DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 1-17 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 1-17 are original.
Response to Amendment
The amendments filed on 18 Feb. 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.
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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) 1-13, and 16-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Darvesh et al. (WO 2010/025368 A1; published 4 Mar. 2010), in view of Patani et al. (Chem. Rev.; published 1996) and Kuhl et al. (Ann Neurol.; published 2006) for the reasons cited in the Office action filed on 18 Sep. 2025.
Applicants Arguments
Applicants assert that if the negatively charged carboxylate is present on the same moiety that contains the radioisotope, then imaging will take place for the leaving group. A radiolabel that remains will diffuse more slowly and may well be impacted by tissue features in the vicinity of the enzyme. There is no motivation to apply the teaching of Kuhl to that of the Patani and Darvesh references. The analysis in the Kuhl reference is entirely divorced from any attempt to establish binding of BuChE in the presence of pathology. The teaching of the Kuhl reference neither discloses nor suggests evidence that a given compound is a substrate for BuChE in the brain.
Applicant's arguments filed 18 Feb. 2026 have been fully considered but they are not persuasive. Darvesh provides for (6-oxo-1,6-dihydropyridin-2-yl)methyl 4-[123I]benzoate
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(compound 21) as a substrate for BuChE to facilitate SPECT detection of diseases associated with dysregulation of BuChE. In addition, Darvesh provides for the N-methyl precursor compound
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obtained using MeI and K2CO3. Darvesh designed the compound 21 so that compound is radiolabeled on a functional group of the compound that remains in contact with the BuChE after enzymatic. Darvesh teaches the available BuChE radioligand 1-[11C]-methyl-4-piperidinyl n-butyrate having a radiolabel attached to a portion of the molecule that is an initial leaving. At example 56, Darvesh provides for SPECT imaging with compound 21 and the result indicate that the compound penetrates into the brain and can be imaged. However, Darvesh does not exemplify or provide a means for quantitative detection of BuChE to determine deviations from the norm. Kuhl teaches and motivates quantitative assessment of BuChE using the [11C]BMP radioligand having a releasable label and kinetic modeling. The data provided by Kuhl and previously support the validity of the PET measure as a method appropriate to the in vivo assessment of BuChE activity. Kuhl teaches a kinetic K3 value obtained using a releasable label that agrees well with regional distributions of BuChE. In the case of Kuhl, the [11C]BMP comprising a releasable radiolabel enabled satisfactory quantitation of BuChE in AD pathology allowing an assessment of BuChE inhibitor therapy for AD. A recognized advantage is the strongest reason to combine. It would have been obvious to a person for ordinary skill in the art before the effective filing date to modify the compound 21 in Darvesh by reversing the ester moiety to arrive at a compound instant formula (I) because the reversed ester derivative would have been expected to advantageously enable quantitative assessment of diseases associated with dysregulation of BuChE. There would have been a reasonable expectation of success since a reversed ester is similar to the well-known reversed amide bioisosteric replacement taught by Patani and therefore the reversed ester would have been expected to be hydrolyzed by BuChE in a manner to compound 21 but advantageously provide a releasable that enabled kinetic modeling and quantitative assessment. A reversed ester of compound 21 in Darvesh would have been expected to function as an inhibitor of BuChE enabling the therapeutic use of the revered ester in BuChE associated pathology. O- and N-methyl derivatives are prima facie obvious to the general expectation of similar properties. See In re Wood, 199 USPQ 137 (CCPA 1978) and In re Lohr, 137 USPQ 548, 549 (CCPA 1963).
Claim(s) 1-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Darvesh et al. (WO 2010/025368 A1; published 4 Mar. 2010), in view of Patani et al. (Chem. Rev.; published 1996) and Kuhl et al. (Ann Neurol.; published 2006), in further view of MacDonald et al. (US 2015/0217004 A1; published 6 Aug. 2015) for the reasons cited in the Office action filed on 18 Sep. 2025.
Applicants Arguments
Applicants assert that MacDonald does not cure the deficiency of the combination of the Darvesh, Patani, and Kuhl references, including that it does not teach or suggest formulas I, II, or III or a pharmaceutical composition thereof or the claimed methods.
