and see the sequence alignment below). Wen also discloses an ATP-phosphoribosyltransferase variant (HisG*) having the amino acid sequence of SEQ ID NO:53, which is a variant of SEQ ID NO:54 wherein glutamic acid is replaced with lysine (E271K amino acid substitution) and the variant has reduced feedback inhibition by histidine ([1198] and see the sequence alignment below). However, the prior art does not disclose variants of any ATP-phosphoribosyltransferase or SEQ ID NO:1, wherein the variants have g unknown structure but has ATP-phosphoribosyltransferase and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1
Fransceus (J Ind Microbiol Biotechnol. 2017 May;44(4-5):687-695. – form PTO-892) 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, Volume 18, 2020, Pages 1968-1979. – form PTO-892) 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 amount of direction or guidance presented and the existence of working examples.
The specification is limited to specific variants of the ATP-phosphoribosyltransferase of SEQ ID NO:1, wherein the variants consist of R250H and one or more T232K, T252A/L/G/V/I, E271K, and S288P amino acid substitutions and wherein the variant has reduced feedback inhibition by histidine compared to SEQ ID NO:1. However, the speciation fails to provide any information as to (1) specific substrates associated with polypeptides having ATP-phosphoribosyltransferase activity and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1 or (2) structural elements required in a polypeptide having ATP-phosphoribosyltransferase activity and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1. No correlation between structure and function of having ATP-phosphoribosyltransferase activity and reduced feedback inhibition by histidine compared to any ATP-phosphoribosyltransferase or the ATP-phosphoribosyltransferase of SEQ ID NO:1 has been presented.
Thus, in view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability of the prior art in regard to structural changes and their effect on function and the lack of knowledge about a correlation between structure and function, an undue experimentation would be necessary one having ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of polypeptides having the desired biological characteristics recited in the claims are 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).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by NCBI, GenBank accession no. WP_054472839.1 (ATP phosphoribosyltransferase, [Escherichia coli MS 200-1], June 2019 -form PTO-1449, “NCBI”).
MPEP 2113 states that “ [P]product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. [E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production.”. In the instant case, the structure of the claimed ATP-phosphoribosyltransferase implied is the same whether the ATP-phosphoribosyltransferase variant is obtained from any recombinant engineering or is obtained from any source (including wild type proteins), as long as the resulting product has the structural limitations recited in the claims (having an histidine residue at the position corresponding to 250 of SEQ ID NO:1).
Regarding claim 1, NCBI discloses an E. coli ATP-phosphoribosyltransferase identical to SEQ ID NO:1 of the instant application except having a His residue at position 250 (page 1 and see the sequence alignment below).
Regarding claim 2, the ATP-phosphoribosyltransferase of NCBI is expressed from E. coli hisG gene (page 1).
Regarding claim 3, MPEP 2112.01. II. states that “[p]roducts of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”. MPEP 2112. II. states that “[t]here is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference.”. In the instant case, the specification of the instant application discloses that an ATP-phosphoribosyltransferase variant of SEQ ID NO:1 containing R250H reduces feedback inhibition by histidine ([0010]). Since the ATP-phosphoribosyltransferase of NCBI has identical structure as the R250H ATP-phosphoribosyltransferase variant of the instant application, the ATP-phosphoribosyltransferase of NCBI has reduced feedback inhibition by histidine. Since (1) both ATP-phosphoribosyltransferases have identical structure and (2) the Office does not have facilities for examining and comparing applicant's ATP-phosphoribosyltransferase with the ATP-phosphoribosyltransferase of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed product and the product of the prior art (i.e., that the ATP-phosphoribosyltransferase of the prior art does not possess the same material structure and functional characteristics of the claimed ATP-phosphoribosyltransferase). See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Figzgerald et al., 205 USPQ 594.
