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 . Claims 1-6, 14-16, 18-20, 22-23, 25, 27, 31, 35, 48 and 54 filed May 24, 2023 are currently pending. Claims 1 ,48 and 54 are independent.
Election/Restrictions
Applicant's election with traverse of Group (II), claims 1-6, 14-16, 18-20, 22-23, 25, 27, 31, 35 and 54 in the reply filed on 12/31/2025 is acknowledged. The traversal is on the ground(s) that there is no undue search burden to search the inventions of Groups (I) and (II). This argument has been considered but is not found persuasive as such argument does not apply when restriction is required under 35 USC 121 and 372, as in the instantly filed application. Thus, when the Office considers international applications as an International Searching Authority, as an International Preliminary Examining Authority, and during the national stage as a Designated or Elected Office under 35 U.S.C. 371, only PCT Rule 13.1 and 13.2 will be followed when considering unity of invention of claims of different categories without regard to the practice in national applications filed under 35 U.S.C. 111. Thus, it is maintained that the technical feature linking the inventions of Groups I-II does not constitute a special technical feature as defined by PCT Rule 13.2 and does not define a contribution over the prior art for the reasons of record. The requirement is still deemed proper and is therefore made FINAL.
Claim 48 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/31/2025.
Secondly, Applicant’s election without specifying traverse of compound T25 as the species of Formula (I) and hand-foot syndrome as the species of disease or disorder associated with the administration of a chemotherapeutic drug in the reply filed on 12/31/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the species election, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claim 5 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/31/2025.
Priority
Acknowledgement is made of the national stage entry of PCT/CN2021/127683 filed 10/29/2021 which claims foreign priority to Application 202011192954.9 filed 10/30/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/17/2024 and 07/14/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112-Paragraph B
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 2-4, 6, 14-16 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 2 is directed to the methodology of claim 1 wherein the thymidine derivative comprises a structure of Formula (I) or a pharmaceutically acceptable salt, solvent, hydrate, prodrug and stereoisomer thereof.
The claims embrace “a pharmaceutically acceptable solvent of Formula (I)”. The metes and bounds of the claim are unclear as compounds of Formula (I) are not pharmaceutically acceptable solvents but rather are synthetic nucleosides. It is unclear of the structural requirements to arrive at a pharmaceutically acceptable solvent of Formula (I). Accordingly, one of ordinary skill in the art prior to the time of the invention would not have been reasonably apprised of the metes and bounds of the subject matter for which Applicant was presently seeking protection.
For the purposes of examination, the examiner has interpreted the phrase “solvent” to read as “solvate” and subsequent examination is based on this interpretation.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-4, 14-16, 18, 27, 31, 35 and 54 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Romantsev (WO2020/226889 published 11/12/2020 with priority U.S. Provisional 62844464 filed 05/07/2019).
Claim interpretation is as follows: Claim 1 is directed to the prevention or treatment of a disease or disorder associated with administration of a chemotherapeutic drug in a subject comprising administering a thymidine derivative to said subject wherein at least one hydroxyl hydrogen of a deoxyribose in said thymidine derivative is substituted. As recited in MPEP 2111.03, the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). In the present case, the pending methodology is open-ended and does not exclude additional unrecited elements such as uridine triacetate.
Romantsev (WO2020/226889 published 11/12/2020 with priority U.S. Provisional 62844464 filed 05/07/2019) is directed to the treatment cutaneous toxicity such as hand-foot syndrome derived from chemotherapeutic agents 5-fluorouracil (5-FU) or capecitabine comprising administering a therapeutically effective amount of uridine triacetate and thymidine diacetate (page 8 line 20 to page 9 line 30, claims 1, 5-9, 33-36).
PNG
media_image1.png
675
539
media_image1.png
Greyscale
As evidenced by CAS REGISTRY DATABASE shown above, thymidine diacetate comprises the following structural limitations of Formula (II): R3-R6 are each independently H, R2 and R7 are each -O-R1 wherein R1 comprises M1 as O and R8 is a unsubstituted C1-C5 alkyl.
PNG
media_image2.png
218
150
media_image2.png
Greyscale
Thymidine diacetate of Romantsev also reads on compound T1 found in claim 18. Romantsev teaches that 5-FU treatments with capecitabine cause cutaneous toxicity including hand-foot syndrome. Romantsev teaches that 5FU toxicity is mediated via two primary mechanisms. 5FU is anabolized to form intracellular fluorouridine nucleotides which cause cytotoxicity by interfering with normal uridine nucleotide metabolism. Fluorodeoxyuridine monophosphate (FdUMP) inhibits thymidylate synthase (TS), the enzyme that produces thymidine from deoxyuridine as a precursor for DNA replication or repair. Fluorouridine triphosphate is misincorporated into RNA, causing cell death. Uridine derived from uridine triacetate can augment intracellular uridine triphosphate (UTP) concentrations; UTP competes with FUTP, reducing its incorporation into RNA and thereby reducing its cytotoxicity. Exogenous thymidine can bypass the blockade of TS by FdUMP by being directly converted to thymidine monophosphate, counteracting toxicity of 5FU or capecitabine mediated by inhibition of TS. As is the case with uridine triacetate, acetylation of thymidine improves its transport across biomembranes and through the epidermis and mucosal epithelium. Romantsev further teaches that in topical formulations for either mucositis or for cutaneous toxicities of 5FU, thymidine diacetate is included with uridine triacetate. Relatively small amounts of thymidine diacetate are sufficient to bypass and compensate for thymidylate synthase inhibition by 5FU, versus the higher amounts of uridine triacetate required to compete with 5FU for misincorporation into RNA. (page 8 line 20 to page 9 line 30).
