UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________
`
`APOTEX INC.,
`Petitioner
`
`v.
`
`NOVO NORDISK A/S,
`PATENT OWNER
`_____________________
`
`CASE IPR2024-00631
`U.S. PATENT NO. 10,335,462
`ISSUED: JULY 2, 2019
`
`TITLE:
`USE OF LONG-ACTING GLP-1 PEPTIDES
`
`DECLARATION OF MARK J. RATAIN, M.D.
`
`March 1, 2024
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0001
`
`

`

`
`
`TABLE OF CONTENTS
`
`Page
`TABLE OF CONTENTS ........................................................................................ i 
`TABLE OF ABBREVIATIONS ............................................................................. v 
`I. 
`QUALIFICATIONS AND BACKGROUND .............................................. 1 
`II. 
`LEGAL STANDARDS .................................................................................. 7 
`III.  PERSON OF ORDINARY SKILL IN THE ART ...................................... 9 
`IV.  BRIEF SUMMARY OF OPINIONS ......................................................... 10 
`V. 
`THE ’462 PATENT [Ex.1001] .................................................................... 12 
`A. 
`THE SPECIFICATION AND CLAIMS OF THE ’462 PATENT ........................ 12 
`B. 
`THE PROSECUTION HISTORY OF THE ’462 PATENT ............................... 14 
`VI.  CLAIM CONSTRUCTION ........................................................................ 16 
`VII.  BACKGROUND .......................................................................................... 18 
`A. 
`PHARMACOKINETICS AND PHARMACODYNAMICS ................................. 18 
`B. 
`DRUG DEVELOPMENT - CLINICAL TRIAL DESIGN ................................. 21 
`C. 
`PHARMACOKINETICS AND PHARMACODYNAMICS RELATED TO
`GLP-1 AND SEMAGLUTIDE ................................................................... 28 
`1. 
`GLP-1 ........................................................................................ 28 
`2. 
`GLP-1 derivatives ..................................................................... 29 
`a. 
`Liraglutide ....................................................................... 32 
`b. 
`Semaglutide .................................................................... 36 
`SEMAGLUTIDE CLINICAL TRIALS .......................................................... 37 
`D. 
`VIII.  SCOPE AND CONTENT OF THE PRIOR ART .................................... 40 
`A.  WO421 [EX.1011] ............................................................................... 42 
`B. 
`LOVSHIN [Ex.1012] .............................................................................. 43 
`C.  WO537 [Ex.1015] ............................................................................... 45 
`D. 
`SEMAGLUTIDE CLINICAL TRIALS .......................................................... 47 
`1. 
`NCT657 [Ex.1013] ................................................................... 47 
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0002
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`2. 
`NCT773 [Ex.1014] ................................................................... 49 
`Public Availability of ClinicalTrials.gov .................................. 51 
`3. 
`KNUDSEN 2004 [Ex.1032] .................................................................. 57 
`E. 
`LUND [Ex.1035] ................................................................................... 58 
`F. 
`SEINO [Ex.1038] .................................................................................. 61 
`G. 
`H.  VICTOZA LABEL [Ex.1039] .................................................................. 63 
`I. 
`SHARGEL [Ex.1045] ............................................................................. 65 
`J. 
`TAMIMI [EX.1047] ............................................................................... 66 
`K. 
`FDA EXPOSURE RESPONSE 2003 [EX.1048] ........................................ 68 
`L. 
`ICH 1994 [Ex.1049] ............................................................................ 70 
`M.  KNUDSEN 2010B [EX.1066] ................................................................ 72 
`N.  ADDITIONAL PRIOR ART AND REFERENCES ........................................... 73 
`IX.  UNPATENTABILITY OF THE ’462 PATENT ....................................... 73 
`A.  GROUND 1: WO421 ANTICIPATED CLAIMS 1-3 OF THE ’462
`PATENT ................................................................................................. 73 
`1. 
