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
Claims 1-38 are pending.
Election/Restrictions
Applicant’s election of species Formula la, Formula lb, Formula lc, Formula ld, R1 and R2 as OH, first and second bases as uracil, uridine phosphorylase, and YeiN in the reply filed on 06/10/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 5 and 12-28 arevwithdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Claims 1-4, 6-11, and 29-38 are examined.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 06/26/2024 is acknowledged and has been considered.
Drawings
The drawings are objected to because “FIGURE” should be replaced with “FIG.”. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: “Figure” on pages 6-7, 27-29, and 31 should be replaced with “FIG.”
Appropriate correction is required.
Claim Objections
Claims 10 and 32 are objected to because of the following informalities:
In claim 10, “the first and second base” should be replaced with “the first and second bases”.
In claim 32, “deoB” should be replaced with “DeoB”.
Appropriate correction is required.
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 29, 31-32, and 34 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
Claim 29 recites the broad recitation “the nucleoside phosphorylase comprises an enzyme selected from purine-nucleoside phosphorylase, pyrimidine nucleoside phosphorylase, thymidine phosphorylase, uridine phosphorylase and guanosine phosphorylase”, and the claim also recites “preferably the nucleoside phosphorylase comprises an enzyme selected from pyrimidine-nucleoside phosphorylase, thymidine phosphorylase and uridine phosphorylase” which is the narrower statement of the range/limitation.
Claim 31 recites the broad recitation “the nucleoside 5' -phosphate C-glycosidase comprises pseudouridylate synthase”, and the claim also recites “optionally wherein the pseudouridylate synthase is selected from YeiN, SdmA, and AlnA” which is the narrower statement of the range/limitation.
Claim 32 recites the broad recitation “the phosphomutase comprises a phosphopentomutase”, and the claim also recites “optionally the phosphpentomutase comprises deoB phosphopentomutase” which is the narrower statement of the range/limitation.
Claim 34 recites “source of phosphate comprises compound selected from soluble alkaline or alkaline earth metal phosphates”, and the claim also recites “optionally wherein the source of phosphate comprises a compound selected from sodium dihydrogen phosphate, trisodium phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, potassium hydrogen phosphate, a potassium phosphate buffer of about pH 7, and a potassium phosphate buffer of about pH 8” which is the narrower statement of the range/limitation.
The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 6-11, and 29-37 are rejected under 35 U.S.C. 103 as being unpatentable over Yao (CN113403356A, published 09/17/2021, reference is herein made to text in the corresponding English language machine translated application; see attached copy) in view of Novick (US 2020/0010823 A1, published 01/09/2020) and Pfeiffer (Nature Communications 11.1 (2020): 6270).
Regarding claims 1, 3-4, 6-8, 10-11, 29-32, and 34, Yao teaches reacting uridine (i.e., N-nucleoside, Formula Ia with R1 OH and base uracil) with uridine phosphorylase (i.e., nucleoside phosphorylase) and potassium dihydrogen phosphate to produce ribose-1-phosphate (i.e., pentose-1-phosphate, Formula Ib) (page 2 para. 2, 3 and 8, Example 4). Yao does not teach reacting ribose-1-phosphate with a phosphomutase to form a pentose-5-phosphate.
However, Novick teaches that phosphopentomutase enzyme (i.e., phosphomutase) catalyzes the isomerization of ribose 1-phosphate to ribose 5-phosphate (i.e., pentose-5-phosphate, Formula Ic) ([0039]).
Yao and Novick do not teach reacting ribose-5-phosphate with a second base in the presence of a nucleoside-5' -monophosphate C-glycosidase to form the C-nucleoside-5 '-monophosphate.
