CTNF 17/919,848 CTNF 87582 DETAILED ACTION This Office action details a non-final action on the merits for the above referenced application No. Claims 1-4, 8, 13, 16-17, 52-53, and 56-59 are pending in this application. Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Continued Examination Under 37 CFR 1.114 07-42-04 AIA A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 29 Apr. 2026 has been entered. 12-151 AIA 26-51 12-51 Status of Claims Claims 1, and 13 are amended. Claims 5-7, 9-12, 14-15, 18-51, and 54-55 are cancel. Claims 56-59 are new. Response to Amendment The amendments filed on 29 Apr. 2026 have been entered. Response to Arguments The rejection of claims 1-4, 7-8, 12, 50 and 52-53 under 35 USC 103 as being unpatentable over Groves et al. (WO 2013/081685 A1; published 2013) is withdrawn. The rejection of claims 1-4, 7-8, 12-13, 16-17, 50, 52, and 53 under 35 USC 103 as being unpatentable over Groves et al. (WO 2013/081685 A1; published 2013), in view of Bryans et al. (J. Med. Chem.; published 1998) and Martarello et al. (J. Med. Chem.; published 2002) is withdrawn. The rejection of claims 54-55 under 35 USC 103 as being unpatentable over Groves et al. (WO 2013/08685 A1; published 2013), in view of Bryans et al. (J. Med. Chem.; published 1998) is withdrawn. 12-256 AIA New Grounds of Rejection Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 In the event the determination of the status of the application as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. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim (s) 1-4, 8, 13, 16-17, 52-53, and 56 is/are rejected under 35 U.S.C. 103 as being unpatentable over Groves et al. (WO 2013/081685 A1; published 2013), in view of Bryans et al. (J. Med. Chem.; published 1998) . Groves et al. teach C-halogen bond formation (see title). Groves et al. teach methods of fluorinating a carbon containing compound comprising halogenation with Cl and Br followed by substitution with F. Methods of direct oxidative C-fluorination of a carbon containing compound having an sp3 C-H bond are provided (see abstract). Groves et al. teach fluorination of protected gabapentin PNG media_image1.png 140 763 media_image1.png Greyscale (see Fig. 15A). Groves et al. teach gabapentin PNG media_image2.png 161 304 media_image2.png Greyscale as an exemplary carbon containing compounds and gabapentin fluorination sites (Fig. 39; [0017]-[0018], [0059]). Gabapentin reads on a compound of instant formula I PNG media_image3.png 104 163 media_image3.png Greyscale wherein R 1 =R 2 =H. The one-step C-H fluorination using fluoride is rapid enough to be applied to 18 F radiofluorination for PET ([0082]-[0083], [0085], [0088], [0090], [0095]). PET yields well resolved images with excellent sensitivity. 18 F has the advantages of a two-hour half-life and a β + emission (see [0088]). Groves et al. teach 11 C labels for positron emission tomography ([0088]). Groves et al. teach deuterium kinetic isotope effects were evaluated by the reaction of a mixture of cyclohexane and cyclohexane- d 12 . Groves et al. teach a cis/trans ratio of 1:1 (pg. 56, table 4, entry 11). Groves et al. teach blocking metabolic pathways ([0141]). Groves et al. do not disclose a compound of formula PNG media_image4.png 120 161 media_image4.png Greyscale wherein R 3 is F or 18 F optionally wherein 1 H is D or optionally wherein 1 C is 11 C isotope and optionally wherein the compound is trans-[ 18 F]4-fluoro-gabapentin such as PNG media_image5.png 105 128 media_image5.png Greyscale . Groves et al. do not further teach a method of treating neuropathic pain or epilepsy in a subject, the method comprising administering a therapeutically effective amount of the composition of claim 1 to a subject in need thereof optionally wherein the composition is administered at doses ranging from 0.001 mg/kg to 100 mg/kg and wherein the composition is administered orally or intravenously. Bryans et al. teach identification of novel ligands for the gabapentin binding site on the α 2 δ subunit of calcium channel and their evaluation as anticonvulsant agents (see title). Bryans et al. teach that gabapentin has been introduced as an anticonvulsant agent which is useful as an add on therapy in the treatment of epileptic seizures and has been shown to be potential