UNITED STATES PATENT AND TRADEMARK OFFICE
`_________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_________________________________
`
`SUN PHARMACEUTICAL INDUSTRIES LTD.
`AND SUN PHARMACEUTICAL INDUSTRIES INC.,
`Petitioners,
`v.
`NOVO NORDISK A/S,
`Patent Owner.
`_________________________________
`Case No. IPR2024-00107
`Patent No. 10,335,462
`_________________________________
`
`DECLARATION OF ALEKHA K. DASH, PH.D.,
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 10,335,462
`_________________________________
`
`
`
`SUN EXHIBIT 1095, IPR2024-00107, PAGE 1
`
`

`

`
`
`TABLE OF CONTENTS
`
`Page
`I. Qualifications and Background .......................................................................... 7
`A. Education and Experience; Prior Testimony .............................................. 7
`B. Basis for Opinions and Materials Considered .......................................... 10
`C. Retention and Compensation .................................................................... 10
`II. Summary of Opinions ...................................................................................... 11
`III. Legal Standards ................................................................................................ 12
`IV. Person of Ordinary Skill in the Art .................................................................. 14
`V. The ’462 Patent (Ex. 1001) .............................................................................. 16
`A. The Formulation Claims of the ’462 Patent ............................................. 16
`B. The Prosecution History of the ’462 Patent ............................................. 18
`VI. Claim Construction .......................................................................................... 21
`VII. Background on GLP-1 Compound Formulations Used to Treat Diabetes ...... 21
`A. Parenteral formulations and components thereof were well-known ........ 21
`B. GLP-1 compounds were well-known ....................................................... 23
`C. GLP-1 agonists and related formulations were well-known .................... 26
`D. Parenteral dosage forms for peptide-based drugs .................................... 26
`1. Tonicity and osmolarity of the parenteral formulation ..................... 28
`2. pH and buffering capacity of the parenteral formulation ................. 29
`3. Avoiding particulates in the parenteral formulation ......................... 30
`4. Vehicles and diluents of the parenteral formulation ......................... 31
`5. Excipients of the parenteral formulation .......................................... 32
`VIII.Scope
`and
`Content
`of
`the
`Prior
`Art
` .......................................................................................................................... 33
`A. WO 2011/138421 (“WO421”) (Ex. 1011) ............................................... 34
`B. U.S. Patent Application Pub. No. US2007/0010424 (’424 publication) (Ex.
`1016) ......................................................................................................... 35
`C. Clinical Trial No. NCT00696657 (NCT657) (Ex. 1013) ......................... 37
`
`2
`
`SUN EXHIBIT 1095, IPR2024-00107, PAGE 2
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`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`D. Clinical Trial No. NCT00851773 (NCT773) (Ex. 1014) ......................... 39
`E. WO 2006/097537 (“WO537”) (Ex. 1015) ............................................... 41
`F. Lovshin (Ex. 1012) ................................................................................... 44
`G. Other Art That Informs the POSA’s Knowledge ..................................... 45
`1. Lund (Ex. 1035) ................................................................................ 45
`2. U.S. Patent No. 7,022,674 (“’674 patent”) (Ex. 1075) ..................... 48
`3. U.S. Patent No. 6,458,924 (“’924 patent”) (Ex. 1073) ..................... 50
`4. U.S. Patent No. 6,284,727 (“’727 patent”) (Ex. 1071) ..................... 50
`5. U.S. Patent No. 6,268,343 (“Knudsen patent”) (Ex. 1034) .............. 51
`6. U.S. Patent No. 5,512,549 (“’549 patent”) (Ex. 1017) ..................... 52
`7. U.S. Patent No. 5,164,366 (“’366 patent”) (Ex. 1072) ..................... 53
`8. U.S. Patent No. 5,118,666 (“’666 patent”) (Ex. 1056) ..................... 54
`9. Victoza label (Ex. 1039) ................................................................... 54
`10. WO 03/002136 (“WO136”) (Ex. 1041) ........................................... 55
`11. WO 00/37098 (“WO098”) (Ex. 1074) ............................................. 57
`12. Additional prior art and references ................................................... 58
`IX. Unpatentability of the Claims of the ’462 Patent ............................................. 58
