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. 8,673,927 to Dugi et al.
`Issue Date: March 18, 2014
`Title: Treatment for Diabetes Patients Inappropriate for Metformin Therapy
`
`Inter Partes Review No.: IPR2016-01563
`
`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 ’927 patent................................................................................................5
`VI.
`State of the Art as of May, 2006......................................................................8
`VII. Anticipation of Claims 18-26 of the ’927 patent...........................................14
`A.
`The Basis of my Analysis with Respect to Anticipation ....................14
`B.
`Ground 1: Claims 18-26 are anticipated by ’510 Publication.............14
`1.
`The ’510 Publication Anticipates Dependent Claims 21-
`26...............................................................................................18
`VIII. Obviousness of Claims 1-26 of the ’927 Patent............................................19
`A.
`The Basis of my Analysis with Respect to Obviousness....................19
`B.
`Ground 2: Claims 1–26 Would Have Been Obvious Under 35
`U.S.C. § 103(a) Over the ’510 Publication and the Glucophage
`Label....................................................................................................20
`1.
`Glucophage Label (Ex. 1004)...................................................20
`2.
`Independent Claims 1-9 Are Obvious ......................................21
`3.
`Claims 10–17 Are Obvious.......................................................24
`4.
`Independent Claims 18-20 and Dependent Claim 21-26
`are Obvious ...............................................................................26
`Ground 3: Claims 1–26 Would Have Been Obvious Under 35
`U.S.C. § 103(a) Over the ’510 Publication and Ahrén, Hughes,
`and/or Brazg ........................................................................................28
`
`C.
`
`ii
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`MYLAN Ex. 1002, Page 2
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`

`
`1.
`2.
`3.
`4.
`5.
`6.
`
`Ahrén (Ex. 1005).......................................................................28
`Hughes (Ex. 1006) ....................................................................30
`Brazg (Ex. 1007).......................................................................31
`Independent Claims 1 and 10 Are Obvious..............................32
`Dependent Claims 2-9 and 11-17 are Obvious.........................37
`Independent Claims 18-20 and Dependent Claims 21-26
`are Obvious ...............................................................................37
`There is no Objective Evidence of Nonobviousness.....................................38
`Conclusion .....................................................................................................40
`
`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. 8,673,927 (the “’927 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. 8,673,927. 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 Drew University. I am board certified in
`
`1 I refer to “type II diabetes mellitus” as “type II diabetes.”
`
`2
`
`MYLAN Ex. 1002, Page 5
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`

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`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.
`
`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
`
`3
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`MYLAN Ex. 1002, Page 6
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`

`
`understand that a POSA is not an extraordinarily innovative person, but is a person
`
`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 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.
`
`12. 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,
`
`4
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`MYLAN Ex. 1002, Page 7
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`
`conducted my analyses, and formed my opinions in my Declaration through the
`
`eyes of the POSA as of May 4, 2006.
`
`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 ’927 Patent
`14.
`I have considered the disclosure and file history of the ’927 patent in
`
`light of general knowledge in the relevant field as of May 4, 2006.
`
`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 ’927 specification
`
`as it would be interpreted by one of ordinary skill in the art.
`
`17.
`
`The claims of the ’927 patent are directed to methods of treating type
`
`II diabetes in a patient 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. (Ex. 1001, ’927 Patent, at 23:45–26:18).
`
`18. Claim 1 of the ’927 patent is reproduced below.
`
`5
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`MYLAN Ex. 1002, Page 8
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`A method of treating type II diabetes mellitus comprising
`1.
`administering to a patient in need thereof a pharmaceutically effective
`oral amount of 1-[(4-methyl-quinazolin-2-yl)-methyl]-3-methyl-7-(2-
`butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine
`[“linagliptin”],
`and a pharmaceutically effective amount of metformin, which is from
`300 mg to 1000 mg once or twice a day, or 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.
`
`(Id. at 23:46–54).
`
`19. Claims 2–9 depend from claim 1 and further recite particular oral
`
`doses of linagliptin. (Id., 23:54–24:20).
`
`20. Claim 10 of the ’927 patent is reproduced below.
`
`10. A method of treating type 2 diabetes mellitus or pre-diabetes
`comprising administering to a patient in need thereof a therapeutically
`effective oral amount of 1-[(4-methyl-quinazolin-2-yl)-methyl]-3-
`methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine
`[“linagliptin”] in combination with a therapeutically effective amount
`of metformin, which is 500 mg, 850 mg or 1000 mg metformin as a
`single dose with a total daily dose of metformin of 500-2850 mg, or
`which is 500 mg, 1000 mg, 1500 mg or 2000 mg metformin in
`delayed release form.
`
`(Id., 24:21–29).
`
`21. Claims 11-17 depend from claim 10 and further recite particular oral
`
`doses of linagliptin. (Id., 24:30–57).
`
`6
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`MYLAN Ex. 1002, Page 9
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`

