DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 1-4, 7-8, 12-13, 16-17, 50, and 52-55 are pending in this application.
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 .
Status of Claims
Claim 1 is amended. Claims 5-6, 9-11, 14-15, 18-49, and 51 are cancelled. Claims 54-55 are new.
Response to Amendment
The amendments filed on 5 Jan. 2026 have been entered.
Response to Arguments
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.
Claim(s) 1-4, 7-8, 12, 50, and 52-53 is/are rejected under 35 U.S.C. 103 as being unpatentable over Groves et al. (WO 2013/081685 A1; published 2013) for the reasons cited in the Office action filed on 4 Aug. 2025.
Applicants Arguments
Applicants assert that the NMRs in Groves show multiple 19F peaks suggestive of a mixture products. Groves does not identify which compounds of the four possible isomers was produced. Groves does not show that the individual products can be isolated and does not show any further characterization confirming that gabapentin derivatives were made. Groves does not show that fluorinated derivatives of gabapentin can be made. Groves does not provide any data that the fluorinated compounds maintain their pharmacokinetics. The fluorinated compounds of Groves do not provide any reasonable expectation of success that the claimed compounds would maintain their activity when 18F-labeled. [18F]AgF is not a good labeling agent. The claimed compounds provides the following unexpected results: i) [18F]F-GBP binds to α2δ-1 receptors, trans-4GBP was more potent; ii) [18F]4F-GBP showed that the injured nerve had significantly higher binding of both cis- and trans-[-F]-GBP; and iii) significant brain penetration for both cis and trans isomers.
Applicant's arguments filed 5 Jan. 2026 have been fully considered but they are not persuasive. At Fig. 49, Groves provides some teaching, suggestion and motivation for a fluoro-gabapentin where the fluorine is placed at the 4-position of gabapentin to form the claimed 4-fluorogabapentin. At [0017] and several other places, Groves describes and motivates gabapentin as a suitable substrate for fluorination. At Fig. 15A-15B, Groves provides a fluorinated protected gabapentin that implies the 4-fluorinated deprotected gabapentin taught and motivated therein. At those Figs, the fluorinated deprotected gabapentin is accompanied by an NMR spectrum indicating the 4-fluoro-gabapentin was enabled by the fluorination method of Groves. A mixture of 3-/4-fluorogabapentin reads on a compound of claim 1 as amended since 4-fluoro-gabapentin would be present in that mixture. A person of ordinary skill in the art would have known how to isolate cis/trans 4-fluorogabapetin from a mixture of 3-/4-fluorogabapentin at least by chromatography such as HPLC since those compounds would be expected to have different retention properties. A person of ordinary skill in the art interested in therapeutic and/or diagnostic application of fluoro-gabapentin would have had adequate reason and motivation to isolate cis/trans 4-fluorogabapetin from the fluoro-gabapentin in Groves for at least purity, pharmacology and toxicology reasons.
Groves additionally teaches chlorination and bromination reactions. In addition to the direct labeling method in Groves, a person of ordinary skill in the art interested in forming cis/trans 4-[18F]fluorogabapetin could have prepared 4-[18F]fluorogabapetin using a protected 4-chloro/bromogabapentin precursor compounds without the use [18F]AgF. Obviousness only requires a reasonable expectation of success. There is no requirement for absolute predictability. At several places, Groves teaches and motivates flouro-gabapentin as a suitable therapeutic and/or diagnostic agent in vitro or in vivo with a reasonable expectation of success. For example, instant claim 1 does not require in vivo imaging method steps.
Groves teaches fluoro-gabapentin as advantageous since fluoro-gabapentin would be expected to decrease instances of toxic metabolism and enable diagnostic/imaging evaluation. Unexpected results require a comparison with the closest prior art. An affidavit or declaration must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). The results described in the response filed on 5 Jan. 2026 do not contain a comparison with or describe an unexpected result over the fluoro-gabapentin in Groves. Instant claim 1 as amended is broad. The results described in the response filed on 5 Jan. 2026 do not describe results commensurate with claim 1.
