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
`
`____________
`
`EXPERT DECLARATION OF
`
`MICHAEL C. PIRRUNG, Ph.D.
`
`
`
`

`

`Table of Contents
`
`I.
`
`II.
`
`QUALIFICATIONS ....................................................................................... 6
`
`SUMMARY OF OPINIONS .......................................................................... 9
`
`III. MATERIALS RELIED UPON .................................................................... 10
`
`IV.
`
`THE UNDERSTANDING APPLIED TO MY ANALYSIS ....................... 13
`
`V.
`
`LEVEL OF ORDINARY SKILL IN THE ART .......................................... 19
`
`VI. CLAIM CONSTRUCTION ......................................................................... 20
`
`VII. BACKGROUND AND STATE OF THE ART ........................................... 20
`
`A.
`
`B.
`
`Small-Molecule GLP-1 Receptor Agonists ....................................... 22
`
`Next-Generation Oral GLP-1 Receptor Agonists .............................. 24
`
`VIII. OVERVIEW OF PRIOR ART AND STATE OF THE ART
`REFERENCES ............................................................................................. 25
`
`A.
`
`B.
`
`C.
`
`D.
`
`Kawai (EX1004) ................................................................................. 25
`
`Su (EX1005) ....................................................................................... 29
`
`Yoshino (EX1008) ............................................................................. 36
`
`Talele (EX1009) ................................................................................. 42
`
`E. Meng (EX1028) .................................................................................. 45
`
`F.
`
`G.
`
`H.
`
`Patel (EX1026) ................................................................................... 47
`
`Ren (EX1030) ..................................................................................... 48
`
`Bethel (EX1032) ................................................................................. 49
`
`IX. OVERVIEW OF THE ’236 PATENT ......................................................... 51
`
`A.
`
`B.
`
`The Specification and Claims of the ’236 patent ............................... 51
`
`The Prosecution History of the ’236 patent ....................................... 78
`
`2
`
`

`

`
`
`C.
`
`The Priority Date of the ’236 patent................................................... 79
`
`X. UNPATENTABILITY OF THE ’236 PATENT ......................................... 87
`
`A. GROUND 1: CLAIMS 1-4, 6, 12-14, 24, and 25 WOULD HAVE
`BEEN OBVIOUS OVER SU, YOSHINO, AND KAIWAI IN
`VIEW OF TALELE ........................................................................... 87
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Claim 1 ..................................................................................... 88
`
`Claim 2 ................................................................................... 109
`
`Claim 3 ................................................................................... 110
`
`Claim 4 ................................................................................... 114
`
`Claim 6 ................................................................................... 118
`
`Claim 12 ................................................................................. 120
`
`Claim 13 ................................................................................. 121
`
`Claim 14 ................................................................................. 122
`
`Claim 24 ................................................................................. 123
`
` Claim 25 ................................................................................. 127
`
`B.
`
`GROUND 2: CLAIMS 1-9, 12-17, 24, and 25 WOULD HAVE
`BEEN OBVIOUS OVER YOSHINO AND KAWAI IN VIEW
`OF TALELE ..................................................................................... 128
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Claim 1 ................................................................................... 128
`
`Claim 2 ................................................................................... 147
`
`Claim 3 ................................................................................... 148
`
`Claim 4 ................................................................................... 151
`
`Claim 5 ................................................................................... 155
`
`Claim 6 ................................................................................... 157
`
`Claim 7 ................................................................................... 159
`
`3
`
`

`

`Claim 8 ................................................................................... 160
`
`Claim 9 ................................................................................... 160
`
`Claim 12 ................................................................................. 161
`
`Claim 13 ................................................................................. 162
`
`Claim 14 ................................................................................. 163
`
`Claim 15 ................................................................................. 164
`
`Claim 16 ................................................................................. 165
`
`Claim 17 ................................................................................. 166
`
`Claim 24 ................................................................................. 167
`
`Claim 25 ................................................................................. 171
`
`C.
`
`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 ....................................... 172
`
`Claim 1 ................................................................................... 173
`
`Claim 2 ................................................................................... 183
`
`Claim 3 ................................................................................... 184
`
`Claim 4 ................................................................................... 187
`
`Claim 21 ................................................................................. 191
`
`Claim 22 ................................................................................. 192
`
`Claim 23 ................................................................................. 193
`
`Claim 24 ................................................................................. 194
`
`Claim 25 ................................................................................. 198
`
`D.
`
`GROUND 4: CLAIMS 4 and 9 WOULD HAVE BEEN
`OBVIOUS OVER SU AND BETHEL ............................................ 199
`
`4
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`

