UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________
`
`APOTEX INC.,
`Petitioner
`
`v.
`
`NOVO NORDISK A/S,
`PATENT OWNER
`_____________________
`
`CASE IPR2024-00631
`U.S. PATENT NO. 10,335,462
`ISSUED: JULY 2, 2019
`
`TITLE:
`USE OF LONG-ACTING GLP-1 PEPTIDES
`
`DECLARATION OF HUGH DAVID CHARLES SMYTH, Ph.D.
`
`March 1, 2024
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0001
`
`

`

`TABLE OF CONTENTS
`
`Page
`TABLE OF CONTENTS ........................................................................................ i
`TABLE OF ABBREVIATIONS ............................................................................. v
`I.
`QUALIFICATIONS AND BACKGROUND .............................................. 1
`A.
`Education and Experience ..................................................................... 1
`B.
`Basis for Opinions and Materials Considered ....................................... 5
`C.
`Retention and Compensation ................................................................ 5
`SUMMARY OF OPINIONS ......................................................................... 6
`II.
`III. LEGAL STANDARDS .................................................................................. 7
`IV. PERSON OF ORDINARY SKILL IN THE ART ...................................... 9
`V.
`THE ’462 PATENT (Ex.1001) .................................................................... 11
`A.
`The Formulation Claims of the ’462 Patent ........................................ 11
`B.
`The Prosecution History of the ’462 Patent ........................................ 12
`VI. CLAIM CONSTRUCTION ........................................................................ 15
`VII. BACKGROUND ON GLP-1 COMPOUND FORMULATIONS
`USED TO TREAT DIABETES .................................................................. 16
`A.
`Parenteral formulations and components thereof were well-
`known .................................................................................................. 16
`GLP-1 compounds were well-known .................................................. 17
`GLP-1 agonists and related formulations were well-known ............... 20
`Parenteral dosage forms for peptide-based drugs ............................... 21
`1.
`Tonicity and osmolarity of the parenteral formulation ............. 23
`2.
`pH and buffering capacity of the parenteral formulation ......... 24
`3.
`Avoiding particulates in the parenteral formulation ................. 25
`4.
`Vehicles and diluents of the parenteral formulation ................. 26
`5.
`Excipients of the parenteral formulation .................................. 27
`VIII. SCOPE AND CONTENT OF THE PRIOR ART .................................... 28
`A. WO 2011/138421 (“WO421”) (Ex.1011) ........................................... 29
`
`B.
`C.
`D.
`
`-i-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0002
`
`

`

`B.
`
`U.S. Patent Application Pub. No. US2007/0010424 (’424
`publication) (Ex.1016) ........................................................................ 30
`Clinical Trial No. NCT00696657 (NCT657) (Ex.1013) ..................... 32
`C.
`Clinical Trial No. NCT00851773 (NCT773) (Ex.1014) ..................... 34
`D.
`E. WO 2006/097537 (“WO537”) (Ex.1015) ........................................... 36
`F.
`Lovshin (Ex.1012) ............................................................................... 39
`G.
`Other Art That Informs the POSA’s Knowledge ................................ 40
`1.
`Lund (Ex.1035) ......................................................................... 40
`2.
`U.S. Patent No. 7,022,674 (“’674 patent”) (Ex.1075) .............. 42
`3.
`U.S. Patent No. 6,458,924 (“’924 patent”) (Ex.1073) .............. 44
`4.
`U.S. Patent No. 6,284,727 (“’727 patent”) (Ex.1071) .............. 45
`5.
`U.S. Patent No. 6,268,343 (“Knudsen patent”) (Ex.1034) ....... 45
`6.
`U.S. Patent No. 5,512,549 (“’549 patent”) (Ex.1017) .............. 47
`7.
`U.S. Patent No. 5,164,366 (“’366 patent”) (Ex.1072) .............. 48
`8.
`U.S. Patent No. 5,118,666 (“’666 patent”) (Ex.1056) .............. 48
`9.
`Victoza label (Ex.1039) ............................................................ 49
`10. WO 03/002136 (“WO136”) (Ex.1041) ..................................... 50
`11. WO 00/37098 (“WO098”) (Ex.1074) ....................................... 52
`12. Additional prior art and references ........................................... 53
`IX. UNPATENTABILITY OF THE CLAIMS OF THE ’462
`PATENT ....................................................................................................... 53
`Grounds 3 and 5: Claims 4-10 of the ’462 patent would have
`A.
`been obvious over WO421 considering the ’424 publication or
`over NCT657 and NCT773 considering the ’424 publication ............ 53
`A POSA would have been motivated to formulate
`1.
`semaglutide as an isotonic aqueous solution for
`subcutaneous injection with a reasonable expectation of
`success ....................................................................................... 55
`A POSA would have been motivated to formulate
`semaglutide with propylene glycol and phenol with a
`reasonable expectation of success ............................................. 60
`
`2.
`
`-ii-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0003
`
`

