Conjupro Biotherapeutics, Inc. et al. v. Ascletis Pharma China Co. Ltd. - PGR2025-00057

Petitioner's Objections to Patent Owner's Evidence

Patent Owner's Response to Petition

Fredrik Bergström and Bo Lindmark, Accelerated drug discovery by rapid candidate drug identification, Drug Discovery Today, Vol. 24, No. 6 (June 2019)

Deposition transcript of Michael Pirrung taken on February 26, 2026

Camile Georges Wermuth, David Aldous, Pierre Raboisson and Didier Rognan, The Practice of Medicinal Chemistry, 4th ed. (2015)

B. Sun et al., RCSB PDB of PDB ID 6XOX, cryo-EM of human GLP-1R bound to non-peptide agonist LY3502970, RCSB PROTEIN DATA BANK,

Michael Reddy, Standard amino acids

Francis A. Carey and Richard J. Sundberg, Advanced Organic Chemistry, Part A: Structure and Mechanisms, 5th Ed. (2007)

Neil Vargesson, Thalidomide-Induced Teratogenesis: History and Mechanisms, Birth Defects Research (Part C) 105:140–156 (2015)

James Burnett et al., A threonine turnstile defines a dynamic amphiphilic binding motif in the AAA ATPase p97 allosteric binding site, Org. Biomol. Chem., Vol. 15, 4096 (2017)

Celeste Alverez, et al., Structure-Activity Study of Bioisosteric Trifluoromethyl and Pentafluorosulfanyl Indole Inhibitors of the AAA ATPase p97, ACS Med. Chem. Lett., Vol. 6, 1225-1230 (2015)

Angela Kerekes, et al., Aurora Kinase Inhibitors Based on the Imidazo[1,2-a]pyrazine Core: Fluorine and Deuterium Incorporation improve Oral Absorption and Exposure, J. Med. Chem., Vol. 54, 201-210 (2011)

Ascletis, Ascletis’ Oral Small Molecule GLP-1, ASC30, Demonstrated Placebo-Adjusted Weight Loss of 7.7% with Better Gastrointestinal Tolerability in its 13-Week U.S. Phase II Study in Participants with Obesity or Overweight (Dec. 8, 2025)

Tong & Whitesell, In Situ Salt Screening, Pharm. Dev. & Tech., 3(2):215, 217 (1998)

Michael J. Bowker, A Procedure for Salt Selection and Optimization, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Ch. 7

Stephen M. Berge, Lyle D. Bighley and Donald C. Monkhouse, Pharmaceutical Salts, J. Pharm. Sci., 66:1-19 (1977)

Faisal Malik and Zhijun Li, Non-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes, British Pharm. Society, 511, 514 (2021)

Edith Wing-Kar Chow and Elaine Chow, Oral small-molecule GLP-1 receptor agonist for type 2 diabetes and obesity, The Lancet (Dec. 20, 2025)

Pfizer Provides Update on GLP-1-RA Clinical Development Program for Adults with Obesity and Type 2 Diabetes Mellitus, Pfizer (June 26, 2023)

Neeta B. Amin et al., Evaluation of an oral small-molecule glucagon-like peptide-1 receptor agonist, lotiglipron, for type 2 diabetes and obesity: A dose-ranging, phase 2, randomized, placebo-controlled study, Diabetes Obesity Metab. 2025; 27:215–227 (2024)

Pfizer Provides Update on GLP-1Receptor Agonist Danuglipron, Pfizer (April 14, 2025)

James Waldron, Pfizer’s Embattled Obesity Program Loses Another GLP-1 Over Poor Data and Strong Competition, Fierce Biotech (Aug. 5, 2025)

Malcolm Huestis and Keith Fagnou, Site-Selective Azaindole Arylation at the Azine and Azole Rings via N-Oxide Activation, Organic Lett., Vol. 11, No. 6 1357-1360 (2009)

Matthew Ward and Niamh O’Boyle, Analysis of the structural diversity of heterocycles amongst European medicines agency approved pharmaceuticals (2014-2023), RSC Medicinal Chem. 16, 4540-4570 (2025),

Edon Vitaku et al., Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals, J. Med. Chem., Vol. 57, Issue 24 (2014),

Aimee Clarke and William Unsworth, A happy medium: the synthesis of medicinally important medium-sized rings via ring expansion, Chem. Sci., Vol. 11, 2846 (2020),

