UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`DR. REDDY’S LABORATORIES INC. and
`DR. REDDY’S LABORATORIES LTD.,
`Petitioners,
`
`v.
`
`NOVO NORDISK A/S,
`Patent Owner
`
`U.S. Patent No. 10,335,462 to Jensen
`Issue Date: July 2, 2019
`Title: Use Of Long-Acting Glp-1 Peptides
`
`Inter Partes Review No. IPR2024-00009
`
`DECLARATION OF JOHN P. FRUEHAUF, M.D., Ph.D.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 1 of 14
`
`

`

`I.
`II.
`III.
`
`TABLE OF CONTENTS
`INTRODUCTION .......................................................................................... 1
`BACKGROUND AND QUALIFICATIONS ................................................. 2
`INFORMATION RELIED UPON AND OPINIONS REGARDING
`THE ’462 PATENT ........................................................................................ 5
`IV. CONCLUSION ............................................................................................... 6
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 2 of 14
`
`

`

`Exhibit
`1001
`1002
`1003
`1004
`1005
`1006
`1007
`1008
`1009
`1010
`1011
`1012
`
`1013
`1014
`1015
`1016
`1017
`1018
`
`1019
`
`1020
`1021
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`TABLE OF EXHIBITS
`Description
`
`U.S. Patent No. 10,335,462
`Prosecution history excerpts for U.S. Patent No. 10,335,462
`Declaration of John Bantle, MD
`CV of John Bantle, MD
`Declaration of William J. Jusko, Ph.D.
`CV of William J. Jusko, Ph.D.
`Declaration of Paul Dalby, Ph.D.
`CV of Paul Dalby, Ph.D.
`Intentionally Left Blank
`Intentionally Left Blank
`WO 2011/138421
`Lovshin, Incretin-Based Therapies for Type 2 Diabetes Mellitus, 5
`NATURE REV. ENDOCRINOLOGY 262 (2009)
`Clinical Trial No. NCT00696657
`Clinical Trial No. NCT00851773
`WO 2006/097537
`U.S. Patent Application Pub. No. US2007/0010424
`U.S. Patent No. 5,512,549
`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)
`Bydureon prescribing information (Jan. 2012)
`Byetta prescribing information (Oct. 2009)
`Drab, Incretin-Based Therapies for Type 2 Diabetes Mellitus: Current
`Status and Future Prospects, 30 PHARMACOTHERAPY 609 (2010)
`Drucker, Enhancing Incretin Action for the Treatment of Type 2
`Diabetes, 26 DIABETES CARE 2929 (2003)
`Drucker, The Incretin System: Glucagon-Like Peptide-1 Receptor
`Agonists and Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes,
`368 LANCET 1696 (2006)
`Glaesner, Engineering and Characterization of the Long-Acting
`Glucagon-Like Peptide-1 Analogue LY2189265, an Fc Fusion
`Protein, 26 DIABETES/METABOLISM RSCH. & REV. 287 (2010)
`HARRISON’S PRINCIPLES OF INTERNAL MED., Chapter 338
`(Fauci et al. eds. 17th ed. 2008)
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 3 of 14
`
`

`

`Exhibit
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`1040
`
`
`
`Description
`Holst, Truncated Glucagon-like Peptide I, an Insulin-Releasing
`Hormone from the Distal Gut, 211 (2) FEBS LETTERS 169 (1987)
`Holst, Glucagon-Like Peptide 1 and Inhibitors of Dipeptidyl
`Peptidase IV in the Treatment of Type 2 Diabetes Mellitus, 4
`CURRENT OP. IN PHARMACOLOGY 589 (2004)
`Jimenez-Solem, Dulaglutide, a Long-Acting GLP-1 Analog Fused
`with an Fc Antibody Fragment for the Potential Treatment of Type 2
`Diabetes, 12 CURRENT OP. IN MOLECULAR THERAPEUTICS
`790 (2010)
`Kim, Effects of Once-Weekly Dosing of a Long-Acting Release
`Formulation of Exenatide on Glucose Control and Body Weight in
`Subjects with Type 2 Diabetes, 30 DIABETES CARE 1487 (2007)
`Knudsen, GLP-1 Derivatives as Novel Compounds for the Treatment
`of Type 2 Diabetes: Selection of NN2211 for Clinical Development,
`26 DRUGS OF THE FUTURE 677 (2001)
`Knudsen, Glucagon-like Peptide-1: The Basis of a New Class of
`Treatment for Type 2 Diabetes, 47 J. MED. CHEMISTRY 4128
`(2004)
`Knudsen, Liraglutide, a GLP-1 Analogue to Treat Diabetes, in
`ANALOGUE-BASED DRUG DISCOVERY II (Fischer & Ganellin
`eds. 2010)
`U.S. Patent No. 6,268,343 (“Knudsen patent”)
`Lund, Emerging GLP-1 Receptor Agonists, 16 EXPERT OP. ON
`EMERGING DRUGS 607 (2011)
`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)
`Nielsen, Pharmacology of Exenatide (Synthetic Exendin-4): A
`Potential Therapeutic for Improved Glycemic Control of Type 2
`Diabetes, 117 REGUL. PEPTIDES 77 (2004)
`Seino, Dose-Dependent Improvement in Glycemia with Once-Daily
`Liraglutide without Hypoglycemia or Weight Gain: A Double- Blind,
`Randomized, Controlled Trial in Japanese Patients with Type 2
`Diabetes, 81 DIABETES RSCH. & CLINICAL PRACTICE 161
`(2008)
`Victoza, PHYSICIANS’ DESK REFERENCE (65th ed. 2010)
`Vilsbøll, Glucagon-Like Peptide-1 and Diabetes Treatment, 21 INT’L
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 4 of 14
`
`

