Detailed Action
The present office action is in response to the amendments filed on 23 Feb 2026.
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
Claims 1-4, 6-8, 11-13, and 20-23 of the pending application have been examined on the merits. Claims 5, 9-10, 15-17, and 19 remain withdrawn. Acknowledgement is made of the cancellation of claims 14 and 18.
Priority
Applicants identify the instant application, Serial #: 17/777,571, filed 17 May 2022, as a National Stage Entry of International Patent Application #: PCT/EP2020/082778, filed 19 Nov 2020, which claims foreign priority from Foreign Application #: EP19210073.3, filed 19 Nov 2019.
Response to Applicant Arguments
Acknowledgement is made of the remarks filed 23 Feb 2026.
The rejection of claim 1 under 35 U.S.C. § 112(b) is rendered moot following applicant amendments.
Regarding the claim interpretation examiner noted in the office action mailed 01 Oct 2025, applicant submits that the claims should be interpreted in view of the specification and under prevailing law.
Examiner previously provided evidence to support the claim interpretation that the pyrazole compounds of the instant application exhibit tautomerization in equilibrium and that the pyridine ring may alternately appear at the 3 or 5 position of the pyrazole core (see office action mailed 01 Oct 2025). Applicant has provided no evidence in the art or specification to show this is not the case for the instant compounds, and thus the arguments are not persuasive. See MPEP § 2145(I). The claim interpretation is restated below.
Regarding the rejection of claims 1-4, 6-8, 11-13, and 20-23 under 35 U.S.C. § 1103 over Maurer et al. (J Label Compd Radiopharm, 2017, 60:554; provided in the office action mailed 01 Oct 2025), Patani et al. (Chem Rev, 1996, 96:3147-3176; provided in the office action mailed 01 Oct 2025), hereinafter Patani, Hitchcock et al. (J Med Chem, 2006, 49:7559-7583; provided in the office action mailed 01 Oct 2025), hereinafter Hitchcock, and WO 2010/000372 (provided in IDS 05/17/22), hereinafter ‘372, applicant arguments have been fully considered but are not persuasive.
Applicant argues on pg. 8 of the remarks, filed 23 Feb 2026, that Table 6 contains three comparison series 1 to 3 and that the comparison compounds include the compounds taught in Maurer. Applicant argues that the phenyl group of Maurer being replaced by the pyridine ring of the instant claims results in much higher binding affinity to alpha-synuclein fibrils than what is seen with the Maurer compounds. Applicant also points to Tables 3a, 3b, 4a, 4b, 5, and 7 to further support the showing of various improved properties. Applicant argues that a person of ordinary skill in the art could not have predicted the greater affinity achieved by swapping the phenyl ring of Maurer for a pyridine ring to arrive at the compound of the instant claims.
This is not persuasive. Tables 3a, 3b, 4a, 4b, and 7 do not indicate that the instantly elected Compound 2 provides unexpected results compared to instant Compounds of 64 and 65 (the Maurer compounds). For tables 5 and 6 where instant compound 2 is compared to instant Compounds 64 and 65, the reported Ki values do not include reported errors. This applies to all the tables referenced by applicant. Further, the claims of unexpected results do not apply to the full range of claimed compounds, as many compounds have similar or lower binding affinity for alpha synuclein fibrils than instant Compounds 64 and 65.
In light of the discussion above, the rejection of claims 1-4, 6-8, 11-13, and 20-23 under 35 U.S.C. § 103 as obvious over Maurer, Patani, Hitchcock, and ‘372 maintained for the reasons of record and restated below
Regarding the obviousness-type double patenting rejections of claims 1-4, 6-8, 11-13, and 20-23 over U.S. Patent No. 10,435,373, claims 1-4, 12-13, and 21 over U.S. Patent No. 10,071,966, and claims 1-6, 6-8, 12-13, and 21 over U.S. Patent No. 10,308,671, all further in view of Patani and Hitchcock, applicant arguments have been fully considered but are not persuasive.
Applicant argues that Patani and Hitchcock cannot render the claims obvious, as neither of these references suggests the unexpected technical improvements achieved by the claimed compounds.
This is not persuasive. Applicant has not provided a showing of unexpected technical improvements as discussed above and so the obviousness-type double patenting rejections are maintained and restated below for the reasons of record.
Claim Interpretation
The instantly elected compound has a pyrazole core, which exhibits tautomerization as exemplified by Secrieru et al. (Molecules, 2020, 25:42; provided in the office action mailed 01 Oct 2025), cited for evidentiary purposes (see pgs. 3-14, Section 3). This tautomer exists in equilibrium and thus the pyridine ring may alternatively appear at the 3 or the 5 position of the pyrazole ring.