`A. Grounds 3 and 5: Claims 4–10 of the ’462 patent would have been obvious
`over WO421 considering the ’424 publication or over NCT657 and
`NCT773 considering the ’424 publication ............................................... 58
`1. A POSA would have been motivated to formulate semaglutide as an
`isotonic aqueous solution for subcutaneous
`injection with a
`reasonable expectation of success .................................................... 60
`2. A POSA would have been motivated to formulate semaglutide with
`propylene glycol and phenol with a reasonable expectation of success
` ........................................................................................................... 64
`3. A POSA would have been motivated to formulate semaglutide with a
`phosphate buffer, such as sodium dihydrogen phosphate, with a
`reasonable expectation of success .................................................... 69
`
`3
`
`SUN EXHIBIT 1095, IPR2024-00107, PAGE 3
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`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`4. A POSA would have been motivated to formulate semaglutide with a
`pH in the range of 7.0-9.0, or at a pH of 7.4, with a reasonable
`expectation of success ....................................................................... 72
`5. The dependent limitations of claim 4 would have been obvious ..... 76
`6. The dependent limitations of claim 5 would have been obvious ..... 78
`7. The dependent limitations of claim 6 would have been obvious ..... 79
`8. The dependent limitations of claim 7 would have been obvious ..... 80
`9. The dependent limitations of claim 8 would have been obvious ..... 81
`10. The dependent limitations of claim 9 would have been obvious ..... 82
`11. The dependent limitations of claim 10 would have been obvious ... 85
`12. Conclusion ........................................................................................ 86
`B. Ground 4: Claims 4–10 of the ’462 patent would have been obvious over
`WO537 considering Lovshin .................................................................... 87
`1. A POSA would have been motivated to formulate semaglutide as an
`isotonic aqueous solution for subcutaneous
`injection with a
`reasonable expectation of success .................................................... 88
`2. A POSA would have been motivated to formulate semaglutide with
`propylene glycol and phenol with a reasonable expectation of success
` ........................................................................................................... 90
`3. A POSA would have been motivated to formulate semaglutide with a
`phosphate buffer, such as sodium dihydrogen phosphate, with a
`reasonable expectation of success .................................................... 91
`4. A POSA would have been motivated to formulate semaglutide with a
`pH in the range of 7.0-9.0, or at a pH of 7.4, with a reasonable
`expectation of success ....................................................................... 93
`5. The dependent limitations of claim 4 would have been obvious ..... 95
`6. The dependent limitations of claim 5 would have been obvious ..... 97
`7. The dependent limitations of claim 6 would have been obvious ..... 98
`8. The dependent limitations of claim 7 would have been obvious ..... 98
`9. The dependent limitations of claim 8 would have been obvious ..... 99
`10. The dependent limitations of claim 9 would have been obvious ...100
`
`4
`
`SUN EXHIBIT 1095, IPR2024-00107, PAGE 4
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`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`11. The dependent limitations of claim 10 would have been obvious .103
`12. Conclusion ......................................................................................103
`C. No Secondary Considerations Overcome Prima Facie Obviousness ....104
`1. The formulations recited in the ’462 patent produce no unexpected
`results ..............................................................................................104
`2. There was no long-felt but unmet need for the formulations recited in
`the ’462 patent ................................................................................105
`3. There was no praise of the formulations recited in the ’462 patent
` .........................................................................................................106
`4. There was no industry skepticism of the formulations recited in the
`’462 patent ......................................................................................106
`X. Reservation of Rights .....................................................................................107
`
`
`5
`
`SUN EXHIBIT 1095, IPR2024-00107, PAGE 5
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`

