UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`ASTRAZENECA AB,
`Patent Owner.
`
`Case IPR2015-01340
`Patent RE44,186
`
`DECLARATION OF M. JAMES LENHARD, M.D.
`
`
`
`
`
`
`
`
`
`AstraZeneca Exhibit 2057
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 40
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`

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`Table of Contents
`
`I.
`
`II.
`
`Introduction ...................................................................................................... 1
`
`Academic and Professional Qualifications ...................................................... 1
`
`III.
`
`Instructions from Counsel ............................................................................... 5
`
`IV. Background ...................................................................................................... 7
`
`A. Glucose Metabolism .............................................................................. 7
`
`B.
`
`Diabetes Mellitus ................................................................................... 8
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Pathophysiology and Symptoms ................................................. 8
`
`The Progressive Nature of Type 2 Diabetes ............................. 10
`
`Diagnosis of Type 2 Diabetes ................................................... 10
`
`Prevalence ................................................................................. 12
`
`Available Treatment Options Were Inadequate........................ 12
`
`C.
`
`DPP-4 as a Target for Treatment of Type 2 Diabetes ......................... 15
`
`1.
`
`2.
`
`The Role of DPP-4 in Glucose Metabolism ............................. 15
`
`DPP-4 Inhibition for the Treatment of Type 2
`Diabetes in the Late 1990s ........................................................ 16
`
`D.
`
`FDA-Approved DPP-4 Inhibitors ....................................................... 18
`
`1.
`
`2.
`
`3.
`
`Saxagliptin ................................................................................ 19
`
`Saxagliptin’s Demonstrated Safety and Efficacy ..................... 20
`
`Other FDA-Approved DPP-4 Inhibitors ................................... 22
`
`V.
`
`The Objective Evidence Supports the Nonobviousness of the
`Saxagliptin Patent .......................................................................................... 22
`
`A.
`
`Saxagliptin Met a Long-Felt Need for an Alternative
`Treatment for Type 2 Diabetes ............................................................ 24
`
`
`
`i
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`B.
`
`Failure of Others to Develop a Safe and Effective FDA-
`Approved DPP-4 Inhibitor .................................................................. 27
`
`C.
`
`Unexpected Properties of Saxagliptin ................................................. 32
`
`1.
`
`2.
`
`3.
`
`Saxagliptin Has a Favorable Side Effect Profile ...................... 32
`
`Saxagliptin’s Benefit of Once-Daily Dosing ............................ 33
`
`Saxagliptin’s Proven Efficacy................................................... 35
`
`VI. Compensation ................................................................................................ 36
`
`VII. Conclusion ..................................................................................................... 36
`
`
`
`
`
`ii
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`I.
`
` Introduction
`
`1.
`
`I, M. James Lenhard, M.D., have been retained by Finnegan,
`
`Henderson, Farabow, Garrett & Dunner, LLP on behalf of Patent Owner
`
`AstraZeneca AB (“Patent Owner”) as an independent expert in the field of
`
`diabetes, including type 2 diabetes. My qualifications in this field are established
`
`by my curriculum vitae. (Ex. 2058.) I am being compensated for the time I spend
`
`on this matter, but no part of my compensation depends on the outcome of this
`
`proceeding.
`
`II. Academic and Professional Qualifications
`I am currently employed at Christiana Care Health System (“CCHS”),
`2.
`
`where I am the Medical Director of the Metabolic Health Services. I am also Chief
`
`of the Section of Endocrinology and Metabolism. I have held these positions since
`
`1999 and 2000, respectively. In addition, I am the Director of the Diabetes and
`
`Metabolic Research Center and the founder of the Weight Management Program. I
`
`have been at CCHS since 1993.
`
`3.
`
`I am board certified by the American Board of Internal Medicine in
`
`Endocrinology, Diabetes and Metabolism, and my certification was most recently
`
`renewed in 2015. My main clinical office is at the Wilmington Hospital. I am a
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`senior attending physician at CCHS, which encompasses two hospitals: Christiana
`
`Hospital and Wilmington Hospital. The CCHS includes more than 1,100 inpatient
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`1
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`beds and a home health nursing service. CCHS trains over 300 residents and
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`fellows in a variety of medical specialties and trains many medical students from
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`Jefferson Medical College in Philadelphia, Pennsylvania, our affiliated institution.
