DETAILED ACTION
Status of the Application
Claims 5-7, 9-18, 28-30, 33-39, 41-42 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment of claim 14 as submitted in a communication filed on 5/28/2026 is acknowledged.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5/28/2026 has been entered.
Applicant elected with traverse Group 1, claims 2-3, 14 drawn in part to an isolated kinase 1 and a composition comprising said kinase, wherein said kinase comprises SEQ ID NO: 43, as submitted in a communication filed on 10/17/2025.
Applicant has amended claim 14 to now be directed to a composition that comprises two kinases, wherein one of the kinases is a variant of the protein of SEQ ID NO: 43 and the other kinase (i) comprises SEQ ID NO: 76, 85, 88, 103, 138, 171, 174, 177, 180, 183, 189, 192, 195, 198, 201, 204, 207, 210, 216, 219, 222, 225, 228, 231, 234, 237, 240, 246, 249, 252, 255, 258, 261, 270, 273, 279, 282, 288, 426, 429, 435, 447, or 483, or (ii) comprises a variant of SEQ ID NO: 76, 85, 88, 103, 138, 171, 174, 177, 180, 183, 189, 192, 195, 198, 201, 204, 207, 210, 216, 219, 222, 225, 228, 231, 234, 237, 240, 246, 249, 252, 255, 258, 261, 270, 273, 279, 282, 288, 426, 429, 435, 447, or 483. While a composition comprising a variant of the protein of SEQ ID NO: 43 has been previously examined and searched, no search or examination has been performed with regard to a composition as now encompassed by amended claim 14. Moreover, it is noted that claim 14 as amended does not encompass the elected invention. Group I, which is the elected invention, did not encompass a composition comprising a variant of the protein of SEQ ID NO: 43 and a second kinase, let alone a second kinase that (i) comprises SEQ ID NO: 76, 85, 88, 103, 138, 171, 174, 177, 180, 183, 189, 192, 195, 198, 201, 204, 207, 210, 216, 219, 222, 225, 228, 231, 234, 237, 240, 246, 249, 252, 255, 258, 261, 270, 273, 279, 282, 288, 426, 429, 435, 447, or 483, or (ii) comprises a variant of SEQ ID NO: 76, 85, 88, 103, 138, 171, 174, 177, 180, 183, 189, 192, 195, 198, 201, 204, 207, 210, 216, 219, 222, 225, 228, 231, 234, 237, 240, 246, 249, 252, 255, 258, 261, 270, 273, 279, 282, 288, 426, 429, 435, 447, or 483. Applicant states that the election of Group 1 did not require the election of a kinase 2 because at the time the restriction was made, Group 1 did not expressly include a kinase 2. Applicant states that the present claims are not inconsistent with Applicant’s election and that the Office did not previously preclude subsequent amendments to require a kinase 2. Applicant states that should an election of species be required, Applicant elects the kinase 2 of SEQ ID NO: 76. Applicant’s arguments have been fully considered. Amended claim 14 requires an election of species for the new component, namely a kinase 2. In view of Applicant’s election of the kinase 2 of SEQ ID NO: 76, and in the interest of advancing prosecution, it is deemed that the elected invention is a composition that comprises a variant of the kinase of SEQ ID NO: 43 and a variant of the kinase of SEQ ID NO: 76.
Claims 5-7, 9-13, 15-18, 28-30, 33-39, 41-42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/17/2025.
Claim 14 will be examined only to the extent it encompasses a variant of the kinase of SEQ ID NO: 43 and a variant of the kinase of SEQ ID NO: 76.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claim Objections
Claim 14 is objected to due to the recitation of “selected from the group consisting of a. an amino acid sequence…, b. an amino acid sequence…., c. an amino acid sequence……, or d. an amino acid sequence …”. To be consistent with commonly used claim language, the term should be amended to recite “selected from the group consisting of a. an amino acid sequence…, b. an amino acid sequence…., c. an amino acid sequence……, and d. an amino acid sequence …”. Appropriate correction is required.
