UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`v.
`
`NOVO NORDISK A/S,
`Patent Owner.
`
`Case No. IPR2023-00724
`Patent No. 10,335,462
`
`DECLARATION OF PAUL DALBY, PH.D., IN SUPPORT OF PETITION
`FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 10,335,462
`
`MPI EXHIBIT 1007 PAGE 1
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0001
`
`

`

`TABLE OF CONTENTS
`
`
`Page
`
`
`I.
`
`Qualifications and Background ............................................................. 8
`A.
`Education and Experience; Prior Testimony .................................. 8
`B.
`Basis for Opinions and Materials Considered............................... 12
`C.
`Retention and Compensation ..................................................... 12
`Summary of Opinions ....................................................................... 13
`II.
`III. Legal Standards ................................................................................ 14
`IV. Person of Ordinary Skill in the Art ...................................................... 16
`V.
`The ’462 Patent (Ex. 1001) ................................................................ 18
`A.
`The Formulation Claims of the ’462 Patent ................................. 18
`B.
`The Prosecution History of the ’462 Patent.................................. 20
`VI. Claim Construction ........................................................................... 23
`VII. Background on GLP-1 Compound Formulations Used to Treat
`Diabetes .......................................................................................... 24
`A.
`Parenteral formulations and components thereof were well-
`known .................................................................................... 24
`B. GLP-1 compounds were well-known .......................................... 25
`C. GLP-1 agonists and related formulations were well-known ........... 28
`D.
`Parenteral dosage forms for peptide-based drugs .......................... 29
`1.
`Tonicity and osmolarity of the parenteral formulation .......... 31
`2.
`pH and buffering capacity of the parenteral formulation ....... 32
`3.
`Avoiding particulates in the parenteral formulation ............. 33
`4.
`Vehicles and diluents of the parenteral formulation ............. 33
`5.
`Excipients of the parenteral formulation............................. 34
`VIII. Scope and Content of the Prior Art ...................................................... 35
`A. WO 2011/138421 (“WO421”) (Ex. 1011) ................................... 36
`B. U.S. Patent Application Pub. No. US2007/0010424 (’424
`publication) (Ex. 1016) ............................................................. 38
`
`2
`
`MPI EXHIBIT 1007 PAGE 2
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0002
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`
`
`Clinical Trial No. NCT00696657 (NCT657) (Ex. 1013)................ 40
`C.
`D. Clinical Trial No. NCT00851773 (NCT773) (Ex. 1014)................ 42
`E. WO 2006/097537 (“WO537”) (Ex. 1015) ................................... 44
`F.
`Lovshin (Ex. 1012) .................................................................. 48
`G. Other Art That Informs the POSA’s Knowledge .......................... 49
`1.
`Lund (Ex. 1035) ............................................................. 49
`2.
`U.S. Patent No. 7,022,674 (“’674 patent”) (Ex. 1075) .......... 51
`3.
`U.S. Patent No. 6,458,924 (“’924 patent”) (Ex. 1073) .......... 53
`4.
`U.S. Patent No. 6,284,727 (“’727 patent”) (Ex. 1071) .......... 53
`5.
`U.S. Patent No. 6,268,343 (“Knudsen patent”) (Ex. 1034) .... 54
`6.
`U.S. Patent No. 5,512,549 (“’549 patent”) (Ex. 1017) .......... 55
`7.
`U.S. Patent No. 5,164,366 (“’366 patent”) (Ex. 1072) .......... 56
`8.
`U.S. Patent No. 5,118,666 (“’666 patent”) (Ex. 1056) .......... 57
`9.
`Victoza label (Ex. 1039) .................................................. 57
`10. WO 03/002136 (“WO136”) (Ex. 1041).............................. 58
`11. WO 00/37098 (“WO098”) (Ex. 1074) ............................... 60
`12. Additional prior art and references .................................... 61
`IX. Unpatentability of the Claims of the ’462 Patent ................................... 61
`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 ......... 61
`1.
