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. IPR2023-00723
`Patent No. 8,129,343
`
`DECLARATION OF JOHN BANTLE, M.D., IN SUPPORT OF PETITION
`FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,129,343
`
`MPI EXHIBIT 1026 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
`Summary of Opinions ....................................................................... 10
`II.
`III. Legal Standards ................................................................................ 12
`IV. Person of Ordinary Skill in the Art ...................................................... 13
`V.
`The ’343 Patent (Ex. 1001) and Its Claims ........................................... 16
`VI. Claim Construction ........................................................................... 18
`VII. Background on Diabetes and the use of GLP-1 Derivatives for the
`Treatment of Diabetes ....................................................................... 19
`A. Diabetes Generally................................................................... 19
`B. Diabetes Treatment .................................................................. 20
`C.
`The Use of GLP-1 Derivatives to Treat Diabetes.......................... 23
`D.
`Liraglutide Behaves like GLP-1 to Treat Diabetes ........................ 23
`VIII. Scope and Content of the Prior Art ...................................................... 25
`A. Bridon (Ex. 1014) .................................................................... 26
`B. Dong (Ex. 1013) ...................................................................... 29
`C. Knudsen 2001 (Ex. 1011) ......................................................... 30
`D. Knudsen 2004 (Ex. 1010) ......................................................... 34
`E. Knudsen patent (U.S. Patent No. 6,268,343) (Ex. 1012) ................ 40
`F.
`Additional Prior Art References and Knowledge .......................... 44
`Drucker (Ex. 1068) ......................................................... 44
`1.
`Gutniak (Ex. 1054).......................................................... 45
`2.
`Nauck (Ex. 1056) ............................................................ 46
`3.
`Orskov (Ex. 1052) ........................................................... 46
`4.
`U.S. Patent No. 5,512,549 (Ex. 1046) ................................ 47
`5.
`
`2
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`MPI EXHIBIT 1026 PAGE 2
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`

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`TABLE OF CONTENTS
`(continued)
`
`Page
`
`
`
`B.
`
`2.
`
`U.S. Patent No. 6,284,727 (Ex. 1053) ................................ 48
`6.
`7. WO 87/06941 (Ex. 1057) ................................................. 49
`8. WO 91/11457 (Ex. 1047) ................................................. 50
`IX. Unpatentability of Claims 3 and 6 of the ’343 Patent ............................. 51
`A. A POSA Would Have Been Motivated to Design a GLP-1
`Agonist with an Extended Half-Life ........................................... 51
`Claims 3 and 6 of the ’343 Patent under Ground 1........................ 54
`1.
`A skilled artisan would have been motivated by Knudsen
`2004, the Knudsen patent, Dong, or Bridon to arrive at
`the invention claimed in claims 3 and 6 of the ’343 patent .... 54
`A skilled artisan would have had a reasonable
`expectation of success of treating type 2 diabetes in a
`subject with an effective amount of a semaglutide-
`containing pharmaceutical composition recited in claims
`3 and 6 .......................................................................... 56
`Claims 3 and 6 of the ’343 Patent under Ground 2........................ 61
`C.
`D. Claims 3 and 6 of the ’343 Patent under Ground 3........................ 62
`E. No Secondary Considerations Overcome Prima Facie
`Obviousness ............................................................................ 65
`No unexpected results...................................................... 65
`1.
`2.
`A POSA would have known there was no long-felt, unmet
`need for a GLP-1 receptor agonist treatment, nor was
`there any skepticism in the art .......................................... 65
`X. Reservation of Rights ........................................................................ 66
`
`3
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`MPI EXHIBIT 1026 PAGE 3
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`
`
`TABLE OF ABBREVIATIONS
`
`Full Name of Cited Reference
`U.S. Patent No. 8,536,122
`U.S. Patent No. 8,129,343
`U.S. Patent No. 5,512,549
`U.S. Patent No. 6,284,727
`Baggio, Glucagon-like Peptide 1 and Glucagon-like
`Peptide 2, 18 BEST PRAC. & RSCH. CLINICAL
`ENDOCRINOLOGY & METABOLISM 531 (2004)
`Banting, The Internal Secretion of the Pancreas, 7 J. LAB.
