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 .
Claims 1-8 and 10 have been amended. Claims 14-18 are newly added. Thus, Claims 1-18, submitted on 20 August 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.
Response to Amendment
The 35 U.S.C. § 112(a) rejection of Claims 1-13 is withdrawn. Applicant has amended the claim to recite “an optical isomer, diastereomer, racemate, or pharmaceutically acceptable salt there”, which is supported by the specification.
The 35 U.S.C. § 112(b) rejection of Claim 1-13 is withdrawn. The Examiner agrees with Applicant that the skilled artisan would understand that when n is less than 4, the remaining positions will be filled with hydrogen.
The 35 U.S.C. § 112(b) rejection of Claims 1 and 3 is withdrawn. Applicant has replaced “may be” with “is”.
The 35 U.S.C. § 112(b) rejection of Claim 6 is withdrawn. Applicant has placed Claim 6 in independent form, obviating the antecedent basis issue.
The 35 U.S.C. § 112(b) rejection of Claim 8 is withdrawn. Applicant has amended the claim to remove the metabolic diseases having a narrower scope.
The 35 U.S.C. § 102 (a)(2) rejections of Claims 1-5 and 7-9 over Ammann (US 20221/0171499) and Claims 1-9 over Zhong (WO 2020/207474), Coates (WO 2020/263695), Lee (WO 2021/112538), and Meng (WO 2021/160127) are each withdrawn. Applicant has amended the Claim 1 to delete the (CH2)m in the definition of A in formula 1, and Claim 6 has been amended to delete compound Nos. 1-3, 10, 15, and 23, which were anticipated by each of the references. Applicant states that the compound of Coates which the Examiner cites, published on 30 December 2020, wherein R1 and R3 are each H, was present in the two provisional applications, and is only found in the publication of 30 December 2020, which is later than the effective filing date of 18 March 2020. The Examiner agrees, and this rejection is withdrawn.
Applicant’s arguments, see 35 U.S.C. § 103 rejection, filed 20 August 2025, with respect to the rejection(s) of claim(s) 1-9 under 35 U.S.C. § 103 over Ammann have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Ammann in view of Thornber.
Applicant’s arguments, see 35 U.S.C. § 103 rejection, filed 20 August 2025, with respect to the rejection(s) of claim(s) 10 under 35 U.S.C. § 103 over Coates have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Ammann, Coates, and Thornber.
Claim Rejections - 35 USC § 112(a)- NEW GROUNDS OF REJECTION
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 7, 9, 15 and 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Factors to be considered in making the determination as to whether one skilled in the art would recognize that applicant was in possession of the claimed invention as a whole at the time of filing include : (a) Actual reduction to practice; (b) Disclosure of drawings of structural chemical formulas; (c) Sufficient identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and
knowledge in the art and (f) Predictability in the art. While all of these factors are
considered, a sufficient number for a prima facie case are discussed below:
The claims are directed to pharmaceutical compositions of the compounds of the invention for the treatment and prevention of various metabolic and neurodegenerative diseases, such as Alzheimer’s disease or Parkinson’s disease. The specification provides documentation that the compounds of the invention are GLP-1R agonists (Experimental Example 1, Page 117). However, the specification does not provide any documentation showing that the compounds, or their formulations, can be used to prevent Alzheimer’s disease or Parkinson’s disease. In the pharmaceutical arts, there are currently no known methods or compounds which can prevent the development of conditions such as Alzheimer’s disease or Parkinson’s disease. The Alzheimer’s Association (https://web.archive.org/web/20250116040206/https://www.alz.org/alzheimers-dementia/research-and-progress/prevention) states that Alzheimer’s prevention has no definitive answers at this time, but research has shown that individuals can take action to reduce their risk of developing the condition. There are certain risk factors, such as age or genes, that cannot be changed; however, other risk factors such as high blood pressure and lack of exercise can usually be changed to help reduce the risk, but not entirely prevent the development of Alzheimer’s disease. Thus, there is currently no known pharmaceutical which can prevent the development of Alzheimer’s disease due to the heterogeneity of the underlying causes. The artisan would generally have the ability to develop the claimed formulations, but without guidance from the specification as to what amount to include, or how to specifically formulate and deliver these compositions for the prevention of conditions such as Alzheimer’s disease, the artisan would not be able to practice the invention as claimed. Therefore, there is no support in the specification that would lead one of ordinary skill in the art to recognize that applicant was in possession of the claimed invention as a whole at the time of filing.
Claim Rejections - 35 USC § 103- NEW GROUNDS OF REJECTION
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Ammann (US 2021/0171499; Publication Date: 10 June 2021, Priority to 25 October 2019) in view of Thornber (Chemical Society Reviews, 4, 1979).