`A POSA would have been motivated to formulate
`semaglutide as an isotonic aqueous solution for
`subcutaneous injection with a reasonable expectation of
`success .......................................................................... 63
`A POSA would have been motivated to formulate
`semaglutide with propylene glycol and phenol with a
`reasonable expectation of success ..................................... 67
`
`2.
`
`3
`
`MPI EXHIBIT 1007 PAGE 3
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0003
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`A POSA would have been motivated to formulate
`semaglutide with a phosphate buffer, such as sodium
`dihydrogen phosphate, with a reasonable expectation of
`success .......................................................................... 72
`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 .................. 75
`The dependent limitations of claim 4 would have been
`obvious.......................................................................... 79
`The dependent limitations of claim 5 would have been
`obvious.......................................................................... 81
`The dependent limitations of claim 6 would have been
`obvious.......................................................................... 82
`The dependent limitations of claim 7 would have been
`obvious.......................................................................... 83
`The dependent limitations of claim 8 would have been
`obvious.......................................................................... 84
`10. The dependent limitations of claim 9 would have been
`obvious.......................................................................... 85
`11. The dependent limitations of claim 10 would have been
`obvious.......................................................................... 88
`12. Conclusion..................................................................... 89
`B. Ground 4: Claims 4–10 of the ’462 patent would have been
`obvious over WO537 considering Lovshin .................................. 90
`1.
`A POSA would have been motivated to formulate
`semaglutide as an isotonic aqueous solution for
`subcutaneous injection with a reasonable expectation of
`success .......................................................................... 91
`A POSA would have been motivated to formulate
`semaglutide with propylene glycol and phenol with a
`reasonable expectation of success ..................................... 93
`
`2.
`
`4
`
`MPI EXHIBIT 1007 PAGE 4
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0004
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`A POSA would have been motivated to formulate
`semaglutide with a phosphate buffer, such as sodium
`dihydrogen phosphate, with a reasonable expectation of
`success .......................................................................... 94
`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 .................. 96
`The dependent limitations of claim 4 would have been
`obvious.......................................................................... 98
`The dependent limitations of claim 5 would have been
`obvious........................................................................ 100
`The dependent limitations of claim 6 would have been
`obvious........................................................................ 101
`The dependent limitations of claim 7 would have been
`obvious........................................................................ 102
`The dependent limitations of claim 8 would have been
`obvious........................................................................ 103
`10. The dependent limitations of claim 9 would have been
`obvious........................................................................ 104
`11. The dependent limitations of claim 10 would have been
`obvious........................................................................ 106
`12. Conclusion................................................................... 107
`C. No Secondary Considerations Overcome Prima Facie
`Obviousness .......................................................................... 107
`1.
`The formulations recited in the ’462 patent produce no
`unexpected results......................................................... 107
`There was no long-felt but unmet need for the
`formulations recited in the ’462 patent ............................. 108
`There was no praise of the formulations recited in the
`’462 patent ................................................................... 109
`
`2.
`
`3.
`
`5
`
`MPI EXHIBIT 1007 PAGE 5
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0005
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`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`
`
`4.
`
`There was no industry skepticism of the formulations
`recited in the ’462 patent................................................ 110
`X. Reservation of Rights ...................................................................... 110
`
`6
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`MPI EXHIBIT 1007 PAGE 6
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0006
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`
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`
`
`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
`
`7
`
`MPI EXHIBIT 1007 PAGE 7
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0007
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`

`

`
`
`
`1. My name is Paul Dalby, Ph.D. I have been retained by Mylan
`
`Pharmaceuticals Inc. (“Mylan”) to provide my expert opinions regarding the
`
`unpatentability of U.S. Patent No. 10,335,462 (“’462 patent”) (Ex. 1001). I
`
`understand that Mylan 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, Mylan 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 Mylan’s IPR petition for the ’462 patent.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`A. Education and Experience; Prior Testimony
`I earned my doctorate at Cambridge University, UK, in 1998 where I
`2.