`

`Exhibit
`
`1041
`1042
`1043
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`1054
`
`
`
`Description
`DIABETES MONITOR 1 (2009)
`WO 03/002136
`WO 91/11457
`U.S. Patent App. Pub. 2004/0102486
`Rohatagi, Model-Based Development of a PPARγ Agonist,
`Rivoglitazone, to Aid Dose Selection and Optimize Clinical Trial
`Designs, 48 J. CLINICAL PHARMACOLOGY 1420 (2008)
`Shargel, APPLIED BIOPHARMACEUTICS &
`PHARMACOKINETICS (5th ed. 2005)
`Yun, Pharmacokinetic and Pharmacodynamic Modelling of the
`Effects of Glimepiride on Insulin Secretion and Glucose Lowering in
`Healthy Humans, 31 J. CLINICAL PHARMACY &
`THERAPEUTICS 469 (2006)
`Tamimi, Drug Development: From Concept to Marketing!, 113
`NEPHRON CLINICAL PRACTICE c125 (2009)
`FDA Guidance for Industry, Exposure-Response Relationships -
`Study Design, Data, Analysis, and Regulatory Applications (Apr.
`2003)
`International Conference on Harmonisation; Dose-Response
`Information to Support Drug Registration; Guideline; Availability, 59
`Fed. Reg. 55972 (Nov. 9, 1994) (“ICH 1994”)
`Garber, Efficacy of Metformin in Type II Diabetes: Results of a
`Double-Blind, Placebo-Controlled, Dose-Response Trial, 102 AM. J.
`MED. 491 (1997)
`Landersdorfer, Pharmacokinetic/Pharmacodynamic Modelling in
`Diabetes Mellitus, 47(7) CLINICAL PHARMACOKINETICS 417
`(2008)
`Madsbad, An Overview of Once-Weekly Glucagon-Like Peptide-1
`Receptor Agonists—Available Efficacy and Safety Data and
`Perspectives for the Future, 13 DIABETES, OBESITY &
`METABOLISM 394 (2011)
`Møller, Mechanism-Based Population Modelling for Assessment of L-
`Cell Function Based on Total GLP-1 Response Following an Oral
`Glucose Tolerance Test, 38 J. PHARMACOKINETICS &
`PHARMACODYNAMICS 713 (2011)
`Landersdorfer, Mechanism-Based Population Pharmacokinetic
`Modelling in Diabetes: Vildagliptin as a Tight Binding Inhibitor and
`Substrate of Dipeptidyl Peptidase IV, 73 BRIT. J. CLINICAL
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 5 of 14
`
`