Ammann (See IDS, 16 September 2022) discloses compounds that are useful as GLP-1 receptor agonists (Abstract). The compounds are of general Formula
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, wherein variable V is analogous to variable A of the examined application (Paragraph 0006). Variable V is selected from -C(O)-, -O-, -N(R6a)- or -C(R6b)(R6c)-, wherein R6a can be H or C1-C6 alkyl, and R6b and R6c can each be H (Paragraphs 0022-0025). The compounds of Ammann can have the general structure of
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(Paragraph 0232). Variable Z1 is selected from alkyl, haloalkyl, alkoxy, haloalkyoxy, alkoxyalkyl, alkenyl, alkynyl, halogen, cyano, nitro, and oxo, among other groups (Paragraph 0181) and p is 1, 2, or 3. Variable R4 is selected from alkyl, alkoxy, haloalkoxy, halogen, and hydrogen (Paragraph 0198). XA and XB are each independently -CH= or -N= (Paragraph 0229). In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the disclosure and a pharmaceutically acceptable excipient (Paragraph 0310). Specific embodiments include
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(Page 35) and
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(Page 48). As described in the prior office action, Ammann discloses several compounds which meet the limitations of compounds of the examined application, but fails to disclose any specific embodiments wherein variable V (analogous to variable A of the examined application) is -O- or -NR6a-.
Ammann fails to demonstrate compounds which have -O- or -NR6a- in the analogous A position.
Thornber teaches the concept of bioisosterism, which describes the similarity of molecules or ions which have the same number of atoms or valence electrons. Bioisosteres are groups or molecules which have chemical and physical similarities producing broadly similar biological properties (Page 563). Table 1 lists the classical isosteres, which includes bivalent atoms and groups, including -CH2-, -S-, -NH-, and -O- (Table 1, Page 564). These bivalent atoms/groups have similar electronic properties.
Ammann and Thornber are considered analogous to the claimed invention as all are involved in drug development. 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 the compounds of Ammann, which state that the analogous variable A can be -O- or -NR6a- as Thornber teaches that -O- and -NH- function as bivalent bioisosteres of one another, and the artisan would recognize that due to their similar electronic properties, their replacement would not be expected to significantly alter the properties of the compound due to the close chemical structure (See MPEP § 2144.09 I). The compounds of Ammann and those of the examined application are GLP-1 inhibitors, and the substitution of -CH2- for -O- or -NH- would not be expected to significantly alter the activity of the compounds disclosed by Ammann.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Ammann (US 2021/0171499; Publication Date: 10 June 2021, Priority to 25 October 2019) in view of Thornber (Chemical Society Reviews, 4, 1979), Coates (WO 2020/026395; Publication Date: 30 December 2020, Priority to 28 June 2019 and 24 September 2019), STN RN 262444-42-8 (Entered STN: 20 Apr 2000), STN RN 330793-01-6 (Entered STN: 11 Apr 2001), STN RN 330794-10-0 (Entered STN: 11 Apr 2001), STN RN 480438-75-3 (Entered STN: 23 Jan 2003), STN RN 910462-31-6 (Entered STN: 16 Oct 2006), STN RN 1310404-08-0 (Entered STN: 24 Jun 2011), and STN RN 2379560-86-6 (Entered STN: 13 November 2019).
The teachings of Ammann and Thornber are described in the prior rejection and are incorporated fully into this rejection.
Ammann and Thornber do not teach the synthesis method of Claim 10.
Coates (See IDS, 16 September 2022) teaches the synthesis of GLP-1 agonists of similar structure to those of the examined application, the difference lying in the presence of a -CH2- moiety in the A position rather than -O- or -NH- or similar group. Coates discloses a synthesis scheme similar to that of Claim 10, differing in the structure of the compound analogous to Formula 5 of the examined application. Scheme 2 (Page 12) shows the synthesis of an intermediate analogous to Formula 7 of the examined application
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. Reactant 8 is analogous to Formula 4 of Claim 10. Reactant 7 is analogous to Formula 5 of Claim 10. Compound 8 is synthesized by reacting 2-bromo-6-fluoropyridine and 3-fluoro-4-(hydroxymethyl)benzonitrile in a base with heat (Page 19). This is then reacted with 7 by coupling reaction using Pd(dppf)Cl2 and potassium carbonate at elevated temperature to produce intermediate 12, which is then hydrolyzed to produce intermediate 13 (analogous to Formula 6). The product 13 is then reacted according to scheme 4
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(Page 14), with intermediate 15 (analogous to Formula 7 of Claim 10), which then undergoes a condensation and hydrolysis reaction to form a compound analogous to Formula 1. This method does not teach the use of a palladium catalyst to generate Formula 4 (compound 8 of scheme 2); however, it would be obvious to one of ordinary skill in the art to incorporate a palladium catalyst in this reaction as it is known in the art to increase the efficiency of coupling reactions.
Coates fails to disclose the use of a reactant of Formula 5 which has an -O- or -NRa- in the variable A location.
STN RN 262444-42-8
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,STN RN 330793-01-6
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, STN RN 330794-10-0
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, STN RN 480438-75-3
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,STN RN 910462-31-6
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, STN RN 1310404-08-0
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, and STN RN 2379560-86-6
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each have structures that meet the limitations for the compound of Formula 5.
