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. 9,173,859 to Dugi et al.
`Issue Date: November 3, 2015
`Title: Uses of DPP-IV Inhibitors
`
`Inter Partes Review No.: IPR2016-01566
`
`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 ’859 Patent................................................................................................5
`VI.
`State of the Art as of May, 2006......................................................................8
`VII. Obviousness of Claims 1-22 of the ’859 Patent............................................14
`A.
`The Basis of my Analysis with Respect to Obviousness....................14
`B.
`Ground 1: Claims 1–22 Are Unpatentable Under 35 U.S.C.
`§ 103(a) over the ’510 Publication in view of the Glucophage
`Label....................................................................................................15
`1.
`The ’510 Publication (Ex. 1003)...............................................15
`2.
`Glucophage Label (Ex. 1004)...................................................16
`3.
`Independent Claims 1, 13, and 16–18.......................................17
`4.
`Dependent Claims 2–4..............................................................23
`5.
`Dependent Claims 5, 6, 19, 21, 22............................................24
`6.
`Dependent Claims 7–12............................................................25
`7.
`Independent Claim 14 and Dependent Claims 15 and 20.........26
`Ground 3: Claims 1–22 are Unpatentable Under 35 U.S.C.
`§ 103(a) over the ’510 Publication in light of Ahrén, Hughes,
`and/or Brazg ........................................................................................27
`1.
`’510 Publication (Ex. 1003)......................................................27
`2.
`Ahrén (Ex. 1005).......................................................................28
`3.
`Hughes (Ex. 1006) ....................................................................30
`
`C.
`
`ii
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`MYLAN Ex. 1002, Page 2
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`

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`Brazg (Ex. 1007).......................................................................31
`4.
`Independent Claims 1, 13, and 16–18.......................................32
`5.
`Dependent Claims 2–4..............................................................36
`6.
`Dependent Claims 5, 6, 19, 21, and 22.....................................37
`7.
`Dependent Claims 7–12............................................................38
`8.
`Independent Claim 14 and Dependent Claims 15 and 20.........38
`9.
`VIII. Anticipation of Claims 18-26 of the ’927 patent...........................................39
`A.
`The Basis of my Analysis with Respect to Anticipation ....................39
`B.
`Ground 2: Claims 14 and 20 Are Unpatentable Under 35
`U.S.C. § 102(b) over the ’510 Publication..........................................40
`1.
`’510 Publication (Ex. 1003)......................................................40
`2.
`Claims 14 and 20.......................................................................40
`There is no Objective Evidence of Nonobviousness.....................................41
`Conclusion .....................................................................................................43
`
`IX.
`X.
`
`iii
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`MYLAN Ex. 1002, Page 3
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`

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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. 9,173,859 (the “’859 patent”), Ex. 1001. I have considered references
`
`published prior to May 4, 2006.
`
`I have been informed that such references are
`
`referred to as “prior art.” And I will refer to these references as such in my
`
`Declaration.
`
`I can confirm that the opinions expressed herein comport with my
`
`own understandings based on an independent review of the prior art cited in my
`
`Declaration.
`
`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. 9,173,859. I refer to the prior art references and other documents
`
`1
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`MYLAN Ex. 1002, Page 4
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`

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`cited in my Declaration using the same terminology as defined and presented in the
`
`Petition.
`
`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 2006. 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 R. Drew University. I am board certified
`
`1 I refer to “type II diabetes mellitus” as “type II diabetes.”
`
`2
`
`MYLAN Ex. 1002, Page 5
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`in Internal Medicine and also board certified in the subspecialty of Diabetes,
`
`Endocrinology, and Metabolism. I have been practicing in the field of diabetes,
`
`endocrinology, and metabolism for 50 years. During my career, I have focused my
`
`practice on the diagnosis and treatment of diabetes.
`
`8.
`
`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)
`9.
`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
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`MYLAN Ex. 1002, Page 6
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`

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`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.
`
`10.
`
`In light of this, it is my opinion that a POSA as of May 4, 2006 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.
