DETAILED ACTION
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 .
Election/Restrictions
Applicant’s election without traverse of Compound 98
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in the reply filed on 15 October 2025 is acknowledged. This compound reads on Claims 1-3, 5, 6, 13, 30, 33-35, and 113-119. A search was performed for the claimed compound with no prior art retrieved. The search was then expanded to R5 as all cycles, with prior art retrieved. The search was further expanded to all R5 options, with prior art retrieved. The search was then expanded to all variable X1 options, with prior art retrieved (See STN Search, Search Notes). The search was then stopped.
Claims 7-12, 17-19, 21-25, 29, 32, 36, 40, 42, 44, 46, 50, 52, and 54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 15 October 2025.
Claims 1-3, 5, 6, 13, 30, 33-35, and 113-119, submitted on 15 October 2025, represent all claims currently under consideration.
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.
Priority
This application is a 371 of PCT/US2021/015271, filed 27 January 2021, which claims priority to provisional US 62/966,978, filed 28 January 2020. The effective filing date is 28 January 2020.
Information Disclosure Statement
Two Information Disclosure Statements (IDSs), submitted on 26 October 2022 and 15 October 2025, are acknowledged and have been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 has several provisos that contain an “and” between each individual proviso. The Examiner believes the “and” should be replaced with an “or” to avoid potential confusion. Appropriate correction is required.
Claims 116-119 are objected to because of the following informalities: “TTR” needs to be defined prior to the abbreviation being used in each claim. The Examiner is assuming that “TTR” stands for Transthyretin Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 5, 6, 13, 30, 33-35, and 114-119 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims are indefinite due to the presence of parentheticals within Claims 1-3 and 114. For example, Claim 1 states “Ar is aryl, heteroaryl, or heteroarlyium (all optionally substituted)”. It is unclear if what is found within each parenthetical is a necessary part of the invention. Claims 5, 6, 13, 30, 33-35, and 115-119 are rejected as indefinite as they depend upon an indefinite claim without resolving the underlying issues of indefiniteness. The Examiner suggests amending each (all optionally substituted) to be stated in a manner such as “Ar is aryl, heteroaryl, or heteroarylium, each of which may be optionally substituted” or similar.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 5, 6, 13, 30, 33-35, and 113-119 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Prasad (WO 2020/243720; Publication Date: 3 December 2020; Priority to 31 May 2019).
Prasad (See IDS, 26 October 2022) discloses methods of treating presbyopia or cataract in a subject in need thereof. The methods require administering an effective amount of a composition that inhibits the formation of high molecular weight aggregates of human α-A-crystallin. A method of preventing and/or treating transthyretin (TTR)-associated amyloidosis using these compounds is also provided (Abstract). Compounds of the invention are capable of preventing the aggregation of human ACC as well as dissolving ACC inclusions (Paragraph 0012). The present disclosure also provides a method for preventing and/or treating transthyretin (TTR)-associated amyloidosis using a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Paragraph 0051 provides exemplary compounds which meet the limitations of the claims of the examined application.
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has variable X1 as O, variables R1 and R2 as H, n as 0, variable X2 as bond, and variable R5 as alkyl substituted with hydroxyl.
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has variable X1 as NH, variable R1 as COOH, variable R2 as H, n as 1, and variable R5 as COOH.
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has variable X1 as O, variables R1 and R2 each as H, n as 0, X2 as bond, and R5 as COOR15 with R15 as alkyl substituted with NH2.
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has variable X1 as O, variables R1 and R2 each as H, n as 1 with R3 as H and R4 as alkyl, X2 as bond, and R5 as COOR15 with R15 as alkyl substituted with alkyl and NH-O-CO.
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has variable X1 as O, variables R1 and R2 as H, n as 0, variable X2 as bond, and variable R5 as alkyl substituted with (-CH2OH)2. Compound CAP4355 (Table 1, Page 27)
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has variable X1 as O, variables R1 and R2 as H, n as 0, variable X2 as bond, and variable R5 as
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with variable R17 as methyl. This compound is identical to Compound 24 of the examined application.
Claim Rejections - 35 USC § 103
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.
Claims 1-3, 5, 6, 13, 30, 33-35, and 113-119 are rejected under 35 U.S.C. 103 as being unpatentable over Prasad (WO 2020/243720; Publication Date: 3 December 2020; Priority to 31 May 2019) in view of Thornber (Chemical Society Reviews, 4, 1979).
Prasad, as described previously teaches compounds which meet the limitations of the compounds of the examined application, as well as their compositions and methods of treatment of TTR aggregation, amyloidosis, and other conditions mediated by TTR using these compounds. The compounds of the invention are of Formula (I)
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wherein variable R3 is selected from the group consisting of hydrogen, amino acid, C1-C10 alkyl, C1-C10 branched alkyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C2-C6 alkenyl, C2-C6 alkylaryl, C1-C6 alkyl (C3-C6) cycloalkyl, C1-C6 alkylNH, NC1-C6 dialkylamine, C1-C6 alkyl-pyrroldine, C1-C6 alkyl-piperidine, C1-C6 alkyl morpholine, pthalidyl,
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wherein n is a number between 0 and 6; R4 and R5 are selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, alkenyl, alkynyl, and 3-6 membered cycloalkyl (Paragraphs 0014, 0028).