Marcelo Polêto, et al., Aromatic Rings Commonly Used in Medicinal Chemistry: Force Fields Comparison and Interactions With Water Toward the Design of New Chemical Entities, Front. Pharmacol., 9:395 (2018),

Juan Rojas and James Bull, Oxetanes in Drug Discovery Campaigns, J. Med. Chem., 66, 12697-12709 (2023),

Mohana Krishna Ramisetty et al., Exploration of Oxetanes and Azetidines in Structure-Based Drug Design, Synlett 37(01):123-134 (2026),

Guang Huang, et al., Applications of oxetanes in drug discovery and medicinal chemistry, E.J. of Med. Chem., 261 (2023),

Volodymyr Semeno et al., Bicyclo[m.n.k]alkane Building Blocks as Promising Benzene and Cycloalkane Isosteres: Multigram Synthesis, Physicochemical and Structural Characterization, Nov. 14, 2023,

Alexander Harmata, et al., Bridged Bicyclic Building Block Upgrading: Photochemical Synthesis of bicyclo[3.1.1]heptan-1-Amines, Univ. of Michican, Oct. 21, 2020,

Bethany Shire and Edward Anderson, Conquering the Synthesis and Functionalization of Bicyclo[1.1.1]pentanes, JACS Au, Vol. 3, 1539-1553 (2023),

Jonas Bostrom, et al., Oxadizaoles in Medicinal Chemistry, J. Med. Chem. Vol. 55, Issue 5 (Dec. 19, 2011),

Yijing Li, et al., Thiadiazole-a Promising Structure in Medicinal Chemistry, ChemMedChem, Vol. 8, Issue 1, 27-41 (Jan. 10, 2013),

Lilly Investors, Lilly’s phase 2 results published in the New England Journal of Medicine show orforglipron, a once-daily oral nonpeptide GLP-1 receptor agonist, achieved up to 14.7% mean weight reduction at 36 weeks in adults with obesity or overweight (June 24, 2023),

Jinzi Jason Wu and Vanessa Wang, Poster: A full analysis of 28-Day MAD Study of Oral GLP-1R Biased Small Molecule Agonist ASC30 for obesity, Obesity Week, Ascletis.com (October 30, 2025),

Oana Cristina Seremet, et al., Small-Molecule GLP-1 Receptor Agonists: A Promising Pharmacological Approach, Medicina, 61(11), 1902 (Oct. 23, 2025),

Scott Childs et al., The Salt-Cocrystal Continuum: The Influence of Crystal Structure on Ionization State, Molecular Pharm., Vol. 4, 323-338 (2007)

Richard Bastin, et al., Salt Selection and Optimisation Procedures for Pharmaceutical New Chemical Entities, Am. Chem. Society, Vol. 4, 427-436 (2000)

Juan Frias et al., Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study, The Lanclet, Vol. 402 (2023)

Marnix van der Kolk, et al., Cyclobutanes in Small-Molecule Drug Candidates, ChemMedChem, 17, e202200020 (2022)

Deepak Gupta, et al., Salts of Therapeutic Agents; Chemical, Physicoshemical, and Biological Considerations, Molecules (2018)

Brett Hopkins et al., Utilization of Metabolite Identification and Structural Data to Guide Design of Low-Dose IDO1 Inhibitors, ACS Med. Chem. Lett. 2021, 12, 1435−1440,

Kuthuru Suresh and Ashwini Nangia, Lornoxicam Salts: Crystal Structures, Conformations and Solubility, Am. Chem. Society, Vol. 14, 2945-2953 (2014)

Anna Astrand, et al., Correlations between metabolism and structural elements of the alicyclic fentanyl analogs cyclopropyl fentanyl, cyclobutyl fentanyl, cyclopentyl fentanyl, cyclohexyl fentanyl and 2,2,3,3-tetramethylcyclopropyl fentanyl studied by human hepatocytes and LC-QTOF-MS, Archives of Toxicology, Vol. 93, 95-106 (2019)

Benjamin D. Cons, et al., Electrostatic Complementarity in Structure-Based Drug Design, J. of Med. Chem., Vol. 65, 7476-7488 (2022)

Paul Koovits, et al., Hit-to-lead optimization of a benzene sulfonamide series for potential antileishmanial agents, RCS Med. Chem., Vol. 11, 1267-1274 (2020)

Declaration of Dr. Peter Wipf in Support of Patent Owner’s Response, dated March 5, 2026

