IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`v.
`BOEHRINGER INGELHEIM INTERNATIONAL GMBH,
`Patent Owner
`U.S. Patent No. 8,853,156 to Dugi et al.
`Issue Date: October 7, 2014
`Title: Treatment for Diabetes Patients Inappropriate for Metformin Therapy
`
`Inter Partes Review No.: IPR2016-01565
`
`DECLARATION OF MAYER B. DAVIDSON, M.D.
`
`MYLAN Ex. 1002, Page 1
`
`
`____________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`v.
`BOEHRINGER INGELHEIM INTERNATIONAL GMBH,
`Patent Owner
`U.S. Patent No. 8,853,156 to Dugi et al.
`Issue Date: October 7, 2014
`Title: Treatment for Diabetes Patients Inappropriate for Metformin Therapy
`
`Inter Partes Review No.: IPR2016-01565
`
`DECLARATION OF MAYER B. DAVIDSON, M.D.
`
`MYLAN Ex. 1002, Page 1
`
`
`
`TABLE OF CONTENTS
`
`Introduction......................................................................................................1
`I.
`List of Documents Considered ........................................................................1
`II.
`III. My Background and Qualifications.................................................................2
`IV.
`Person of Ordinary Skill in the Art (POSA)....................................................3
`V.
`The ’156 patent................................................................................................5
`VI.
`State of the Art as of August, 2008 .................................................................8
`VII. Anticipation of Claims 1, 2, 4, 5, and 23 of the ’156 patent .........................13
`A.
`The Basis of my Analysis with Respect to Anticipation ....................13
`B.
`Ground 1: Claims 1, 2, 4, 5, and 23 are anticipated by Mikhail.........14
`1.
`Mikhail Anticipates Independent Claims 1 and 23...................15
`2.
`Mikhail Anticipates Dependent Claims 2, 4, and 5..................16
`VIII. Obviousness of Claims 1-2, 4-8, and 10-18, and 23-25................................17
`A.
`The Basis of my Analysis with Respect to Obviousness....................17
`B.
`Ground 2: Claims 1–2, 4–8, and 10–18, and 23–25 Would
`Have Been Obvious Under 35 U.S.C. § 103(a) Over the Januvia
`Label in View of Huettner together with the Knowledge of a
`POSA or Mikhail.................................................................................18
`1.
`Januvia Label (Ex. 1006) ..........................................................18
`2.
`Huettner (Ex. 1004)...................................................................20
`3.
`Eckhardt 2007 (Ex. 1005).........................................................21
`4.
`Independent Claims 1 and 23–25 Are Obvious........................22
`5.
`Dependent Claims 2, 4–8 and 10–18 Are Obvious ..................25
`
`ii
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`MYLAN Ex. 1002, Page 2
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`
`
`IX.
`X.
`
`There is no Evidence of Secondary Considerations......................................30
`Conclusion .....................................................................................................30
`
`iii
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`MYLAN Ex. 1002, Page 3
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`
`
`I.
`
`Introduction
`1.
`I am over the age of eighteen (18) and otherwise competent to make
`
`this Declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Mylan
`
`Pharmaceuticals Inc. (“Mylan”) for the above captioned inter partes review
`
`(“IPR”). I am being compensated for my time in connection with this IPR at my
`
`standard consulting rate, which is $500 per hour for non-testifying work. My
`
`compensation is in no way dependent on the outcome of this IPR.
`
`3.
`
`I understand that the petition for inter partes review involves U.S.
`
`Patent No. 8,853,156 (the “’156 patent”), Ex. 1001. I have considered references
`
`published prior to August 6, 2008. I have been informed that such references are
`
`referred to as “prior art.” I can confirm that the opinions expressed herein comport
`
`with my own understandings based on an independent review of the prior art cited
`
`herein.
`
`II.
`
`List of Documents Considered
`4.
`In formulating my opinion, I have considered all documents cited in
`
`this Declaration and all documents cited in the Petition for Inter Partes Review of
`
`U.S. Patent No. 8,853,156. I refer to the prior art references and other documents
`
`cited in my Declaration using the same terminology as defined and presented in the
`
`Petition.
`
`1
`
`MYLAN Ex. 1002, Page 4
`
`
`
`III. My Background and Qualifications
`5.
`I am an expert in the field of medicine, specifically diagnosing and
`
`treating type II diabetes mellitus,1 and I have been an expert in this field since well
`
`before 2008. Throughout the remainder of this Declaration, I will refer to the field
`
`of diagnosing and treating type II diabetes as the relevant field or the relevant art.
