1
`
`Reference P005
`
`MRL Clinical Study Report, Multicenter Study: A Randomized,
`Multicenter, Placebo-Controlled, 3-Period, Crossover Study to
`Assess the Glucose-Lowering Activity, Pharmacokinetics, and
`Safety and Tolerability of Single Oral Doses of MK-0431 in Pa-
`tients with Type 2 Diabetes (Protocol 005)
`
`Merck Exhibit 2106, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`2
`
`
`
`
`
`Reference P005
`Reports of Human Pharmacokinetic (PK) Studies
`
`Patient PK & Initial Tolerability Study Reports
`
`
`
`CLINICAL STUDY REPORT
`
`MK-0431
`
`A RANDOMIZED, MULTICENTER, PLACEBO-CONTROLLED,
`3-PERIOD, CROSSOVER STUDY TO ASSESS THE GLUCOSE-
`LOWERING ACTIVITY, PHARMACOKINETICS, AND SAFETY
`AND TOLERABILITY OF SINGLE ORAL DOSES OF MK-0431 IN
`PATIENTS WITH TYPE 2 DIABETES
`
`Generic Name: Generic Name
`Dosage Form: Capsules
`Indication: Type 2 Diabetes
`
`
`Sponsor Name:
`Clinical Monitor:
`
`Study Initiation Date (FPI):
`Study Completion Date (LPO):
`
`Investigator Name/Affiliation:
`
`
`GCP Compliance:
`
`
`Clinical Study Report Date:
`
`
`
`
`Protocol 005
`Phase I
`Study Design: Randomized, Placebo-
`Controlled, 3-Period Crossover Study
`
`Merck & Co., Inc.
`Gary A. Herman
`
`14-Oct-2002
`07-Jan-2003
`
`Multicenter (6)
`
`
`
`Information regarding GCP compliance can
`be found in Sections 5.6 and 6.2
`
`07-Nov-2005
`
`CSR Title Page_0431_005_P005 VERSION 2.0 APPROVED
`
`Restricted
` Confidential – Limited Access
`
`09-Nov-2005
`
`Merck Exhibit 2106, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`3
`
`CLINICAL STUDY REPORT
`
`A Randomized, Multicenter, Placebo-Controlled,
` 3-Period, Crossover Study to Assess the Glucose-Lowering
` Activity, Pharmacokinetics, and Safety and Tolerability of
` Single Oral Doses of MK-0431 in Patients with Type 2
`Diabetes (Protocol 005)
`
`TABLE OF CONTENTS
`
`Contents
`
`Application
`Starting
`Page
`
`I. SYNOPSIS
`
`II. COMPREHENSIVE STUDY SUMMARY
`
`1.
`
`Introduction
`
`2. Ethics
`
`2.1 Ethics Review Committee/Independent Ethics
`Committee/Institutional Review Board
`
`2.2 Ethical Conduct of the Study
`
`2.3 Patient Information and Informed Consent Form
`
`3.
`
`Investigators and Study Administrative Structure
`
`4. Study Hypotheses and Objectives
`
`5.
`
`Investigational Plan
`
`5.1 Overall Study Design and Plan: Description
`
`5.2 Discussion of Study Design, Including Choice of
`Control Groups
`
`5.3 Selection of Study Population
`
`5.3.1
`
`Inclusion Criteria
`
`5.3.2 Exclusion Criteria
`
`5.3.3 Discontinuation of Patients From Therapy or
`Study Observation
`
`5.4 Treatments
`
`5.4.1 Treatments Administered
`
`5.4.2
`
`Identity of Clinical Supplies
`
`17
`
`24
`
`24
`
`27
`
`27
`
`27
`
`27
`
`28
`
`28
`
`30
`
`30
`
`34
`
`35
`
`35
`
`36
`
`38
`
`39
`
`39
`
`39
`
`Merck Exhibit 2106, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`4
`
`TABLE OF CONTENTS (CONT.)
`
`Contents
`
`Application
`Starting
`Page
`
`5.4.3 Method of Assigning Patients to Treatment
`Groups
`
`5.4.4 Selection of Doses in the Study and Timing of
`Dose For Each Patients
`
`5.4.5 Study Blinding
`
`5.4.6 Prior and Concomitant Therapies
`
`5.4.7 Treatment Compliance
`
`5.5 Pharmacokinetic, Pharmacodynamic, Safety and
`Tolerability Parameters
`
`5.5.1 Measurements Assessed and Timing of
`Assessment
`
`5.5.1.1 Pharmacokinetic Parameters
`
`5.5.1.2 Pharmacodynamics
`
`5.5.1.3 Safety
`
`5.5.2 Primary Response Parameter(s)
`
`5.5.3 Drug Concentration and Pharmacodynamic
`Measurements
`
`5.5.3.1 Plasma for MK-0431 and DPP-IV Assay
`
`5.5.3.2 Plasma for Active and Total GLP-1 and
`Incretin Archive
`
`5.5.3.3 Plasma for Glucose
`
`5.5.3.4 Plasma for Glucose, Insulin and C-Peptide
`
`5.5.3.5 Plasma for Glucagon
`
`5.5.4 Analytical Measurements
`
`5.5.5 Pharmacokinetic Methods
`
`5.5.6 Pharmacokinetics/Pharmacodynamics
`
`5.6 Data Quality Assurance
`
`5.7 Statistical Methods Planned in the Protocol and
`Determination of Sample Size
`
`5.7.1 Statistical and Analytical Plans to Address Study
`Objectives
`
`41
`
`41
`
`41
`
`42
`
`42
`
`43
`
`43
`
`43
`
`43
`
`44
`
`46
`
`47
`
`47
`
`47
`
`48
`
`48
`
`48
`
`48
`
`49
`
`49
`
`51
`
`51
`
`51
`
`Merck Exhibit 2106, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`5
`
`TABLE OF CONTENTS (CONT.)
