DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 14-26 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
Claims 1-13 are cancelled. Claims 25-26 are new.
Response to Amendment
The amendments filed on 11 Sep. 2026 have been entered.
Response to Arguments
In view of Applicants amendments, the rejection of claims 14-24 on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of US patent No. 12,129,235 B2, in view of Cappelli et al. (Bioorg. Med. Chem.; published 2006) and Wadsworth et al. (US 2011/0190618 A1; published 4 Aug. 2011) is withdrawn.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 14-17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Stevenson et al. (Bioorg. Med. Chem. Lett.; published 22 Dec. 2009) for the reasons cited in the Office action filed on 11 May 2026.
Regarding claims 14-17, Stevenson et al. disclose compound 11
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(Ki =173 nM, table 1) prepared by reaction of compound 10 with NBS to for Br substituted congener which is then reacted with NaI to form compound 11 (see pg. 955, scheme 1). The reaction of compound 10 with NBS implies the formation of (III) having (R-III) as part of the racemic mixture. Regarding the recitations of wherein the compound is used for the preparation of formula (I) or formula (II), the recitations merely recite an intended use. A recitation of intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In the instant (R-III) disclosed in Stevenson et al. is capable of being used in the preparations of instant formulas (I) and (II) by reaction ([18F])F-.
Applicants’ Arguments
Applicants assert that Stevenson does not specifically disclose the R enantiomer of formula (III) or a racemic mixture. One of ordinary skill in the art cannot know what enantiomers are present. Stevenson does not report the stereochemistry of the sec-butyl amine and reports no optical rotation and no enantiomeric excess for the compound disclosed in the supplementary experimental data. Stevenson does not teach every feature of the claimed invention.
Applicants’ arguments filed 11 Sep. 2026 have been fully considered but they are not persuasive. At scheme 1, Stevenson provides for the synthesis of compound 11 where at step (e) (ii) sec-butyl amine gets reacted with the acid chloride derived from compound 9 to form compound 10. The chemical name sec-butyl amine also refers to (±)-sec-butylamine both of which comprising (R)-sec-butylamine and (S)-sec-butylamine. In other words, neither (R)-sec-butylamine nor (S)-sec-butylamine alone can be purchased or referred to as sec-butylamine since sec-butyl amine means (±)-sec-butylamine. The reaction conditions applied at steps (e-(g) are not expected to alter the stereoisomeric ratio of the (±)-sec-butylamine that forms the amide of compound 10. Stevenson teaches that compounds 10, 11 and the intermediate bromide in instant formula (III) as a mixture of stereoisomers. Accordingly, Stevenson anticipates claims 14-17 since the compound of instant formula (III) formed by Stevenson at scheme 1 and S6 comprises the claimed (R-III).
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) 14-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stevenson et al. (Bioorg. Med. Chem. Lett.; published 22 Dec. 2009), in view of Cappelli et al. (Bioorg. Med. Chem.; published 2006) and Wadsworth et al. (US 2011/0190618 A1; published 4 Aug. 2011) for the reasons cited in the Office action filed on 11 May 2026.
Stevenson et al. teach as discussed above. Stevenson et al. teach new iodinated quinoline-2-carboxamides for SPECT imaging of translocator protein (see title). A number of PET and SPECT ligands for molecular imaging of TSPO have been developed (pg. 954). These analogues have the potential to be used for PET (18F) imaging (pg. 596).
Stevenson et al. do not teach instant formulas (I) or (II) or a method of preparing formulas (I) and (II) wherein the method comprises the step of substituting the bromine of the compound of formula ((R-)III) with (18F-)fluorine. Stevenson et al. do not teach a method wherein the compound of formula (IV) is prepared from the compound of formula (III) by substitution of the bromine in the compound of formula (III) with chlorine. Stevenson et al. do not teach a kit comprising (R-)III and fluorine anion optionally as a fluorine salt.
Cappelli et al. teach the synthesis, labeling, and biological evaluation of halogenated 2-quinolinecarboxamides as potential radioligands for the visualization of peripheral benzodiazepine receptors (see title). Cappelli et al. teach compounds 6a-d
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: 6a (X=F, IC50=11 nM), 6b (X=Cl, IC50=0.30 nM), 6c (X=Br, IC50=0.61 nM), and 6d (X=I, IC50=0.40 nM) (pg. 4058, table 1). The compounds were prepared by the reactions in scheme 3
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(pg. 4058). The most potent 3-fluoromethyl derivative 6a shows an IC50 value of 0.11 nM and is about 20 times more potent than reference compound 1 and represents an interesting candidate for labeling with 18F and PET studies (pg. 4058). The halogen effect is particularly evident in the case of fluoromethyl derivative 6a and appears to correlate with the electron withdrawing properties of the halogen atom (pg. 4058).
Wadsworth et al. teach imaging neuroinflammation (see title). Wadsworth et al. teach (R)-[11C]PK11195 of imaging of central nervous system (CNS) inflammation ([0005]). Wadsworth et al. teach a kit for the preparation of in vivo imaging agent. The kit comprises a precursor compound and means for fluorinating with fluoride ion ([0110]-[0118]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the Stevenson et al. by preparing compounds of instant formulas (II) or (III) using a method that comprises the step of substituting the bromine of a compound of formula (III), (R-III), or (II), optional prepared by substituting the bromine of cited bromine precursor in Stevenson et al. with chloride ion, with (18F-)fluoride ion to arrive at compounds of instant formulas (I) and (II) as taught by Cappelli et al. and Stevenson et al. because the preparing would have been expected to advantageously enable (18)F-labeled quinoline-2-carboxamide congeners capable of PET imaging expected to have lower lipophilicity and increased binding affinity possibly due to a halogen effect that activates the methylene hydrogen atoms which could interact with D157 by establishing a non-classical hydrogen bond. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Stevenson et al. by further forming a kit comprising the (III), (R-III) or the obvious (IV) and a fluoride ion such as ([18F])KF as taught by Cappelli et al. and Wadsworth et al. because that kit would have been expected to enable facile 18F-labeling to arrive at the formula (II) or (R-II). Stereoisomers are prima facie obvious. See In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978). In addition, Wadsworth et al. teach the (R) enantiomer as the preferred sec-butyl enantiomer of PK11195.
