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
The response filed on May 27, 2026 has been entered.
Claims 1-11 are pending.
Election/Restrictions
Applicant's election with traverse of the species
Species 1: for the first Enzyme, an isolated or engineered polypeptide comprising a homologous protein sequence that is more than 70% identical to SEQ ID NO: 1; wherein said polypeptide sequentially comprises: an ATP-binding domain, comprising active catalytic sites of Lys27, Arg102, and Glu282; a substrate-binding domain, comprising a conserved motif of DDHHFYIDAMLDAKAR (SEQ ID NO: 2), and comprising active catalytic sites of Asp627, His629, and His630; and a phosphorylated histidine catalytic domain, comprising His795;
Species 2: for the second Enzyme, a polypeptide having a sequence that is more than 65% identical to ErPPK from an unclassified Erysipelotrichaceae bacterium (SEQ ID NO: 11); wherein said polypeptide sequentially comprises: a conserved walker A (GXDXXGK) motif of AXDXXGK for coordinating the divalent cation and polyphosphate; a conserved walker B (DR) motif of NR or DR for coordinating the nucleotide phosphate groups; active catalytic sites of Asp66, Lys70, Arg192, and Asp206 in ErPPK (SEQ ID NO: 11) and equivalent residues;
Species 3: for the substrate, luteolin (LUT); and
Species 4: for the product, polyphenol phosphates of the luteolin.
in the reply filed on May 27, 2026 is acknowledged.
The traversal is on the ground(s) that the first enzyme, the second enzyme, the substrate, and the resulting product are functionally interrelated components that cooperate to achieve a single inventive concept and the different species identified by the Examiner do not represent separate inventions, but rather constitute closely related variations within a unified biochemical system. This is not found persuasive an election of species requirement was issued not restriction among the components of the coupled enzyme system.
The traversal is also on the ground(s) that the election of species Requirement has not demonstrated a serious search and/or examination burden that would justify restriction because the claims share substantial overlapping structural and functional features, and the core limitations, particularly those relating to the enzymes and their catalytic functions-would be subject to substantially similar prior art searches. This is not found persuasive because each of the four species identified require a different field of search (e.g., searching different classes/subclasses or electronic resources, or employing different search strategies or search queries). Therefore, there is a search and/or examination burden for the above species.
The requirement is still deemed proper and is therefore made FINAL.
The amino acids sequence of SEQ ID NO:1 is comprised of (i) ATP-binding domain of amino acids 24-312 of SEQ ID NO:1, (ii) substrate binding domain of amino acids 313-761 of SEQ ID NO:13, and (iii) phosphorylated histidine catalytic domain of amino acids 762-831 of SEQ ID NO:1.
Claim for Domestic Priority
Applicants' claim for domestic priority under 35 USC 119(e) to US provisional application 63/451,238, filed 03/10/2023, is acknowledged.
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.
Claims 2-3 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.
Claims 2-3 recite the limitation “(SEQ ID NO:.)”. The metes and bounds of the limitation in the context of the above claims are not clear. The usage of parentheses renders the claims indefinite because it is unclear whether the limitation(s) enclosed in the parentheses are part of the claimed invention or is a representative sequence for the recited motif and enzymes. See MPEP § 2173.05(d).
Claims 5-6 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.
Claims 5-6 recite the limitation "wherein the reaction" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claims 5-6 depend from claim 1 and claim 1 does not recite “a reaction”. Therefore, it is unclear if the “reaction” is phosphorylation of a substrate or if the “reaction” is another reaction. Clarification is requested.
Claim 9 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 9 recites the limitation "wherein the divalent metal" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 9 depends from claim 1 and claim 1 does not recite “a divalent metal”. Clarification is requested.
Claim 11 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 11 recites the limitation "wherein the surfactant" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 11 depends from claim 1 and claim 1 does not recite “a surfactant”. Clarification is requested.
Claim 11 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 11 contains the trademark/trade name “TWEEN”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe polysorbates 20 or 80 and, accordingly, the identification/description is indefinite.
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 1-11 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.'' In this case, the claims have been broadly interpreted to encompass a couple enzyme system comprising (1) any polyphenol phosphorylation synthetase or any polyphenol phosphorylation synthetase having at least 70% sequence identity SEQ ID NO:11 and comprising (i) an ATP-binding domain comprising of catalytic sites Lys27, Arg102, and Glu282, (ii) a substrate binding domain comprising the conserved motif of DDHHFYIDAMLDAKAR and comprising catalytic sites of Asp627, His629, and His630, and (iii) a catalytic domain comprising His795, (2) any ATP regeneration enzyme or the polyphosphate kinase of SEQ ID NO:11, wherein the polyphenol phosphorylation synthetase phosphorylates (3) any substrate, any substrate having formula I, II, III, or IV, or luteolin. Therefore, the claims are drawn to a couple enzyme system comprising (1) a genus of polyphenol phosphorylation synthetase having unknown structure, (2) a genus of ATP regenerating enzyme or polyphosphate kinase having unknown structure, and (3) a genus of substrates having unknown structure, genus of substrates having formula I, II, III, or IV, or luteolin, wherein the polyphenol phosphorylation synthetase phosphorylates said genus of substrates, genus of substrates having formula I, II, III, or IV, or luteolin.
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 “polyphenol phosphorylation synthetase” and “ATP regeneration enzyme”, “polyphosphate kinase”, wherein the “substrate” or a substrate having formula I, II, III, or IV is phosphorylated by the synthetase fails to provide a sufficient description of the genus of coupled system 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.
Bacillus subtilis benzopyrone phosphate synthetase having 100% sequence identity to the phenolic phytochemical phosphate synthetases SEQ ID NO:3 of the instant application was known in the art, see AYF57920.1 (GenBank Database. October 10, 2018 – form PTO-892) and the sequence alignment below. However, polypeptides having polyphenol phosphorylation synthetase activity or polypeptides having at least 70% sequence identity to SEQ ID NO:3 and comprising (i) an ATP-binding domain comprising of catalytic sites Lys27, Arg102, and Glu282, (ii) a substrate binding domain comprising the conserved motif of DDHHFYIDAMLDAKAR and comprising catalytic sites of Asp627, His629, and His630, and (iii) a catalytic domain comprising His795 but having the function of phosphorylating a genus of substrates were not known in the art.
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 a coupled enzyme system comprising (1) B. subtilis polyphenol phosphorylation synthetase having the amino acid sequence of SEQ ID NO:1, (2) polyphosphate kinase having the amino acid sequence of SEQ ID NO:8, 9, 10 or 11, and (3) specific substrates having the formula of I, II, III, or IV, such as luteolin, genistein, hesperetin, quercetin, silybins, and resveratrol. 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 polyphenol phosphorylation synthetase described above are 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 polypeptides having 70% sequence identity with SEQ ID NO:1 and comprising of the conserved motif of the substrate binding domain and seven catalytic sites. However, there is no teaching regarding which 30% of the amino acids of SEQ ID NO:1 other than said conserved motif and seven catalytic sites, can be modified and result in polypeptide having the function of phosphorylating a genus of substrates. Similarly, one of skill in the art could identify variants of the polyphosphate kinase of SEQ ID NO:8, 9, 10, or 11. However, there is no teaching regarding which amino acids of SEQ ID NO:8, 9, 10, or 11 that can be modified and result in polypeptide having polyphosphate kinase activity.
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.