`

`
`
`
`
`
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`Claim 4 ................................................................................... 199
`
`Claim 9 ................................................................................... 206
`
`XI. CONCLUSION ........................................................................................... 207
`
`
`
`
`
`5
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`

`

`
`
`I, Michael C. Pirrung, Ph.D., declare as follows:
`
`1.
`
`I have been retained by counsel for Conjupro Biotherapeutics, Inc.,
`
`(“Petitioner”). I understand that Petitioner is submitting a petition for post grant
`
`review (“PGR”) of U.S. Patent No. 12,234,236 (“the ’236 patent,” attached as
`
`EX1001), which is assigned to Ascletis Pharma China Co Ltd. (“Patent Owner”). It
`
`is my understanding that Petitioner is requesting that the United States Patent and
`
`Trademark Office (“USPTO”) cancel claims 1-9, 12-17, and 21-25 of the ’236 patent
`
`as unpatentable. I submit this expert declaration in support of Petitioner’s PGR
`
`petition for the ’236 patent. I make the following statements based on personal
`
`knowledge and, if called to testify to them, could and would do so.
`
`I.
`
`QUALIFICATIONS
`
`2.
`
`I am Distinguished Professor of Chemistry at the University of
`
`California, Riverside. I also hold an appointment as Professor of Pharmaceutical
`
`Sciences at the University of California, Irvine. I have over four decades of
`
`experience in the field of organic chemistry, with expertise spanning medicinal
`
`chemistry, chemical biology, bioorganic chemistry, and pharmaceutical sciences.
`
`3.
`
`I received my B.A. in Chemistry with Highest Honors from the
`
`University of Texas at Austin in 1975, and a Ph.D. in Organic Chemistry from the
`
`University of California, Berkeley in 1980. I completed postdoctoral research in
`
`organic chemistry at Columbia University as an NSF Postdoctoral Fellow.
`
`6
`
`

`

`
`
`4. My academic appointments have included faculty positions at Stanford
`
`University, Duke University, and the University of California, Riverside. I have also
`
`served as Director of the Duke University Program in Biological Chemistry and have
`
`held various visiting professorships at leading institutions including the University
`
`of Oxford and Caltech.
`
`5.
`
`I have conducted research and published extensively in the fields of
`
`synthetic and medicinal chemistry. I am an author or co-author of over 170 peer-
`
`reviewed papers that include technical subject matter relating to the fields of organic
`
`and bioorganic chemistry, combinatorial chemistry, and drug discovery. I have
`
`received a number of honors and awards in my fields of study, including the
`
`Chemical Pioneer Award from the American Institute of Chemists. I have been
`
`elected a Fellow of the American Association for the Advancement of Science
`
`(AAAS) and the National Academy of Inventors. Along with several co-authors, I
`
`received the Newcomb Cleveland Prize from the AAAS for the best paper published
`
`in the journal Science in 1991. This group also received a Distinguished Inventor
`
`Award from Intellectual Property Owners and the European Inventor of the Year
`
`Award for small- and medium-sized enterprises from the European Patent Office.
`
`6.
`
`I have served on editorial boards of major scientific journals such as
`
`Cell Chemical Biology and Journal of Combinatorial Chemistry, have reviewed
`
`7
`
`