`

`Description
`PHARMACOLOGY 391 (2011) (“Landersdorfer 2011a”)
`Landersdorfer, Mechanism-Based Population Modelling of the Effects
`of Vildagliptin on GLP-1, Glucose and Insulin in Patients with Type 2
`Diabetes, 73 BRIT. J. CLINICAL PHARMACOLOGY 373 (2011)
`“(Landersdorfer 2011b”)
`U.S. Patent No. 5,118,666
`WO 2011/073328
`Blonde, Comparison of Liraglutide Versus Other Incretin-Related
`Anti-Hyperglycaemic Agents, 14 (suppl. 2) DIABETES, OBESITY &
`METABOLISM 20 (2012)
`Murphy, Review of the Safety and Efficacy of Exenatide Once Weekly
`for the Treatment of Type 2 Diabetes Mellitus, 46 ANNALS OF
`PHARMACOTHERAPY 812 (2012)
`WO 2011/058193
`U.S. Patent App. Pub. No. 2011/0166321
`Zarin, The ClinicalTrials.gov Results Database—Update and Key
`Issues, 364 NEW ENGL. J. MED. 852 (2011)
`Kirillova, Results and Outcome Reporting in ClinicalTrials.gov, What
`Makes it Happen?, 7(6) PLOS ONE 1 (2012)
`Monami, Effects of Glucagon-Like Peptide-1 Receptor Agonists on
`Body Weight: A Meta-Analysis, 2012 EXPERIMENTAL DIABETES
`RSCH. 1 (2012)
`Tasneem, The Database for Aggregate Analysis of ClinicalTrials.gov
`(AACT) and Subsequent Regrouping by Clinical Specialty, 7(3) PLOS
`ONE 1(2012)
`Knudsen, Liraglutide: The Therapeutic Promise from Animal Models,
`64(suppl 167) INT’L J. CLINICAL PRACTICE 4 (2010) (“Knudsen
`2010b”)
`U.S. Patent No. 8,536,122
`U.S. Patent No. 8,129,343
`REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY
`(Alfonso R. Gennaro ed., 20th ed. 2000)
`Boylan, Parenteral Products, in MODERN PHARMACEUTICS
`(Gilbert S. Banker et al. eds., 3d ed. 1996)
`U.S. Patent No. 6,284,727
`U.S. Patent No. 5,164,366
`U.S. Patent No. 6,458,924
`
`Exhibit
`
`1055
`
`1056
`1057
`1058
`
`1059
`
`1060
`1061
`1062
`
`1063
`
`1064
`
`1065
`
`1066
`
`1067
`1068
`1069
`
`1070
`
`1071
`1072
`1073
`
`
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 6 of 14
`
`

`

`Description
`
`WO 00/37098
`U.S. Patent No. 7,022,674
`ClinicalTrials.gov Background, CLINICALTRIALS.GOV,
`https://clinicaltrials.gov/ct2/about-site/background (last visited Mar.
`10, 2023)
`Award: ClinicalTrials.gov,
`https://ash.harvard.edu/news/clinicaltrials.gov (last visited Mar. 10,
`2023)
`U.S. Patent App. Pub. No. 2004/0102486
`NCT00167115, CLINICALTRIALS.GOV,
`https://www.clinicaltrials.gov/ct2/show/NCT00167115 (last visited
`Mar. 10, 2023)
`NCT01933490, CLINICALTRIALS.GOV,
`https://www.clinicaltrials.gov/ct2/show/NCT01933490 (last visited
`Mar. 10, 2023)
`Ozempic prescribing information (Oct. 2022)
`Scheduling Order, Novo Nordisk Inc. v. Rio Biopharmaceuticals Inc.,
`No. 22-294 (CFC) (D. Del. June 30, 2022), ECF No. 22
`Transfer Order, In re: Ozempic (Semaglutide) Patent Litigation, No.
`3038 (MDL Aug. 5, 2022)
`EMA, ICH Topic S 7 A Safety Pharmacology Studies for Human
`Pharmaceuticals (June 2001)
`ACS Publications, https://pubs.acs.org/toc/jmcmar/47/17;
`https://pubs.acs.org/doi/10.1021/jm030630m
`“Last Update Posted” definition from ClinicalTrials.gov
`https://clinicaltrials.gov/ct2/show/NCT00696657
`Prosecution history excerpts for U.S. Patent No. 9,764,003
`Declaration of Dr. Russell M. Zusman
`CV of Dr. Russell M. Zusman
`Declaration of Dr. John P. Fruehauf
`CV of Dr. John P. Fruehauf
`Declaration of Dr. Maureen M. Donovan
`CV of Dr. Maureen M. Donovan
`Mylan Pharmaceuticals Inc., v. Novo Nordisk A/S, IPR2023-00724,
`Paper 10 (PTAB Oct. 4, 2023)
`
`
`Exhibit
`1074
`1075
`1076
`
`1077
`
`1078
`1079
`
`1080
`
`1081
`1082
`
`1083
`
`1084
`
`1085
`
`1086
`
`1087
`1091
`1092
`1093
`1094
`1095
`1096
`1097
`
`
`
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 7 of 14
`
`

