HETEROCYCLIC INHIBITORS OF IGF-1R FOR TREATMENT OF DISEASE

§102 §112

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 . DETAILED ACTION Response to Amendment The amendment to the claims filed on 07/29/2026 does not comply with the requirements of 37 CFR 1.121(c) because claims 84-87 are missing. Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states: (c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered). (1) Claim listing. All of the claims presented in a claim listing shall be presented in ascending numerical order. Consecutive claims having the same status of “canceled” or “not entered” may be aggregated into one statement (e.g., Claims 1–5 (canceled)). The claim listing shall commence on a separate sheet of the amendment document and the sheet(s) that contain the text of any part of the claims shall not contain any other part of the amendment. (2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn—currently amended.” (3) When claim text in clean version is required. The text of all pending claims not being currently amended shall be presented in the claim listing in clean version, i.e., without any markings in the presentation of text. The presentation of a clean version of any claim having the status of “original,” “withdrawn” or “previously presented” will constitute an assertion that it has not been changed relative to the immediate prior version, except to omit markings that may have been present in the immediate prior version of the claims of the status of “withdrawn” or “previously presented.” Any claim added by amendment must be indicated with the status of “new” and presented in clean version, i.e., without any underlining. (4) When claim text shall not be presented; canceling a claim. (i) No claim text shall be presented for any claim in the claim listing with the status of “canceled” or “not entered.” (ii) Cancellation of a claim shall be effected by an instruction to cancel a particular claim number. Identifying the status of a claim in the claim listing as “canceled” will constitute an instruction to cancel the claim. (5) Reinstatement of previously canceled claim. A claim which was previously canceled may be reinstated only by adding the claim as a “new” claim with a new claim number. Nevertheless, the amendment and claim set as filed has been treated on the merits. Status of the Claims Claims 1-83 are pending and presented. Claims 35-48 and 56-83 are withdrawn. Claims 1, 3-9, 11-20, 22-27, 30-34, 49-53 and 55 are rejected. Claims 2, 10, 21, 28-29 and 54 are objected to. Election/Restrictions Applicant's election of the elected compound species PNG media_image1.png 87 282 media_image1.png Greyscale and the disease thyroid eye disease (TED) without traverse in the reply filed on July 29, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 1-5, 9 and 17- 21 read on Applicant’s species election of PNG media_image1.png 87 282 media_image1.png Greyscale . Examination of the elected invention was conducted in accordance with the MPEP 803.02. The elected species is allowable in view of the prior art; therefore, examination of the Markush-type claim has been extended to the scope of Formula (I) of claims 1-21, Formula (II) of claims 22-34 and Formula (IIIB) of claims 49-55 wherein x is 3; s is 0; X is -O-; R3 is hydrogen; k is 0; A is CR4 wherein R4 is hydrogen; Ra, Rc and Rd are each hydrogen; and Rb is C1 alkyl substituted with three fluoro substituents. Since art was found on a nonelected species, subject matter not embraced by the above-identified non-elected species is therefore withdrawn from further consideration. Claims 35-48 and 56-81 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant is reminded that upon the cancellation of claims to a non-elected invention, the inventorship must be amended in compliance with 37 CFR 1.48(b) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. Any amendment of inventorship must be accompanied by a request under 37 CFR 1.48(b) and by the fee required under 37 CFR 1.17(i). Priority This application claims benefit to PRO 63/517,285 filed 08/02/2023. Information Disclosure Statement The information disclosure statement(s) (IDS) dated 10/18/2024 has been considered. Specification The disclosure is objected to because of the following informalities: - the structure of compound 111 does not match the name in Table 1: PNG media_image2.png 76 599 media_image2.png Greyscale . Appropriate correction is required. Claim Objections Claim 1 is objected to because of the following informalities: - “-OR20” is duplicated in the definition of R1, and - “independently” is duplicated in the definition of “each R14” on page 3. 