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.
Claim(s) 1-4, 14-16, 18, 27, 31, 35 and 54 is/are rejected under 35 U.S.C. 103 as being unpatentable over Romantsev (WO2020/226889 published 11/12/2020 with priority U.S. Provisional 62844464 filed 05/07/2019).
Romantsev (WO2020/226889 published 11/12/2020 with priority U.S. Provisional 62844464 filed 05/07/2019) is directed to the treatment cutaneous toxicity such as hand-foot syndrome derived from chemotherapeutic agents 5-fluorouracil (5-FU) or capecitabine comprising administering a therapeutically effective amount of uridine triacetate and thymidine diacetate (page 8 line 20 to page 9 line 30, claims 1, 5-9, 33-36).
PNG
media_image1.png
675
539
media_image1.png
Greyscale
As evidenced by CAS REGISTRY DATABASE shown above, thymidine diacetate comprises the following structural limitations of Formula (II): R3-R6 are each independently H, R2 and R7 are each -O-R1 wherein R1 comprises M1 as O and R8 is a unsubstituted C1-C5 alkyl.
PNG
media_image2.png
218
150
media_image2.png
Greyscale
Thymidine diacetate of Romantsev also reads on compound T1 found in claim 18. Romantsev teaches that 5-FU treatments with capecitabine cause cutaneous toxicity such as hand-foot syndrome. Romantsev teaches that 5FU toxicity is mediated via two primary mechanisms. 5FU is anabolized to form intracellular fluorouridine nucleotides which cause cytotoxicity by interfering with normal uridine nucleotide metabolism. Fluorodeoxyuridine monophosphate (FdUMP) inhibits thymidylate synthase (TS), the enzyme that produces thymidine from deoxyuridine as a precursor for DNA replication or repair. Fluorouridine triphosphate is misincorporated into RNA, causing cell death. Uridine derived from uridine triacetate can augment intracellular uridine triphosphate (UTP) concentrations; UTP competes with FUTP, reducing its incorporation into RNA and thereby reducing its cytotoxicity. Exogenous thymidine can bypass the blockade of TS by FdUMP by being directly converted to thymidine monophosphate, counteracting toxicity of 5FU or capecitabine mediated by inhibition of TS. As is the case with uridine triacetate, acetylation of thymidine improves its transport across biomembranes and through the epidermis and mucosal epithelium. Romantsev further teaches that in topical formulations for either mucositis or for cutaneous toxicities of 5FU, thymidine diacetate is included with uridine triacetate. Relatively small amounts of thymidine diacetate are sufficient to bypass and compensate for thymidylate synthase inhibition by 5FU, versus the higher amounts of uridine triacetate required to compete with 5FU for misincorporation into RNA (page 8 line 20 to page 9 line 30).
Therefore, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to treat a subject comprising the 5-FU and capecitabine mediated cutaneous toxicity of hand-foot syndrome comprising administering a composition comprising thymidine diacetate in combination with uridine triacetate in view of Romantsev, arriving at the claimed methodology with a reasonable expectation of success.
Applicant is reminded of MPEP 2144.07 wherein the selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). Applicant is also reminded that “[I]t is well settled that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands. Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985).”
In the instant case, Romantsev teaches that for cutaneous toxicities of 5FU, thymidine diacetate is included with uridine triacetate. Relatively small amounts of thymidine diacetate are sufficient to bypass and compensate for thymidylate synthase inhibition by 5FU, versus the higher amounts of uridine triacetate required to compete with 5FU for misincorporation into RNA, thereby inhibiting the pathway of 5-FU mediated toxicity (page 8 line 20 to page 9 line 30, claims 1, 5-9, 33-36). Accordingly, said skilled artisan would have readily predicted that administration of the composition comprising thymidine diacetate and uridine triacetate would have treated 5-FU mediated hand-foot syndrome in the afflicted patient.
