IMIDAZOPYRIDINYL INHIBITORS OF PLASMA KALLIKREIN

§103 §112 §DOUBLEPATENT

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 . Priority The present application claims priority to the applications, 63/162,494 and PCT/US2022/02474, with the effective filing dates of 17 March 2021 and 16 March 2022, respectively. Claim Status This Office Action is in response to Applicant’s Amendment filed, 2 July 2026, wherein Applicant amended claims 1-3, 7, 13, 15, 22-24, and 26-27 and canceled claim 6. Claims 16-21 were previously canceled. Applicant previously elected Group I (claims 1-28) and Compound I-26 ( PNG media_image1.png 168 320 media_image1.png Greyscale ) as the species. Claims 29-30 were withdrawn as they were directed to a nonelected group. The elected species, I-26, was free of the prior art. Accordingly, claims 1-28 are under consideration in the instant office action. Information Disclosure Statement The Information Disclosure Statement filed 29 July 2026 and the references cited therein have been considered, unless indicated otherwise. The references, WO 2014/074715 and RN 2472497-53-1, were lined through, because these were missing. The reference, Longhurst, was lined through, because it is illegible. Rejections Withdrawn Claim Objections 1. Claims 3, 7, 13, 22-24, and 26 were objected to the following informalities: lack of comma and/or conjunction to separate the options. Claims 3, 7, 13, 22-24, and 26 were amended to include a comma and/or conjunction. The objection of claims 3, 7, 13, 22-24, and 26 has been withdrawn. Claim Rejections – 35 U.S.C. § 112 2. Claims 26-27 were rejected as being indefinite for failing to particularly point out and distinctly claim the subject matter the inventor regards as the invention. Claim 26 was amended to define R0. Claim 27 was amended to recite the names and structures of Compounds I-1 – I-34. Applicant’s amendments and arguments, see pages 7-13, with respect to claims 26-27 have been fully considered and are persuasive. The rejection of claims 26-27 has been withdrawn. Claim Rejections – Nonstatutory Double Patenting 3. Claims 1-12, 22-24, 26, and 28 were rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 27-28 of U.S. Application No. 18/550,504 in view of Xie (Euro. J. Med. Chem.¸2020, 190(112137), 1-14; of record, see PTO-892 mailed 3 Apr 2026), Ghosh 1 (J. Med. Chem.¸2020, 63, 2751-2788; of record, see PTO-892 mailed 3 Apr 2026), and Ghosh 2 (J. Med. Chem.¸2015¸58¸2895-2940; of record, see PTO-892 mailed 3 Apr 2026). Applicant’s amendments and arguments, see pages 2-3 and 20-21, with respect to claims 1-5, 7-12, 22-24, 26, and 28 have been fully considered and are persuasive. The Examiner notes that claim 1 of ‘504 was amended to recite that CyC is not PNG media_image2.png 70 102 media_image2.png Greyscale with 0-6 Lc-Rc groups. Claim 6 was canceled. The rejection of claims 1-5, 7-12, 22-24, 26, and 28 has been withdrawn. Rejections New/Modified or Maintained 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 Rejections – 35 U.S.C. § 112 4. (New) Claim 4 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 4 specifies that CyA is a 7- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 RA groups, but claim 1 (the claim upon which claim 4 depends) recites that CyA is selected from the group consisting of: PNG media_image3.png 268 585 media_image3.png Greyscale , which all are 9-membered bicyclic heteroarylenes. Thus, claim 4 expands the scope of claim 1. 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 U.S.C. § 103 5. (Maintained) Claims 1-15 and 22-28 were rejected as being unpatentable over Papaioannou (WO 2019/178129, published 19 Sept 2019; see IDS filed 17 Feb 2019) in view of Xie (Euro. J. Med. Chem.¸2020, 190(112137), 1-14; of record, see PTO-892 mailed 3 Apr 2026), Ghosh 1 (J. Med. Chem.¸2020, 63, 2751-2788; of record, see PTO-892 mailed 3 Apr 2026), and Ghosh 2 (J. Med. Chem.