`
`In formulating my opinions, I have relied upon my training, knowledge, and
`
`experience in the relevant art. A copy of my current curriculum vitae is provided
`
`as Ex. 1008, and it provides a comprehensive and current description of my
`
`academic and employment history.
`
`6.
`
`I received a M.D. from Harvard Medical School in 1961.
`
`I took 2
`
`years of my residency at Cornell Medical School, Bellevue Hospital in Internal
`
`Medicine from 1961 to 1963. I then completed my residency at the University of
`
`Washington in Seattle in 1964 following which I completed a research fellowship
`
`at the University of Washington King County Hospital in Endocrinology and
`
`Metabolism in 1966.
`
`7.
`
`I am currently a Professor of Medicine at both the David Geffen
`
`School of Medicine at UCLA and Charles Drew University. I am board certified in
`
`Internal Medicine and also board certified in the subspecialty of Diabetes,
`
`1 I refer to “type II diabetes mellitus” as “type II diabetes.”
`
`2
`
`MYLAN Ex. 1002, Page 5
`
`
`
`Endocrinology, and Metabolism. I have been practicing in the field of diabetes,
`
`endocrinology, and metabolism for 50 years.
`
`8.
`
`During my career, I have focused my practice on the diagnosis and
`
`treatment of diabetes.
`
`9.
`
`I served as President of the American Diabetes Association from
`
`1997–1998.
`
`(Id. at 6).
`
`I have conducted considerable research on diabetes and
`
`spoken on diabetes both nationally and internationally.
`
`I have served on the
`
`Editorial Boards of many medical journals, including Diabetes Care, Diabetes
`
`Spectrum, Clinical Diabetes, Geriatrics and the Journal of Clinical Endocrinology
`
`and Metabolism. I was the Founding Editor of Current Diabetes Reports and the
`
`Editor-in-Chief of Diabetes Care, the leading diabetes clinical journal in the world,
`
`from 2002 – 2006. I have also written 168 scientific papers, 31 book chapters, and
`
`numerous reviews and editorials as well as three complete books on diabetes. In
`
`2016, the American Diabetes Association presented me with their Outstanding
`
`Physician Clinician Award in Diabetes.
`
`IV.
`
`Person of Ordinary Skill in the Art (POSA)
`10.
`I understand that a person of ordinary skill in the art (“POSA”) is a
`
`hypothetical person who is presumed to be aware of all pertinent art, thinks along
`
`conventional wisdom in the art, and is a person of ordinary creativity.
`
`I also
`
`understand that a POSA is not an extraordinarily innovative person, but is a person
`
`3
`
`MYLAN Ex. 1002, Page 6
`
`
`
`who thinks conventionally in matters affecting the art in which he or she is skilled.
`
`I understand that the factors that may be considered for determining the level of a
`
`skilled practitioner include: the educational level of the inventor; types of problems
`
`encountered in the art; prior art solutions to these problems; rapidity with which
`
`innovations are made; sophistication of the technology; and educational level of
`
`active workers in the field.
`
`11.
`
`In light of this, it is my opinion that a POSA as of August, 2008
`
`would have an advanced degree in the field of medicine, pharmaceuticals,
`
`medicinal chemistry, and/or a related discipline with at least 5 years of clinical
`
`experience treating type II diabetes and related disorders, experience with the
`
`pharmaceutical and clinical properties of DPP-IV Inhibitors, and preferably some
`
`experience investigating pharmaceutical compositions for treating diabetes and
`
`diabetes-related disorders.
`
`12. As an expert in the relevant field since prior to 2008, I am qualified to
`
`provide an opinion as to what a POSA would have understood, known, or
`
`concluded as of 2008. Since 1966, I have accumulated significant training and
`
`experience in the relevant field and related fields.
`
`In formulating my opinions, I
`
`have relied upon my experience in the relevant art. I have reviewed the materials,
`
`conducted my analyses, and formed my opinions in my Declaration through the
`
`eyes of the POSA as of August 6, 2008.
`
`4
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`MYLAN Ex. 1002, Page 7
`
`
`
`13.
`
`In my opinion, the POSA would easily have understood the prior art
`
`references referred to in my Declaration. The POSA would also have the
`
`capability to draw inferences from them.
`
`V.
`
`The ’156 patent
`14.
`I have considered the disclosure and portions of the file history of the
`
`’156 patent in light of general knowledge in the relevant field as of August 6, 2008.
`
`15.
