PGR2025-00057
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`CONJUPRO BIOTHERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`Ascletis Pharma China Co Ltd,
`Patent Owner.
`____________
`Case No. PGR2025-00057
`Patent No. 12,234,236
`Title: GLP-1R agonist and therapeutic method thereof
`
`PETITION FOR POST GRANT REVIEW OF Claims 1-9, 12-17, and 21-25
`OF U.S. PATENT NO. 12,234,236
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`

`

`PGR2025-00057
`
`TABLE OF CONTENTS
`
`Page
`TABLE OF EXHIBITS ........................................................................................... vii
`I.
`INTRODUCTION ........................................................................................... 1
`II. MANDATORY NOTICES .............................................................................. 5
`III. PAYMENT OF FEES ...................................................................................... 6
`IV. GROUNDS FOR STANDING ........................................................................ 6
`V.
`IDENTIFICATION OF CHALLENGE UNDER 37 C.F.R. § 42.204(b) ....... 6
`VI. BACKGROUND ............................................................................................. 8
`VII. THE ’236 PATENT ........................................................................................ 10
`A.
`The Prosecution of the ’236 Patent ..................................................... 10
`B.
`The Effective Filing Date .................................................................... 12
`VIII. SUMMARY OF THE PRIOR ART REFERENCES..................................... 20
`A. Yoshino (EX1008) ............................................................................... 20
`B.
`Su (EX1005) ........................................................................................ 25
`C.
`Kawai (EX1004) .................................................................................. 31
`D.
`Talele (EX1009) .................................................................................. 35
`E. Meng (EX1028) ................................................................................... 38
`F.
`Patel (EX1026) .................................................................................... 40
`G.
`Ren (EX1030) ...................................................................................... 41
`H.
`Bethel (EX1032) .................................................................................. 43
`IX. PERSON OF ORDINARY SKILL IN THE ART ......................................... 44
`X.
`CLAIM CONSTRUCTION .......................................................................... 45
`
`i
`
`

`

`PGR2025-00057
`
`XI. LEGAL STANDARDS .................................................................................. 45
`XIII. DETAILED EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY ................................................................................... 46
`A. GROUND 1: CLAIMS 1-4, 6, 12-14, 24, AND 25 ARE
`OBVIOUS OVER SU, YOSHINO, AND KAWAI IN VIEW OF
`TALELE .............................................................................................. 46
`Claim 1: ............................................................................................... 46
`Claim 2: ............................................................................................... 65
`Claim 3: ............................................................................................... 66
`Claim 4: ............................................................................................... 69
`Claim 6: ............................................................................................... 73
`Claim 12: ............................................................................................. 75
`Claim 13: ............................................................................................. 76
`Claim 14: ............................................................................................. 77
`Claim 24: ............................................................................................. 78
`Claim 25: ............................................................................................. 82
`GROUND 2: CLAIMS 1-9, 12-17, 24, AND 25 ARE OBVIOUS
`OVER YOSHINO AND KAWAI IN VIEW OF TALELE ................. 83
`(i)
`Compound 1 .............................................................................. 83
`(ii) Compound 19 ............................................................................ 94
`(iii) Compound 20 ............................................................................ 98
`Claim 2: .............................................................................................101
`Claim 3: .............................................................................................101
`Claim 4: .............................................................................................101
`Claim 5: .............................................................................................101
`
`B.
`
`ii
`
`

