Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
This application is a 371 of PCT/KR2019/002242.
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 9, 2026 has been entered.
Election/Restrictions
Applicant elected without traverse of Group I with a species election of (1)(a) E. coli for the microorganism, (b) enhancing AroG activity as the modification made in the microorganism, and (c) SEQ ID NO:1 and 2 for the 2-dehydro-3-deoxyphosphoheptonate aldolase, (2) pyruvate as the substrate, and (3) shinorine as the mycosporine-like amino acid in the reply filed on January 20, 2024.
Claims 7, 9-10, 12, and 21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on January 10, 2024.
Newly submitted claim 28 is directed to an invention that lacks unity of invention from the invention originally claimed for the following reasons: claim 28 is directed to a method of increasing production of a mycosporine-like amin acid in a microorganism, thereby producing the microorganism of claim 1. Claim 28 lacks unity of invention with Group I and II because the technical feature linking Group I, Group II, and claim 28, a corynebacterium microorganism with increased enzyme activities of 20-dehydro-3-deoxyphosphoheptonate aldolase, PEP synthetase, and transketolase, does not constitute a special technical feature as it does not define a contribution over the prior art, see the 103 rejection below.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claim 28 withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
In the amendment filed on December 13, 2024, claim 1 was amended to exclude E. coli. Therefore, search and examination was extended to subsequent species, Corynebacterium glutamicum (claim 19), which is disclosed in the prior art, see the 103 rejections below. Therefore, search and examination has not been extended to any other species.
Status of Claims
Claims 1, 6-7, 9-10, 12, 16-19, 21-24, and 28 are pending.
Claims 7, 9-10, 12, 21, and 28 are withdrawn.
Claims 1, 6, 16-19, and 22-24 are under examination.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1 and claims 6, 16-19, and 22-24 depending therefrom are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation “a non-modified microorganism” in line 2 and “a non-modified microorganism” in line 5. The metes and bounds of the limitation in the context of the above claim are not clear. (1) It is unclear if the “non-modified microorganism” recited in lines 2 and 5 are the same non-modified microorganism or different non-modified microorganism. (2) It is unclear if the non-modified microorganism is a Corynebacterium without MAA biosynthesis gene cluster and without increased enzyme activities of 2-dehydro-3- deoxyphosphoheptonate aldolase, phosphoenolpyruvate synthetase, and transketolase or if the non-modified microorganism is any non-modified microorganism. Clarification is requested.
Response to Amendments/Arguments
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.
Withdrawn Rejection
Applicant’s arguments, see page 5 of the Remarks, filed December 12, 2025, with respect to claims 1 and 26-27 have been fully considered and are partially persuasive. Claims 26-27 have been cancelled. Claim 1 remains rejected, see the 103 rejection below. Therefore, the rejections of claims 26-27 under 35 U.S.C. 103 has been withdrawn.
Maintained Rejections
Claims 1, 6, 16-19, and 22-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ikeda (US 2017/0202762 – form PTO-892), Miyamoto (Discovery of gene cluster for mycosporine-like amino acid biosynthesis from Actinomycetales microorganisms and production of a novel mycosporine-like amino acid by heterologous expression. Appl Environ Microbiol. 2014 Aug;80(16):5028-36. – cited previously on form PTO-892), Gao (An ATP-grasp ligase involved in the last biosynthetic step of the iminomycosporine shinorine in Nostoc punctiforme ATCC 29133. J Bacteriol. 2011 Nov;193(21):5923-8 - form-PTO-1449), Pope (O-Methyltransferase is shared between the pentose phosphate and shikimate pathways and is essential for mycosporine-like amino acid biosynthesis in Anabaena variabilis ATCC 29413. Chembiochem. 2015 Jan 19;16(2):320-7 – form PTO-1449), Liao (US 6,489,100 – cited previously on form PTO-892), and Stewart (Biotechnology and Genetic Engineering Reviews, 14:67-143, 1997 - cited previously on form PTO-892).
Ikeda discloses heterologous mycosproine-like amino acid (MAA) production in Corynebacterium (abstract).
Regarding claims 1, 6, and 19, Ikeda discloses a mycosporine-like amino acid (MAA) or shinorine producing Corynebacterium glutamicum ATCC 13032 modified to introduce an MAA biosynthesis gene cluster, wherein the Corynebacterium glutamicum has increased production of MAA (abstract, [0018], [0028], [0034], [0039], [0043], [0053], [0055], Example 3, and claims 1-11). Since MAA is naturally produced in cyanobacterium, fungi, and marine micro-and macroalgae and is not produced in Corynebacterium glutamicum ([0008] and page 5028 of Miyamoto), the modified Corynebacterium glutamicum of Ikeda comprising the MAA biosynthesis gene cluster has increased MAA/shinorine production compared to Corynebacterium glutamicum not comprising the MAA biosynthesis gene cluster. The enzyme activity of 3-dehydroquinate dehydratase (aroD) is not inactivated in the Corynebacterium glutamicum of Ikeda. Ikeda discloses MAA biosynthesis gene clusters, such as (1) Ananbaena variabilis MAA biosynthesis genes Ava 3855, Ava 3856, Ava 3857, and Ava 3858, (2) Nostoc punctiforme genes mysA, mysB, mysC and mysD, and (3) Actinosynnema mirum MAA biosynthesis genes amir 4256, amir 4257, amir 4258, and amir 4259 ([0053]).
Regarding claims 16, Ava 3858, mysA (R5600), and amir 4259 encode 2-demethyl 4-deoxygadusol (DDG, synonymous with 4-deoxygadusol) synthase, see Miyamoto (abstract, Fig. 2, pages 5028-5029, and page 5034) and Gao (abstract, 2nd full paragraph at page 5923, and Results and Discussion at pages 5924-5925).