`
`I understand that a dependent claim is defined as a claim that refers to
`
`another claim and therefore “depends from” that other claim.
`
`I also understand
`
`that a dependent claim will incorporate and include all features of the claim from
`
`which it depends.
`
`16.
`
`In reviewing the claims of the ’927 Patent, I have been asked to give
`
`the claims their broadest reasonable interpretation in light of the specification as it
`
`would be interpreted by one of ordinary skill in the art.
`
`17.
`
`The claims of the ’156 patent are directed to method of treating type 2
`
`diabetes in a patient for whom metformin is inappropriate due to intolerability or
`
`contraindication against metformin using a DPP-IV inhibitor, including 1-[(4-
`
`methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-
`
`piperidin-1-yl)-xanthine (“linagliptin”). (Ex. 1001, Abstract).
`
`18. Claim 1 of the ’156 patent is reproduced below.
`
`a method of treating and/or preventing metabolic diseases in a
`1.
`patient for whom metformin therapy is inappropriate due to at least
`5
`
`MYLAN Ex. 1002, Page 8
`
`
`
`orally
`comprising
`against metformin
`contraindication
`one
`administering to the patient a DPP-IV inhibitor wherein the
`contraindication is selected from the group consisting of:
`Renal disease, renal impairment or renal dysfunction, unstable
`or acute congestive heart failure, acute of chronic metabolic
`acidosis, and hereditary galactose intolerance.
`
`(Ex. 1001, ’156 Patent, 29:2–11).
`
`19. Claims 2, 4, 5, and 18 depend from claim 1 and further recite
`
`particular contraindications against metformin. (Id., 29:12–14; 29:18–22; 32:13–
`
`15).
`
`20. Claim 4 depends from claim 1 and further recites the metabolic
`
`disease as type II diabetes. (Id., 29:18–19).
`
`21. Claim 6-8 depend from claim 1 and further recite the DPP-IV
`
`inhibitor used in claim 1, including linagliptin (Claim 8). (Id., 29:23–31:17).
`
`22. Claims 10-17 depend from claim 1 and further recite the elimination
`
`parameters of the DPP-IV inhibitor used in claim 1. (Id., 31:56–32:12).
`
`23. Claim 23 of the ’156 patent is reproduced below.
`
`23. A method of treating type 2 diabetes mellitus in a patient for
`whom metformin therapy is inappropriate due to at
`least one
`contraindication against metformin comprising orally administering to
`the patient a DPP-IV inhibitor wherein the contraindication is selected
`from the group consisting of: renal disease, renal impairment or renal
`
`6
`
`MYLAN Ex. 1002, Page 9
`
`
`
`dysfunction, unstable or acute congestive heart failure, acute or
`chronic metabolic acidosis, and hereditary galactose intolerance.
`
`(Id., 32:38–46).
`
`24.
`
`Claim 24 of the ’156 patent is reproduced below.
`
`24. A method of treating type 2 diabetes mellitus in a patient for
`whom metformin therapy is inappropriate due to at
`least one
`contraindication against metformin comprising orally administering to
`the
`patient
`1-[(4-methyl-quinazolin-2-yl)-methyl]-3-methyl-7-(2-
`butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,
`[linagliptin]
`wherein the contraindication is selected from the group consisting of:
`renal disease, renal impairment or renal dysfunction, unstable or acute
`congestive heart failure, acute or chronic metabolic acidosis, and
`hereditary galactose intolerance.
`
`(Id., 32:47–57.)
`
`25. Claim 25 of the ’156 patent is reproduced below.
`
`25. A method of treating type 2 diabetes mellitus in a patient for
`whom metformin therapy is inappropriate due to at
`least one
`contraindication against metformin comprising orally administering to
`the
`patient
`1-[(4-methyl-quinazolin-2-yl)-methyl]-3-methyl-7-(2-
`butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,
`[linagliptin]
`wherein the contraindication is selected from the group consisting of
`mild, moderate or severe renal impairment or end-stage renal disease.
`
`(Id., 32:57–65).
`
`7
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`MYLAN Ex. 1002, Page 10
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`
`
`VI.
`
`State of the Art as of August, 2008
`26. As explained below, as of the earliest claimed priority date (i.e.,
`
`August 6, 2008), it was well-known to those skilled in the art that DPP-IV
`
`Inhibitors, including sitagliptin and linagliptin, could be used as monotherapy to
`
`treat type II diabetes in patients contraindicated against metformin.
`
`27.