`
`11. As an expert in the relevant field since prior to 2006, I am qualified to
`
`provide an opinion as to what a POSA would have understood, known, or
`
`concluded as of 2006. 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 May 4, 2006.
`
`4
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`MYLAN Ex. 1002, Page 7
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`12.
`
`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 ’859 Patent
`13.
`I have considered the disclosure and file history of the ’859 patent in
`
`light of general knowledge in the relevant field as of May 4, 2006.
`
`14.
`
`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.
`
`15.
`
`In reviewing the claims of the ’859 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.
`
`16.
`
`The Challenged Claims of the ’859 patent are directed to methods of
`
`treating type II diabetes mellitus by administering 1-[(4-methyl-quinazolin-2-yl)-
`
`methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine
`
`(“linagliptin”)
`
`and metformin and to oral
`
`tablet
`
`formulations comprising
`
`linagliptin and optionally metformin. (Ex. 1001, ’859 Patent, 23:27–24:66).
`
`17.
`
`Independent claim 1 is directed to a method of treating type II
`
`diabetes mellitus by administering 2.5 mg or 5 mg of linagliptin in combination
`
`5
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`MYLAN Ex. 1002, Page 8
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`with metformin “wherein the dose of metformin is 100 mg to 500 mg or 200 mg to
`
`850 mg (1–3 times a day), or 300 mg to 1000 mg once or twice a day, or as
`
`delayed-release metformin in a dose of 500 mg to 1000 mg once or twice a day, or
`
`500 mg to 2000 mg once a day, or wherein the dose of metformin is 500 mg, 850
`
`mg or 1000 mg as a single dose with a total daily dose of metformin of 500–2850
`
`mg, or 500 mg, 1000 mg, 1500 mg or 2000 mg metformin in delayed release form,
`
`or wherein the dose of metformin is 500 mg to 1000 mg.” (Ex. 1001, ’859 Patent,
`
`23:27–43).
`
`18.
`
`Independent claims 13 and 16–18 are similar to claim 1, but recite in a
`
`fixed combination different specified amounts of linagliptin and metformin that
`
`fall within the doses or dosage ranges specified in claim 1.
`
`19.
`
`Independent claim 13 recites 2.5 mg of
`
`linagliptin in a fixed
`
`combination with 500 mg to 1000 mg of metformin. (Ex. 1001, ’859 Patent, 24:9–
`
`14).
`
`20.
`
`Independent claim 16 recites 5 mg of
`
`linagliptin in a fixed
`
`combination with 100 mg to 500 mg or 200 mg to 850 mg (1–3 times a day), or
`
`300 mg to 1000 mg once or twice a day of metformin or 500 mg to 1000 mg once
`
`or twice a day or 500 mg to 2000 mg once a day of delayed-release metformin.
`
`(Ex. 1001, ’859 Patent, 24: 23–32).
`
`6
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`MYLAN Ex. 1002, Page 9
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`21.
`
`Independent claim 17 recites 5 mg of
`
`linagliptin,
`
`in a fixed
`
`combination with 500 mg, 850 mg, or 1000 mg as a single dose of metformin with
`
`a total daily dose of metformin of 500–2850 mg, or 500 mg, 1000 mg, 1500 mg or
`
`2000 mg metformin in delayed released form. (Ex. 1001, ’859 patent, 24:33–42).
`
`22.
`
`Independent claim 18 recites 5 mg of
`
`linagliptin in a fixed
`
`combination with 500 mg to 1000 mg of metformin.
`
`(Ex. 1001, ’859 Patent,
`
`24:43–48).
`
`23.
`
`Independent claim 14 is directed to an oral
`
`tablet
`
`formulation
`
`comprising 2.5 mg or 5 mg of linagliptin optionally in combination with metformin
`
`and a pharmaceutically acceptable carrier or diluent.
`
`(Ex. 1001, ’859 patent,
`
`24:16–20).
`
`24.