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`Previously, I have been the Education Coordinator for our section, responsible for
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`the Endocrinology training of residents and fellows. Since assuming the position
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`of Chief of the Section of Endocrinology and Metabolism, our institution has been
`
`featured at least 3 times in U.S. News & World Report as one of the top fifty
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`hospital programs in the country for endocrinology and metabolism.
`
`4.
`
`I have a Bachelor of Science in Biochemistry from Cornell University
`
`in Ithaca, New York, and Doctor of Medicine degree from Albany Medical
`
`College in Albany, New York. My Internal Medicine residency training took place
`
`at the Miriam Hospital of Brown University in Providence, Rhode Island.
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`Following this, I was the Harvard Joint Longwood Fellow in Endocrinology and
`
`Metabolism. This three-year fellowship included clinical rotations through
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`Harvard University affiliated hospitals in Boston, Massachusetts, as well as post-
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`doctoral research training at the Joslin Diabetes Center.
`
`5.
`
`I have faculty appointments at Jefferson Medical College of Thomas
`
`Jefferson University and the University of Delaware. In addition, I have been
`
`elected a fellow in the American College of Clinical Endocrinology and in the
`
`American College of Physicians.
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`2
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`6.
`
`The majority of the patients I treat have diabetes, obesity, or both. In
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`addition, I frequently consult on inpatient treatments. In the most recent year, I
`
`recorded over 4,000 patient visits (inpatients and outpatients combined).
`
`7.
`
`I regularly prescribe DPP-4 inhibitors to my patients and am very
`
`familiar with their benefits and side effect profiles. I have been personally
`
`involved in a number of clinical trials evaluating the safety and efficacy of DPP-4
`
`inhibitors seeking approval from the United States Food and Drug Administration
`
`(FDA).
`
`8. My research interests include autonomic and peripheral neuropathy,
`
`gestational diabetes, obesity, and pharmacologic care of people with diabetes. I
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`have published over fifty original articles and seventy scientific abstracts in various
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`journals including Diabetes Care, The Journal of the American Medical
`
`Association, Obesity, Chest, and The Journal of Clinical Endocrinology &
`
`Metabolism. I have been a reviewer for medical journals, and as a reviewer, I
`
`provided written expert opinions on the suitability of scientific manuscripts for
`
`publication. I have authored several book chapters, including one on the effects of
`
`drugs.
`
`9.
`
`I have been a member of the American Diabetes Association (“ADA”)
`
`since 1993. At a national level, I have served on the Editorial Board of Diabetes
`
`Forecast, the Research Grant and Review Committee, and the Professional
`
`3
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`Practice Committee. At a regional level, I have been the President of our local
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`affiliate (the Delmar region) since 1995, and I have been on the Volunteer
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`Leadership Board since 1993. I am the originator and organizer of Diabetes
`
`Update, the yearly local professional education symposium sponsored by the ADA.
`
`10.
`
`I have participated in local diabetes initiatives, including the
`
`Governor’s Task Force on diabetes, which succeeded in reforming diabetes
`
`insurance coverage laws within the state of Delaware. I was the chair of the
`
`Diabetes Uniform Treatment Guideline Committee for the Medical Society of
`
`Delaware. Our Committee created uniform treatment guidelines for inpatient
`
`diabetes, outpatient diabetes, and prediabetes. They were accepted by every
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`hospital, managed care organization, and professional society within the state; we
`
`were the first state in the nation to do this. I have served on local health
`
`maintenance organization committees, institutional review boards, and quality
`
`improvement organizations. I have been a member or chair of many committees at
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`CCHS, including the Diabetes Management Group, Clinical Research Committee,
`
`Resident Education Committee, and Department of Medicine Executive
`
`Committee.
`
`4
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`III.
`
`Instructions from Counsel
`
`11.
`
`I have relied on counsel representing Patent Owner in this case for the
`
`applicable legal standards governing my analyses and opinions. The legal
`
`standards provided to me are set forth below.
`
`12.
`
`I understand that to obtain a patent, the differences between the
`
`claimed invention and the prior art must be such that the claimed invention as a
`
`whole would not have been obvious to a person skilled in the art at the time of
`
`invention.