`
`studied protein folding mechanisms, using protein engineering to alter the relative
`
`stabilities of the native, denatured, intermediate and transition states, and evaluating
`
`the effects of a range of temperature, pH and presence of viscosity modifiers in the
`
`formulation. From 1998 to 2000, I was a postdoctoral fellow at the University of
`
`Pennsylvania, where I studied the relationship between protein structure, stability
`
`and function through protein engineering and biophysical characterisation, and also
`
`methods to improve stability and minimize aggregation in protein therapeutic
`
`formulations. In 2000, I was appointed Lecturer at University College London
`
`(UCL) in the Department of Biochemical Engineering. My research focused on new
`
`8
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`MPI EXHIBIT 1007 PAGE 8
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0008
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`
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`strategies for evolutionary protein and enzyme design, researching factors to
`
`
`
`strengthen protein stability during biopharmaceutical downstream processes, and
`
`developing stability analysis methods to optimise the process and maintain proper
`
`protein formulation.
`
`3.
`
`From 2004-2006, I was principal investigator on a project funded by
`
`the Department of Trade and Industry in conjunction with the Health Protection
`
`Agency, UK, to establish protein, process, and formulation engineering methods for
`
`novel protein fusions. During that time, I was an active member of the Protein
`
`Society, the Royal Society of Chemistry, the RSC Biotechnology Group Committee,
`
`the Institution of Chemical Engineers, and the American Chemical Society. I
`
`organized conferences on behalf of these organizations including the 2006
`
`“Therapeutic Proteins: Chemical & Enzymatic Modification” in London. Based on
`
`my work with the previous organizations, I was invited to a joint BIA & Bioprocess
`
`UK workshop in 2005. The workshop led to the establishment of biopharmaceutical
`
`formulation as a funding priority in the DTI technology transfer program.
`
`4.
`
`In 2006, I began a long-term collaboration with the National Institute
`
`of Biological Standards and Controls in the UK to improve the tools and techniques
`
`used in liquid and freeze-dried protein formulation development. The projects
`
`undertaken used biophysical analysis and statistical design of experiments
`
`9
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`MPI EXHIBIT 1007 PAGE 9
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0009
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`

`

`
`
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`approaches, to optimise formulations, and to characterise and understand the impact
`
`
`
`of different excipients on their properties.
`
`5.
`
`In 2007, I was appointed Senior Lecturer at UCL and in 2009 I was
`
`appointed Reader at UCL in the Department of Biochemical Engineering. From
`
`2011 until 2016, I was Co-Director of the Engineering and Physical Sciences
`
`Research Council (EPSRC) Centre for Innovative Manufacturing at UCL.
`
`6.
`
`I am currently Co-Director of the EPSRC Future Targeted Healthcare
`
`Manufacturing Hub and Director of the EPSRC Doctoral Training Centre for
`
`Innovative Manufacturing at UCL. In 2013, I was appointed Professor at UCL,
`
`Department of Biochemical Engineering, and in 2016 was named Deputy Head,
`
`Department of Biochemical Engineering (Research) at UCL. Over the course of my
`
`career at UCL, I have supervised numerous projects resulting in novel research and
`
`development in the field of protein stability. These projects resulted in developing a
`
`novel method for measuring protein stability in microtiter plates; development of
`
`enhanced bioprocessing for advanced pharmaceutical proteins, using directed
`
`evolution; and new methods of protein engineering and formulation resulting in
`
`improved biopharmaceutical stability. The various projects are listed in my CV. I
`
`have presented the results of my research on protein therapeutics and formulation at
`
`numerous international conferences including the Protein Science Forum 2005, the
`
`Cambridge Healthtech Institute 2006, ACHEMA 2006, BioProcess International
`
`10
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`MPI EXHIBIT 1007 PAGE 10
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0010
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`
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`2007, 2011 & 2012, Recovery XIV 2010, World Biopharm Forum 2011, and the
`
`
`
`Royal Society of Chemistry MiBIO 2012.
`
`7.