Claim 14 is objected to due to the recitation of “…sequence selected from the group consisting of a…..b…..c…d….wherein the second kinase is selected from the group consisting of f….g….h…i… or j…”. The use of f-j to provide options for the second kinase is confusing because that is the continuation of a-d, which have been disclosed as options for a different kinase. The options for the second kinase should use different itemization labels, such as (i)-(v). Also, to be consistent with commonly used claim language, the term should be amended to recite “wherein the second kinase is selected from the group consisting of X, Y…… and Z”. Appropriate correction is required.
Claim 14 is objected to due to the recitation of “wherein the first kinase as defined …is capable of-catalyzing..”. The hyphen between “of” and “catalyzing” should be removed. Appropriate correction is required.
Claim Rejections - 35 USC § 101
Claims 14 was rejected under 35 U.S.C. 101 because the claimed invention was directed to a product of nature without significantly more.
In view of Applicant’s amendment of claim 14 which now requires a first kinase, a second kinase, at least one of isoprenol and prenol, and at least one of isopentenylphosphate and dimethylallyl phosphate, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
Claim 14 remains 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 pre-AIA the applicant regards as the invention. New grounds of rejection are necessitated by amendment. New grounds of rejection are necessitated by amendment.
Claim 14 is indefinite in the recitation of “wherein the first kinase comprises a sequence selected from the group consisting of…b. an amino acid sequence having at least 50% identity to the amino acid molecule of SEQ ID NO: 43, c. an amino acid sequence encoded by a nucleic acid molecule of SEQ ID NO: 44 and 45…d. an amino acid sequence encoded by a nucleic acid molecule having at least 50% identity to SEQ ID NOs: 44 and 45” for the following reasons. The term “an amino acid molecule” implies a molecule of a single amino acid. Therefore, it is unclear as to how an amino acid molecule can have an entire sequence of several amino acids. SEQ ID NO: 43 has 275 amino acids. If the intended limitation is “b. an amino acid sequence having at least X% identity to SEQ ID NO: 43”, the claim should be amended accordingly. The term “amino acid sequence encoded by the nucleic acid molecule of SEQ ID NO: 44 and 45” is unclear because both the nucleic acid of SEQ ID NO: 44 and the nucleic acid of SEQ ID NO: 45 encode the protein of SEQ ID NO: 43. Therefore, it is unclear if the intended first kinase is a dimer of the protein of SEQ ID NO: 43. If the intended limitation is an amino acid sequence encoded by the nucleic acid sequence of SEQ ID NO: 44 or SEQ ID NO: 45, the claim should be amended accordingly. The term “amino acid sequence encoded by a nucleic acid molecule having at least 50% identity to SEQ ID NOs: 44 and 45” is unclear because both the nucleic acid of SEQ ID NO: 44 and the nucleic acid of SEQ ID NO: 45 encode the protein of SEQ ID NO: 43. Therefore, it is unclear if the intended first kinase is a variant of a dimer of the protein of SEQ ID NO: 43. If the intended limitation is an amino acid sequence encoded by a nucleic acid sequence that is at least X% identical to SEQ ID NO: 44 or SEQ ID NO: 45, the claim should be amended accordingly. Correction is required.
Claim 14 is indefinite in the recitation of “…the amino acid molecule of SEQ ID NOs: 76… g. an amino acid molecule having at least 50% identity to the amino acid molecule of SEQ ID NOs: 76….h. an amino acid molecule encoded by a nucleic acid molecule of SEQ ID NOs: 77….i. an amino acid molecule encoded by a nucleic acid molecule having at least 59% identity to SEQ ID NOs: 77….or j. an amino acid molecule encoded by a nucleic acid molecule hybridizing under stringent conditions to a fragment of at least 250 bases complementary to SEQ ID NOs: 77…” for the following reasons. As indicated above, an amino acid molecule cannot have a sequence of several amino acids because an amino acid molecule is a single amino acid. SEQ ID NO: 76 has 266 amino acids. If the intended limitation is “…the protein of SEQ ID NO: 76…” “ a protein having at least 50% sequence identity to the polypeptide of SEQ ID NO: 76”, “a protein encoded by the polynucleotide of SEQ ID NO: 77”, and “a protein encoded by a polynucleotide having at least X% sequence identity to polynucleotide of SEQ ID NO: 76”, the claim should be amended accordingly. The term “stringent conditions” is indefinite because it is unclear which nucleic acid is recited absent a statement of the experimental conditions under which the hybridization reaction is performed. Nucleic acids which will hybridize under some hybridization conditions will not necessarily hybridize under different conditions. The art does not recognize a single set of experimental conditions as “stringent”. For examination purposes, it will be assumed that the nucleic acid hybridizes under any conditions to the recited fragment. Correction is required.