`
`Independent claim 20 is directed to a method of treatment, but
`
`specifies the administration of the formulation in independent claim 14 and an
`
`amount of 5 mg of linagliptin. (Ex. 1001, ’859 Patent, 24:53–58).
`
`25.
`
`The remaining method claims 2–12 and 19–22 are ultimately
`
`dependent from either of the independent claims 1 or 14. These dependent claims
`
`recite various oral doses of linagliptin and metformin within the doses or dosage
`
`ranges of the independent claims.
`
`26. Dependent claim 15 recites the oral dosage form of claim 14 with a
`
`particular dosage range of metformin within the dosage range stated in claim 1.
`
`7
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`MYLAN Ex. 1002, Page 10
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`VI.
`
`State of the Art as of May, 2006
`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)—the body's important source of fuel. With type II diabetes, the body
`
`either resists the effects of insulin—a hormone secreted by the pancreas that
`
`regulates the movement of sugar into cells—or does not produce enough insulin to
`
`maintain a normal glucose level. While there is no cure for type II diabetes, it can
`
`be managed by eating well, exercising, and maintaining a healthy weight. If diet
`
`and exercise are not enough to adequately manage a diabetic’s blood sugar, then he
`
`or she will require 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.
`
`(Ex.
`
`1002 ¶ 28; Ex. 1006, Hughes at 3; Ex. 1007, Brazg at A3; Ex. 1012, Chiasson at
`
`989). Specifically, metformin is a known biguanide that was first approved by the
`
`U.S. Food & Drug Administration for the therapeutic treatment of diabetes in
`
`1994. (See Ex. 1004, Glucophage Label).
`
`29. Metformin has been available in several
`
`forms,
`
`including an
`
`immediate release form (e.g., Glucophage IR in 1994), and long-acting form (e.g.,
`
`Glucophage XR in 2000), among other forms. (See Ex. 1004, Glucophage Label).
`
`The standard dose of metformin IR was well known to be 500 mg twice a day or
`
`8
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`MYLAN Ex. 1002, Page 11
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`850 mg once a day up to a total of 2,000 mg a day with a maximum of 2,550 mg a
`
`day (Ex. 1004 at 6).
`
`30. Metformin works by decreasing the amount of glucose made by the
`
`liver and increasing the amount of glucose absorbed into body tissues. (Ex. 1015,
`
`Kirpichnikov at E-26-E-27). As a result, metformin can help the body respond
`
`better
`
`to its own insulin and decrease blood glucose levels.
`
`(Ex. 1015
`
`Kirpichnikov at E-27).
`
`Figure 1 below illustrates generally how metformin
`
`reduces blood glucose levels.
`
`9
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`MYLAN Ex. 1002, Page 12
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`Fig. 1: Metformin’s Mechanism of Action.
`
`31. DPP-IV Inhibitors were also known to be beneficial in treating type II
`
`diabetes patients. (See e.g., ’510 publication ¶¶ [0004], [0297]; Ex. 1010 at 1092).
`
`DPP-IV Inhibitors have a completely different mechanism of action as compared
`
`to metformin. (Ex. 1009, Demuth at 40; Ex. 1014, Nielson at 707-708; Ex. 1015,
`
`Kirpichnikov at E-26-E-27). 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.
`
`(See Ex. 1014, Nielson at 708; Ex. 1011 at Gwaltney at 149-
`
`150).
`
`In addition, these drugs help prevent the liver from producing an excess
`
`amount of sugar.
`
`(See Ex. 1014, Nielson at 707–708; Ex. 1011 at Gwaltney at
`
`149–150). Figure 2 below illustrates how DPP-IV Inhibitors reduce blood glucose
`
`levels.
`
`10
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`MYLAN Ex. 1002, Page 13
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`Fig. 2: Mechanism of Action of DPP-IV Inhibitors
`
`32. As of May 4, 2006, treating type II diabetes with DPP-IV Inhibitors
`
`was also well-known.
`
`(See e.g., ’510 publication ¶ [0004], [0297]).