`Teachings of WO421 ................................................................ 73 
`2.  WO421 anticipated claim 1 ...................................................... 73 
`3.  WO421 anticipated claim 2 ...................................................... 79 
`4.  WO421 anticipated claim 3 ...................................................... 79 
`GROUND 2: LOVSHIN ANTICIPATED CLAIMS 1-3 OF THE ’462
`PATENT ................................................................................................. 80 
`1. 
`Teachings of Lovshin ................................................................ 80 
`2. 
`Lovshin anticipated claim 1 ...................................................... 80 
`3. 
`Lovshin anticipated claim 2 ...................................................... 83 
`4. 
`Lovshin anticipated claim 3 ...................................................... 84 
`GROUND 3: CLAIMS 1-10 OF THE ’462 PATENT WOULD HAVE
`BEEN OBVIOUS OVER WO421 ............................................................. 84 
`1. 
`Claim 1 would have been obvious over WO ’421 .................... 84 
`a. 
`Teachings of WO421 ...................................................... 85 
`
`C. 
`
`B. 
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0003
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`b. 
`
`2. 
`3. 
`4. 
`
`2. 
`
`3. 
`
`Skilled artisans would have been motivated to
`pursue, with a reasonable expectation of success,
`the treatment of type 2 diabetes with a once
`weekly 1.0 mg dose of semaglutide ............................... 85 
`Claim 2 would have been obvious over WO ’421 .................... 93 
`Claim 3 would have been obvious over WO ’421 .................... 93 
`Claims 4-10 would have been obvious over WO ’421
`considering the ’424 publication ............................................... 94 
`D.  GROUND 4: CLAIMS 1-10 OF THE ’462 PATENT WOULD HAVE
`BEEN OBVIOUS OVER WO537 CONSIDERING LOVSHIN ....................... 94 
`1. 
`Claim 1 would have been obvious over WO537
`considering Lovshin .................................................................. 95 
`a. 
`Teachings of WO537 and Lovshin ................................. 95 
`b. 
`Skilled artisans would have been motivated to
`pursue, with a reasonable expectation of success,
`the treatment of type 2 diabetes with a once
`weekly 1.0 mg dose of semaglutide ............................... 95 
`Claim 2 would have been obvious over WO537
`considering Lovshin ................................................................103 
`Claim 3 would have been obvious over WO537
`considering Lovshin ................................................................104 
`Claims 4-10 would have been obvious over WO537
`considering Lovshin ................................................................105 
`GROUND 5: CLAIMS 1-10 OF THE ’462 PATENT WOULD HAVE
`BEEN OBVIOUS OVER NCT657 AND NCT773 ...................................105 
`1. 
`Claim 1 would have been obvious over NCT657 and
`NCT773 ...................................................................................105 
`a. 
`Teachings of NCT657 and NCT773 .............................106 
`b. 
`Skilled artisans would have been motivated to
`pursue, with a reasonable expectation of success,
`the treatment of type 2 diabetes with a once
`weekly 1.0 mg dose of semaglutide .............................106 
`
`4. 
`
`E. 
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0004
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`F. 
`
`
`
`2. 
`
`3. 
`
`4. 
`
`Claim 2 would have been obvious over NCT657 and
`NCT773 ...................................................................................113 
`Claim 3 would have been obvious over NCT657 and
`NCT773 ...................................................................................114 
`Claims 4-10 would have been obvious over NCT657,
`NCT773, and the ’424 publication .........................................115 
`NO SECONDARY CONSIDERATIONS OVERCOME PRIMA FACIE
`OBVIOUSNESS OF THE CLAIMED ALLEGED INVENTIONS .....................115 
`1. 
`No unexpected results .............................................................115 
`2. 