`
`Contents
`
`Application
`Starting
`Page
`
`5.7.2 Determination of Sample Size and Power to
`Address Study Hypotheses
`
`5.7.3 Statistical/Analytical Methods and Issues
`
`5.7.3.1 Adjustments for Covariates
`
`5.7.3.2
`
`Interim Analyses
`
`5.7.3.3 Multicenter Studies
`
`5.7.3.4 Multiplicity
`
`5.8 Changes in the Conduct of the Study or Planned
`Analyses
`
`6. Study Patients and Data Sets Analyzed
`
`6.1 Accounting for Patients in the Study
`
`6.2 Protocol Deviations
`
`6.3 Patients Whose Treatment Was Prematurely Unblinded
`
`6.4 Pharmacokinetic, Pharmacodynamic and Safety
`Populations Analyzed
`
`6.5 Demographic and Other Baseline Characteristics
`
`6.6 Measurements of Treatment Compliance
`
`7. Pharmacodynamic and Pharmacokinetic Evaluation Results
`
`7.1 Plasma Glucose
`
`7.1.1 Post-OGTT Incremental Glucose AUC
`
`7.1.2 Subgroup Analyses
`
`7.2 Plasma DPP-IV Activity
`
`7.3 GLP-1
`
`7.3.1 Active GLP-1
`
`7.3.2 Total GLP-1
`
`7.3.3 Ratio of Active to Total GLP-1
`
`7.4 GIP
`
`7.4.1 Active GIP
`
`53
`
`53
`
`55
`
`56
`
`56
`
`56
`
`56
`
`57
`
`57
`
`57
`
`58
`
`58
`
`59
`
`69
`
`69
`
`71
`
`73
`
`75
`
`75
`
`77
`
`77
`
`81
`
`85
`
`89
`
`89
`
`Merck Exhibit 2106, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`6
`
`TABLE OF CONTENTS (CONT.)
`
`Contents
`
`Application
`Starting
`Page
`
`7.4.2 Total GIP
`
`7.4.3 Ratio of Active to Total GIP
`
`7.5 Plasma Insulin, C-peptide, and Glucagon
`
`7.6 Pharmacokinetics
`
`7.7 Pharmacokinetic/Pharmacodynamic Relationships
`
`8. Safety Evaluation
`
`8.1 Extent of Exposure
`
`8.2 Clinical Adverse Experiences
`
`8.3 Laboratory Adverse Experiences
`
`8.4 Adverse Experiences of Special Interest
`
`8.5 Clinical Evaluation of Laboratory Safety Tests
`
`8.6 Vital Signs, ECG and Other Physical Observations
`Related to Safety
`
`9. Discussion
`
`10. Overall Pharmacodynamic, Pharmacokinetic, and Safety
`Conclusions
`
`11. Supplemental Tables, Figures, and/or Narratives
`
`93
`
`97
`
`101
`
`107
`
`112
`
`119
`
`120
`
`120
`
`126
`
`128
`
`128
`
`139
`
`155
`
`160
`
`161
`
`Merck Exhibit 2106, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`7
`
`MK-0431 Prot. No. 005
`MK-0431 Single Dose Study in Patients with Type 2 Diabetes
`
`
`
`LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
`
`Abbreviation
`
`
`
`Definition
`
`
`
`
`AN
`ANOVA
`ANCOVA
`AUC
`BMI
`BP
`BUN
`CI
`Cmax
`CSS
`CSR
`CV
`DAP
`DPP-IV
`ECG
`FPG
`GI
`GIP
`GLP-1
`GMR
`HbAIC
`hCG
`HR
`HRT
`IV
`LS means
`MED
`MRL
`mse
`NSAID
`OTC
`PD
`PK
`RBC
`SC
`SD
`SEM
`Tmax
`ULN
`WBC
`
`Allocation number
`Analysis of variance
`Analysis of covariance
`Area under the concentration-time curve
`Body mass index
`Blood pressure
`Blood urea nitrogen
`Confidence interval
`Maximum concentration
`Clinical study summary
`Clinical study report
`Coefficient of variation
`Data analysis plan
`Dipeptidyl peptidase IV
`Electrocardiogram
`Fasting plasma glucose
`Gastrointestinal
`Gastrointestinal peptide
`Glucagon-like peptide 1
`Geometric mean ratio
`hemoglobin AIC
`Human chorionic gonadotropin
`Heart rate
`Hormone replacement therapy
`Intravenous
`Least-squares means
`Minimal effective dose
`Merck Research Laboratories
`Mean square error
`Nonsteroidal anti-inflammatory drug
`Over the counter
`Pharmacodynamic(s)
`Pharmacokinetic(s)
`Red blood (cell) count
`Subcutaneous
`Standard deviation
`Standard error of the mean
`Time to aximum concentration
`Upper limit of normal
`White blood (cell) count
`
`CSR List of Abbreviations_0431_005_P005 VERSION 2.0 APPROVED
`
`Restricted
` Confidential – Limited Access
`
`09-Nov-2005
`
`Merck Exhibit 2106, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`8
`
`LIST OF TABLES
`