`
`Type II diabetes, once known as adult-onset or noninsulin-dependent
`
`diabetes, is a chronic condition that affects the way the body metabolizes sugar
`
`(glucose). With type II diabetes, the body both resists the effects of insulin—a
`
`hormone secreted by the pancreas that regulates the movement of sugar into
`
`cells—and does not produce enough insulin to maintain a normal glucose level.
`
`While there is no cure for type II diabetes, it can initially be managed by eating
`
`well, exercising, and maintaining a healthy weight. When diet and exercise are not
`
`enough to adequately manage a diabetic’s blood glucose, then he or she may
`
`require non-insulin diabetes medications, insulin therapy, or both.
`
`28.
`
`First discovered in the 1920’s, metformin is considered “first line”
`
`treatment for type II diabetes and has been used worldwide for many years.
`
`It
`
`works mainly by decreasing the amount of glucose made by the liver and, some
`
`studies suggest that it also increases the amount of glucose utilized by certain body
`
`tissues. See Figure 1, below. As a result, metformin can help the body respond
`
`better to its own insulin and decrease blood glucose levels. Metformin has been
`
`8
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`MYLAN Ex. 1002, Page 11
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`
`
`available in several forms, including an immediate release form (e.g., Glucophage
`
`IR in 1994), and long-acting form (Glucophage XR in 2000), among others.
`
`Figure 1 below illustrates generally how metformin reduces blood glucose levels in
`
`type II diabetes patients.
`
`Fig. 1: Metformin’s Mechanism of Action.
`
`29. DPP-IV Inhibitors have also been commonly used to treat type II
`
`diabetes patients. These drugs were first approved for the treatment of type II
`
`diabetes in 2008. (Ex. 1006 at 1). DPP-IV Inhibitors have a different mechanism
`
`9
`
`MYLAN Ex. 1002, Page 12
`
`
`
`of action as compared to metformin. DPP-IV Inhibitors work to increase the level
`
`of insulin in the body by preventing the breakdown of GLP-1, a naturally occurring
`
`substance that helps reduce blood glucose by stimulating the pancreas to produce
`
`insulin and by inhibiting the release of glucagon, a substance that causes the liver
`
`to release glucose. As a result, these drugs help prevent the liver from producing
`
`an excess amount of glucose. Figure 2 below illustrates how DPP-IV Inhibitors
`
`reduce blood glucose levels in type II diabetes patients.
`
`Fig. 2: Mechanism of Action of DPP-IV Inhibitors
`
`30. DPP-IV Inhibitors were known, widely used, and many were
`
`commercially available before August 6, 2008. (Ex. 1001, col. 3–9). Prior to that
`
`time, DPP-IV Inhibitors were used as monotherapy or in combination with other
`
`therapies in treating type II diabetes.
`
`(Ex. 1015, ’510 Publication at ¶ [0298],
`
`10
`
`MYLAN Ex. 1002, Page 13
`
`
`
`[0300]; Ex. 1011, Flatt at 3654). For example, the DPP-IV Inhibitors sitagliptin
`
`and vildagliptin were used both in monotherapy and in combination therapy with
`
`metformin.
`
`(Ex. 1011, Flatt at 3654).
`
`It was also known that DPP-IV Inhibitors
`
`can be used as monotherapy for “[p]atients who cannot take metformin due to
`
`adverse effects.” (Ex. 1003, Mikhail 2008 at 851).
`
`31. Metformin is eliminated through the renal excretion pathway.
`
`(Ex.
`
`1001, 1:62–65; Ex. 1008, Glucophage at Pharmacokinetics). High blood
`
`concentrations of metformin will result if renal excretion of the drug is impaired,
`
`which in turn can lead to severe side effects, such as lactic acidosis, a potentially
`
`life-threatening condition.
`
`(Ex. 1008, Glucophage Label at Pharmacokinetics,
`
`Warnings). Thus, metformin has been contraindicated for patients with renal
`
`disease or renal
`
`impairment for many years.
`
`(Ex. 1008, Glucophage label,
`
`“Glucophage and Glucophage XR are contraindicated in patients with . . . Renal
`
`disease or renal dysfunction . . . .”). Accordingly, it was understood on August 6,
`
`2008 that more preferable diabetic medications suitable for patients with renal
`
`impairment would need to avoid excretion by the kidneys. (Id.).
`
`32. DPP-IV Inhibitors are metabolized differently than metformin, and
`
`most DPP-IV Inhibitors, except for linagliptin, are primarily excreted through the
`
`kidneys.