`No long-felt, unmet need or skepticism ..................................116 
`X.  CONCLUSION ..........................................................................................116 
`
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0005
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`TABLE OF ABBREVIATIONS
`
`Full Name of Cited Reference
`U.S. Patent App. Pub. No. 2011/0166321
`U.S. Patent App. Pub. No. US2007/0010424
`U.S. Patent No. 10,335,462
`U.S. Patent App. Pub. No. 2004/0102486
`U.S. Patent No. 5,512,549
`Bell, Hamster Preproglucagon Contains the Sequence of
`Glucagon and Two Related Peptides, 302 NATURE 716
`(1983)
`Blonde, Comparison of Liraglutide Versus Other Incretin-
`Related Anti-Hyperglycaemic Agents, 14 (suppl. 2)
`DIABETES, OBESITY & METABOLISM 20 (2012)
`Drab, Incretin-Based Therapies for Type 2 Diabetes
`Mellitus: Current Status and Future Prospects, 30
`PHARMACOTHERAPY 609 (2010)
`FDA Guidance for Industry, Exposure-Response
`Relationships - Study Design, Data, Analysis, and
`Regulatory Applications (Apr. 2003)
`Garber, Efficacy of Metformin in Type II Diabetes: Results
`of a Double-Blind, Placebo-Controlled, Dose-Response
`Trial, 102 AM. J. MED. 491 (1997)
`Holst, Truncated Glucagon-like Peptide I, an Insulin-
`Releasing Hormone from the Distal Gut, 211 (2) FEBS
`LETTERS 169 (1987)
`International Conference on Harmonisation; Dose-
`Response Information to Support Drug Registration;
`Guideline; Availability, 59 Fed. Reg. 55972 (Nov. 9, 1994)
`Kirillova, Results and Outcome Reporting in
`ClinicalTrials.gov, What Makes it Happen?, 7(6) PLOS
`ONE 1 (2012)
`
`Abbreviation
`’321 publication
`’424 publication
`’462 patent
`’486 publication
`’549 patent
`Bell
`
`Blonde
`
`Drab
`
`FDA Exposure Response
`2003
`
`Garber
`
`Holst
`
`ICH 1994
`
`Kirillova
`
`-v-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0006
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`

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`
`
`
`Full Name of Cited Reference
`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: The Therapeutic Promise from
`Animal Models, 64(suppl 167) INT J CLIN PRACT 4 (2010)
`Landersdorfer, Pharmacokinetic/Pharmacodynamic
`Modelling in Diabetes Mellitus, 47(7) CLIN
`PHARMACOKINET 417 (2008)
`Landersdorfer, Mechanism-Based Population
`Pharmacokinetic Modelling in Diabetes: Vildagliptin as a
`Tight Binding Inhibitor and Substrate of Dipeptidyl
`Peptidase IV, 73 Br J Clin Pharmacol 391 (2011)
`Landersdorfer, Mechanism-Based Population Modelling of
`the Effects of Vildagliptin on GLP-1, Glucose and Insulin
`in Patients with Type 2 Diabetes, 73 BR J CLIN
`PHARMACOL 373 (2011)
`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)
`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)
`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. CLIN.
`INVEST. 616 (1987)
`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.