`Tables
`
`Application
`Starting
`Page
`
`Table 5-1
`
`Table 5-2
`
`Table 5-3
`
`Table 5-4
`
`Table 5-5
`
`Table 6-1
`
`Table 6-2
`
`Table 6-3
`
`Table 7-1
`
`Table 7-2
`
`Table 7-3
`
`Table 7-4
`
`Schedule of Clinical Observations and Laboratory
`Measurements as Stated in the Protocol MK-0431
`Protocol 005 (Periods 1 to 3)
`
`Laboratory Safety Tests as Stated in the Protocol
`MK-0431 Protocol 005
`
`Treatment Administered by Allocation Number MK-
`0431 Protocol 005
`
`Identity of Clinical Supplies
`
`Composition and Physicochemical Properties of
`Capsule Formulations of MK-0431
`
`Baseline Patient Demographic Characteristics MK-
`0431 Protocol 005
`
`Active Secondary Diagnoses by Patient MK-0431
`Protocol 005
`
`Listing of Prior and Concomitant Therapies by
`Patient MK-0431 Protocol 005
`Post-OGTT Incremental Glucose AUC0-240 min
`(mg·hr/dL) Following Administration of Single Oral
`Doses of MK-0431 or Placebo and an OGTT at 2
`Hours Postdose in Patients With Type 2 Diabetes
`Post-OGTT Incremental Glucose AUC0-120 min
`(mg·hr/dL) Following Administration of Single Oral
`Doses of MK-0431 or Placebo and an OGTT at 24
`Hours Postdose in Patients With Type 2 Diabetes
`
`Weighted Average Inhibition of Plasma DPP-IV
`Activity Through 24 Hours Postdose Following
`Administration of Single Oral Doses of MK-0431 or
`Placebo in Patients With Type 2 Diabetes (Percent
`Inhibition From Baseline)
`
`Weighted Average Active GLP-1 Levels (pM) Over
`4 Hours Following Administration of Single Oral
`Doses of MK-0431 or Placebo and an OGTT at 2
`Hours Postdose in Patients With Type 2 Diabetes
`
`31
`
`33
`
`34
`
`40
`
`40
`
`60
`
`62
`
`63
`
`74
`
`75
`
`77
`
`80
`
`Merck Exhibit 2106, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`9
`
`LIST OF TABLES (CONT.)
`
`Tables
`
`Application
`Starting
`Page
`
`Table 7-5
`
`Table 7-6
`
`Table 7-7
`
`Table 7-8
`
`Table 7-9
`
`Table 7-10
`
`Table 7-11
`
`Table 7-12
`
`Weighted Average Active GLP-1 Levels (pM) Over
`2 Hours Following Administration of Single Oral
`Doses of MK-0431 or Placebo and an OGTT at 24
`hours Postdose in Patients With Type 2 Diabetes
`
`Weighted Average Total GLP-1 Levels (pM) Over 4
`Hours Following Administration of Single Oral Doses
`of MK-0431 or Placebo and an OGTT at 2 Hours
`Postdose in Patients With Type 2 Diabetes
`
`Weighted Average Total GLP-1 Levels (pM) Over 2
`Hours Following Administration of Single Oral Doses
`of MK-0431 or Placebo and an OGTT at 24 Hours
`Postdose in Patients With Type 2 Diabetes
`
`Weighted Average Ratio of Active to Total GLP-1
`Levels Over 4 Hours Following Administration of
`Single Oral Doses of MK-0431 or Placebo and an
`OGTT at 2 Hours Postdose in Patients With Type 2
`Diabetes
`
`Weighted Average Ratio of Active to Total GLP-1
`Levels Over 2 Hours Following Administration of
`Single Oral Doses of MK-0431 or Placebo and an
`OGTT at 24 Hours Postdose in Patients With Type 2
`Diabetes
`
`Weighted Average Active GIP Levels (pmol/L) Over
`4 Hours Following Administration of Single Oral
`Doses of MK-0431 or Placebo and an OGTT at 2
`Hours Postdose in Patients With Type 2 Diabetes
`
`Weighted Average Active GIP Levels (pmol/L) Over
`2 Hours Following Administration of Single Oral
`Doses of MK-0431 or Placebo and an OGTT at 24
`Hours Postdose in Patients With Type 2 Diabetes
`
`Weighted Average Total GIP Levels (pmol/L) Over 4
`Hours Following Administration of Single Oral
`Doses of MK-0431 or Placebo an OGTT at 2 Hours
`Postdose in Patients With Type 2 Diabetes
`
`81
`
`84
`
`85
`
`88
`
`89
`
`92
`
`93
`
`96
`
`Merck Exhibit 2106, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`10
`
`LIST OF TABLES (CONT.)