Regarding claim 17, Ava 3857, mysB (R5599), and amir 4258 encode O-methyltransferase, see Miyamoto (abstract, Fig. 2, pages 5028-5029, and page 5034) and Gao (abstract, 2nd full paragraph at page 5923, and Results and Discussion at pages 5924-5925).
Regarding claim 18, Ava 3856, mysC (R5598), and amir 4257 encode C-N ligase (synonymous with ATP-grasp that catalyzes addition of glycine to 4-DG), see Miyamoto (abstract, Fig. 2, pages 5028-5029, and page 5034) and Gao (abstract, 2nd full paragraph at page 5923, and Results and Discussion at pages 5924-5925).
Regarding claims 22-23, Ava 3855 encodes nonribosomal peptide synthetase (NRPS) homolog, see Miyamoto (abstract, Fig. 2, pages 5028-5029, and page 5034) and Gao (abstract, 2nd full paragraph at page 5923, and Results and Discussion at pages 5924-5925).
Regarding claim 24, mysD (F5597) and amir 4256 encodes D-alanine D-alanine ligase (D-Ala D-Ala lipase), see Miyamoto (abstract, Fig. 2, pages 5028-5029, and page 5034) and Gao (abstract, 2nd full paragraph at page 5923, and Results and Discussion at pages 5924-5925).
Ikeda does not disclose a C. glutamicum modified to increase enzyme activities of 2-dehydro-3-deoxyphosphoheptonate aldolase, phosphoenolpyruvate synthetase, and transketolase.
DAHP synthase (2-dehydro-3-deoxyphosphoheptonate aldolase) is the first enzyme of the shikimate pathway. Pope discloses that MAA biosynthesis occurs via the shikimate pathway and the pentose phosphate pathway (abstract and Scheme 3 and “Conclusion” at page 325).
Regarding claim 1, Pope discloses that DAHP synthase converts phosphoenolpyruvate (PEP) + erythrose-4-phosphate (E4P) → 3-deoxy-D-arabionoheptulosinate phosphate (DAHP), which is then subsequently converted to MAAs via DHQ (Scheme 3 and page 325).
Regarding claim 1, Liao discloses increasing DAHP in Corynebacterum glutamicum by overexpressing DAHP synthase, transketolase, and PEP synthetase (Claims 7-10, Column 4 lines 1-17, Column 5 lines 6-40 and 54-64, Column 11 lines 7-15, Column 12 lines 11-17, and Column 13 lines 22-24). Since DAHP synthase, transketolase, and PEP synthetase is overexpressed in Corynebacterum glutamicum, the resulting modified Corynebacterum glutamicum has increased enzyme activities of DAHP synthase, transketolase, and PEP synthetase compared to an unmodified Corynebacterum glutamicum. Liao discloses that improvement of productivity and yield of a desired product call for the alteration of central metabolic pathways which supply necessary precursor for the desired biosynthesis of the desired product (Column 1 lines 58-65). The enzyme activity of 3-dehydroquinate dehydratase (aroD) is not inactivated in the Corynebacterum glutamicum of Liao.
Stewart reviews the use of genetically engineered microorganism to catalyze a desired chemical reaction or pathway (page 68). Stewart et al. discloses that with the advent of molecular cloning in the mid-1970s, it became possible to one having ordinary skill in the art to tailor metabolisms in microorganisms by over-expression of genes (page 68). Stewart discloses improving production of a compound of interest by increasing production of precursors of a compound of interest (pages 69-70).
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 modify the C. glutamicum of Ikeda (comprising Anabaena variabilis, Nostoc punctiforme, or Actinosynnema mirum MAA biosynthesis genes) by overexpressing DAHP synthase, phosphoenolpyruvate synthetase, and transketolase. One of ordinary skill in the art would have been motivated to overexpress DAHP synthase, phosphoenolpyruvate synthetase, and transketolase in order to increase availability of MAA precursors, thereby increasing production of MAAs/shinorine. One of ordinary skill in the art would have had a reasonable expectation of success since Ikdea discloses MAA/shinorine producing C. glutamicum having increased MAA/shinorine production compared to unmodified C. glutamicum, Pope discloses that MAA producing proceeds via the shikimate pathway and the pentose phosphate pathway, Liao discloses increasing DAHP in C. glutamicum by overexpressing DAHP synthase, phosphoenolpyruvate synthetase, and transketolase, and Stewart discloses improving production of a compound of interest by increasing production of precursors of the compound of interest.
Therefore, the above references render claims 1, 6, 16-19, and 22-24 prima facie obvious.
Applicant has addressed the two rejections under 35 USC 103 together. See below for Applicant’s rebuttal.
Claims 1, 6, 16-19, and 22-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ikeda (US 2017/0202762– form PTO-892), Miyamoto (Discovery of gene cluster for mycosporine-like amino acid biosynthesis from Actinomycetales microorganisms and production of a novel mycosporine-like amino acid by heterologous expression. Appl Environ Microbiol. 2014 Aug;80(16):5028-36. – cited previously on form PTO-892), Gao (An ATP-grasp ligase involved in the last biosynthetic step of the iminomycosporine shinorine in Nostoc punctiforme ATCC 29133. J Bacteriol. 2011 Nov;193(21):5923-8 - form-PTO-1449), Pope (O-Methyltransferase is shared between the pentose phosphate and shikimate pathways and is essential for mycosporine-like amino acid biosynthesis in Anabaena variabilis ATCC 29413. Chembiochem. 2015 Jan 19;16(2):320-7 – form PTO-1449), Liao (US 6,489,100 – cited previously on form PTO-892), Davies (The nucleotide sequence of aroG, the gene for 3-deoxy-D-arabinoheptulosonate-7-phosphate synthetase (phe) in Escherichia coli K12. Nucleic Acids Res. 1982 Jul 10;10(13):4045-58 – cited previously on form PTO-892) and Stewart (Biotechnology and Genetic Engineering Reviews, 14:67-143, 1997 - cited previously on form PTO-892).