`PHARMACOKINET PHARMACODYN 713 (2011)
`
`Abbreviation
`Knudsen 2004
`
`Knudsen 2010b
`
`Landersdorfer 2008
`
`Landersdorfer 2011a
`
`Landersdorfer 2011b
`
`Lovshin
`
`Lund
`
`Madsbad
`
`Mojsov
`
`Moller
`
`-vi-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0007
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`
`
`Full Name of Cited Reference
`Monami, Effects of Glucagon-Like Peptide-1 Receptor
`Agonists on Body Weight: A Meta-Analysis, 2012
`EXPERIMENTAL DIABETES RSCH. 1 (2012)
`Murphy, Review of the Safety and Efficacy of Exenatide
`Once Weekly for the Treatment of Type 2 Diabetes
`Mellitus, 46 ANN PHARMACOTHER 812 (2012)
`Clinical Trial No. NCT00696657
`Clinical Trial No. NCT00851773
`Rohatagi, Model-Based Development of a PPARγ Agonist,
`Rivoglitazone, to Aid Dose Selection and Optimize Clinical
`Trial Designs, 48 J. CLIN. PHARM. 1420 (2008)
`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)
`Shargel, APPLIED BIOPHARMACEUTICS &
`PHARMACOKINETICS (5th ed. 2005)
`Tamimi, Drug Development: From Concept to Marketing!,
`113 NEPHRON CLIN PRACT C125 (2009)
`Tasneem, The Database for Aggregate Analysis of
`ClinicalTrials.gov (AACT) and Subsequent Regrouping by
`Clinical Specialty, 7(3) PLOS ONE 1(2012)
`Victoza, PHYSICIANS’ DESK REFERENCE (65th ed. 2010)
`International Patent App. Pub. No. WO 2011/058193
`International Patent App. Pub. No. WO 2011/073328
`International Patent App. Pub. No. WO 2011/138421
`International Patent App. Pub. No. WO 91/11457
`International Patent App. Pub. No. WO 2006/097537
`
`Abbreviation
`Monami
`
`Murphy
`
`NCT657
`NCT773
`Rohatagi
`
`Seino
`
`Shargel
`
`Tamimi
`
`Tasneem
`
`Victoza label
`WO193
`WO328
`WO421
`WO457
`WO537
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0008
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`
`
`Full Name of Cited Reference
`Yun, Pharmacokinetic and Pharmacodynamic Modelling
`of the Effects of Glimepiride on Insulin Secretion and
`Glucose Lowering in Healthy Humans, 31 J. CLIN. PHARM.
`& THER. 469 (2006)
`Zarin, The ClinicalTrials.gov Results Database—Update
`and Key Issues, 364 NEW ENGL. J. MED. 852 (2011)
`
`Abbreviation
`Yun
`
`Zarin
`
`-viii-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0009
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`I, Mark J. Ratain, M.D., of Chicago, Illinois, declare as follows:
`
`1.
`
`I have been retained by counsel for Petitioner Apotex Inc. (“Apotex”).
`
`I understand that Apotex is submitting a petition for inter partes review (“IPR”) of
`
`U.S. Patent No. 10,335,462 (“’462 patent,” attached as Ex.1001), which is assigned
`
`to Novo Nordisk A/S. It is my understanding that Apotex is requesting that the
`
`United States Patent and Trademark Office (“USPTO”) cancel all claims of the
`
`’462 patent as unpatentable. I submit this expert declaration in support of
`
`Apotex’s IPR petition for the ’462 patent. I also understand that Mylan
`
`Pharmaceuticals Inc. has filed an IPR with respect to the ’462 patent in IPR2023-
`
`00724 (the “Mylan IPR”), which the Board has instituted. In support of the Mylan
`
`IPR, William J. Jusko, Ph.D. submitted a declaration (Ex.1005). I have reviewed
`
`and considered Dr. Jusko’s declaration. I agree with Dr. Jusko’s opinions set forth
`
`in his declaration, so I have adopted them. Accordingly, I submit this expert
`
`declaration in support of Apotex’s IPR petition for the ’462 patent.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`2.
`I graduated from Harvard University magna cum laude in 1976 with
`
`an A.B. in Biochemical Sciences. I obtained my M.D. from Yale University
`
`School of Medicine in 1980. I completed my internship and residency in internal
`
`medicine at the Johns Hopkins Hospital in Baltimore, MD from 1980-1983. I
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`-1-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0010
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`completed a fellowship in Hematology and Medical Oncology at the University of
`
`Chicago Medical Center from 1983-1986.
`
`3.
`
`I am board-certified in Internal Medicine, Medical Oncology,
`
`Hematology, and Clinical Pharmacology. I know of no other individuals in the
`
`United States with all these certifications.
