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
2. This Office Action is responsive to Applicant’s Amendment and Remarks, filed December 19, 2025. The amendment, filed December 19, 2025, is entered, wherein claims 1, 7, 30, 55, and 60 are amended, claims 65 – 73 are new, and claims 2 – 6, 10 – 21, 23 – 28, 31 – 54, 56, 59, and 61 – 64 are canceled.
Claims 1, 7 – 9, 22, 29 – 30, 55, 57 – 58, 60, and 65 – 73 are pending in this application and are currently examined.
Priority
This application is a national stage application of PCT/US21/48488, filed August 31, 2021, which claim benefit of domestic application 63/072,369, filed August 31, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/19/2025 was filed after the mailing date of the previous Office Action on August 19, 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Rejections
5. The rejection of claims 1 – 12, 22, 32, 55, 57 – 58, and 60 in the previous Office Action, mailed August 19, 2025, under 35 U.S.C. 102(a)(1) as being anticipated by Painter et al. has been considered and is withdrawn in view of the amended claim 1.
The rejection of claims 1 – 12, 22, 32 and 57 in the previous Office Action, mailed August 19, 2025, on the ground of nonstatutory double patenting as being unpatentable over claim 2 of copending Application No. 16/979,108 has been considered and is withdrawn because ‘108 is abandoned.
The rejection of claims 1 – 12, 22, 32 and 57 in the previous Office Action, mailed August 19, 2025, on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of U.S. Patent No. 11192914B2 has been considered and is withdrawn in view of the amended claim 1.
The following are maintained / modified grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed December 19, 2025, wherein claims 1, 7, 30, 55, and 60 are amended, claims 65 – 73 are new, and claims 2 – 6, 10 – 21, 23 – 28, 31 – 54, 56, 59, and 61 – 64 are canceled. Previously cited references have been used to establish the maintained / modified grounds of rejection.
Modified / New 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:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. 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.
Claims 1, 7 – 9, 22, 55, 57 – 58, 60, 65 – 70, and 73 are rejected under 35 U.S.C. 103 as being unpatentable over Painter et al. (WO2017/155923A1, cited in the previous Office Action).
a. Regarding Claims 1, 7 – 9, 22, 55, 57 – 58, 60, 65 – 70, and 73, Painter et al. teach inventions related to nucleoside and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer (Abstract). Painter et al. teach nucleosides conjugated to a phosphorus moiety or pharmaceutically acceptable salts thereof. The compound has a structure of Formula I (page 16, lines 4 – 8):
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Painter et al. teach an exemplary compound (page 72, line 5):
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which reads on the limitations R1 is hydrogen; R2 is methyl; U, V, W, X are oxygen; R3 and R4 are hydrogen; R5 and R6 are hydroxyl; R7 is optionally substituted alkyl; and R8 is hydrogen of claim 1. Painter et al. teach that R1 is
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wherein Y is O and Y2 is OH (page 16, lines 5 – 18; page 17, lines 3 – 18). Painter et al. teach that optically active materials can be obtained using first- and second-order asymmetric transformations. This is a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all material is converted to the crystalline diastereomer from the desired enantiomer (page 126, lines 16 – 17; page 127, lines 1 – 5). In certain embodiments, the pharmaceutical compositions comprising any of the compounds disclosed and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is in the form of a capsule (page 3, lines 20 – 24). Furthermore, the disclosure relates to a method of treating cancer comprising administering an effective amount of the pharmaceutical composition disclosed to subjects in need thereof (page 9, lines 1 – 3), wherein the cancers are breast cancer, colorectum cancer, and cancer of the bile duct (page 118, lines 20 – 24). The compounds can be administered orally or intravenously (page 122, lines 31 – 32).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the exemplary compound containing the triphosphate as taught by Painter et al. for the substitution of the monophosphate because Painter et al. teach that R1 may be a monophosphate:
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wherein Y is O and Y2 is OH. One would have been motivated to modify the exemplary compound containing the triphosphate as taught by Painter et al. for the substitution of the monophosphate because the substitution is known in the art and would yield compound with predictable effect, which is the anticancer bioactivity. One of the ordinary skill in the art would have had a reasonable expectation of success to modify the exemplary compound containing the triphosphate as taught by Painter et al. for the substitution of the monophosphate because Painter et al. teach the exemplary compound and disclose that monophosphate may be the alternative moiety at the R1 position, thereby, the substitution yield predictable results.
Claims 1 and 29 – 30 are rejected under 35 U.S.C. 103 as being unpatentable over Chidgeavadze et al. (Bioorganicheskaya Khimiya, 1991, Vol. 17, Issue 5, page 678 – 684, cited in the previous Office Action) in view of Brown (Wiley-Vch, Cop, 2012, cited in the previous Office Action).