Applicant's arguments filed 18 Feb. 2026 have been fully considered but they are not persuasive. Darvesh, Patani, and Kuhl are not deficient for the reasons discussed above. MacDonald teaches compounds that are BuChE inhibitors. The compounds have utility in the treatment and diagnosis of AD, PD, and HD and other diseases in which alteration of quantities, location, or regulation of BuChE in brain may be diagnostic of a pathology. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Darvesh so that the method of diagnosing further includes the diagnosing of PD and HD as BuChE associated pathologies because the further diagnosing of PD and HD would have been expected to provide in vivo diagnosis of PD and HD based on quantities, location or regulation of BuChE.
Claim(s) 1-2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hayashi et al. (Bioorg. Med. Chem. Lett.; published 2007), in view of D’Armiento et al. (WO 2017/201441 A1; published 23 Nov. 2017) for the reasons cited in the Office action filed on 18 Sep. 2025.
Applicants Arguments
Applicants assert that the Hayashi reference teaches MMP inhibitors which are a different are of drug design than BuChE. A person of ordinary skill in the art would not have been motivated to substitute I-123 for any of the halogens taught in table 1 because even if the D’Armiento reference shows this would be desirable in an imaging agent, the SAR specific to MMP does not support it. Methylating the proximal NH position as in claimed formula II would substantially alter keto-enol interaction and affect binding.
Applicant's arguments filed 18 Feb. 2026 have been fully considered but they are not persuasive. Instant claims 1 and 2 are only directed to compounds of formula (I) and (II). Nothing in claims 1 and 2 require inhibition of BuChE. Hayashi teaches MMP inhibitors 17, 26, and 29 that differ from a compound of instant formula (I) by mere halogen substitution. It is prima facie obvious to substitute one halogen for another due to the general expectation of similar properties. Indeed, all of 17, 26, and 29 that differ by halogen substitution exhibited affinity for MMP-1, MMP-2, MMP-9, and MMP-12. Hayashi does not teach that I substitution would result in a complete loss of MMP affinity. D’Armiento teaches and motivates SPECT imaging of MMPs using the 123I radiolabel. 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 cited compounds of Hayashi by substituting the halogen substituent with 123I as taught by D”Armiento because the 123I substituent would have been expected to provide the advantage of MMP associated disease including cancer. Hayashi provides the following description a hypothetical binding of pyridinone-based MPIs
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. The obvious N-methyl derivative of instant formula (II) that is a pyridinone would be expected to show a similar binding interaction.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 8,795,630 B2, in view of Darvesh et al. (WO 2010/025368 A1; published 4 Mar. 2010), Kuhl et al. (Ann Neurol.; published 2006), and MacDonald et al. (US 2015/0217004 A1; published 6 Aug. 2015) for the reasons cited in the Office action filed on 18 Sep. 2025.
Applicants Arguments
Applicants assert that the Kuhl reference actually teaches away from the claimed invention. Changing the direction of the amide changes the ring that bears the carboxyl group upon hydrolysis of BuChE. A radiolabel that remains will diffuse more slowly and may well be impacted by tissue features in the vicinity of the enzyme. The analysis in the Kuhl reference is entirely divorced from any attempts to establish binding of BuChE in the presence of pathology. The teachings of the Kuhl reference neither disease nor suggest evidence that a given compound is a substrate for BuChE in the brain.
Applicant's arguments filed 18 Feb. 2026 have been fully considered but they are not persuasive. The claims of the ‘630 patent claim the above discussed compound 21 in Darvesh and methods of diagnosing neurological conditions. As discussed above, Kuhl provides adequate reason and motivation to modify the compound 21 to arrive at a reversed ester of instant formula (I). As discussed above, MacDonald provides adequate reason and motivation to use a BuChE inhibitor for diagnosing PD and HD. It would have been obvious to a person of ordinary skill in the before the effective filing date to the claims of the ‘630 patent by reversing the ester derivative of the claimed compound 21 to arrive at the compound of instant formula (I) as taught by Kuhl because the reversed ester derivative would have been expected to enable quantitative assessment of BuChE in BuChE associated pathologies using kinetic modeling.
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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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618