`
`Tables
`
`Application
`Starting
`Page
`
`Table 7-13
`
`Table 7-14
`
`Table 7-15
`
`Table 7-16
`
`Table 7-17
`
`Table 7-18
`
`Table 7-19
`
`Table 7-20
`
`Weighted Average Total GIP Levels (pmol/L) Over 2
`Hours Following Administration of Single Oral
`Doses of MK-0431 or Placebo and an OGTT at 24
`Hours Postdose in Patients With Type 2 Diabetes
`
`Weighted Average Ratio of Active to Total GIP
`Levels Through Over 4 Hours Following
`Administration of Single Oral Doses of MK-0431 or
`Placebo and an OGTT at 2 Hours Postdose in Patients
`With Type 2 Diabetes
`
`Weighted Average Ratio of Active to Total GIP
`Levels Over 2 Hours Following Administration of
`Single Oral Doses of MK-0431 or Placebo and an
`OGTT at 24 Hours Postdose in Patients With Type 2
`Diabetes
`Post-OGTT Plasma Insulin AUC0-120 min
`(mcIU·hr/mL) Following Administration of Single
`Oral Doses of MK-0431 or Placebo and an OGTT at
`2 Hours Postdose in Patients With Type 2 Diabetes
`Post-OGTT Plasma C-Peptide AUC0-120 min
`(ng·hr/mL) Following Administration of Single Oral
`Doses of MK-0431 or Placebo and an OGTT at 2
`Hours Postdose in Patients With Type 2 Diabetes
`Post-OGTT Plasma Glucagon AUC0-120 min
`(pg·hr/mL) Following Administration of Single Oral
`Doses of MK-0431 or Placebo and an OGTT at 2
`Hours Postdose in Patients With Type 2 Diabetes
`
`Summary Statistics of MK-0431 Plasma
`Pharmacokinetic Parameters Following
`Administration of MK-0431 25 mg and 200 mg to
`Patients With Type 2 Diabetes
`
`Summary Statistics and Between-Group Comparisons
`of MK-0431 Plasma AUC0-24 hr (M·hr), Cmax (nM),
`and C24 hr (nM) Following Administration of MK-
`0431 25 mg and 200 mg to Patients With Type 2
`Diabetes and Healthy Control Subjects From Proto-
`cols 001, 002, 004, and 033
`
`97
`
`100
`
`101
`
`103
`
`105
`
`107
`
`108
`
`110
`
`Merck Exhibit 2106, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`11
`
`LIST OF TABLES (CONT.)
`
`Tables
`
`Application
`Starting
`Page
`
`Table 7-21
`
`Table 7-22
`
`Table 7-23
`
`Table 7-24
`
`Table 8-1
`
`Table 8-2
`
`Table 8-3
`
`Table 8-4
`
`Table 8-5
`
`Summary Statistics of MK-0431 Plasma Tmax
`(Hours) Following Administration of MK-0431 25
`mg and 200 mg in Patients With Type 2 Diabetic
`and Healthy Subjects From Protocols 001, 002, 004,
`and 033
`Mean Plasma MK-0431 AUC0-∞ and Apparent t½ In
`a Subset of Patients With Plasma Sampling Up To
`72 Hours Following Single Oral Doses of 25 mg or
`200 mg MK-0431 to Patients With Type 2 Diabetes
`
`Mean Pharmacodynamic and Pharmacokinetic
`Parameters for Patients With Type 2 Diabetes
`Receiving Single Oral Doses of MK-0431 or Placebo
`and Patients Completing an OGTT at Both 2 and 24
`Hours postdose (N=19)
`Fitted PK/PD Model Parameters and Predicted EC75
`Values for MK-0431 Plasma Concentration Versus
`Post-OGTT Incremental Glucose AUC0-120 min,
`Weighted Average Active GLP-1 and Weighted Aver-
`age Active GIP GMR (MK-0431/Placebo) Following
`Single Oral Doses of MK-0431 and OGTTs to Pa-
`tients With Type 2 Diabetes
`
`Summary of Clinical Adverse Experiences MK-0431
`Protocol 005
`
`MK-0431 Protocol 005 Listing of All Patients With
`Clinical Adverse Experiences
`
`MK-0431 Protocol 005 Laboratory Adverse
`Experiences
`
`Summary of Supine Blood Pressure Measurements
`(mm Hg) for AN 305 MK-0431 Protocol 005 and Drug
`Rechallenge
`Baseline Summary Statistics for QTC Interval (msec)
`for Patients With Type 2 Diabetes Receiving Single
`Oral Doses of MK-0431 or Placebo
`
`111
`
`111
`
`113
`
`119
`
`121
`
`122
`
`127
`
`140
`
`149
`
`Merck Exhibit 2106, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`12
`
`LIST OF TABLES (CONT.)