When amending the claims, applicant is advised to carefully review all examined claims and make the necessary changes to ensure proper antecedent basis and dependency.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
Claim 14 is 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. This rejection is necessitated by the introduction of new matter.
As set forth in MPEP 2163 (I)(B), new or amended claims which introduce elements or limitations that are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971) (subgenus range was not supported by generic disclosure and specific example within the subgenus range); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (an adequate description of a genus may not support claims to a subgenus or species within the genus). Claim 14 is now directed to a composition that requires a kinase encoded by (i) the nucleic acid of SEQ ID NO: 44 and the nucleic acid of SEQ ID NO: 45, or (ii) a nucleic acid having at least 50% sequence identity to the nucleic acid of SEQ ID NO: 44 and the nucleic acid of SEQ ID NO: 45. See Claim Rejections under 35 USC § 112(b) or Second Paragraph (pre-AIA ) above. While the specification refers to a kinase encoded by (i) the nucleic acid of SEQ ID NO: 44 or the nucleic acid of SEQ ID NO: 45, and (ii) a nucleic acid having at least 50% sequence identity to the nucleic acid of SEQ ID NO: 44 or the nucleic acid of SEQ ID NO: 45, the Examiner is unable to locate adequate support or any mention of a kinase which is a dimer of the protein of SEQ ID NO: 43, or a kinase which is a variant of a dimer of the protein of SEQ ID NO: 43. As indicated in Claim Rejections under 35 USC § 112(b) or Second Paragraph (pre-AIA ), the nucleic acid of SEQ ID NO: 44 encodes the protein of SEQ ID NO: 43 and the nucleic acid of SEQ ID NO: 45 also encodes the protein of SEQ ID NO: 43. Therefore, a kinase encoded by the nucleic acid of SEQ ID NO: 44 and the nucleic acid of SEQ ID NO: 45 is a protein that comprises a dimer of the protein of SEQ ID NO: 43. There is no mention whatsoever in the specification of a kinase encoded by both the nucleic acid of SEQ ID NO: 44 and the nucleic acid of SEQ ID NO: 45, or a kinase encoded by a nucleic acid having at least 50% sequence identity to the nucleic acid of SEQ ID NO: 44 and the nucleic acid of SEQ ID NO: 45. Thus, there is no indication that a composition that comprises a kinase encoded by (i) the nucleic acid of SEQ ID NO: 44 and the nucleic acid of SEQ ID NO: 45, or (ii) a nucleic acid having at least 50% sequence identity to the nucleic acid of SEQ ID NO: 44 and the nucleic acid of SEQ ID NO: 45 was within the scope of the invention as conceived by Applicant at the time of the invention. Accordingly, Applicant is required to cancel the new matter in the response to this Office Action.
Claim 14 remains 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.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that a person of ordinary skill in the art would reasonably expect proteins meeting the identity recited in the claims to retain the disclosed kinase functionality since the claims recite both structural and functional limitations.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges that claim 14 recites structural and functional limitations. However, the examiner disagrees with Applicant’s contention that the entire genus of kinases required is adequately described.