`

`
`
`
`
`TABLE OF ABBREVIATIONS
`
`Abbreviation
`’366 patent
`’424 publication
`’462 patent
`’549 patent
`’666 patent
`’674 patent
`’727 patent
`’924 patent
`Knudsen patent
`Lovshin
`
`Full Name of Cited Reference
`U.S. Patent No. 5,164,366
`U.S. Patent Application Pub. No. US2007/0010424
`U.S. Patent No. 10,335,462
`U.S. Patent No. 5,512,549
`U.S. Patent No. 5,118,666
`U.S. Patent No. 7,022,674
`U.S. Patent No. 6,284,727
`U.S. Patent No. 6,458,924
`U.S. Patent No. 6,268,343
`Lovshin, Incretin-Based Therapies for Type 2 Diabetes
`Mellitus, 5 NATURE REVIEWS ENDOCRINOLOGY 262
`(2009)
`Lund, Emerging GLP-1Receptor Agonists, 16 EXPERT
`OPINION ON EMERGING DRUGS 607 (2011)
`Boylan,
`Products,
`in MODERN
`Parenteral
`PHARMACEUTICS (Gilbert S. Banker et al. eds., 3d ed.
`1996)
`Clinical Trial No. NCT00696657
`Clinical Trial No. NCT00851773
`Ozempic prescribing information (Oct. 2022)
`REMINGTON:
` THE SCIENCE AND PRACTICE OF
`PHARMACY (Alfonso R. Gennaro ed., 20th ed. 2000)
`Victoza, PHYSICIANS’ DESK REFERENCE (65th ed. 2010) Victoza label
`WO 00/37098
`WO098
`WO 03/002136
`WO136
`WO 2011/058193
`WO193
`WO 2011/073328
`WO328
`WO 2011/138421
`WO421
`WO 2006/097537
`WO537
`
`Lund
`
`Modern Pharmaceutics
`
`NCT657
`NCT773
`Ozempic label
`Remington
`
`6
`
`SUN EXHIBIT 1095, IPR2024-00107, PAGE 6
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`

`

`
`
`1. My name is Alekha K. Dash, Ph.D. I have been retained by Sun
`
`Pharmaceutical Industries Ltd. and Sun Pharmaceutical Industries Inc. (collectively
`
`“Sun”) to provide my expert opinions regarding the unpatentability of U.S. Patent
`
`No. 10,335,462 (“’462 patent”) (Ex. 1001). I understand that Sun intends to petition
`
`for inter partes review (“IPR”) of the ’462 patent, which is assigned to Novo Nordisk
`
`A/S. I also understand that, in the IPR petition, Sun will request that the United States
`
`Patent and Trademark Office cancel all claims of the ’462 patent as unpatentable. I
`
`submit this expert declaration to address and support Sun’s IPR petition for the ’462
`
`patent.
`
`I.
`
`Qualifications and Background
`A. Education and Experience; Prior Testimony
`2.
`I am a formulation scientist and professor of pharmacy sciences at
`
`Creighton University with more than 30 years of experience in research and
`
`consulting, with a broad range of expertise in the design and evaluation of sterile
`
`injectable formulations, novel drug delivery systems, pre-formulation studies, solid-
`
`state characterization of drugs and dosage forms, among other areas.
`
`3.
`
`I received my Bachelor of Pharmacy, First of the class with Honors,
`
`from Jadavpur University in 1981, my Master of Pharmacy in Pharmaceutics, First
`
`of the class, from Jadavpur University in 1983, and my Doctor of Philosophy in
`
`Pharmaceutics from the University of Minnesota in 1990.
`
`7
`
`SUN EXHIBIT 1095, IPR2024-00107, PAGE 7
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`