`
`Tables
`
`Application
`Starting
`Page
`
`Table 8-6
`
`Table 8-7
`
`Table 8-8
`
`Table 8-9
`
`Table 8-10
`
`Summary Statistics for QTC Interval (msec) Change
`From Predose Baseline Following Administration of
`Single Oral Doses of 25 mg, 200 mg MK-0431 or
`Placebo to Patients With Type 2 Diabetes
`
`Summary Statistics and Between Treatment
`Comparisons of QTC Interval Change From Predose
`Baseline Following Administration of Single Oral
`Doses of 25 mg, 200 mgMK-0431 or Placebo to
`Patients With Type 2 Diabetes
`
`Categorical Analysis of Change From Predose
`Baseline in QTC Interval (msec) Following Adminis-
`tration of Single Oral Doses of 25 mg or 200 mg
`MK-0431 or Placebo to Patients With Type 2 Diabe-
`tes Number (Percent) of Patients in Each Category
`Categorical Analysis of Absolute Values of QTC In-
`terval (msec) Following Administration of Single
`Oral Doses of 25 mg or 200 mg MK-0431 or Pla-
`cebo to Patients With Type 2 Diabetes Number (Per-
`cent) of Patients in Each Category
`Listing of QTC Interval Values for All Patients With
`Absolute QTC Interval ≥500 msec or QTC Interval
`Change From Baseline ≥30 msec Following Admin-
`istration of Single Oral Doses of 25 mg MK-0431,
`200 mg MK-0431 or Placebo to Patients With Type
`2 Diabetes
`
`149
`
`150
`
`151
`
`152
`
`153
`
`Merck Exhibit 2106, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`13
`
`LIST OF FIGURES
`
`Figures
`
`Application
`Starting
`Page
`
`Figure 7-1
`
`Figure 7-2
`
`Figure 7-3
`
`Figure 7-4
`
`Figure 7-5
`
`Figure 7-6
`
`Figure 7-7
`
`Figure 7-8
`
`Figure 7-9
`
`Plasma Glucose (mg/dL) Following Administration
`of Single Oral Doses of MK-0431 or Placebo and an
`OGTT at 2 Hours Postdose in Patients With Type 2
`Diabetes (Geometric Mean ± SE)
`
`Plasma Glucose (mg/dL) Following Administration
`of Single Oral Doses of MK-0431 or Placebo and an
`OGTT at 24 Hours Postdose in Patients With Type
`2 Diabetes (Geometric Mean ± SE)
`
`Plasma DPP-IV Percent Inhibition From Baseline
`Following Administration of Single Oral Doses of
`MK-0431 or Placebo in Patients With Type 2 Diabetes
`(Mean ± SE)
`
`Active GLP-1 Levels (pM) Following Administration
`of Single Oral Doses of MK-0431 or Placebo and
`an OGTT at 2 Hours Postdose in Patients With Type
`2 Diabetes (Geometric Mean ± SE)
`
`Active GLP-1 Levels (pM) Following Administration
`of Single Oral Doses of MK-0431 or Placebo and
`an OGTT in Patients With Type 2 Diabetes (Geometric
`Mean ± SE)
`
`Total GLP-1 Levels (pM) Following Administration
`of Single Oral Doses of MK-0431 or Placebo and an
`OGTT at 2 Hours Postdose in Patients With Type 2
`Diabetes (Geometric Mean ± SE)
`
`Total GLP-1 (pM) Levels Following Administration
`of Single Oral Doses of MK-0431 or Placebo and an
`OGTT at 24 hours Postdose in Patients With Type 2
`Diabetes (Geometric Mean ± SE)
`
`Ratios of Active to Total GLP-1 Levels Following
`Administration of Single Oral Doses of MK-0431 or
`Placebo and an OGTT at 2 Hours Postdose in Patients
`With Type 2 Diabetes (Geometric Mean ± SE)
`
`Ratios of Active to Total GLP-1 Levels (pM)
`Following Administration of Single Oral Doses of
`MK-0431 or Placebo and an OGTT at 24 Hours
`Postdose in Patients With Type 2 Diabetes (Geometric
`Mean ± SE)
`
`72
`
`73
`
`76
`
`78
`
`79
`
`82
`
`83
`
`86
`
`87
`
`Merck Exhibit 2106, Page 13
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`14
`
`LIST OF FIGURES (CONT.)
`
`Figures
`
`Application
`Starting
`Page
`
`Figure 7-10
`
`Figure 7-11
`
`Figure 7-12
`
`Figure 7-13
`
`Figure 7-14
`
`Figure 7-15
`
`Figure 7-16
`
`Figure 7-17
`
`Figure 7-18
`
`Active GIP Levels (pmol/L) Following Administration
`of Single Oral Doses of MK-0431 or Placebo and
`an OGTT at 2 Hours Postdose in Patients With Type
`2 Diabetes (Geometric Mean ± SE)
`
`Active GIP Levels (pmol/L) Following Administration
`of Single Oral Doses of MK-0431 or Placebo and
`an OGTT at 24 Hours Postdose in Patients With Type
`2 Diabetes (Geometric Mean ± SE)
`
`Total GIP Levels (pmol/L) Following Administration
`of Single Oral Doses of MK-0431 or Placebo and an
`OGTT at 2 Hours Postdose in Patients With Type 2
`Diabetes (Geometric Mean ± SE)
`
`Total GIP Levels (pmol/L) Following Administration
`of Single Oral Doses of MK-0431 or Placebo and an
`OGTT at 24 Hours Postdose in Patients With Type
`2 Diabetes (Geometric Mean ± SE)
`
`Ratios of Active to Total GIP Levels Following
`Administration of Single Oral Doses of MK-0431 or
`Placebo and an OGTT at 2 Hours Postdose in Patients
`With Type 2 Diabetes (Geometric Mean ± SE)
`
`Ratios of Active to Total GIP Levels Following
`Administration of Single Oral Doses of MK-0431 or
`Placebo and an OGTT at 24 Hours Postdose in
`Patients With Type 2 Diabetes (Geometric Mean ± SE)
`Plasma Insulin Levels (mcIU/mL) Following
`Administration of Single Oral Doses of MK-0431 or
`Placebo and an OGTT at 2 Hours Postdose in Patients
`With Type 2 Diabetes (Geometric Mean ± SE)
`
`Plasma C-Peptide Levels (ng/mL) Following
`Administration of Single Oral Doses of MK-0431 or
`Placebo and an OGTT at 2 Hours Postdose in Patients
`With Type 2 Diabetes (Geometric Mean ± SE)
`
`Plasma Glucagon (pg/mL) Following Administration
`of Single Oral Doses of MK-0431 or Placebo and an
`OGTT at 2 Hours Postdose in Patients With Type 2
`Diabetes (Geometric Mean ± SE)
`
`90
`
`91
`
`94
`
`95
`
`98
`
`99
`
`102
`
`104
`
`106
`
`Merck Exhibit 2106, Page 14
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`15
`
`LIST OF FIGURES (CONT.)