The claim encompass a large genus of proteins which are substantially unrelated. The claim requires not only variants of the polypeptide of SEQ ID NO: 43 and the polypeptide of SEQ ID NO: 76 having the recited % sequence identity or variants encoded by polynucleotides that are variants of the polynucleotide of SEQ ID NO: 44/45 or the polynucleotide of SEQ ID NO: 77 having the recited % sequence identity, but it also requires variants of the polypeptide of SEQ ID NO: 76 having essentially any structure. A nucleic acid that hybridizes under any conditions to at least 250 bases of the polynucleotide of SEQ ID NO: 77 can encode a protein having almost no sequence identity with the polypeptide of SEQ ID NO: 76 (has 266 amino acids) because the polynucleotide of SEQ ID NO: 77 has 801 nucleotides long and hybridization of 250 bases would imply that the nucleic acid encoding the second kinase would have 551 mismatches with respect to the polynucleotide of SEQ ID NO: 77 (551 = 801-250). Those 551 mismatches can potentially correspond to bases that alter almost every codon in the polynucleotide of SEQ ID NO: 77 such that the protein encoded by said nucleic acid that hybridizes to at least 250 bases of the polynucleotide of SEQ ID NO: 77 could have essentially any structure. Similarly, a protein encoded by a polynucleotide having at least 50% sequence identity to the polynucleotide of SEQ ID NO: 77 can have essentially any structure because a polynucleotide having the recited 50% sequence identity can be a polynucleotide having up to 401 nucleotides modified compared to the polynucleotide of SEQ ID NO: 77. Those 401 nucleotides that can be modified can alter almost every codon in the polynucleotide of SEQ ID NO: 77, thus encoding a protein with essential any structure.
A polypeptide having at least 50% sequence identity with the polypeptide of SEQ ID NO: 43 allows for any combination of 138 amino acid modifications within SEQ ID NO: 43 (69 = 0.5x275; SEQ ID NO: 43 has 275 amino acids). A polypeptide having at least 50% sequence identity with the polypeptide of SEQ ID NO: 76 allows for any combination of 133 amino acid modifications within SEQ ID NO: 76 (133 = 0.5x266; SEQ ID NO: 76 has 266 amino acids). A polynucleotide having at least 50% sequence identity to the polynucleotide of SEQ ID NO: 44/45 allows for any combination of 414 nucleotides within SEQ ID NO: 44/45 (414 = 0.5x828; SEQ ID NO: 44 and 45 have 828 nucleotides). Since a large number of these 414 nucleotide modifications can alter a corresponding codon, a polynucleotide having at least 50% sequence identity to the polynucleotide of SEQ ID NO: 44/45 can encode a protein having any number of amino acid modifications within the polypeptide of SEQ ID NO: 43. Using the previously provided equation, the total number of variants having 50% sequence identity with the polypeptide of SEQ ID NO: 43 that result from amino acid substitutions is 275!x19138/(275-138)!/138! or 8.55x10257 variants while the total number of variants having 50% sequence identity with the polypeptide of SEQ ID NO: 76 that result from amino acid substitutions is 266!x19133/(266-133)!/133! or 6.87x10248 variants.
While Applicant argues that a person of ordinary skill in the art would reasonably expect proteins meeting the identity recited in the claims to retain the disclosed kinase functionality, it is reiterated herein that the art, as evidenced by Witkowski et al., Seffernick et al. and Tang et al., teaches several examples of how even highly structurally homologous polypeptides can have different enzymatic activities. In addition, the specification and the prior art fail to disclose the structural features required in any variant having the recited % sequence identity or any variant encoded by a polynucleotide having the recited % sequence identity, for such variant to have the desired kinase activity. Moreover, neither the specification nor the prior art provide a structure/function correlation that would allow one of skill in the art to determine a priori from an infinite number of structural variants of the polypeptide of SEQ ID NO: 43 or the polypeptide of SEQ ID NO: 76 having the recited % sequence identity those that have the ability to catalyze the reactions recited in the claim. Therefore, since minor structural differences may result in changes affecting function, and no additional information correlating structure with the desired functional characteristics has been provided, one cannot reasonably conclude that the polypeptide of SEQ ID NO: 43 and the polypeptide of SEQ ID NO: 76 are representative of the structure of all the kinases required by the claims. As such, one cannot reasonably conclude that the entire genus of kinases required by the claim is adequately described by the specification and/or the prior art.