Pyrazole Tautomer I
Pyrazole Tautomer II
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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, 6-8, 11-13, and 20-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maurer, further in view of Patani, Hitchcock, and ‘372.
Instant claim 1 is drawn to compounds of the following structures:
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Applicant has elected Compound 2 (below) which reads on Formula IIa:
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When X1 is N; X2 is NH; X3 is CH; Y1 is N; Y2, Y3, Y4, Y5, Y6, Y7, and Y8 are CH; Hal is Br; R4 is CH3; and R5 is H. These compounds read on instant claims 1-4, 6-8, and 21. Further claims require Compound 2 to be detectably labeled (claims 11 and 22-23), in a composition with a pharmaceutically acceptable carrier (claims 12-13), and in a kit for preparing a detectably labeled Compound 2.
Maurer teaches anle253b and a precursor compound (Fig. 1):
Precursor Compound
Anle253b
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Maurer further teaches that anle253b was successfully radiolabeled with 11C and binds to alpha-synuclein in vivo (Methods and Conclusions) and that this is good indication of anle253b’s ability to bypass the blood-brain barrier (Conclusions). Maurer also teaches adding the precursor molecule in aqueous buffer prior to being labeled to produce anle253b. The pyrazole core is in tautomeric equilibrium such that the bromobenzene ring is present on both the 3 and 5 position on the pyrazole (see “Claim Interpretation” above). However, Maurer does not teach the elected Compound 2.
Patani teaches that the trivalent substitution of -CH= with -N= is commonly used in modern drug design and provides examples such as the replacement of CH with N to create the antibacterial agent enoxacin (pg. 3159, column 2).
Hitchcock teaches the influence chemical structure has on penetration of the blood-brain barrier and that there are five suggested physicochemical property ranges for increasing the potential for blood-brain barrier penetration (pg. 7560, column 1; and pg. 7561, column 2 to pg. 7562, column 2). These physicochemical properties include polar surface area, hydrogen bond donors, cLogP, cLogD, and molecular weight (pg. 7562, Table 1). Hitchcock also teaches that modifying -CH= for -N= can keep many of the same properties for a molecule, but modifies the cLogP and cLogD to test blood-brain barrier penetration (pg. 7569, Fig. 16).
‘372 teaches preparing a kit containing compounds of Formula (B) for diagnostic imaging of alpha-synuclein (pg. 14, line 10; and pg. 31, lines 15-26):
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‘372 further teaches that radioactive labels which emit positrons and which have a short half-life such as 11C will be useful and that due to such a short half-life the labelled compounds should be prepared shortly before they are used for testing. ‘372 teaches that providing a diagnostic composition of the disclosed invention can be provided in the form of a kit which consists of precursors of the compounds of the invention which are reacted to form the desired compound (pg. 31, lines 19-24).
Based on the teachings of Maurer, Patani, and Hitchcock, a person of ordinary skill in the art would know that pyridine is a commonly used bioisostere of phenyl, as taught by Patani. Further, as taught by Maurer and Hitchcock, the artisan would modify the bromophenyl ring of anel253b to a pyridine ring and arrive at the instant invention. The artisan would be motivated to perform this bioisosteric swap to lower cLogP and cLogD to better enable blood-brain barrier penetration of anel253b.
By possessing the modified anel253b, it would be obvious to a person having skill in the art that Maurer would also possess a modified precursor, which is identical to the instantly elected invention.
Further, by having the precursor in an aqueous solution, Maurer teaches having a pharmaceutical and diagnostic composition of the instantly elected invention.
Based on the teachings of Maurer and ‘372, a person having ordinary skill in the art would wait to form the radiolabeled molecule until shortly before testing. The artisan, as taught by ‘372, would prepare a kit with precursors that could be reacted to form the diagnostic molecule. The artisan would be motivated to make this kit because the half-lives of radiolabels, such as 11C, are so short and so are only detectable for a short time after being prepared.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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 1-4, 6-8, 11-13 and 20-23 are rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 10,435,373 in view of Patani and Hitchcock.
The reference claims are drawn to pharmaceutical compositions containing compounds represented by Formula (E) and a pharmaceutically acceptable carrier (claim 1):
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Formula (E) includes structures that are close to the instant claims, such as:
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or
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where Hal is Cl or Br. The reference also claims a diagnostic composition comprising a radiolabeled compound of Formula (E) and a pharmaceutically acceptable carrier (claim 12). However, the reference has a phenyl ring in place of pyridinyl as in the instant claims.
Patani teaches that the trivalent substitution of -CH= with -N= is commonly used in modern drug design and provides examples such as the replacement of CH with N to create the antibacterial agent enoxacin (pg. 3159, column 2).