`
`Figures
`
`Application
`Starting
`Page
`
`Figure 7-19
`
`Figure 7-20
`
`Figure 7-21
`
`Figure 7-22
`
`Figure 7-23
`
`Figure 8-1
`
`Figure 8-2
`
`Figure 8-3
`
`Figure 8-4
`
`Figure 8-5
`
`MK-0431 Plasma Concentrations (nM) Following
`Administration of Single Oral Doses of MK-0431 or
`Placebo in Patients With Type 2 Diabetes (Mean ± SE)
`Inhibition of Plasma DPP-IV Activity Versus MK-
`0431 Plasma Concentrations Following
`Administration of Single Oral Doses of MK-0431 to
`Type 2 Diabetes Patients
`
`Individual and Mean MK-0431 Plasma Concentrations
`and Post-OGTT Incremental Glucose AUC0-120 min
`Geometric Mean Ratios (MK-0431/placebo) Follow-
`ing Single Oral Doses of MK-0431 and an OGTT in
`Patients With Type 2 Diabetes
`
`Individual and Mean MK-0431 Plasma Concentrations
`and Weighted Average Active GLP-1 Geometric
`Mean Ratios (MK-0431/Placebo) Following
`Administration of Single Oral Doses of MK-0431
`and an OGTT in Patients With Type 2 Diabetes
`
`Individual and Mean MK-0431 Plasma Concentrations
`and Active GIP Geometric Mean Ratios (MK-
`0431/Placebo) Following Single Oral Doses of MK-
`0431 and an OGTT in Patients With Type 2 Diabetes
`Leukocytes (Mean Percent Change From Baseline
`±SE) Following Single Oral Doses of MK-0431 or
`Placebo to Patients With Type 2 Diabetes
`
`Lymphocytes (Mean Percent Change From Baseline
`±SE) Following Single Oral Doses of MK-0431 or
`Placebo to Patients With Type 2 Diabetes
`
`Segmented Neutrophils (Mean Percent Change From
`Baseline ±SE) Following Single Oral Doses of MK-
`0431 or Placebo to Patients With Type 2 Diabetes
`
`Eosinophils (Mean Percent Change From Baseline
`±SE) Following Single Oral Doses of MK-0431 or
`Placebo to Patients With Type 2 Diabetes
`
`Platelets (Mean Percent Change From Baseline ±SE)
`Following Single Oral Doses of MK-0431 or
`Placebo to Patients With Type 2 Diabetes
`
`109
`
`114
`
`116
`
`117
`
`118
`
`129
`
`130
`
`131
`
`132
`
`133
`
`Merck Exhibit 2106, Page 15
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`16
`
`LIST OF FIGURES (CONT.)
`
`Figures
`
`Application
`Starting
`Page
`
`Figure 8-6
`
`Figure 8-7
`
`Figure 8-8
`
`Figure 8-9
`
`Figure 8-10
`
`Figure 8-11
`
`Figure 8-12
`
`Figure 8-13
`
`Figure 8-14
`
`Figure 8-15
`
`Figure 8-16
`
`Figure 8-17
`
`Figure 8-18
`
`ALT (Mean Percent Change From Baseline ±SE)
`Following Single Oral Doses of MK-0431 or Placebo
`to Patients With Type 2 Diabetes
`
`AST (Mean Percent Change From Baseline ±SE)
`Following Single Oral Doses of MK-0431 or Placebo
`to Patients With Type 2 Diabetes
`
`Alkaline Phosphatase (Mean Percent Change From
`Baseline ±SE) Following Single Oral Doses of MK-
`0431 or Placebo to Patients With Type 2 Diabetes
`
`Total Bilirubin (Mean Percent Change From
`Baseline ±SE)
`
`Serum Creatinine [mg/dL] (Mean Change From
`Baseline ±SE) Following Single Oral Doses of MK-
`0431 or Placebo to Patients With Type 2 Diabetes
`
`Pulse Rate Supine (beats/min) Mean Change From
`Baseline ±SE
`
`Diastolic Blood Pressure Supine (mm/Hg) Mean
`Change From Baseline ±SE
`
`Systolic Blood Pressure Supine (mm/Hg) Mean
`Change From Baseline ±SE
`
`Pulse Rate Increase From Supine to Standing
`(mm/Hg) Mean Change From Baseline ±SE
`
`Diastolic Blood Pressure Reduction From Supine to
`Standing (mm/Hg) Mean Change From Baseline ±SE
`Systolic Blood Pressure Reduction From Supine to
`Standing (mm/Hg) Mean Change From Baseline ±SE
`PR Interval (msec) [Mean Change From Baseline
`±SE] Following Single Oral Doses of MK-0431 or
`Placebo to Patients With Type 2 Diabetes
`QTC Interval (msec) [Mean Change From Predose
`Baseline ±SE] Following Administration of Single
`Oral Doses of 25 mg, 200 mg MK-0431 or Placebo
`to Patients With Type 2 Diabetes
`
`134
`
`135
`
`136
`
`137
`
`138
`
`141
`
`142
`
`143
`
`144
`
`145
`
`146
`
`147
`
`148
`
`Merck Exhibit 2106, Page 16
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`17
`
`MERCK RESEARCH
`LABORATORIES
`
`CLINICAL STUDY REPORT
`I. SYNOPSIS
`
`MK-0431
`MK-0431, Capsules
`Type 2 Diabetes
`
`
`
`
`
`
`
`I
`
`#005
`
`PROTOCOL TITLE/NO.: A Randomized, Multicenter, Placebo-Controlled, 3-Period,
`Crossover Study to Assess the Glucose-Lowering Activity, Pharmacokinetics, and
`Safety and Tolerability of Single Oral Doses of MK-0431 in Patients with Type 2
`Diabetes
`INVESTIGATOR(S)/STUDY CENTER(S): The study was conducted at 6 sites, 4 in Europe and 2 in
`the United States.