`

`
`
`thousands of scientific manuscripts, and have submitted many nominations for major
`
`career awards such as the Nobel Prize and the MacArthur Fellowship.
`
`7.
`
`I have also served in advisory and consultancy roles for numerous
`
`pharmaceutical and biotechnology companies, including Abbott Laboratories,
`
`Wyeth Pharmaceuticals, and Affymax Research Institute.
`
`8. My current research interests include organic synthesis, molecular
`
`diversity, peptide and nucleic acid chemistry, and the development of novel
`
`pharmaceutical compounds. I have trained over 100 graduate students and
`
`postdoctoral fellows in these subjects, many of whom now hold prominent positions
`
`in academia and industry.
`
`9.
`
`Additional
`
`information
`
`regarding my education, experience,
`
`publications, awards and honors, patents, publications, and presentations is detailed
`
`in a true and correct copy of my curriculum vitae as of April 1, 2025 (Appendix A).
`
`10. A list of the materials relied upon, in addition to my experience,
`
`education, and training, to provide the opinions contained in this declaration is listed
`
`below in Section III.
`
`11.
`
`I am being compensated for my time in connection with this PGR at my
`
`standard consulting rate, which is $450 per hour. My compensation is not dependent
`
`in any way upon the outcome of this matter.
`
`8
`
`

`

`
`
`12.
`
`I have reviewed the ’236 patent (EX1001) and relevant portions of its
`
`prosecution history at the USPTO (EX1003). Specifically, I have reviewed the ’236
`
`patent and its prosecution history in relation to the asserted prior art and arguments
`
`at issue in the present PGR.
`
`13. Based on my experience described above and contained in my CV, I
`
`have an established understanding of the relevant field in the relevant timeframe and
`
`the knowledge that would have been known by a person of ordinary skill in the art,
`
`as defined above and during the relevant time frame (on or before September 14,
`
`2023 – the claimed priority date of the ’236 patent.
`
`II.
`
`SUMMARY OF OPINIONS
`
`14.
`
`I have been asked to consider whether claims 1-9, 12-17, and 21-25 (the
`
`“Challenged Claims”) of the ’236 patent are obvious in view of the references
`
`discussed in Section VIII. The Challenged Claims are directed to one or more of
`
`seven GLP-1R modulating compounds (i.e., Compounds 1, 13, 18, 19, 20, 21, and
`
`65) or a pharmaceutically acceptable salt thereof.
`
`15.
`
`In my opinion, claims 1-4, 6, 12-14, 24, and 25 would have been
`
`obvious at least with respect to Compound 19 in view of the state of the art and
`
`general knowledge of a person of ordinary skill in the art (“POSA”) before the
`
`effective filing date of the ’236 patent, in particular, Su (EX1005), Yoshino
`
`(EX1008), and Kawai (EX1004) in view of Talele (EX1009).
`
`9
`
`

`

`
`
`16.
`
`In my opinion, claims 1-9, 12-17, 24, and 25 would have been obvious,
`
`at least with respect to Compounds 1, 19, or 20, based on the state of the art and the
`
`general knowledge of a POSA before the effective filing date of the ’236 patent, in
`
`particular, in view of Yoshino and Kawai combined with Talele.
`
`17.
`
`In my opinion, claims 1-4 and 21-25 would have been obvious, at least
`
`with respect to Compound 65, based on the state of the art and the general knowledge
`
`of a POSA before the effective filing date of the ’236 patent, in particular, in view
`
`of Su, Yoshino, Kawai, Talele, Meng (EX1028) combined with Patel (EX1026) and
`
`Ren (EX1030).
`
`18.
`
`In my opinion, claims 4 and 9 would have been obvious at least with
`
`respect to ½ calcium salt of Compound 1 in view of the state of the art and the general
`
`knowledge of a POSA before the effective filing date of the ’236 patent, in particular,
`
`Su and Bethel (EX1032).
`
`19. Finally, there are no apparent secondary considerations supporting non-
`
`obviousness of the claims. I reserve the right to address any secondary
`
`considerations put forth by Patent Owner (e.g., unexpected results) in any later
`
`response to this declaration or the petition it accompanies.
`
`III. MATERIALS RELIED UPON
`
`20.
`
`I have reviewed the Petition and supporting evidence. I have also
`
`reviewed all Challenged Claims of the ’236 patent, as well as the specification of the
`
`10
`
`