¸2015¸58¸2895-2940; of record, see PTO-892 mailed 3 Apr 2026). Claim 6 was canceled. Applicant's arguments, see pages 13-20 have been fully considered but they are not persuasive. The Examiner notes that Applicant has support for the amendment to claim 1 regarding CyA in paragraph [0046] on page 13. Applicant argues that CyB in Papaioannou is not in the same relative location of CyB in the instantly claimed invention with Applicant’s labeling: PNG media_image4.png 143 409 media_image4.png Greyscale and that Papaioannou does not include urea or carbamate. Applicant further argues that there is no motivation to modify the compounds to provide a urea or carbamate or a CyB that is phenyl, an 8- to 10-membered bicyclic aryl, or a 5-6-membered heteroaryl. Applicant argues that Xie gives no motivation to replace the amide in Papaioannou with urea or carbamate and that Ghosh 1 and Ghosh 2 do not give motivation to further modify Papaioannou in view of Xie by specifically replacing another hydrogen-bonding functionality with urea or carbamate. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to 1) modify CyA of Compound I-5 (as mapped by the Examiner below) of Papaioannou to capitalize on hydrogen bonding opportunities with Ser478 and Gly480; 2) modify CyB of Compound I-5 to capitalize on hydrogen bonding opportunities with Asp572; and 3) incorporate a urea or a carbamate as taught by Ghosh 1 and Ghosh 2 to better facilitate hydrogen bonding capabilities, enhance water solubility, and act as a peptide bond surrogate (due to chemical stability and capability to permeate cell membranes). One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because: -Papaioannou teaches compounds of a core scaffold: PNG media_image5.png 149 177 media_image5.png Greyscale that are inhibitors of plasma kallikrein, -Papaioannou teaches PNG media_image6.png 121 316 media_image6.png Greyscale , having the following mapping: Formula (I) components of 18/550,474 Formula (I) of 18/550,474 Compound I-5 of Papaioannou R6 CyC PNG media_image7.png 34 50 media_image7.png Greyscale R3-R5, R7 H PNG media_image8.png 64 104 media_image8.png Greyscale L C1-3 hydrocarbon chain (methylene) PNG media_image9.png 28 18 media_image9.png Greyscale CyA* Phenyl, 6-membered monocyclic heteroaryl, selected group of 7-12 membered bicyclic heteroaryl missing R8 missing missing X NRy, Ry = H PNG media_image10.png 36 22 media_image10.png Greyscale L’ C1-3 hydrocarbon chain (methylene) PNG media_image11.png 25 13 media_image11.png Greyscale CyB** Phenyl, 8-10-membered bicyclic aryl, 5-6-membered heteroaryl missing *The Examiner notes that CyA was amended to remove 5-membered monocyclic heteroarylene having 1-3 heteroatoms, which described the pyrazole of Compound I-5 (Papaioannou). **The Examiner notes that CyB was amended to remove 7-10-membered heteroaryl having 1-4 heteroatoms, which described the 2-azaindolizine of Compound I-5 (Papaioannou). -Papioannou teaches that Compound I-5 has an in vitro dose response of A, which corresponds to ≤ 1.0 nM (Table 1, page 632), -Papaioannou teaches that plasma kallikrein is a serine protease zymogen in blood that contributes to the innate inflammatory response and intrinsic cascade of blood coagulation ([0001]), -Papaioannou teaches that plasma kallikrein is associated with a number of disorders, such as hereditary angioedema, an autosomal dominant disease, characterized by painful, recurrent attacks of inflammation ([0002]), -Papaioannou teaches Compound I-3 ( PNG media_image12.png 135 304 media_image12.png Greyscale ; page 89), wherein CyA is pyridine (a 6-membered heteroaryl), -Papaioannou teaches incorporation of a triazolopyridinyl group ([0056]; [0058]), -Xie teaches plasma kallikrein is a zymogen of trypsin-like serine protease, is involved in potent inflammatory mediator, bradykinin, and displays important roles in diabetic retinopathy, diabetic macular edema, and diabetic nephropathy, -Xie teaches the SAR of several plasma kallikrein inhibitors, -Xie teaches nicotinamide scaffolds are potent plasma kallikrein inhibitors (Compound 42; page 8, column 2, paragraph 1), -Xie teaches an additional inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors that encompass three components: Fragment A, middle scaffold, and Fragment B, -Xie teaches inhibitor-target model for non-peptidomimetic plasma kallikrein inhibitors (specifically Compound 26: PNG media_image13.png 126 206 media_image13.png Greyscale ) in a crystal complex of plasma kallikrein (Figure 4, page 7; Figure 11, page 12), -Xie teaches CyB is a phenyl or a 5-6-membered heteroaryl: Compounds 42 and 43 ( PNG media_image14.png 152 239 media_image14.png Greyscale and PNG media_image15.png 134 129 media_image15.png Greyscale ; Figure 7, page 9), -Xie teaches that Compounds 42-44 showed good