`PUBLICATION(S): Herman G.A., Zhao P.L., Dietrich B, Golor G, Schrodter A, Keymeulen B, Lasseter
`K.C, Kipnes M.S., Hilliard D, Tanen M, De Lepeleire I, Cilissen C, Stevens C, Tanaka W, Gottesdiener
`KM and Wagner JA, The DP-IV inhibitor MK-0431 enhances active GLP-1 and reduces glucose
`following an OGTT in type 2 diabetics, Diabetes 53 (Suppl. 2): A82-A82 (#353-OR0, 2004).
`PRIMARY THERAPY PERIOD: 14-Oct-2002 to 16-Mar-03. The
`CLINICAL PHASE:
`frozen file date was 3-Dec-03.
`DURATION OF TREATMENT: Each patient received each of 3 treatments which consisted of single-
`dose administration of 25-mg MK-0431, 200-mg MK-0431, and placebo capsules. Between each
`treatment period there was a minimum washout interval of 7 days. The study duration for each patient
`was approximately 7 weeks.
`OBJECTIVE(S): Primary: (1) To assess the safety and tolerability of single doses of MK-0431 in
`patients with type 2 diabetes. (2) To assess the effects of single doses of MK-0431 on postchallenge
`glucose [incremental glucose AUC] following administration of an oral glucose tolerance test (OGTT)
`in patients with type 2 diabetes. Secondary: (1) To assess the effects of single doses of MK-0431 on
`postchallenge glucose following the administration of standardized meals. (2) To obtain plasma
`pharmacokinetic data (AUC0-24 hr, Cmax, Tmax,, C24 hr, terminal half-life) following single dose
`administration of MK-0431 in patients with type 2 diabetes. (3) To assess the effects over time of single
`doses of MK-0431 on plasma dipeptidyl peptidase IV (DPP-IV) activity in patients with type 2 diabetes.
`(4) To assess the effects over time of single doses of MK-0431 on active and total GLP-1 levels
`following the administration of an OGTT (and standardized meals) in patients with type 2 diabetes and
`following an overnight fast. Exploratory: (1) To explore the effects of single doses of MK-0431 on
`plasma insulin, plasma c-peptide, and plasma glucagon levels as well as on active and total GIP levels
`in patients with type 2 diabetes. (2) To explore the relationship between baseline HbA1C (i.e., prestudy)
`and the effects of MK-0431 on the post-OGTT incremental glucose.
`STUDY DESIGN: This was a multicenter, randomized, double-blind, placebo-controlled, 3-period,
`crossover study involving patients with mild to moderate type 2 diabetes. Patients were randomized to 1
`of 6 treatment sequences wherein they received single oral doses of 25 mg MK-0431 or 200 mg
`MK-0431 or placebo, separated by at least a 7-day washout interval. Patients were fasted for 10 hours
`prior to study drug administration in each period, followed by an OGTT at 2 hours postdose. Plasma
`sampling for MK-0431 levels, plasma DPP-IV activity, active and total GLP-1, glucose, insulin,
`C-peptide and glucagon, and archive for total and active GIP was obtained. Safety and tolerability was
`assessed by repeated clinical and laboratory measurements. Patients received standard meal challenges
`at 6 and 24 hours postdose (a subset of patients received an OGTT in lieu of meal at 24 hours postdose)
`to assess pharmacodynamic effects and prespecified meals at other times. A subset of patients had
`additional sampling for plasma MK-0431 levels at 48 and 72 hours postdose in order to obtain a more
`complete single-dose plasma pharmacokinetic profile.
`
`
`
`
`
`
`
`
`
`CSR Synopsis_0431_005_P005 VERSION 2.1 APPROVED
`
`Restricted
` Confidential – Limited Access
`
`15-Nov-2005
`
`Merck Exhibit 2106, Page 17
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`18
`
`CSR Synopsis (Cont.)