`

`I.
`
`INTRODUCTION
`1.
`I have been retained by the law firm Winston & Strawn LLP on
`
`behalf of Dr. Reddy’s Laboratories, Ltd. and Dr. Reddy’s Laboratories, Inc.,
`
`(hereinafter, collectively, “DRL” or “Petitioner”) to provide expert opinions
`
`concerning the administration of semaglutide for the treatment of type 2 diabetes.
`
`2.
`
`I have been asked to provide my opinions related to U.S. Patent
`
`No. 10,335,462 (“the ’462 patent”) (Ex. 1001) and the scientific and technical
`
`knowledge regarding the subject matter of the ’462 patent. I understand that
`
`Mylan Pharmaceuticals Inc. (“Mylan”) filed an inter partes review petition
`
`(“Mylan’s petition”) against claims 1-10 of the ’462 patent, and the Patent Trial
`
`and Appeal Board instituted Mylan’s petition on October 4, 2023. See Ex. 1097,
`
`Mylan Pharmaceuticals Inc., v. Novo Nordisk A/S, IPR2023-00724, Paper 10
`
`(“Mylan IPR”). I understand that DRL petitions for inter partes review of the
`
`same claims of the ’462 patent as the Mylan IPR on the same grounds, and DRL
`
`requests to join the Mylan IPR. I submit this declaration in support of DRL’s
`
`petition for inter partes review.
`
`3.
`
`My opinions in this declaration are based on the documents I cite
`
`along with my professional training, experience and knowledge that I have
`
`acquired working in the field of oncology over the past 45 years. I am being
`
`compensated for my services as an expert at my standard consulting rate of $750
`
`
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 8 of 14
`
`

`

`per hour. My compensation is in no way contingent on the substance of my
`
`opinions or the outcome of this case.
`
`II. BACKGROUND AND QUALIFICATIONS
`
`4.
`
`I am currently Professor of Clinical Medicine at the University of
`
`California, Irvine and Director of Clinical Pharmacology and Developmental
`
`Therapeutics at the University of California at Irvine’s (“UC Irvine”) Chao
`
`Family Comprehensive Cancer Center (“CFCCC”).
`
`5.
`
`I am involved in the direct oversight of multiple clinical trials at the
`
`CFCCC in the role of principal investigator. Several of the trials I have brought
`
`into our Cancer Center were phase I first-in-man studies, which means they were
`
`the first clinical study conducted in humans for a drug. Among other
`
`responsibilities, I work on the development and execution of clinical trials that
`
`incorporate translational endpoints, including phase I, II and III clinical trials. I
`
`also teach undergraduate students, graduate students, medical students, residents,
`
`and medical oncology fellows the principles of clinical trials in various courses.
`
`6.
`
`Since starting to work as a medical oncologist faculty member in
`
`the Division of Hematology/Oncology, Department of Internal Medicine in 1993,
`
`I have participated in weekly UC Irvine cancer clinics in the outpatient setting as
`
`a clinician and instructor for medical oncology fellows. I have also rotated on an
`
`
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 9 of 14
`
`

`

`annual basis as the in-patient Attending Physician overseeing the cancer patient
`
`service at the UC Irvine University Hospital. I have experience treating patients
`
`with mantle-cell lymphoma (“MCL”), among other types of cancers (including
`
`lymphomas and leukemias). I also have clinical experience using the Bruton’s
`
`Tyrosine Kinase (“BTK”) inhibitor ibrutinib (brand name: Imbruvica).
`
`7.
`
`I obtained an M.D. from Rush University in 1985 and a Ph.D. in
`
`Pharmacology from Rush University. I received my undergraduate degree in
`
`Cellular and Organismal Biology, with a minor in Chemistry, from the University
`
`of California, Santa Barbara, in 1977.
`
`8.
`
`I completed my Internal Medicine Residency at UC Irvine in 1987.
`
`I completed my Medical Oncology Fellowship in 1990 at the National Cancer
`
`Institute in Bethesda, Maryland, which was followed by a biotechnology
`
`fellowship at the same institution, which was completed in 1992.
`
`9.
`
`I am a member of the American Association for Cancer Research,
`
`the American Society of Clinical Oncology, the Breast and Melanoma
`
`Committees of SWOG (a National Cancer Institute supported organization that
`
`conducts clinical trials in adult cancers), and the Medical Oncology Association
`
`of Southern California (“MOASC”).
`
`10.
`
`I have published more than 91 peer reviewed articles, book
`
`
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 10 of 14
`
`