However, Pfeiffer teaches reacting ribose 5-phosphate with uracil and YeiN (i.e., nucleoside-5' -monophosphate C glycosidase) to form pseudouridine-5'-monophosphate (i.e., C-nucleoside-5 '-monophosphate, Formula Id) (Abstract, Fig.1c-d, Fig. 2, page 3 left column para. 2).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify Yao’s method by reacting the produced ribose-1-phosphate with a phosphopentomutase in order to produce ribose 5-phosphate, and to react the latter with uracil and YeiN in order to produce pseudouridine-5'-monophosphate, as suggested by Novick and Pfeiffer. One of ordinary skill in the art would be motivated to do so in order to produce pseudouridine-5'-monophosphate. Since Novick teaches a desire to enzymatically catalyze ribose 5-phosphate from ribose 1-phosphate, and since Pfeiffer teaches that ribose 5-phosphate can be enzymatically catalyzed to form pseudouridine-5'-monophosphate, there is a reasonable expectation of success.
Regarding claim 2, Yao, Novick, and Pfeiffer do not teach steps a, b, c are performed as one-pot reaction. However, it would be obvious to one of ordinary skill in the art to add the enzymes in one-pot reaction in order to simplify and speed up the process. Since step b requires the product of step a, and since step c requires the product of step b, the simultaneous addition of the enzymes would not impede the activity of the enzymes. Pfeiffer teaches successfully performing one pot reaction of enzymatic synthesis of pseudouridine-5'-monophosphate using YeiN, a kinase, and a phosphatase (Fig. 1). Selection of any order of mixing ingredients is prima facie obvious. See MPEP 2144.04(IV)(C).
Regarding claim 9, Yao teaches that uridine phosphorylase catalyzes the conversion of uridine to ribose-1 phosphate. The reaction also produces uracil as a second product. Pfeiffer teaches YeiN converts ribose 5-phosphate with uracil to form pseudouridine-5'-monophosphate.
Regarding claim 33, Pfeiffer teaches treating pseudouridine-5'-monophosphate with CIP, calf intestine phosphatase (i.e., alkaline phosphatase) (Fig. 1d).
Regarding claim 35, Yao teaches that the reaction was performed at 37oC (Example 4). Novick teaches that the phosphopentomutase was incubated at 35oC and at 40oC ([0203], [0217]). Pfeiffer teaches that the reaction was performed at 37oC (page 10 “Synthesis of ΨMP derivatives”). One of ordinary skill in the art would be motivated to optimize the incubation temperature of the phosphopentomutase in order to optimize the activity of the enzyme and the yield of the reaction.
Regarding claim 36, Pfeiffer teaches purifying pseudouridine-5'-monophosphate using HPLC (Supplementary Figure 35).
Regarding claim 37, Pfeiffer teaches using 15 µM YeiN which equals to about 0.4 mg/ml (YeiN’s molecular weight is equal to about 32,980 Da or 32980 g/mol).
Claim 38 is rejected under 35 U.S.C. 103 as being unpatentable over Yao, Novick, and Pfeiffer as applied to claim 1 above, and further in view of Rinaldi (Bioresource Technology 307 (2020): 123258).
Regarding claim 38, Yao, Novick, and Pfeiffer do not teach the enzymes are immobilized.
However, Rinaldi teaches immobilizing uridine phosphorylase in a reactor in order to synthesize pharmaceutically relevant nucleoside analogues (Title, Abstract). Rinaldi teaches that the immobilization of the enzyme to a solid support allows its stabilization and the reuse of the biocatalyst for multiple cycles (Introduction).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to further modify Yao’s method by immobilizing the enzymes as suggested by Rinaldi. One of ordinary skill in the art would be motivated to do so in order to increase the stability of the enzymes as suggested by Rinaldi. Since Yao and Rinaldi teach a desire to use uridine phosphorylase to synthesize nucleoside analogues, there in a reasonable expectation of success.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY A CRUM whose telephone number is (571)272-1661. The examiner can normally be reached M-F 8:00-5:00 CT with alternate Fridays off.
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/MARY A CRUM/Examiner, Art Unit 1657
/THANE UNDERDAHL/Primary Examiner, Art Unit 1699
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