Prasad does not teach the use of heterocyclic groups such as
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as variable R3.
Thornber teaches the concept of isosterism and bioisosterism. Isosterism was used to describe the similarity of molecules or ions which have the same number of atoms or valence electrons. The term bioisosterism is used to describe the phenomenon in which compounds which are related in structure have similar properties (Introduction). Table 1 (Page 564) lists the classical isosteres as defined by Burger, with ring equivalents being listed in group five. This includes =CH-, -O-, -S-, -CH2-, and =N-. These two ring equivalents have largely similar electronic properties. Bioisosteric replacements are useful in searching for potency, selectivity, absorption, and duration (Page 567).
Prasad and Thornber are considered analogous to the claimed invention as all are involved in the development of pharmaceuticals. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify Compound CAP4355 by replacing the
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moiety with other heterocyclic moieties such as
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and because Thornber teaches that oxygen and CH2 function as ring equivalents, the artisan would not expect this modification to significantly alter the properties of the resulting compound due to the close chemical structure (See MPEP § 2144.09 I). Moreover, the compounds of the examined application are prodrugs of tafamidis, and by substituting the
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moeity with other similar heterocyclic groups, the artisan would not expect significant alterations in the biological properties of the resulting compound.
Prasad does not explicitly disclose compounds identical to those of Claim 113. However, several compounds are rendered prima facie obvious in view of what is disclosed and taught by Prasad in the description of their compounds. Compound 13 of the examined application
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has variable R3 as piperidinyl, with Prasad disclosing that variable R3 can be a C1-C6 alkyl piperidinyl. Similarly, compounds 7
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, 11
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, 14
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, and 12
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would be obvious in view of the teachings of Prasad as the artisan would not expect these to have significantly different properties than what is taught due to the close chemical structure (See MPEP § 2144.09 I). Compounds 15
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and 25
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have variable R3 as (CH2)2NH2 and (CH2)3NH2, which is taught as an option for variable R3 by Prasad. Compound 31
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has variable R3 as
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with variable R5 as tert-butyl. Compounds such as compound 34
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have an alkyl-piperidinyl group, while compounds 36, 37, 39, 40, 41, 59-62, 74, and 75 differ by the size of the nitrogen-containing ring, length of linker, or presence of substituents on the ring. The artisan would not expect these compounds to have different properties than what is disclosed due to the close chemical structure. Compounds such as 80
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, 81, 82, 83, 85, and 86 contain morpholinyl groups, or other heterocyclic groups.
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 1-3, 5, 6, 13, 30, 33-35, and 113-119 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 142, and 144-149 of copending Application No. 18/419,081 (Amended claims of 3 May 2024) (‘081).
Claim 1 of ‘081 is directed to a compound of formula I
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wherein A is
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; X1 is O or NR5; X2 is H, halo, heteroaryl, CN, OR6, or NR7R*; n is an integer from 0-3, p is an integer from 0-3; Ar1 is an optionally substituted aryl or heteroaryl; R1-R8 are selected from (i)-(viii):
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; R9 is H, haloalkyl, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl (all optionally substituted); and R10 and R11 are H, halogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aralkyl, heteroarlkyl (all optionally substituted) or OR9. Claim 142 claims the compound of claim 1 wherein the compound of formula I has the structure
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. Claim 144 claims several specific compounds which meet the limitations of the examined application, such as Compound 1
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, which has variable X1 as NH, variables R1 and R2 each as H, n as 0, X2 as bond, and variable R5 as ethyl substituted with fluorine and Compound 41
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, which has variable X1 as O, variable R1 as methyl, variable R2 as H, n as 0, X2 as bond, and variable R5 as ethyl substituted with hydroxyl. Claim 145 claims a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. Claim 146 claims a method of inhibiting or preventing TTR aggregation and/or amyloid formation in the eye or CNS of a subject comprising administering a compound of Claim 1. Claim 147 claims a method of inhibiting or preventing TTR aggregation and/or amyloid formation in peripheral nerves or cardiac tissue of a subject comprising administering a compound of claim 1. Claim 148 claims a method of treating a subject having peripheral TTR amyloidosis or ocular or cerebral amyloid angiopathy comprising administering a compound of claim 1. Claim 149 claims aa method of treating a subject having familial amyloid polyneuropathy, familial amyloid cardiomyopathy, TTR oculoleptomeningeal amyloidosis or senile systemic amyloidosis comprising administering a compound of Claim 1.
Regarding Claim 113, several of the claimed compounds are obvious variations of what is disclosed by ‘081. Compound 6 of the examined application
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differs from Compound 9 of ‘081
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by changing variable X1 to NCH3, , which is within the limitations of the compounds of ‘081. Compound 9 of the examined application
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differs from compound 9 of ‘081
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by changing variable X1 to NCH3, , which is within the limitations of the compounds of ‘081. Compound 89 of the examined application
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differs from Compound 35 of ‘081
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by increasing the length of the alkyl chain connecting the heteroaromatic ring system to the ester, and altering the location of the attachment point on the heteroaromatic ring.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-3, 5, 6, 13, 30, 33-35, and 113-119 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 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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/P.M.R./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625