`

`
`
`’236 patent and relevant parts of its file history. I have examined the prior art
`
`references asserted against the ’236 patent in the Petition. My opinions are based on
`
`my own knowledge, experience, and education and with further reference to the
`
`exhibits cited herein. I will use the exhibit numbers listed on the “Table of Exhibits”
`
`on pages vii-viii of the Petition (Paper 1), which I have included for ease of reference
`
`below:
`
`LIST OF EXHIBITS
`
`Exhibit
`
`Description
`
`EX1001 U.S. Patent No. 12,234,236 (“the ’236 patent”)
`
`EX1003 Excerpts of File History of U.S. Patent No. 12,234,236
`
`EX1004 Kawai, et al., Proc Natl Acad Sci U S A., 117(47):29959-29967
`(2020) (“Kawai”)
`International Publication No. WO 2025/026270A1 (“Su”)
`
`EX1005
`
`EX1006 Chinese Patent Application No. 202311372605.9 (“Su II”), which is a
`priority document of Su
`Certified English Translation of Chinese Patent Application No.
` EX1007
`202311372605.9 (“Su II”)
`
`EX1008 U.S. Patent No. 10,858,356 (“Yoshino”)
`
`EX1009 Talele, Journal of Medicinal Chemistry, 59(19):8712–8756 (2016)
`(“Talele”)
`EX1010 Liu, et al., Expert Opinion on Therapeutic Patents, 30(10):781-794
`(2020)
`Pratt, et al., Diabetes Obes Metab., 25(9):2642-2649 (2023)
`
`EX1011
`
`EX1012
`
`Frias, et al., Lancet, 402(10400):472–483 (2023)
`
`EX1013 Chinese Patent Application No. 202311371725 (“the ’725
`Provisional”)
`EX1014 Certified English Translation of Chinese Patent Application No.
`202311371725
`
`11
`
`

`

`
`
`Exhibit
`
`Description
`
`EX1015 Chinese Patent Application No. 202311189557 (“the ’557
`Provisional”)
`EX1016 Certified English Translation of Chinese Patent Application No.
`202311189557
`EX1017 U.S. Patent Provisional Application No. US 63/538,892 (“the ’892
`Provisional”)
`EX1018 Chinese Patent Application No. 202410142451 (“the ’451
`Provisional”)
`EX1019 Certified English Translation of Chinese Patent Application No.
`202410142451 (“the ’451 Provisional”)
`EX1020 Chinese Patent Application No. 202311582240 (“the ’240
`Provisional”)
`EX1021 Certified English Translation of Chinese Patent Application No.
`202311582240
`EX1022 Chinese Patent Application No. 202311686034 (“the ’034
`Provisional”)
`EX1023 Certified English Translation of Chinese Patent Application No.
`202311686034
`EX1024 U.S. Patent Provisional Application No. 63/545,615 (“the ’615
`Provisional”)
`EX1025 U.S. Patent Provisional Application No. 63/603,854 (“the ’854
`Provisional”)
`EX1026 Patel SC, Burns NZ. Conversion of Aryl Azides to Aminopyridines. J
`Am Chem Soc. 2022 Oct 5;144(39):17797-17802 (“Patel”)
`EX1027 Pennington LD, Moustakas DT. J Med Chem. 2017 May
`11;60(9):3552-3579
`EX1028 Chinese Patent Publication No. CN117069743A (“Meng”)
`
`EX1029 Certified English Translation of Chinese Patent Publication No.
`CN117069743A
`EX1030 U.S. Patent No. 12,037,339 (“Ren”)
`
`EX1031 Certified English Translation of International Publication No. WO
`2025/026270 (“Su”)
`International Publication No. WO 2024/129676A1 (“Bethel”)
`
`EX1032
`
`
`
`12
`
`

`

`
`
`IV. THE UNDERSTANDING APPLIED TO MY ANALYSIS
`
`21.
`
`In preparing and forming my opinions set forth in this declaration, I
`
`have been informed by counsel of relevant legal principles. I applied my
`
`understanding of those principles in forming my opinions. My understanding of
`
`those principles is summarized below. In performing my analysis and reaching my
`
`opinions and conclusions, I have been informed of and have been advised to apply
`
`various legal principles relating to unpatentability, which I set forth herein. In setting
`
`forth these legal standards, it is not my intention to testify about the law. I only
`
`provide my understanding of the law, as explained to me by counsel, as a context for
`
`the opinions and conclusions I am providing.
`
`22.
`
`I understand that my opinions regarding unpatentability are presented
`
`from the viewpoint of a POSA in the field of technology of the patent as of the
`
`patent’s priority date. In this declaration, my opinions are premised on the
`
`perspective of a POSA at the time of the earliest claimed priority date for the ’236
`
`patent, which I have been informed for this proceeding is September 14, 2023.
`
`(EX1001 at 1.) To the extent Patent Owner asserts that the claims of the ’236 patent
`
`are entitled to an earlier priority or invention date, I reserve the right to supplement
`
`this declaration.
`
`23.
`
`I understand that in a PGR proceeding, claims should be construed as
`
`having their ordinary and customary meaning as understood by a POSA at the time
`
`13
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`