`
`13.
`
`I understand that the analysis of whether a patent would have been
`
`obvious takes into consideration a number of inquiries, but I have been asked to
`
`opine only on various factors referred to as “objective evidence” or “real world
`
`factors” that I understand are considered in connection with an obviousness
`
`analysis. These factors may include: (1) a long-felt but unmet need for the claimed
`
`invention; (2) the failure of others in the prior art to fulfill this need; (3)
`
`unexpected or surprising results of the claimed invention; (4) skepticism as to the
`
`inventor’s chances for success; (5) industry praise for the claimed invention; and/or
`
`(6) commercial success of the claimed invention.
`
`14. Specifically, I was asked to review U.S. Patent No. RE44,186 (“the
`
`RE’186 patent”) and its claims. I understand that the RE’186 patent is a Reissue of
`
`U.S. Patent 6,395,767, filed on February 16, 2001, issued on May 28, 2002, and
`
`5
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`claiming priority to U.S. Provisional Application No. 60/188,555, filed on March
`
`10, 2000.
`
`15.
`
`I understand claims 1-2, 4, 6-22, 25-30, 32-37, and 39-42 have been
`
`challenged in this proceeding, each of which encompasses the compound
`
`saxagliptin. I understand that claims 25-30, 32-37, and 39-42 are directed to the
`
`compound saxagliptin specifically, and that claim 25 recites:
`
`A compound that is:
`
`
`
`or a pharmaceutically acceptable salt thereof.
`
`16. My consideration of the objective evidence of non-obviousness is in
`
`connection with the chemical compound saxagliptin.
`
`17.
`
`I have been told by counsel for Patent Owner to assume the “time of
`
`the invention” mentioned above is no later than February 16, 2001. I have been
`
`informed that the inventors at Bristol-Myers Squibb invented saxagliptin earlier, by
`
`at least October 2000. My opinions herein are the same regardless of which date
`
`may apply.
`
`6
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`IV. Background
`A. Glucose Metabolism
`18. The sugar “glucose” is a major source of metabolic energy in the
`
`body. (Ex. 2061 at 345.) The concentration of glucose in the blood fluctuates and
`
`depends on the rate at which glucose enters and leaves the bloodstream. For
`
`example, blood glucose levels will rise following a meal (referred to as the
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`“postprandial” or “fed” state), and the body will work to remove glucose from the
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`blood and store excess in tissues. (Id. at 347.) Between meals or following
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`exercise, blood glucose levels will fall (referred to as the “fasting” state), and the
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`body will work to deliver glucose back into the bloodstream. (Id. at 345-346.)
`
`The body’s goal is to maintain homeostasis of blood glucose levels.
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`19. Homeostasis of blood glucose levels is maintained by the action of
`
`key hormones, insulin and glucagon, among others. (Ex. 2061 at 346.) When
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`blood glucose levels rise, pancreatic beta cells secrete insulin, which stimulates
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`glucose-utilizing tissues such as muscle and adipose tissue to remove the glucose
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`from the blood and use it or store it as glycogen through a process called
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`glycogenesis. (Id.) When blood glucose levels fall, however, pancreatic alpha
`
`cells secrete glucagon, which stimulates glycogen-storing tissues to convert stored
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`glycogen back into glucose though a process called gluconeogenesis. (Id. at 346-
`
`347.) This regulatory process is illustrated in Figure 1.
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`7
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`Figure 1: Blood Glucose Regulation
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`
`
`
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`20. Glucose levels that are too high or too low can have serious, adverse
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`health consequences. “Hyperglycemia” occurs when blood glucose levels are
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`abnormally high and can result in a diabetic coma, a condition called ketoacidosis.
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`(Ex. 2062 at 5.) On the other hand, “hypoglycemia” occurs when blood glucose
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`levels are abnormally low and can result in seizures, heart palpitations, headaches,
`
`or a coma. (Id. at 4.)
`
`B. Diabetes Mellitus
`Pathophysiology and Symptoms
`1.