Applicants’ Arguments
Applicants assert that the Examiner has already acknowledged in the parent case that the compounds of formula (I) and (II) are non-obvious in view of Stevenson and Cappelli. In the interest of compact prosecution, the full arguments and inventor declaration from the parent case are not repeated herein. A prima facie case of obviousness has not been established because the cited combination of references fails to teach or suggest every feature of the presently claimed invention. Cappelli does not teach how to achieve this 18F radiolabeling. In scheme 1, fluorine is introduced by cold fluorination using KF and 18-crown-6 under reflux for 14 h. The reaction time is too long for 18F radiolabeling and a large proportion of the 18F would decay during the reaction. The scheme 3 of Cappelli is not suitable for 18F radiolabeling since the fluorine is present from an early stage. From Wadsworth, there is no expectation that this teaching in the context of PK11195 would be transferable to the claimed compounds. There is no suggestion that the R enantiomer is superior to the S enantiomer. The cited combination of references fails to teach or suggest every feature of the claimed invention and one of ordinary skill would have no apparent reason to modify the teachings of the cited references to arrive at the claimed invention.
Applicants’ arguments filed 11 Sep. 2026 have been fully considered but they are not persuasive. As discussed above, Stevenson anticipates claims 14-17. An allegation of unexpected results cannot be used to overcome a rejection of claims under 35 USC 102. A declaration of unexpected results has not been filed in the instant application. The instant specification does not provide a showing of unexpected results for the claimed compounds. In addition, Stevenson teaches the compounds (III) as precursor for iodination. Wadsworth teaches the (R)-enantiomer of the sec-butyl amine as the preferred enantiomer for the TSPO binding compound PK11195. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Stevenson so that the compounds (III) is the compound (R-III) because it would have been expected to advantageously enable preparation of a (R)-11 exhibiting enhance TSPO binding.
Instant claim 22 is merely directed to a kit comprising a compound of the formula (III) and fluoride ion. At pg. 4057 and scheme 1, Cappelli teaches reaction of the compound 6b, analogous to instant formula (III) where Cl replaces the Br) with KF (fluoride ion) and 18-Crown-6 to replace the Cl with F. Wadsworth teaches kits comprising a precursor compound and means for fluorinating with fluoride ion. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Stevenson so that the instant formula (III) compound is provided together with fluoride ion as part of a kit because that kit would have been expected to enable facile fluorination. Regarding Wadsworths’ teaching of (R)-[11C]PK11195 containing only the (R)-sec-butylamine, at pg. 954 Stevenson provides a teaching of the PK11195. A person of ordinary skill in the art would have understood from Wadsworth that the (R)-enantiomer is the preferred enantiomer for PET imaging of central nervous system inflammation. It would have been obvious to a person of ordinary skill in the art before the effective filing date to use instant (R-III) or instant (R-IV) in lieu of instant (III) or instant (VI) as precursors for fluorination because those precursors would have been expected to provide (R-I) by direct fluorination. At pg. 4062, Cappelli prepared mg quantity of 6a by direct fluorination reaction and provides no optimization discussion. For Cappelli could have let the reaction stir overnight without checking it. In contrast, [18F]fluorination by direct nucleophilic substitution using reactive [18F]fluoride ion is routinely carried out at tracer amounts and within a time frame suitable for PET imaging studies. See Wadsworth at example 7(vi). Application should provide evidence that [18F]fluorination by direct nucleophilic substitution using reactive [18F]fluoride ion analogous to the fluoride ion disclosed at scheme 1 in Cappelli is not suitable to preparing instant formula (II)
New Grounds of Rejection
Claim Rejections - 35 USC § 103
Claim(s) 25-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stevenson et al. (Bioorg. Med. Chem. Lett.; published 22 Dec. 2009), in view of Shah et al. (Nucl. Med. Biol.; published 1994; see attached 892).
Stevenson et al. teach new iodinated quinoline-2-carboxamides for SPECT imaging of translocator protein (see title). A number of PET and SPECT ligands for molecular imaging of TSPO have been developed (pg. 954). These analogues have the potential to be used for PET (18F) imaging (pg. 596). Stevenson et al. teach 4-phenyl-3-bromomethylquinoline-2-N-methyl-N-sec-butylcarboxamide (pg. S6) as a precursor to compound 11 (scheme 1; pgs. S6-S7; table 1).
Stevenson et al. do not teach a compound of instant formula (R-III) that is at least 90% optically pure or at least 99% optically pure.
Shah et al. teach the synthesis of enantiomers of [N-methyl-11C]PK11195 and comparison of their behaviours as radioligands for PK binding sites in rats (see title). Shah et al. teach R-(-)- and S-(+)-sec-butylamine (99% purity) and the synthesis of R-[11C]I and S-[11C]I (scheme 1). Shah et al. teach an approximately 2-fold greater affinity of the R-enantiomer for PK binding sites in vitro and that the use of this enantiomer has advantages over the use of the racemate currently used for PET studies (see abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Stevenson et al. (4-phenyl-3-bromomethylquinoline-2-N-methyl-N-sec-butylcarboxamide) so that the compound is at least 90% optically pure or 99% optically pure as taught by Shah et al. because those optical purities would have been expected to advantageously enable the preparation of an R-11 having enhanced TSPO binding affinity.
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