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. Claims 1, 3-9, 11-20, 22-27 and 30-32 are rejected under 35 U.S.C. 112(b) being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. Claim 1 recites the limitation "-OR19" in the definition of R3 about halfway down page 3. There is insufficient antecedent basis for this limitation in the claim since R19 is not present/defined elsewhere in the claim. Dependent claims 4-8 and 16-20 are rejected as indefinite for the same reason since they do not correct the indefiniteness issue of their parent claims. Applicant may overcome the rejection by, for instance, amending the claim to delete the "-OR19" limitation. Claim 1 recites the limitation "each Xa" in the definition at the bottom of page 3. There is insufficient antecedent basis for this limitation in the claim since there is no “Xa” in the structure or elsewhere in the claim. Dependent claims 3-9, 11-20 are rejected as indefinite for the same reason since they do not correct the indefiniteness issue of their parent claims. Applicant may overcome the rejection by, for instance, amending the claim to delete the paragraph beginning with "each Xa". Claim 22 recites the limitation "-OR19" in the definition of R3 at the bottom of page 13. There is insufficient antecedent basis for this limitation in the claim since R19 is not present/defined elsewhere in the claim. Dependent claims 23-27 and 30-32 are rejected as indefinite for the same reason since they do not correct the indefiniteness issue of their parent claims. Applicant may overcome the rejection by, for instance, amending the claim to delete the "-OR19" limitation. Claim Rejections - 35 USC § 112(d) The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. Claims 27, 33-34, 52-53 and 55 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 27 recites the limitation wherein PNG media_image3.png 114 74 media_image3.png Greyscale is PNG media_image4.png 71 96 media_image4.png Greyscale , however there is no definition in parent claim 22 where two R5 substituents come together to form a bridged ring. As a result, there is improper dependency such that claim 27 does not properly limit claim 22. Applicant may overcome the rejection by, for instance, amending the claim to delete the PNG media_image4.png 71 96 media_image4.png Greyscale limitation. Claim 33 recites the limitation wherein PNG media_image5.png 77 84 media_image5.png Greyscale is PNG media_image6.png 110 65 media_image6.png Greyscale , however R6 as H and R7 as a halogen is not embraced by parent claim 22. As a result, there is improper dependency such that claim 27 does not properly limit claim 22. Applicant may overcome the rejection by, for instance, amending the claim to delete the PNG media_image6.png 110 65 media_image6.png Greyscale limitation. Claim 34 recites several compounds that are not embraced by parent claim 22: They have a PNG media_image5.png 77 84 media_image5.png Greyscale ring wherein R6 and R7 are not taken together to form a ring as specified in claim 22: PNG media_image7.png 101 259 media_image7.png Greyscale (page 18), PNG media_image8.png 87 261 media_image8.png Greyscale (page 22), PNG media_image9.png 84 270 media_image9.png Greyscale (page 22), PNG media_image10.png 99 282 media_image10.png Greyscale (page 24), PNG media_image11.png 86 314 media_image11.png Greyscale (page 24); They have PNG media_image3.png 114 74 media_image3.png Greyscale as PNG media_image4.png 71 96 media_image4.png Greyscale : PNG media_image12.png 65 279 media_image12.png Greyscale (page 24), PNG media_image13.png 65 279 media_image13.png Greyscale (page 24), PNG media_image14.png 70 655 media_image14.png Greyscale ; They have replaced the pyridine ring, PNG media_image15.png 94 97 media_image15.png Greyscale , with something else: PNG media_image16.png 70 306 media_image16.png Greyscale (page 20), PNG media_image17.png 88 302 media_image17.png Greyscale (page 20), PNG media_image18.png 85 289 media_image18.png Greyscale (page 23), PNG media_image19.png 66 281 media_image19.png Greyscale (page 24), PNG media_image20.png 87 304 media_image20.png Greyscale (page 25), PNG media_image21.png 71 303 media_image21.png Greyscale (page 25), PNG media_image22.png 69 307 media_image22.png Greyscale (page 25); or The ring B formed by R6 and R7 has a substituent that is not embraced by R11 or R12: PNG media_image23.png 77 336 media_image23.png Greyscale (page 21). The alkynyl is distinct from alkyl, esp. since alkynyl is defined separately in para. [0158] on page 98 of the spec. Applicant may overcome the rejection by, for instance, amending the claim to delete the improperly dependent structures. Claims 52 and 53 specify that the C1-6 alkyl, C1-C6 fluoroalkyl, and C3-C8 cycloalkyl groups may be substituted or unsubstituted, whereas parent claim 49 does not. As a result, the claims do not properly limit their parent claim. Applicant may overcome the rejection by, for instance, amending the claims to recite that the relevant groups may be substitute or unsubstituted as indicated in the