`CLINICAL MED. 251 (1922)
`Bell, Hamster Preproglucagon Contains the Sequence of
`Glucagon and Two Related Peptides, 302 NATURE 716
`(1983)
`U.S. Patent No. 6,514,500
`Dong, Glucagon-Like Peptide-1 Analogs with Significantly
`Improved in vivo Activity, in PEPTIDES: THE WAVE OF THE
`FUTURE (Michal Lebl et al. eds., 2001)
`Drucker, Enhancing Incretin Action for the Treatment of
`Type 2 Diabetes, 26 DIABETES CARE 2929 (2003)
`Giannoukakis, CJC-1131 ConjuChem, 4(10) CURRENT OP.
`IN INVESTIGATIONAL DRUGS 1245 (2003)
`Gutniak, Antidiabetogenic Effect of Glucagon-Like Peptide-
`1 (7-36)Amide in Normal Subjects and Patients with
`Diabetes Mellitus, 326 NEW ENG. J. MED. 1316 (1992)
`HARRISON’S PRINCIPLES OF INTERNAL MED., Chapter 333
`(Braunwald et al. eds. 15th ed. 2001)
`Holst, Truncated Glucagon-like Peptide I, an Insulin-
`Releasing Hormone from the Distal Gut, 211 (2) FEBS
`LETTERS 169 (1987)
`Holst, The Incretin Approach for Diabetes Treatment:
`Modulation of Islet Hormone Release by GLP-1 Agonism,
`53 (suppl. 3) DIABETES S197 (2004)
`
`Abbreviation
`’122 patent
`’343 patent
`’549 patent
`’727 patent
`Baggio 2004b
`
`Banting
`
`Bell
`
`Bridon
`Dong
`
`Drucker 2003
`
`Giannoukakis
`
`Gutniak
`
`Harrison’s
`
`Holst
`
`Holst 2004
`
`4
`
`MPI EXHIBIT 1026 PAGE 4
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`
`
`
`TABLE OF ABBREVIATIONS
`(continued)
`
`Full Name of Cited Reference
`Holst, Glucagon-Like Peptide 1 and Inhibitors of Dipeptidyl
`Peptidase IV in the Treatment of Type 2 Diabetes Mellitus,
`4 CURRENT OP. IN PHARM. 589 (2004)
`Knudsen, GLP-1 Derivatives as Novel Compounds for the
`Treatment of Type 2 Diabetes: Selection of NN2211 for
`Clinical Development, 26(7) DRUGS OF THE FUTURE (2001)
`Knudsen, Glucagon-Like Peptide-1: The Basis of a New
`Class of Treatment for Type 2 Diabetes, 47(17) J. MED.
`CHEM. 4128 (2004)
`U.S. Patent No. 6,268,343
`Madsbad, Improved Glycemic Control with No Weight
`Increase in Patients with Type 2 Diabetes After Once-Daily
`Treatment with the Long-Acting Glucagon-Like Peptide 1
`Analog Liraglutide (NN2211): A 12-Week, Double-Blind,
`Randomized, Controlled Trial, 27 DIABETES CARE 1335
`(2004)
`Mojsov, Insulinotropin: Glucagon-like Peptide I (7-37) Co-
`encoded in the Glucagon Gene is a Potent Simulator of
`Insulin Release in the Perfused Rat Pancreas, 79 J.
`CLINICAL INVESTIGATION 616 (1987)
`Nauck, Normalization of Fasting Hyperglycaemia by
`Exogenous Glucagon-Like Peptide 1 (7-36 amide) in Type
`(Non-Insulin-Dependent) Diabetic Patients, 36
`2
`DIABETOLOGIA 741 (1993)
`Ørskov, Biological Effects and Metabolic Rates of
`Glucagonlike Peptide-1 7–36 Amide and Glucagonlike
`Peptide-1 7–37 in Healthy Subjects are Indistinguishable,
`42 DIABETES 658 (1993)
`Polonsky, What’s So Tough About Taking Insulin?