Therefore, the reference of NCBI anticipates claims 1-3.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-4 is/are rejected under 35 U.S.C. 103 as being unpatentable over NCBI, GenBank accession no. WP_054472839.1 (ATP phosphoribosyltransferase, [Escherichia coli MS 200-1], June 2019 -form PTO-1449, “NCBI”), Wen (US 2019/0338282 – form PTO-892) and Zhang (Genetic and biochemical characterization of Corynebacterium glutamicum ATP phosphoribosyltransferase and its three mutants resistant to feedback inhibition by histidine. Biochimie. 2012 Mar;94(3):829-38. – form PTO-892).
Regarding claim 1, NCBI discloses an E. coli ATP-phosphoribosyltransferase identical to SEQ ID NO:1 of the instant application except having a His residue at position 250 (page 1 and see the sequence alignment below).
Regarding claim 2, the ATP-phosphoribosyltransferase of NCBI is expressed from E. coli hisG gene (page 1).
Regarding claim 3, MPEP 2112.01. II. states that “[p]roducts of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”. MPEP 2112. II. states that “[t]here is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference.”. In the instant case, the specification of the instant application discloses that an ATP-phosphoribosyltransferase variant of SEQ ID NO:1 containing R250H reduces feedback inhibition by histidine ([0010]). Since the ATP-phosphoribosyltransferase of NCBI has identical structure as the R250H ATP-phosphoribosyltransferase variant of the instant application, the ATP-phosphoribosyltransferase of NCBI has reduced feedback inhibition by histidine. Since (1) both ATP-phosphoribosyltransferases have identical structure and (2) the Office does not have facilities for examining and comparing applicant's ATP-phosphoribosyltransferase with the ATP-phosphoribosyltransferase of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed product and the product of the prior art (i.e., that the ATP-phosphoribosyltransferase of the prior art does not possess the same material structure and functional characteristics of the claimed ATP-phosphoribosyltransferase). See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Figzgerald et al., 205 USPQ 594.
NCBI does not disclose ATP-phosphoribosyltransferase variant having H232K, T252A, E271K, and S288P amino acid substitutions.
Regarding claim 4, Wen discloses an ATP-phosphoribosyltransferase variant (HisG*) having the amino acid sequence of SEQ ID NO:53 ([1198] and see the sequence alignment below). The ATP-phosphoribosyltransferase variant of Wen is identical to the ATP-phosphoribosyltransferase of SEQ ID NO:1 except having a lysine residue at position 271 of SEQ ID NO:1 of the instant application.
Regarding claim 2, the ATP-phosphoribosyltransferase variant of Wen is expressed from E. coli hisG gene ([1198]).
Regarding claim 3, the ATP-phosphoribosyltransferase variant of Wen has reduced feedback inhibition by histidine ([1198]).
Regarding claim 4, Zhang discloses 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/L231F/T235A, wherein the variant is resistant 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 discloses substitutions of amino acids in the histidine binding sites with nonpolar hydrophobic residues, which includes prolines (5th full paragraph at page 835). Zhang discloses that mutating multiple residues in the histidine binding site simultaneously can significantly increase the resist to histidine inhibition (4th full paragraph at page 836).
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 ATP-phosphoribosyltransferase of NCBI by introducing H232K/A248F/T252A amino acid substitutions, S288X/P amino acid substitution, and E271K amino acid substitution into the ATP-phosphoribosyltransferase of NCBI. One having ordinary skill in the art would have been motivated to do so in order to further reduce feedback inhibition by histidine in the ATP-phosphoribosyltransferase of NCBI. One having ordinary skill in the art would have has a reasonable expectation of success since Zhang discloses that H232 and T252 are located in the histidine binding site of E. coli ATP-phosphoribosyltransferase, Zhang discloses that S288 binds histidine, and Zhang discloses that substitution of these residues feedback inhibition by histidine. The rationale supporting that the claims would have been obvious is that a method of enhancing a particular class of devices (amino acid substitutions that reduce feedback inhibition by histidine) has been made part of the ordinary capabilities of one skilled in the art based upon the teaching of such improvement in other situations. One of ordinary skill in the art would have been capable of applying this known method of enhancement to a “base” device (ATP-phosphoribosyltransferase variant of NCBI) in the prior art and the results would have been predictable to one of ordinary skill in the art.
