CTNF 18/351,154 CTNF 99541 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. 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. Priority The instant application claims domestic benefit to US provisional application no. 63/388,470 filed on 07/12/2022. Information Disclosure Statement The information disclosure statement (IDS) submitted on 08/18/2023 and 06/17/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. Status of the Claims Claims 1-27 are pending and being examined on the merits herein. Specification The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Paragraph 0011 recites the link https:// zogenix- pharmawrite.ipostersessions.com /Default.aspx?s=C5-40-1F-93-C3-22-F7-19-E2-D1-D2-97-D7-33-58-7A . The bolded portions in the link are now allowed in the specification. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Claim Rejections - 35 USC § 112(a) 07-30-01 AIA The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. 07-31-01 Claims 1-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 1 recites “A method of increasing the oral bioavailability of deoxycytidine (dC) and deoxythymidine (dT) to a patient … comprising administering … a therapeutically effective amount of dC and dT with food.”, Claim 2 recites “A method of increasing the amount of deoxycytidine (dC) absorbed by a patient’s body comprising administering a dose with a combined weight of dC and deoxythymidine (dT) … , wherein the administering is with food.” Claim 21 recites “A method of treating a mitochondrial depletion syndrome patient comprising, administering to the patient a therapeutically effective amount of deoxycytidine (dC) and … deoxythymidine (dT) and directing the patient to take the dC and dT with food”. Here, these instant claims recite a method of increasing the oral bioavailability of dC and/or dT comprising administering the recited compounds with food as well a method of treating a mitochondrial depletion syndrome comprising administering dC and dT with food. The disclosure, however, does not identify a representative number of food species within the claimed genus as well as the time window for administering the food to perform the claimed function of increasing oral bioavailability and/or treating a mitochondrial depletion syndrome patient, nor does the disclosure provide a structure-function relationship which would allow one of ordinary skill in the art to identify which foods and in what time windows to administer the food to perform the claimed function and/or treating a mitochondrial depletion syndrome patient . MPEP 2173.05(g) states that “A claim term is functional when it recites a feature ‘by what it does rather than by what it is’” and that “Unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description or may not be commensurate in scope with the enabling disclosure, both of which are required by 35 U.S.C. 112(a) and pre-AIA 35 U.S.C. 112, first paragraph.” Applicant tests the food effect on the recited compounds in Example 1 (pages 17-29), by determining the AUCs and Cmax for four different treatment groups as disclosed on page 25. Here, treatment groups A, B, and C had varying dosages of the recited compounds following an overnight fast, and treatment C received a dosage within 5 minutes of consumption of a standard high-fat, breakfast meal. Applicant discloses this meal included eggs, bacon, and toast with butter (see paragraph 0076 on page 19). The comparison data are found on Table 2 (page 24), Table 3 (page 26), and Tables 4-5 (pages 27-28). Here, Applicant demonstrates that that administration of MT1621 (combination product of dT and dC) under fed conditions increased baseline adjusted Cmax and AUC by 79% and 137%, respectively, for plasma dC, and by 27% and 74%, respectively, for plasma dT compared to fasted conditions, indicating a significant food effect (see paragraph 0106 on page 29). Applicant further tests in Example 2 (pages 29-34) and confirmed that this food effect was a statistically significant covariate of the pharmacokinetics (PK) of dC including for TK2 deficient participants (see paragraph 0119 and Table 6 on pages 31-32). Applicant concludes from these examples that PK changes induced by a standardized high-fat, high-calorie meal reflect the greatest effects on gastrointestinal physiology (paragraph 0124 on page 34). Applicant states that this increased oral bioavailability effect for the recited compounds are generalizable to all subjects including healthy and TK2 deficient patients (paragraph 0124). Here, while Applicant has demonstrated an increased bioavailability effect for the recited compounds when administered with food for TK2 deficient patients, Applicant has not demonstrated or suggested that this food effect would occur for any type of food because the food effect data suggests that this effect is only significant when administered with a high-fat, high calorie meal. Furthermore, Applicant provides comparisons between an overnight fasted state and a fed state, in which food was administered within 5 minutes of taking the recited compounds. Additionally, Applicant discloses that a fasted state refers to administration of a drug at least 4 hours after a meal and continued fasting at least 2 hours after the administration (paragraph 0044 on page 9). Therefore, while Applicant has demonstrated a significant oral bioavailability effect in the fed state, Applicant has not demonstrated that the increased oral bioavailability effect would be observed when the recited compounds are administered in any time window with food. The state of the art discloses that food-drug interactions are unpredictable, and that the timing of when the food is administered can have significant impact on the oral bioavailability of a drug/compound. Koziolek (in PTO-892) teaches that the simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration (see Abstract). Koziolek illustrates in Fig. 2 on page 33 that drugs/compound taken with a meal can have no effect, negative effect, or positive food effect on the pharmacokinetics. Koziolek teaches that the oral bioavailability effect from foods strongly depends on the type and composition of the food as well as on the dietary protocol (see second paragraph right column page 32). Therefore, Koziolek teaches that the FDA issued guidance for a standardized fed state condition to evaluate bioavailability effect from foods (see second paragraph right column page 32). Koziolek teaches that the intake of food leads to an increase in the motility that is different in each part of the gastrointestinal tract, and this motor response is expected to affect the dissolution and absorption of a drug (see first paragraph under section 3.2 left column page 36). Koziolek teaches that the physical consistency, fat content, and caloric load of the meal plays a relevant role in regulating the motor response of the stomach (see third paragraph right column page 36). Koziolek teaches that depending on these variables, the gastric resident time of non-digestible solids can be up to several hours and also applies to non-disintegration formulations such as enteric-coated or matrix tables (see third paragraph right column page 36). Koziolek teaches that adding further to the complication of the presence of food, the timing of the meal further influences the transit of oral modified release formulations (see fourth paragraph left column page 51). Koziolek exemplifies a study in which the transit of a formulation in the small intestine was investigated under three different feeding conditions: 1) under the fasted state (tablet administered on an empty stomach), 2) fed state (tablet administered after food) and 3) pre-feed (tablet administered 45 min before food) (see fourth paragraph left column page 51). Koziolek teaches that under the pre-feed regimen, small intestinal transit time was significantly shorter (100 min) when compared with the fasted (204 min) or fed conditions (210 min). Here, the teachings of Koziolek demonstrate that food – drug interactions are highly unpredictable and can depend on the type of food being administered including its physical consistency, fat content, and caloric load. Furthermore, Koziolek teaches that the timing of when these foods are administered can have significant differences on the PK of the drug, which suggests it is would also not be predictable to determine at what time windows a food would need to be administered with a drug / compound to have an increased oral bioavailability effect. Hermann (in PTO-892) teaches food effects with cladribine, which is a nucleoside analog compound (see Abstract and section 3.1 “Food Effects” right column on page 170). Hermann teaches that in a food effect study with an antiviral nucleoside analog ribavirin, the maximum exposure and extent of absorption was reduced and further disclosed this was probably owing to competition of dietary nucleosides with ribavirin for intestinal CNT and ENT transporter (see section 3.1 “Food Effects” right column on page 170 and left column page 176). Furthermore, Hermann teaches that in a cladribine food-interaction study employing a typical FDA-recommended high fat high calorie breakfast, the rate of cladribine absorption was delayed in the fed state as compared with the fasted state and the Cmax was reduced by 29% (see second paragraph left column page 176). Hermann teaches that the high-fat, high-calorie test meal employed in the study only contained relatively low amounts of dietary purines of approximately 24 mg, which is about eight-fold less than the high-purine meal employed in the ribavirin study, and that it remains therefore unknown whether purine-rich meals [including certain fish and seafood (such as anchovies, haddock, herring, mussels, sardines, scallops, and trout) and some meats (such as bacon, turkey, veal, venison, and organ meats like liver)] may have the potential to alter the bioavailability of cladribine tablets (see second paragraph left column page 176). Here, the teachings of Hermann demonstrate that food – nucleoside interactions are unpredictable with studies suggesting reduced bioavailability or unknown effects and can depend on the type of food being administered. Therefore, it is not evident by the disclosure or the prior art, that the Applicant was in possession of a representative number of species of food as well as the timing of when the food is administered that would have the increased oral bioavailability effect and/or for treating a mitochondrial depletion syndrome patient. Furthermore, as discussed above, there is no disclosed or art recognized correlation between structure and function which would allow for the predictable identification of food and when it is administered that would be increase the oral bioavailability of the recited compounds and/or for treat a mitochondrial depletion syndrome patient. Therefore, the instant claim does not meet the written description requirement under 35 USC 112(a). It is noted that the instant claims may have written description support if instant claims 11 and 12 are added into each base claim (claims 1, 2, and 21). Conclusion No claim is found allowable. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /D.H.C./Examiner, Art Unit 1693 /SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693 Application/Control Number: 18/351,154 Page 2 Art Unit: 1693 Application/Control Number: 18/351,154 Page 3 Art Unit: 1693 Application/Control Number: 18/351,154 Page 4 Art Unit: 1693 Application/Control Number: 18/351,154 Page 5 Art Unit: 1693 Application/Control Number: 18/351,154 Page 6 Art Unit: 1693 Application/Control Number: 18/351,154 Page 7 Art Unit: 1693 Application/Control Number: 18/351,154 Page 8 Art Unit: 1693