Hitchcock teaches the influence chemical structure has on penetration of the blood-brain barrier and that there are five suggested physicochemical property ranges for increasing the potential for blood-brain barrier penetration (pg. 7560, column 1; and pg. 7561, column 2 to pg. 7562, column 2). These physicochemical properties include polar surface area, hydrogen bond donors, cLogP, cLogD, and molecular weight (pg. 7562, Table 1). Hitchcock also teaches that modifying -CH= for -N= can keep many of the same properties for a molecule, but modifies the cLogP and cLogD to test blood-brain barrier penetration (pg. 7569, Fig. 16).
Based on the teachings of the reference patent, Patani, and Hitchcock, a person of ordinary skill in the art would know that pyridine is a commonly used bioisostere of phenyl, as taught by Patani. Further, as taught by the reference patent and Hitchcock, the artisan would modify the halophenyl ring of the reference patent to a pyridine ring and arrive at the instant invention. The artisan would be motivated to perform this bioisosteric swap to lower cLogP and cLogD to better enable blood-brain barrier penetration of the reference compounds.
Claims 1-4, 6-8, 12-13 and 21 are rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 10,071,966 in view of Patani and Hitchcock.
The reference claims are drawn to a method of treating a disease of protein aggregation in a subject by administering to a subject compounds represented by Formula (E) (claim 1):
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Formula (E) includes structures that are close to the instant claims, such as:
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or
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where Hal is Cl or Br. By claiming a method of treating by administering the reference compounds, the reference shows inherent possession of the claimed compounds. However, the reference has a phenyl ring in place of pyridinyl as in the instant claims.
Patani teaches that the trivalent substitution of -CH= with -N= is commonly used in modern drug design and provides examples such as the replacement of CH with N to create the antibacterial agent enoxacin (pg. 3159, column 2).
Hitchcock teaches the influence chemical structure has on penetration of the blood-brain barrier and that there are five suggested physicochemical property ranges for increasing the potential for blood-brain barrier penetration (pg. 7560, column 1; and pg. 7561, column 2 to pg. 7562, column 2). These physicochemical properties include polar surface area, hydrogen bond donors, cLogP, cLogD, and molecular weight (pg. 7562, Table 1). Hitchcock also teaches that modifying -CH= for -N= can keep many of the same properties for a molecule, but modifies the cLogP and cLogD to test blood-brain barrier penetration (pg. 7569, Fig. 16).
Based on the teachings of the reference patent, Patani, and Hitchcock, a person of ordinary skill in the art would know that pyridine is a commonly used bioisostere of phenyl, as taught by Patani. Further, as taught by the reference patent and Hitchcock, the artisan would modify the halophenyl ring of the reference patent to a pyridine ring and arrive at the instant invention. The artisan would be motivated to perform this bioisosteric swap to lower cLogP and cLogD to better enable blood-brain barrier penetration of the reference compounds.
Claims 1-4, 6-8, 12-13 and 21 are rejected on the ground of obviousness-type nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,308,671 in view of Patani and Hitchcock.
The reference claims are drawn to compounds of formulas (Ia) and (Ib):
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Formulas (Ia) and (Ib) include structures that are close to the instant claims, such as:
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where Hal is Cl or Br. However, the reference has a phenyl ring in place of pyridinyl as in the instant claims.
Patani teaches that the trivalent substitution of -CH= with -N= is commonly used in modern drug design and provides examples such as the replacement of CH with N to create the antibacterial agent enoxacin (pg. 3159, column 2).
Hitchcock teaches the influence chemical structure has on penetration of the blood-brain barrier and that there are five suggested physicochemical property ranges for increasing the potential for blood-brain barrier penetration (pg. 7560, column 1; and pg. 7561, column 2 to pg. 7562, column 2). These physicochemical properties include polar surface area, hydrogen bond donors, cLogP, cLogD, and molecular weight (pg. 7562, Table 1). Hitchcock also teaches that modifying -CH= for -N= can keep many of the same properties for a molecule, but modifies the cLogP and cLogD to test blood-brain barrier penetration (pg. 7569, Fig. 16).
Based on the teachings of the reference patent, Patani, and Hitchcock, a person of ordinary skill in the art would know that pyridine is a commonly used bioisostere of phenyl, as taught by Patani. Further, as taught by the reference patent and Hitchcock, the artisan would modify the halophenyl ring of the reference patent to a pyridine ring and arrive at the instant invention. The artisan would be motivated to perform this bioisosteric swap to lower cLogP and cLogD to better enable blood-brain barrier penetration of the reference compounds.
Conclusion
No claims are allowed. 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jonathan D. Mahlum whose telephone number is (703)756-4691. The examiner can normally be reached 8:30 AM - 5:00 PM ET, M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached on (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.D.M./Examiner, Art Unit 1625
/Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625