DETAILED ACTION
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 February 4, 2026. The amendment, filed February 4, 2026, is entered, wherein claim 23 is amended, claims 1 – 18 are canceled, and claims 24 – 33 are new.
Claims 19 – 33 are pending in this application and are currently examined.
Priority
3. This application is a national stage application of PCT/US2021/021913, filed March 11, 2021, which claims benefit of domestic application 63/027,198, filed May 19, 2020.
The following are maintained / modified / new grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed February 4, 2026, wherein claim 23 is amended, claims 1 – 18 are canceled, and claims 24 – 33 are new. Previously and newly cited references have been used to establish the maintained / modified / new grounds of rejection.
Maintained / 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 19 – 20 are rejected under 35 U.S.C. 103 as being unpatentable over Bethesda (National Institute of Diabetes and Digestive and Kidney Diseases, 2017, cited in the previous Office Action mailed June 12, 2025) in view of Yano et al. (Bioorganic & Medicinal Chemistry, 2004, Vol. 12, Issue 13, page 3431 – 3411, cited in the previous Office Action mailed October 29, 2025).
a. Regarding claims 19 – 20, Bethesda teaches the structure of tipiracil (page 3):
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Tipiracil is used in combination with trifluridine for inhibiting thymidine phosphorylase (TYMP), thus providing a longer half-life and increased intracellular concentrations of active phosphorylated trifluridine (page 1, para. 2).
However, Bethesda does not teach that the claimed R12 is –(CR13R14)n-R15, wherein n is 0 and R15 is alkyl.
Yano et al. teach a series of novel 6-methylene-bridged uracil derivatives as inhibitors of human TYMP (Abstract). Yano et al. teach that the derivatives have a core structure of:
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wherein R is N-Pyrrolidinyl, X is Cl, and Y is CH3 (page 3434, Left Col., Table 1, Compound 31). The inhibitory effect is reported as an IC50, wherein compound 31 has a IC50 of >100 μM (page 3434, Left Col., Table 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 H (circled) in tipiracil shown below:
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as taught by Bethesda with a methyl group in view of Yano et al. because Bethesda teaches that tipiracil is a potent inhibitor of TYMP and Yano et al. disclose structurally similar analogs of tipiracil, wherein Y is substituted with a methyl group, and the other substituents (X = Cl and R = N-heterocycle) are consistent with the tipiracil scaffold. Although Yano et al. report reduced inhibitory activity of TYMP when Y is methyl, the compound is still disclosed as a member of the same structural class and is tested for the same biological target. One of the ordinary skill in the art would have been motivated to substitute the H (circled) in tipiracil shown below:
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as taught by Bethesda with a methyl group in view of Yano et al. because methylation is a common modification in medicinal chemistry to explore structure-activity relationships and metabolic stability. One would have performed routine experimentation to discover the best substituent for the optimal TYMP inhibition. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success to substitute the H (circled) in tipiracil shown below:
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as taught by Bethesda with a methyl group in view of Yano et al. because such substitution is expected to produce a compound with similar or somewhat modified biological properties.
Claims 21 – 26 are rejected under 35 U.S.C. 103 as being unpatentable over Bethesda (National Institute of Diabetes and Digestive and Kidney Diseases, 2017, cited in the previous Office Action mailed June 12, 2025) in view of Yano et al. (Bioorganic & Medicinal Chemistry, 2004, Vol. 12, Issue 13, page 3431 – 3411, cited in the previous Office Action mailed October 29, 2025) as applied to claims 19 – 20 above, and further in view of Focher et al. (Journal of Medicinal Chemistry, 2000, Vol. 43, Issue 13, page 2601 – 2607, cited in the previous Office Action mailed October 29, 2025).
b. Regarding claims 21 – 26, Bethesda and Yano et al. teach the limitation discussed above.
However, these references do not teach that the claimed R12 are –(CH2)2OCH3, –(CH2)2OH, –(CH2)3OH, or –(CH2)3OCH3.
Focher et al. teach novel nonsubstrate inhibitors of human thymidine phosphorylase (Title). Focher et al. disclose compounds 18 – 20 with the core structure of
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wherein R1 is (CH2)4C6H5; R2 and R3 are H; and R4 is CH3, (CH2)2OCH3, and (CH2)2OH, respectively. The percentages inhibition of TYMP for compounds 18 – 20 are 25, 30, and 17, respectively (page 2603, Right Col., Table 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 methyl group in the tipiracil analogs as taught by Bethesda and Yano et al. to (CH2)2OCH3 in view of Focher et al. because Focher et al. teach that such substitution increases the TYMP inhibition. One would have been motivated to substitute the methyl group in the tipiracil analogs as taught by Bethesda and Yano et al. to (CH2)2OCH3 in view of Focher et al because of the increased TYMP inhibition. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success because Focher et al. teach that the substitution is known in the art and would yield a compound with improved biological properties.
