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 .
This Office action is responsive to Applicant’s amendment and remarks, filed 17 June 2026, in which claim 1 is amended to change the scope and breadth of the claim, claim 7 is amended to correct informalities, and new claims 8-9 are added.
This application is a domestic application, filed 05 Dec 2023; claims benefit of provisional application 63/513,525, filed 13 July 2023; and claims benefit of provisional application 63/386,271, filed 06 Dec 2022.
Claims 1-9 are pending in the current application and are examined on the merits herein.
The following are modified grounds of rejection necessitated by Applicant’s amendment, filed 17 June 2026, in which claim 1 is amended to change the scope and breadth of the claim, and new claims 8-9 are added.
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.
Amended Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over US’359 (Spector, US 2011/0130359, published 02 June 2011, provided by Applicant in IDS filed 04 June 2024).
US’359 teaches methods for improved administration and dosing of DPD inhibitors in combination with 5-FU and/or 5-FU prodrugs, comprising first administering to a patient in need thereof a DPD inhibitor that substantially eliminates activity of the enzyme within the patient and thereafter administering 5-FU or a 5-FU prodrug (abstract). The invention relates generally to cancer therapy, and more particularly to methods for preventing or minimizing neurotoxicity associated with cancer therapy using DPD inhibitors in combination with 5-FU and/or 5-FU prodrugs (page 1, paragraph 3), addressing limitations of the preamble of claim 1. The invention is drawn to avoiding the unexpected neurotoxicity observed in human patients (page 5, paragraph 61), implying the treatment of a human subject and addressing the preamble of claim 1. In a preferred embodiment, the DPD inhibitor is eniluracil and the anticancer agent is capecitabine (page 3, paragraph 27). In other embodiments, an eniluracil dose range used according to the invention may advantageously comprise from about 16-23 mg/m2, 15-31 mg/m2, and 19-39 mg/m2, which corresponds to doses of 30 mg, 40 mg, or 50 mg, respectively (page 6, paragraphs 63-64), addressing limitations of claims 1 and 2. In embodiments of the invention the 5-FU administration schedule used can be a daily schedule, or the daily schedule where 5-FU is dosed for more than one day following the administration of eniluracil, which is dosed prior to 5-FU and on every day, every other day, or every third day during 5-FU therapy (page 6, paragraph 71). In an illustrative embodiment, the DPD inhibitor is eniluracil, the anticancer agent is a 5-FU prodrug, and the 5-FU prodrug is administered about 11-16 hours thereafter at a dose between about 40-150 mg/m2 (page 3, paragraph 33), where the patient’s body surface area ranges from 1.3 m2 to 2.8 m2 (page 6, table 1), addressing limitations of claim 1 step (b) and claim 3. In exemplary embodiments, an administration schedule may be used which comprises a weekly or 5-day dosing schedule, where eniluracil is dosed the night before 5-FU and 5-FU is only dosed one day per week or once per day for 5 days (page 5, paragraph 56), where the 5-day dosing schedule addresses limitations of claim 1 step (b). For certain embodiments of the invention that employ eniluracil as the DPD inhibitor, in order to allow the level of eniluracil to be sufficiently decreased by elimination prior to administration of the 5-FU or 5-FU prodrug, the 5-FU or 5-FU prodrug is administered at least about 3 hours, about 6 hours, about 8 hours, about 11 hours, about 16 hours, about 20 hours, about 36 hours, about 48 hours, or about 72 hours after administration of the eniluracil (page 4, paragraph 49), addressing limitations of claims 4-5. The compounds can be formulated into separate pharmaceutical formulations, and oral administration will typically be a preferred route of administration (page 6, paragraph 75 to page 7, paragraph 76), addressing limitations of claim 1 steps (a) and (b). US’359 further teaches in the background of the invention that two Phase III studies were conducted in patients with colorectal cancer using a combination pill containing eniluracil in ten-fold excess to 5-FU. Patients received 10 mg per square meter body surface area (mg/m2) eniluracil and 1 mg/m2 5-FU every 12hr for 28 days. After one week off drug, the cycle was repeated (page 2, paragraph 12).