`Addressing
`the Problem of Psychological Insulin
`Resistance in Type 2 Diabetes, 22(3) CLINICAL DIABETES
`147 (2004)
`WO 91/11457
`
`5
`
`Abbreviation
`Holst 2004b
`
`Knudsen 2001
`
`Knudsen 2004
`
`Knudsen patent
`Madsbad
`
`Mojsov
`
`Nauck
`
`Orskov
`
`Polonsky
`
`WO457
`
`MPI EXHIBIT 1026 PAGE 5
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`

`

`TABLE OF ABBREVIATIONS
`(continued)
`
`Full Name of Cited Reference
`WO 87/06941
`
`Abbreviation
`WO941
`
`
`
`
`
`
`
`
`
`6
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`MPI EXHIBIT 1026 PAGE 6
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`
`
`1. My name is John P. Bantle, M.D. I have been retained by Mylan
`
`Pharmaceuticals Inc. (“Mylan”) to provide my expert opinions regarding the
`
`unpatentability of U.S. Patent No. 8,129,343 (“’343 patent”) (Ex. 1001). I
`
`understand that Mylan intends to petition for inter partes review (“IPR”) of the ’343
`
`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 claims 1-6 of the ’343 patent as unpatentable. I submit this expert declaration
`
`to address and support Mylan’s IPR petition for the ’343 patent.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`A. Education and Experience; Prior Testimony
`I am a medical endocrinologist and Professor Emeritus of Medicine in
`2.
`
`the Division of Endocrinology and Diabetes, Department of Medicine, at the
`
`University of Minnesota. I have substantial experience in clinical research, treatment
`
`of patients, and academic publications in the field of the treatment of diabetes and
`
`related conditions.
`
`3.
`
`I earned a Bachelor of Science degree in 1970 from the University of
`
`Minnesota and a Doctor of Medicine degree in 1972 from the University of
`
`Minnesota Medical School. I completed an internship at Cleveland Metropolitan
`
`General Hospital in 1973; residencies in internal medicine at the Mayo Clinic in
`
`Rochester, Minnesota, and Dunedin Public Hospital in Dunedin, New Zealand, in
`
`7
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`MPI EXHIBIT 1026 PAGE 7
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`1975 and 1976, respectively; and a fellowship in endocrinology and metabolism at
`
`
`
`the University of Minnesota in 1978. I was a long-time medical practitioner in
`
`Minnesota, and earned board certifications from the American Board of Internal
`
`Medicine and in Endocrinology and Metabolism.
`
`4.
`
`For nearly 40 years, I was an instructor, assistant professor, associate
`
`professor, and then full professor, in the Department of Medicine of the University
`
`of Minnesota Medical School. Since 2017, I have held the position of Professor
`
`Emeritus at the medical school. I also held significant administrative and research
`
`positions: I was the Associate Director of the General Clinical Research Center at
`
`the University of Minnesota Medical School from 1983-2009, the Medical Staff
`
`Clinical Service Chief for Internal Medicine at Fairview-University Medical Center
`
`from 2001-2007, and the Clinical Research Implementation Services Leader of the
`
`Clinical and Translational Science Institute at the University of Minnesota from
`
`2011-2013. Finally, I was the Interim Director and then the full Director of the
`
`Division of Endocrinology and Diabetes in the Department of Medicine at the
`
`University of Minnesota Medical School from 2008 to 2015.
`
`5.
`
`I participated in numerous clinical trials, both as principal investigator
`
`and co-investigator, and remained current on treatment methods for patients with
`
`diabetes, including developing nutritional recommendations for people with diabetes
`
`and developing the national standards of care for diabetes patients.
`
`8
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`MPI EXHIBIT 1026 PAGE 8
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`6.
`
`I have authored approximately 120 publications and book chapters, and
`
`
`
`made numerous presentations on the topic of diabetes at national and international
`
`medical meetings.
`
`7.
`
`I have received numerous honors and awards for my teaching, clinical
`
`excellence, and treatment of patients. For example, I was selected by my peers to be
`
`named by the Best Doctors Organization as one of the Best Doctors in America for
`
`twenty-two consecutive years from 1996-2017; I was named a Top Doctor by
`
`Minneapolis/St. Paul Magazine in 1992, 1994, 1996, 1999-2002, 2004, and 2006-
`
`2017; and I received the University of Minnesota Department of Medicine Clinical
`
`Excellence Award in 2002, 2004, and 2011.
`
`8.
`
`In the previous four years, I have provided testimony in the following
`
`proceedings:
`
`• Boehringer Ingelheim Pharms. Inc. v. Mankind Pharma Ltd.,
`No. 18-cv-01689 (D. Del.);
`• BTG Int’l, Ltd. v Amneal Pharms. LLC, Amerigen Pharms., Inc., Teva
`Pharms. USA, Inc., Nos. 15-cv-5909, 16-cv-2449 and 17-cv-6435
`(D.N.J.);
`
`• Janssen, Inc., Janssen Oncology, Inc. and BTG Int’l LTD v. Dr.