`

`chapters, and reviews in the field of oncology. I am an inventor on eight U.S.
`
`patents. I am also a peer reviewer for the following journal publications:
`
`Gynecologic Oncology, Breast Cancer Research and Treatment, Clinical Cancer
`
`Research, Anti-Cancer Drugs. The Cancer Journal, European Journal of Cancer,
`
`Pharmacological Research, and Cancer.
`
`11.
`
`A current copy of my curriculum vitae is included as Ex. 1094.
`
`III.
`
`INFORMATION RELIED UPON AND OPINIONS REGARDING
`THE ’462 PATENT
`
`12.
`
`In addition to my general knowledge gained as a result of my
`
`education and experience as a medical doctor and pharmaceutical scientist, I have
`
`reviewed and considered, among other things, the ’462 patent, the prosecution
`
`history of the ’462 patent, and the prior art of record discussed herein.
`
`13.
`
`I also reviewed the Institution Decision issued by the Board in
`
`IPR2023-00724 instituting inter partes review of the same challenged claims of
`
`the ’462 patent with respect to all grounds in Mylan’s petition. See Ex. 1097,
`
`IPR2023-00724, Institution Decision, Paper 10. I agree with the Board’s
`
`reasoning in its Institution Decision, which concerns the same claims of the same
`
`patent challenged here.
`
`14.
`
`I have also reviewed and considered the declaration of William
`
`J. Jusko, Ph.D. (Ex. 1005) submitted in connection with Mylan’s petition for inter
`
`
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 11 of 14
`
`

`

`partes review of the ’462 patent, including materials and exhibits cited therein.
`
`See Ex. 1005, IPR2023-00724, Mylan’s Petition, Paper 1. I agree with, and
`
`hereby adopt and incorporate by reference, a l l o f the opinions set forth in the
`
`declaration of Dr. Jusko.
`
`15.
`
`In my opinion, International Patent Application Publication No. WO
`
`2011/138421 (“WO421”) anticipates claims 1-3 of the ’462 patent.
`
`16.
`
`In my opinion, a review article titled “Incretin-Based Therapies for
`
`Type 2 Diabetes Mellitus” (“Lovshin”) authored by Julie A. Lovshin and Daniel
`
`J. Drucker, which was published in May 2009, anticipates claims 1-3 of the ’462
`
`patent.
`
`17.
`
`In my opinion, claims 1-10 of the ’462 patent would have been
`
`obvious over WO421 considering U.S. Patent Application Publication No.
`
`2007/0010424 A1 (“’424 Publication”). It is my understanding that DRL’s expert
`
`Dr. Maureen Donovan is offering an opinion that claims 4-10 would have been
`
`obvious over WO421 considering the ’424 Publication, and I defer to her opinion
`
`for claims 4-10. Ex. 1095.
`
`18.
`
`In my opinion, claims 1-10 of the ’462 patent would have been
`
`obvious over International Patent Application Publication No. WO 2006/097537
`
`A2 (“WO537”) considering Lovshin. It is my understanding that Dr. Donovan is
`
`offering an opinion that claims 4-10 would have been obvious over WO537
`
`
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 12 of 14
`
`

`

`considering Lovshin, and I defer to her opinion for claims 4-10.
`
`19.
`
`In my opinion, claims 1-10 of the ’462 patent would have been
`
`obvious over Clinical Trial No. NCT00696657 (“NCT657”), Clinical Trial No.
`
`NCT00851773 (“NCT773”), and the ’424 Publication. It is my understanding
`
`that Dr. Donovan is offering an opinion that claims 4-10 would have been obvious
`
`over NCT657, NCT773, and the ’424 Publication, and I defer to her opinion for
`
`claims 4-10.
`
`IV. CONCLUSION
`
`20. This declaration is based on my present assessment of material and
`
`information currently available to me.
`
`21.
`
`I understand that this declaration will be filed as evidence in a
`
`contested case before the Patent Trial and Appeal Board of the United States
`
`Patent and Trademark Office. I also understand that I may be subject to cross-
`
`examination concerning this declaration, and I will appear for cross-examination,
`
`if required of me, during the time allotted for cross-examination.
`
`22.
`
`I hereby declare that all statements made herein of my own
`
`knowledge are true and that all statements made herein on information and belief
`
`are believed to be true. Further, these statements were made with the knowledge
`
`that willful false statements and the like so made are punishable by fine,
`
`imprisonment, or both, under Section 1001 of Title 18 of the United States Code.
`
`
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 13 of 14
`
`

`

` Date: October @ 2023
`
`P. Fruehauf, M'D., Ph.D.
`
`DRL EXHIBIT 10XX PAGE 10
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 14 of 14
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1093, p. 14 of 14
`
`