DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 4, 6-7, and 9-12 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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5 Jun. 2026 as being considered by the examiner.
Response to Amendment
The amendments filed on 5 Jun. 2026 have been entered.
Response to Arguments
In view of Applicants amendments, the objections to claims 9, and 11-12 because of minor informalities is withdrawn.
In view of Applicants amendments, the rejection of claim 11 under 35 USC 112(b) as being indefinite for failing to particularly point out and distinctly claim the invention is withdrawn.
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) 4, 6-7, and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Coe et al. (WO 2014/072881 A1; published 15 May 2014) for the reasons cited in the Office action filed on 8 Dec. 2025.
Claim(s) 4, 6-7, and 9-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Coe et al. (WO 2014/072881 A1; published 15 May 2014), in view of Kusmierek et al. (US 2008/0096926 A1; published 24 Apr. 2008) and Beadle et al. (US 2014/0357664 A1; published 4 Dec. 2014) for the reasons cited in the Office action filed on 8 Dec. 2025.
Applicants Arguments
Applicants assert that one of ordinary skill in the art would recognize that incorporation of a 18F at the benzylic methyl substituent to form [18F]FMe-215 (-) would not necessarily have led to an orthosteric modulator of the D1 like receptors having high D1 binding affinity and that is capable of being used in PET studies as suggested by the Office. Any pharmacokinetic data reported for compounds of formula (Ia) or (Ic) in the instant specification would also apply to the compounds of formula (Ib). The claimed compound has an unexpectedly high affinity for D1 receptors. Not only does the compound of formula (I) have a high affinity for human D1 receptor (pKi=9.2) but the compounds are also highly selective for human D1 receptor (pKi<6 for the other 79 tested compounds). The modification of compound 1 to include a benzylic fluorine atom leads to an increase in Ki. Applicants does not concede that the pair of compounds 1 and 21 of Coe would have given one of ordinary skill in the art any reason to modify compound 215 with a benzylic 18F to arrive at the claimed compound.
Applicants assert that the claimed compound has an unexpectedly desirable brain kinetics. The prior art of Becker teaches that removal of one additional fluorine can result in vastly different brain kinetics.
Applicants assert that the claimed compound has an unexpectedly desirable metabolite profiled. Radio-metabolites that are more lipophilic than the parent radioligand can lead to issues in brain imaging studies. The claimed compound is susceptible to low metabolic conversion. The compounds of formula (I) have desirable brain kinetics and can cross the BBB. The metabolic conversion of the compound of formula (Ib) is sufficiently low, in view of the half-life of 18F, to result in an effective amount of compound in the brain.
One of ordinary skill would appreciate that the metabolism of D1 PET tracers can result in metabolites that have undesirable brain kinetics, and thereby potentially lower the signal to noise ratio.
Applicants assert that the claimed compound has a high specific to non-specific binding ratio in autoradiography studies. See specification, pp 36-27 and Fig. 4. Only 20% of the significant binding in the caudate putamen was non-specific binding. The binding is enhanced in the present of a positive allosteric modulator. There is nothing in Coe that suggests that compound 215 of Coe, much less a benzylic version would have highly specific binding when used in autoradiography.
Applicant's arguments filed 5 Jun. 2026 have been fully considered but they are not persuasive. Coe provides for example 215 as the closest prior art compound having a human D1 receptor pIC50 value of about 9 which is similar to pKi value determined for the claimed formula (Ib). Allegations of unexpected results must compare the claimed subject matter with the closest prior art in order to be effective to rebut a prima facie case of obviousness. See In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). In this case, the Examiner is unable to locate a direct comparison with the example 215 in the same experiments to demonstrate an unexpected improvement in binding affinity resulting the incorporation of the benzylic 18F. At page 18, Coe teaches that positron emitters 18F can be useful in PET studies for examining substrate receptor occupancy. At example 21, Coe provides some teach and suggestion for claimed benzylic F with a reasonable expectation of success. 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 example 215 by incorporating a benzylic 18F with a reasonable expectation of success because the incorporating would have been expected to advantageously enable 18F PET imaging human D1 receptors in diseased and non-diseased states. Like instant formula (Ib), example 215 is amenable to isotopologues that would allow for comparative evaluation of brain kinetics and metabolism studies. Applicants have not provided any comparative testing that demonstrates an unexpectedly improved metabolism profile in comparison the example 215 in Coe. In addition, Applicants have not provided any comparative experiments to demonstrate an unexpectedly improved specific to non-specific binding ratio in autoradiographic studies in comparison the prior art example 215 in Coe.
Conclusion
THIS ACTION IS MADE FINAL. 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 SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST.
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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.
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/SEAN R. DONOHUE/
Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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