`
`The
`
`development of DPP-IV Inhibitors began in the 1970’s after the discovery of DPP
`
`IV in the 1960’s as an amino peptidase. (Ex. 1009, Demuth at 34). More than a
`
`year before May 4, 2006, several DPP-IV Inhibitors, including sitagliptin and
`
`vildagliptin, were well-known treatments for type II diabetes. (See e.g., Ex. 1006,
`
`Hughes at 12; Ex. 1005, Ahrén at 2874; Ex. 1007, Brazg at A3; Ex. 1014, Nielson
`
`at 708; Ex. 1009, Demuth at 40–41).
`
`33. Moreover, as of May 4, 2006, linagliptin was also a known DPP-IV
`
`Inhibitor that was effective in treating type II diabetes. (Ex. 1003, ’510 Publication
`
`11
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`MYLAN Ex. 1002, Page 14
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`

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`at ¶¶ [0004], [0245], and [0297]).
`
`In fact, linagliptin had been reported as more
`
`potent
`
`than the DPP-IV Inhibitors vildagliptin and sitagliptin.
`
`Specifically,
`
`Gwaltney disclosed that vildagliptin and sitagliptin had higher IC50 values and
`
`therefore less potency than linagliptin. (Ex. 1011, Gwaltney at 158; compare Ex.
`
`1003, ’510 publication at ¶ [0295] with Ex. 1011, Gwaltney at 158)).
`
`34. Because type II diabetes is a progressive disease, patients who
`
`initially respond well
`
`to monotherapy often require increased dosages or
`
`combination therapy with other antidiabetic agents in order to maintain adequate
`
`glycemic control.
`
`(Ex. 1006, Hughes at 2; Ex. 1012, Chiasson at 989).
`
`It was
`
`well-known in the art
`
`that metformin was commonly combined with other
`
`antidiabetic agents having separate and distinct mechanisms of action than
`
`metformin’s mechanism of action used to treat type II diabetes, including insulin,
`
`sulfonylureas, thiazolidinediones, and DPP-IV Inhibitors. (Ex. 1015, Kirpichnikov
`
`at E-25; Ex. 1004, Glucophage Label at 6; Ex. 1006, Hughes at 12–13; Ex. 1005,
`
`Ahrén at 2874; Ex. 1007, Brazg at A3). For instance, taking advantage of these
`
`different mechanism of action, it had been demonstrated that metformin could be
`
`combined with the DPP-IV Inhibitors, vildagliptin and sitagliptin, with such
`
`combinations providing a significantly improved patient outcome than use of
`
`metformin or either DPP-IV Inhibitor alone. (Ex. 1006, Hughes at 32; Ex. 1005,
`
`Ahrén at 2874; Ex. 1007, Brazg at A3).
`
`12
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`MYLAN Ex. 1002, Page 15
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`35. Moreover, the interactions between the two drug families—metformin
`
`and DPP-IV Inhibitors—were “known to be encouraging and mechanistically
`
`predictable.” (Ex. 1010, Deacon at 1096; Ex. 1009, Demuth at 40).
`
`In fact, the
`
`combination of valine-pyrrolidide, another DPP-IV Inhibitor, and metformin even
`
`showed “synergistic” effects compared to either metformin or valine-pyrrolidide
`
`alone. (Ex. 1013, Yasuda at 614–15).
`
`36.
`
`Finally, the specific combination therapy of linagliptin and metformin
`
`was taught in the ’510 Publication. (Ex. 1003, ’510 Publication at ¶ [0298] (“The
`
`compounds according to the invention [including linagliptin] may also be used in
`
`conjunction with other active substances. Therapeutic agents which are suitable
`
`for such combination include, for example, antidiabetics, such as me[t]formin.”)).
`
`Thus, the state of the prior art was such that the use of linagliptin in combination
`
`with metformin for treatment of type II diabetes was known.
`
`37.
`
`Similarly, prior to May 4, 2006, it was well-known 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 of 1nM)
`
`with Ex. 1020, Gwaltney at 158, (disclosing IC50 value 18nM for sitagliptin)).