`

`PGR2025-00057
`
`Claim 6: .............................................................................................102
`Claim 7: .............................................................................................102
`Claim 8: .............................................................................................102
`Claim 9: .............................................................................................102
`Claim 12: ...........................................................................................103
`Claim 13: ...........................................................................................103
`Claim 14: ...........................................................................................103
`Claim 15: ...........................................................................................103
`Claim 16: ...........................................................................................104
`Claim 17: ...........................................................................................104
`Claim 24: ...........................................................................................104
`Claim 25: ...........................................................................................104
`GROUND 3: CLAIMS 1-4 AND 21-25 WOULD HAVE BEEN
`OBVIOUS OVER SU, YOSHINO, KAWAI, TALELE, AND
`MENG IN VIEW OF PATEL AND REN .........................................105
`Claim 1: .............................................................................................105
`Claim 2: ............................................................................................. 112
`Claim 3: ............................................................................................. 112
`Claim 4: ............................................................................................. 113
`Claim 21: ........................................................................................... 113
`Claim 22: ........................................................................................... 113
`Claim 23: ........................................................................................... 114
`Claim 24: ........................................................................................... 114
`Claim 25: ........................................................................................... 114
`
`iii
`
`C.
`
`

`

`PGR2025-00057
`
`D. GROUND 4: CLAIMS 4 and 9 ARE OBVIOUS OVER SU AND
`BETHEL ............................................................................................ 115
`Claim 9: ............................................................................................. 116
`XIV. DISCRETIONARY DENIAL UNDER 35 U.S.C. §325(d) ........................ 116
`XV. CONCLUSION ............................................................................................120
`
`
`iv
`
`

`

`TABLE OF AUTHORITIES
`
`PGR2025-00057
`
` Page(s)
`
`Cases
`Advanced Bionics, LLC v. Med-El Elektromedizinische Geräte
`GmbH.,
`IPR2019-01469, Paper 6 (PTAB Feb. 13, 2020) .............................................. 117
`Graham v. John Deere Co. of Kansas City,
`383 U.S. 1 (1966) ................................................................................................ 45
`KSR Int’l v. Teleflex Inc.,
`550 U.S. 398 (2007) ........................................................................................... 45
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .......................................................................... 45
`Wellman, Inc. v. Eastman Chem. Co.,
`642 F.3d 1355 (Fed. Cir. 2001) .......................................................................... 45
`ZUP, LLC v. Nash Mfg., Inc.,
`896 F.3d 1365 (Fed. Cir. 2018) .......................................................................... 46
`Statutes
`35 U.S.C. § 102(a) ............................................................................................passim
`35 U.S.C. § 102(a)(2) ......................................................................................... 26, 43
`35 U.S.C. § 102(b) ............................................................................................passim
`35 U.S.C. § 103 ................................................................................................ 6, 7, 45
`35 U.S.C. §325(d) .......................................................................................... 116, 120
`Other Authorities
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 5
`37 C.F.R. § 42.8(b)(2) ................................................................................................ 5
`37 C.F.R. § 42.8 (b)(3) ............................................................................................... 5
`
`v
`
`

`

`PGR2025-00057
`
`37 C.F.R. § 42.8 (b)(4) ............................................................................................... 5
`37 C.F.R. § 42.15(a) ................................................................................................... 6
`37 C.F.R. § 42.202 ..................................................................................................... 6
`37 C.F.R. § 42.203(a) ................................................................................................. 6
`37 C.F.R. § 42.204(a) ................................................................................................. 6
`37 C.F.R. § 42.204(b) ................................................................................................ 6
`U.S. Patent No. 10,858,356 .................................................................................. 7, 20
`U.S. Patent No. 12,037,339 .................................................................................. 7, 41
`U.S. Patent No. 12,234,236 ...............................................................................passim
`
`
`
`
`
`
`
`vi
`
`