Regarding claims 1 and 29 – 30, Chidgeavadze et al. teach compound X:
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wherein R1 is PO3H2 and R2 is H (page 679).
However, Chidgeavadze et al. do not teach the -CF in
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Brown teaches that the classical bioisosteres of -CH3 is -F. Due to the high strength of the C-F bond, fluorine is often introduced to achieve metabolic stability (page 17, 2.3.1 Monovalent Atoms and Groups, para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the -CH3 in Thy as taught by Chidgeavadze et al. with -F in view of Brown because Brown teaches that -F is a classical bioisosteres of -CH3. Such substitution will yield predictable results. One would also have been motivated to substitute the -CH3 in Thy as taught by Chidgeavadze et al. with -F in view of Brown because Brown teaches that such replacement with fluorine will enhance the metabolic stability. Therefore, a person of ordinary skill in the art would have had a reasonable expectation of success to substitute the -CH3 in Thy as taught by Chidgeavadze et al. with -F in view of Brown because Chidgeavadze et al. teach the very similar structure and Brown teaches that substitution of -CH3 with -F is known in the art, which yields predictable results.
Claims 1 and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Painter et al. (WO2017/155923A1, cited in the previous Office Action) in view of Brown (Wiley-Vch, Cop, 2012, cited in the previous Office Action).
c. Regarding claims 1 and 71, Painter et al. teach inventions related to nucleoside and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer (Abstract). Painter et al. teach nucleosides conjugated to a phosphorus moiety or pharmaceutically acceptable salts thereof. The compound has a structure of Formula I:
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wherein U is O; X is OCHF; R is OH; W is CR7, wherein R7 is fluoro; Z is CR8, wherein R8 is H; and R1 is
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wherein Y is O and Y2 is OH (page 16, lines 5 – 18; page 17, lines 3 – 18).
However, Painter et al. do not teach that R2 of the compound of Formula I is -CF3.
Brown teaches that the bioisostere of F is -CF3 (page 23, 2.4.5 Halogens).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the F of OCHF as taught by Painter et al. with -CF3 in view of Brown because Brown teaches that -CF3 is a bioisostere of -F and such substitution will yield predictable results. One would have been motivated to substitute the F of OCHF as taught by Painter et al. with -CF3 in view of Brown because Painter et al. explicitly teach that the substituent X can be varied and Brown teaches that the substitution of F with CF3 is well known bioisosteric modification used to achieve similar or predictable changes in physiochemical properties. Therefore, a person of ordinary skill in the art would have had a reasonable expectation of success to substitute the F of OCHF as taught by Painter et al. with -CF3 in view of Brown because Painter et al. teach the very similar structure and Brown teaches that substitution of F with -CF3 is known in the art, which yields predictable results.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed December 19, 2025, have been considered and are found to be not persuasive.
Regarding the rejection over Chidgeavadze et al. in view of Brown, Applicant argues that there is no compound recited in Chideavadze et al. or Brown having a structure of Formula I as described in amended claim 1 because Brown does not report that fluorine is a bioisostere for a methyl group. However, the argument is not persuasive because Brown clearly identifies bioisosteric relationship of fluorine and methyl in the disclosure (page 17, 2.3.1 Monovalent Atoms and Groups):
[AltContent: oval][AltContent: oval]
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In addition, Bhatia et al. indicate the [AltContent: oval]same idea based on Grimm’s hydride displacement law (page 275, Table 1):
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wherein each vertical column represent a group of isosteres (page 275, para. 1). The bioisosteric relationship of fluorine and methyl is also disclosed under classical bioisosteres (page 277, Table 1):
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which teaches that F is a bioisosteres of CH3. Therefore, it is confirmed that the bioisosteric relationship exists between F and CH3.
Regarding unexpected results, Applicant argues that the claimed compounds exhibit unexpected activity based on the computational modeling and hTS inhibition data reported in Examples 13 and 14, which demonstrate that substitution at the 5’position on one side does not perturb binding to hTS, whereas substitution on the opposite site would result in inactivity, for example, 5’-S-methyl FdUMP and 5’-gem-dimethyl FdUMP, both having a methyl group at the R1 position require a larger binding energy to hTS than FdUMP and 5’-R-methyl FdUMP. Applicant further argues that these results show a link between the 5’-substitution pattern and activity. However, the argument is not persuasive because the results are not commensurate in scope with the claims. The claims encompass a broad genus of compounds and substituents alternatives. The limited number of exemplified derivatives evaluated does not establish any assertion of unexpected property across the full scope of the claims. Moreover, the results are actually consistent with expected steric and conformational effects. Applicant explains that certain substituents at the 5’position lead to steric clashes and conformational changes that reduce activity. However, it is well understood in the art that different stereochemical orientations may affect the bioactivity of a drug. The different activity based on stereochemistry does not establish unexpected results, it only shows routine structure-activity relationships that a person of ordinary skill in the art would have anticipated.