US’359 does not specifically disclose the method comprising the step (c) 7 to 14 days after step (b), repeat the steps (a) and (b) (claim 1). US’359 does not specifically disclose the method where the cancer is colorectal cancer, gastrointestinal tract tumor, breast cancer, pancreatic cancer, head and neck cancer, lung cancer, or advanced biliary tract cancer (claim 7). US’359 does not specifically disclose the method wherein capecitabine is administered at 450 mg/day (claim 8). US’359 does not specifically disclose the method wherein capecitabine is administered twice daily (b.i.d.) at 225 mg (claim 9).
US’359 further teaches the method where the 5-FU or 5-FU prodrug is administered at a dose such that the 5-FU or 5-FU generated from the 5-FU prodrug is present in the patient in substantial excess of the DPD inhibitor (page 2, paragraph 16). US’359 further teaches the embodiment where the 5-FU or 5-FU prodrug is administered at a dose such that at its time of administration the 5-FU or 5-FU generated from a prodrug is present in the patient in at least 10-fold excess of the DPD inhibitor (page 2, paragraph 21). US’359 further teaches in another illustrative embodiment, a 28-day b.i.d. (twice daily for 28 days) schedule may be used (page 6, paragraph 73).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of US’359 in order to repeat the treatment cycle steps after a period of time off drug, or to select the cancer treated to be colorectal cancer. One of ordinary skill in the art would have been motivated to modify the teachings of US’359 with a reasonable expectation of success because US’359 teaches methods for improved administration and dosing by optimizing the dosing regimen, teaches known dosing regimens for the combination of eniluracil and 5-FU including a period of one week off drug between treatment cycles, and teaches the combination of eniluracil and 5-FU is known for the treatment of colorectal cancer, suggesting it would have been obvious to modify the method of US’359 by optimizing the dosing regimen or to select the cancer treated to be colorectal cancer. Regarding the dose of the capecitabine administered, US’359 teaches the embodiment where the 5-FU prodrug is administered at a dose between about 40-150 mg/m2, teaches the patient’s body surface area ranges from 1.3 m2 to 2.8 m2, and teaches daily administration, providing guidance for the dosage range of 112-420 mg/day for the 5-FU prodrug capecitabine and suggesting it would have been obvious to select the optimal dosage. See also MPEP 2144.05 at I. providing “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)” and at II. providing ““[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” In this case the range of claim 1 overlaps with the dosage ranges taught by the prior art to be effective for the same purpose, and the prior art suggest it would have been obvious to discover the optimum or workable ranges by routine experimentation. Regarding claims 8-9, US’359 further teaches the method where the 5-FU or 5-FU prodrug is administered to be a substantial excess compared to the DPD inhibitor eniluracil, such as in at least a 10-fold excess. Further regarding claim 9, US’359 further teaches in another illustrative embodiment a b.i.d. schedule may be used.
Regarding claim 1 reciting “(b) at least after 10 hours of step (a), orally administering a fixed dose of capecitabine at about 140-700 mg/day to the subject for 2 to 14 consecutive days…”, as detailed above, US’359 teaches a daily schedule where 5-FU is dosed for more than one day following the administration of eniluracil, such as every third day during 5-FU therapy, meaning the 5-FU is dosed for two days after the administration of eniluracil. However, claim 1 recites the open transitional phrase “comprising”, and it is unclear that the claimed method excludes additional steps of administering eniluracil on every day during 5-FU therapy as further taught by US’359.
Response to Applicant’s Remarks:
Applicant’s remarks, filed 17 June 2026, have been fully considered and not found to be persuasive.
Regarding the claim language of “administering a fixed dose of capecitabine”, US’359 in Table 1 at page 6 describing the dose of eniluracil that delivers 16-20 mg/m2 for patients of the indicated BSA and at page 6, paragraph 63 stating “For examples, if all patients were dosed with 40 mg eniluracil, the dosing range would encompass about 15-31 mg/m2.” This indicates that one of ordinary skill in the art would have understood the teaching in US’359 that the 5-FU prodrug is administered at a dose between about 40-150 mg/m2 to mean that the patients would be dosed with a fixed dose such that the dose falls within the range described in terms of mg/m2, allowing for individual patient variation, as shown in Table 1. Therefore one of ordinary skill in the art would have understood US’359 as teaching the administration of the 5-FU prodrug capecitabine as a fixed dose.
Similarly, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As detailed above, one of ordinary skill in the art would have understood US’359 as teaching the administration of the 5-FU prodrug capecitabine as a fixed dose, taking into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made.