`

`
`
`4.
`
`I am a Registered Pharmacist and Professor with teaching interest in
`
`pharmaceutical analysis, pharmaceutics (basic, solid state, and biopharmaceutics),
`
`physical pharmacy, dosage form and drug delivery systems, and industrial
`
`pharmacy; and research interest in design and evaluation of novel drug delivery
`
`systems, preformulation studies, solid state characterization of drugs and dosage
`
`forms, pharmaceutical analysis utilizing HPLC, GC, GPC, LC-MS/MS, GC-MS,
`
`thermoanalytical methods, IR, powder x-ray diffraction, scanning electron
`
`microscopy, in vitro cell culture, and evaluation and design of dosage forms for
`
`nutraceuticals.
`
`5.
`
`I am currently the Co-Director of Drug Delivery and Discovery Core,
`
`Associate Dean for Research in the School of Pharmacy, and Professor in the
`
`Department of Pharmacy Sciences at Creighton University. I am also currently an
`
`Adjunct Professor in the Department of Pharmaceutical Sciences at the University
`
`of Nebraska Medical Center and have been since 1994. I served as the Chair of the
`
`Department of Pharmacy Science at Creighton University from 2004 until 2023. I
`
`have been the Taffe endowed chair in the school of Pharmacy (the only endowed
`
`chair in the school) since 2008. I have previously held positions as Manufacturing
`
`Supervisor at a pharmaceutical company and a Pharmacy Technician at the
`
`University of Minnesota Hospital and Clinic.
`
`8
`
`SUN EXHIBIT 1095, IPR2024-00107, PAGE 8
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`

`

`
`
`6.
`
`I have extensive consulting and professional services experience with
`
`many pharmaceutical companies worldwide. I am currently a Member of the
`
`American Association of Pharmaceutical Scientists (“AAPS”). I served on the
`
`Preformulation Focus Group Steering Committee for many years, was also a
`
`member of the AAPS SPOD Committee from 2015 to 2017, Fellow of the AAPS in
`
`2012, Chair of the AAPS (Analysis and Pharmaceutical Quality section) Awards
`
`Committee from 2006 to 2010, Chair of the AAPS Preformulation Focus Group
`
`from 2004 to 2005, and a member of the AAPS Pharmaceutical Technology,
`
`Planning Committee from 2004 to 2006. I am also a member of numerous other
`
`professional organizations.
`
`7.
`
`In addition to my academic and industrial experience, I have authored
`
`and coauthored over 70 peer reviewed publications, am an inventor on multiple
`
`patents and a trademark, have over 190 abstracts and poster presentations, have
`
`authored multiple chapters and textbooks, including “Chapter 13: Special Dosage
`
`Forms and Drug Delivery System” in Pharmaceutics: Basic Principles and
`
`Application to Pharmacy Practice, Second Edition, 2023, covering topics including
`
`drug substances, drug delivery systems, pharmaceutics, and drug dosage forms, and
`
`have given over 50 invited lectures.
`
`8.
`
`I am a reviewer for multiple journals including Pharmaceutical
`
`Research, Molecular Pharmaceutics, AAPS PharmSciTech, International Journal of
`
`9
`
`SUN EXHIBIT 1095, IPR2024-00107, PAGE 9
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`

`

`
`
`Pharmaceutics, Pharmaceutical Development and Technology, Journal of
`
`Controlled Release, Journal of Pharmaceutical and Biomedical Analysis, Journal
`
`of Pharmaceutical Research, and Journal of Pharmaceutical Sciences.
`
`9.
`
`In the previous four years, I have provided testimony in the following
`
`proceedings:
`
`• Gilead Sciences, Inc et al. v. Natco Pharma (Canada) Inc., Federal
`Court File Nos. T-1555-22, T-1556-22 (Ottawa, Ontario, Canada),
`2023;
`• Azurity Pharmaceuticals, Inc. v Annora Pharma Private Limited,
`No. 1:21-cv-00196 (D. Del.); and
`• Noven Pharm., Inc. v. Amneal Pharms. LLC, No. 1:18-cv-00699
`(D. Del.)
`10. My qualifications are further described on my curriculum vitae, found
`
`at Exhibit 1096.
`
`B.
`Basis for Opinions and Materials Considered
`11. Exhibit A includes a list of the materials I considered, in addition to my
`
`experience, education, and training, to provide the opinions contained in this
`
`declaration.
`
`C. Retention and Compensation
`12. Sun retained me as a technical expert to provide various opinions about
`
`the ’462 patent. I am being compensated at a rate of $500 per hour plus expenses for
`
`this work. My compensation is in no way tied to the outcome of this proceeding or
`
`to the content of this declaration, and it has not altered my opinions.
`
`10
`
`SUN EXHIBIT 1095, IPR2024-00107, PAGE 10
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`