Further, the claimed invention requires a defined set of (1) polyphenol phosphorylation synthetase, (2) ATP regenerating enzyme or polyphosphate kinase, and (3) substrates having formula I, II, III, or IV. Although the specification discloses exemplary (1) polyphenol phosphorylation synthetase, (2) ATP regenerating enzyme or polyphosphate kinase, and (3) substrates having formula I, II, III, or IV, a “laundry list” disclosure of every possible moiety does not necessarily constitute a written description of every species in a genus because it would not “reasonably lead” those skilled in the art to any particular species, see Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) or MPEP 2163. While the exemplary (1) polyphenol phosphorylation synthetase, (2) ATP regenerating enzyme or polyphosphate kinase, and (3) substrates having formula I, II, III, or IV were known in the art, this knowledge alone would not allow one level of skill in the art to immediately envisage the claimed genus. Therefore, the level of skill and knowledge in the art is such that one of ordinary skill would not be able to identify without further testing which combination of (1) polyphenol phosphorylation synthetase, (2) ATP regenerating enzyme or polyphosphate kinase, and (3) substrates having formula I, II, III, or IV to use in the claimed system.
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 1-11
Claims 1-11 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 a coupled enzyme system comprising (1) B. subtilis polyphenol phosphorylation synthetase having the amino acid sequence of SEQ ID NO:1, (2) polyphosphate kinase having the amino acid sequence of SEQ ID NO:8, 9, 10 or 11, and (3) specific substrates having the formula of I, II, III, or IV, such as luteolin, genistein, hesperetin, quercetin, silybins, and resveratrol, does not reasonably provide enablement for a couple enzyme system comprising (1) any polyphenol phosphorylation synthetase having unknown structure, (2) any ATP regenerating enzyme or any polyphosphate kinase having unknown structure, and (3) any substrates having unknown structure, genus of substrates having formula I, II, III, or IV, or luteolin, wherein the polyphenol phosphorylation synthetase phosphorylates said substrates having formula I, II, III, or IV, or luteolin. 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.'' In this case, the claims have been broadly interpreted to encompass a couple enzyme system comprising (1) any polyphenol phosphorylation synthetase or any polyphenol phosphorylation synthetase having at least 70% sequence identity SEQ ID NO:11 and comprising (i) an ATP-binding domain comprising of catalytic sites Lys27, Arg102, and Glu282, (ii) a substrate binding domain comprising the conserved motif of DDHHFYIDAMLDAKAR and comprising catalytic sites of Asp627, His629, and His630, and (iii) a catalytic domain comprising His795, (2) any ATP regeneration enzyme or the polyphosphate kinase of SEQ ID NO:11, wherein the polyphenol phosphorylation synthetase phosphorylates (3) any substrate, any substrate having formula I, II, III, or IV, or luteolin. Therefore, the claims are drawn to a couple enzyme system comprising (1) any polyphenol phosphorylation synthetase having unknown structure, (2) any ATP regenerating enzyme or any polyphosphate kinase having unknown structure, and (3) any substrates having unknown structure, genus of substrates having formula I, II, III, or IV, or luteolin, wherein the polyphenol phosphorylation synthetase phosphorylates said substrates having formula I, II, III, or IV, or luteolin.
The claims are not commensurate with the enablement provided by the disclosure with regard to the extremely large number of polypeptides having any function, unknown function or having the function of phosphorylating any substrate comprising of any phenolic phytochemical, any compound of formula I, natural or any modified curcuminoid, or natural or any modified curcumin. In the instant case, the specification is limited to a coupled enzyme system comprising (1) B. subtilis polyphenol phosphorylation synthetase having the amino acid sequence of SEQ ID NO:1, (2) polyphosphate kinase having the amino acid sequence of SEQ ID NO:8, 9, 10 or 11, and (3) specific substrates having the formula of I, II, III, or IV, such as luteolin, genistein, hesperetin, quercetin, silybins, and resveratrol.
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 a coupled enzyme system comprising (1) any polyphenol phosphorylation synthetase, (2) any ATP regenerating enzyme or any polyphosphate kinase, and (3) any substrates having formula I, II, III, or IV, and (b) a correlation between structure and function of phosphorylating said substrates, 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 the function of phosphorylating any substrate having formula I, II, III, or IV. 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 deoxyribose-phosphate aldolase 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 other than the 16 conserved motif of the substrate binding domain and seven catalytic sites that can be modified and which ones are conserved such that one of skill in the art can make the recited encoded polypeptides having the function of phosphorylating any substrate having formula I, II, III, or IV, (2) which segments of the polypeptide of SEQ ID NO:1 are essential for having the function of phosphorylating any substrate having formula I, II, III, or IV, and (3) the general tolerance of the polypeptide of SEQ ID NO:1 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.
Bacillus subtilis benzopyrone phosphate synthetase having 100% sequence identity to the phenolic phytochemical phosphate synthetases SEQ ID NO:3 of the instant application was known in the art, see AYF57920.1 (GenBank Database. October 10, 2018 – form PTO-892) and the sequence alignment below. However, polypeptides having polyphenol phosphorylation synthetase activity or polypeptides having at least 70% sequence identity to SEQ ID NO:3 and comprising (i) an ATP-binding domain comprising of catalytic sites Lys27, Arg102, and Glu282, (ii) a substrate binding domain comprising the conserved motif of DDHHFYIDAMLDAKAR and comprising catalytic sites of Asp627, His629, and His630, and (iii) a catalytic domain comprising His795 but having the function of phosphorylating a genus of substrates were not known in the art.
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 co
The amount of direction or guidance presented and the existence of working examples.
The specification is limited to a coupled enzyme system comprising (1) B. subtilis polyphenol phosphorylation synthetase having the amino acid sequence of SEQ ID NO:1, (2) polyphosphate kinase having the amino acid sequence of SEQ ID NO:8, 9, 10 or 11, and (3) specific substrates having the formula of I, II, III, or IV, such as luteolin, genistein, hesperetin, quercetin, silybins, and resveratrol. However, the specification fails to provide any information as to (1) specific substrates associated with any polyphenol phosphorylation synthetase or any polyphenol phosphorylation synthetase having 70% sequence identity to SEQ ID NO:1 and comprising (i) an ATP-binding domain comprising of catalytic sites Lys27, Arg102, and Glu282, (ii) a substrate binding domain comprising the conserved motif of DDHHFYIDAMLDAKAR and comprising catalytic sites of Asp627, His629, and His630, and (iii) a catalytic domain comprising His795 or (2) structural elements required in a polypeptide having the function of phosphorylating any substrate having formula I, II, III, or IV. No correlation between structure and function of phosphorylating any substrate of formula I, II, III, or IV 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 § 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.
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) 1-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over
Su (US 10,421,768 - form PTO-892), Kameda (A novel ATP regeneration system using polyphosphate-AMP phosphotransferase and polyphosphate kinase. J Biosci Bioeng. 2001;91(6):557-63. – form PTO-892), and UKS89443.1 (GenBank Database. February 15, 2022 – form PTO-892).
Regarding claims 1-2, Su discloses a Bacillus subtilis benzopyrone phosphate synthetase comprising of (i) ATP-binding domain of SEQ ID NO:2, (ii) substrate binding domain of SEQ ID NO:1, and (iii) catalytic domain of SEQ ID NO:3 (Fig.1b and claim 1). The ATP-binding domain of SEQ ID NO:2 of Su has 100% sequence identity to the ATP-binding domain of amino acids 24-312 of SEQ ID NO:1 of the instant application and comprises catalytic site Lys27, Arg102, and Glu282 (see the sequence alignment below). The substrate binding domain of SEQ ID NO:1 of Su has 100% sequence identity to the substrate binding domain of amino acids 313-761 of SEQ ID NO:1 of the instant application and comprises the conserved motif of DDHHFYIDAMLDAKAR and catalytic sites of Asp627, His629, and His630 (see the sequence alignment below). The catalytic domain of SEQ ID NO:3 of Su has 100% sequence identity to the catalytic domain of amino acids 762-831 of SEQ ID NO:1 of the instant application and comprises of comprising His795 (see the sequence alignment below). Therefore, the benzopyrone phosphate synthetase of Su has at least 70% sequence identity to SEQ ID NO:13 of the instant application. Further, Su discloses that the benzopyrone phosphate synthetase phosphorylates flavanone, which is a polyphenol (Column 4, lines 61-67). Therefore, the synthetase of Su is a polyphenol phosphorylation synthetase.