`Protocol 005
`
`-2-
`
`
`
`
`
`MERCK RESEARCH
`LABORATORIES
`
`MK-0431
`MK-0431, Capsules
`Type 2 Diabetes
`
`
`
`PATIENT DISPOSITION:
`
`
`
`
`RANDOMIZED:
`
`
`
`42 (33 to 60 yrs)
`Male (age range)
`
`
`
`16 (36 to 60 yrs)
`Female (age range)
`
`
`
`57
`COMPLETED:
`
`
`
`1
`DISCONTINUED:
`Note: It was discovered following the study that 3 patients were inadvertently randomized twice,
`completing the study at 2 different study centers; the above numbers reflect only 1 enrollment for these
`patients (Section 6.2).
`
`DOSAGE/FORMULATION NOS.:
`
`Drug
`
`
`MK-0431
`Placebo MK-0431
`(5-mg image)
`MK-0431
`Placebo MK-0431
`(20-mg image)
`MK-0431
`Placebo MK-0431
`(100-mg image)
`
`Dosage
`Form
`
`Capsule
`Capsule
`
`Capsule
`Capsule
`
`Capsule
`Capsule
`
`Potency
`
`5 mg
`--
`
`Formulation No.
`
`0431DFC001E001
`P0431DFC001T001
`
`Control No.
`
`GB-B251
`GB-B251
`
`20 mg
`--
`
`0431DFC001G001
`P0431DFC001R001
`
`GB-B251
`GB-B251
`
`100 mg
`--
`
`0431DFC002D001
`P0431DFC001S001
`
`GB-B251
`GB-B251
`
`DIAGNOSIS/INCLUSION CRITERIA: Patients with mild to moderate type 2 diabetes between the
`ages of 21 and 60 years of age and treated with diet and exercise alone were enrolled in this study. All
`patients were to have a fasting plasma glucose (FPG) greater than or equal to 126 mg/dL and less than
`or equal to 250 mg/dL (after an overnight fast ≥8 hours); a HbA1C greater than or equal to 6.5% and less
`than or equal to 11.0%; and a C-peptide >0.8 ng/mL. At least half of the patients completing the study
`were to have a HbA1C greater than 7.5%.
`EVALUATION CRITERIA:
`PHARMACODYNAMICS: Plasma for DPP-IV activity, active (i.e., the intact form) and total GLP-1
`levels, archive for GIP, glucose, insulin, glucagon and C-peptide were obtained at selected time points.
`PHARMACOKINETICS: Plasma concentrations of MK-0431 were used to calculate the AUC0-24 hr,
`Cmax, C24 hr and Tmax following administration of single doses of 25 mg and 200 mg MK-0431. In a
`subset of patients with plasma sampling at 48 and 72-hr postdose, terminal half-life and AUC0-∞ were
`also computed.
`
`SAFETY: Safety and tolerability were assessed by clinical assessment of adverse experiences, physical
`examinations, vital signs measurements, 12-lead electrocardiograms, blood glucometer measurements
`(if signs and symptoms of hypoglycemia were observed), and laboratory safety tests. Adverse
`experiences were evaluated as to their intensity, seriousness, and relationship to study drug.
`
`
`
`
`
`
`
`CSR Synopsis_0431_005_P005 VERSION 2.1 APPROVED
`
`Restricted
` Confidential – Limited Access
`
`15-Nov-2005
`
`Merck Exhibit 2106, Page 18
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`0431, Reference P005
`
`19
`
`CSR Synopsis (Cont.)
`Protocol 005
`
`-3-
`
`
`
`
`
`MERCK RESEARCH
`LABORATORIES
`
`MK-0431
`MK-0431, Capsules
`Type 2 Diabetes
`
`
`
`STATISTICAL PLANNING AND ANALYSIS:
`PHARMACODYNAMICS: Post-OGTT incremental glucose AUC0-120 min and AUC0-240 min (i.e., the
`glucose excursion above the pre-OGTT baseline over a 2- or 4-hour interval following the OGTT)
`were analyzed in the log scale using an appropriate analysis of variance (ANOVA) model for a
`complete 3-period, crossover design. A step-down testing procedure was used to compare the 2 doses
`of MK-0431 versus placebo for the primary efficacy hypothesis. Back-transformed summary
`statistics, 95% CIs for the within-treatment geometric mean and for the between-treatment geometric
`mean ratio (GMR), and p-values for the MK-0431 doses versus placebo comparisons were provided.
`For doses of MK-0431 which were significantly different from placebo, the observed GMRs over
`placebo were used to assess the treatment effects of MK-0431 on postchallenge glucose excursion.
`Post-meal glucose AUC0-120 min was analyzed similarly.
`The weighted average inhibition (WAI) of plasma DPP-IV activity (through 12 hours postdose) from
`baseline was compared between MK-0431 and placebo using the above ANOVA model. A similar
`analysis for the WAI of plasma DPP-IV activity (through 24 hours postdose) from baseline as well as
`the time course of plasma DPP-IV inhibition (through 24 hours) was provided. Analyses were carried
`out in the log-percent scale and final results were reported in the percent inhibition scale. Similar
`analyses for the weighted average augmentation (WAA) of active, total and the ratio of active to total
`GLP-1 levels through 2 hours post-OGTT relative to prechallenge levels, and the average