Claim(s) 1-4, 7-8, 12-13, 16-17, 50, 52, and 53 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) and Martarello et al. (J. Med. Chem.; published 2002) for the reasons cited in the Office action filed on 4 Aug. 2025.
Applicants Arguments
Applicants assert that Bryans and Martarello cannot cure the deficiencies in Groves. The SAR of Table 1 of Bryans suggests that meta substitution is preferred over para substitution. The compounds of Bryans do not provide any reasonable expectation of success that the claimed compounds would maintain their activity when 18F-labeled. The fact that cis/trans 4-methyl gabapentin have different IC50s makes it impossible to predict if any of the fluorinated derivatives will work. The different that the inventors found between cis/trans 4- fluorogabapentin was unexpected. Many drugs are not suitable due to slow pharmacokinetics. The 18F of the compounds of Martarello do not provide any reasonable expectation of success that the claimed compounds would maintain their activity when 18F-labeled.
Applicant's arguments filed 5 Jan. 2026 have been fully considered but they are not persuasive. Groves is not deficient for the reasons discussed above. Bryans teaches that gabapentin binds to the α2δ subunit of a calcium channel. A person of ordinary skill in the art would have expected the advantageous fluorogabapentin taught by Groves to bind to the α2δ subunit of a calcium channel.
At scheme 3, Bryans teaches the spirolactam compound 13 that reads in part on instant formula (II) wherein R1=H and R3=Me as an intermediate or precursor to trans 4-methylgabapentin.
At table 1, Grove teaches a trans 4-methylgabapentin that maintains binding affinity for α2δ subunit of a calcium channel. At pg. 1839, Groves attributes a reduction in binding affinity to steric factors around the 4-position. It is well known that a methyl group (-Me) is significantly larger than a single fluorine atom (-F) and a single fluorine is only slightly larger than hydrogen. Accordingly, a person of ordinary skill in the art would have had a reasonable expectation of success that the 4-fluorogabapentiin taught by Groves would bind to the α2δ subunit of a calcium channel. A table 1, Bryans teaches the 3-methyl gabapentin as mixture of stereoisomers potentially requiring laborious separation such as chiral resolution. In further view of Bryans, it would have been further obvious to a person of ordinary skill in the art before the effective filing date to modify Groves by for forming or isolating the trans 4-([18F])fluorogabapentin optionally using a spirolactam precursor of instant formula (II) wherein R1 is H or Boc and R3 is F or 18F because the trans 4-([18F])fluorogabapentin would have been expected to advantageously enable labeled gabapentin derivative suitable for therapeutic and/or diagnostic application. Martarello was cited for teaching the preparation of an 18F-labeled amino acid using a Boc protection strategy.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
Claim(s) 54-55 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 as discussed above. In addition, 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
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(see Fig. 15A). Groves et al. teach gabapentin
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as an exemplary carbon containing compounds and gapapentin fluorination sites (Fig. 39; [0017]-[0018], [0059]). Cl or Br may be replaced with F by nucleophilic substitution ([0072]). Gapapentin reads on a compound of instant formula I
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wherein R1=R2=H. The one-step C-H fluorination using fluoride is rapid enough to be applied to 18F radiofluorination for PET ([0082]-[0083], [0085], [0088], [0090], [0095]). PET yields well resolved images with excellent sensitivity. 18F has the advantages of a two-hour half-life and a β+ emission (see [0088]). Groves et al. teach 11C 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-d12. 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 further expressly teach the compound
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or the compound
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.
Bryans et al. teach identification of novel ligands for the gabapentin binding site on the α2δ 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 precursor compounds 9
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and 13
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(pg. 1839; schemes 1 and 2).
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 the fluorogabapentin is an cis/trans 4-[18F]fluorogabapentin optionally formed from the obvious spirolactam intermediate
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obtained by nucleophilic fluorination as taught by Groves et al. and Bryans et al. because it would have been expected to advantageously enable a PET detectable 18F-labeled gabapentin capable binding to the α2δ subunit of a calcium channel in vitro and in vivo.
Conclusion
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.
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618