`

`
`
`II.
`
`Summary of Opinions
`13. My opinions are limited to semaglutide formulations used in the
`
`treatment of diabetes, as claimed in the ’462 patent. I present my opinions from the
`
`perspective of a POSA, who is defined in Section IV.
`
`14.
`
`I understand that Mylan’s expert in IPR2023-00724, Dr. John Bantle,
`
`offers the opinions that it would have been obvious to a POSA to treat diabetes with
`
`a once-weekly, 1.0 mg semaglutide injectable formulation, as recited in the
`
`limitations of claims 1–3, containing the components recited in claims 4–10 (which
`
`I address herein), with a reasonable expectation of success in doing so. See Exhibit
`
`1003.
`
`15. Based on my view of the prior art and, for certain claims, Dr. Bantle’s
`
`additional views of the prior art, it is my opinion that the claims of the ’462 patent
`
`would have been obvious over the following combinations of references:
`
`a) Claims 4–10 of the ’462 patent would have been obvious over
`
`WO421 considering the ’424 publication (Ground 3) or over
`
`NCT657 and NCT773 considering the ’424 publication (Ground 5);
`
`and
`
`b) Claims 4–10 of the ’462 patent would have been obvious over
`
`WO537 considering Lovshin (Ground 4).
`
`11
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`

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`
`
`16. These references would have motivated a POSA to formulate a 1.0 mg
`
`semaglutide injectable formulation containing the components recited in claims 4–
`
`10 to treat type 2 diabetes, as described by Dr. Bantle (claims 1–10), with a
`
`reasonable expectation of success doing so.
`
`17.
`
`I understand that Patent Owner may present expert opinions regarding
`
`“secondary considerations” of non-obviousness of the formulations recited in the
`
`method of treatment claims in response to my declaration, and that I may be asked
`
`to address such opinions in the future. I therefore expressly reserve the right to
`
`address later all issues of secondary considerations that Patent Owner’s experts may
`
`raise.
`
`III. Legal Standards
`18. To prepare and form my opinions set forth in this declaration, I have
`
`been informed of the relevant legal principles.1 I applied my understanding of those
`
`
`1 To support my analysis and to help me reach my opinions and conclusions, I was
`
`informed of and advised to apply various legal principles relating to unpatentability,
`
`which I set forth here. By setting forth these legal standards, I do not intend 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 provide in this case.
`
`12
`
`SUN EXHIBIT 1095, IPR2024-00107, PAGE 12
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`

`

`
`
`principles in forming my opinions. My understanding of those principles is
`
`summarized below.
`
`19.
`
`I have been informed that Sun bears the burden of proving
`
`unpatentability by a preponderance of the evidence. I have been told that this means
`
`it must be more likely than not that the claims are unpatentable.
`
`20.
`
`I understand that my opinions regarding unpatentability are from the
`
`viewpoint of a person of ordinary skill in the art (“POSA”) in the field of technology
`
`of the patent as of the patent’s priority date. I have also been informed by counsel
`
`that when defining a POSA, the following factors may be considered: (1) the
`
`educational level of the inventor; (2) the type of problems encountered in the art;
`
`(3) prior art solutions to those problems; (4) rapidity with which innovations are
`
`made; and (5) sophistication of the technology and educational level of active
`
`workers in the field. Further, I understand a POSA is generally skilled in the relevant
`
`art (i.e., the subject matter claimed and described in the patent).
`
`21.
`
`I am told that for a patent to be anticipated, a prior art reference must
`
`disclose all elements of that claim expressly and/or inherently as arranged in the
`
`claim. With respect to inherent disclosure, there is no requirement that a POSA
`
`would have recognized the inherent disclosure at the time of the invention, but only
`
`that the subject matter is in fact inherent, or necessarily present, in the prior art
`
`reference.
`
`13
`
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`