`
`4.
`
`In 1986, I joined the faculty of The University of Chicago as an
`
`Instructor and was promoted to Professor in 1995. In 2002, I was appointed to an
`
`endowed chair, the Leon O. Jacobson Professor in the Department of Medicine.
`
`5.
`
`From 1992-2010, I served as Chairman of the University’s
`
`interdepartmental unit in clinical pharmacology, then known as the Committee on
`
`Clinical Pharmacology. The Committee’s main purpose is postdoctoral training in
`
`clinical pharmacology, primarily supported by a training grant from the National
`
`Institute of Health (“NIH”). In 2010, I founded a new Center for Personalized
`
`Therapeutics, and was also appointed the first Chief Hospital Pharmacologist at the
`
`University of Chicago Medical Center.
`
`6.
`
`I have also had leadership roles in the University of Chicago’s
`
`National Cancer Institute-designated Cancer Center since 1991, initially serving as
`
`Director of the Developmental Therapeutics Program. From 1999-2022, I served
`
`as the Associate Director for Clinical Sciences, with responsibility for strategic
`
`-2-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0011
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`oversight of all oncology clinical trials at the Cancer Center. I continue to advise
`
`Cancer Centers around the country on research involving oncology drugs.
`
`7.
`
`I also directed University of Chicago Medicine’s Developmental
`
`Therapeutics Clinic for more than 35 years, and which focused on developing new
`
`treatment strategies for patients with a variety of malignancies, including the use of
`
`inhibitors of drug-metabolizing enzymes to enhance oral bioavailability.
`
`8.
`
`I have extensive experience in the development of therapeutics,
`
`including small molecules, peptides, and proteins. This experience included
`
`membership on the Investigational Drug Steering Committee of the National
`
`Cancer Institute from 2005-2016, including leadership of that Committee from
`
`2005-2008 and of its Clinical Trials Design Task Force from 2012-2016.
`
`9.
`
`I have been directly involved in the design, conduct, and analysis of
`
`phase 1, 2, and 3 trials of more than 100 drugs, including small molecule, peptide,
`
`and protein drugs.
`
`10.
`
`I have also consulted extensively to the pharmaceutical industry for
`
`over 25 years, primarily in the area of the development and commercialization of
`
`oncology drugs. I have also interacted extensively with the pharmaceutical
`
`industry as an investigator.
`
`11.
`
`I have been extensively involved with the American Society of
`
`Clinical Oncology (“ASCO”) since 1990, when I was appointed Chair of ASCO’s
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`-3-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0012
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`Audit and Finance Committee. I was later elected to Secretary-Treasurer of
`
`ASCO, and served as an Officer and Director from 1994-1997. I also chaired a
`
`Subcommittee on Phase I Clinical Trials for ASCO’s Public Issues Committee in
`
`1996.
`
`12.
`
`I have also been extensively involved with the American Society of
`
`Clinical Pharmacology and Therapeutics (“ASCPT”), an international organization
`
`comprised of clinical pharmacologists from academics, industry, and government
`
`(including FDA). Among other roles, I have served as a Director from 1997-2001,
`
`and also chaired ASCPT’s Program Committee for its 2003 meeting.
`
`13.
`
`I have received numerous honors and awards, including from major
`
`societies in both oncology and clinical pharmacology. I received the 2011
`
`Translational Research Professorship from ASCO for my work in the
`
`pharmacogenomics of anticancer agents. I have also been recognized for my work
`
`in clinical pharmacology by the Pharmaceutical Research and Manufacturer’s
`
`Association of America Foundation (2015 Award in Excellence in Clinical
`
`Pharmacology), the American College of Clinical Pharmacology (2011 Honorary
`
`Fellow), ASCPT (2010 Rawls-Palmer Progress in Medicine Award), and the
`
`American Association of Pharmaceutical Scientists (2009 Research Achievement
`
`Award in Clinical Pharmacology and Translational Research).