`
`(Ex. 1003, Mikhail at 851; Ex. 1004, Huettner at Table 2; Ex. 1018,
`
`Heise at Results-Pharmacokinetics; Ex. 1016, Dugi 2006). However, unlike
`
`11
`
`MYLAN Ex. 1002, Page 14
`
`
`
`metformin, high levels of DPP-IV Inhibitors in the blood will not lead to such
`
`severe side effects, like lactic acidosis.
`
`33.
`
`For example, the prior art taught that the DPP-IV Inhibitor sitagliptin
`
`is excreted mainly unchanged through the kidneys; that metabolism of sitagliptin
`
`represents a minor elimination pathway; and that sitagliptin has a safety/tolerability
`
`profile that is comparable to placebo.
`
`(See, e.g., Ex. 1009, Mathieu at 35; Ex.
`
`1010, Vincent at 537; Ex. 1011, Flatt at 3654; Ex. 1012, Zerilli at 2614-15).
`
`Sitagliptin was therefore recommended as a safe alternative to metformin for
`
`patients with mild renal insufficiency and with dose adjustments for patients with
`
`moderate to severe renal insufficiency.
`
`(Ex. 1003, Mikhail at 851; Ex. 1006,
`
`Januvia Label at 2).
`
`34.
`
`Similarly, prior to the date of invention, it was known that DPP-IV
`
`Inhibitor, BI 1356 (linagliptin), was a “potent” and “long lasting” DPP-IV Inhibitor
`
`that could be used to treat type II diabetes. (Ex. 1018, Heise; Ex. 1019 Thomas).
`
`Linagliptin (BI 1356) was characterized as having “the potential to be a best in
`
`class DPP-IV Inhibitor.”
`
`(Id.; see also Ex. 1005, Eckhardt 2007 at 6450
`
`(explaining that BI 1356 is linagliptin)).
`
`It was also well-known at the time that
`
`linagliptin was an even more potent DPP-IV Inhibitor than sitagliptin. (Compare
`
`Ex. 1015, ’510 publication at ¶ [0245], [0295] (disclosing linagliptin’s IC50 value
`
`12
`
`MYLAN Ex. 1002, Page 15
`
`
`
`of 1nM) with Ex. 1020, Gwaltney at 158, (disclosing IC50 value 18nM for
`
`sitagliptin)).
`
`35.
`
`The term, IC50 (i.e., the half maximal concentration), is a measure of
`
`the effectiveness of a substance in inhibiting a specific biochemical function. An
`
`IC50 value indicates how much of a particular drug is needed to inhibit the
`
`biochemical function by half. A lower value indicates that less of the substance is
`
`needed to inhibit the function than a higher value.
`
`The values are typically
`
`expressed as molar concentration.
`
`36.
`
`Linagliptin was also known to have extremely low (according to one
`
`study,
`
`less than 1%) renal excretion. (Ex. 1004, Huettner; Ex. 1018, Heise
`
`(disclosing approximately 3% renal excretion); Ex. 1016, Dugi 2006 at Abstract
`
`P821 (“[r]enal clearance represented a minor elimination pathway”)). Because it
`
`was known that linagliptin had extremely low renal excretion, a POSA would have
`
`understood that it could be safely used in patients with renal impairment.
`
`VII. Anticipation of Claims 1, 2, 4, 5, and 23 of the ’156 patent
`A.
`The Basis of my Analysis with Respect to Anticipation
`37.
`I understand that an anticipation analysis involves comparing a patent
`
`claim to a prior art reference through the eyes of the POSA to determine whether
`
`the prior art reference inherently or explicitly discloses every element of the
`
`claimed invention.
`
`13
`
`MYLAN Ex. 1002, Page 16
`
`
`
`Ground 1: Claims 1, 2, 4, 5, and 23 are anticipated by Mikhail
`B.
`38. Mikhail was published in June 2008. (Ex. 1003 at Cover). Mikhail
`
`reports that:
`
`sitagliptin was evaluated as monotherapy in several double-blind
`placebo-controlled trials in patients with type II diabetes. Given as a
`single daily oral dose of 100mg,
`treatment with sitagliptin was
`associated with average reduction of HbA1c values of around 0.7%,
`compared with baseline and placebo values. The average proportions
`of patients who achieved HbAlc levels < 7% at the trial’s end were
`44% and 18% in the sitagliptin and placebo groups, respectively.
`
`(Id. at 847).
`
`39. Mikhail further reports similar decreases in HbA1c values were
`
`generally observed in trials using vildagliptin.