`
`38.
`
`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
`
`13
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`MYLAN Ex. 1002, Page 16
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`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.
`
`VII. Obviousness of Claims 1-22 of the ’859 Patent
`A.
`The Basis of my Analysis with Respect to Obviousness
`39.
`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 as of May 4, 2006, and in light of the
`
`general knowledge in the art.
`
`40.
`
`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, knowledge of the POSA at the relevant time period, and common sense
`
`available to a POSA.
`
`14
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`MYLAN Ex. 1002, Page 17
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`41.
`
`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.
`
`42.
`
`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.
`
`43.
`
`Ground 1: Claims 1–22 Are Unpatentable Under 35 U.S.C. § 103(a)
`over the ’510 Publication in view of the Glucophage Label
`
`The ’510 Publication (Ex. 1003)
`1.
`The ’510 Publication was published on May 20, 2004. The ’510
`
`publication discloses novel DPP-IV inhibitors that are capable of treating type II
`
`diabetes. (Ex. 1003, ’510 publication at ¶ [0004]).
`
`44.
`
`The ’510 Publication explicitly discloses linagliptin in Example
`
`2(142) as 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
`
`(R)-amino-piperidin-1-yl)-xanthine.
`
`(Id. at ¶ [0245]).
`
`The ’510 publication
`
`teaches the potency of test substances, expressed as IC50 values, which are
`
`15
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`MYLAN Ex. 1002, Page 18
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`

`
`calculated from dosage/activity curves consisting of 11 measuring points in each
`
`case.
`
`(Id. at ¶ [0295]). According to the potency test, Example 2(142)
`
`(linagliptin), exhibited a DPP-IV inhibition IC50 value of 1nM.
`
`(Id.). Thus, the
`
`linagliptin was one of the five most potent compounds disclosed. (Id.).
`
`45.
`
`The ’510 publication also discloses that
`
`the disclosed DPP-IV
`
`inhibitors may be used in conjunction with antidiabetics such as metformin. (Id. at
`
`¶ [0298]). The disclosed DPP-IV inhibitors are administered “by oral route, 1 to
`
`1000 mg, preferably 1 to 100 mg,” 1 to 4 times a day. (Id. at ¶ [0300]).
`
`46.
`
`Finally, the ’510 Publication teaches:
`
`[T]he compounds of formula I . . ., optionally combined with other active
`substances, may be incorporated together with one or more inert
`conventional carriers and/or diluents,
`.
`.
`.
`into conventional galenic
`preparations such as plain or coated tablets, capsules, powders, suspensions
`or suppositories.
`
`(Id.).
`
`47.
`
`Thus,
`
`the ’510 Publication discloses linagliptin/metformin fixed
`
`combination dosage forms, and their use to treat type II diabetes.
`
`Glucophage Label (Ex. 1004)
`2.
`The Final Printed Labeling for Glucophage® (“Glucophage Label”)
`
`48.
`
`was approved and published by the U.S. Food and Drug Administration (“FDA”)
`
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`MYLAN Ex. 1002, Page 19
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`

`
`for treating type II diabetes in February 2001, and is prior art to the ’927 patent
`
`under 35 U.S.C. § 102(b).
`
`49. Glucophage IR is a metformin hydrochloride immediate release tablet.
`
`(Ex. 1004, Glucophage Label at 2). The Glucophage Label discloses a dosing
`
`schedule for Immediate-Release metformin monotherapy in the “Recommended
`
`Dosing Schedule” section:
`
`The usual starting dose of GLUCOPHAGE (metformin hydrochloride
`tablets) is 500 mg twice a day or 850 mg once a day, given with meals.
`Dosage increases should be made in increments of 500 mg weekly or
`850 mg every 2 weeks, up to a total of 2000 mg per day, given in
`divided doses. Patients can also be titrated from 500 mg twice a day to
`850 mg twice a day after 2 weeks. For those patients requiring
`additional glycemic control, GLUCOPHAGE may be given to a
`maximum daily dose of 2550 mg per day. Doses above 2000 mg may
`be better tolerated given three times a day with meals.
