3,4,6,7-TETRAHYDRO-2,7-NAPHTHYRIDINE-2(1H)-CARBOXAMIDE DERIVATIVES AS GPR65 INHIBITORS FOR THE TREATMENT OF CANCER AND AUTOIMMUNE DISEASES

§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 Claims 1-4, 7-9, 11, 13, 16-21, 24, 25, 27, 28, 30, 32, 33, 37, 39, 43, 44, 46 and 56 are pending in the instant application. Election/Restrictions Applicant’s election without traverse of Group I, Group I, claims 1-4, 7-9, 11, 13, 16-21, 24, 25, 27, 28, 30, 32, 39 and 56, drawn to products of formula (Ia), PNG media_image1.png 192 332 media_image1.png Greyscale , and the species of Compound (4), disclosed on page 58 of the instant specification (reproduced below), PNG media_image2.png 210 338 media_image2.png Greyscale , in the reply filed on September 2, 2026 is acknowledged. The requirement is still deemed proper and is therefore made FINAL. Applicant’s claimed compound genus of instant formula (Ia) has a number of variables and their permutations and combinations result in a vast number of compounds that are generically claimed. In an initial attempt to examine the full scope of compounds of elected Group I, over 14,900 Chemical Abstract Registry numbers were recovered in one database search alone. PNG media_image3.png 172 622 media_image3.png Greyscale Therefore, the claims embraced by the elected products of Group I will be examined according to MPEP §803.02. The product claims have been examined to the extent that they are readable on the elected species of Compound (4). Since no prior art was found on the elected species, the examination was expanded within elected Group I until prior art was found, in which case, the examination stopped and prior art has been applied against the claims. Note, MPEP §803.02. The subject matter of the expanded search and examination thus far, inclusive of the elected species of Compound (4), is as follows: a product of instant formula (Ia) PNG media_image4.png 188 330 media_image4.png Greyscale , wherein ring A represents a 5- or 6-membered monocyclic aromatic or heteroaromatic ring, which is optionally substituted; ring B is a monocyclic heteroaromatic group containing at least one nitrogen atom, which is optionally substituted; and all other variables are as defined in independent claim 1. Claims embraced by the above identified subject matter which has been searched and examined so far are claims 1-4, 7, 9, 11, 13, 16-21, 24, 25, 27, 28, 30, 32, 39 and 56. Subject matter not embraced by the above identified search and examination and Claims 8, 33, 37, 38, 43, 44, 46, 54 and 55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 2, 2026. Priority Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Information Disclosure Statement The Examiner has considered the Information Disclosure Statement filed on September 26, 2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Claim Objections Claim 9 is objected to because of the following informalities: in claim 9, an “and” should be added before ring A-(xxxiv) for proper Markush language format (page 7, line 2 of the page). Appropriate correction is required. Claim Rejections - 35 USC § 112 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. Claim 24 is 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. Claim 24 lacks antecedent basis from claim 16 because there is no earlier recitation in claim 16 that the 5-membered heteroaromatic group formed from X1-X4 can be substituted with “cycloalkyl” or “heterocycloalkyl” as found in claim 24. Therefore, claim 24 is indefinite. 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. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], 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. Claim 24 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, 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 24 fails to further limit claim 16 because claim 24 is broader in scope than claim 16. Claim 16 does not state that the 5-membered heteroaromatic group formed from X1-X4 can be substituted with “cycloalkyl” or “heterocycloalkyl” as found in claim 24. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Claim Rejections - 35 USC § 102 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 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 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. Claims 1-4, 7, 9, 11, 16-21, 24, 25, 27, 28, 30 and 39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by: the compound of Chemical Abstracts Registry Number 1945022-87-6 {indexed in the Registry file on STN CAS ONLINE July 4, 2016}, PNG media_image5.png 180 330 media_image5.png Greyscale {a compound of instant formula (Ia), PNG media_image4.png 188 330 media_image4.png Greyscale , wherein ring A = a 6-membered monocyclic heteroaromatic ring, which is substituted with hydroxy, [i.e., ring A-(xiii)]; ring B = a monocyclic heteroaromatic group containing at least one ring nitrogen, which is substituted with one alkyl [i.e., thiazol-2-yl, substituted with ethyl]; Y = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen; and Z = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen}; the compound of Chemical Abstracts Registry Number 2419297-23-5 {indexed in the Registry file on STN CAS ONLINE June 5, 2020}, PNG media_image6.png 230 302 media_image6.png Greyscale {a compound of instant formula (Ia), PNG media_image4.png 188 330 media_image4.png Greyscale , wherein ring A = a 6-membered monocyclic heteroaromatic ring, [i.e., ring A-(vii)], substituted with NR11R11’ where R11 = alkyl (i.e., methyl), and R11’ = alkyl (i.e., methyl); ring B = a monocyclic heteroaromatic group containing at least one ring nitrogen, which is substituted with one F [i.e., pyridin-4-yl, substituted with fluoro – ring B-(ii)]; Y = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen; and Z = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen}; the compound of Chemical Abstracts Registry Number 1954424-93-1 {indexed in the Registry file on STN CAS ONLINE July 18, 2016}, PNG media_image7.png 148 306 media_image7.png Greyscale {a compound of instant formula (Ia), PNG media_image4.png 188 330 media_image4.png Greyscale , wherein ring A = a 6-membered monocyclic heteroaromatic ring, which is substituted with hydroxy, [i.e., ring A-(xiii)]; ring B = a monocyclic heteroaromatic group containing at least one ring nitrogen, which is substituted with one cycloalkyl [i.e., thiazol-5-yl, substituted with cyclopropyl – ring B-(iv)]; Y = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen; and Z = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen}; the compound of Chemical Abstracts Registry Number 2134639-83-9 {indexed in the Registry file on STN CAS ONLINE October 13, 2017}, PNG media_image8.png 222 382 media_image8.png Greyscale {a compound of instant formula (Ia), PNG media_image4.png 188 330 media_image4.png Greyscale , wherein ring A = a 5-membered monocyclic heteroaromatic ring, which is substituted with two alkyls [i.e., imidazolyl substituted with methyl and isopropyl]; ring B = a monocyclic heteroaromatic group containing at least one ring nitrogen, which is substituted with two halo [i.e., ring B-(iii)]; Y = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen; and Z = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen}; the compound of PubChem CID 47401101 {National Center for Biotechnology Information. "PubChem Compound Summary for CID 47401101, N-pyridin-2-yl-3,4-dihydro-1H-isoquinoline-2-carboxamide" PubChem, https://pubchem.ncbi.nlm.nih.gov/ compound/47401101. Accessed 23 September, 2026, create date November 26, 2010} PNG media_image9.png 128 258 media_image9.png Greyscale {a compound of instant formula (Ia), PNG media_image4.png 188 330 media_image4.png Greyscale , wherein ring A = a 6-membered monocyclic aromatic ring, which is unsubstituted [i.e., ring A-(i)]; ring B = a monocyclic heteroaromatic group containing at least one ring nitrogen, which is unsubstituted [i.e., ring B-(iii)]; Y = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen; and Z = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen}; the compound of PubChem CID 45820186 {National Center for Biotechnology Information. "PubChem Compound Summary for CID 45820186, N-(1,3,4-thiadiazol-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxamide" PubChem, https://pubchem.ncbi.nlm. nih.gov/compound/45820186. Accessed 23 September, 2026, create date June 21, 2010} PNG media_image10.png 122 252 media_image10.png Greyscale {a compound of instant formula (Ia), PNG media_image4.png 188 330 media_image4.png Greyscale , wherein ring A = a 6-membered monocyclic aromatic ring, which is unsubstituted [i.e., ring A-(i)]; ring B = a monocyclic heteroaromatic group containing at least one ring nitrogen, which is unsubstituted [i.e., ring B-(v)]; Y = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen; and Z = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen}; the compound of PubChem CID 108811921 {National Center for Biotechnology