`

`PGR2025-00057
`
`TABLE OF EXHIBITS
`
`Exhibit
`EX1001
`EX1002
`EX1003
`EX1004
`
`EX1005
`EX1006
`
`EX1007
`
`EX1008
`EX1009
`
`EX1010
`
`EX1011
`EX1012
`EX1013
`
`EX1014
`
`EX1015
`
`EX1016
`
`EX1017
`
`EX1018
`
`EX1019
`
`EX1020
`
`Description
`U.S. Patent No. 12,234,236 (“the ’236 Patent”)
`Declaration of Michael C. Pirrung, Ph.D.
`Excerpts of File History of U.S. Patent No. 12,234,236
`Kawai, et al., Proc Natl Acad Sci U S A., 117(47):29959-29967
`(2020) (“Kawai”)
`International Publication No. WO 2025/026270A1 (“Su”)
`Chinese Patent Application No. 202311372605.9 (“Su II”), which is a
`priority document of Su
`Certified English Translation of Chinese Patent Application No.
`202311372605.9 (“Su II”)
`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 Application No.
`202311371725
`Chinese Patent Application No. 202311189557 (“the ’557
`Provisional”)
`Certified English Translation of Chinese Patent Application No.
`202311189557
`U.S. Patent Provisional Application No. US 63/538,892 (“the ’892
`Provisional”)
`Chinese Patent Application No. 202410142451 (“the ’451
`Provisional”)
`Certified English Translation of Chinese Patent Application No.
`202410142451 (“the ’451 Provisional”)
`Chinese Patent Application No. 202311582240 (“the ’240
`
`vii
`
`

`

`PGR2025-00057
`
`Exhibit
`
`EX1021
`
`EX1022
`
`EX1023
`
`EX1024
`
`EX1025
`
`EX1026
`
`EX1027
`EX1028
`EX1029
`
`EX1030
`EX1031
`
`EX1032
`
`Description
`
`Provisional”)
`Certified English Translation of Chinese Patent Application No.
`202311582240
`Chinese Patent Application No. 202311686034 (“the ’034
`Provisional”)
`Certified English Translation of Chinese Patent Application 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.
`CN117069743A
`U.S. Patent No. 12,037,339 (“Ren”)
`Certified English Translation of International Publication No. WO
`2025/026270 (“Su”)
`International Publication No. WO 2024/129676A1 (“Bethel”)
`
`viii
`
`

`

`PGR2025-00057
`
`I.
`
`INTRODUCTION
`
`Conjupro Biotherapeutics, Inc. (“Petitioner”) requests post grant review of
`
`claims 1-9, 12-17, and 21-25 (the “Challenged Claims”) of U.S. Patent No.
`
`12,234,236 (“the ’236 Patent”) (EX1001), assigned to Ascletis Pharma China Co
`
`Ltd. (“Patent Owner”). For the reasons set forth below and in the accompanying
`
`Declaration of Dr. Michael C. Pirrung (EX1002), it is more likely than not that at
`
`least one of the Challenged Claims is unpatentable as being obvious over the prior
`
`art.
`
`The Challenged Claims are directed to a class of compounds that function as
`
`modulators of the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R). The ’236
`
`Patent has two independent Markush claims, claims 1 and 24, both of which claim—
`
`among other compounds—Compound 1, Compound 19, Compound 20, and
`
`Compound 65. (See EX1001, 204:1-220:58.)
`
`As of the relevant priority date, it was well known that orforglipron was an
`
`orally bioavailable, non-peptidic small-molecule GLP-1R agonist developed by Eli
`
`Lilly & Co. (EX1002, ¶48.) This compound exhibited full agonist efficacy,
`
`promoting cAMP accumulation at levels comparable to native GLP-1, with an EC50
`
`of 1.1 nM at both human and cynomolgus monkey GLP-1 receptors. (Id., ¶49 (citing
`
`EX1010, 4).) Unlike traditional peptide-based GLP-1R agonists, orforglipron was
`
`structurally optimized for once-daily oral administration, addressing compliance
`
`1
`
`