Claim 14 remains 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 the polypeptide of SEQ ID NO: 43 and the polypeptide of SEQ ID NO: 76, and a composition comprising the polypeptide of SEQ ID NO: 43 and the polypeptide of SEQ ID NO: 76, does not reasonably provide enablement for a kinase that catalyzes the conversion of isoprenol to isopentenylphosphate or catalyze the conversion of prenol to dimethylallyl phosphate, wherein said kinase is a variant of the polypeptide of SEQ ID NO: 43, a kinase that catalyzes the conversion of isopentenylphosphate to isopentenyl pyrophosphate and/or dimethylallyl phosphate to dimethylallyl pyrophosphate, wherein said kinase is a variant of the polypeptide of SEQ ID NO: 76, or a composition comprising said kinases. 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/or use the invention commensurate in scope with these claims.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that a person of ordinary skill in the art using routine methods available at the time of filing would have been able to make and use the recited kinases without undue experimentation.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges that routine methods were available at the time of filing. However, the Examiner disagrees with Applicant’s contention that the entire scope of kinases required is fully enabled by the teachings of the specification and/or the prior art.
As indicated above, the claim requires proteins which are substantially unrelated. The claim requires not only variants of the polypeptide of SEQ ID NO: 43 and the polypeptide of SEQ ID NO: 76 having the recited % sequence identity or variants encoded by polynucleotides that are variants of the polynucleotide of SEQ ID NO: 44/45 or the polynucleotide of SEQ ID NO: 77 having the recited % sequence identity, but it also requires variants of the polypeptide of SEQ ID NO: 43 and 76 having essentially any structure. See Claim Rejections under 35 USC § 112(b) or Second Paragraph (pre-AIA ) below for claim interpretation. For the reasons extensively discussed above, a nucleic acid that hybridizes under any conditions to at least 250 bases of the polynucleotide of SEQ ID NO: 77 can encode a protein having almost no sequence identity with the polypeptide of SEQ ID NO: 76. Similarly, a protein encoded by a polynucleotide having at least 50% sequence identity to the polynucleotide of SEQ ID NO: 44, 45 or 77 can have essentially any structure because a polynucleotide having the recited 50% sequence identity can be a polynucleotide having up to 401 nucleotides modified compared to the polynucleotide of SEQ ID NO: 77, or a polynucleotide having up to 411 nucleotides modified compared to the polynucleotide of SEQ ID NO: 44/45. Those 401 nucleotides that can be modified in the polynucleotide of SEQ ID NO: 77 can alter almost every codon in the polynucleotide of SEQ ID NO: 77, while those 411 nucleotides that can be modified in the polynucleotide of SEQ ID NO: 44/45 can alter almost any codon in the polynucleotide of SEQ ID NO: 44/45, thus encoding a protein with essential any structure.
With regard to the argument that a person of ordinary skill in the art using routine methods available at the time of filing would have been able to make and use the recited kinases without undue experimentation, it is noted that the issue is not whether or not one could make proteins with the recited % sequence identity, or that enzymatic assays were not available. Instead, the issue is the amount of experimentation that would have to be required to enable the entire scope of the claim.
It is reiterated herein that the number of structural variants of the polypeptide of SEQ ID NO: 43 and 76 that meet the recited structural limitations is essentially infinite. See calculations above. No structure/function correlation has been provided to determine which of these variants are more likely to have the desired kinase activity. There is no disclosure of those structural features found in the polypeptide of SEQ ID NO: 43 and 76 that should be present in a variant as recited to have the desired kinase activity. The art clearly teaches that (a) determining function based solely on structural homology, and (b) modification of a protein’s amino acid sequence to obtain the desired activity without any guidance/knowledge as to which amino acids in a protein are tolerant of modification and which ones are conserved are highly unpredictable. See the teachings of Singh et al., Sadowski et al., Witkowski et al., Seffernick et al. and Tang et al. previously discussed.
It was not routine in the art to screen by a trial and error process for an essentially infinite number of proteins to find a protein with the required kinase activity. In the absence of (i) a rational and predictable scheme for selecting those proteins most likely to have the desired functional features, and/or (ii) a correlation between structure and the recited kinase activity, one of skill in the art would have to test an essentially infinite number of proteins to determine which ones have the desired functional characteristics. This is not deemed routine experimentation. Therefore, for the reasons of record and those set forth above, one cannot reasonably conclude that the claimed invention is fully enabled by the teachings of the specification and/or the prior art.
Claim Rejections - 35 USC § 102 (AIA )
Claim 14 was rejected under 35 U.S.C. 102(a)(1) as being anticipated by Goeker et al. (EMBL accession No. PPK45289 3/9/2018; cited in the IDS).