`

`
`
`of the invention. I understand that claims should be read in the context of the claim
`
`language of which they are a part. I further understand that the specification and file
`
`history can also inform the scope of the claims. If, after a review of this evidence,
`
`the construction is not apparent, I understand that extrinsic evidence, such as
`
`dictionary definitions, treatises, and trade journals, may be consulted to discern the
`
`meaning of a term. For terms where no construction is necessary, I have simply read
`
`the terms according to their ordinary and customary meaning. My understandings
`
`herein are made in light of how a POSA in or around 2023 would view the ordinary
`
`and customary meaning of the claim terms. I reserve the right to supplement my
`
`Declaration should any claim terms be given different constructions.
`
`24.
`
`I understand that a claim is anticipated if a single prior art reference
`
`discloses each and every limitation of the claimed invention. I understand that a
`
`limitation can be expressly disclosed by the reference or be inherent. I further
`
`understand that for a feature to be inherently disclosed, a POSA would understand
`
`the inherent feature would necessarily and inevitably be present when the teaching
`
`of the reference is practiced. That is, I understand that if a feature is not necessarily
`
`and inevitably present, it is not inherently disclosed.
`
`25.
`
`I understand that a patent claim may be unpatentable for obviousness if
`
`the difference between the claimed subject matter and the prior art is such that the
`
`subject matter as a whole would have been obvious to a POSA at the time the
`
`14
`
`

`

`
`
`invention was made. I understand that a finding of obviousness requires a
`
`determination of: (1) the scope and content of the prior art; (2) the difference(s)
`
`between the claimed invention and the prior art; and (3) the level of skill of the
`
`ordinary artisan in the pertinent art. I understand this analysis looks at whether the
`
`differences are such that the claimed invention as a whole would have been obvious
`
`to one of ordinary skill in the art at the time the invention was made.
`
`26.
`
`It is my understanding from counsel that when there is some recognized
`
`reason to solve a problem, and there are a finite number of identified, predictable,
`
`and known solutions, a person of ordinary skill in the art has good reason to pursue
`
`the known options within his or her technical grasp. If such an approach leads to the
`
`expected success, it is likely not the product of innovation but of ordinary skill and
`
`common sense. It is my understanding that any need or problem known in the field
`
`of endeavor at the time of invention or addressed by the patent can provide a reason
`
`for combining prior art elements to arrive at the claimed subject matter. I understand
`
`that only a reasonable expectation of success is necessary to show obviousness.
`
`27. My understanding is that the obviousness inquiry is not limited to just
`
`the prior art references being applied, but includes the knowledge and understanding
`
`of one of ordinary skill in the art. However, I understand that merely demonstrating
`
`that each element, independently, was known in the prior art is, by itself, insufficient
`
`to establish a claim was obvious. My understanding is that the test for obviousness
`
`15
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`

`

`
`
`is not whether the features of one reference can be incorporated into the structure of
`
`another reference, but rather what the combined teachings would have suggested to
`
`those of ordinary skill in the art. I further understand that a party seeking to invalidate
`
`a patent must show a person of ordinary skill in the art would have been motivated
`
`to combine the teachings of the prior art references to achieve the claimed invention.
`
`28.
`
`I understand that a combination of old, familiar, or known elements
`
`used according to known methods is likely to be obvious when it does no more than
`
`yield predictable results. Predictable variations of a work from one field are likely
`
`to be obvious, even if the variation is in another field. For example, where a
`
`technique has been used to improve a device, use of the same technique to improve
`
`similar devices is a predictable variation and likely obvious. Likewise, if the use of
`
`prior art for improvements is simply done according to the prior art’s established
`
`functions, a POSA has simply implemented a predictable variation. If there existed
`
`at the time of invention a known problem for which there was an obvious solution,
`
`a patent claim encompassing that solution is not patentable.
`
`29.
`
`I further understand that any obviousness analysis must consider
`
`objective evidence of non-obviousness, where such evidence is present. I understand
`
`that objective evidence of non-obviousness includes (1) copying, (2) long-felt but
`
`unsolved need, (3) failure of others, (4) commercial success of the invention, (5)
`
`unexpected results created by the claimed invention, (6) unexpected properties of
`
`16
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`