`

`PGR2025-00057
`
`issues associated with injectable therapies for type 2 diabetes and obesity. (Id. (citing
`
`EX1011, 2); EX1004.)
`
`Kawai (EX1004) provides a detailed structural analysis of orforglipron
`
`binding to the GLP-1 receptor, revealing that the region surrounding the methyl
`
`group on the indazole moiety is both flexible and hydrophobic, and can
`
`accommodate bulkier substituents without compromising receptor engagement.
`
`(EX1002, ¶58 (citing EX1004, FIG. 1I).) A person of ordinary skill in the art
`
`(POSA), armed with this structural insight, would have been motivated to explore
`
`alternative substituents for the methyl group. (Id., ¶¶58-59.)
`
`Yoshino (EX1008) further confirms that replacing the methyl group, such as
`
`with a tetrahydrofuran ring, preserves biological activity, thereby validating that
`
`small ring substitutions, including carbocyclic moieties like cyclopropyl, are viable
`
`alternatives. (EX1002, ¶73 (citing EX1008, 50, 99, Table 3).) Cyclopropyl rings, in
`
`particular, are well-established in medicinal chemistry for enhancing drug properties
`
`such as metabolic stability and receptor binding affinity. (Id., ¶81.) Talele (EX1009)
`
`underscores the prevalence and utility of cyclopropyl substitution in pharmaceutical
`
`design, where such rings are often employed to replace methyl groups for improved
`
`pharmacokinetics and resistance to metabolic degradation. (EX1002, ¶¶82-84 (citing
`
`EX1009, 1, 2).)
`
`2
`
`

`

`PGR2025-00057
`
`Accordingly, based on the combined teachings of Yoshino, Kawai, and Talele,
`
`a POSA would have had clear motivation to replace the methyl group in orforglipron
`
`with a cyclopropyl group, thereby arriving at the structure of claimed Compound 1.
`
`(Id., ¶¶208-219.)
`
`As to claimed Compound 19, its structure would have been obvious in view
`
`of the combined teachings of Su (EX1006) and Yoshino. Su discloses more than 200
`
`working examples but selects only seven stereoisomerically pure compounds and in
`
`some cases their respective stereoisomeric mixtures for deuteration, underscoring
`
`their potential as development leads. (EX1002, ¶¶61-62; infra Section VIII.B.) This
`
`selective deuteration, given the time and resource-intensive nature of the process,
`
`suggests a belief in the value of the unique substitution on the underlying scaffolds.
`
`(Id., ¶¶62-64.)
`
`Su discloses a Compound 175 (as well as its deuterated analog, Compound
`
`176) that share the same core scaffold as orforglipron, differing only in a peripheral
`
`cyclopropyl substitution for the original methyl group. (Id., ¶¶63-65.) Similarly, Su’s
`
`Compound 44 maintains the same core scaffold but lacks the two peripheral methyl
`
`groups on the tetrahydropyran ring. (Id., ¶66.) The structural proximity of Su’s
`
`Compounds 175/176 and 44 to orforglipron, coupled with their selection for
`
`deuteration, would have led a POSA to identify them as lead compounds. (Id., ¶¶63-
`
`64.) By applying the peripheral modifications observed in these compounds, namely,
`
`3
`
`

`

`PGR2025-00057
`
`the introduction of a cyclopropyl group to Su’s Compound 175 or the removal of the
`
`dimethyl substituents from Su’s Compound 44, a POSA would have arrived at the
`
`structure of claimed Compound 19. (Id., ¶69.)
`
`A POSA would also have found claimed Compound 20 to be obvious. As
`
`explained by Dr. Pirrung, minor structural modifications—such as elongating alkyl
`
`chains or cyclizing them—are routine in medicinal chemistry. (Id., ¶¶223-226.) A
`
`POSA would have reasonably found it obvious to replace the methyl group on the
`
`4-fluoro-1-methyl-indazole moiety of orforglipron with a small cycloalkyl group,
`
`such as cyclobutyl, leading directly to the structure of Compound 20. (Id.)
`
`Claimed Compound 65 would likewise have been obvious. A POSA seeking
`
`to improve the potency and/or pharmacokinetic profile of Compound 19 would have
`
`been motivated to introduce a nitrogen atom at the corresponding position—
`
`consistent with the structural modifications disclosed in Compound (II) of Meng
`
`(EX1028) and Compound 90 of Ren (EX1030). (EX1002, ¶¶268-287.) Such a
`
`substitution would have been understood as a rational and routine medicinal
`
`chemistry strategy to enhance potency, oral bioavailability, and the overall
`
`pharmacological profile of the compound. (Id.) Accordingly, Compound 65
`
`represents nothing more than a predictable variation of Compound 19, derived
`
`through the application of well-established design principles in view of express
`
`teachings in the prior art. (Id.)
`
`4
`
`