`Reddy’s Labs. Ltd., Dr. Reddy’s Labs., Inc. and Pharmascience, Inc, T-
`978-19 (Ottawa, Ontario); and
`• Novo Nordisk Inc. v. Mylan Institutional LLC,
`No. 19-cv-01551 (D. Del.).
`
`9
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`
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`9. My qualifications are further described on my curriculum vitae,
`
`
`
`attached as Exhibit 1027.
`
`B. Basis for Opinions and Materials Considered
`10. 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
`11. Mylan retained me as a technical expert to provide various opinions
`
`about the ’343 patent. I am being compensated at a rate of $400 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.
`
`II.
`
`SUMMARY OF OPINIONS
`12. My opinions are limited to the treatment of diabetes with semaglutide,
`
`as claimed in the ’343 patent. I present my opinions from the perspective of a POSA
`
`who is a medical doctor.
`
`13.
`
`I understand that Mylan’s experts Drs. Peter Flatt, Christopher Soares,
`
`and Paul Dalby are offering opinions that semaglutide falls within the scope of the
`
`GLP-1(7-37) derivative claimed in claims 1-6 of the ’343 patent, and that
`
`semaglutide and its formulations would have been obvious to a POSA in view of the
`
`10
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`prior art. Specifically, I understand that there are three obviousness grounds
`
`
`
`presented:
`
`(1) these claims would have been obvious over Knudsen 2004 in view of the
`
`Knudsen patent, Dong, and Bridon (“Ground 1”);
`
`(2) these claims would have been obvious over Knudsen 2001 in view of the
`
`Knudsen patent, Dong, and Bridon (“Ground 2”); and
`
`(3) these claims would have been obvious in view of common drug
`
`development principles (“Ground 3”).
`
`14. My opinions are limited to the treatment of diabetes with a GLP-1
`
`derivative-containing pharmaceutical composition claimed in the ’343 patent. My
`
`opinions are from the perspective of a medical doctor who would collaborate with
`
`other experts.
`
`15. First, with respect to motivation as it relates to the development of the
`
`semaglutide peptide, I offer the opinion that a POSA would have been motivated to
`
`make a longer-acting GLP-1 peptide.
`
`16. Second, it is my opinion that the dependent “method of treatment”
`
`limitations contained in claims 3 and 6 of the ’343 patent would have been obvious
`
`on the same grounds that render claims 1, 2, 4, and 5 unpatentable.
`
`17. These references, in view of the state of the art, would have motivated
`
`a skilled artisan to treat type 2 diabetes in a subject who has diabetes, such as a
`
`11
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`human patient having diabetes, by administering to that patient an effective amount
`
`
`
`of a semaglutide-containing pharmaceutical composition, with a reasonable
`
`expectation of success when doing so.
`
`III. LEGAL STANDARDS
`18. To prepare and form my opinions set forth in this declaration, I have
`
`been informed of the relevant legal principles. I applied my understanding of those
`
`principles in forming my opinions. My understanding of those principles is
`
`summarized below.1 I took these principles into account when forming my opinions
`
`in this case.
`
`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
`
`the Board must find it 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.
`
`
`1 As support for 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
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`21.
`
`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.
`
`22.
`
`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
`I understand my analysis is to be conducted from the perspective of a
`23.
`
`POSA as of the priority date of the ’343 patent. 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
`
`13
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`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).
`
`24.
`
`In my opinion, the following definition of a POSA applies to claims 1–
`
`6 of the ’343 patent. The subject matter of the claims of the ’343 patent falls within
`
`the medicinal chemical and pharmacological arts and encompasses the skills,
`
`education, and expertise of a team of individuals working together to develop and
`
`formulate GLP-1 analogues, as well as to use the GLP-1 analogues to treat patients
`
`having type-2 diabetes or related conditions. Such a team would have included
`
`individuals with an M.D., Pharm.D., or doctoral degree(s) in chemistry,
`
`biochemistry, pharmaceutics, pharmaceutical sciences, chemical engineering,
`
`biochemical engineering or related fields, with at least two years of experience
`
`developing therapeutic peptides or proteins, and experience with the development,
`
`design, manufacture, formulation, or administration of therapeutic peptides or
`
`proteins, and the literature concerning protein or peptide formulation and design or
`
`diabetes treatments.