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`-4-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0013
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`14.
`
`I was one of approximately 60 physicians across the country elected
`
`to the Association of American Physicians in 2007, and have received awards from
`
`multiple institutions for my research accomplishments in medical oncology and
`
`clinical pharmacology, including MD Anderson Cancer Center (2008 Emil J.
`
`Freireich Award for Clinical Research), the University of North Carolina (2008
`
`Institute for Pharmacogenomics and Individualized Therapy Clinical Service
`
`Award), the University of Nebraska (2011 Robert Hart Waldman, M.D. Annual
`
`Lecture), the University of Utah (2012 Special Recognition, Department of
`
`Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy), and The
`
`University of Chicago (Arthur H. Rubenstein Mentorship in Academic Medicine
`
`Award, Department of Medicine).
`
`15.
`
`I am frequently asked to speak at national and international meetings
`
`on drug development. Recent examples include FDA meetings (FDA-ASCO
`
`Virtual Workshop, May 2022; FDA OCP and ISoP Public Workshop, November
`
`2023) and in sessions (which also included an FDA speaker) at international
`
`oncology meetings focused on drug development (EORTC-NCI, AACR, October
`
`2022; ESMO, October 2023). I was also the keynote speaker at the European
`
`Cancer Drug Development Forum Dose Optimization Workshop (April 2023).
`
`Most recently, I was asked to speak at the 2024 T Cell Lymphoma Forum.
`
`-5-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0014
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`16.
`
`I have served as a research reviewer for multiple committees and
`
`working groups at the NIH, as well as for several cancer societies and state
`
`departments of health. I have served as an editor for numerous journals, including
`
`the Journal of Clinical Oncology (2001-2007; Associate Editor); Current
`
`Pharmacogenomics (2001-2004; Editor-in-Chief); Pharmacogenetics and
`
`Genomics (2005 to 2020; Co-Editor-in-Chief); and Clinical Cancer Research
`
`(1996-2002; Associate Editor).
`
`17.
`
`I have authored more than 500 articles in peer-reviewed journals,
`
`many of which concern clinical studies and/or pharmacology of drugs. Many of
`
`these articles relate to protein or peptide drugs. I am additionally a named inventor
`
`on eight issued patents, which include both diagnostic and therapeutic methods for
`
`the treatment of cancer.
`
`18.
`
`I conceived the concept, including submission of a Technology
`
`Disclosure Form to my employer’s technology transfer office, and am an
`
`investigator of a recently initiated clinical trial of liraglutide
`
`(https://classic.clinicaltrials.gov/ct2/show/NCT06171152), another GLP-1 agonist
`
`discussed infra §VII.C.2.a.
`
`19. A summary of my education, experience, publications, awards and
`
`honors, patents, publications, and presentations is provided in my CV, a copy of
`
`which is provided as Ex.1504.
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`-6-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0015
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`20. A list of the materials I considered, in addition to my experience,
`
`education, and training, to provide the opinions contained in this declaration is
`
`attached as Exhibit A hereto.
`
`21.
`
`I am being compensated for my time in connection with this IPR at
`
`my standard consulting rate, which is $950 per hour. My compensation is not
`
`dependent in any way upon the outcome of this matter.
`
`II. LEGAL STANDARDS
`22.
`In preparing and forming my opinions set forth in this declaration, I
`
`have been informed by counsel of the relevant legal principles. I applied my
`
`understanding of those principles in forming my opinions. My understanding of
`
`those principles is summarized below. In performing my analysis and reaching my
`
`opinions and conclusions, I have been informed of and have been advised to apply
`
`various legal principles relating to unpatentability, which I set forth herein. In
`
`setting forth these legal standards, it is not my intention 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 am providing.
`
`23.