New 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, 7 – 9, 22, 57, and 70 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of U.S. Patent No. 11192914B2.
a. Regarding claims 1, 7 – 9, 22, 57, and 70, ‘914B2 teaches a compound of Formula XXXIX:
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wherein X is OCHMe; W is CR7, wherein R7 is fluoro; R1 is
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wherein Y is O and Y2 are OH (claim 1). ‘914B2 teaches a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier (claim 5).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the compound of Formula XXXIX by selecting X = OCHMe; W = CR7, wherein R7 = fluoro; Y = O, and Y2 = OH from the alternatives disclosed in ‘914B2 to arrive at the claimed compound because ‘914B2 explicitly teaches that these substituents are suitable options within the disclosed genus for the achieving the same function. It would have been obvious to do this because such modification is selected among known alternatives. One of the ordinary skill in the art would have had a reasonable expectation of success to modify the compound of Formula XXXIX by selecting X = OCHMe; W = CR7, wherein R7 = fluoro; Y = O, and Y2 = OH from the alternatives disclosed in ‘914B2 to arrive at the claimed compound because ‘914B2 teaches that compounds within the disclosed genus perform the same function, and the modification yields predictable results.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed December 19, 2025, have been fully considered and are found to be not persuasive.
Regarding ‘914B2, Applicant argues that example 14 clearly shows a link between the 5’-substitution pattern and activity. The arguments regarding unexpected results are addressed above. Applicant further argues that ‘914B2 does not focus on inhibitors selective against hTS. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., hTS inhibition) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Claims 1, 7 – 9, 29, 55, 57 – 58, 70, and 73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/258,216 in view of Painter et al. (WO2017/155923A1, cited in the previous Office Action).
b. Regarding claims 1, 7 – 9, 29, 55, 57 – 58, 70, and 73, ‘216 teaches a compound of Formula Ia for treating viral infection (claim 1 and Title):
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wherein U is O; X is CD2; R1 is monophosphate; R2, R3, and R5 are H; R6 is C1 alkyl substituted with R9, wherein R9 is halogen; R4 and R7 are OH; and Q is
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However, ‘216 does not teach R2 is methyl. ‘216 does not teach the compound is greater than 98% diastereomeric or enantiomeric excess. ‘216 does not teach a pharmaceutical formulation of the claimed compound further comprises a pharmaceutically acceptable excipient and wherein the formulation is an oral formulation and is in the form of capsule.
Painter et al. teach inventions related to nucleoside and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer (Abstract). Painter et al. teach nucleosides conjugated to a phosphorus moiety or pharmaceutically acceptable salts thereof. The compound has a structure of Formula I (page 16, lines 4 – 8):
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Painter et al. teach an exemplary compound (page 72, line 5):
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which reads on the limitations R1 is hydrogen; R2 is methyl; U, V, W, X are oxygen; R3 and R4 are hydrogen; R5 and R6 are hydroxyl; R7 is optionally substituted alkyl; and R8 is hydrogen of claim 1. Painter et al. teach that R1 is
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wherein Y is O and Y2 is OH (page 16, lines 5 – 18; page 17, lines 3 – 18). Painter et al. further disclose X may be OCD2 (page 16, line 12). Painter et al. teach that optically active materials can be obtained using first- and second-order asymmetric transformations. This is a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all material is converted to the crystalline diastereomer from the desired enantiomer (page 126, lines 16 – 17; page 127, lines 1 – 5). In certain embodiments, the pharmaceutical compositions comprising any of the compounds disclosed and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is in the form of a capsule (page 3, lines 20 – 24).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the CH2 at X position as taught by ‘216 with CHMe in view of Painter et al. because both ‘216 and Painter et al. teach the same compound by selecting the alternatives in the disclosed genus and Painter et al. also disclose that OCHMe is the alternative of OCD2. One would have been motivated to substitute the CH2 at X position as taught by ‘216 with CHMe in view of Painter et al. because both ‘216 and Painter et al. teach compounds for treating viral infection and Painter et al. also disclose that OCHMe is the alternative of OCD2. One of the ordinary skill in the art would have had a reasonable expectation of success to substitute the CH2 at X position as taught by ‘216 with CHMe in view of Painter et al. because both ‘216 and Painter et al. teach the compounds with the same substituents and Painter et al. further teach that OCHMe is the alternative of OCD2.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is found to be allowable.
THIS ACTION IS MADE NON-FINAL.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693