`

`PGR2025-00057
`
`Accordingly, the claimed subject matter, when considered as a whole, would
`
`have been obvious to a POSA in view of the prior art and the general knowledge in
`
`the field. Petitioner therefore requests that this Petition be granted and that the
`
`Challenged Claims be canceled as unpatentable.
`
`II. MANDATORY NOTICES
`
`A. Real Party-in-Interest (37 C.F.R. § 42.8(b)(1))
`The real parties-in-interest are CSPC Pharmaceutical Group Limited, CSPC
`
`Baike (Shandong) Bio-Pharmaceutical Co., Ltd., and Conjupro Biotherapeutics, Inc.
`
`B. Related Matters (37 C.F.R. § 42.8(b)(2))
`Petitioner is unaware of any judicial or administrative proceedings that would
`
`either affect or be affected by a decision regarding this Petition.
`
`C. Counsel and Service Information (37 C.F.R. §§ 42.8 (b)(3) and (4))
`Petitioner identifies its lead and backup counsel as shown below:
`
`Lead Counsel
`Jin Zhu, Ph.D. (Reg. No. 62,869)
`jzhu@foxrothschild.com
`Fox Rothschild LLP
`212 Carnegie Center, Suite 400
`Princeton, NJ 08540
`Tel: (609) 895-6297
`Fax: (609) 896-1469
`
`Backup Counsel
`Joe G. Chen, Ph.D. (Reg. No. 70,066)
`joechen@foxrothschild.com
`Fox Rothschild LLP
`212 Carnegie Center, Suite 400
`Princeton, NJ 08540
`Tel: (609) 844-3024
`Fax: (609) 896-1469
`Luke Toft (Reg. No. 75,311)
`ltoft@ foxrothschild.com
`Fox Rothschild LLP
`33 South 6th Street, Suite 3600
`Minneapolis, MN 55402
`
`5
`
`

`

`PGR2025-00057
`
`Tel: (612) 607-7336
`Fax: (612) 607-7100
`
`Please address all correspondence to the lead and backup counsel at the above
`
`addresses. Petitioner consents to electronic service to the e-mail addresses above for
`
`lead and backup counsel (jzhu@foxrothschild.com, joechen@foxrothschild.com,
`
`ltoft@ foxrothschild.com) with a copy to ipdocket@foxrothschild.com (referencing
`
`Attorney Docket No. 340008.00025).
`
`III. PAYMENT OF FEES
`
`Pursuant to 37 C.F.R. §§ 42.203(a) and 42.15(a), the required fees are
`
`submitted herewith. If additional fees are due during this proceeding, the Office is
`
`authorized to charge Deposit Account 50-1943.
`
`IV. GROUNDS FOR STANDING
`
`Petitioner certifies, pursuant to 37 C.F.R. § 42.204(a), that the ’236 Patent is
`
`available for PGR, and that Petitioner is not the patent owner nor barred or estopped
`
`from requesting PGR of the Challenged Claims on the grounds identified in this
`
`Petition. This Petition is filed within nine months of the ’236 Patent issuance,
`
`February 25, 2025. See 37 C.F.R. § 42.202.
`
`V.
`
`IDENTIFICATION OF CHALLENGE UNDER 37 C.F.R. § 42.204(b)
`
`The Challenged Claims are unpatentable under 35 U.S.C. § 103.
`
`The following is a list of prior art that renders obvious the Challenged Claims:
`
`
`
`6
`
`