Therefore, the above references render claims 1-4 prima facie obvious.
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 1-3 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 interpretation
MPEP 2113 states that “ [P]product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. [E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production.”. In the instant case, the structure of the claimed ATP-phosphoribosyltransferase implied is the same whether the ATP-phosphoribosyltransferase variant is obtained from any recombinant engineering or is obtained from any source (including wild type proteins), as long as the resulting product has the structural limitations recited in the claims (having an histidine residue at the position corresponding to 250 of SEQ ID NO:1). MPEP 2112.01. II. states that “[p]roducts of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”. MPEP 2112. II. states that “[t]here is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference.”.
Therefore, the claims 1-3 have been broadly interpreted as an ATP-phosphoribosyltransferase having the amino acid sequence of SEQ ID NO:1, except having an R250H amino acid substitution. NCBI discloses an E. coli ATP-phosphoribosyltransferase identical to SEQ ID NO:1 of the instant application except having a His residue at position 250 (page 1 and see the sequence alignment below). Thus, claims 1-3 are directed to a product of nature.
Step 1: This part of the eligibility analysis evaluates whether the claim falls within any statutory category (see MPEP 2106.03). Since the claims are directed to a protease mutant, the claims are directed to a composition of matter, which is one of the statutory categories of invention. (Step 1: YES)
Step 2A Prong 1: This part of the eligibility analysis evaluates whether the claim recites a judicial exception (see MPEP 2106.04). The claimed ATP-phosphoribosyltransferase variant is not considered to have markedly different characteristics from what occurs in nature, E. coli ATP-phosphoribosyltransferase as discussed above, and is considered to be a law of nature exception. Because there is no difference in characteristics (structural, functional, or otherwise) between the claimed ATP-phosphoribosyltransferase variant and the naturally occurring E. coli ATP-phosphoribosyltransferase, the claimed ATP-phosphoribosyltransferase variant is directed to a judicial exception.
Step 2A Prong 2: This part of the eligibility analysis evaluates whether the claim as a whole integrates the recited judicial exception into a practical application (see MPEP 2106.04(d)). This evaluation is performed by (a) identifying whether there are any additional recited elements in the claim beyond the judicial exception and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. There are no additional elements recited in the claim beyond the judicial exception. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claimed ATP-phosphoribosyltransferase variant is found naturally occurring in nature (E. coli). (Step2 A: YES)
Step 2B: This part of the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim (see MPEP § 2106.05). The claims only recite the laws of nature and do not include any additional elements that could add significantly more to the judicial exceptions. (Step 2B: NO)
As such, the claims do not qualify as eligible subject matter.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of copending Application No. 18/269,689 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the instant application and the claims of the reference application are directed to ATP-phosphoribosyltransferase variants of SEQ ID NO:1. The ATP-phosphoribosyltransferase of SEQ ID NO:1 of the instant application is identical to the ATP-phosphoribosyltransferase of SEQ ID NO:1 of the reference application.
Regarding claims 1 and 4 of the instant application, claims 1 and 4 of the reference application recite an ATP-phosphoribosyltransferase variant of SEQ ID NO:1, wherein the variant contains R250H, T232K, T252A/L/G/V/I, E271K, and S288P amino acid substitutions. Therefore, claims 1 and 4 of the instant application are anticipated by claims 1 and 4 of the reference application.
Regarding claim 2 of the instant application, claim 2 of the reference application, recites that the ATP-phosphoribosyltransferase variant is expressed from E. coli hisG gene. Therefore, claim 2 of the instant application are anticipated by claim 2 of the reference application.
Regarding claim 3 of the instant application, claim 3 of the reference application, recites that the ATP-phosphoribosyltransferase variant is reduced feedback inhibition of the variant by histidine. Therefore, claim 3 of the instant application are anticipated by claim 3 of the reference application.
Therefore, the conflicting claims are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4 are provisionally rejected on