parent claim. Claim 55 recites several compounds that are not embraced by parent claim 49: They have Ra, Rb, Rc, and Rd as H when the parent claim requires at least one is not hydrogen: PNG media_image24.png 86 306 media_image24.png Greyscale (page 36), PNG media_image25.png 94 306 media_image25.png Greyscale (page 37), PNG media_image26.png 84 310 media_image26.png Greyscale (page 37), PNG media_image27.png 89 310 media_image27.png Greyscale (page 37), PNG media_image28.png 66 295 media_image28.png Greyscale (page 37), PNG media_image29.png 92 310 media_image29.png Greyscale (page 37), PNG media_image30.png 103 306 media_image30.png Greyscale (page 37), PNG media_image31.png 89 308 media_image31.png Greyscale (page 37), PNG media_image32.png 86 310 media_image32.png Greyscale (page 37), PNG media_image33.png 86 305 media_image33.png Greyscale (page 37), PNG media_image34.png 99 307 media_image34.png Greyscale (page 37), PNG media_image35.png 87 312 media_image35.png Greyscale (page 38), PNG media_image36.png 86 306 media_image36.png Greyscale (page 38); or They have an Rc group that is not embraced in the parent claim: PNG media_image37.png 84 356 media_image37.png Greyscale (page 38), PNG media_image38.png 92 340 media_image38.png Greyscale (page 38). Applicant may overcome the rejection by, for instance, amending the claim to delete the improperly dependent structures. 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 49-53 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Harmange et al. in US 2004/0063705 A1. Harmange et al. disclose the compound 144, PNG media_image39.png 460 361 media_image39.png Greyscale , on page 61 which is embraced by Formula (IIIB), PNG media_image40.png 145 305 media_image40.png Greyscale , of instant claim 49 wherein: - x is 3 (see also claim 50-51); - s is 0; - X is -O- (see also claims 50-51); - R3 is hydrogen (see also claim 50); - k is 0; - A is CR4 wherein R4 is hydrogen; - Ra, Rc and Rd are each hydrogen (see also claims 52-53); and - Rb is C1 alkyl substituted with three fluoro substituents (see also claims 52-53). Where claims 49, 52, and 53 specify that Rb is defined as a C1-6-alkyl, but not a C1-C6fluoroalkyl as included in the definitions of Ra, Rc and Rd, the Examiner interprets the claim such that the alkyl may be further substituted by fluorine groups as shown in the prior art reference, especially due to the inclusion of the following species in instant dependent claim 55: PNG media_image41.png 87 347 media_image41.png Greyscale (see page 38, left column, second compound). Thus, the claims are anticipated by the prior art. Allowable Subject Matter Claims 2, 10, 21, 28-29 and 54 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. Claims 1-34 and 54-55 are free of the prior art. The closest prior art is from Harmange et al. in US 2004/0063705 A1. Harmange et al. teach compounds of the formula IIIa, PNG media_image42.png 114 316 media_image42.png Greyscale see page 5, para. [0141], that are nearly embraced by instant formula (I) PNG media_image43.png 137 221 media_image43.png Greyscale and formula (II) PNG media_image44.png 181 242 media_image44.png Greyscale . Compound 188 for instance, PNG media_image45.png 159 449 media_image45.png Greyscale (see page 74) is nearly embraced by formula (II) wherein each n is 2; s is 0; X is -CH-; R3 is hydrogen; k is 0; A is C(R4) wherein R4 is H; R6 and R7 are taken together to form a C6 aryl; and p is 0. However, Formula (II) does not embrace a compound wherein PNG media_image46.png 82 70 media_image46.png Greyscale is a phenoxy group as shown in prior art compound 188. The prior art also does not provide motivation to a person having ordinary skill in the art to modify compound 188 in such a way as to identify the compounds according to claims 22-34 and expect the compounds to inhibit IGF-1R. As it relates to instant claim 54, which depends from claim 49 with formula (IIIB), PNG media_image47.png 150 313 media_image47.png Greyscale , the teaching from Harmange does not include compounds that are embraced by the instant formula wherein at least one of Ra, Rb, Rc or Rd is a halogen. The prior art also does not provide motivation to a person having ordinary skill in the art to modify the compounds in such a way as to identify the compounds according to claim 54 and expect the compounds to inhibit IGF-1R. Likewise, the prior art does not teach or suggest the species of present claim 55. Contact Information Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jalisa H. Ferguson whose telephone number is (703)756-1489. The examiner can normally be reached Monday - Friday 9:00am - 5:00pm. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L. Clark can be reached on (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /J.H.F./Examiner, Art Unit 1626 /MATTHEW P COUGHLIN/Primary Examiner, Art Unit 1626