In view of Applicant’s amendment of claim 14 which now requires a composition that comprises a first kinase, a second kinase, at least one of isoprenol and prenol, and at least one of isopentenylphosphate and dimethylallyl phosphate, and the fact that Goeker et al. do not teach such composition, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 103 (AIA )
Claim 14 remains rejected under 35 U.S.C. 103 as being unpatentable over Goeker et al. (EMBL accession No. PPK45289 3/9/2018; cited in the IDS) in view of Clomburg et al. (PNAS 116(26):12810-12815, 6/11/2019; cited in the IDS and admitted as prior art in the specification) as evidenced by Chen et al. (GenBank accession No. WP_432703844 6/13/2025).
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that the combination of Goeker et al. and Clomburg et al. does not teach, suggest or render obvious an aqueous solution comprising a first kinase, a second kinase, at least one of isoprenol and prenol, and at least one of isopentenyl phosphate (IP) and dimethylallyl phosphate (DMAP). Applicant states that Goeker et al merely discloses a sequence listing of an E. coli hydroxyethylthiazole kinase (ThiM) and reports its ability to phosphorylate prenol in an enzymatic assay. Applicant states that Clomburg et al. do not teach or suggest the specific kinases claimed, nor do they provide guidance that would lead a person of ordinary skill in the art to select or modify the disclosed sequences to achieve the claimed combination of structural features and functional activity.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the amendments made to the claim, which now requires a second kinase. However, the Examiner disagrees with Applicant’s contention that the claimed invention is not obvious over the cited prior art.
Claim 14 is directed in part to an aqueous composition that comprises the kinase of SEQ ID NO: 43, at least one of prenol and isoprenol, at least one of IP and DMAP, and a second kinase, wherein the second kinase is a variant of the polypeptide of SEQ ID NO: 76 which is encoded by any nucleic acid that hybridizes under any conditions to at least 250 bases to the polynucleotide of SEQ ID NO: 77. As previously indicated, a nucleic acid that hybridizes under any conditions to at least 250 bases of the polynucleotide of SEQ ID NO: 77 can encode a protein having almost no sequence identity with the polypeptide of SEQ ID NO: 76 because the polynucleotide of SEQ ID NO: 77 is 801 nucleotides long and hybridization of 250 bases would imply that the nucleic acid encoding the second kinase would have 551 mismatches with respect to the polynucleotide of SEQ ID NO: 77 (551 = 801-250). Those 551 mismatches can potentially correspond to bases that alter almost every codon in the polynucleotide of SEQ ID NO: 77 such that the protein encoded by said nucleic acid that hybridizes to at least 250 bases of the polynucleotide of SEQ ID NO: 77 could have essentially any structure.
Clomburg et al. teach an E. coli hydroxyethylthiazole kinase (ThiM) that catalyzes the phosphorylation of prenol (page 12811, right column, lines 10-13) to produce dimethylallyl phosphate (DMAP). Clomburg et al. teach that ThiM also catalyzes the phosphorylation of isoprenol to IP (page 12811, right column, last 9 lines). Clomburg et al. teach transforming E. coli cells so that they can express ThiM and IPK from M. thermautotrophicus (IPKMTH), which is a kinase that catalyzes the conversion of DMAP to DMAPP (dimethylallyl diphosphate) as well as the conversion of IP to IPP (isopentenyl diphosphate), and determine if isoprenol/prenol could be converted to isoprenoids (page 12811, right column; page 12814, Figure 4, lower IPA pathway in red; pages 6-7, Supplementary Table S1). Clomburg et al. teach cultivation of these transformed E. coli cells (page 12815, right column, first paragraph; Supplementary Information, page 3). The IPK from M. thermautotrophicus has an amino acid sequence disclosed by Chen et al. An alignment of SEQ ID NO: 76 and the amino acid sequence of Chen et al. shows that the IPK from M. thermautotrophicus used by Clomburg et al. has 28% sequence identity to the kinase of SEQ ID NO: 76 (28% = 74x100/266; SEQ ID NO: 76 has 266 amino acids). See alignment below. The intracellular contents of the transformed E. coli cells of Clomburg et al. constitute a composition that would comprise at least water, a first kinase (ThiM), a second kinase (IPKMTH), at least one of prenol and isoprenol, and at least one of IP or DMAP.