`
`25. Alternatively, the skilled artisan would be (1) a highly skilled scientist
`
`lacking an M.D., Pharm.D., or doctoral degree, but would have (2) (a) more than
`
`five years of experience in the area of developing therapeutic proteins or peptides
`
`and/or (b) experience with the development, design, manufacture, formulation, or
`
`administration of therapeutic agents for diabetes, and the literature concerning
`
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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.
`
`26. Such a team also would have included persons with an appropriate level
`
`of skill in medicinal synthetic chemistry, including the synthesis and chemical
`
`modification of peptides or proteins.
`
`27. With respect to the subject matter of claims 3 and 6 of the ’343 patent,
`
`the team would have included an individual with an M.D. and experience treating
`
`patients having type 2 diabetes or related conditions.
`
`28. With respect to claims 2 and 5 of the ’343 patent, the team would have
`
`included an individual with a Ph.D. in chemistry, biochemistry, pharmaceutics,
`
`pharmaceutical sciences, chemical engineering, biochemical engineering, or related
`
`fields, with at least two years of experience in the formulation of therapeutic peptides
`
`or proteins.
`
`29. A skilled artisan would have understood the prior art references referred
`
`to herein and would have the capability to draw inferences. It is understood that, to
`
`the extent necessary, a skilled artisan may collaborate with one or more other skilled
`
`artisans for one or more aspects with which the other skilled artisan may have
`
`expertise, experience, and/or knowledge. Additionally, a skilled artisan could have
`
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`had a lower level of formal education than what I describe here if the person has a
`
`
`
`higher degree of experience.
`
`30. As explained in this declaration and exemplified by the information
`
`provided in my CV, I met the qualifications of a skilled artisan for purposes of claims
`
`3 and 6 as of the priority date of the ’343 patent.
`
`V. THE ’343 PATENT (EX. 1001) AND ITS CLAIMS
`I have read the ’343 patent, which is titled “Acylated GLP-1
`31.
`
`compounds,” including its claims, and relevant portions of the file histories of the
`
`’343 and ’122 patents (Exs. 1004 and 1003, respectively).
`
`32.
`
`I have assumed that the earliest priority date to which the claims of the
`
`’343 patent are entitled is March 18, 2005, which is the date recited on the face of
`
`the patent for foreign reference EP05102171, listed under “Foreign Application
`
`Priority Data.” Therefore, references that pre-date March 18, 2005, are prior art. To
`
`the extent Patent Owner later asserts and/or proves that the claims are entitled to an
`
`earlier priority or invention date, I reserve the right to supplement this declaration.
`
`33. The ’343 patent has six claims, each of which is independent.2
`
`34. Claim 1 of the ’343 patent recites:
`
`1. A compound of the structure
`
`
`2 Claims 1–3 were the subject of a certificate of correction, reflected here.
`
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`where the amino acid sequence is that of SEQ ID NO: 7.
`
`35. Claim 2 of the ’343 patent recites:
`
`2. A pharmaceutical composition comprising a compound
`of the structure
`
`
`
`where the amino acid sequence is that of SEQ ID NO: 7,
`and a pharmaceutically acceptable excipient.
`
`36. Claim 3 of the ’343 patent recites:
`
`3. A method for treating type 2 diabetes in a subject, said
`method comprising administering to a subject in need of
`such treatment an effective amount of a pharmaceutical
`composition comprising a compound of the structure
`
`where the amino acid sequence is that of SEQ ID NO: 7,
`and a pharmaceutically acceptable excipient.
`
`
`
`37. Claim 4 of the ’343 patent recites:
`
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`4. A compound having the following name N-ε26-[2-(2-[2-
`(2-[2-(2-[4-(17-Carboxyheptadecanoylamino)-4(S)-
`carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy
`]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)peptide.
`
`38. Claim 5 of the ’343 patent recites:
`
`5. A pharmaceutical composition comprising a compound
`having the following name N-ε26-[2-(2-[2-(2-[2-(2-[4-(17-
`Carboxyheptadecanoylamino)-4(S)-
`carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy
`]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)peptide and a
`pharmaceutically acceptable excipient.
`
`39. Claim 6 of the ’343 patent recites:
`
`6. A method for treating type 2 diabetes in a subject, said
`method comprising administering to a subject in need of
`such treatment an effective amount of a pharmaceutical
`composition comprising a compound having the following
`N-ε26-[2-(2-[2-(2-[2-(2-[4-(17-Carboxyhepta
`name
`decanoylamino)-4(S)-carboxybutyrylamino]ethoxy)
`ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]
`GLP-1-(7-37)peptide and a pharmaceutically acceptable
`excipient.