Ikeda discloses heterologous mycosproine-like amino acid (MAA) production in Corynebacterium (abstract).
Regarding claims 1, 6, and 19, Ikeda discloses mycosporine-like amino acid (MAA) or shinorine producing Corynebacterium glutamicum ATCC 13032 modified to introduce an MAA biosynthesis gene cluster, wherein the Corynebacterium glutamicum has increased production of MAA (abstract, [0018], [0028], [0034], [0039], [0043], [0053], [0055], Example 3, and claims 1-11). Since MAA is naturally produced in cyanobacterium, fungi, and marine micro-and macroalgae and is not produced Corynebacterium glutamicum ([0008] and see page 5028 of Miyamoto), the modified Corynebacterium glutamicum of Ikeda comprising the MAA biosynthesis gene cluster has increased MAA/shinorine production compared to Corynebacterium glutamicum not comprising the MAA biosynthesis gene cluster. The enzyme activity of 3-dehydroquinate dehydratase (aroD) is not inactivated in the Corynebacterium glutamicum of Ikeda. Ikeda discloses MAA biosynthesis gene clusters, such as (1) Ananbaena variabilis MAA biosynthesis genes Ava 3855, Ava 3856, Ava 3857, and Ava 3858, (2) Nostoc punctiforme genes mysA, mysB, mysC and mysD, and (3) Actinosynnema mirum MAA biosynthesis genes amir 4256, amir 4257, amir 4258, and amir 4259 ([0053]).
Regarding claims 16, Ava 3858, mysA (R5600), and amir 4259 encode 2-demethyl 4-deoxygadusol (DDG, synonymous with4-deoxygadusol) synthase, see Miyamoto (abstract, Fig. 2, pages 5028-5029, and page 5034) and Gao (abstract, 2nd full paragraph at page 5923, and Results and Discussion at pages 5924-5925).
Regarding claim 17, Ava 3857, mysB (R5599), and amir 4258 encode O-methyltransferase, see Miyamoto (abstract, Fig. 2, pages 5028-5029, and page 5034) and Gao (abstract, 2nd full paragraph at page 5923, and Results and Discussion at pages 5924-5925).
Regarding claim 18, Ava 3856, mysC (R5598), and amir 4257 encode C-N ligase (synonymous with ATP-grasp that catalyzes addition of glycine to 4-DG), see Miyamoto (abstract, Fig. 2, pages 5028-5029, and page 5034) and Gao (abstract, 2nd full paragraph at page 5923, and Results and Discussion at pages 5924-5925).
Regarding claims 22-23, Ava 3855 encodes nonribosomal peptide synthetase (NRPS) homolog, see Miyamoto (abstract, Fig. 2, pages 5028-5029, and page 5034) and Gao (abstract, 2nd full paragraph at page 5923, and Results and Discussion at pages 5924-5925).
Regarding claim 24, mysD (F5597) and amir 4256 encodes D-alanine D-alanine ligase (D-Ala D-Ala lipase), see Miyamoto (abstract, Fig. 2, pages 5028-5029, and page 5034) and Gao (abstract, 2nd full paragraph at page 5923, and Results and Discussion at pages 5924-5925).
Ikeda does not disclose C. glutamicum with increased enzyme activity of 2-dehydro-3-deoxyphosphoheptonate aldolase having the amino acid sequence of SEQ ID NO:2, phosphoenolpyruvate synthetase, and transketolase.
DAHP synthase (2-dehydro-3-deoxyphosphoheptonate aldolase) is the first enzyme of the shikimate pathway. Pope discloses that MAA biosynthesis occurs via the shikimate pathway and the pentose phosphate pathway (abstract and Scheme 3 and “Conclusion” at page 325).
Regarding claim 1, Pope discloses that DAHP synthase converts phosphoenolpyruvate (PEP) + erythrose-4-phosphate (E4P) → 3-deoxy-D-arabionoheptulosinate phosphate (DAHP), which is then subsequently converted to MAAs via DHQ (Scheme 3 and page 325).
Regarding claim 1, Liao discloses increasing DAHP in Corynebacterum glutamicum by overexpressing DAHP synthase, transketolase, and PEP synthetase (Claims 7-10, Column 4 lines 1-17, Column 5 lines 6-40 and 54-64, Column 11 lines 7-15, Column 12 lines 11-17, and Column 13 lines 22-24). Since DAHP synthase, transketolase, and PEP synthetase is overexpressed in Corynebacterum glutamicum, the resulting modified Corynebacterum glutamicum has increased enzyme activities of DAHP synthase, transketolase, and PEP synthetase compared to an unmodified Corynebacterum glutamicum. Liao discloses that improvement of productivity and yield of a desired product call for the alteration of central metabolic pathways which supply necessary precursor for the desired biosynthesis of the desired product (Column 1 lines 58-65). The enzyme activity of 3-dehydroquinate dehydratase (aroD) is not inactivated in the Corynebacterum glutamicum of Liao.
Regarding claim 1, Davies discloses E. coli AroG gene encoding DAHP synthase, wherein said AroG gene has 100% sequence identity to SEQ ID NO:1 of the instant application and said DAHP synthase has 100% sequence identity to SEQ ID NO:2 of the instant application (abstract and pages 4050-4051 and see the sequence alignment below).