Further, regarding Applicant’s remarks regarding the specification detailing the known problems associated with dose adjustment based on body surface and individualized treatment doses, as detailed above, US’359 at page 6, paragraph 63 teaches the example where if all patients were dosed with the same fixed dose of 40 mg eniluracil, the dosing range would encompass about 15-31 mg/m. US’359 teaches the 5-FU prodrug is administered at a dose between about 40-150 mg/m2. By analogous reasoning to the discussion of the dose of eniluracil taught in US’359, the teachings of US’359 taken as a whole suggest to one of ordinary skill in the art the method wherein the 5-FU prodrug is administered at a fixed dose such that the dose falls within the range expressed in units of mg/m2.
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.
Amended Claims 1-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8-9, 11-18, 20, 22-23, 25-31, 33, 35-36, and 38-40 of U.S. Patent No. 8,658,618 in view of US’359 (Spector, US 2011/0130359, published 02 June 2011, provided by Applicant in IDS filed 04 June 2024).
U.S. Patent No. 8,658,618 is assigned to Elion Oncology, LLC, and deemed to be commonly owned with the examined application.
Reference claims 1-4, 6, 8-9, 11-18, 20, 22-23, 25-31, 33, 35-36, and 38-40 of the reference patent are drawn to method for minimizing neurotoxicity associated with treating a cancer patient with a combination comprising a DPD inhibitor and an anticancer agent selected from 5-FU or a 5-FU prodrug, comprising first administering a DPD inhibitor at a dose sufficient to substantially eliminate DPD activity in both nervous and non-nervous tissues, wherein the DPD inhibitor is eniluracil, and thereafter administering the 5-FU or 5-FU prodrug, wherein the 5-FU or 5-FU prodrug. Reference Claims 6, 9, 12, 20, 23, 26, 33, 36, and 39 recite the anticancer agent is the 5-FU prodrug capecitabine. Reference claims 2, 16, 29, 35, and 40 recite the 5-FU or prodrug is administered about 11-16 hours after the DPD inhibitor is administered. Reference claim 1 recites the eniluracil is administered at a dose of 50 mg. Reference claim 15 recites the eniluracil is administered at a dose of 20-50 mg/m2. Reference claims 8, 22, and 35 recite the 5-FU prodrug is administered at a dose of 40-150 mg/m2.
The reference claims do not specifically recite the method wherein the agents are administered orally or the dose is administered per day, orally administering a fixed dose of capecitabine at about 140-700 mg/day to the subject for 2 to 14 consecutive days, or the step (c) 3 to 14 days after step (b), repeat the steps (a) and (b) (claim 1). The reference claims do not specifically recite the method where the cancer is colorectal cancer, gastrointestinal tract tumor, breast cancer, pancreatic cancer, head and neck cancer, lung cancer, or advanced biliary tract cancer (claim 7). The reference claims do not specifically recite the method wherein capecitabine is administered at 450 mg/day (claim 8). The reference claims do not specifically recite the method wherein capecitabine is administered twice daily (b.i.d.) at 225 mg (claim 9).
US’359 is the pre-grant publication of the application issued as U.S. Patent No. 8,658,618, and qualifies as prior art under 35 U.S.C. 102(a)(1). US’359 as prior art teaches as above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the Reference claims in view of US’359 in order to optimize the dosing regimen through routine experimentation and to select the cancer treated to be colorectal cancer. One of ordinary skill in the art would have been motivated to combine the Reference claims in view of US’359 with a reasonable expectation of success because US’359 teaches the same invention as the Reference claims and teaches optimizing the dosing regimen through routine experimentation for the same purpose, as detailed above.
Response to Applicant’s Remarks:
Applicant’s remarks, filed 17 June 2026, have been fully considered and not found to be persuasive.
Applicant’s remarks regarding the teachings of US’359 are addressed above, and are not persuasive with regard to combination of the Reference claims in view of US’359 for the same reasons.
Conclusion
No claim is found to be allowable.
Applicant's amendment necessitated the 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jonathan S Lau whose telephone number is (571)270-3531. The examiner can normally be reached Monday-Friday 9a-5p Eastern.
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/JONATHAN S LAU/ Primary Examiner, Art Unit 1693
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