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 methyl group in the tipiracil analogs as taught by Bethesda and Yano et al. to (CH2)2OH in view of Focher et al. because Focher et al. teach that such substitution increases the TYMP inhibition. One would have been motivated to substitute the methyl group in the tipiracil analogs as taught by Bethesda and Yano et al. to (CH2)2OH in view of Focher et al because of the increased TYMP inhibition. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success because Focher et al. teach that the substitution is known in the art and would yield a compound with improved biological properties.
It would have been prima facie obvious to substitute –(CH2)2OH and –(CH2)2OCH3 of the 6-aminouracil base analogues as taught by Focher et al. to –(CH2)3OH, and –(CH2)3OCH3, respectively, because it has long been established that this type of difference, which is varying the size of a chain, constitutes a form of homology, and is a fact of very close structural similarity, rending the homolog obvious. As was stated in In re Grose, 201 USPZ 57, 63, “The known structural relationship between adjacent homologues, for example, supplies a chemical theory upon which a prima facie case of obviousness of a compound may rest.” See specifically In re Shetty, 195 USPQ 753; In re Wilder, 195 USPQ 426 and Ex Parte Greshem, 121 USPQ 422, all of which feature a compound with a C2 link rejected over a compound with a C1 link. Similarly, In re Chupp, 2 USPQ2d 1437 and In re Coes, 81 USPQ 369 have a compound with a C1 link unpatentable over prior art showing C2 link. Note Ex parte Agouridas, 65 USPQ2d 1142, where a C4 chain was held obvious over a C3 chain. Note also In re Schaub, 190 USPQ 324, 326, where compounds with C5 and C6 chains were called “adjacent homologs in the classic sense”. Ex parte Ruddy, 121 USPQ 427 has a C3 link unpatentable over a C1 link. Ex parte Nathan, 121 USPQ 349 found the insertion of a C2H4 link obvious. In all of these cases, the variation was found to be obvious on the basis of close structural similarity; no secondary teaching was employed. As was stated directly in THE GENERAL TIRE & RUBBER COMPANY v. JEFFERSON CHEMICAL COMPANY, INC., 182 USPQ 70 (1974): “If any structural change is obvious to one skilled in the art, a substitution of the next higher homolog would seem to be.” Note also In re Jones, 21 USPQ2d 1942, which states at 1943 “Particular types or categories of structural similarity without more, have, in past cases, given rise to prima facie obviousness”; one of those listed is “adjacent homologues and structural isomers”. Similar is In re Schechter and LaForge, 98 USPQ 144, 150, which states “a novel useful chemical compound which is homologous or isomeric with compounds of the prior art is unpatentable unless it possesses some unobvious or unexpected beneficial property not possessed by the prior art compounds.” Note also In re Deuel, 34 USPQ2d 1210, 1214 which states, “Structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its homologs because homologs often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved properties.” Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to substitute –(CH2)2OH and –(CH2)2OCH3 of the 6-aminouracil base analogues as taught by Focher et al. to –(CH2)3OH, and –(CH2)3OCH3, respectively, because it is known in the art that homologs often have similar properties and the result is predictable.
Claims 27 – 28 are rejected under 35 U.S.C. 103 as being unpatentable over Bethesda (National Institute of Diabetes and Digestive and Kidney Diseases, 2017, cited in the previous Office Action mailed June 12, 2025) in view of Yano et al. (Bioorganic & Medicinal Chemistry, 2004, Vol. 12, Issue 13, page 3431 – 3411, cited in the previous Office Action mailed October 29, 2025) and Focher et al. (Journal of Medicinal Chemistry, 2000, Vol. 43, Issue 13, page 2601 – 2607, cited in the previous Office Action mailed October 29, 2025) as applied to claims 19 – 26 above, and further in view of Brown (Wiley-Vch, Cop, 2012, Reference included with PTO-892).
c. Regarding claims 27 – 28, the references teach the limitation discussed above.
However, these references do not teach R12 are –(CH2)2NH2 or –(CH2)2N(CH3)2.