`

`Exhibit Description
`EX1004 Kawai, et al., Proc Natl Acad Sci U S A.,
`117(47):29959-29967 (2020) (“Kawai”)
`EX1007 PCT/CN2024/108192 (published as WO
`2025/026270) to Su Yidong et al. (“Su”)
`EX1008 U.S. Patent No. 10,858,356 to Yoshino et
`al. (“Yoshino”)
`EX1009 Talele, Journal of Medicinal Chemistry,
`59(19):8712–8756 (2016) (“Talele”)
`EX1026 Patel & Burns, J Am Chem Soc.,
`144(39):17797-17802 (2022) (“Patel”)
`EX1028 Chinese Patent Publication No.
`CN117069743A (“Meng”)
`EX1030 U.S. Patent No. 12,037,339 (“Ren”)
`
`EX1032 PCT/CN2024/108192 (published as WO
`2025/026270) to Mary Angelyn Bethel et
`al. (“Bethel”)
`
`PGR2025-00057
`
`Publication/Filing Date
`Published on November
`11, 2020
`Published on February 6,
`2025
`Published on December
`8, 2020
`Published on June 14,
`2016
`Published on September
`22, 2022
`Published on November
`17, 2023
`Published on February
`16, 2023
`Published on June 20,
`2024
`
`Petitioner requests cancellation of claims 1-9, 12-17, and 21-25 on the
`
`following grounds:
`
`2
`
`3
`
`1-9, 12-17, 24, and 25
`
`1-4 and 21-25
`
`Description
`Ground Claims
`1
`1-4, 6, 12-14, 24, and 25 Obvious under 35 U.S.C. § 103 over Su,
`Yoshino, and Kawai, in view of Talele.
`Obvious under 35 U.S.C. § 103 over
`Yoshino and Kawai in view of Talele.
`Obvious under 35 U.S.C. § 103 over Su,
`Yoshino, Kawai, Talele, and Meng in view
`of Patel and Ren
`Obvious under 35 U.S.C. § 103 over Su
`and Bethel
`
`4
`
`4 and 9
`
`
`
`7
`
`

`

`PGR2025-00057
`
`
`VI. BACKGROUND
`
`Glucagon-like peptide-1 (GLP-1) is an endogenous incretin hormone secreted
`
`predominantly by enteroendocrine L-cells in the distal intestine in response to
`
`nutrient ingestion. (See, e.g., EX1010, 1; EX1002, ¶38.) Through activation of the
`
`GLP-1 receptor (GLP-1R), GLP-1 exerts multiple metabolic effects, including
`
`glucose-dependent stimulation of insulin secretion, inhibition of glucagon release,
`
`promotion of satiety, delayed gastric emptying, and a reduction in energy intake.
`
`(EX1010, 1.) Several years prior to the earliest filing date of the ’236 Patent,
`
`pharmacological GLP-1R agonists were known to replicate these effects and
`
`demonstrated substantial clinical benefit in managing hyperglycemia and promoting
`
`weight loss in both diabetic and non-diabetic populations. (Id.)
`
`Obesity, a chronic metabolic disorder affecting over 10% of the global adult
`
`population, is primarily driven by sustained caloric excess—often from high-fat and
`
`high-carbohydrate diets—and is further exacerbated by psychosocial stress,
`
`sedentary lifestyles, and disordered eating behaviors. (EX1010, 1; EX1002, ¶39.)
`
`Obesity is closely associated with a range of chronic diseases, including diabetes,
`
`nonalcoholic fatty liver disease, heart disease, and cancer. (EX1010, 1; EX1002,
`
`¶39.)
`
`GLP-1R agonists have emerged as a transformative class of therapeutics for
`
`the treatment of those who are obese and overweight, offering durable weight loss
`
`8
`
`