`21. Diabetes mellitus is a complex metabolic disease characterized by
`
`chronic high blood glucose levels (hyperglycemia) resulting from insufficient
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`8
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`insulin production, insulin use, or both. (Ex. 2062 at 9.) The hyperglycemic
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`characteristic of diabetes can result in a variety of co-morbidities, including, for
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`example, heart disease, stroke, vision loss, kidney failure, sensory loss, amputation,
`
`and premature death. (Id. at 5-7; Ex. 2063 at 281.)
`
`22. The most common types of diabetes are type 1 diabetes and type 2
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`diabetes. (Ex. 2062 at 9-10.)
`
`23. Type 1 diabetes is most commonly diagnosed in the mid-teens and
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`develops when pancreatic beta cells are destroyed by the body’s immune system.
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`(Id. at 9.) Without these pancreatic beta cells, the production and secretion of
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`insulin is limited or completely eliminated. (Id.) Patients with type 1 diabetes
`
`must have insulin delivered by injection or a pump. (Id.)
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`24.
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`In contrast, type 2 diabetes is most commonly diagnosed in adulthood
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`and develops when glucose-utilizing tissues become resistant to insulin and
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`pancreatic beta cells are incapable of secreting sufficient insulin to compensate for
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`the tissues’ resistance. (Id.) The roles of insulin resistance and insufficient insulin
`
`secretion differ among patients. (Id.) That is, some patients suffer primarily from
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`insulin resistance and only slightly from insufficient insulin secretion whereas
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`others suffer only slightly from insulin resistance and primarily from insufficient
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`insulin secretion. (Id.)
`
`9
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`The Progressive Nature of Type 2 Diabetes
`
`2.
`25. Type 2 diabetes is a progressive disease. (Ex. 2064 at 771.) Diet,
`
`exercise, and weight management can slow, but not prevent, its progression.
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`Moreover, the disease does not progress linearly; it progresses erratically. I
`
`analogize the progression of type 2 diabetes more to a boulder falling from a rocky
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`mountainside than down a smooth hillside. Like the boulder falling down the
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`rocky mountainside, the disease may progress quickly and abruptly at times, but it
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`may also reach plateaus, remaining controlled for extended periods of time, before
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`progressing again.
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`26. Even today, type 2 diabetes cannot be cured. Rather, it is managed
`
`through combinations of anti-diabetic drugs depending upon the particular needs of
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`the patient. (See e.g., Ex. 2064 at 778-779; Ex. 2062 at 4-5.) And while the
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`disease may be initially treated with one therapeutic agent, treatment will
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`eventually require the addition and/or substitution of a second (or third) agent.
`
`(Ex. 2063 at 285-286.)
`
`Diagnosis of Type 2 Diabetes
`
`3.
`27. Type 2 diabetes often times progresses for several years before
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`diagnosis. (Ex. 2064 at 774.) Diagnosis is established by documentation of
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`abnormal blood glucose levels. Abnormal blood glucose levels may be detected by
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`testing plasma glucose (“PG”) concentrations:
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`10
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`(1) after fasting (no caloric intake for at least eight hours), referred to as the
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`fasting plasma glucose test (“FPG”); or
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`(2) two hours after an oral glucose tolerance test (“OGTT”), referred to as
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`the two-hour plasma glucose test (“2-h PG”). (Ex. 2065 at S13-14.)
`
`28. Another way to detect abnormal blood glucose levels is by measuring
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`the level of glycated hemoglobin in the blood (i.e., “A1C”), referred to as the A1C
`
`test. (Id.) The A1C test measures the average of a person’s blood glucose levels
`
`over the past 3 months and does not show daily fluctuations. (Id.) The three tests
`
`and criteria for diagnosis are shown in Table 1.
`
`Table 1: Blood Test Levels for Diagnosis of Diabetes1
`
`Test
`
`FPG
`
`2-h PG
`
`A1C
`
`Criteria for Diagnosis
`
`≥ 126 mg/dL (7.0 mmol/L)
`
`≥ 200 mg/dL (11.1 mmol/L) during an OGTT
`
`≥ 6.5% (48 mmol/mol)
`
`
`
`29. An abnormal test result needs to be repeated on a separate day to
`
`confirm the diagnosis. (Id. at S14.)
`
`
`1 See id. at S14, Table 2.1.
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`11
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`Prevalence
`
`4.
`In the late 1990s, an estimated 16 million Americans had type 2
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`30.