Stewart reviews the use of genetically engineered microorganism to catalyze a desired chemical reaction or pathway (page 68). Stewart et al. discloses that with the advent of molecular cloning in the mid-1970s, it became possible to one having ordinary skill in the art to tailor metabolisms in microorganisms by over-expression of genes (page 68). Steward discloses improving production of a compound of interest by increasing production of precursors of a compound of interest (pages 69-70).
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 modify the C. glutamicum of Ikeda (comprising Anabaena variabilis, Nostoc punctiforme, or Actinosynnema mirum MAA biosynthesis genes) by overexpressing (1) DAHP synthase encoded by E. coli AroG gene of Davies, phosphoenolpyruvate synthetase, and transketolase or (2) DAHP synthase encoded by E. coli AroG gene of Davies and phosphoenolpyruvate synthetase. One of ordinary skill in the art would have been motivated to overexpress DAHP synthase, phosphoenolpyruvate synthetase, and transketolase in order to increase availability of MAA precursors, thereby increasing production of MAAs/shinorine. Regarding overexpression of DAHP synthase encoded by the E. coli AroG gene of Davies, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was effectively filed to replace the prior art DAHP synthase with other known DAHP synthase that converts phosphoenolpyruvate (PEP) + erythrose-4-phosphate (E4P) → 3-deoxy-D-arabionoheptulosinate phosphate (DAHP), such as the DAPH synthase of Davies, because one of ordinary skill in the art would have been able to carry out such a substitution, and the results were reasonably predictable. Further, the normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine the optimum enzymes of a biosynthesis pathway. One of ordinary skill in the art would have had a reasonable expectation of success since Ikea discloses MAA/shinorine producing C. glutamicum, Pope discloses that MAA producing proceeds via the shikimate pathway and the pentose phosphate pathway, Liao discloses increasing DAHP in C. glutamicum by overexpressing DAHP synthase, phosphoenolpyruvate synthetase, and transketolase, E. coli AroG gene encoding DAHP was well known in the art, and Stewart discloses improving production of a compound of interest by increasing production of precursors of the compound of interest.
Therefore, the above references render claims 1, 6, 16-19, and 22-24 prima facie obvious.
Applicant’s Rebuttal of the above rejections
Applicant's arguments filed December 12, 2025 have been fully considered but they are not persuasive.
(i) (a) Applicant argues that unexpected results need not be explicitly stated in the claims or specification or even be known at the time of filing the application in order to overcome an obviousness rejection and (b) Applicant showed unexpectedly superior increased production of a MAA.
This is not found persuasive. (a) Since Applicant’s assertion of unexpected results was not commensurate in scope with the instant claims and not sufficient to overcome the obviousness rejection, the rebuttal to Applicant’s arguments addressed the full scope of the claims, that the references fail to show certain features (i.e., increased production of mycosporine-like amino acid). (b) As discussed previously, it appeared that Applicant was relying on results from Table 5 (“increased production of a mycosporine-like amino acid by 41%” section (ii) at page 6 of the Remarks filed on August 25, 2025). However, Table 5 discloses increased shinorine production in E. coli expressing pps and Ava_ABCD. However, the instant claims are not directed to E. coli expressing pps and Ava_ABCD. Tables 12, 14, and 16 are limited to C. glutamicum expressing Ava-ABCD and DAHP synthase, phosphoenolpyruvate synthetase, and transketolase. However, the instant claims are not directed to C. glutamicum expressing Ava-ABCD and DAHP synthase, phosphoenolpyruvate synthetase, and transketolase. Therefore, Applicant’s assertion of unexpected results is not commensurate in scope with the instant claims.
(ii) Applicant argues that the claims are not obvious because Tables 16 and 27 of the specification demonstrate unexpectedly superior property of MAA producing microorganism having an enhanced enzyme activity of DAHP synthase, phosphoenolpyruvate synthetase, and transketolase.
This is not found persuasive. MPEP 716.02 (d) states that “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range”. In the instant case, Table 16 is limited to C. glutamicum expressing Ava-ABCD and DAHP synthase, phosphoenolpyruvate synthetase, and transketolase and Table 27 is limited to S. cerevisiae expressing Ava-ABCD and DAHP synthase, phosphoenolpyruvate synthetase, and transketolase. However, the instant claims are directed to any Corynebacterium or yeast expressing any MAA biosynthesis gene cluster and DAHP synthase, phosphoenolpyruvate synthetase, and transketolase. Therefore, Applicant’s assertion of unexpected results is not commensurate in scope with the instant claims.
Further, increased MAA/shinorine production would have been an expected property of the of C. glutamicum expressing Ava_ABCD DAHP synthase, phosphoenolpyruvate synthetase, and transketolase compared to unmodified C. glutamicum because (1) the unmodified C. glutamicum ATCC 13032 (“c.gl 13032”) does not naturally produce MAA/shinorine, (2) C. glutamicum has been modified to express MAA/shinorine biosynthesis gene cluster (comprising Anabaena variabilis, Nostoc punctiforme, or Actinosynnema mirum MAA biosynthesis genes) resulting in increased MAA/shinorine production, and (3) the C. glutamicum has been modified to express enzymes leading to increased availability of DAHP, the precursor for MAA/shinorine production.
Hence the rejections have been maintained.
Conclusion
Claims 1, 6-7, 9-10, 12, 16-19, 21-24, and 28 are pending.
Claims 7, 9-10, 12, 21, and 28 are withdrawn.