`
`VI. CLAIM CONSTRUCTION
`I understand that the claims that are the subject of this Petition for inter
`40.
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`partes review are to be understood to have their plain and ordinary meaning as
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`understood by a POSA considering the patent specification and prosecution file
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`
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`history.
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`VII. BACKGROUND ON DIABETES AND THE USE OF GLP-1
`DERIVATIVES FOR THE TREATMENT OF DIABETES
`A. Diabetes Generally
`Insulin is a hormone produced and secreted by the pancreatic islets, Ex.
`41.
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`1109 (Harrison’s) at 16, which is responsible for regulating the metabolism of blood
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`sugar. Diabetes mellitus, commonly referred to as diabetes, is a metabolic disorder
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`in which the body either fails to produce enough insulin or does not respond
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`normally to insulin. Id. at 13. Thus, diabetes is characterized by elevated, and
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`sometimes abnormally and dangerously high, levels of glucose in the blood. Id. at
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`14.
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`42. There are three main types of diabetes: type 1, type 2, and gestational
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`diabetes. Ex. 1109 (Harrison’s) at 14. Type 1 diabetes, sometimes referred to as
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`insulin-dependent diabetes, refers to a condition in which insulin production by the
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`body is insufficient or absent. Id. at 6. Type 2 diabetes, sometimes referred to as non-
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`insulin dependent diabetes (or NIDDM), involves both insulin resistance, which
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`leads to an ineffective use of insulin by the body, and an inability to augment insulin
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`secretion sufficiently to overcome that resistance. Id. at 18. The result is high blood
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`glucose levels. Finally, gestational diabetes is a form of diabetes that affects pregnant
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`women, which can be caused by either insulin resistance or a lack of insulin
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`production. Id. at 14.
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`43. Diabetes is diagnosed by measuring a patient’s blood glucose levels,
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`testing glucose tolerance, and/or watching for signs and symptoms of diabetes. Id.
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`at 15. Thus, diabetes may be diagnosed if the patient has a) symptoms of diabetes
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`plus random blood glucose ≥11.1 mmol/L (200 mg/dL); or b) fasting plasma glucose
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`≥7.0 mmol/L (126 mg/dL); or c) two-hour plasma glucose ≥11.1 mmol/L (200
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`mg/dL) during an oral glucose tolerance test. Id. at 15, Table 333-2. If diabetes is
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`not treated, the metabolic dysregulation can cause pathophysiologic changes in
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`multiple organ systems, resulting in such medical problems as retinopathy, which
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`may lead to blindness, end-stage renal disease, and nontraumatic lower extremity
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`amputations; uncontrolled diabetes can also predispose a patient to cardiovascular
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`disease. Id. at 13.
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`B. Diabetes Treatment
`44. The goals when treating patients with type 1 or type 2 diabetes are to:
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`1) eliminate symptoms related to hyperglycemia (high blood glucose levels); 2)
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`reduce or eliminate long-term complications (i.e., those affecting the eyes, kidneys,
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`nervous system, and circulatory system); and 3) allow the patient a lifestyle as close
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`to normal as possible. Ex. 1109 (Harrison’s) at 31. To reach these goals, lowering
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`plasma glucose is a primary aim. Id.
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`45.
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`In 1922, Dr. Fredrick Banting and Charles Best discovered that insulin
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`
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`was secreted by the pancreas. Ex. 1048 (Banting). After isolating insulin, they found
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`that it could be effective in the treatment of diabetes. Id. Specifically, insulin is a key
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`mediator of glucose lowering and either administering exogenous insulin or
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`stimulating the body’s insulin production will lower blood glucose levels. Thus,
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`beginning in the 1920s, patients diagnosed with diabetes could be treated with
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`insulin injections. For patients with type 1 diabetes, an important goal is designing
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`and implementing an insulin treatment regimen that mimics physiologic insulin
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`secretion. Ex. 1109 (Harrison’s) at 34.
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`46.