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`22. Claim 18 of the ’927 patent is reproduced below.
`
`18. A method of treating type II diabetes mellitus comprising
`administering to a patient in need thereof a pharmaceutically effective
`oral amount of 1-[(4-methyl-quinazolin-2-yl)-methyl]-3-methyl-7-(2-
`butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine
`[“linagliptin”]
`which is an oral daily dose from 2.5 mg to 10 mg, and a
`pharmaceutically effective amount of metformin.
`
`(Id., 24:58–64.)
`
`23. Claim 19 of the ’927 patent is reproduced below.
`
`19. A method of treating type II diabetes mellitus comprising
`administering to a patient in need thereof a pharmaceutically effective
`oral amount of 1-[(4-methyl-quinazolin-2-yl)-methyl]-3-methyl-7-(2-
`butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine
`[“linagliptin”]
`which is an oral daily dose of 5 mg, and a pharmaceutically effective
`amount of metformin.
`
`(Id., 24:65–25:3).
`
`24. Claim 20 of the ’927 patent is reproduced below.
`
`20. A method of treating type II diabetes mellitus comprising
`administering to a patient in need thereof a pharmaceutically effective
`oral amount of 1-[(4-methyl-quinazolin-2-yl)-methyl]-3-methyl-7-(2-
`butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine [“linagliptin”] in
`combination with a therapeutically effective dose of metformin,
`wherein
`the
`1-[(4-methyl-quinazolin-2-yl)-methyl]-3-methyl-7-(2-
`butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is administered
`in an oral dosage of from 0.5 mg to 50 mg.
`7
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`MYLAN Ex. 1002, Page 10
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`(Id., 25:4–12).
`
`25. Claims 21–26 depend from claim 20 and further recite particular oral
`
`doses of linagliptin. (Id., 24:30–57).
`
`VI.
`
`State of the Art as of May, 2006
`26.
`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.
`
`27.
`
`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). Metformin has been available in several
`
`forms, including an immediate release form (e.g., Glucophage IR in 1994), and
`
`8
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`MYLAN Ex. 1002, Page 11
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`

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`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 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). 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.
`
`28. 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
`
`10
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`MYLAN Ex. 1002, Page 13
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`

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`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.
`
`Fig. 2: Mechanism of Action of DPP-IV Inhibitors
`
`29. 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
`
`11
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`MYLAN Ex. 1002, Page 14
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`

`
`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). 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 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)).
`
`30. 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,
`
`12
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`MYLAN Ex. 1002, Page 15
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`

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`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).
`
`31. 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).
`
`32.
`
`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)). 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
`
`13
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`MYLAN Ex. 1002, Page 16
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`

`
`inhibit the function than a higher value. The values are typically expressed as
`
`molar concentration.
`
`33.
`
`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.
`
`VII. Anticipation of Claims 18-26 of the ’927 patent
`A.
`The Basis of my Analysis with Respect to Anticipation
`34.
`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.
`
`B.
`35.
`
`Ground 1: Claims 18-26 are anticipated by ’510 Publication
`The ’510 Publication discloses orally administering a combination of
`
`metformin and the DDP-IV Inhibitor, linagliptin, as an effective combination
`
`therapy for treating type II diabetes, and thus anticipates independent claims 18–
`
`20.
`
`(Ex. 1003 at ¶ [0004], [0297], and [0298]). Table 1 below identifies for
`
`14
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`MYLAN Ex. 1002, Page 17
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`

`
`representative claim 18 where each respective element (i.e., elements i–iv) for this
`
`claim is disclosed in the ’510 Publication.
`
`Claim 18 of the ’927 Patent
`18[i] A method of treating
`type II diabetes mellitus
`comprising
`
`[ii] administering to a patient
`in need thereof a
`pharmaceutically effective
`oral amount of 1-[(4-methyl-
`quinazolin-2-yl)-methyl]-3-
`methyl-7-(2-butyn-1-yl)-8-(3-
`(R)-amino-piperidin-1-yl)-
`xanthine (“linagliptin”)
`
`Table 1
`
`The ’510 Publication
`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 present invention relates to new substituted
`xanthines of general formula I:”
`
`(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)-
`
`15
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`MYLAN Ex. 1002, Page 18
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`

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`xanthine.” (“linagliptin”) (Id. at ¶ [0245]).
`
`The ’510 Publication discloses linagliptin, whose
`activity is also specified in Example 2(142).
`(Ex. 1003 at ¶ [0245], [0295]).
`
`The compounds of this publication are described
`as suitable for a medical use, namely, for the
`prevention and treatment of type II diabetes.
`Therefore, the ’510 Publication also discloses
`pharmaceutically effective oral doses of
`linagliptin. (See Ex. 1003 at ¶ [0297] (“In view
`of their ability to inhibit DPP-IV activity, … [i]t
`is therefore expected that the compounds
`according to the invention … will be suitable for
`the prevention or treatment of diseases … such
`as … type 2 diabetes mellitus); ¶ [0300] (The
`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”);
`¶ [0296] (“The compounds prepared according to
`the invention are well-tolerated….”).
`“The 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]).
`
`16
`
`[iii] which is an oral daily
`dose of from 2.5 mg to 10
`mg,
`
`MYLAN Ex. 1002, Page 19
`
`