activity as plasma kallikrein inhibitors (IC50 < 0.1 uM; page 9). -Xie teaches that Fragment B has a hydrogen bonding opportunity with Asp572 (Figure 11, page 12), -Xie teaches CyA is a 7- to 12-membered heteroarylene as Compound 36: PNG media_image16.png 164 120 media_image16.png Greyscale (Figure 5, page 8), which would engage in hydrogen-bonding, -Xie teaches the middle scaffold (CyA) has hydrogen-bonding opportunities with Gly 480 and Ser478 and that a heterocyclic ring in fragment A or in the middle scaffold typically forms the H- bonding bridges (page 10, column 2, paragraph 2; Figure 11B, page 12), -Ghosh 1 teaches that urea has a central role in drug development and medicinal chemistry due to its ability to form multiple stable hydrogen bonds with protein and receptor targets and that drug-target interactions are responsible for specific biological activity, drug actions, and drug properties (page 2751, column 1, paragraph 1), -Ghosh 1 teaches modulation of hydrogen bonding capabilities of urea via electron donating and electron withdrawing functionalities (page 2754, column 1, paragraph 1), -Ghosh 1 teaches that water solubility is enhanced by disrupting molecular planarity of the solutes in order to reduce their crystal packing energy via introduction of a substituent onto the urea (page 2754, column 2, paragraph 2; Figure 9, page 2754), -Ghosh 2 teaches incorporation of carbamates (urethane) in medicinal chemistry, -Ghosh 2 teaches that carbamates are a key structural motif in many approved drugs and prodrugs and that drugs that utilize the carbamates functionality are designed as peptide surrogates, -Ghosh 2 teaches that carbamates are widely utilized as a peptide bond surrogate in medicinal chemistry due to their chemical stability and capability to permeate cell membranes (page 2895, column 1, paragraph 1), -Ghosh 2 teaches that carbamates are able to modulate inter- and intramolecular interactions with target enzymes or receptor and impose a degree of conformational restriction due to delocalization of non-bonded electrons on the nitrogen into the carboxyl moiety (page 2895, column 1, paragraph 1), and -Ghosh 2 teaches that carbamates engage in hydrogen bonding (page 2895, column 1, paragraph 1). As such, an artisan having ordinary skill in the art would have been motivated to modify one known element for another to predictably arrive at a compound of Formula (I): PNG media_image17.png 125 289 media_image17.png Greyscale . Accordingly, the rejection of claims 1-5, 7-15, and 22-28 as being unpatentable over Papaioannou in view of Xie, Ghosh 1, and Ghosh 2 is maintained. Claim Rejections – Nonstatutory Double Patenting 6. Claims 1-4, 6-12, 22-24, 26, and 28 were rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 31-32 of U.S. Application No. 18/550,306 in view of Xie (Euro. J. Med. Chem.¸2020, 190(112137), 1-14; of record, see PTO-892 mailed 3 Apr 2026), Ghosh 1 (J. Med. Chem.¸2020, 63, 2751-2788; of record, see PTO-892 mailed 3 Apr 2026), and Ghosh 2 (J. Med. Chem.¸2015¸58¸2895-2940; of record, see PTO-892 mailed 3 Apr 2026). Claim 6 was canceled. Applicant's arguments, see pages 21-22, have been fully considered but they are not persuasive. Applicant argues because the compounds claimed in 18/550,306 include a cyclopropyl and do not include a urea/carbamate, the claims are patentably distinct. Applicant further asserts that the considerations previously noted in the response regarding Xie, Ghosh 1, and Ghosh 2 apply as well. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In response to the previously mentioned considerations of Xie, Ghosh 1, and Ghosh 2, Applicant relies upon the amendment and arguments over claims 1-5, 7-15, and 22-28 to overcome the rejection of claims 1-4, 7-12, 22-24, 26, and 28. However, Applicant’s amendment and arguments over claims 1-5, 7-15, and 22-28 were not persuasive. Accordingly, the rejection of claims 1-4, 7-12, 22-24, 26, and 28 on the ground of nonstatutory double patenting is maintained. 7. Claims 1-4, 6-12, 22-24, 26, and 28 were rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 17-18 of U.S. Patent No. 11,787,796 in view of Xie (Euro. J. Med. Chem.¸2020, 190(112137), 1-14; of record, see PTO-892 mailed 3 Apr 2026), Ghosh 1 (J. Med. Chem.¸2020, 63, 2751-2788; of record, see PTO-892 mailed 3 Apr 2026), and Ghosh 2 (J. Med. Chem.