Query = SEQ ID NO:76
Sbjct = WP_432703844 (IPK from M. thermautotrophicus)
NW Score Identities Positives Gaps
126 74/285(26%) 114/285(40%) 38/285(13%)
Query 1 MTPDFLAIKVGGSLFSRKD-EPGSLDDDAVTRFARNFARLAETYRGRMVLISGGGAFGH- 58
M + +K+GGS+ +RKD E ++D D + R A + + ++++ G G+FGH
Sbjct 1 M----IILKLGGSVITRKDSEEPAIDRDNLERIASEIGNASPS---SLMIVHGAGSFGHP 53
Query 59 --GAIRDHDSTHAFSLAGLTEATFEVKKRWAEKLRGI--------GVDAFPLQLAAMCTL 108
G R F + + W +KL G+ A +Q +A
Sbjct 54 FAGEYRIGSEIENEEDLRRRRFGFALTQNWVKKLNSHVCDALLAEGIPAVSMQPSAFIRA 113
Query 109 RNG-IPQLRSEVLRDVLDHGALPVLAGDALFDEHGKLW--AFSSDRVPEVLLPMVEGRL- 164
G I ++R L+ G +PV+ GD + D +L S D+ L+ RL
Sbjct 114 HAGRISHADISLIRSYLEEGMVPVVYGDVVLDSDRRLKFSVISGDQ----LINHFSLRLM 169
Query 165 --RVVTLTDVDGIVTDGAGGDTILPEVDARSPEQAYAALWGSSEWDATGAMHTKLDALVT 222
RV+ TDVDG+ T +D +L G+ D TG M K+ L+
Sbjct 170 PERVILGTDVDGVYTRNPKKHPDARLLDVIGSLDDLESLDGTLNTDVTGGMVGKIRELLL 229
Query 223 CARRGAECFIMRGD-PGSDLEFLTAPFSSWPAHVRSTRITTTASA 266
A +G E I+ PG+ L VR TRIT
Sbjct 230 LAEKGVESEIINAAVPGNIERALLGE------EVRGTRIT--GKH 266
With regard to the arguments that Goeker et al merely discloses a sequence listing of an E. coli hydroxyethylthiazole kinase (ThiM) and reports its ability to phosphorylate prenol in an enzymatic assay, and that Clomburg et al. do not teach or suggest the specific kinases claimed, nor do they provide guidance that would lead a person of ordinary skill in the art to select or modify the disclosed sequences to achieve the claimed combination of structural features and functional activity, it is noted that Goeker et al. teach the kinase of SEQ ID NO: 43. While it is agreed that Clomburg et al. do not teach the kinase of SEQ ID NO: 43, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the hydroxyethylthiazole kinase of Goeker et al. in the recombinant cells of Clomburg et al. A person of ordinary skill in the art is motivated to use the hydroxyethylthiazole kinase of Goeker et al. because that enzyme has the exact same enzymatic activity as the hydroxyethylthiazole kinase of Clomburg et al. As such, the use of the protein of Goeker et al. in the cells of Clomburg et al. is merely a replacement with a functional equivalent to obtain predictable results. The teachings of Clomburg et al. disclose all the elements in the composition of claim 14 except for a hydroxyethylthiazole kinase that comprises SEQ ID NO: 43. One of the skill in the art could have replaced the kinase of Clomburg et al. with the kinase of Goeker et al. by known methods and obtain predictable results in view of the fact that the polypeptide of Goeker et al. has the same enzymatic activity, i.e., hydroxyethylthiazole kinase, as that of the hydroxyethylthiazole kinase of Clomburg et al. See MPEP 2143 (B). One of ordinary skill in the art has a reasonable expectation of success at using the hydroxyethylthiazole kinase of Goeker et al. in the cells of Clomburg et al. because the protein of Goeker et al. has the exact same enzymatic activity as that of the enzyme in the cells of Clomburg et al. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is in condition for allowance.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
August 5, 2026
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