Claim(s) 19-20, 22-23 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Romantsev (WO2020/226889 published 11/12/2020 with priority U.S. Provisional 62844464 filed 05/07/2019) as applied to claim(s) 1-4, 14-16, 18, 27, 31, 35 and 54 above, in view of Lacouture (WO2014/160628 published 10/02/2014) and Encinas (Chemical Communications Vol. 20 pages 2572-2574 published 2005).
As disclosed above, Romantsev teaches treating 5-FU and capecitabine mediated hand-foot syndrome in a subject in need comprising administering a therapeutically effective amount of thymidine diacetate in combination with uridine triacetate (page 8 line 20 to page 9 line 30, claims 1, 5-9, 33-36).
Romantsev teaches that 5FU toxicity is mediated via two primary mechanisms. 5FU is anabolized to form intracellular fluorouridine nucleotides which cause cytotoxicity by interfering with normal uridine nucleotide metabolism. Fluorodeoxyuridine monophosphate (FdUMP) inhibits thymidylate synthase (TS), the enzyme that produces thymidine from deoxyuridine as a precursor for DNA replication or repair. Fluorouridine triphosphate is misincorporated into RNA, causing cell death. Uridine derived from uridine triacetate can augment intracellular uridine triphosphate (UTP) concentrations; UTP competes with FUTP, reducing its incorporation into RNA and thereby reducing its cytotoxicity. Exogenous thymidine can bypass the blockade of TS by FdUMP by being directly converted to thymidine monophosphate, counteracting toxicity of 5FU or capecitabine mediated by inhibition of TS.
Romantsev teaches that as is the case with uridine triacetate, esterification of thymidine by acetylation the hydroxyl moieties of thymidine improves its transport across biomembranes and through the epidermis and mucosal epithelium. Romantsev further teaches that in topical formulations for either mucositis or for cutaneous toxicities of 5FU, thymidine diacetate is included with uridine triacetate. Relatively small amounts of thymidine diacetate are sufficient to bypass and compensate for thymidylate synthase inhibition by 5FU, versus the higher amounts of uridine triacetate required to compete with 5FU for misincorporation into RNA. (page 8 line 20 to page 9 line 30).
The difference between the presently claimed methodology and that of Romantsev is that Romantsev does not specifically teach administering a compound of Formula (II).
Lacouture (WO2014/160628 published 10/02/2014) teaches treating hand-foot syndrome in a subject in need (abstract, [0005]-[0006]). Lacouture teaches that patients with hand-foot syndrome comprise significant pain due to blisters or lesions on the skin which negatively affect their quality of life ([0005]-[0006]). Lacouture teaches that since pain is the most important symptom, treatment of said patient with NSAIDs is suggested ([0006], claims 14-16, 31).
Encinas (Chemical Communications Vol. 20 pages 2572-2574 published 2005) teaches compound 1 and 2 (scheme 1). Compounds 1 and 2 of Encinas read on the elected species of Formula (II) T-41 of the present claims.
PNG
media_image3.png
167
331
media_image3.png
Greyscale
PNG
media_image4.png
315
242
media_image4.png
Greyscale
Encinas teaches that compounds 1 and 2 are conjugates comprising the art-recognized NSAID naproxen conjugated to the 5’-position of a thymidine nucleoside via a ester linkage (page 2572 left col.)
Therefore, one of ordinary skill in the art prior to the time of the invention knowing that administration of a composition of thymidine diacetate and uridine triacetate is efficacious at treating 5-FU and capecitabine mediated hand-foot syndrome in a subject in need, coupled with the knowledge that ester-mediated acetylation of thymidine improves its transport across biomembranes and through the epidermis and mucosal epithelium to treat the disorder as taught by Romantsev, said skilled artisan would have readily predicted that administration of the esterified thymidine compound comprising naproxen at R7, or compound 1 as taught by Encinas to a patient with hand-foot disease would have effectively treated said cutaneous disorder in the afflicted patient.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, Romantsev teaches that administration of exogenous thymidine can bypass the blockade of thymidine synthase by FdUMP by being directly converted to thymidine monophosphate, counteracting toxicity of 5-FU or capecitabine mediated by inhibition of thymidine synthase, coupled with the knowledge that acetylation of thymidine improves its transport across biomembranes and through the epidermis and mucosal epithelium. Considering compound 1 of Encinas is taught as an comprising the art-recognized NSAID naproxen conjugated to the 5’-position of a thymidine nucleoside via a ester linkage, said skilled artisan would have readily predicted that administration of the naproxen comprising thymidine ester compound of Encinas (compound 1) would have improved transport of the thymidine across biomembranes, followed by cleavage of the ester by enzymatic processes, yielding the delivery of hand-foot syndrome treating thymidine and NSAID naproxen to the targeted tissues, thereby counteracting toxicity of 5-FU or capecitabine mediated by inhibition of TS.
Conclusion
In view of the rejections set forth above, no claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGE W KOSTURKO whose telephone number is (571)270-5903. The examiner can normally be reached M-F 9:00-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CLINTON A BROOKS can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621