Claims 1, 6, 16-19, and 22-24 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 DHAP synthase of SEQ ID NO:2 of the instant application (“Qy”) and DAHP synthase of Davies (“Db”)
AROG_ECOLI
ID AROG_ECOLI Reviewed; 350 AA.
AC P0AB91; P00886;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 21-JUL-1986, sequence version 1.
DT 24-JAN-2024, entry version 137.
DE RecName: Full=Phospho-2-dehydro-3-deoxyheptonate aldolase, Phe-sensitive;
DE EC=2.5.1.54;
DE AltName: Full=3-deoxy-D-arabino-heptulosonate 7-phosphate synthase;
DE AltName: Full=DAHP synthase;
DE AltName: Full=Phospho-2-keto-3-deoxyheptonate aldolase;
GN Name=aroG; OrderedLocusNames=b0754, JW0737;
OS Escherichia coli (strain K12).
OC Bacteria; Pseudomonadota; Gammaproteobacteria; Enterobacterales;
OC Enterobacteriaceae; Escherichia.
OX NCBI_TaxID=83333;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=K12;
RX PubMed=6125934; DOI=10.1093/nar/10.13.4045;
RA Davies W.D., Davidson B.E.;
RT "The nucleotide sequence of aroG, the gene for 3-deoxy-D-
RT arabinoheptulosonate-7-phosphate synthetase (phe) in Escherichia coli
RT K12.";
RL Nucleic Acids Res. 10:4045-4058(1982).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=K12 / W3110 / ATCC 27325 / DSM 5911;
RX PubMed=8905232; DOI=10.1093/dnares/3.3.137;
RA Oshima T., Aiba H., Baba T., Fujita K., Hayashi K., Honjo A., Ikemoto K.,
RA Inada T., Itoh T., Kajihara M., Kanai K., Kashimoto K., Kimura S.,
RA Kitagawa M., Makino K., Masuda S., Miki T., Mizobuchi K., Mori H.,
RA Motomura K., Nakamura Y., Nashimoto H., Nishio Y., Saito N., Sampei G.,
RA Seki Y., Tagami H., Takemoto K., Wada C., Yamamoto Y., Yano M.,
RA Horiuchi T.;
RT "A 718-kb DNA sequence of the Escherichia coli K-12 genome corresponding to
RT the 12.7-28.0 min region on the linkage map.";
RL DNA Res. 3:137-155(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=K12 / MG1655 / ATCC 47076;
RX PubMed=9278503; DOI=10.1126/science.277.5331.1453;
RA Blattner F.R., Plunkett G. III, Bloch C.A., Perna N.T., Burland V.,
RA Riley M., Collado-Vides J., Glasner J.D., Rode C.K., Mayhew G.F.,
RA Gregor J., Davis N.W., Kirkpatrick H.A., Goeden M.A., Rose D.J., Mau B.,
RA Shao Y.;
RT "The complete genome sequence of Escherichia coli K-12.";
RL Science 277:1453-1462(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=K12 / W3110 / ATCC 27325 / DSM 5911;
RX PubMed=16738553; DOI=10.1038/msb4100049;
RA Hayashi K., Morooka N., Yamamoto Y., Fujita K., Isono K., Choi S.,
RA Ohtsubo E., Baba T., Wanner B.L., Mori H., Horiuchi T.;
RT "Highly accurate genome sequences of Escherichia coli K-12 strains MG1655
RT and W3110.";
RL Mol. Syst. Biol. 2:E1-E5(2006).
RN [5]
RP PROTEIN SEQUENCE OF 1-12.
RC STRAIN=K12 / EMG2;
RX PubMed=9298646; DOI=10.1002/elps.1150180807;
RA Link A.J., Robison K., Church G.M.;
RT "Comparing the predicted and observed properties of proteins encoded in the
RT genome of Escherichia coli K-12.";
RL Electrophoresis 18:1259-1313(1997).
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-244, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RC STRAIN=K12 / JW1106, and K12 / MG1655 / ATCC 47076;
RX PubMed=18723842; DOI=10.1074/mcp.m800187-mcp200;
RA Zhang J., Sprung R., Pei J., Tan X., Kim S., Zhu H., Liu C.F.,
RA Grishin N.V., Zhao Y.;
RT "Lysine acetylation is a highly abundant and evolutionarily conserved
RT modification in Escherichia coli.";
RL Mol. Cell. Proteomics 8:215-225(2009).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
RX PubMed=10425687; DOI=10.1016/s0969-2126(99)80109-9;
RA Shumilin I.A., Kretsinger R.H., Bauerle R.H.;
RT "Crystal structure of phenylalanine-regulated 3-deoxy-D-arabino-
RT heptulosonate-7-phosphate synthase from Escherichia coli.";
RL Structure 7:865-875(1999).
CC -!- FUNCTION: Stereospecific condensation of phosphoenolpyruvate (PEP) and
CC D-erythrose-4-phosphate (E4P) giving rise to 3-deoxy-D-arabino-
CC heptulosonate-7-phosphate (DAHP).
CC -!- CATALYTIC ACTIVITY:
CC Reaction=D-erythrose 4-phosphate + H2O + phosphoenolpyruvate = 7-
CC phospho-2-dehydro-3-deoxy-D-arabino-heptonate + phosphate;
CC Xref=Rhea:RHEA:14717, ChEBI:CHEBI:15377, ChEBI:CHEBI:16897,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58394, ChEBI:CHEBI:58702; EC=2.5.1.54;
CC -!- PATHWAY: Metabolic intermediate biosynthesis; chorismate biosynthesis;
CC chorismate from D-erythrose 4-phosphate and phosphoenolpyruvate: step
CC 1/7.
CC -!- SUBUNIT: Homotetramer.