Regarding claim 4, Su discloses substrates of the benzopyrone phosphate synthetase as a compound having formula II, which is identical to the compound having formula IV of the instant application (Column 2, line 46 through Column 4, line 55 and claim 3). Formula II of Su is provided below:
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178
463
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Regarding the elected species, luteolin, Su discloses that a substrate of the benzopyrone phosphate synthetase is luteolin (claim 3).
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188
344
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Luteolin is a compound having formula I of Su,
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171
400
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wherein R2 is H and R1 is:
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197
197
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Regarding claim 5, Su discloses that the optimal temperature of the benzopyrone phosphate synthetase is 30°C to 30°C and the most preferable temperature is 40°C, which falls within the recited temperature range of 35°C to 40°C (Column 8, lines 11-26).
Regarding claim 6, Su discloses that the optimal pH of the benzopyrone phosphate synthetase is 6.5 to 8.5 and the most preferable pH is 7.5, which falls within the recited pH range of 7.0 to 8.0 (Column 8, lines 11-26).
Regarding claims 7-8, Su discloses using the divalent metal Mg2+ (Column 14, lines 34-42).
The reference of Su does not disclose a coupled system comprising the benzopyrone phosphate synthetase, an ATP regeneration enzyme or an Erysipelotrichaceae bacterium ErPPK having the amino acid sequence of SEQ ID NO:11 sequentially comprising a conserved walker A (GXDXXGK) motif of AXDXXGK for coordinating the divalent cation and polyphosphate, a conserved walker B (DR) motif of NR or DR for coordinating the nucleotide phosphate groups, and active catalytic sites of Asp66, Lys70, Arg192, and Asp206 in ErPPK of SEQ ID NO: 11.
The benzopyrone phosphate synthetase of Su has an ATP binding domain, as discussed above, and uses ATP in its catalysis (Column 14, lines 34-42).
Regarding claims 1 and 7, Kameda discloses a system for enzymatic regeneration of ATP from both ADP and AMP by using an economical phosphate donor, a polyphosphate (polyP), and a polyphosphate kinase (abstract, page 557 and FIG.3 at page 560).
Regarding claims 7-8, Kameda discloses uses polyP and a divalent metal Mg2+(abstract).
Regarding claim 9, Kameda discloses that the Mg2+ and polyP concentrations was optimized because high concentrations of polyP may chelate Mg2+ and inhibit enzyme activity and (abstract). Kameda discloses that increased concentration of polyP results in increased synthesis of ATP and a sufficient amount of polyP for regenerating
both ADP and ATP should be added to the reaction mixture, but optimization of the Mg2+ concentration is also important. (“Effect of initial polyP concentration on ATP formation” at pages 560-561). Kameda discloses that the Mg2+ concentration was optimized to 24 mM in the presence of 30 mM polyP in the reaction, which equates to a ratio of Mg2+ to polyP of 1:1.25 (abstract and “Optimization of Mg 2+ concentration in the PAP-PPK ATP regeneration system” at pages 561-562). Regarding the recited ratio of 1:1, it would have been well within the knowledge of one having ordinary skill in the art to vary and optimize the concentrations of Mg2+ and polyP when coupling the benzopyrone phosphate synthetase of Su with a polyphosphate kinase disclosed by Kameda or another polyphosphate kinase to regenerate ATP. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”, see MPEP 2144.
Regarding claims 1 and 3, UKS89443.1 discloses a Erysipelotrichaceae bacterium polyphosphate kinase having 100% sequence identity to SEQ ID NO:11 of the instant application (page 1 and see the sequence alignment below) and therefore comprises sequentially a conserved walker A (GXDXXGK) motif of AXDXXGK for coordinating the divalent cation and polyphosphate, a conserved walker B (DR) motif of NR or DR for coordinating the nucleotide phosphate groups, and active catalytic sites of Asp66, Lys70, Arg192, and Asp206.
Therefore, in combining the above references, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to make a coupled enzyme system comprising (1) the benzopyrone phosphate synthetase of Su, (2) a polyphosphate kinase or the polyphosphate kinase of UKS89443.1, and (3) a substrate of the benzopyrone phosphate synthetase and optimize the ratio of the polyP and Mg2+ to arrive at ratio of around 1:1.25, such as 1:1. Further, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to substitute the polyphosphate kinase of Kameda with other known polyphosphate kinases, such as the polyphosphate kinase of UKS89443.1, because one of ordinary skill in the art would have been able to carry out such a substitution, and the results were reasonably predictable. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to substitute other known polyphosphate kinases. One of ordinary skill in the art would have been motivated to couple the benzopyrone phosphate synthetase of Su with a polyphosphate kinase in order to regenerate ATP that is needed by the benzopyrone phosphate synthetase instead of supplying ATP to the reaction. One of ordinary skill in the art would have had a reasonable expectation of success since Su teaches a benzopyrone phosphate synthetase, UKS89443.1 teaches a polyphosphate kinase, and Kameda teaches an enzymatic ATP regeneration system.
Therefore, the above references render claims 1-9 prima facie obvious.
Claim(s) 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Su (US 10,421,768 - form PTO-892), Kameda (A novel ATP regeneration system using polyphosphate-AMP phosphotransferase and polyphosphate kinase. J Biosci Bioeng. 2001;91(6):557-63. – form PTO-892), and UKS89443.1 (GenBank Database. February 15, 2022 – form PTO-892) as applied to claims 1-9 above, and further in view of Kerwin (Polysorbates 20 and 80 used in the formulation of protein biotherapeutics: structure and degradation pathways. J Pharm Sci. 2008 Aug;97(8):2924-35 – form PTO-892).
The combined teachings of Su, Kameda, and UKS89443.1 do not disclose using a cosolvent and a surfactant, such as TWEEN® 20 (polysorbate 20) or TWEEN® 80 (polysorbate 80)
Regarding claim 10, Su discloses using a solvent Tris and water (Column 14, lines 34-42).
Regarding claim 11, Kerwin discloses that polysorbate 20 and polysorbate 80 are stabilizers against protein aggregation (abstract).
Therefore, in combining the above references, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to add polysorbate 20 and polysorbate 80 to the coupled enzyme system. One of ordinary skill in the art would have been motivated to do so in order to stabilize the benzopyrone phosphate synthetase and polyphosphate kinase. One of ordinary skill in the art would have had a reasonable expectation of success since Kerwin teaches that polysorbate 20 and polysorbate 80 are stabilizers against protein aggregation.
Therefore, the above references render claims 1-11 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 1-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (composition of matter) without significantly more.
Claim interpretation
The claims recite a coupled enzyme system comprising (1) a polyphenol phosphorylation synthetase having at least 70% sequence identity to SEQ ID NO:1, (2) a polyphosphate kinase or the Erysipelotrichaceae bacterium polyphosphate kinase, (3) a substrate of the polyphenol phosphorylation synthetase, (4) polyphosphate, and (5) Mg2+. The polyphenol phosphorylation synthetase of SEQ ID NO:1 of the instant application is identical to a naturally occurring Bacillus subtilis benzopyrone phosphate synthetase, which as the recited ATP binding domain, substrate binding domain, and catalytic domain (see AYF57920.1. GenBank Database. October 10, 2018 – form PTO-892 and the sequence alignment below). Polyphosphate kinase and the Erysipelotrichaceae bacterium is also a naturally occurring enzyme (see Kameda (A novel ATP regeneration system using polyphosphate-AMP phosphotransferase and polyphosphate kinase. J Biosci Bioeng. 2001;91(6):557-63. – form PTO-892)). The polyphenol substrates, such as flavanone or luteolin, are also naturally occurring (see Su (US 10,421,768 - form PTO-892)). Polyphosphate and Mg2+ are also naturally occurring (see Kameda (A novel ATP regeneration system using polyphosphate-AMP phosphotransferase and polyphosphate kinase. J Biosci Bioeng. 2001;91(6):557-63. – form PTO-892)).