Declaration of John Gargiulo in Support of Patent Owner’s Response, dated March 5, 2026

Ascletis laboratory notebook no. GLNB007230-3

Kazancioglu, M. Z., Quirion, K., Wipf, P. and Skoda, E. M., Enantioselective Synthesis and Selective Functionalization of 4-Aminotetrahydroquinolines as Novel Glp-1 Secretagogues, Chirality 2022, 34(3), 521-536

Sean Wharton et al., Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment, New England Journal of Medicine 2025; 393:1796-806

Updated Table of Exhibits

Patent Owner Power of Attorney

Patent Owner Updated Mandatory Notice

ORDER Conditionally Granting Patent Owner’s Motion for Admission Pro Hac Vice of Tae Yeon (Zoe) Kim 37 C.F.R. § 42.10

Notice of Deposition of Dr. Michael C. Pirrung Ph.D.

Joint Stipulation to Modify Due Dates 1-3

Patent Owner’s Notice of Intent to Designate a Provisionally Recognized PTAB Attorney As Back-Up Counsel Pursuant to 37 CFR § 42.10(c)(2) - Agarwal

Ex 2029 - Decl of Agarwal ISO PHV

Patent Owner’s Motion for Pro Hac Vice to Admit Kim per 37 CFR 42.10(c)

Bio Tae Yeon Zoe Kim

Decl of Tae Yeon Zoe Kim ISO Pro Hac Vice Motion

Patent Owner's Updated Exhibit List

Order: Scheduling Order

Institution Decision: Grant

Director Discretionary Decision: Refer

Patent Owner's Updated Mandatory Notices Under 37 C.F.R. § 42.8

Patent Owner's Preliminary Response

Patent Owner's Updated Exhibit List

Guang Huang et al., Applications of Oxetanes in Drug Discovery and Medicinal Chemistry, European Journal of Medicinal Chemistry (2023), 261

Juan J. Rojas and James A. Bull, Oxetanes in Drug Discovery Campaigns, Journal of Medicinal Chemistry (2023), 66 , 12697-12709

Jonas Boström et al., Oxadiazoles in Medicinal Chemistry, Journal of Medicinal Chemistry (2011), 55, 1817-1830

Yijing Li et al., Thiadiazole—a Promising Structure in Medicinal Chemistry, ChemMedChem (2013), 27-41

Bethany R. Shire and Edward A. Anderson, Conquering the Synthesis and Functionalization of Bicyclo[1.1.1]pentanes, An Open Access Journal of the American Chemical Society (2023), 3, 1539-1553

Edon Vitaku, et al, Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals, Journal of Medicinal Chemistry (2014), 57, 10257-10274

Marcelo D. Polêto et al., Aromatic Rings Commonly Used in Medicinal Chemistry: Force Fields Comparison and Interactions With Water Toward the Design of New Chemical Entities, Frontiers in Pharmacology (2018), 9, 1-20

Aimee K. Clarke and William P. Unsworth, A happy medium: the synthesis of medicinally important medium-sized rings via ring expansion, The Royal Society of Chemistry (2020), 11, 2876-2881

Alexander S. Harmata, et al., Bridged bicyclic building block upgrading: Photochemical synthesis of bicyclo[3.1.1]heptan-1-amines, Willard Henry Dow Laboratory, Dept. of Chemistry, Univ. of Michigan

Jang Won Son and Soo Lim, Glucagon-Like Peptide-1 Based Therapies: A New Horizon in Obesity Management, Endocrinology and Metabolism (2024), 39, 206-221

Sean Wharton, M.D. et al., Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity, The New England Journal of Medicine (2023), 389, 877-888

A Study of Orforlipron (LY3502970) in Adult Participants with Obesity or Overweight With Weight-Related Comorbidities (ATTAIN-1), Lilly Trials

International Publication No. WO 2024/169952 A1

International Publication No. WO 2023/016546 A1

International Publication No. WO 2024/153070 A1

Ascletis Presented Results from Cohorts 1 and 2 of 28-day Multiple Ascending Dose Study of Its Oral Small Molecule GLP-1R Agonist ASC30 at the 61st European Association for the Study of Diabetes (EASD) Annual Meeting, Ascletis

Jinzi Jason Wu and Vanessa Wang, Poster number: 750-P, ASC30, an Oral GLP-1R Biased Small Molecule Agonist in Participants with Obesity -A First-in-Human Single Ascending Dose Study, (June 20, 2025)