treatment for neurogenic (neuropathic) pain (pg. 1838; ref. 3). For each monoalkylated gabapentin analogues, either the cis or trans isomer may exist. These can be accessed individually (pg. 1838). Bryans et al. teach compound 14 PNG media_image6.png 107 116 media_image6.png Greyscale (IC 50 =440 nM) and the cis isomer 10 (>1000 nM). These compounds read on compounds of instant formula (II) wherein R 1 =H and R 3 =Me. Test compounds were administered intracerebroventricularly or subcutaneously. Each compound was dosed at 30 mg/kg (pg. 1841). It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Groves et al. (protected fluoro-gabapentin and gabapentin to be fluorinated by F or 18 F) to arrive at trans 4-[ 18 F]fluoro-gabapentin as taught by Groves et al. and Bryans et al. because the trans isomer would have been expected to advantageously exhibit the highest binding affinity and because the trans-4-([ 18 F])fluoro-gabapentin would have been expected to advantageously enable in vivo PET imaging of disorders associated with alterations in the α2δ subunit of the calcium channel such as epilepsy or a gabapentin derivative having enhanced metabolic stability. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Groves et al. so that at least one hydrogen of the fluoro-gabapentin is a deuterium as taught by Groves et al. because it would have been expected to enable an equivalent isotopologue having improved stability and/or evaluation of the kinetic isotope effect. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Groves et al. so that at least one carbon atom is an 11 C isotope as taught by Groves et al. because the 11 C-isotope substitution would have been expected to enable PET imaging of fluorogabapentin in vivo. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Groves et al. by further treating neuropathic pain or epilepsy in a subject, the method comprising administering a therapeutically effective amount optionally 30 mg/kg and optionally intravenously a composition comprising trans-4-([ 18 F])fluoro-gabapentin as taught by Groves et al. and Bryans et al. because the administering would have been expected to advantageously enable in vivo treating and/or PET the neuropathic pain or epilepsy in a subject in need thereof . 07-21-aia AIA Claim (s) 1-4, 8, 13, 16-17, 52-53, and 56-59 is/are rejected under 35 U.S.C. 103 as being unpatentable over Groves et al. (WO 2013/081685 A1; published 2013), in view of Bryans et al. (J. Med. Chem.; published 1998), in further view of Gallop et al. (US 2006/0229361 A1; published 12 Oct. 2006; see attached 892) and Hwang et al. (US 2004/0248811 A1; published 9 Dec. 2004; see attached 892) . Groves et al. teach as discussed above. Groves et al. do not further teach the following compounds PNG media_image7.png 140 195 media_image7.png Greyscale , PNG media_image8.png 138 241 media_image8.png Greyscale , or PNG media_image9.png 110 136 media_image9.png Greyscale . Bryans et al. teach as discussed above. Gallop et al. teach prodrugs of GABA analogs, compositions and uses thereof (see title). Gallop et al. teach gabapentin as a potentially useful therapeutic in chronic pain states (e.g. neuropathic pain) and psychiatric disorders ([0006]). The formation of lactam presents serious difficulties in formulating gabapentin because of its toxicities ([0007]). Rapid systemic clearance is another significant problem with many GABA analogs ([0009]). The prodrugs provided by the present invention may possess significant pharmaceutical advantages of particular use in medicine ([0013]). Gallop et al. teach 1-{[(α-Isobutanoyloxyisopropoxy)carbonyl]aminomethyl}-1-Cyclohexane Acetic Acid ([0336], example 23). Hwang et al. teach compound and derivative of gabapentin (see title). Hwang et al. teach that according to the prodrug concepts, if gabapentin can be designed as a highly bioavailable prodrug to reduce the dosage amount and regime such that it need to be taken only one time per day, the convenience to patients will largely promoted (see [0004]-[0005]). Hwang et al. teach the compound PNG media_image10.png 117 102 media_image10.png Greyscale (GBPOEt([0022], [0036]) and 1-tert-butoxy-carbonylamino-methyl)-cyclohexyl]-acetic acid (BocN-GBPOH([0036]). It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify the compounds of Groves et al. by arriving at PNG media_image8.png 138 241 media_image8.png Greyscale as a prodrug of the obvious trans-[ 18 F]4-fluoro-gabapentin as taught by Gallop et al. because that prodrug would have been expected to advantageously provide cleavage of the pro-moiety from the prodrug and any metabolite thereof is typically non-toxic. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify the compounds of Groves et al. by further arriving at PNG media_image7.png 140 195 media_image7.png Greyscale and PNG media_image9.png 110 136 media_image9.png Greyscale as taught by Groves et al. and Hwang et al. because those compounds would have been expected to provide protected intermediates capable of deprotection of trans-[ 18 F]4-fluoro-gabapentin and/or the production of prodrugs thereof advantageously capable of increasing bioavailability. Applicants Arguments Applicants assert that as amended the claims are directed to compounds of the formula shown below where R 3 can only be in the para position and is trans to the amine group. By contrast the gabapentin derivatives in Groves can be fluorinated at any position on the cyclohexane ring and Groves does not specify the stereochemistry of the fluorinated gabapentin. In Groves not only is fluoro-gabapentin a hypothetic example, Groves also suggests that gabapentin can be fluorinated at multiple positions. The claimed compounds provide unexpected results that could not have been predicted based on the teachings of Groves. In autoradiography, it was observed that trans-[ 18 F]4F-gabapentin was more potent than cis-[ 18 F]4F-gabapentin. The results as seen in Fig. 4D show that trans-[ 18 F]4F-gabapentin had higher binding affinity that gabapentin whereas cis-[ 18 F]4F-gabapentin had lower binding affinity. One of ordinary skill would not expect that the trans isomer would perform better that the cis-isomer . 07-37 AIA Applicant's arguments filed 29 Apr. 2026 have been fully considered but they are not persuasive. Groves teaches and motivates ([ 18 F])fluoro-gabapentin and Fig. 39 Groves only points to two positions for the incorporation of fluorine with one position being the 4-position. Groves teaches and suggests of mixture of fluoro-gabapentin stereoisomers where the mixture includes the trans-[ 18 F]4-fluoro-gabapentin. The claims as amended do not exclude trans-[ 18 F]4-fluoro-gabapentin as part of a stereoisomeric mixture. Bryans teaches substituent modification of gabapentin at the claimed 4-position and Bryans teaches that the trans-substituent modification of 4-position results in higher binding affinity. A recognized advantage is the strongest reason to combine. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Groves et al. to arrive at trans-[ 18 F]4-fluoro-gabapentin because that compound would have been expected to provide a fluorinated gabapentin derivative suitable for PET imaging and exhibiting reduced metabolism and having spatial arrangement that provides the highest binding affinity for substituent modification at that position. Expected beneficial results are evidence of obviousness. In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). From the teachings of Bryans, a person of ordinary skill in the art would have expected the trans-[ 18 F]4-fluoro-gabapentin to exhibit improved properties including binding affinity over the cis-[ 18 F]4-fluoro-gabapentin . Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST. 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, Michael Hartley can be reached on (571)272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618 / SEAN R. DONOHUE/ Examiner, Art Unit 1618 Application/Control Number: 17/919,848 Page 2 Art Unit: 1618 Application/Control Number: 17/919,848 Page 3 Art Unit: 1618 Application/Control Number: 17/919,848 Page 4 Art Unit: 1618 Application/Control Number: 17/919,848 Page 5 Art Unit: 1618 Application/Control Number: 17/919,848 Page 6 Art Unit: 1618 Application/Control Number: 17/919,848 Page 7 Art Unit: 1618 Application/Control Number: 17/919,848 Page 8 Art Unit: 1618 Application/Control Number: 17/919,848 Page 9 Art Unit: 1618 Application/Control Number: 17/919,848 Page 10 Art Unit: 1618 Application/Control Number: 17/919,848 Page 11 Art Unit: 1618
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