`
`(Ex. 1004 at 6).
`
`Independent Claims 1, 13, and 16–18
`3.
`50. As show in Table 1 below, independent claim 1 of the ’859 patent
`
`recites three elements: (i) a method of treatment for type II diabetes comprising (ii)
`
`administering to a patient in need thereof a pharmaceutically effective oral dose of
`
`linagliptin or a therapeutically active salt thereof in a dose of 2.5mg or 5mg, and
`
`(iii) metformin, in a dose of 100 mg to 500 mg or 200 mg to 850 mg (1–3 times a
`
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`

`
`day), or 300 mg to 1000 mg once or twice a day, or as delayed-release metformin
`
`in a dose of 500 mg to 1000 mg once or twice a day, or 500 mg to 2000 mg once a
`
`day, or wherein the dose of metformin is 500 mg, 850 mg or 1000 mg as a single
`
`dose with a total daily dose of metformin of 500–2850 mg, or 500 mg, 1000 mg,
`
`1500 mg or 2000 mg metformin in delayed release form, or wherein the dose of
`
`metformin is 500 mg to 1000 mg. (Ex. 1001, ’859 Patent, 23:28–43).
`
`51.
`
`The ’510 Publication and Glucophage Label disclose claimed
`
`elements (i)–(iii) as produced below in Table 1.
`
`Table 1
`The ’510 Publication and
`the Glucophage Label
`Compounds with “an inhibiting effect on the
`activity of the enzyme dipeptidylpeptidase-IV
`(DPP-IV)” are useful “for the prevention or
`treatment of … type II diabetes mellitus.” (Ex.
`1003 at ¶ [0004]; see also Ex. 1003 at ¶ [0297]
`(explaining that the compounds disclosed therein
`can treat type II diabetes)).
`The ’510 publication discloses that its “present
`invention relates to new substituted xanthines of
`general formula I:”
`
`Claim 1 of the ’859 Patent
`1[i] A method of treatment
`for type II diabetes
`comprising
`
`[ii] administering to a patient
`in need thereof a
`pharmaceutically effective
`oral dose of linagliptin or a
`therapeutically active salt
`thereof in a dose of 2.5mg or
`
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`MYLAN Ex. 1002, Page 21
`
`

`
`5mg, and
`
`(Ex. 1003 at ¶ [0003]).
`
`“Most particularly preferred are the following
`compounds of general formula I: “…1-[(4-
`methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-
`butyn-1-y1)-8-(3-(R)-amino-piperidin-1-y1)-
`xanthine.” (“linagliptin”) (Id. at ¶ [0245]).
`
`The ’510 Publication thus discloses linagliptin,
`whose activity is also specified in Example
`2(142). (Ex. 1003 at ¶¶ [0245], [0295).
`
`The ’510 Publication discloses that “[t]he dosage
`required to achieve such an effect . . . by oral
`route [is][sic] 1 to 1000 mg, preferably 1 to 100
`mg, in each case 1 to 4 times a day.” (Ex. 1003
`at ¶ [0300]).
`As seen from this passage, the most preferable
`oral dosage range for linagliptin encompasses
`and thus anticipates the claimed dose recited in
`
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`
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`
`

`
`[iii] metformin, in a dose of
`100 mg to 500 mg or 200 mg
`to 850 mg (1–3 times a day),
`or 300 mg to 1000 mg once
`or twice a day, or as delayed-
`release metformin in a dose
`of 500 mg to 1000 mg once
`or twice a day, or 500 mg to
`2000 mg once a day, or
`wherein the dose of
`metformin is 500 mg, 850 mg
`or 1000 mg as a single dose
`with a total daily dose of
`metformin of 500–2850 mg,
`or 500 mg, 1000 mg, 1500
`mg or 2000 mg metformin in
`delayed release form, or
`wherein the dose of
`metformin is 500 mg to 1000
`mg.