CC -!- INTERACTION:
CC P0AB91; P0AB91: aroG; NbExp=5; IntAct=EBI-1120055, EBI-1120055;
CC -!- MISCELLANEOUS: There are 3 DAHP synthases, AroG is feedback-inhibited
CC by Phe. The other 2 DAHP synthases are Tyr- and Trp-sensitive,
CC respectively.
CC -!- SIMILARITY: Belongs to the class-I DAHP synthase family. {ECO:0000305}.
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DR EMBL; J01591; AAA23492.1; -; Genomic_DNA.
DR EMBL; U00096; AAC73841.1; -; Genomic_DNA.
DR EMBL; AP009048; BAA35416.1; -; Genomic_DNA.
DR PIR; A01106; ADECHF.
DR RefSeq; NP_415275.1; NC_000913.3.
DR RefSeq; WP_001109196.1; NZ_SSZK01000002.1.
DR PDB; 1GG1; X-ray; 2.00 A; A/B/C/D=1-350.
DR PDB; 1KFL; X-ray; 2.80 A; A/B/C/D/E/F/G/H=2-350.
DR PDB; 1N8F; X-ray; 1.75 A; A/B/C/D=1-350.
DR PDB; 1QR7; X-ray; 2.60 A; A/B/C/D=1-350.
DR PDB; 5CKS; X-ray; 2.12 A; A/B/C/D=1-350.
DR PDB; 7RUD; X-ray; 2.80 A; A/B/C/D=1-350.
DR PDB; 7RUE; X-ray; 2.50 A; A/B/C/D=1-350.
DR PDB; 8E0S; X-ray; 1.65 A; A/B/C/D=1-350.
DR PDB; 8E0T; X-ray; 1.94 A; A/B/C/D=1-350.
DR PDB; 8E0U; X-ray; 2.42 A; A/B/C/D=1-350.
DR PDB; 8E0V; X-ray; 2.30 A; A/B/C/D=1-350.
DR PDB; 8E0X; X-ray; 1.97 A; A/B/C/D=1-350.
DR PDB; 8E0Y; X-ray; 2.01 A; A/B/C/D=1-350.
DR PDB; 8E0Z; X-ray; 2.40 A; A/B/C/D=1-350.
DR PDBsum; 1GG1; -.
DR PDBsum; 1KFL; -.
DR PDBsum; 1N8F; -.
DR PDBsum; 1QR7; -.
DR PDBsum; 5CKS; -.
DR PDBsum; 7RUD; -.
DR PDBsum; 7RUE; -.
DR PDBsum; 8E0S; -.
DR PDBsum; 8E0T; -.
DR PDBsum; 8E0U; -.
DR PDBsum; 8E0V; -.
DR PDBsum; 8E0X; -.
DR PDBsum; 8E0Y; -.
DR PDBsum; 8E0Z; -.
DR AlphaFoldDB; P0AB91; -.
DR SMR; P0AB91; -.
DR BioGRID; 4261709; 17.
DR DIP; DIP-35898N; -.
DR IntAct; P0AB91; 3.
DR STRING; 511145.b0754; -.
DR BindingDB; P0AB91; -.
DR DrugBank; DB02726; 2-Phosphoglycolic Acid.
DR DrugBank; DB01819; Phosphoenolpyruvate.
DR iPTMnet; P0AB91; -.
DR SWISS-2DPAGE; P0AB91; -.
DR jPOST; P0AB91; -.
DR PaxDb; 511145-b0754; -.
DR EnsemblBacteria; AAC73841; AAC73841; b0754.
DR GeneID; 75170753; -.
DR GeneID; 945605; -.
DR KEGG; ecj:JW0737; -.
DR KEGG; eco:b0754; -.
DR PATRIC; fig|1411691.4.peg.1525; -.
DR EchoBASE; EB0077; -.
DR eggNOG; COG0722; Bacteria.
DR HOGENOM; CLU_030903_0_1_6; -.
DR InParanoid; P0AB91; -.
DR OMA; DINTGLR; -.
DR OrthoDB; 9807331at2; -.
DR PhylomeDB; P0AB91; -.
DR BioCyc; EcoCyc:AROG-MONOMER; -.
DR BioCyc; MetaCyc:AROG-MONOMER; -.
DR BRENDA; 2.5.1.54; 2026.
DR SABIO-RK; P0AB91; -.
DR UniPathway; UPA00053; UER00084.
DR EvolutionaryTrace; P0AB91; -.
DR PRO; PR:P0AB91; -.
DR Proteomes; UP000000318; Chromosome.
DR Proteomes; UP000000625; Chromosome.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:EcoCyc.
DR GO; GO:0003849; F:3-deoxy-7-phosphoheptulonate synthase activity; IDA:EcoCyc.
DR GO; GO:0042802; F:identical protein binding; IDA:EcoCyc.
DR GO; GO:0008652; P:amino acid biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0009073; P:aromatic amino acid family biosynthetic process; IBA:GO_Central.
DR GO; GO:0009423; P:chorismate biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 3.20.20.70; Aldolase class I; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR006218; DAHP1/KDSA.
DR InterPro; IPR006219; DAHP_synth_1.
DR NCBIfam; TIGR00034; aroFGH; 1.
DR PANTHER; PTHR21225; PHOSPHO-2-DEHYDRO-3-DEOXYHEPTONATE ALDOLASE DAHP SYNTHETASE; 1.
DR PANTHER; PTHR21225:SF12; PHOSPHO-2-DEHYDRO-3-DEOXYHEPTONATE ALDOLASE, PHE-SENSITIVE; 1.
DR Pfam; PF00793; DAHP_synth_1; 1.