`

`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`11.
`
`A POSA would have been motivated to formulate
`semaglutide with a phosphate buffer, such as sodium
`dihydrogen phosphate, with a reasonable expectation of
`success ....................................................................................... 64
`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 ...................... 69
`The dependent limitations of claim 4 would have been
`obvious ...................................................................................... 72
`The dependent limitations of claim 5 would have been
`obvious ...................................................................................... 74
`The dependent limitations of claim 6 would have been
`obvious ...................................................................................... 76
`The dependent limitations of claim 7 would have been
`obvious ...................................................................................... 77
`The dependent limitations of claim 8 would have been
`obvious ...................................................................................... 78
`The dependent limitations of claim 9 would have been
`obvious ...................................................................................... 79
`The dependent limitations of claim 10 would have been
`obvious ...................................................................................... 82
`12. Conclusion ................................................................................ 83
`Ground 4: Claims 4-10 of the ’462 patent would have been
`obvious over WO537 considering Lovshin ......................................... 84
`A POSA would have been motivated to formulate
`1.
`semaglutide as an isotonic aqueous solution for
`subcutaneous injection with a reasonable expectation of
`success ....................................................................................... 85
`A POSA would have been motivated to formulate
`semaglutide with propylene glycol and phenol with a
`reasonable expectation of success ............................................. 87
`A POSA would have been motivated to formulate
`semaglutide with a phosphate buffer, such as sodium
`
`10.
`
`B.
`
`2.
`
`3.
`
`-iii-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0004
`
`

`

`4. 
`
`5. 
`
`6. 
`
`7. 
`
`8. 
`
`9. 
`
`dihydrogen phosphate, with a reasonable expectation of
`success ....................................................................................... 89 
`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 ...................... 91 
`The dependent limitations of claim 4 would have been
`obvious ...................................................................................... 92 
`The dependent limitations of claim 5 would have been
`obvious ...................................................................................... 94 
`The dependent limitations of claim 6 would have been
`obvious ...................................................................................... 95 
`The dependent limitations of claim 7 would have been
`obvious ...................................................................................... 96 
`The dependent limitations of claim 8 would have been
`obvious ...................................................................................... 97 
`10.  The dependent limitations of claim 9 would have been
`obvious ...................................................................................... 98 
`11.  The dependent limitations of claim 10 would have been
`obvious ....................................................................................101 
`12.  Conclusion ..............................................................................102 
`No Secondary Considerations Overcome Prima Facie
`Obviousness .......................................................................................102 
`1. 
`The formulations recited in the ’462 patent produce no
`unexpected results ...................................................................102 
`There was no long-felt but unmet need for the
`formulations recited in the ’462 patent ...................................103 
`There was no praise of the formulations recited in the
`’462 patent ...............................................................................104 
`There was no industry skepticism of the formulations
`recited in the ’462 patent .........................................................105 
`X.  RESERVATION OF RIGHTS .................................................................105 
`
`
`
`C. 
`
`2. 
`
`3. 
`
`4. 
`
`
`
`-iv-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0005
`
`

`

`TABLE OF ABBREVIATIONS
`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, PARENTERAL PRODUCTS, IN MODERN
`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)
`WO 00/37098
`WO 03/002136
`WO 2011/058193
`WO 2011/073328
`WO 2011/138421
`WO 2006/097537
`
`Abbreviation
`’366 PATENT
`’424 PUBLICATION
`’462 PATENT
`’549 PATENT
`’666 PATENT
`’674 PATENT
`’727 PATENT
`’924 PATENT
`KNUDSEN PATENT
`LOVSHIN
`
`LUND
`
`MODERN
`PHARMACEUTICS
`NCT657
`NCT773
`OZEMPIC LABEL
`REMINGTON
`
`VICTOZA LABEL
`WO098
`WO136
`WO193
`WO328
`WO421
`WO537
`
`-v-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0006
`
`