`
`I understand that my opinions regarding unpatentability are presented
`
`from the viewpoint of a person of ordinary skill in the art (“POSA” or “skilled
`
`artisan”) in the field of technology of the patent as of the patent’s priority date. In
`
`this declaration, my opinions are premised on the perspective of a POSA at the
`
`-7-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0016
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`time of the earliest claimed priority date for the ’462 patent, which I have been
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`informed for this proceeding is July 1, 2012. See Ex.1001 (’462 patent) at 1. To
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`the extent Patent Owner asserts that the claims of the ’462 patent are entitled to an
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`earlier priority or invention date, I reserve the right to supplement this declaration.
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`24.
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`I have been informed that Apotex bears the burden of proving
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`unpatentability by a preponderance of the evidence. I am informed that this
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`“preponderance-of-the-evidence” standard means that the Patent Trial and Appeal
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`Board must find it more likely than not that the claims are unpatentable.
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`25.
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`I understand that for a patent claim to be unpatentable as anticipated, a
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`prior art reference must disclose each element of the claim expressly and/or
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`inherently as arranged in the claim.
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`26. Counsel has informed me that the concept of patent obviousness
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`involves four factual inquiries: (1) the scope and content of the prior art; (2) the
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`differences between the claimed invention and the prior art; (3) the level of
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`ordinary skill in the art; and (4) secondary considerations of non-obviousness.
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`27.
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`It is my understanding from counsel that when there is some
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`recognized reason to solve a problem, and there are a finite number of identified,
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`predictable and known solutions, a person of ordinary skill in the art has good
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`reason to pursue the known options within his or her technical grasp. If such an
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`approach leads to the expected success, it is likely not the product of innovation
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`-8-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0017
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`but of ordinary skill and common sense. It is my understanding that any need or
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`problem known in the field of endeavor at the time of invention or addressed by
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`the patent can provide a reason for combining prior art elements to arrive at the
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`claimed subject matter. I understand that only a reasonable expectation of success
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`is necessary to show obviousness.
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`III. PERSON OF ORDINARY SKILL IN THE ART
`28.
`In my opinion, the following definition of a person of ordinary skill in
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`the art (“POSA” or “skilled artisan”) applies to the claims of the ’462 patent.
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`29. A POSA here would have had (1) an M.D., a Pharm. D., or a
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`Ph.D. in pharmacy, chemical engineering, bioengineering, chemistry, or
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`related discipline; (2) at least two years of experience in protein or peptide
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`therapeutic development and/or manufacturing or diabetes treatments; and
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`(3) experience with the development, design, manufacture, formulation, or
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`administration of therapeutic agents, and the literature concerning protein or
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`peptide formulation and design, or diabetes treatments.
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`30. Alternatively, the POSA would be (1) a highly skilled scientist
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`lacking an M.D., Pharm. D., or Ph.D., but would have (2) more than five years of
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`experience in the area of protein or peptide therapeutic development and/or
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`manufacturing or diabetes treatments; and/or (3) experience with the development,
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`design, manufacture, formulation, or administration of therapeutic agents, and the
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`-9-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0018
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`literature concerning protein or peptide formulation and design, or diabetes
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`treatments.
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`31. A POSA would have understood the prior art references referred to
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`herein and would have the capability to draw inferences. It is understood that, to
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`the extent necessary, a POSA may collaborate with one or more other POSAs for
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`one or more aspects with which the other POSA may have expertise, experience,
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`and/or knowledge. Additionally, a POSA could have had a lower level of formal
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`education than what I describe here if the person has a higher degree of experience.
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`32. As shown by my qualifications provided in my CV and as explained
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`in this declaration, I met the qualifications of a POSA for purposes of the ’462
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`patent.
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`33.
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`I understand that Apotex’s formulation expert Dr. Hugh Smyth is
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`submitting a declaration with his opinions about why claims 4-10 of the ’462
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`patent, directed to formulation-related elements, are obvious over the prior art.