¸2015¸58¸2895-2940; of record, see PTO-892 mailed 3 Apr 2026). Claim 6 was canceled. Applicant's arguments, see pages 22-23, have been fully considered but they are not persuasive. Applicant argues because the compounds claimed in 11,787,796 require that CyA is either a 5-membered heteroarylene or a 7-10-membered partially unsaturated bicyclic heterocyclelene and thus the instant claims are distinct. Applicant further asserts that the considerations previously noted in the response regarding Xie, Ghosh 1, and Ghosh 2 apply as well. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In response to the previously mentioned considerations of Xie, Ghosh 1, and Ghosh 2, Applicant relies upon the amendment and arguments over claims 1-5, 7-15, and 22-28 to overcome the rejection of claims 1-4, 7-12, 22-24, 26, and 28. However, Applicant’s amendment and arguments over claims 1-5, 7-15, and 22-28 were not persuasive. Accordingly, the rejection of claims 1-4, 7-12, 22-24, 26, and 28 on the ground of nonstatutory double patenting is maintained. 8. Claims 1-4, 6-12, 22-24, 26, and 28 were rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 9, and 13 of U.S. Patent No. 11,370,803 in view of Xie (Euro. J. Med. Chem.¸2020, 190(112137), 1-14; of record, see PTO-892 mailed 3 Apr 2026), Ghosh 1 (J. Med. Chem.¸2020, 63, 2751-2788; of record, see PTO-892 mailed 3 Apr 2026), and Ghosh 2 (J. Med. Chem.¸2015¸58¸2895-2940; of record, see PTO-892 mailed 3 Apr 2026). Claim 6 was canceled. Applicant's arguments, see pages 23-24, have been fully considered but they are not persuasive. Applicant argues because the compounds claimed in 11,370,803 do not require a urea or carbamate and that CyB cannot be phenyl, 8-10-membered bicyclic aryl, or a 5-6-membered heteroaryl and thus the instant claims are distinct. Applicant further asserts that the considerations previously noted in the response regarding Xie, Ghosh 1, and Ghosh 2 apply as well. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In response to the previously mentioned considerations of Xie, Ghosh 1, and Ghosh 2, Applicant relies upon the amendment and arguments over claims 1-5, 7-15, and 22-28 to overcome the rejection of claims 1-4, 7-12, 22-24, 26, and 28. However, Applicant’s amendment and arguments over claims 1-5, 7-15, and 22-28 were not persuasive. Accordingly, the rejection of claims 1-4, 7-12, 22-24, 26, and 28 on the ground of nonstatutory double patenting is maintained. 9. Claims 1-12, 22-24, 26, and 28 were rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 9, and 13 of U.S. Patent No. 10,730,874 in view of Xie (Euro. J. Med. Chem.¸2020, 190(112137), 1-14; of record, see PTO-892 mailed 3 Apr 2026), Ghosh 1 (J. Med. Chem.¸2020, 63, 2751-2788; of record, see PTO-892 mailed 3 Apr 2026), and Ghosh 2 (J. Med. Chem.¸2015¸58¸2895-2940; of record, see PTO-892 mailed 3 Apr 2026). Claim 6 was canceled. Applicant's arguments, see pages 24-25, have been fully considered but they are not persuasive. Applicant argues because the compounds claimed in 10,730,874 do not require a urea or carbamate and that CyB cannot be phenyl, 8-10-membered bicyclic aryl, or a 5-6-membered heteroaryl and thus the instant claims are distinct. Applicant further asserts that the considerations previously noted in the response regarding Xie, Ghosh 1, and Ghosh 2 apply as well. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In response to the previously mentioned considerations of Xie, Ghosh 1, and Ghosh 2, Applicant relies upon the amendment and arguments over claims 1-5, 7-15, and 22-28 to overcome the rejection of claims 1-5, 7-12, 22-24, 26, and 28. However, Applicant’s amendment and arguments over claims 1-5, 7-15, and 22-28 were not persuasive. Accordingly, the rejection of claims 1-5, 7-12, 22-24, 26, and 28 on the ground of nonstatutory double patenting is maintained. Conclusion No claim is 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. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Madeline M Dekarske whose telephone number is (571)272-1789. The examiner can normally be reached Monday - Thursday 10am - 4pm. 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, James Alstrum-Acevedo can be reached at 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. /MADELINE M. DEKARSKE/Examiner, Art Unit 1622 /JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622