Therefore, claims 1-2 and 4-9 directed to (1) a polyphenol phosphorylation synthetase, a nature-based product, (2) a polyphosphate kinase, a nature-based product, (3) polyphenol substrates, such as flavanone or luteolin, a natured-based product, (4) polyphosphate, a nature-based product, and (5) Mg2+, a nature-based product.
Step 1: This part of the eligibility analysis evaluates whether the claims fall within any statutory category (see MPEP 2106.03). Since the claims are directed to a composition comprising nature-base products, 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 claims recite a judicial exception (see MPEP 2106.04). The (1) polyphenol phosphorylation synthetase, (2) polyphosphate kinase, (3) polyphenol substrates, such as flavanone or luteolin, (4) polyphosphate, and (5) Mg2+ comprised in the claimed system are not considered to have markedly different characteristics from what occurs in nature, (1) naturally occurring polyphenol phosphorylation synthetase, (2) naturally occurring polyphosphate kinase, (3) naturally occurring polyphenol substrates, such as flavanone or luteolin, (4) naturally occurring polyphosphate, and (5) naturally occurring Mg2+, and are considered to be a law of nature exception. There is no indication in the specification that placing the (1) naturally occurring polyphenol phosphorylation synthetase, (2) naturally occurring polyphosphate kinase, (3) naturally occurring polyphenol substrates, such as flavanone or luteolin, (4) naturally occurring polyphosphate, and (5) naturally occurring Mg2+ into a system result in the (1) polyphenol phosphorylation synthetase, (2) polyphosphate kinase, (3) polyphenol substrates, such as flavanone or luteolin, (4) polyphosphate, and (5) Mg2+ having any characteristics (structural, functional, or otherwise) that are different from the naturally occurring (1) polyphenol phosphorylation synthetase, (2) polyphosphate kinase, (3) polyphenol substrates, such as flavanone or luteolin, (4) polyphosphate, and (5) Mg2+. Because there is no difference in characteristics (structural, functional, or otherwise) between the claimed (1) polyphenol phosphorylation synthetase, (2) polyphosphate kinase, (3) polyphenol substrates, such as flavanone or luteolin, (4) polyphosphate, and (5) Mg2+and the naturally occurring (1) polyphenol phosphorylation synthetase, (2) polyphosphate kinase, (3) polyphenol substrates, such as flavanone or luteolin, (4) polyphosphate, and (5) Mg2+, the claimed composition 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 is no indication in the specification that placing (1) polyphenol phosphorylation synthetase, (2) polyphosphate kinase, (3) polyphenol substrates, such as flavanone or luteolin, and (4) polyphosphate and Mg2+ in the recited ratios in a composition results in a transformation of (1) polyphenol phosphorylation synthetase, (2) polyphosphate kinase, (3) polyphenol substrates, such as flavanone or luteolin, (4) polyphosphate, and (5) Mg2+ (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 claim only recites the laws of nature and do not include any additional elements that could add significantly more to the judicial exceptions. Because the component elements ((1) polyphenol phosphorylation synthetase, (2) polyphosphate kinase, (3) polyphenol substrates, such as flavanone or luteolin, (4) polyphosphate, and (5) Mg2+) do not occur together in nature as claimed and are not markedly changed by their combination into a composition, each component is considered as an additional element to the other to determine whether their combination results in significantly more than the products of nature. Combining (1) polyphenol phosphorylation synthetase, (2) polyphosphate kinase, (3) polyphenol substrates, such as flavanone or luteolin, (4) polyphosphate, and (5) Mg2+ does not markedly change the characteristics of either component, because each component continues to have the same properties in the mixture as it had alone. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the (1) polyphenol phosphorylation synthetase, (2) polyphosphate kinase, (3) polyphenol substrates, such as flavanone or luteolin, (4) polyphosphate, and (5) Mg2+ comprised in the composition is not markedly different form its naturally occurring counterpart because it conveys the same structural and functional information. Thus, the combination of (1) polyphenol phosphorylation synthetase, (2) polyphosphate kinase, (3) polyphenol substrates, such as flavanone or luteolin, (4) polyphosphate, and (5) Mg2+ does not meaningfully limit the claims, and the claims as a whole do not amount to significantly more than each “product of nature by itself (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 1-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 10,421,768 (reference patent) in view of Su (US 2017/0305944 – form PTO-892, which is the PGPUB of U.S. Patent No. 10,421,768), Kameda (A novel ATP regeneration system using polyphosphate-AMP phosphotransferase and polyphosphate kinase. J Biosci Bioeng. 2001;91(6):557-63. – form PTO-892) and UKS89443.1 (GenBank Database. February 15, 2022 – form PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because they are claiming common subject matter, as follows:
Regarding claims 1-2 of the instant application, Claim 1 of the reference patent recites a Bacillus subtilis benzopyrone phosphate synthetase comprising of (i) ATP-binding domain of SEQ ID NO:2, (ii) substrate binding domain of SEQ ID NO:1, and (iii) catalytic domain of SEQ ID NO:3. The ATP-binding domain of SEQ ID NO:2 of the reference patent has 100% sequence identity to the ATP-binding domain of amino acids 24-312 of SEQ ID NO:1 of the instant application and comprises catalytic site Lys27, Arg102, and Glu282 (see the sequence alignment below). The substrate binding domain of SEQ ID NO:1 of the reference patent has 100% sequence identity to the substrate binding domain of amino acids 313-761 of SEQ ID NO:3 of the instant application and comprises the conserved motif of DDHHFYIDAMLDAKAR and catalytic sites of Asp627, His629, and His63 (see the sequence alignment below). The catalytic domain of SEQ ID NO:3 of the reference patent has 100% sequence identity to the catalytic domain of amino acids 762-831 of SEQ ID NO:3 of the instant application and comprises of His795 (see the sequence alignment below). Therefore, the benzopyrone phosphate synthetase of the reference patent has at least 70% sequence identity to SEQ ID NO:1 of the instant application. Further, the benzopyrone phosphate synthetase of the reference patent phosphorylates flavanone, which is a polyphenol (see Column 4, lines 61-67 of the reference patent and see [0017] of Su). Therefore, the synthetase of the reference patent is a polyphenol phosphorylation synthetase.
Regarding claim 4 of the instant application claim 3 of the reference patent recites substrates of the benzopyrone phosphate synthetase as a compound having formula II, which is identical to the compound having formula IV of the instant application. Formula II of the reference patent is provided below:
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Regarding the elected species, luteolin, claim 3 of the reference patent recites that a substrate of the benzopyrone phosphate synthetase is luteolin (claim 3).
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Luteolin is a compound having formula I of the reference patent,
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wherein R2 is H and R1 is:
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Regarding claim 5 of the instant application, Su discloses that the optimal temperature of the benzopyrone phosphate synthetase is 30°C to 30°C and the most preferable temperature is 40°C, which falls within the recited temperature range of 35°C to 40°C ([0038]).
Regarding claim 6 of the instant application, Su discloses that the optimal pH of the benzopyrone phosphate synthetase is 6.5 to 8.5 and the most preferable pH is 7.5, which falls within the recited pH range of 7.0 to 8.0 ([0038]).
Regarding claims 7-8 of the instant application, Su discloses using the divalent metal Mg2+ ([0067).