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`(Ex.1501). I defer to Dr. Smyth’s opinion on the formulation-related elements of
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`claims 4-10 of the ’462 patent.
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`IV. BRIEF SUMMARY OF OPINIONS
`34.
`In my opinion, International Patent Application Publication No. WO
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`2011/138421 (“WO421”) anticipates claims 1-3 of the ’462 patent.
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`-10-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0019
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`35.
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`In my opinion, a review article titled “Incretin-Based Therapies for
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`Type 2 Diabetes Mellitus” (“Lovshin”) authored by Julie A. Lovshin and Daniel J.
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`Drucker, which was published in May 2009, anticipates claims 1-3 of the ’462
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`patent.
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`36.
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`In my opinion, claims 1-10 of the ’462 patent would have been
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`obvious over WO421 considering U.S. Patent Application Publication No.
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`2007/0010424 A1 (“’424 Publication”) (Ex.1016). It is my understanding that Dr.
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`Smyth is offering an opinion that claims 4-10 would have been obvious over
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`WO421 considering the ’424 Publication, and I defer to his opinion for claims 4-
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`10.
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`37.
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`In my opinion, claims 1-10 of the ’462 patent would have been
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`obvious over International Patent Application Publication No. WO 2006/097537
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`A2 (“WO537”) considering Lovshin. It is my understanding that Dr. Smyth is
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`offering an opinion that claims 4-10 would have been obvious over WO537
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`considering Lovshin, and I defer to his opinion for claims 4-10.
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`38.
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`In my opinion, claims 1-10 of the ’462 patent would have been
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`obvious over Clinical Trial No. NCT00696657 (“NCT657”), Clinical Trial No.
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`NCT00851773 (“NCT773”), and the ’424 Publication. It is my understanding that
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`Dr. Smyth is offering an opinion that claims 4-10 would have been obvious over
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`-11-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0020
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`NCT657, NCT773, and the ’424 Publication, and I defer to his opinion for claims
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`4-10.
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`39. Finally, there are no apparent secondary considerations supporting
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`nonobviousness of the claims. I reserve the right to address any secondary
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`considerations put forth by Patent Owner in any later response to this declaration
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`or the petition it accompanies.
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`V. THE ’462 PATENT [Ex.1001]
`A. THE SPECIFICATION AND CLAIMS OF THE ’462 PATENT
`40.
`I have read the ’462 patent, titled “Use of Long-Acting GLP-1
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`Peptides,” and reviewed the relevant portions of the prosecution history of the ’462
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`patent (Ex.1002). The ’462 patent issued from U.S. Patent Application No.
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`15/656,042 (“’042 Application”), filed July 21, 2017, which is a continuation of
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`U.S. Application No. 14/409,493, filed as PCT/EP2013/063004, filed June 21,
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`2013, and claims priority to Provisional Application No. 61/708,162, filed October
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`1, 2012, and Provisional Application No. 61/694,837, filed August 30, 2012, and
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`European patent 12174535, filed July 1, 2012, and European patent 12186781,
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`filed October 1, 2012. Ex.1001 (’462 patent) at 1. The ’462 patent lists Christine
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`Bjoern Jensen as the sole inventor and Novo Nordisk A/S as the Assignee. Id.
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`41. The ’462 patent has one independent claim and nine dependent
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`claims.
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`-12-
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`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1503-0021
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`42.
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`Independent claim 1 recites “[a]method for treating type 2 diabetes,
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`comprising administering semaglutide once weekly in an amount of 1.0 mg to a
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`subject in need thereof.”
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`43. Claim 2 recites, “[t]he method according to claim 1, wherein the
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`semaglutide is administered by parenteral administration.”
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`44. Claim 3 recites, “[t]he method according to claim 2, wherein the
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`solution is administered by subcutaneous injection.”
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`45. Claim 4 recites, “[t]he method according to claim 1, wherein the
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`semaglutide is administered in the form of an isotonic aqueous solution compri