`

`PGR2025-00057
`
`and improvement in metabolic parameters. (EX1010, 1; EX1002, ¶40.) Originally
`
`approved for type 2 diabetes, these agents are now recognized for their weight-
`
`reducing properties, driven primarily by appetite suppression and thus decreased
`
`caloric intake through central and peripheral mechanisms. (EX1010, 1; EX1002,
`
`¶41-42.) Mechanistic studies show that GLP-1R agonists activate both hypothalamic
`
`pathways and gastrointestinal signaling via vagal afferents, reinforcing satiety and
`
`reducing food consumption. (EX1010, 1; EX1002, ¶41-42.)
`
`Although under clinical evaluation for weight loss efficacy, several small-
`
`molecule GLP-1R agonists have demonstrated in vitro and in vivo activity
`
`comparable to peptide-based counterparts. (EX1010, 4; EX1002, ¶44.) Orforglipron,
`
`also known as LY3502970 and formerly designated OWL-833 (initially discovered
`
`by Chugai Pharmaceutical), was regarded as a next-generation, non-peptidic small-
`
`molecule GLP-1R agonist being developed by Eli Lilly & Co. (EX1010, 4; EX1002,
`
`¶48.) Engineered for once-daily oral administration, orforglipron addresses
`
`adherence challenges inherent to injectable peptide therapies. (EX1004; EX1011, 2.)
`
`Orforglipron exhibits full agonist activity, promoting cAMP accumulation to
`
`levels comparable to native GLP-1, with EC50 values of 1.1 nM for both human and
`
`cynomolgus monkey GLP-1 receptors. (EX1010, 4; EX1002, ¶49.) Unlike
`
`conventional peptide-based agonists, orforglipron binds the GLP-1R at a distinct
`
`allosteric site and displays biased agonism, preferentially activating G protein
`
`9
`
`

`

`PGR2025-00057
`
`pathways while minimizing β-arrestin recruitment. (EX1004, 2.) Clinical data
`
`confirm that orforglipron significantly improves glycemic control and reduces body
`
`weight. (Id; EX1002, ¶51.) Eli Lilly initiated its first Phase 3 study for orforglipron
`
`in April 2023 to evaluate the safety and efficacy of once-daily oral orforglipron
`
`(https://clinicaltrials.gov/study/ NCT05803421).
`
`VII. THE ’236 PATENT
`
`A. The Prosecution of the ’236 Patent
`
`The application that issued as the ’236 Patent, U.S. Patent Application No.
`
`18/884,965 (“the ’965 Application”), was filed on September 13, 2024. The ’965
`
`Application was filed with a total of 25 claims. Between November 2 and November
`
`4, 2024, Patent Owner submitted six different information disclosure statements
`
`(IDSs) that disclosed more than 250 prior art references. (EX1003, 704-812.)
`
`On November 6, 2024, less than two months after the filing of the ‘965
`
`Application and just a couple days after the disclosure of hundreds of prior art
`
`references, the U.S. Patent and Trademark Office issued a Notice of Allowance
`
`citing only one reference and allowing all claims 1–25. (Id., 168-170.) The Notice
`
`of Allowance contains only the following Examiner’s statement for the reason for
`
`allowance:
`
`Claims 1-25 are patentable over Yoshino et al., US
`10858356, which includes the exemplified compound:
`
`10
`
`

`

`PGR2025-00057
`
`
`
`, which has [a] different structure. Therefore, the claims
`are free of prior art.
`
`(Id., 168.)
`Notably, the image of the compound cited in the Notice of Allowance (and
`
`reproduced above) came directly from the October 28, 2024 search report
`
`Examiner’s search strategy and results. (Compare EX1003, 547 with generally
`
`EX1008 (which does not disclose the image reproduced above).) This report, run
`
`just a week before the Examiner issued the Notice of Allowance, identified hundreds
`
`of compounds from dozens of references, including Yoshino and Kawai, but did not
`
`otherwise include information about the disclosures in the references. (EX1003, 176-
`
`703.)
`
`That is, the Examiner considered and cited just one compound in Yoshino,
`
`(one of at least 159 compounds in Yoshino, see EX1008), and, it appears, did not
`
`address or even consider other disclosures in any of the prior art references or
`
`11
`
`