`
`diabetes. (Ex. 2064 at 782.) Further, it was estimated that only half of the
`
`population with diabetes had been diagnosed and was actively being treated. (Id.)
`
`Moreover, type 2 diabetes was estimated to account for 95% of all diabetes. (Ex.
`
`2066 at 389.)
`
`31. The prevalence of diabetes was increasing rapidly. (Ex. 2064 at 781.)
`
`The rising prevalence was thought to be due to a number of factors, including, for
`
`example, aging, reductions in mortality, obesity, and diet. (Id. at 781-782.)
`
`32. At the time, diabetes was the leading cause of new cases of adult
`
`blindness, end stage renal disease, and non-traumatic amputations in the United
`
`States. (See e.g., Ex. 2063 at 281.)
`
`Available Treatment Options Were Inadequate
`
`5.
`In the late 1990s, the available treatment options for patients with type
`
`33.
`
`2 diabetes were the subject of serious safety concerns. (See generally Ex. 2067.)
`
`And because of the progressive nature of the disease, treatment regimens would
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`often (and eventually) consist of multiple therapeutic agents, further potentiating
`
`safety concerns and the risk of adverse events. (See Ex. 2063 at 285-286.)
`
`34. The available treatment options included compounds from five
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`different pharmacological classes, each with differing mechanisms of action,
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`adverse event profiles, and toxicities. (Ex. 2067 at 68.) These five different
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`pharmacological classes—sulfonylureas, meglitinides, biguanides, alpha-glucose
`
`inhibitors, and thiazolidinediones (“TZDs”)—can be generalized into three
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`categories based on their primary physiological action. As shown in Table 2,
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`sulfonylureas and meglitinides increase insulin secretion, biguanides and TZDs
`
`improve insulin action, and alpha-glucosidase inhibitors reduce glucose absorption.
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`(Id. at 69-73.) Moreover, each class has a particular side effect profile.
`
`
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`
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`13
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`Table 2: Available Treatment Options
`Side Effects2
`
`Compounds
`
`Class
`
`Increase Insulin Secretion
`
`Sulfonylureas
`
`Tolbutamide
`Chlorpropamide
`Tolazamide
`Acetohexamide
`Glyburide
`Glipizide
`Glimepiride
`
`Hypoglycemia
`Weight gain
`Hyponatremia
`Cholestatic jaundice
`Agranulocytosis
`Thrombocytopenia
`Anemia
`Gastrointestinal distress
`Abnormal liver function
`test results
`Headaches
`Dizziness
`Leukopenia
`
`Meglitinides
`
`Repaglinide
`Nateglinide
`
`Hypoglycemia
`Weight gain
`
`Biguanides
`
`Increase Insulin Action
`Metformin3
`
`Lactic acidosis
`
`
`2 See Ex. 2067 at 69-74; Ex. 2063 at 289, 297.
`
`3 Butformin was not available in the United States, and phenformin was withdrawn
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`from the market in the United States due to its association with lactic acidosis.
`
`(Ex. 2067 at 71.)
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`14
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`TZDs
`
`Rosiglitazone4
`Poglitazone
`
`Gastrointestinal distress
`
`Edema
`Weight gain
`Fractures
`Hepatic toxicity
`Congestive heart failure
`
`Reduce Glucose Absorption
`
`Alpha-Glucosidase
`Inhibitors
`
`Acarbose
`Miglitol
`
`Gastrointestinal distress
`Hepatic toxicity
`
`
`
`C. DPP-4 as a Target for Treatment of Type 2 Diabetes
`The Role of DPP-4 in Glucose Metabolism
`1.
`35. By the 1990s, it was known that a metabolic protein called glucagon-
`
`like peptide 1 (GLP-1) stimulates insulin secretion in response to increased blood
`
`glucose levels. In addition, GLP-1 was known to inhibit glucagon secretion,
`
`thereby resulting in lower blood glucose levels. (See generally Ex. 2069 at 159.)
`
`As a result, GLP-1 was recognized as a potential target for the treatment of type 2
`
`diabetes. (Ex. 2069 at 159.)
`
`36. DPP-4 is a complex enzyme that exists as a cell-membrane associated
`
`peptidase and in a soluble form present in the bloodstream. (Ex. 2070 at 367-368.)