`

`I, Hugh David Charles Smyth, Ph.D., declare as follows:
`
`1.
`
`I have been retained by counsel for Petitioner Apotex Inc.
`
`(“Apotex”). I understand that Apotex is submitting a petition for inter partes
`
`review (“IPR”) of U.S. Patent No. 10,335,462 (“’462 patent,” attached as
`
`Ex.1001), which is assigned to Novo Nordisk A/S. It is my understanding that
`
`Apotex is requesting that the United States Patent and Trademark Office
`
`(“USPTO”) cancel all claims of the ’462 patent as unpatentable. I submit this
`
`expert declaration in support of Apotex’s IPR petition for the ’462 patent. I also
`
`understand that Mylan Pharmaceuticals Inc. has filed an IPR with respect to the
`
`’462 patent in IPR2023-00724 (the “Mylan IPR”), which the Board has
`
`instituted. In support of the Mylan IPR, Paul Dalby, Ph.D., submitted a
`
`declaration (Ex.1007). I have reviewed and considered Dr. Dalby’s declaration.
`
`I agree with Dr. Dalby’s opinions set forth in his declaration, so I have adopted
`
`them. Accordingly, I submit this expert declaration in support of Apotex’s IPR
`
`petition for the ’462 patent.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`A. Education and Experience
`I am currently a Professor with Tenure (Alcon Centennial
`2.
`
`Professor) in the College of Pharmacy at the University of Texas, Austin. Prior
`
`to 2018, I was an Associate Professor with Tenure at the University of Texas at
`
`-1-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0007
`
`

`

`Austin and the Alan W. Hamm Centennial Fellow in Pharmacy within the
`
`College of Pharmacy. From 2009 to 2011, I served as an Assistant Professor in
`
`the College of Pharmacy at the University of Texas, Austin. From 2005 to
`
`2009, I was an Assistant Professor in the College of Pharmacy at the University
`
`of New Mexico. And from 2004 to 2005, I was a Research Assistant Professor
`
`in the College of Pharmacy at the University of North Carolina, Chapel Hill.
`
`3.
`
`I received a Bachelor of Pharmacy in 1995 from the University of
`
`Otago, in Dunedin, New Zealand. In 1997, I earned a Post Graduate Diploma in
`
`Pharmaceutics (with Distinction), from the University of Otago. In 2000, I
`
`received my Ph.D. in Pharmaceutical Sciences from the University of Otago. I
`
`also worked as a visiting scientist at Glaxo Wellcome, Research Triangle Park,
`
`North Carolina from 1998 to 1999. From 2001 to 2003, I was a Post-Doctoral
`
`Fellow at the School of Pharmacy at the University of North Carolina, Chapel
`
`Hill.
`
`4.
`
`I am currently, or have been in the past, a member of various
`
`professional societies, including the American Association of Pharmaceutical
`
`Scientists and the American Chemical Society. I have co-authored numerous
`
`publications in peer reviewed journals relating to the pharmaceutical sciences
`
`and frequently give presentations at national and international conferences for
`
`-2-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0008
`
`

`

`pharmaceutical scientists.
`
`5.
`
`As part of my research, teaching, and involvement in the
`
`pharmaceutical industry, I routinely consider the formulation of biologics such
`
`as proteins and peptide therapeutics. In fact, my Ph.D. dissertation focused on
`
`the formulation and delivery of a peptide, luteinizing hormone releasing
`
`hormone (LHRH). Since this time (1998-2000) I have been involved in many
`
`projects and development programs that focus on biologic entities including
`
`peptides. Over the span of my research career I have been involved in several
`
`project that focus on the parenteral delivery of therapeutics. This includes
`
`studies in which molecules have been studied by multiple routes of
`
`administration including subcutaneous injection.
`
`6.
`
`Formulation of biologics, particularly proteins and peptide
`
`therapeutics, has been a recurring theme in my career. Following Ph.D.
`
`dissertation, mentioned above, my work expanded to encompass various
`
`projects and development programs centered around biologic entities,
`
`prominently peptides.
`
`7.
`
`Notable publications of mine include a 2019 paper in Molecular
`
`Pharmaceutics on particle formation processes affecting respirable protein
`
`powders and a 2018 paper in the International Journal of Pharmaceutics
`
`-3-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0009
`
`