`

`
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`the claimed invention, (7) licenses showing industry respect for the invention, (8)
`
`skepticism of skilled artisans before the invention, (9) recognition of the invention’s
`
`advancement, and (10) contemporaneous invention by others or absence thereof. In
`
`general, there must be a connection between any of the factors and the claimed
`
`invention. For instance, the “commercial success” of a product practicing the
`
`claimed invention is relevant to the obviousness analysis only if the commercial
`
`success is attributable to advantages from the use of the invention that were not
`
`available to the purchasing public before the invention was made.
`
`30.
`
`I understand that a claim in a granted patent must be sufficiently
`
`supported by the original disclosure of the granted patent, read in the context of what
`
`one of ordinary skill in the art would have known at the time of the claimed
`
`invention. I understand that the basic inquiry for written description is whether the
`
`specification provides sufficient information for a skilled artisan to recognize that
`
`the named inventors possessed the full scope of the claimed invention. To satisfy the
`
`written description requirement for such claims, I understand that the specification
`
`must disclose either a representative number of species falling within the scope of
`
`the claimed genus or structural features common to the members of the genus such
`
`that one skilled in the art can “visualize or recognize” the members of the claimed
`
`genus. I understand that a disclosure of a species may be insufficient to demonstrate
`
`17
`
`

`

`
`
`possession of a larger claimed genus. However, I understand the same disclosure in
`
`a prior art reference may be sufficient to render a claim to that genus obvious.
`
`31.
`
`I also understand that claims must be enabled by the original disclosure
`
`of the patent. For the claims to be enabled, the information contained in the
`
`disclosure must be sufficient to inform those skilled in the relevant art how to make
`
`and use the claimed invention without undue experimentation. I understand that the
`
`enablement requirement is separate and distinct from the written description
`
`requirement.
`
`32.
`
`I understand that to establish priority to a previously filed patent
`
`application, the earlier application must describe the later-claimed invention in
`
`sufficient detail so that a POSA can clearly conclude that the inventor invented and
`
`had possession of each element of the claimed invention as of the earlier filing date
`
`being sought. I understand that this requires that the earlier disclosure must describe
`
`and enable every limitation of the later-claimed invention. I understand that a
`
`showing of possession of a single species may be insufficient to demonstrate that the
`
`inventor had possession of the larger genus. I understand that to establish possession
`
`of the larger genus may require a showing that, as of the earlier desired filing date,
`
`the inventor disclosed use of multiple species of the genus and/or that the inventor
`
`understood that each species of the genus would create the same result, i.e., could be
`
`substituted without modification.
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`18
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`