`
`(Ex. 1003 at 847). The terms
`
`“HbA1c” or “A1c” refer
`
`to glycated haemoglobin. By measuring glycated
`
`haemoglobin (HbA1c), clinicians are able to get an overall picture of what an
`
`individual’s average blood sugar levels have been over a period of weeks/months.
`
`In these studies, vildagliptin “was given as a 50 mg tablet b.i.d. or 100 mg once
`
`daily, with no significant difference in efficacy between the two dosing regimens.”
`
`(Ex. 1003 at 847). Mikhail found that “in clinical trials lasting ≤ 52 weeks, the use
`
`of sitagliptin and vildagliptin was well tolerated. Withdrawal rates in patients
`
`randomized to these two DPP-4 inhibitors were similar to placebo.” (Ex. 1003 at
`
`847).
`
`14
`
`MYLAN Ex. 1002, Page 17
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`
`
`40. Based on the above results, Mikhail recommended that:
`
`DPP-4 inhibitors can be used as monotherapy in the following
`situations:
`• Patients who cannot take metformin due to adverse effects or
`renal insufficiency. In the latter condition, sitagliptin should be
`used as safety data regarding the use of vildagliptin in renal
`insufficiency is not yet available.
`• Patients who are not willing to take a [sulfonylurea] because
`of concerns about hypoglycemia and/or weight gain.
`
`(Ex. 1003 at 851 (emphasis added)).
`1.
`Mikhail Anticipates Independent Claims 1 and 23
`41.
`Independent claim 1 is directed to a method of treating and/or
`
`preventing metabolic diseases in a patient for whom metformin therapy is
`
`inappropriate due to at least one contraindication against metformin comprising
`
`orally administering to the patient a DPP-IV Inhibitor wherein the contraindication
`
`is selected from the group consisting of: renal disease, renal impairment or renal
`
`dysfunction among other medical conditions. (Ex. 1001, 29:2–11).
`
`42. Claim 23 is nearly identical to claim 1, except that it is limited to a
`
`method of treating type II diabetes mellitus.2
`
`(Ex. 1001, 32:38–46). Claim 23
`
`recites other contraindications not recited in claim 1, but those contraindications
`
`are not relevant here. (Id.)
`
`2 Type II diabetes mellitus is commonly known as type II diabetes.
`
`15
`
`MYLAN Ex. 1002, Page 18
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`
`
`43. Mikhail discloses the use of DPP-IV Inhibitors, specifically sitagliptin
`
`and vildagliptin, through a single oral dose, for the treatment of type II diabetes,
`
`which is a known metabolic disorder.
`
`(Ex. 1003 at 847). Mikhail specifically
`
`discloses that sitagliptin should be used as monotherapy for “patients who cannot
`
`take metformin due to adverse effects or renal insufficiency.” (Ex. 1003 at 851).
`
`Accordingly, Mikhail discloses all of the limitations of independent claims 1 and
`
`23 and thus anticipates those claims.
`
`Mikhail Anticipates Dependent Claims 2, 4, and 5
`2.
`44. Claim 2 recites the method according to claim 1, wherein the patient
`
`is ineligible for metformin due to a contraindication against metformin. (Ex. 1001,
`
`29:12-14).
`
`45. Claim 4 recites the method according to claim 1, wherein the
`
`metabolic disease is type II diabetes. (Ex. 1001, 29:18-19).
`
`46. Claim 5 recites the method according to claim 1, wherein the
`
`contraindication is renal disease, renal impairment, or renal dysfunction. (Ex. 1001,
`
`29:20-22)
`
`47. As discussed above, Mikhail discloses each of
`
`these further
`
`limitations of claims 2, 4, and 5. Specifically, Mikhail discloses the use of a DPP-
`
`IV Inhibitor for the treatment of type II diabetes. (Ex. 1003 at 845). Mikhail also
`
`discloses that sitagliptin should be used as monotherapy for “patients who cannot
`
`16
`
`MYLAN Ex. 1002, Page 19
`
`
`
`take metformin due to adverse effects or renal insufficiency.” (Ex. 1003 at 851).
`
`Accordingly, Mikhail discloses all of the limitations of dependent claims 2, 4, and
`
`5.
`
`VIII. Obviousness of Claims 1-2, 4-8, and 10-18, and 23-25
`A.
`The Basis of my Analysis with Respect to Obviousness
`
`48.
`
`I understand that an obviousness analysis involves comparing a patent
`
`claim to the prior art to determine whether the claimed invention would have been
`
`obvious to a POSA in view of the prior art, and in light of the general knowledge
`
`in the art.