Ammann, Thornber, Coates, and the cited STN compounds are considered analogous to the claimed invention as all are related to the synthesis and development of chemical compounds. 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 synthesize the compounds of Ammann using the methods of Coates, wherein the cited compounds are substituted in place of Formula 7, arriving at the claimed method. The artisan would recognize these materials could be substituted in, and could be used to synthesize compounds which differ only from what is synthesized by Coates by the A variable, which is an obvious bioisosteric substitution. Further, while the method of Coates contains a product which is already hydrolyzed, the artisan would recognize that the cited compounds would undergo the same reaction, and could be hydrolyzed to generate the same intermediate, which would then undergo the same reactions to generate similar products. The substitution of these known compounds into the method of Coates is prima facie obvious simple substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)); the methods of Coates are used to synthesize GLP-1 inhibitors of similar structure to those of the examined application, and the artisan would recognize that this method could be used to arrive at the compounds of Ammann by substituting the cited compounds into the reaction, predictably arriving at a GLP-1 inhibitor.
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 1-10 and 14-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5, 6, and 8-12 of copending Application No. 18/554,345 (‘345) (reference application) (Amended claims of 24 April 2024) in view of Thornber.
Claim 1 is directed to a compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt
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wherein A is –(CH2)m-, -O-, or -N(Ra)- wherein m is an integer from 1 to 3 and Ra is hydrogen or alkyl, Z1-Z7 are each independently CH, CF, CCl, CBr, CI, or N. Z8 and Z9 are each independently C or N substituted with an -O-CH2-R group, with R as cycloalkyl or
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Variable R1 is (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, or (heteroaryl)alkyl, Variables R2-R4 are each hydrogen, deuterium, halo, alkyl, alkoxy, alkylamine, or nitrile. N1 to n3 are each independently an integer of 1 to 4, wherein when N1 to N3 are 2 or more each R2-R4 can be the same or different from each other, and the alkyl, alkoxy, alkylamine, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted. Claim 2 claims a compound of chemical formula 1
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Chemical formula 1 is identical to the compounds of examined application when R is
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. Claim 3 claims the compound or isomer of claim 1 wherein A is -CH2-, -O-, or -N(Ra)- wherein Ra is hydrogen or C1-C3 alkyl. Claim 4 claims the compound or isomer of claim 1 wherein R is C3-C8 cycloalkyl or
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. Variable R1 is (C3-C8 cycloalkyl)(C1-C3 alkyl), (4- to 10-membered heterocycloalkyl)(C1-C3 alkyl), (C6-C10 aryl)alkyl or (4- to 10-membered heteroaryl)(C1-C3 alkyl), and variables R2-R4 are each hydrogen, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamine, or nitrile group, with n1-n3 as integer of 1 to 3, and when n1 to n3 is 2 or more, they may be the same or different from each other. Claim 5 claims that Z1-Z7 are each independently CH, CF, or CCl. Claim 6 claims the compound or isomer of claim 1 wherein R is bicycloalkyl or
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and R1 is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, oxytanylmethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, oxazolylmethyl, benzyl, unsubstituted or triazoloylmethyl substituted with propyl, or unsubstituted or substituted imidazolylmethyl substituted with ethyl. Claim 7 claims several specific compounds which are obvious variants of what is taught, specifically variants wherein variable A is -CH2-, where compounds of the examined application have -O- or -NH-. Claim 8 claims a pharmaceutical composition for the prevention or treatment of metabolic or neurodegenerative diseases, comprising a compound a claim 1 or an isomer thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. Claim 9 claims the composition of claim 8 wherein the metabolic disease is selected from a group identical to those of the examined application. Claim 10 claims the composition of claim 8 wherein the neurodegenerative disease is selected from the group consisting of Parkinson’s disease and Alzheimer’s disease. Claim 11 claims a method for preparing Chemical Formula 1 of claim 2, which is identical to the claimed method when variable R of the reference application is
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.
Thornber, as described previously, teaches the concept of bioisosterism and that -O- and -NH- are bioisosteres of -CH2-, and have similar electronic properties of one another.
‘345 and Thornber are considered analogous to the claimed invention as all are involved in drug development. 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 the compounds of ‘345, which state that variable A can be -O- or -NR6a- as Thornber teaches that -O- and -NH- function as bivalent bioisosteres of one another, and the artisan would recognize that due to their similar electronic properties, their replacement would not be expected to significantly alter the properties of the compound due to the close chemical structure (See MPEP § 2144.09 I). The compounds of ‘345 and those of the examined application are GLP-1 inhibitors, and the substitution of -CH2- for -O- or -NH- would not be expected to significantly alter the activity of the compounds disclosed by ‘345.
This is a provisional nonstatutory double patenting rejection.
Allowable Subject Matter
Claims 11-13 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is an examiner’s statement of reasons for allowance: The prior art does not teach the methods of synthesizing the compounds of Formula I of Claims 11-13. There is no art teaching the intermediates of these claims for the synthesis of similar compounds (See STN Search, Previous Office Action). The closest prior art comes from Coates (WO 2020/026395). Coates, as described above, teaches the synthesis of compounds similar to the compounds of Formula I, using the method of Claim 10 of the examined application. However, Coates does not teach, suggest, or provide motivation for modifying this synthesis method to arrive at the methods of Claims 11-13.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Claims 1-10 and 14-18 are rejected.
Claims 11-13 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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