`

`addressing dosing considerations for inhaled biologics. As an Associate
`
`Professor with Tenure at The University of Texas at Austin (2011–2018), I
`
`focused on challenges and future prospects for biologics delivery, with
`
`published work in the AAPS Journal (2018) and Current Pharmaceutical Design
`
`(2016). I also presented similar work at professional conferences, such as
`
`“Challenges and Future Prospects for the Delivery of Biologics: Oral Mucosal,
`
`Pulmonary, and Transdermal Routes” at the AAPS Annual Meeting in 2019.
`
`Overall, much of my career has been spent advancing the applications of
`
`peptides, biologics, and proteins in drug delivery.
`
`8.
`
`Beyond my academic roles, I have played pivotal roles in the
`
`pharmaceutical industry and startup ventures. Currently, I am the Co-Founder
`
`and Chief Scientific Officer of Cloxero Therapeutics in Austin, TX, and have
`
`been involved as a Co-Founder in Via Therapeutics and a Consulting Chief
`
`Technology Officer in Nob Hill Therapeutics, both stemming from technologies
`
`developed in my lab. My association with startup ventures dates back to 2010,
`
`where I served as a Consulting Chief Scientist for Respira Therapeutics, a
`
`venture originating from technology developed in my lab and progressing to
`
`clinical development.
`
`9.
`
`In addition to my academic and industry engagements, I have held
`
`-4-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0010
`
`

`

`editorial responsibilities as the Editor-in-Chief of Drug Development and
`
`Industrial Pharmacy from 2014 to 2022. My dedication to advancing
`
`pharmaceutical sciences has also extended to adjunct positions, including being
`
`an Adjunct Associate Scientist at Lovelace Respiratory Research Institute,
`
`Albuquerque, NM, and a Member of the University of New Mexico Cancer
`
`Research and Treatment Center from 2006 to 2009.
`
`10. A summary of my education, experience, publications, awards and
`
`honors, patents, publications, and presentations is provided in my CV, a copy of
`
`which is provided as Ex.1506.
`
`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. Apotex retained me as a technical expert to provide various
`
`opinions about the ’462 patent. I am being compensated at a rate of $800 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.
`
`-5-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0011
`
`

`

`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 Apotex’s expert Dr. Judith Korner 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.
`
`15. Based on my view of the prior art and, for certain claims, Dr.
`
`Korner’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).
`
`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. Korner (claims 1-10),
`
`-6-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0012
`
`

`

`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 principles in forming my opinions. My understanding of
`
`those principles is summarized below.
`
`19.
`
`I have been informed that Apotex 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
`
`
`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.
`
`-7-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0013
`
`

`

`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.
`
`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.
`
`-8-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0014
`
`

`

`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
`In my opinion, the following definition of a person of ordinary skill
`24.
`
`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. 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.
`
`-9-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0015
`
`

`

`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 protein or peptide formulation and design or diabetes
`
`-10-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0016
`
`

`

`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)
`I have read the ’462 patent, which is titled “Use of Long-Acting
`29.
`
`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.
`32. Dependent claims 4-10 depend from claim 1, directly or indirectly,
`
`and are provided below.
`
`-11-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0017
`
`

`

`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 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,
`
`-12-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0018
`
`

`

`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.
`
`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
`
`-13-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0019
`
`

`

`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
` reduction of HbA1c;
` treatment of type 2 diabetes, hyperglycemia, impaired glucose tolerance, or
`non-insulin dependent diabetes; or
` 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
` has a half-life of at least 72 hours;
` 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
` 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
`
`-14-
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1505-0020
`
`

`

`Terminal disclaimer) at 336.
`
`44. The Examiner then withdrew the anticipation rejections and
`
`allowed the claims, stating:
`
`The ’657 clinical trial compared semaglutide and 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.
`
`VI. CLAIM CONSTRUCTION
`I have been informed that claim terms should be given their plain
`45.
`
`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 intrin