The reference patent does not disclose a coupled system comprising the benzopyrone phosphate synthetase, an ATP regeneration enzyme or an Erysipelotrichaceae bacterium ErPPK having the amino acid sequence of SEQ ID NO:11 sequentially comprising a conserved walker A (GXDXXGK) motif of AXDXXGK for coordinating the divalent cation and polyphosphate, a conserved walker B (DR) motif of NR or DR for coordinating the nucleotide phosphate groups, and active catalytic sites of Asp66, Lys70, Arg192, and Asp206 in ErPPK of SEQ ID NO: 11.
The benzopyrone phosphate synthetase of the reference patent has an ATP binding domain, as discussed above, and uses ATP in its catalysis ([0067]).
Regarding claims 1 and 7 of the instant application, Kameda discloses a system for enzymatic regeneration of ATP from both ADP and AMP by using an economical phosphate donor, a polyphosphate (polyP), and a polyphosphate kinase (abstract, page 557 and FIG.3 at page 560).
Regarding claims 7-8 of the instant application, Kameda discloses uses polyP and a divalent metal Mg2+(abstract).
Regarding claim 9 of the instant application, Kameda discloses that the Mg2+ and polyP concentrations was optimized because high concentration of polyP may chelate Mg2+ and inhibit enzyme activity and (abstract). Kameda discloses that increased concentration of polyP results in increased synthesis of ATP and a sufficient amount of polyP for regenerating both ADP and ATP should be added to the reaction mixture, but optimization of the Mg2+ concentration is also important. (“Effect of initial polyP concentration on ATP formation” at pages 560-561). Kameda discloses that the Mg2+ concentration was optimized to 24 mM in the presence of 30 mM polyP in the reaction, which equates to a ratio of Mg2+ to polyP of 1:1.25 (abstract and “Optimization of Mg 2+ concentration in the PAP-PPK ATP regeneration system” at pages 561-562). Regarding the recited ratio of 1:1, it would have been well within the knowledge of one having ordinary skill in the art to vary and optimize the concentrations of Mg2+ and polyP when coupling the benzopyrone phosphate synthetase of Su with a polyphosphate kinase disclosed by Kameda or another polyphosphate kinase to regenerate ATP. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”, see MPEP 2144.
Regarding claims 1 and 3 of the instant application, UKS89443.1 discloses a Erysipelotrichaceae bacterium polyphosphate kinase having 100% sequence identity to SEQ ID NO:11 of the instant application (page 1 and see the sequence alignment below) and therefore comprises sequentially a conserved walker A (GXDXXGK) motif of AXDXXGK for coordinating the divalent cation and polyphosphate, a conserved walker B (DR) motif of NR or DR for coordinating the nucleotide phosphate groups, and active catalytic sites of Asp66, Lys70, Arg192, and Asp206.
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 claims of the reference patent by using a coupled enzyme system comprising (1) the benzopyrone phosphate synthetase of the reference patent, (2) a polyphosphate kinase or the polyphosphate kinase of UKS89443.1, and (3) a substrate of the benzopyrone phosphate synthetase and optimize the ratio of the polyP and Mg2+ to arrive at ratio of around 1:1.25, such as 1:1 in the claimed method of the reference patent. Further, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to substitute the polyphosphate kinase of Kameda with other known polyphosphate kinases, such as the polyphosphate kinase of UKS89443.1, because one of ordinary skill in the art would have been able to carry out such a substitution, and the results were reasonably predictable. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to substitute other known polyphosphate kinases. One of ordinary skill in the art would have been motivated to couple the benzopyrone phosphate synthetase of the reference patent with a polyphosphate kinase in order to regenerate ATP that is needed by the benzopyrone phosphate synthetase instead of supplying ATP to the reaction. One of ordinary skill in the art would have had a reasonable expectation of success since the claims of the reference recite a benzopyrone phosphate synthetase, UKS89443.1 teaches a polyphosphate kinase, and Kameda teaches an enzymatic ATP regeneration system.
Therefore, the conflicting claims are not patentably distinct from each other.
Claims 1-2 and 10-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 10,421,768 (reference patent) in view of Su (US 2017/0305944 – form PTO-892, which is the PGPUB of U.S. Patent No. 10,421,768), Kameda (A novel ATP regeneration system using polyphosphate-AMP phosphotransferase and polyphosphate kinase. J Biosci Bioeng. 2001;91(6):557-63. – form PTO-892) and Kerwin (Polysorbates 20 and 80 used in the formulation of protein biotherapeutics: structure and degradation pathways. J Pharm Sci. 2008 Aug;97(8):2924-35 – form PTO-892).
Regarding claims 1-2 of the instant application, Claim 1 of the reference patent recites a Bacillus subtilis benzopyrone phosphate synthetase comprising of (i) ATP-binding domain of SEQ ID NO:2, (ii) substrate binding domain of SEQ ID NO:1, and (iii) catalytic domain of SEQ ID NO:3. The ATP-binding domain of SEQ ID NO:2 of the reference patent has 100% sequence identity to the ATP-binding domain of amino acids 24-312 of SEQ ID NO:1 of the instant application and comprises catalytic site Lys27, Arg102, and Glu282 (see the sequence alignment below). The substrate binding domain of SEQ ID NO:1 of the reference patent has 100% sequence identity to the substrate binding domain of amino acids 313-761 of SEQ ID NO:3 of the instant application and comprises the conserved motif of DDHHFYIDAMLDAKAR and catalytic sites of Asp627, His629, and His63 (see the sequence alignment below). The catalytic domain of SEQ ID NO:3 of the reference patent has 100% sequence identity to the catalytic domain of amino acids 762-831 of SEQ ID NO:3 of the instant application and comprises of His795 (see the sequence alignment below). Therefore, the benzopyrone phosphate synthetase of the reference patent has at least 70% sequence identity to SEQ ID NO:1 of the instant application. Further, the benzopyrone phosphate synthetase of the reference patent phosphorylates flavanone, which is a polyphenol (see Column 4, lines 61-67 of the reference patent and see [0017] of Su). Therefore, the synthetase of the reference patent is a polyphenol phosphorylation synthetase.
The claims of the reference patent do not recite using a cosolvent and a surfactant, such as TWEEN® 20 (polysorbate 20) or TWEEN® 80 (polysorbate 80).
Regarding claim 10, Su discloses using a solvent Tris and water ([0051]).
Regarding claim 11, Kerwin discloses that polysorbate 20 and polysorbate 80 are stabilizers against protein aggregation (abstract).
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 claims of the reference patent by using a coupled enzyme system comprising (1) the benzopyrone phosphate synthetase of the reference patent, (2) a polyphosphate kinase, (3) a substrate of the benzopyrone phosphate synthetase, (5) polyphosphate, and (6) solvents and surfactants TWEEN® 20 (polysorbate 20) or TWEEN® 80 (polysorbate 80). One of ordinary skill in the art would have been motivated to couple the benzopyrone phosphate synthetase of the reference patent with a polyphosphate kinase in order to regenerate ATP that is needed by the benzopyrone phosphate synthetase instead of supplying ATP to the reaction. One of ordinary skill in the art would have been motivated add TWEEN® 20 (polysorbate 20) or TWEEN® 80 (polysorbate 80) to stabilize the benzopyrone phosphate synthetase and polyphosphate kinase. One of ordinary skill in the art would have had a reasonable expectation of success since the claims of the reference recite a benzopyrone phosphate synthetase, Kameda teaches an enzymatic ATP regeneration system, and Kerwin teaches that polysorbate 20 and polysorbate 80 are stabilizers against protein aggregation.
Therefore, the conflicting claims are not patentably distinct from each other.