`
`I am considered a key influencer of research priorities in the UK in the
`
`area of biopharmaceutical formulation. I have been appointed to lead government
`
`and industry groups for establishment of biopharmaceutical formulation protocols. I
`
`have provided consultancy services to a number of companies, including:
`
`Ajinomoto, Angel Biotechnology, Cambridge Antibody Technology (now
`
`MedImmune and owned by AstraZeneca), and Clear Capital Ltd. I also serve on the
`
`Scientific Advisory Board for Leukocare GmbH in Germany, and UMabs in the
`
`USA and China, and have presented my work at international conferences on
`
`biopharmaceutical formulation development.
`
`8.
`
`I have been given numerous research grants to research and supervise
`
`projects impacting the biochemical protein industry. My research interests include:
`
`accelerating therapeutic protein and vaccine formulation design for stability in both
`
`liquid and lyophilized forms; biophysical characterisation of protein aggregation and
`
`stability in formulations and bioprocess manufacturing; protein engineering for
`
`stability; using directed evolution, structural analysis, bioinformatics and
`
`computational design, high-throughput bioprocess design, including precipitation
`
`and inclusion body refolding; design and development of novel analytical methods
`
`for bioprocess monitoring and characterisation of formulations.
`
`11
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`MPI EXHIBIT 1007 PAGE 11
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0011
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`9.
`
`In the previous four years, I have provided testimony in the following
`
`
`
`proceedings:
`
`• Celltrion, Inc. v. Genentech, Inc. et al., IPR2022-00578 (PTAB);
`• XOMA (US) LLC v. MorphoSys AG, Case No. 01-21-0004-4508
`(ICDR, Nov. 2022);
`• Novo Nordisk Inc. v. Mylan Institutional LLC, C.A. No. 1:19-cv-01551-
`KAJ-SRF (D. Del.); and
`
`• Merck & Co Inc. v. Wyeth, NSD1381/2017 (Australia).
`10. My qualifications are further described on my curriculum vitae, found
`
`at Exhibit 1008.
`
`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. Mylan retained me as a technical expert to provide various opinions
`
`about the ’462 patent. I am being compensated at a rate of 360 GBP 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.
`
`12
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`MPI EXHIBIT 1007 PAGE 12
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0012
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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 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.
`
`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).
`
`16. These references would have motivated a POSA to formulate a 1.0 mg
`
`semaglutide injectable formulation containing the components recited in claims 4–
`
`13
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`MPI EXHIBIT 1007 PAGE 13
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0013
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`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
`
`principles in forming my opinions. My understanding of those principles is
`
`summarized below.
`
`
`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.
`
`14
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`MPI EXHIBIT 1007 PAGE 14
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0014
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`19.
`
`I have been informed that Mylan 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.
`
`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
`
`15
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`MPI EXHIBIT 1007 PAGE 15
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0015
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`
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`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
`In my opinion, the following definition of a person of ordinary skill in
`24.
`
`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
`
`16
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`MPI EXHIBIT 1007 PAGE 16
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1007-0016
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`
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`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
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`pharmacy, chemical engineering, bioengineering, chemistry, or related discipline;
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`(2) at least two years of experience in protein or peptide therapeutic development
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`and/or manufacturing or diabetes treatments; and (3) experience with the
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`development, design, manufacture, formulation, or administration of therapeutic
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`agents, and the literature concerning protein or peptide formulation and design, or
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`diabetes treatments.
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`27. Alternatively, a POSA would be (1) a highly-skilled scientist lacking
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`an M.D., Pharm.D., or Ph.D., but would have (2) more than five years of experience
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`in the area of protein or peptide therapeutic development and/or manufacturing or
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`diabetes treatments; and/or (3) experience with the development, design,
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`manufacture, or formulation of therapeutic agents, and the literature concerning
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`protein or peptide formulation and design or diabetes treatments. In either case, a
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`higher educational level could substitute for some amount of the requisite
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`experience.
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`28. As explained above, and as is evident from my CV, I met the
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`qualifications of a POSA as of the priority date of the ’462 patent.
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`V. THE ’462 PATENT (EX. 1001)
`I have read the ’462 patent, which is titled “Use of Long-Acting GLP-
`29.