DR PIRSF; PIRSF001361; DAHP_synthase; 1.
DR SUPFAM; SSF51569; Aldolase; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Amino-acid biosynthesis;
KW Aromatic amino acid biosynthesis; Direct protein sequencing;
KW Reference proteome; Transferase.
FT CHAIN 1..350
FT /note="Phospho-2-dehydro-3-deoxyheptonate aldolase, Phe-
FT sensitive"
FT /id="PRO_0000140835"
FT MOD_RES 244
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:18723842"
FT STRAND 10..14
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 19..25
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 30..47
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 54..59
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 66..82
FT /evidence="ECO:0007829|PDB:8E0S"
FT TURN 83..86
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 87..92
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 100..102
FT /evidence="ECO:0007829|PDB:8E0S"
FT TURN 107..109
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 113..115
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 119..135
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 140..144
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 146..148
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 150..153
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 154..156
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 158..162
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 164..166
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 170..177
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 183..186
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 194..204
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 208..212
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 216..223
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 229..233
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 236..238
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 243..255
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 262..265
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 268..271
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 275..277
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 278..290
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 295..303
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 305..308
FT /evidence="ECO:0007829|PDB:8E0S"
FT STRAND 312..314
FT /evidence="ECO:0007829|PDB:1N8F"
FT STRAND 324..326
FT /evidence="ECO:0007829|PDB:8E0S"
FT HELIX 331..349
FT /evidence="ECO:0007829|PDB:8E0S"
SQ SEQUENCE 350 AA; 38010 MW; 7477D361962E8710 CRC64;
Query Match 100.0%; Score 1815; Length 350;
Best Local Similarity 100.0%;
Matches 350; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MNYQNDDLRIKEIKELLPPVALLEKFPATENAANTVAHARKAIHKILKGNDDRLLVVIGP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MNYQNDDLRIKEIKELLPPVALLEKFPATENAANTVAHARKAIHKILKGNDDRLLVVIGP 60
Qy 61 CSIHDPVAAKEYATRLLALREELKDELEIVMRVYFEKPRTTVGWKGLINDPHMDNSFQIN 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 CSIHDPVAAKEYATRLLALREELKDELEIVMRVYFEKPRTTVGWKGLINDPHMDNSFQIN 120
Qy 121 DGLRIARKLLLDINDSGLPAAGEFLDMITPQYLADLMSWGAIGARTTESQVHRELASGLS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 DGLRIARKLLLDINDSGLPAAGEFLDMITPQYLADLMSWGAIGARTTESQVHRELASGLS 180
Qy 181 CPVGFKNGTDGTIKVAIDAINAAGAPHCFLSVTKWGHSAIVNTSGNGDCHIILRGGKEPN 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 CPVGFKNGTDGTIKVAIDAINAAGAPHCFLSVTKWGHSAIVNTSGNGDCHIILRGGKEPN 240
Qy 241 YSAKHVAEVKEGLNKAGLPAQVMIDFSHANSSKQFKKQMDVCADVCQQIAGGEKAIIGVM 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 YSAKHVAEVKEGLNKAGLPAQVMIDFSHANSSKQFKKQMDVCADVCQQIAGGEKAIIGVM 300
Qy 301 VESHLVEGNQSLESGEPLAYGKSITDACIGWEDTDALLRQLANAVKARRG 350
||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 VESHLVEGNQSLESGEPLAYGKSITDACIGWEDTDALLRQLANAVKARRG 350
Sequence alignment of AroG gene of SEQ ID NO:1 of the instant application (“Qy”) and AroG gene of Davies (“Db”)
ECOAROG
LOCUS ECOAROG 2107 bp DNA linear BCT 26-APR-1993
DEFINITION E.coli aroG gene coding for DAHP synthetase (phenylalanine
repressible).
ACCESSION J01591
VERSION J01591.1
KEYWORDS 3-deoxy-D-arabinoheptulosonate-7-phosphate synthetase; DAHP
synthetase; aroG gene; synthetase.
SOURCE Escherichia coli
ORGANISM Escherichia coli
Bacteria; Proteobacteria; Gammaproteobacteria; Enterobacterales;
Enterobacteriaceae; Escherichia.
REFERENCE 1 (bases 1 to 2107)
AUTHORS Davies,W.D. and Davidson,B.E.
TITLE The nucleotide sequence of aroG, the gene for
3-deoxy-D-arabinoheptulosonate-7-phosphate synthetase (phe) in
Escherichia coli K12
JOURNAL Nucleic Acids Res. 10 (13), 4045-4048 (1982)
PUBMED 6125934
COMMENT Original source text: Escherichia coli K12 DNA.