`

`PGR2025-00057
`
`whether additional prior art references, or combinations thereof, could potentially
`
`render the claims of the ’965 Application obvious. For instance, the Examiner did
`
`not consider the multitude of other compounds disclosed in Yoshino et al., such as
`
`Compound 67, which the Petitioner relies upon as a reference compound against
`
`claimed Compounds 1 and 19 in Ground 2.
`
`B. The Effective Filing Date
`
`Under the “Cross-Reference to Related Application” section of the ’236
`
`Patent, the ’965 Application, from which the ’236 Patent issued, claims the benefit
`
`of the following fourteen prior applications, including ten Chinese provisional patent
`
`applications and four U.S. provisional patent applications, as summarized in the
`
`table below (EX1001, 1:1-45):
`
`Country Code Appl. No.
`CN
`202311189557
`US
`63/538,892
`CN
`202311371725
`US
`63/545,615
`CN
`202311582240
`US
`63/603,854
`CN
`202311686034
`CN
`202410142451
`CN
`202410202078
`CN
`202410398964
`CN
`202410584679
`CN
`202410963587
`US
`63/673,453
`CN
`202411237048
`
`Filing Date
`9/14/2023
`9/18/2023
`10/23/2023
`10/25/2023
`11/24/2023
`11/29/2023
`12/8/2023
`1/31/2024
`2/22/2024
`4/2/2024
`5/11/2024
`7/17/2024
`7/19/2024
`9/4/2024
`
`12
`
`
`
`

`

`PGR2025-00057
`
`As Dr. Pirrung explains, the written description of one or more of the seven
`
`compounds recited in the Challenged Claims was not provided in the priority
`
`documents to which they claim priority. (EX1024, ¶¶128-140.) For example, the
`
`chemical structures of Compounds 19, 20, and 21 were only first disclosed in CN
`
`202311371725, filed on October 23, 2023 (“the ’725 Provisional”). (EX1002,
`
`¶¶135-138; EX1013, EX1014.) In contrast, the earlier-filed applications, including
`
`CN 202311189557.X, filed on September 14, 2023 (“the ’557 Provisional”) and US
`
`63/538,892, filed on September 18, 2023 (“the ’892 Provisional”), do not disclose
`
`the specific chemical structures of at least Compounds 19, 20, and 21. (EX1002,
`
`¶¶135-138; EXS. 1015, 1016, 1017.)
`
`As Dr. Pirrung explains, both the ’892 Provisional and the ’557 Provisional
`
`disclose the following chemical genus encompassing millions of compounds (see,
`
`e.g., claim 1 of both the ’892 Provisional and the ’557 Provisional). (EX.1002,
`
`¶¶135-137; EX1016, claim 1; EX1017, claim 1.) Notably, none of the exemplified
`
`compounds disclosed in either application includes an unsubstituted tetrahydropyran
`
`ring.
`
`13
`
`

`

`PGR2025-00057
`
`
`
`
`
`These earlier-filed provisional applications fail to provide an adequate written
`
`description of Compounds 19, 20, and 21. (EX1002, ¶¶135-138.) Specifically, the
`
`structural formulas disclosed therein define each variable in terms of an unduly
`
`broad and diverse range of atoms or chemical groups. (Id.) As a result, a person of
`
`ordinary skill in the art would not have reasonably concluded that the inventors were
`
`in possession of the specific compounds as of the filing dates of those provisional
`
`applications. For example, the variables Q₂ and Z₂ are defined as follows:
`
`wherein Q2 is selected from the group consisting of 3- to
`12-membered heterocyclic, bridged, spiro and 5- to 10-
`membered heteroaryl, wherein 3-
`to 12-membered
`heterocyclic, bridged, spiro and