Information. "PubChem Compound Summary for CID 108811921, N-(1,2-oxazol-3-yl)-3,4-dihydro-1H-isoquinoline-2-carboxamide" PubChem, https://pubchem.ncbi.nlm.nih.gov/compound/108811921. Accessed 23 September, 2026, create date January 15, 2016} PNG media_image11.png 116 248 media_image11.png Greyscale {a compound of instant formula (Ia), PNG media_image4.png 188 330 media_image4.png Greyscale , wherein ring A = a 6-membered monocyclic aromatic ring, which is unsubstituted [i.e., ring A-(i)]; ring B = a monocyclic heteroaromatic group containing at least one ring nitrogen, which is unsubstituted [i.e., ring B-(vii)]; Y = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen; and Z = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen}; Shipps et al. {WO 2012/036997 A1} – who disclose Compound ID No. 45 on page 78 and Compound ID No. 42 on page 83, PNG media_image12.png 254 698 media_image12.png Greyscale PNG media_image13.png 192 696 media_image13.png Greyscale {a compound of instant formula (Ia), PNG media_image4.png 188 330 media_image4.png Greyscale , wherein ring A = a 5-membered monocyclic heteroaromatic ring, which is substituted with heteroaryl [i.e., pyrazolyl substituted with pyridin-4-yl]; ring B = a monocyclic heteroaromatic group containing at least one ring nitrogen, which is unsubstituted as found in Compound ID No. 45 [i.e., thiazol-2-yl – ring B-(iv)], -AND- a monocyclic heteroaromatic group containing at least one ring nitrogen substituted with halo and with alkyl as found in Compound ID No. 42 [i.e., ring B-(vi)]; Y = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen; and Z = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen}; and Bentley et al. {WO 2021/142006 A1} – who disclose, for instance, Example 166 on page 70, PNG media_image14.png 324 518 media_image14.png Greyscale {a compound of instant formula (Ia), PNG media_image4.png 188 330 media_image4.png Greyscale , wherein ring A = a 6-membered monocyclic heteroaromatic ring, which is substituted with Cl, [i.e., ring A-(v)]; ring B = a monocyclic heteroaromatic group containing at least one ring nitrogen, which is substituted with one heteroaryl [i.e., 1,2,4-triazolyl, substituted with pyridinyl]; Y = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen; and Z = CR10R10’ where R10 = hydrogen, and R10’ = hydrogen}. Each of the above cited prior art disclose at least one compound that is embraced by the instant claimed invention. Further, the Registry records for some of the compounds cited above disclose the predicted solubility of the compound in water (see page 41, lines 25-27 of the instant specification wherein “water” is listed as a diluent). Shipps et al. (pages 33-35) and Bentley et al. (page 169-173) each disclose pharmaceutical compositions comprising their compounds together with pharmaceutically acceptable carriers and/or excipients. Therefore, each of the above cited prior art anticipates the instant claimed invention. Note to Applicant: Not every piece of prior art found in the database search or class/subclass search which would anticipate and/or render obvious the instant claimed invention under examination has been applied against the instant currently pending claims under examination. See MPEP §904.03. Allowable Subject Matter The elected species of Compound (4) is free of the prior art of record. Claims 13, 32 and 56 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. Reminder to Applicant As a reminder, Applicant should specifically point out the support in the original disclosure {i.e., page number(s) and line number(s)} for any new claims or amended claims and for any amendments made to the disclosure. Making generic statements such as “all amendments are fully supported in the originally filed disclosure or the originally filed claims” without specifying page numbers and originally filed claim numbers are insufficient. See MPEP §714.02 and MPEP §2163.06(I). Telephone Inquiry Any inquiry concerning this communication or earlier communications from the examiner should be directed to: Laura L. Stockton (571) 272-0710. The examiner can normally be reached on Monday-Friday from 8:30 am to 6 pm, Eastern Standard Time. 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 acting supervisor, James Alstrum-Acevedo can be reached on 571/272-5548. 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. /LAURA L STOCKTON/ Primary Examiner, Art Unit 1626 Work Group 1620 Technology Center 1600 September 23, 2026 Book XXIX, page 117