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`1 Peptides,” including its claims, and reviewed relevant portions of the file history
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`of the ’462 patent (Ex. 1002).
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`30.
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`I have assumed that the earliest priority date to which the asserted
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`claims of the ’462 patent are entitled is July 1, 2012, which is the date recited on the
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`face of the patent for foreign reference EP12174535, listed under “Foreign
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`Application Priority Data.” To the extent Patent Owner later asserts and/or proves
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`that the asserted claims are entitled to an earlier priority or invention date, I reserve
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`the right to supplement this declaration.
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`A. The Formulation Claims of the ’462 Patent
`31. The ’462 patent has one independent claim, which recites:
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`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.
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`32. Dependent claims 4–10 depend from claim 1, directly or indirectly, and
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`are provided below.
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`33. Dependent claim 4 recites:
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`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.
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`34. Dependent claim 5 recites:
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`5. The method according to claim 4, wherein the solution
`further comprises propylene glycol and phenol.
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`35. Dependent claim 6 recites:
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`6. The method according to claim 4, wherein the pH is 7.4.
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`36. Dependent claim 7 recites:
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`7. The method according to claim 6, wherein the solution
`further comprises propylene glycol and phenol.
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`37. Dependent claim 8 recites:
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`8. The method according to claim 4, wherein the
`phosphate buffer is a sodium dihydrogen phosphate
`buffer.
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`38. Dependent claim 9 recites:
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`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.
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`39. Dependent claim 10 recites:
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`10. The method according to claim 9, wherein the pH is
`7.4.
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`B. The Prosecution History of the ’462 Patent
`40. When the application for the ’462 patent was filed on July 21, 2017,
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`independent claim 1 recited:
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`1. A method for
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`a) reduction of HbA1c;
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`b) treatment of type 2 diabetes, hyperglycemia, impaired
`glucose tolerance, or non-insulin dependent diabetes; or
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`c) treatment of obesity, reducing body weight and/or food
`intake, or inducing satiety;
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`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;
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`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
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`iii) is administered once weekly or less often.
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`Ex. 1002 at 8.
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`41. The Examiner rejected the filed claims on July 23, 2018, based on
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`NCT00696657, which disclosed the use of semaglutide and liraglutide, Madsbad
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`(2011), which disclosed the use of several GLP-1 agonists, and Kim (2007), which
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`disclosed the use of exenatide, anticipated the claims because they each disclosed a
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`method of treatment with at least 0.8 mg of GLP-1 agonist once weekly (NCT657
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`with 0.8 mg semaglutide; Madsbad with 4, 15, and 30 mg albiglutide; and Kim with
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`0.8 and 2.0 mg exenatide), with all the other requirements satisfied (treating type 2
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`diabetes and reducing HbA1c, with a half-life in the required range, etc.). See Ex.
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`1002 (July 23, 2018 Office Action) at 312.
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`42. The applicants then amended claim 1 to recite:
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`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
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`a) reduction of HbA1c;
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`b) treatment of type 2 diabetes, hyperglycemia, impaired
`glucose tolerance, or non-insulin dependent diabetes; or
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`c) treatment of obesity, reducing body weight and/or food
`intake, or inducing satiety;
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`wherein said method comprises administration of a GLP-
`1 agonist to a subject in need thereof,
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`wherein said GLP-1 agonist
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`i) has a half-life of at least 72 hours;
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`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
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`iii) is administered once weekly or less often.
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`See Ex. 1002 (January 23, 2019 listing of claims) at 332.
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`43. The applicants also filed a terminal disclaimer over U.S. Patent No.
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`9,764,003, which claims “[a] method for reducing body weight, comprising
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`administering [only] semaglutide once weekly in an amount of at least 0.7 mg and
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`up to 1.6 mg to a subject in need thereof.” See Ex. 1002 (February 28, 2019 Terminal
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`disclaimer) at 336.
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`44. The Examiner then withdrew the anticipation rejections and allowed
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`the claims, stating:
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`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
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`to type 2 diabetic patients already taking metformin.
`Efficacy of treatment was further assessed by a reduction
`in HbA1c levels. Patient