FEATURES Location/Qualifiers
source 1..2107
/organism="Escherichia coli"
/mol_type="genomic DNA"
/db_xref="taxon:562"
CDS 507..1559
/note="DAHP synthetase (aroG)"
/codon_start=1
/transl_table=11
/protein_id="AAA23492.1"
/translation="MNYQNDDLRIKEIKELLPPVALLEKFPATENAANTVAHARKAIH
KILKGNDDRLLVVIGPCSIHDPVAAKEYATRLLALREELKDELEIVMRVYFEKPRTTV
GWKGLINDPHMDNSFQINDGLRIARKLLLDINDSGLPAAGEFLDMITPQYLADLMSWG
AIGARTTESQVHRELASGLSCPVGFKNGTDGTIKVAIDAINAAGAPHCFLSVTKWGHS
AIVNTSGNGDCHIILRGGKEPNYSAKHVAEVKEGLNKAGLPAQVMIDFSHANSSKQFK
KQMDVCADVCQQIAGGEKAIIGVMVESHLVEGNQSLESGEPLAYGKSITDACIGWEDT
DALLRQLANAVKARRG
Query Match 100.0%; Score 1053; Length 2107;
Best Local Similarity 100.0%;
Matches 1053; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ATGAATTATCAGAACGACGATTTACGCATCAAAGAAATCAAAGAGTTACTTCCTCCTGTC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 507 ATGAATTATCAGAACGACGATTTACGCATCAAAGAAATCAAAGAGTTACTTCCTCCTGTC 566
Qy 61 GCATTGCTGGAAAAATTCCCCGCTACTGAAAATGCCGCGAATACGGTTGCCCATGCCCGA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 567 GCATTGCTGGAAAAATTCCCCGCTACTGAAAATGCCGCGAATACGGTTGCCCATGCCCGA 626
Qy 121 AAAGCGATCCATAAGATCCTGAAAGGTAATGATGATCGCCTGTTGGTTGTGATTGGCCCA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 627 AAAGCGATCCATAAGATCCTGAAAGGTAATGATGATCGCCTGTTGGTTGTGATTGGCCCA 686
Qy 181 TGCTCAATTCATGATCCTGTCGCGGCAAAAGAGTATGCCACTCGCTTGCTGGCGCTGCGT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 687 TGCTCAATTCATGATCCTGTCGCGGCAAAAGAGTATGCCACTCGCTTGCTGGCGCTGCGT 746
Qy 241 GAAGAGCTGAAAGATGAGCTGGAAATCGTAATGCGCGTCTATTTTGAAAAGCCGCGTACC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 747 GAAGAGCTGAAAGATGAGCTGGAAATCGTAATGCGCGTCTATTTTGAAAAGCCGCGTACC 806
Qy 301 ACGGTGGGCTGGAAAGGGCTGATTAACGATCCGCATATGGATAATAGCTTCCAGATCAAC 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 807 ACGGTGGGCTGGAAAGGGCTGATTAACGATCCGCATATGGATAATAGCTTCCAGATCAAC 866
Qy 361 GACGGTCTGCGTATAGCCCGTAAATTGCTGCTTGATATTAACGACAGCGGTCTGCCAGCG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 867 GACGGTCTGCGTATAGCCCGTAAATTGCTGCTTGATATTAACGACAGCGGTCTGCCAGCG 926
Qy 421 GCAGGTGAGTTTCTCGATATGATCACCCCACAATATCTCGCTGACCTGATGAGCTGGGGC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 927 GCAGGTGAGTTTCTCGATATGATCACCCCACAATATCTCGCTGACCTGATGAGCTGGGGC 986
Qy 481 GCAATTGGCGCACGTACCACCGAATCGCAGGTGCACCGCGAACTGGCATCAGGGCTTTCT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 987 GCAATTGGCGCACGTACCACCGAATCGCAGGTGCACCGCGAACTGGCATCAGGGCTTTCT 1046
Qy 541 TGTCCGGTCGGCTTCAAAAATGGCACCGACGGTACGATTAAAGTGGCTATCGATGCCATT 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1047 TGTCCGGTCGGCTTCAAAAATGGCACCGACGGTACGATTAAAGTGGCTATCGATGCCATT 1106
Qy 601 AATGCCGCCGGTGCGCCGCACTGCTTCCTGTCCGTAACGAAATGGGGGCATTCGGCGATT 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1107 AATGCCGCCGGTGCGCCGCACTGCTTCCTGTCCGTAACGAAATGGGGGCATTCGGCGATT 1166
Qy 661 GTGAATACCAGCGGTAACGGCGATTGCCATATCATTCTGCGCGGCGGTAAAGAGCCTAAC 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1167 GTGAATACCAGCGGTAACGGCGATTGCCATATCATTCTGCGCGGCGGTAAAGAGCCTAAC 1226
Qy 721 TACAGCGCGAAGCACGTTGCTGAAGTGAAAGAAGGGCTGAACAAAGCAGGCCTGCCAGCA 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1227 TACAGCGCGAAGCACGTTGCTGAAGTGAAAGAAGGGCTGAACAAAGCAGGCCTGCCAGCA 1286
Qy 781 CAGGTGATGATCGATTTCAGCCATGCTAACTCGTCCAAACAATTCAAAAAGCAGATGGAT 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1287 CAGGTGATGATCGATTTCAGCCATGCTAACTCGTCCAAACAATTCAAAAAGCAGATGGAT 1346
Qy 841 GTTTGTGCTGACGTTTGCCAGCAGATTGCCGGTGGCGAAAAGGCCATTATTGGCGTGATG 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1347 GTTTGTGCTGACGTTTGCCAGCAGATTGCCGGTGGCGAAAAGGCCATTATTGGCGTGATG 1406
Qy 901 GTGGAAAGCCATCTGGTGGAAGGCAATCAGAGCCTCGAGAGCGGGGAGCCGCTGGCCTAC 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1407 GTGGAAAGCCATCTGGTGGAAGGCAATCAGAGCCTCGAGAGCGGGGAGCCGCTGGCCTAC 1466
Qy 961 GGTAAGAGCATCACCGATGCCTGCATCGGCTGGGAAGATACCGATGCTCTGTTACGTCAA 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1467 GGTAAGAGCATCACCGATGCCTGCATCGGCTGGGAAGATACCGATGCTCTGTTACGTCAA 1526
Qy 1021 CTGGCGAATGCAGTAAAAGCGCGTCGCGGGTAA 1053
|||||||||||||||||||||||||||||||||
Db 1527 CTGGCGAATGCAGTAAAAGCGCGTCGCGGGTAA 1559