`

`
`
`22.
`
`I am told that the concept of patent obviousness involves four factual
`
`inquiries: (1) the scope and content of the prior art; (2) the differences between the
`
`claimed invention and the prior art; (3) the level of ordinary skill in the art; and (4)
`
`secondary considerations of non-obviousness.
`
`23.
`
`I understand 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. I understand 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.
`
`IV. Person of Ordinary Skill in the Art
`24.
`In my opinion, the following definition of a person of ordinary skill in
`
`the art applies to the claims of the ’462 patent. I reserve the right to amend and/or
`
`supplement my opinions on unpatentability if a different definition of a POSA is
`
`adopted or agreed to.
`
`25. A POSA would have understood the prior art references referred to
`
`herein and would have the capability to draw inferences from the prior art references.
`
`14
`
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`

`

`
`
`It is understood that, to the extent necessary, a POSA may collaborate with one or
`
`more other POSAs for one or more aspects with which the other POSA may have
`
`expertise, experience, and/or knowledge. Additionally, a POSA could have had a
`
`lower level of formal education than what I describe in the following definition if
`
`the person has a higher degree of experience. In view of the relatively high level of
`
`skill and the clear teachings in the prior art, the level of skill of a POSA is not
`
`dispositive of any issue raised in this Petition.
`
`26.
`
`In my opinion, the following definition of a POSA applies to the claims
`
`of the ’462 patent. A POSA would have (1) an M.D., Pharm.D., or Ph.D. in
`
`pharmacy, chemical engineering, bioengineering, chemistry, or related discipline;
`
`(2) at least two years of experience in protein or peptide therapeutic development
`
`and/or manufacturing or diabetes treatments; and (3) experience with the
`
`development, design, manufacture, formulation, or administration of therapeutic
`
`agents, and the literature concerning protein or peptide formulation and design, or
`
`diabetes treatments.
`
`27. Alternatively, a POSA would be (1) a highly-skilled scientist lacking
`
`an M.D., Pharm.D., or Ph.D., but would have (2) more than five years of experience
`
`in the area of protein or peptide therapeutic development and/or manufacturing or
`
`diabetes treatments; and/or (3) experience with the development, design,
`
`manufacture, or formulation of therapeutic agents, and the literature concerning
`
`15
`
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`
`

`

`
`
`protein or peptide formulation and design or diabetes treatments. In either case, a
`
`higher educational level could substitute for some amount of the requisite
`
`experience.
`
`28. As explained above, and as is evident from my CV, I met the
`
`qualifications of a POSA as of the priority date of the ’462 patent.
`
`V. The ’462 Patent (Ex. 1001)
`29.
`I have read the ’462 patent, which is titled “Use of Long-Acting GLP-1
`
`Peptides,” including its claims, and reviewed relevant portions of the file history of
`
`the ’462 patent (Ex. 1002).
`
`30.
`
`I have assumed that the earliest priority date to which the asserted
`
`claims of the ’462 patent are entitled is July 1, 2012, which is the date recited on the
`
`face of the patent for foreign reference EP12174535, listed under “Foreign
`
`Application Priority Data.” To the extent Patent Owner later asserts and/or proves
`
`that the asserted claims are entitled to an earlier priority or invention date, I reserve
`
`the right to supplement this declaration.
`
`A. The Formulation Claims of the ’462 Patent
`31. The ’462 patent has one independent claim, which recites:
`
`1. A method for treating type 2 diabetes, comprising
`administering semaglutide once weekly in an amount of
`1.0 mg to a subject in need thereof.
`
`16
`
`SUN EXHIBIT 1095, IPR2024-00107, PAGE 16
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`