`
`
`4 Troglitazone was withdrawn from the market in the United States due to its
`
`association with hepatic toxicity. (Id. at 73.)
`
`15
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`It cleaves a large number of chemokines and peptides in vitro, including GLP-1.
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`(Id. at 371, Table 1.) By at least 1998, it was known that GLP-1 is rapidly
`
`metabolized by DPP-4 to a metabolite that antagonizes the GLP-1 receptor. (Ex.
`
`2005 at 1663.) It was therefore thought that inhibiting DPP-4 might protect
`
`endogenous and exogenous GLP-1 from DPP-4-mediated metabolism, as shown in
`
`Figure 2. (Id.)
`
`
`
`
`
`Figure 2: GLP-1 Secretion and Inactivation by DPP-4
`
`2.
`
`DPP-4 Inhibition for the Treatment of Type 2
`Diabetes in the Late 1990s
`
`37. While DPP-4 inhibition had been proposed for the treatment of type 2
`
`diabetes by the late 1990s, “many questions [were] yet unanswered.” (Id. at 1664-
`
`1669.) Concerns included whether side effects would result from mechanism-
`
`based and non-mechanism-based toxicities and whether DPP-4 inhibition and
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`protection of endogenous GLP-1 levels would prove safe and effective over time.
`
`(Id.)
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`16
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`38. DPP-4 was known to be expressed throughout the body. In particular,
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`DPP-4 is identical to the cell-membrane associated protein called “CD26,” which
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`is found on activated T cells of the immune system. (Ex. 2070 at 367.) CD26 (or
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`DPP-4) is expressed extensively on epithelial cells (kidney, intestine, and bile duct)
`
`and on several types of endothelial cells, fibroblasts, and leukocyte subsets. (Id. at
`
`368.) In addition to the cell-membrane associated form, a soluble form of DPP-4
`
`is found in the bloodstream. (Id.) The potential impact of DPP-4 inhibition on
`
`immune, nerve, and endocrine networks was unknown and raised serious concerns.
`
`(See generally id.)
`
`39. There were also concerns that inhibiting DPP-4 would not effectively
`
`treat type 2 diabetes. (Ex. 2005 at 1666-67.) In particular, there were concerns
`
`that the effects of DPP-4 inhibition would show tachyphylaxis (rapidly diminishing
`
`response to successive doses of a drug, rendering it less effective) due to the
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`continued presence of elevated levels of active GLP-1. (Id.)
`
`40. By 2000, the only available clinical data for any DPP-4 inhibitor were
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`limited Phase I clinical data for two DPP-4 inhibitorsNVP-DPP728 and P32/98.
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`(Ex. 2012; Ex. 2010.) As the only compounds to reach the clinical setting, these
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`two compounds were the most clinically advanced DPP-4 inhibitors for treating
`
`type 2 diabetes at the time.
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`41. Specifically, in 2000, Rothenberg et al. reported that a single dose of
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`the DPP-4 inhibitor NVP-DPP728 in twelve healthy volunteers increased peak
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`plasma levels of active GLP-1 and also increased active GLP-1 prandial exposures.
`
`(Ex. 2012 at A39.) Also in 2000, Demuth reported that the DPP-4 inhibitor P32/98
`
`(also called “Ile-thia”) caused a significant glucose tolerance improvement in
`
`diabetic patients. (Ex. 2010 at A102.) Demuth concluded that “[w]hether insulin
`
`resistance can be reduced or islet responsiveness will improve, mediated by [DPP-
`
`4] inhibition, remains to be proven by longer term application of P32/98 in such
`
`patients.” (Id.) These Phase I clinical studies were limited to single dose
`
`administrations in acute settings and, therefore, did not resolve the long-term safety
`
`and efficacy concerns with DPP-4 inhibition.
`
`D.
`42.
`
`FDA-Approved DPP-4 Inhibitors
`
`In general, DPP-4 inhibitors are a unique class within the general
`
`space of treatments for type 2 diabetes. DPP-4 inhibitors provide treating
`
`physicians with another class of safe and effective treatment options with favorable
`
`side-effect profiles necessary to treat a large population of type 2 diabetes patients.