Claims 1-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of copending Application No. 19/031,879 (reference application) in view of Su (US 10,421,768 - form PTO-892), which is the PGPUB of U.S. Patent No. 10,421,768), Kameda (A novel ATP regeneration system using polyphosphate-AMP phosphotransferase and polyphosphate kinase. J Biosci Bioeng. 2001;91(6):557-63. – form PTO-892) and UKS89443.1 (GenBank Database. February 15, 2022 – form PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because they are claiming common subject matter, as follows:
Regarding claims 1-2 of the instant application, claim 1 of the reference application recites a phenolic phytochemical phosphate synthetase of SEQ ID NO:13 comprising of (i) ATP-binding domain, (ii) substrate binding domain, and (iii) catalytic domain, which has 100% sequence identity to SEQ ID NO:1 of the instant application (see the sequence alignment below). The ATP-binding domain comprises catalytic site Lys27, Arg102, and Glu282 (see the sequence alignment below). The substrate binding domain comprises the conserved motif of DDHHFYIDAMLDAKAR and catalytic sites of Asp627, His629, and His630 (see the sequence alignment below). The catalytic domain comprises of His795 (see the sequence alignment below). The (i) ATP-binding domain, (ii) substrate binding domain, and (iii) catalytic domain of the phenolic phytochemical phosphate synthetase of SEQ ID NO:13 of the reference application is identical to the (i) ATP-binding domain, (ii) substrate binding domain, and (iii) catalytic domain benzopyrone phosphate synthetase of Su (see the sequence alignments below).
Regarding claim 4 of the instant application, claim 1 of the reference application recites substrates of the phenolic phytochemical phosphate synthetase as a compound having formula I, II, III, or IV which are identical to the compound having formula I, II, III, or IV of the instant application.
Regarding claim 5 of the instant application, Su discloses that the optimal temperature of the benzopyrone phosphate synthetase is 30°C to 30°C and the most preferable temperature is 40°C, which falls within the recited temperature range of 35°C to 40°C (Column 8, lines 11-26).
Regarding claim 6 of the instant application, Su discloses that the optimal pH of the benzopyrone phosphate synthetase is 6.5 to 8.5 and the most preferable pH is 7.5, which falls within the recited pH range of 7.0 to 8.0 (Column 8, lines 11-26).
Regarding claims 7-8 of the instant application, Su discloses using the divalent metal Mg2+ (Column 14, lines 34-42).
The reference application does not disclose a coupled system comprising the benzopyrone phosphate synthetase, an ATP regeneration enzyme or an Erysipelotrichaceae bacterium ErPPK having the amino acid sequence of SEQ ID NO:11 sequentially comprising a conserved walker A (GXDXXGK) motif of AXDXXGK for coordinating the divalent cation and polyphosphate, a conserved walker B (DR) motif of NR or DR for coordinating the nucleotide phosphate groups, and active catalytic sites of Asp66, Lys70, Arg192, and Asp206 in ErPPK of SEQ ID NO: 11.
The phenolic phytochemical phosphate synthetase/benzopyrone phosphate synthetase of the reference application has an ATP binding domain, as discussed above, and uses ATP in its catalysis (see Su, Column 14, lines 34-42).
Regarding claims 1 and 7 of the instant application, Kameda discloses a system for enzymatic regeneration of ATP from both ADP and AMP by using an economical phosphate donor, a polyphosphate (polyP), and a polyphosphate kinase (abstract, page 557 and FIG.3 at page 560).
Regarding claims 7-8 of the instant application, Kameda discloses uses polyP and a divalent metal Mg2+(abstract).
Regarding claim 9 of the instant application, Kameda discloses that the Mg2+ and polyP concentrations was optimized because high concentration of polyP may chelate Mg2+ and inhibit enzyme activity and (abstract). Kameda discloses that increased concentration of polyP results in increased synthesis of ATP and a sufficient amount of polyP for regenerating both ADP and ATP should be added to the reaction mixture, but optimization of the Mg2+ concentration is also important. (“Effect of initial polyP concentration on ATP formation” at pages 560-561). Kameda discloses that the Mg2+ concentration was optimized to 24 mM in the presence of 30 mM polyP in the reaction, which equates to a ratio of Mg2+ to polyP of 1:1.25 (abstract and “Optimization of Mg 2+ concentration in the PAP-PPK ATP regeneration system” at pages 561-562). Regarding the recited ratio of 1:1, it would have been well within the knowledge of one having ordinary skill in the art to vary and optimize the concentrations of Mg2+ and polyP when coupling the benzopyrone phosphate synthetase of Su with a polyphosphate kinase disclosed by Kameda or another polyphosphate kinase to regenerate ATP. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”, see MPEP 2144.
Regarding claims 1 and 3 of the instant application, UKS89443.1 discloses a Erysipelotrichaceae bacterium polyphosphate kinase having 100% sequence identity to SEQ ID NO:11 of the instant application (page 1 and see the sequence alignment below) and therefore comprises sequentially a conserved walker A (GXDXXGK) motif of AXDXXGK for coordinating the divalent cation and polyphosphate, a conserved walker B (DR) motif of NR or DR for coordinating the nucleotide phosphate groups, and active catalytic sites of Asp66, Lys70, Arg192, and Asp206.
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 claims of the reference application by using a coupled enzyme system comprising (1) the phenolic phytochemical phosphate synthetase/benzopyrone phosphate synthetase of the reference application, (2) a polyphosphate kinase or the polyphosphate kinase of UKS89443.1, and (3) a substrate of the synthetase and optimize the ratio of the polyP and Mg2+ to arrive at ratio of around 1:1.25, such as 1:1 in the claimed method of the reference patent. Further, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to substitute the polyphosphate kinase of Kameda with other known polyphosphate kinases, such as the polyphosphate kinase of UKS89443.1, because one of ordinary skill in the art would have been able to carry out such a substitution, and the results were reasonably predictable. The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to substitute other known polyphosphate kinases. One of ordinary skill in the art would have been motivated to couple the phenolic phytochemical phosphate synthetase/benzopyrone phosphate synthetase of the reference application with a polyphosphate kinase in order to regenerate ATP that is needed by the phenolic phytochemical phosphate synthetase/benzopyrone phosphate synthetase instead of supplying ATP to the reaction. One of ordinary skill in the art would have had a reasonable expectation of success since the claims of the reference recite a phenolic phytochemical phosphate synthetase/benzopyrone phosphate synthetase, UKS89443.1 teaches a polyphosphate kinase, and Kameda teaches an enzymatic ATP regeneration system.
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 1-2 and 10-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of copending Application No. 19/031,879 (reference application) in view of Su (US 2017/0305944 – form PTO-892, which is the PGPUB of U.S. Patent No. 10,421,768), Kameda (A novel ATP regeneration system using polyphosphate-AMP phosphotransferase and polyphosphate kinase. J Biosci Bioeng. 2001;91(6):557-63. – form PTO-892) and Kerwin (Polysorbates 20 and 80 used in the formulation of protein biotherapeutics: structure and degradation pathways. J Pharm Sci. 2008 Aug;97(8):2924-35 – form PTO-892).
Regarding claims 1-2 of the instant application, claim 1 of the reference application recites a phenolic phytochemical phosphate synthetase of SEQ ID NO:13 comprising of (i) ATP-binding domain, (ii) substrate binding domain, and (iii) catalytic domain, which has 100% sequence identity to SEQ ID NO:1 of the instant application (see the sequence alignment below). The ATP-binding domain comprises catalytic site Lys27, Arg102, and Glu282 (see the sequence alignment below). The substrate binding domain comprises the conserved motif of DDHHFYIDAMLDAKAR and catalytic sites of Asp627, His629, and His630 (see the sequence alignment below). The catalytic domain comprises of His795 (see the sequence alignment below). The (i) ATP-binding domain, (ii) substrate binding domain, and (iii) catalytic domain of the phenolic phytochemical phosphate synthetase of SEQ ID NO:13 of the reference application is identical to the (i) ATP-binding domain, (ii) substrate binding domain, and (iii) catalytic domain benzopyrone phosphate synthetase of Su (see the sequence alignments below).