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`In 1983, two peptides related to the hormone glucagon were found in
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`the gut, and were named glucagon-like peptide 1 (“GLP-1”) and glucagon-like
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`peptide 2 (“GLP-2”). See generally Ex. 1049 (Bell). Additional studies discovered
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`that the body naturally synthesizes truncated forms of the GLP-1 peptide, including
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`GLP-1(7-37). See, e.g., Ex. 1051 (Mojsov); Ex. 1050 (Holst 1987). GLP-1(7-37)
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`was found to have an insulinotropic (stimulating insulin secretion) effect while also
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`inhibiting the secretion of glucagon, a hormone that raises blood glucose. Ex. 1051
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`(Mojsov) at 1-3; Ex. 1050 (Holst 1987) at 4-6. A POSA therefore would have known
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`since the 1980s that GLP-1 and certain of its truncated forms (e.g., GLP-1(7-37))
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`were potential therapeutic agents for the treatment of diseases such as type 2 diabetes
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`because of their ability to stimulate insulin, inhibit glucagon, and ultimately lower
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`
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`blood glucose levels.
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`47. As of the priority date of the ’122 patent, in addition to traditional
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`lifestyle modifications like improved diet and increased exercise, there were several
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`types of glucose-lowering therapies available to treat type 2 diabetics. The avenues
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`for medical intervention typically fell into two categories: oral and parenteral,
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`though more types of oral treatment were available, and insulin was the primary
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`parenteral. Ex. 1109 (Harrison’s) at 36-38, Table 333-12. In the former category, a
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`medical practitioner would most commonly choose from among biguanides, α-
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`glucosidase inhibitors, insulin secretagogues, and thiazolidinediones. Id.
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`48. The mechanisms of action of the various oral diabetes treatments are
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`summarized below:
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`Mechanism (e.g.)
`Example
`Oral-Therapy Class
`Lower liver glucose production
`Metformin
`Biguanides
`Lower gut glucose absorption
`Acarbose
`α-glucosidase inhibitors
`Stimulate insulin secretion
`Sulfonylurea secretagogues Glyburide
`Non-sulfonylurea
`Repaglinide Stimulate insulin secretion
`secretagogues
`Pioglitazone Lower insulin resistance
`Thiazolidinediones
`Ex. 1109 (Harrison’s) at 36-38, Tables 333-12, -13.
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`49.
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`In the category of parenteral medications, a medical practitioner would
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`most commonly choose an insulin formulation, to provide greater glucose
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`utilization, id. at 37-38, but other injectables, especially those based on GLP-1, were
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`
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`also being developed.
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`C. The Use of GLP-1 Derivatives to Treat Diabetes
`50. For almost 100 years before the priority date, it was known that gut
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`hormones are responsible for insulin secretion. See generally Ex. 1048 (Banting).
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`And, researchers had long investigated hormones and other peptides derived from
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`the gastrointestinal tract to develop treatments for endocrine disorders such as
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`diabetes. Thus, the use of gut hormones for the treatment of diabetes was long
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`considered a therapeutic option.
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`51. GLP-1 derivatives (including derivatives of GLP-1(7-37)) were a
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`stronger focus of development in the early and mid-1990s, and these derivatives
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`possessed improved pharmacological properties. See, e.g., Ex. 1046 (’549 patent) at
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`Abstract, 1:9-11, 2:27-32, 3:9-11, 25-30; Ex. 1047 (WO457) at 4:24-29, 5:2-7. The
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`literature repeatedly encouraged the use of these derivatives of GLP-1(7-37) for the
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`treatment of diabetes. Ex. 1046 (’549 patent) at Abstract, 1:9-11, 3:9-11, 55-60; Ex.
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`1047 (WO457) at Abstract.
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`D. Liraglutide Behaves like GLP-1 to Treat Diabetes
`52. Liraglutide was developed as one of the first GLP-1(7-37) analogs or
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`derivatives with protracted effect (i.e., longer half-life). Ex. 1068 (Drucker) at 5; Ex.
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`1011 (Knudsen 2001) at 3-5; Ex. 1010 (Knudsen 2004) at 2; see also Ex. 1069
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`(Baggio 2004b) at 10 (“Liraglutide, is a fatty-acyl-derivatized, DPP-IV-resistant
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`
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`human GLP-1 analogue. Addition of the fatty acid group enables non-covalent
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`binding to serum albumin, thereby prolonging the circulating half-life and reducing
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`renal clearance. In humans, the half-life of liraglutide is approximately 12 hours,
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`suggesting that a once-daily dosing regimen may be all that is required
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`therapeutically.”).
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`53. Liraglutide was known in the prior art to “reduce[] fasting and
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`postprandial glycemia in dia