`
`43. To date, the FDA has approved only four DPP-4 inhibitors. They are
`
`saxagliptin, sitagliptin, linagliptin, and alogliptin.
`
`44.
`
`I understand that saxagliptin was the first invented from these four
`
`FDA-approved DPP-4 inhibitors.
`
`18
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`Saxagliptin
`
`1.
`45. Saxagliptin is an orally active DPP-4 inhibitor. It is the active
`
`pharmaceutical ingredient of two FDA-approved drugs sold under the trade name
`
`Onglyza® and,
`
`in combination with metformin, under
`
`the
`
`trade name
`
`Kombiglyze™ XR. (Ex. 2047 at 2; Ex. 2048 at 1; see also Ex. 2196 at 2; Ex. 2197
`
`at 1.)
`
`46. Onglyza® is a DPP-4 inhibitor indicated as an adjunct to diet and
`
`exercise to improve glycemic control in adults with type 2 diabetes mellitus in
`
`multiple clinical settings. (Ex. 2047 at 1; see also Ex. 2196 at 1.) Kombiglyze™
`
`XR is a combination of saxagliptin and metformin, a biguanide, indicated as an
`
`adjunct to diet and exercise to improve glycemic control in adults with type 2
`
`diabetes mellitus when treatment with both saxagliptin and metformin is
`
`appropriate. (Ex. 2048 at 1; see also Ex. 2197 at 1.) The active ingredient
`
`saxagliptin increases the concentrations of incretin hormones in the bloodstream,
`
`reduces fasting and postprandial glucose concentrations in a glucose-dependent
`
`manner, and lowers FPG, 2-hr PG, and A1C levels in patients with type 2 diabetes.
`
`(Ex. 2047 at 9-10, 15; see also Ex. 2196 at 4-5, 6-9.)
`
`47. Onglyza® was approved in 2009, and Kombiglyze™ XR was
`
`approved in 2010. The recommended dose of saxagliptin is 2.5 mg or 5 mg once
`
`daily. (Ex. 2047 at 2; Ex. 2048 at 2-3; see also Ex. 2196 at 2; Ex. 2197 at 2.)
`
`19
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`Saxagliptin’s Demonstrated Safety and Efficacy
`
`2.
`48. After successful Phase I and Phase II clinical trials, BMS conducted a
`
`comprehensive Phase III clinical program for saxagliptin, evaluating its use as a
`
`monotherapy and combination with other type 2 diabetes treatments. (Ex. 2047 at
`
`15; see also Ex. 2196 at 6-9.) A total of 4,148 patients with type 2 diabetes were
`
`randomized in six, double-blinded, controlled clinical trials conducted to evaluate
`
`the safety and efficacy of saxagliptin. (Id.) Of these 4,148 patients, 3,021 were
`
`treated with saxagliptin. (Id.) The results of these Phase III clinical trials are
`
`summarized in Table 3.
`
`
`
`
`
`20
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`

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`Table 3: A1C Difference [95% CI] from Placebo in Adjusted Mean Change
`from Baseline5
`Saxagliptin 2.5
`Saxagliptin 5 mg Saxagliptin 10 mg
`mg
`
`Study Number
`
`Monotherapy Trials
`
`-0.62 [-0.90, -
`0.33]
`
`-0.45 [-0.74, -
`0.16]
`
`-0.64 [-0.93 -
`0.36]
`
`-0.40 [-0.69, -
`0.12]
`
`Add-On Trials
`
`-0.36 [-0.57, -
`0.15]
`
`-0.73 [-0.92, -
`0.53]
`
`-0.62 [-0.78, -
`0.45]
`
`-0.63 [-0.84, -
`0.42]
`
`-0.83 [ -1.02, -
`0.63]
`
`-0.72 [-0.88, -
`0.56]
`
`Combination Trials
`
`-0.73 [-1.02, -
`0.44]
`
`
`
`
`
`-0.72 [-0.91, -
`0.52]
`
`
`
`
`
`-0.54 [-0.73, -
`0.35]
`
`-0.50 [-0.70, -
`0.31]
`
`CV181011
`
`CV181038
`
`CV181013 (TZD)
`
`CV181014
`(metformin)
`
`CV181040
`(sulfonylurea)
`
`CV181039
`(metformin) 6
`
`
`
`5 Ex. 2198 at 25; Ex. 2199 at 6.