`
`49.
`
`I understand that obviousness can be established by combining or
`
`modifying the teachings of the prior art to achieve the claimed invention. It is also
`
`my understanding that where there is a reason to modify or combine the prior art to
`
`achieve the claimed invention, there must also be a reasonable expectation of
`
`success in so doing. I understand that reasons to combine prior art references can
`
`come from a variety of sources, not just the prior art itself or the specific problem
`
`the patentee was trying to solve. And I understand that the prior art references
`
`themselves need not provide a specific hint or suggestion of the alteration needed
`
`to arrive at the claimed invention; the analysis may include recourse to logic,
`
`judgment, and common sense available to a POSA.
`
`17
`
`MYLAN Ex. 1002, Page 20
`
`
`
`50.
`
`I understand that patent claims may be considered obvious if they
`
`recite subject matter that would have been obvious to a POSA to try and develop. I
`
`understand that claims are obvious to try when there is market pressure to solve a
`
`problem, and when there are only a finite number of identified, predictable
`
`solutions to that problem.
`
`51.
`
`I understand that when considering the obviousness of an invention,
`
`one should also consider whether there is any objective evidence that could support
`
`the nonobviousness of the invention. I have been informed that objective evidence
`
`of nonobviousness includes unexpected results,
`
`long-felt need, commercial
`
`success, copying, skepticism, praise, acquiescence, copying, or failure of others. I
`
`understand that Patent Owner has yet to provide any evidence of this kind.
`
`B.
`
`Ground 2: Claims 1–2, 4–8, and 10–18, and 23–25 Would Have
`Been Obvious Under 35 U.S.C. § 103(a) Over the Januvia Label in
`View of Huettner together with the Knowledge of a POSA or
`Mikhail
`
`1.
`52.
`
`Januvia Label (Ex. 1006)
`Januvia® is a commercially available sitagliptin tablet. (Ex. 1006 at
`
`1). Januvia® (sitagliptin phosphate) tablets were first approved by the FDA on
`
`October 16, 2006. The Januvia Label published in 2006. (Ex. 1006 at 1).
`
`53.
`
`The Januvia Label describes the use of sitagliptin phosphate tablets as
`
`monotherapy and “as an adjunct to diet and exercise to improve glycemic control
`
`in patients with type 2 diabetes mellitus.” (Ex. 1006 at 1). The Januvia Label lists
`
`18
`
`MYLAN Ex. 1002, Page 21
`
`
`
`no contraindications for Januvia.
`
`(Ex. 1006 at 2).
`
`Instead, the Januvia Label
`
`provides
`
`the following dosage recommendations
`
`for patients with renal
`
`insufficiency:
`
`For patients with mild renal insufficiency (creatinine clearance [CrCl]
`≥50 mL/min, approximately corresponding to serum creatinine levels
`of ≤1.7 mg/dL in men and ≤1.5 mg/dL in women), no dosage
`adjustment for JANUVIA is required.
`
`For patients with moderate renal insufficiency (CrCl ≥30 to <50
`mL/min, approximately corresponding to serum creatinine levels of
`>1.7 to ≥3.0 mg/dL in men and >1.5 to ≤2.5 mg/dL in women), the
`dose of JANUVIA is 50 mg once daily.
`
`insufficiency (CrCl <30 mL/min,
`For patients with severe renal
`approximately corresponding to serum creatinine levels of >3.0
`mg/dL in men and >2.5 mg/dL in women) or with end-stage renal
`disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose
`of JANUVIA is 25 mg once daily. JANUVIA may be administered
`without regard to the timing of hemodialysis.
`
`Because there is a need for dosage adjustment based upon renal
`function, assessment of renal function is recommended prior to
`initiation of
`JANUVIA and periodically thereafter. Creatinine
`clearance can be estimated from serum creatinine using the Cockcroft-
`Gault formula.
`
`(Ex. 1003 at 2).
`
`54.
`
`Januvia further discloses “[i]n controlled clinical studies as both
`
`monotherapy and combination therapy, the overall incidence of adverse reactions
`
`with JANUVIA was similar to that reported with placebo. Discontinuation of
`
`therapy due to clinical adverse reactions was . . . similar to placebo.” (Id. at 3).
`
`19
`
`MYLAN Ex. 1002, Page 22
`
`
`
`55.
`
`Finally, Januvia discloses that “six [sitagliptin] metabolites were
`
`detected at trace levels and are not expected to contribute to the plasma DPP-4
`
`inhibitory activity of sitagliptin.” (Id. at 6).