`

`
`
`33. Although the following analysis cites to particular pages, lines,
`
`paragraphs, or figures of many of the references discussed, these citations are
`
`intended to assist in understanding the various bases of my conclusions, and prior
`
`art teachings used to reach them. These citations are not intended to be an exhaustive
`
`recitation of every page, line number, or paragraph in which these teachings may be
`
`found. Similar teachings or disclosures may be found at other pages, lines, figures,
`
`or paragraphs, as well as in other references, and it is to be understood that my
`
`opinions and statements are made in view of all of the references and teachings I
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`have reviewed.
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`V. LEVEL OF ORDINARY SKILL IN THE ART
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`34.
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`In my opinion, the following definition of a POSA applies to the claims
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`of the ’236 patent.
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`35. A POSA would have had least a Bachelor’s, Master’s, or Doctoral
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`degree in chemistry, medicinal chemistry, organic chemistry, biochemistry, or a
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`closely related discipline, along with a minimum of two to five years of experience
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`in small-molecule drug discovery or development. Such experience would include
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`the design, chemical synthesis, and structure–activity relationship (SAR) analysis of
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`therapeutic compounds.
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`19
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`VI. CLAIM CONSTRUCTION
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`36.
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`I understand that claims of a patent subject to PGR should be construed
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`in accordance with the plain and ordinary meaning of such claim as understood by a
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`POSA in view of the specification of the patent and the prosecution history
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`pertaining to the patent.
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`VII. BACKGROUND AND STATE OF THE ART
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`37. The ’236 patent relates to glucagon-like peptide-1 (GLP-1) receptor
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`(GLP-1R) modulating compounds. In this Section, I present a brief overview of
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`certain aspects of GLP-1R and GLP-1R modulating compounds, that will assist in
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`better understanding the ’236 patent.
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`38. GLP-1 is an endogenous incretin hormone secreted primarily by
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`enteroendocrine L cells in the distal intestine in response to nutrient ingestion. (See,
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`e.g., EX1010 at 1.) Pharmacological GLP-1R agonists mimic the actions of native
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`GLP-1 by enhancing glucose-dependent insulin secretion, suppressing glucagon
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`release, promoting satiety, delaying gastric emptying, and ultimately reducing
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`caloric intake and energy balance dysregulation. (See id.)
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`39. Globally, over 10% of the adult population is affected by obesity, a
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`multifactorial metabolic disorder primarily driven by chronic caloric surplus,
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`especially from high-fat and high-carbohydrate diets. (Id.) In addition to dietary
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`contributors, psychosocial stress, disordered eating behaviors, sedentary lifestyle,
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`20
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`

`
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`and psychological factors such as low self-esteem also play critical roles. (Id.)
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`Obesity is strongly associated with a spectrum of metabolic and systemic
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`pathologies, including type 2 diabetes mellitus, nonalcoholic fatty liver disease
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`(NAFLD), cardiovascular diseases, and certain forms of cancer. (Id.)
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`40. GLP-1R agonists have emerged as a breakthrough therapeutic class for
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`the treatment of obesity and overweight, offering clinically meaningful benefits that
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`extend beyond their initial indications in type 2 diabetes. (Id. at 1, 2.) These agents
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`facilitate sustained weight loss through multiple mechanisms while simultaneously
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`improving metabolic parameters. (Id.)
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`41. Significant research efforts are currently directed
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`toward
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`the
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`development of next-generation anti-obesity pharmacotherapies that address the
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`limitations of earlier agents. (Id.) Among these, GLP-1R agonists have demonstrated
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`robust efficacy in reducing body weight in both diabetic and non-diabetic
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`populations. (Id.) Clinical data suggest that the weight-reducing effects are primarily
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`attributable to central appetite suppression and reduction in overall energy intake.
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`(Id.)
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`42. Mechanistic studies indicate that GLP-1R agonists exert pleiotropic
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`physiological effects, with the anorexigenic and insulinotropic actions being most
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`relevant for obesity pharmacotherapy. (Id. at 1.) The anorexigenic effects are
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`mediated through both central nervous system pathways—via activation of
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`21
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`
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`hypothalamic and brainstem GLP-1Rs—and peripheral pathways involving vagal
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`afferents and gastrointestinal signaling, leading to enhanced satiety and reduced food
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`intake. (Id.)
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`43. Structural optimization of GLP-1R agonists has followed two principal
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`strategies. (Id. at 2.) The first aims to improve resistance to enzymatic degradation
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`by dipeptidyl peptidase-IV, commonly achieved
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`through substitution or
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`modification at the N-terminal region and chemical stabilization of the C-terminal,
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`including cyclization, glycosylation, or amino acid extension. (Id.) The second
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`strategy involves prolonging the plasma half-life by reducing renal clearance
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`through PEGylation, lipidation (e.g., fatty acid conjugation), incorporation of
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`coumarin groups, formation of dimers, or fusion to albumin or Fc-containing
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`proteins. (Id.) In parallel, medicinal chemistry efforts have led to the identification
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`of non-peptidic small-molecule GLP-1R agonists that demonstrate potent in vivo
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`activity, potentially offering an orally bioavailable alternative to injectable peptide
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`therapeutics. (Id.)
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`A.
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`Small-Molecule GLP-1 Receptor Agonists
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`44. Although t