`
`6 A1C difference [95% CI] from placebo in combination with metformin in
`
`adjusted mean change from baseline.
`
`21
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`

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`49. Each trial showed saxagliptin resulted in significant improvements in
`
`A1C versus placebo. (Ex. 2047 at 15-21; see also Ex. 2196 at 6-9.) Treatment
`
`with saxagliptin also resulted in statistically significant improvements in FPG and
`
`2-hr PG following a standard oral glucose tolerance test, compared to control. (Id.)
`
`In addition, the incidence of adverse events was similar between saxagliptin and
`
`placebo. (Id.) Saxagliptin was not associated with significant changes from
`
`baseline in body weight or fasting serum lipids compared to placebo. (Id.)
`
`3. Other FDA-Approved DPP-4 Inhibitors
`50. Sitagliptin, sold under the trade name Januvia®, was approved in
`
`2006. The recommended dose of sitagliptin is 100 mg once daily. (Ex. 2049 at 2.)
`
`51. Linagliptin, sold under the trade name Tradjenta®, was approved in
`
`2011. The recommended dose of linagliptin is 5 mg once daily. (Ex. 2077 at 2.)
`
`52. Alogliptin, sold under the trade name Nesina®, was approved in 2013.
`
`The recommended dose of alogliptin is 25 mg once daily. (Ex. 2079 at 2.)
`
`V. The Objective Evidence Supports the Nonobviousness of the
`Saxagliptin Patent
`
`53. Saxagliptin has been widely prescribed by physicians in the United
`
`States for treatment of type 2 diabetes since 2009. Many thousands of patients
`
`suffering from type 2 diabetes have benefited from treatment with this new drug.
`
`54.
`
`In my opinion, physicians prescribe saxagliptin based on its
`
`significant therapeutic properties and advantages, including its safety, efficacy,
`
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`mechanism of action, and favorable side effect profile. These properties and
`
`advantages are directly tied to the active pharmaceutical ingredient saxagliptin,
`
`which is claimed in RE’186 patent.
`
`55. As a treating physician, I prescribe pharmaceutical drug products to
`
`patients suffering from type 2 diabetes based primarily on a drug’s safety and
`
`efficacy as well as its side-effect profile and tolerability. The active ingredients of
`
`these drug products, in this case saxagliptin, are directly responsible for these
`
`clinical profiles. And I base these decisions on medical evidence, most notably
`
`randomized, double-blinded, Phase III clinical trials, which are the gold standard
`
`of medicine-based evidence. (See ¶¶ 48-49 above.)
`
`56.
`
`I do not base my treatment decisions on a company’s promotional
`
`campaigns or marketing literature. My decision to prescribe a drug is based on its
`
`safety and efficacy. It is my opinion that saxagliptin is prescribed by treating
`
`physicians as a direct result of its properties and FDA-approved indication, not as a
`
`result of its marketing.
`
`57.
`
`I believe the compound saxagliptin, as it is claimed in the RE’186
`
`patent, correlates to the beneficial properties and results observed with Onglyza®
`
`and Kombiglyze™ XR in the clinic.
`
`23
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`
`A.
`
`Saxagliptin Met a Long-Felt Need for an Alternative
`Treatment for Type 2 Diabetes
`
`58.
`
`I understand that evidence of a long-felt, but unmet need for the
`
`claimed invention may support a showing of nonobviousness. I also understand
`
`that long-felt need is analyzed based on the date when the problem to be solved
`
`was identified. I further understand that whether a long-felt need is unmet must be
`
`judged as of the filing date of the claimed invention and not as of the date that the
`
`patented product is first introduced into the market if that date of market entry is
`
`later. I also understand that prior art treatment options that were not generally
`
`available for use by the public as of the filing date of the patent application cannot
`
`satisfy a long-felt need.
`
`59.
`
`In the late 1990s and at the time of invention, there was an unmet
`
`need for an alternative treatment for type 2 diabetes that was both safe and
`
`effective. (See ¶¶ 33-34 above.) As discussed above, all therapeutic agents
`
`marketed in the United States at the time caused serious side effects, such as
`
`hypoglycemia, weight gain, lactic acidosis, and h