The claims of the reference application do not recite using a cosolvent and a surfactant, such as TWEEN® 20 (polysorbate 20) or TWEEN® 80 (polysorbate 80).
Regarding claim 10 of the instant application, Su discloses using a solvent Tris and water (Column 14, lines 34-42).
Regarding claim 11 of the instant application, Kerwin discloses that polysorbate 20 and polysorbate 80 are stabilizers against protein aggregation (abstract).
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 claims of the reference application by using a coupled enzyme system comprising (1) the phenolic phytochemical phosphate synthetase/benzopyrone phosphate synthetase of the reference application, (2) a polyphosphate kinase, (3) a substrate of the phenolic phytochemical phosphate synthetase/benzopyrone phosphate synthetase, (4) polyphosphate, and (5) solvents and surfactants TWEEN® 20 (polysorbate 20) or TWEEN® 80 (polysorbate 80). One of ordinary skill in the art would have been motivated to couple the phenolic phytochemical phosphate synthetase/benzopyrone phosphate synthetase of the reference application with a polyphosphate kinase in order to regenerate ATP that is needed by the phenolic phytochemical phosphate synthetase/benzopyrone phosphate synthetase instead of supplying ATP to the reaction. One of ordinary skill in the art would have been motivated add TWEEN® 20 (polysorbate 20) or TWEEN® 80 (polysorbate 80) to stabilize the phenolic phytochemical phosphate synthetase/benzopyrone phosphate synthetase and polyphosphate kinase. One of ordinary skill in the art would have had a reasonable expectation of success since the claims of the reference application recite a phenolic phytochemical phosphate synthetase/benzopyrone phosphate synthetase, Kameda teaches an enzymatic ATP regeneration system, and Kerwin teaches that polysorbate 20 and polysorbate 80 are stabilizers against protein aggregation.
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.
Conclusion
Claims 1-11 are pending.
Claims 1-11 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YONG D PAK whose telephone number is (571)272-0935. The examiner can normally be reached M-Th: 5:30 am - 3:30 pm.
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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.
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/YONG D PAK/Primary Examiner, Art Unit 1652
Sequence alignment of SEQ ID NO:1 of the instant application (“Qy”) and the substrate binding domain of SEQ ID NO:1 of Su (“Db”)
US-15-496-534-1
Sequence 1, US/15496534
Patent No. 10421768
GENERAL INFORMATION
APPLICANT: NTU
TITLE OF INVENTION: polypeptide of benzopyrone synthase
FILE REFERENCE: P171304
CURRENT APPLICATION NUMBER: US/15/496,534
CURRENT FILING DATE: 2017-04-25
PRIOR APPLICATION NUMBER: 105112812
PRIOR FILING DATE: 2016-04-25
NUMBER OF SEQ ID NOS: 14
SEQ ID NO 1
LENGTH: 449
TYPE: PRT
ORGANISM: Bacillus subtilis
FEATURE:
NAME/KEY: DOMAIN
LOCATION: (1)..(449)
Query Match 54.8%; Score 2369; Length 449;
Best Local Similarity 100.0%;
Matches 449; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 313 SFMITDTDMNDFWLNMESNIEGPVSPLFSSFIVPALEYGLKKSMQKFPIGVVVDEVKLYR 372
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 SFMITDTDMNDFWLNMESNIEGPVSPLFSSFIVPALEYGLKKSMQKFPIGVVVDEVKLYR 60
Qy 373 GHIYSKNQGGQQPPSEDCGKELFPILSEHMYDIINHTYLPFYRTLDQLAQTEHTAESALD 432
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GHIYSKNQGGQQPPSEDCGKELFPILSEHMYDIINHTYLPFYRTLDQLAQTEHTAESALD 120
Qy 433 AFQKLKAFYLTAYEEHFNIVFPQILLTNKLQAMYQDIQGESENAHFYEMLTGKMNKSLET 492
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 AFQKLKAFYLTAYEEHFNIVFPQILLTNKLQAMYQDIQGESENAHFYEMLTGKMNKSLET 180
Qy 493 DRCLWLFSMEVQENPNLLTIFENNKPEQLQEKLEQTDEGRHFLKNVHEFLQEYGWRSVKS 552
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DRCLWLFSMEVQENPNLLTIFENNKPEQLQEKLEQTDEGRHFLKNVHEFLQEYGWRSVKS 240
Qy 553 HDLIEQIWVENPYFALANIQNYVRNGYHFDNEFQKTKEKREKLYNEFLENIEDPGLRTEF 612
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 HDLIEQIWVENPYFALANIQNYVRNGYHFDNEFQKTKEKREKLYNEFLENIEDPGLRTEF 300
Qy 613 DRYYQWTLNSANIKDDHHFYIDAMLDAKARIFLLKIGELLAENGVIQDREDLWFLYDDEV 672
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 DRYYQWTLNSANIKDDHHFYIDAMLDAKARIFLLKIGELLAENGVIQDREDLWFLYDDEV 360
Qy 673 EQALLHPVSLQEKAEKRRQIFHEYELAQAPAYLGTPTKEQLKAAEEIVGAVIEDEKNTEN 732
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 EQALLHPVSLQEKAEKRRQIFHEYELAQAPAYLGTPTKEQLKAAEEIVGAVIEDEKNTEN 420
Qy 733 HIFGIAASSGIATGPVKIIRDANEFSQFA 761
|||||||||||||||||||||||||||||
Db 421 HIFGIAASSGIATGPVKIIRDANEFSQFA 449
Sequence alignment of SEQ ID NO:1 of the instant application (“Qy”) and the ATP- binding domain of SEQ ID NO:2 of Su (“Db”)
US-15-496-534-2
Sequence 2, US/15496534
Patent No. 10421768
GENERAL INFORMATION
APPLICANT: NTU
TITLE OF INVENTION: polypeptide of benzopyrone synthase
FILE REFERENCE: P171304
CURRENT APPLICATION NUMBER: US/15/496,534
CURRENT FILING DATE: 2017-04-25
PRIOR APPLICATION NUMBER: 105112812
PRIOR FILING DATE: 2016-04-25
NUMBER OF SEQ ID NOS: 14
SEQ ID NO 2
LENGTH: 289
TYPE: PRT
ORGANISM: Bacillus subtilis
FEATURE:
NAME/KEY: DOMAIN
LOCATION: (1)..(289)
Query Match 33.5%; Score 1448; Length 289;
Best Local Similarity 100.0%;
Matches 289; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 24 AGAKGMNLIKLTKHGLPVPDGFIIQTNALARFMEDNQLQETSENVESGIISGTFSDELKD 83
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AGAKGMNLIKLTKHGLPVPDGFIIQTNALARFMEDNQLQETSENVESGIISGTFSDELKD 60
Qy 84 ELTSSFYKLRESYRSVAVRSSSASEDLEGASFAGQYETYLNIKTEEEFLAKVKECWASFF 143