`
`Huettner (Ex. 1004)
`2.
`56. Huettner was published in June 2007.
`
`It discloses that “a novel
`
`approach in the treatment of diabetes targets the incretins (e.g. GLP-1), hormones
`
`secreted in the intestine in response to food intake.” (Ex. 1004 at Introduction).
`
`GLP-1 regulates insulin and glucagon secretion.
`
`“DPP-4 inhibitors increase
`
`plasma levels of intact GLP-1.” (Ex. 1004, Huettner at Introduction).
`
`57. Huettner conducted “a randomised, double-blind, placebo controlled
`
`single rising dose study in healthy male volunteers aged 21–65 years” of BI 1356
`
`(i.e., linagliptin), “a xanthine analogue, which exhibits a high potency for DPP-4
`
`inhibition, increases the half-life of circulating incretin hormones, and improves
`
`glucose homeostasis in preclinical studies.” (Ex. 1004, at Abstract).
`
`58.
`
`Huettner discloses that “renal excretion was low and does not
`
`constitute the main pathway for elimination of BI 1356.” (Ex. 1004, at Abstract).
`
`More specifically, Huettner reports that “[r]enal excretion of BI 1356 was below
`
`1% for doses up to 5mg and increased dose dependently.” (Ex. 1004, at Abstract,
`
`Table 2).
`
`20
`
`MYLAN Ex. 1002, Page 23
`
`
`
`59. Huettner also discloses that “2.5 mg and 5 mg BI 1356 reduced DPP-4
`
`activity by 73% and 86% within 3 hrs, respectively.”
`
`(Ex. 1004, Huettner at
`
`Results – Pharmacodynamics). Based on this, a POSA would understand that these
`
`doses would be common therapeutic dosages for linagliptin.
`
`(Id.; see also, Ex.
`
`1016, Dugi 2006 (disclosing 5mg as a “therapeutic dose”)). Huettner concludes
`
`that “BI 1356 is a potent DPP-4 inhibitor with a wide therapeutic window of >100-
`
`fold based on an expected therapeutic dose of 5 mg.” (Ex. 1004, at Conclusions).
`
`3.
`60.
`
`Eckhardt 2007 (Ex. 1005)
`Eckhardt 2007 discloses that BI 1356 is linagliptin.
`
`(Ex. 1005 at
`
`6450). Eckhardt 2007 was published in December 2007. Eckhardt 2007 discloses
`
`that BI 1356 corresponds with species 1 (Figure 3 below), which was known at the
`
`time to be linagliptin.
`
`(Ex. 1005 at 6450; see also Ex. 1017 ’940 Publication at
`
`[0032] (disclosing the above chemical structure as 1-[(4-methyl-quinazolin-2-
`
`yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)-xanthine (i.e.,
`
`linagliptin)).
`
`Fig. 3: Chemical Structure for Linagliptin
`
`21
`
`MYLAN Ex. 1002, Page 24
`
`
`
`Independent Claims 1 and 23–25 Are Obvious
`4.
`61. Claim 1 is directed to a method of (i) treating and/or preventing
`
`metabolic diseases; (ii) in a patient for whom metformin therapy is inappropriate
`
`due
`
`to at
`
`least one
`
`contraindication against metformin, wherein the
`
`contraindication is selected from the group consisting of: renal disease, renal
`
`impairment or renal dysfunction, among other medical conditions; and (iii)
`
`comprising orally administering to the patient a DPP-IV Inhibitor.
`
`(Ex. 1001,
`
`29:1–11).
`
`62.
`
`The Januvia Label discloses administration of sitagliptin, a DPP-IV
`
`Inhibitor, as monotherapy for the treatment of type II diabetes, which is a known
`
`metabolic disease. (Ex. 1006 at 1). Thus, the Januvia Label discloses elements (i)
`
`and (iii) of claim 1.
`
`63.
`
`Element (ii) of claim 1 is met by the Januvia Label, and a POSA’s
`
`knowledge of the limitations in administering metformin to type II diabetes
`
`patients.
`
`In particular, at August 6, 2008, the POSA would have understood that
`
`metformin is contraindicated for patients with renal impairment because metformin
`
`is largely eliminated unmetabolized through the kidneys. Thus, in patients with
`
`renal impairment, the potential exists for metformin to build up in the patient’s
`
`blood, leading to harmful side effects such as lactic acidosis.
`
`(See Ex. 1008,
`
`Glucophage Lab
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