`
`claim 1.
`The ’510 Publication discloses that “[t]he
`compounds according to the invention may also
`be used in conjunction with other active
`substances. Therapeutic agents which are
`suitable for such combinations include, for
`example, antidiabetics, such as me[t]formin….”
`(Ex. 1003 at ¶ [0298]).
`
`The Glucophage Label discloses that
`Glucophage IR is a metformin hydrochloride
`immediate release tablet. (Ex. 1004, Glucophage
`Label at 2). The Glucophage Label discloses a
`dosing schedule for Immediate-Release
`metformin monotherapy in the “Recommended
`Dosing Schedule” section:
`“The usual starting dose of GLUCOPHAGE
`(metformin hydrochloride tablets) is 500 mg
`twice a day or 850 mg once a day, given with
`meals. Dosage increases should be made in
`increments of 500 mg weekly or 850 mg every 2
`weeks, up to a total of 2000 mg per day, given in
`divided doses. Patients can also be titrated from
`500 mg twice a day to 850 mg twice a day after 2
`weeks. For those patients requiring additional
`glycemic control, GLUCOPHAGE may be given
`
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`MYLAN Ex. 1002, Page 23
`
`

`
`to a maximum daily dose of 2550 mg per day.
`Doses above 2000 mg may be better tolerated
`given three times a day with meals.” (Ex. 1004
`at 6 (emphases added)).
`
`52. A POSA would have been motivated to employ the known standard
`
`metformin dosages as taught in the Glucophage Label to the linagliptin/metformin
`
`combination discussed in the ’510 Publication.
`
`Indeed, a POSA would have
`
`understood that when metformin was used in combination with other known, less
`
`potent DPP-IV Inhibitors—sitagliptin and vildagliptin—to treat type II diabetes,
`
`the amounts of metformin used were substantially the same standard monotherapy
`
`dosage disclosed in the Glucophage Label. (Ex. 1006, Hughes at 24; Ex. 1005,
`
`Ahrén at 2874; Ex. 1007, Brazg at A3).
`
`53. A POSA would have also had a reasonable expectation that
`
`administering standard monotherapy doses of metformin with oral doses of
`
`linagliptin would have been effective in treating type II diabetes, particularly given
`
`the ’510 Publication’s disclosure that metformin can be combined with DPP-IV
`
`Inhibitors, including linagliptin, to treat type II diabetes. (Ex. 1003 at ¶ [0298]). In
`
`the end, the alleged invention simply includes use of two well-known drugs—
`
`metformin and DPP-IV Inhibitors (linagliptin)—performing the same function they
`
`have been known to perform (reducing blood glucose levels) and yielding no more
`
`than one would have expected from combining metformin with other, less potent
`
`21
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`
`

`
`DPP-IV Inhibitors having the same mechanism of action as linagliptin—which
`
`were already known as effective combination therapies for treating type II
`
`diabetes. Accordingly, the combination of DPP-IV Inhibitors (linagliptin) and
`
`metformin recited in claim 1 would have been obvious in view of the ’510
`
`Publication and the Glucophage Label.
`
`54.
`
`Independent claims 13 and 16–18 are similar to claim 1, but recite in a
`
`fixed combination different specified amounts of linagliptin and metformin that
`
`fall within the doses or dosage ranges specified in claim 1. Independent claim 13
`
`recites 2.5 mg of linagliptin in a fixed combination with 500 mg to 1000 mg of
`
`metformin. (Ex. 1001, ’859 Patent, 24:9–14).
`
`55.
`
`Independent claim 16 recites 5 mg of
`
`linagliptin in a fixed
`
`combination with 100 mg to 500 mg or 200 mg to 850 mg (1–3 times a day), or
`
`300 mg to 1000 mg once or twice a day of metformin or 500 mg to 1000 mg once
`
`or twice a day or 500 mg to 2000 mg once a day of delayed-release metformin.
`
`(Ex. 1001, ’859 Patent, 24: 23–32).
`
`56.
`
`Independent claim 17 recites