`

`
`
`32. Dependent claims 4–10 depend from claim 1, directly or indirectly, and
`
`are provided below.
`
`33. Dependent claim 4 recites:
`
`4. The method according to claim 1, wherein the
`semaglutide is administered in the form of an isotonic
`aqueous solution comprising phosphate buffer at a pH in
`the range of 7.0-9.0.
`
`34. Dependent claim 5 recites:
`
`5. The method according to claim 4, wherein the solution
`further comprises propylene glycol and phenol.
`
`35. Dependent claim 6 recites:
`
`6. The method according to claim 4, wherein the pH is 7.4.
`
`36. Dependent claim 7 recites:
`
`7. The method according to claim 6, wherein the solution
`further comprises propylene glycol and phenol.
`
`37. Dependent claim 8 recites:
`
`8. The method according to claim 4, wherein the
`phosphate buffer is a sodium dihydrogen phosphate
`buffer.
`
`38. Dependent claim 9 recites:
`
`9. The method according to claim 1, wherein the
`semaglutide is administered by subcutaneous injection in
`the form of an isotonic aqueous solution comprising at a
`
`17
`
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`

`

`
`
`sodium dihydrogen phosphate buffer at a pH in the range
`of 7.0-9.0, and wherein the solution further comprises
`propylene glycol and phenol.
`
`39. Dependent claim 10 recites:
`
`10. The method according to claim 9, wherein the pH is
`7.4.
`
`B.
`The Prosecution History of the ’462 Patent
`40. When the application for the ’462 patent was filed on July 21, 2017,
`
`independent claim 1 recited:
`
`1. A method for
`
`a) reduction of HbA1c;
`
`b) treatment of type 2 diabetes, hyperglycemia, impaired
`glucose tolerance, or non-insulin dependent diabetes; or
`
`c) treatment of obesity, reducing body weight and/or food
`intake, or inducing satiety;
`
`wherein said method comprises administration of a GLP-1
`agonist to a subject in need thereof, wherein said GLP-1
`agonist
`
`i) has a half-life of at least 72 hours;
`
`ii) is administered in an amount of at least 0.7 mg per
`week, such an amount equivalent to at least 0. 7 mg
`semaglutide per week; and
`
`iii) is administered once weekly or less often.
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`

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`
`
`Ex. 1002 at 8.
`
`41. The Examiner rejected the filed claims on July 23, 2018, based on
`
`NCT00696657, which disclosed the use of semaglutide and liraglutide, Madsbad
`
`(2011), which disclosed the use of several GLP-1 agonists, and Kim (2007), which
`
`disclosed the use of exenatide, anticipated the claims because they each disclosed a
`
`method of treatment with at least 0.8 mg of GLP-1 agonist once weekly (NCT657
`
`with 0.8 mg semaglutide; Madsbad with 4, 15, and 30 mg albiglutide; and Kim with
`
`0.8 and 2.0 mg exenatide), with all the other requirements satisfied (treating type 2
`
`diabetes and reducing HbA1c, with a half-life in the required range, etc.). See
`
`Ex. 1002 (July 23, 2018 Office Action) at 312.
`
`42. The applicants then amended claim 1 to recite:
`
`1. (Currently Amended) A method for treating type 2
`diabetes, comprising administering semaglutide once
`weekly in an amount of 1.0 mg to a subject in need thereof
`
`a) reduction of HbA1c;
`
`b) treatment of type 2 diabetes, hyperglycemia, impaired
`glucose tolerance, or non-insulin dependent diabetes; or
`
`c) treatment of obesity, reducing body weight and/or food
`intake, or inducing satiety;
`
`wherein said method comprises administration of a GLP 1
`agonist to a subject in need thereof,
`
`wherein said GLP 1 agonist
`
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`