Brown teaches that amino group is a classical bioisostere of -OH and -CH3 is classical bioisostere of hydrogen (page 17, 2.3.1 Monovalent Atoms and Groups).
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 hydroxyl group in –(CH2)2OH as taught by Yano et al. with an amino group in view of Brown because Brown teaches that amino group is a classical bioisostere of hydroxyl group. This substitution will yield to predictable results. It would also have been prima facie obvious for a person of ordinary skill in the art to substitute the modified R12 with –(CH2)2NH2 as taught by Yano et al. and Brown and further modify it to –(CH2)2N(CH3)2 because Brown teaches that methyl group is a common bioisostere of hydrogen. Such substitution will yield to predictable results. One of ordinary skill in the art would have had a reasonable expectation of success to substitute the hydroxyl group in –(CH2)2OH as taught by Yano et al. with an amino group in view of Brown and further modify it to –(CH2)2N(CH3)2 because the substitutions are known in the art for yielding similar properties and predictable results.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed February 4, 2026, have been fully considered and are found to be not persuasive.
Regarding Yano et al., Applicant argues that the teaching of Yano et al. is to modify the tipiracil of Bethesda away from its (2-iminopyrrolidine-1-yl)methyl group at the 6-position of the thymine-like ring for achieving a reasonable pharmacokinetic profile of trifluridine of Bethesda and an ability of increasing plasma concentration of trifluridine of Bethesda because Yano et al. states that the best compound is compound 42:
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wherein X is iodine (page 3433, Scheme 4).
Regarding Focher et al., Applicant argues that no compound in Focher et al. has the (2-iminopyrrolidine-1-yl)methyl group at the 6-position of the thymine-like ring and most compounds have a bridging secondary amine at the 6-position.
Applicant concludes that the only compound in Bethesda, Yano et al., and Focher et al. with the (2-iminopyrrolidine-1-yl)methyl group at the 6-position is tipiracil, and not a single other compound contains this group. Thus, Yano et al. and Focher et al. teach one of ordinary skill in the art to have other substituents at the 6-position of the thymine-like ring for improving the effectiveness of the trifluridine of Bethesda.
However, these arguments are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Instead of relying on Yano et al. or Focher et al. alone to disclose the claimed compounds, the rejection is based on the combination of Bethesda, Yano et al., and Focher et al. for the achieving the claimed compound as well as for providing motivation. Bethesda teaches the tipiracil, which includes the (2-iminopyrrolidine-1-yl)methyl group at the 6-position of the thymine-like ring, while Yano et al. and Focher et al. are relied upon for the teachings of modifying the R12 substituent, Obviousness does not require a single reference disclose the exact claimed combination, but only that the prior art as a whole would have suggested the claimed subject matter to a person of ordinary skill in the art. Also, Yano et al. do not teach away from the claimed compounds because a reference teaches away only when it criticizes, discredits, or otherwise discourages the claimed modification. Yano et al. investigates alternative substituents and identifies certain compounds as preferred for particular biological or pharmacokinetic properties. The disclosure of alternative or preferred substituents does not amount to a teaching away from having the (2-iminopyrrolidine-1-yl)methyl group while modifying the substituent at other position of the ring. Furthermore, the fact that a reference investigates on one region of a molecule more than another does not mean that other positions would have been excluded from routine modification by one of ordinary skill in the art. The combination of Bethesda, Yano et al., and Focher et al. yields the claimed compound because Bethesda teaches the tipiracil with the (2-iminopyrrolidine-1-yl)methyl group while Yano et al. and Focher et al. teach the closely related TYMP inhibitor analogs derived from tipiracil. It would have been obvious to modify the substituents based on the examples disclosed by Yano et al. and Focher et al. while retaining the known beneficial substituents, such as the (2-iminopyrrolidine-1-yl)methyl group. Finally, the claims are directed to compounds and do not require any particular level of TYMP inhibition, pharmacokinetic profile, or superiority over tipiracil.
Allowable Subject Matter
Claims 29 – 33 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
Claims 29 – 33 have been indicated as being allowable or as containing allowable subject matter because claims 29 – 33 require the recitations of “–(CH2)2CO2CH3”, “–(CH2)3CO2CH3”, “–(CH2)4CO2CH3”, “–(CH2)2NHCO2H3”, and “–(CH2)2NHCO2CH3”. There is no available prior art that teaches these subject matter.
Conclusion
Applicant's amendment necessitated the maintained / modified / new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693