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ELTSSFYKLRESYRSVAVRSSSASEDLEGASFAGQYETYLNIKTEEEFLAKVKECWASFF 120
Qy 144 SGRVSSYKKKMNNQIAEPLMGIVVQGLIDSEMSGVIFSRNPVTHDDRELLISASYGLGEA 203
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SGRVSSYKKKMNNQIAEPLMGIVVQGLIDSEMSGVIFSRNPVTHDDRELLISASYGLGEA 180
Qy 204 VVSGSVTPDTFIVNKSSFEIQKEIGAKEIYMESAAEGIAEKETSEDMRSRFCLTDEQVIE 263
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VVSGSVTPDTFIVNKSSFEIQKEIGAKEIYMESAAEGIAEKETSEDMRSRFCLTDEQVIE 240
Qy 264 LAEITKKTEDLYGYPVDIEFGIADHQIYLLQARPITTIDQDKKAAEEKR 312
|||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LAEITKKTEDLYGYPVDIEFGIADHQIYLLQARPITTIDQDKKAAEEKR 289
Sequence alignment of SEQ ID NO:1 of the instant application (“Qy”) and the catalytic domain of SEQ ID NO:3 of Su (“Db”)
US-15-496-534-3
Sequence 3, US/15496534
Patent No. 10421768
GENERAL INFORMATION
APPLICANT: NTU
TITLE OF INVENTION: polypeptide of benzopyrone synthase
FILE REFERENCE: P171304
CURRENT APPLICATION NUMBER: US/15/496,534
CURRENT FILING DATE: 2017-04-25
PRIOR APPLICATION NUMBER: 105112812
PRIOR FILING DATE: 2016-04-25
NUMBER OF SEQ ID NOS: 14
SEQ ID NO 3
LENGTH: 70
TYPE: PRT
ORGANISM: Bacillus subtilis
FEATURE:
NAME/KEY: DOMAIN
LOCATION: (1)..(70)
Query Match 8.3%; Score 357; Length 70;
Best Local Similarity 100.0%;
Matches 70; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 762 PGDVLVCKMTTPLWTSLFQDAKAIITDTGGILSHAAIIAREYGIPAVLGTRTATERLRDG 821
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 PGDVLVCKMTTPLWTSLFQDAKAIITDTGGILSHAAIIAREYGIPAVLGTRTATERLRDG 60
Qy 822 DIITVDGSSG 831
||||||||||
Db 61 DIITVDGSSG 70
Sequence alignment between SEQ ID NO:1 of the instant application (“Query”) and the benzopyrone phosphate of AYF57920.1 (“Sbjct”)
PNG
media_image5.png
994
1026
media_image5.png
Greyscale
Sequence alignment between the Erysipelotrichaceae bacterium polyphosphate kinase (ErPPK) of SEQ ID NO:11 of the instant application (“Query”) and the ErPPK of UKS89443.1 (“Sbjct”)
PNG
media_image6.png
706
1052
media_image6.png
Greyscale
Sequence alignment of SEQ ID NO:1 of the instant application (“Qy”) and SEQ ID NO:13 of 19/031,879 (“Db”)
US-19-031-879-13
Filing date in PALM: 2025-01-18
Sequence 13, US/19031879
Publication No. US20250257336A1
GENERAL INFORMATION
APPLICANT: National Taiwan University (en)
TITLE OF INVENTION: Isolated or Engineered Polypeptides, Microorganisms as well as Method for Synthesizing Phenolic Phytochemical Phosphate Derivatives using the Polypeptides or Microorganisms (en)
FILE REFERENCE: P201888US
CURRENT APPLICATION NUMBER: US/19/031,879
CURRENT FILING DATE: 2025-01-18
NUMBER OF SEQ ID NOS: 30
SEQ ID NO 13
LENGTH: 839
TYPE: PRT
FEATURE:
NAME/KEY: source
LOCATION: 1..839
QUALIFIERS: mol_type = protein
organism = Bacillus subtilis
Query Match 100.0%; Score 4320; Length 839;
Best Local Similarity 100.0%;
Matches 839; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MKKRGVSNMYSVLFRQAEESSQLAGAKGMNLIKLTKHGLPVPDGFIIQTNALARFMEDNQ 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MKKRGVSNMYSVLFRQAEESSQLAGAKGMNLIKLTKHGLPVPDGFIIQTNALARFMEDNQ 60
Qy 61 LQETSENVESGIISGTFSDELKDELTSSFYKLRESYRSVAVRSSSASEDLEGASFAGQYE 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 LQETSENVESGIISGTFSDELKDELTSSFYKLRESYRSVAVRSSSASEDLEGASFAGQYE 120
Qy 121 TYLNIKTEEEFLAKVKECWASFFSGRVSSYKKKMNNQIAEPLMGIVVQGLIDSEMSGVIF 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TYLNIKTEEEFLAKVKECWASFFSGRVSSYKKKMNNQIAEPLMGIVVQGLIDSEMSGVIF 180
Qy 181 SRNPVTHDDRELLISASYGLGEAVVSGSVTPDTFIVNKSSFEIQKEIGAKEIYMESAAEG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SRNPVTHDDRELLISASYGLGEAVVSGSVTPDTFIVNKSSFEIQKEIGAKEIYMESAAEG 240
Qy 241 IAEKETSEDMRSRFCLTDEQVIELAEITKKTEDLYGYPVDIEFGIADHQIYLLQARPITT 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 IAEKETSEDMRSRFCLTDEQVIELAEITKKTEDLYGYPVDIEFGIADHQIYLLQARPITT 300
Qy 301 IDQDKKAAEEKRSFMITDTDMNDFWLNMESNIEGPVSPLFSSFIVPALEYGLKKSMQKFP 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 IDQDKKAAEEKRSFMITDTDMNDFWLNMESNIEGPVSPLFSSFIVPALEYGLKKSMQKFP 360
Qy 361 IGVVVDEVKLYRGHIYSKNQGGQQPPSEDCGKELFPILSEHMYDIINHTYLPFYRTLDQL 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 IGVVVDEVKLYRGHIYSKNQGGQQPPSEDCGKELFPILSEHMYDIINHTYLPFYRTLDQL 420
Qy 421 AQTEHTAESALDAFQKLKAFYLTAYEEHFNIVFPQILLTNKLQAMYQDIQGESENAHFYE 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 AQTEHTAESALDAFQKLKAFYLTAYEEHFNIVFPQILLTNKLQAMYQDIQGESENAHFYE 480
Qy 481 MLTGKMNKSLETDRCLWLFSMEVQENPNLLTIFENNKPEQLQEKLEQTDEGRHFLKNVHE 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 MLTGKMNKSLETDRCLWLFSMEVQENPNLLTIFENNKPEQLQEKLEQTDEGRHFLKNVHE 540
Qy 541 FLQEYGWRSVKSHDLIEQIWVENPYFALANIQNYVRNGYHFDNEFQKTKEKREKLYNEFL 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 FLQEYGWRSVKSHDLIEQIWVENPYFALANIQNYVRNGYHFDNEFQKTKEKREKLYNEFL 600
Qy 601 ENIEDPGLRTEFDRYYQWTLNSANIKDDHHFYIDAMLDAKARIFLLKIGELLAENGVIQD 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 ENIEDPGLRTEFDRYYQWTLNSANIKDDHHFYIDAMLDAKARIFLLKIGELLAENGVIQD 660
Qy 661 REDLWFLYDDEVEQALLHPVSLQEKAEKRRQIFHEYELAQAPAYLGTPTKEQLKAAEEIV 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 REDLWFLYDDEVEQALLHPVSLQEKAEKRRQIFHEYELAQAPAYLGTPTKEQLKAAEEIV 720
Qy 721 GAVIEDEKNTENHIFGIAASSGIATGPVKIIRDANEFSQFAPGDVLVCKMTTPLWTSLFQ 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 GAVIEDEKNTENHIFGIAASSGIATGPVKIIRDANEFSQFAPGDVLVCKMTTPLWTSLFQ 780
Qy 781 DAKAIITDTGGILSHAAIIAREYGIPAVLGTRTATERLRDGDIITVDGSSGKITVVSRS 839
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 DAKAIITDTGGILSHAAIIAREYGIPAVLGTRTATERLRDGDIITVDGSSGKITVVSRS 839
Prosecution Insights