`
`
`i) has a half-life of at least 72 hours;
`
`is administered in an amount of at least 0.7 mg per
`ii)
`week, such an amount equivalent to at least 0.7 mg
`semaglutide per week; and
`
`iii) is administered once weekly or less often.
`
`See Ex. 1002 (January 23, 2019 listing of claims) at 332.
`
`43. The applicants also filed a terminal disclaimer over U.S. Patent
`
`No. 9,764,003, which claims “[a] method for reducing body weight, comprising
`
`administering [only] semaglutide once weekly in an amount of at least 0.7 mg and
`
`up to 1.6 mg to a subject in need thereof.” See Ex. 1002 (February 28, 2019 Terminal
`
`disclaimer) at 336.
`
`44. The Examiner then withdrew the anticipation rejections and allowed
`
`the claims, stating:
`
`trial compared semaglutide and
`The ’657 clinical
`liraglutide in treatment of type 2 diabetic patients. The
`semaglutide or liraglutide was used as on add-on therapy
`to type 2 diabetic patients already taking metformin.
`Efficacy of treatment was further assessed by a reduction
`in HbA1c levels. Patients in the Arm Labels D and E of
`the clinical trial were administered 0.8 mg once weekly by
`subcutaneous injection. However, the reference does not
`teach or disclose a higher amount of 1 mg semaglutide.
`
`See Ex. 1002 (March 6, 2019 Notice of Allowance) at 344-45.
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`VI. Claim Construction
`45.
`I have been informed that claim terms should be given their plain and
`
`ordinary meaning in light of the intrinsic evidence (i.e., the specification and the
`
`prosecution history) from the perspective of a POSA. I also understand that while
`
`extrinsic evidence (e.g., scientific publications) may be considered when interpreting
`
`the meaning of claim terms in some circumstances, it is generally given less weight
`
`than intrinsic evidence. I am not offering any opinions related to claim construction
`
`because in my view all the claim terms related to pharmaceutical formulations can
`
`be understood based on their plain and ordinary meaning. I understand that others
`
`are offering opinions related to methods of treatment.
`
`VII. Background on GLP-1 Compound Formulations Used to Treat Diabetes
`A.
`Parenteral formulations and components thereof were well-known
`46. Substantial guidance was available to POSAs to prepare parenteral
`
`formulations well before the priority date of the ’462 patent. For example, POSAs
`
`were well-aware that parenteral formulations can be administered though
`
`intravenous, subcutaneous, intradermal, intramuscular, intraarticular, and intrathecal
`
`injection. Ex. 1069 (Remington) at 37; Ex. 1070 (Modern Pharmaceutics) at 8-9
`
`(Table 1). POSAs were well aware of the various components that were important
`
`for preparing successful parenteral formulations. For example, POSAs understood
`
`that “[s]olutions to be administered subcutaneously require strict attention to tonicity
`
`adjustment, otherwise irritation of the plentiful supply of nerve endings in this
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`
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`anatomical area would give rise to pronounced pain.” Ex. 1069 (Remington) at 37;
`
`see also Ex. 1070 (Modern Pharmaceutics) at 22. Thus, POSAs were aware of the
`
`importance of using isotonic agents, such as sodium chloride, in parenteral
`
`formulations to prevent osmotic pressure changes upon injection. Ex. 1070 (Modern
`
`Pharmaceutics) at 18-19 (Table 2), 22. POSAs were also aware of the importance of
`
`including a preservative, such as phenol or cresol, in the parenteral preparation to
`
`prevent the growth of microorganisms. Ex. 1069 (Remington) at 41; Ex. 1070
`
`(Modern Pharmaceutics) at 18-19 (Table 2). Finally, the importance of buffers to
`
`maintain product stability in parenteral formulations was also well-known to
`
`POSAs. Ex. 1069 (Remington) at 41-42; Ex. 1070 (Modern Pharmaceutics) at 20.
`
`47. The prior art also taught the use of GLP-1 derivatives, containing
`
`various modifications on GLP-1 (7-3