Compound Summary for CID 8028, Tetrahydrofuran, National Center for Biotechnology Information, PubChem

Compound Summary for CID 9253, Cyclopentane, National Center for Biotechnology Information, PubChem

Arun K Ghosh and David D Anderson, Tetrahydrofuran, Tetrahydropyran, Triazoles and Related Heterocyclic Derivatives as Hiv Protease Inhibitors, Future Med Chem. (2011), 3, 1181-1197

Seung-Hwa Kwak et al., Evaluation of Manassantin A Tetrahydrofuran Core Region Analogues and Cooperative Therapeutic Effects with EGFR Inhibition, Journal of Medicinal Chemistry (2020), 63, 6821-6833

Pedro de Sena Murteira Pinheiro, Lucas Silva Franco and Carlos Alberto Manssour Fraga, The Magic Methyl and Its Tricks in Drug Discovery and Development, MDPI (2023), 16, 1157

Petitioner's Response to Patent Owner Request for Discretionary Denial

Corrected English Translation of Int. Pub. No. WO 2025/026270A1 (Su)

International Pub. No. WO 2024/169952A1 (Huang)

Patent Owner’s Brief in Support of Discretionary Denial

Patent Owner's Updated Exhibit List

Excerpts of File History of U.S. Patent No. 12,234,236

Excerpts of File History of U.S. Patent Application No. 18/885,065

International Publication No. WO 2025/131043A1

Certified English Translation of International Publication No. WO 2025/131043A1

U.S. Patent No. 12,291,530

Patent Owner’s Notice of Intent to Designate a Provisionally Recognized PTAB Attorney as Back-Up Counsel Pursuant to 37 CFR § 42.10(c)(2)

Declaration of Geoffrey D. Biegler Pursuant to 37 CFR § 42.10(c)(2)

Patent Owner’s Exhibit List

Notice: Mandatory Notice

Notice: Power of Attorney

Notice: Notice filing date accorded

U.S. Patent No. 12,234,236

Kawai, et al., Proc Natl Acad Sci U S A., 117(47):29959-29967 (2020)

International Publication No. WO 2025/026270A1

Chinese Patent Application No. 202311372605.9 (“Su II”)

Certified English Translation of Chinese Patent App. No. 20231137260.9

U.S. Patent No. 10,858,356 to Yoshino, et al (“Yoshino”)

Talele, Journal of Medicinal Chemistry, 59(19):8712–8756 (2016) (“Talele”)

Liu, et al., Expert Opinion on Therapeutic Patents, 30(10):781-794 (2020)

Pratt, et al., Diabetes Obes Metab., 25(9):2642-2649 (2023)

Frias, et al., Lancet, 402(10400):472–483 (2023)

Chinese Patent Application No. 202311371725 (“the ’725 Provisional”)

Certified English Translation of Chinese Patent App. No. 202311371725

Chinese Patent Application No. 202311189557 (“the ’557 Provisional”)

Certified English Translation of Chinese Patent App. No. 202311189557

U.S. Patent Provisional App. No. US 63/538,892 (“the ’892 Provisional")

Chinese Patent Application No. 202410142451 (“the ’451 Provisional”)

Certified English Translation of Chinese Patent App. No. 202410142451

Chinese Patent Application No. 202311582240 (“the ’240 Provisional”)

Certified English Translation of Chinese Patent App. No. 202311582240

Chinese Patent Application No. 202311686034 (“the ’034 Provisional”)

Certified English Translation of Chinese Patent App. No. 202311686034

U.S. Patent Provisional Application No. 63/545,615 (“the ’615 Provisional”)

U.S. Patent Provisional Application No. 63/603,854 (“the ’854 Provisional”)

Patel & Burns, J Am Chem Soc., 144(39):17797-17802 (2022) (“Patel”)

Pennington & Moustakas, J Med Chem., 60(9):3552-3579 (2017)

Chinese Patent Publication No. CN117069743A (“Meng”)

Certified English Translation of Chinese Patent Publication No. CN117069743

U.S. Patent No. 12,037,339 (“Ren”)

Certified English Translation of International Publication No. WO 2025/0262

Certified English Translation of International Pub. No. WO 2025/026272

Excerpts of File History of U.S. Patent No. 12,234,236

Declaration of Michael C. Pirrung, Ph.D.

Petition: as filed

Notice: Power of Attorney