`
`[iv] and a pharmaceutically
`effective amount of
`metformin.
`
`As seen from this passage, the most preferable
`oral dosage range for linagliptin encompasses
`and thus anticipates the claimed dose recited in
`claim 18.
`“The 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]).
`
`A POSA would understand that the ’510
`Publication’s reference to “metformin” refers to
`a “pharmaceutically effective amount of
`metformin” because the compound is described
`as being suitable for a medical use, namely, for
`combination therapy with DPP-IV inhibitors,
`including linagliptin, for the prevention and
`treatment of type II diabetes. (See Ex. 1003 at
`¶ [0297])
`Claims 19 and 20 are similar to claim 18, but respectively limit the
`
`36.
`
`linagliptin dose to 5mg and from 0.5mg to 50mg. (Ex. 1001, 24:58-25:3). Those
`
`claimed amounts are anticipated for the same reasons set forth in Table 1 above for
`
`claim 18(iii). Claims 19 and 20 also require administering a “therapeutically”
`
`effective amount of linagliptin and metformin. This limitation is anticipated
`
`17
`
`MYLAN Ex. 1002, Page 20
`
`

`
`because the ’510 Publication discloses a pharmaceutically effective amount of
`
`linagliptin and metformin (see Table 1, claim 18(ii) above). Prior to May 4, 2006,
`
`the POSA would have understood that a “therapeutically effective” amount refers
`
`to an amount sufficient to produce an intended biological response, and that such
`
`amount would
`
`include
`
`a
`
`“pharmaceutically effective
`
`amount”
`
`because
`
`administering an amount suitable for a medical use will elicit a biological response.
`
`The ’510 Publication Anticipates Dependent Claims 21-26
`1.
`37. Claims 21–26 depend from claim 20. Each claim recites various oral
`
`doses of linagliptin for administering to the patient.
`
`(Ex. 1001, 25:13–26:18).
`
`Those amounts are subsets of the amounts recited in claim 20, as shown below in
`
`Table 2.
`
`Table 2
`Linagliptin Dose Limitation of Claims 21–26 of the ’927 Patent
`21. “. . . . in an oral dosage of from 2.5 mg to 50 mg . . . .”
`22. “. . . . in an oral dosage of from 2.5 mg to 10 mg . . . .”
`23. “. . . . in an oral dosage of 0.5 mg, 1 mg, 2.5 mg, 5 mg, or 10 mg . . . .”
`24. “. . . . in an oral dosage of 1 mg, 2.5 mg, or 5 mg . . . .”
`25. “. . . . in an oral dosage of 2.5 mg or 5 mg . . . .”
`26. “. . . . in an oral daily dose of 5 mg . . . .”
`
`38.
`
`The ’510 Publication discloses each oral dose of linagliptin recited in
`
`claims 21-26.
`
`(See Ex. 1003 at ¶ [0300]). Thus, these claims are anticipated for
`
`the same reasons as set forth above with respect to claim 20. See also Table 1,
`
`18
`
`MYLAN Ex. 1002, Page 21
`
`

`
`claim 18(iii). Accordingly, in my opinion, claims 21-26 are anticipated by the
`
`’510 Publication.
`
`VIII. Obviousness of Claims 1-26 of the ’927 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.
`
`19
`
`MYLAN Ex. 1002, Page 22
`
`

`
`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.
`
`1.
`43.
`
`Ground 2: Claims 1–26 Would Have Been Obvious Under 35
`U.S.C. § 103(a) Over the ’510 Publication and the Glucophage
`Label
`
`Glucophage Label (Ex. 1004)
`The Final Printed Labeling for Glucophage® (“Glucophage Label”)
`
`was approved and published by the U.S. Food and Drug Administration (“FDA”)
`
`for treating type II diabetes in February 2001.
`
`44. Glucophage IR is a metformin hydrochloride immediate release tablet.
`
`(Ex. 1004, Glucophage Label at 2). Glucophage Label discloses a dosing schedule
`
`20
`
`MYLAN Ex. 1002, Page 23
`
`

`
`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 (emphases added)).
`
`Independent Claims 1-9 Are Obvious
`2.
`45. Claim 1 is directed to a method of treating type II diabetes by
`
`administering a pharmaceutically effective oral dose of
`
`linagliptin and a
`
`pharmaceutically effective amount of metformin from 300 mg to 1000 mg once or
`
`twice a day.
`
`Claims 1-9 also recite various amounts for delayed-release
`
`metformin. Those amounts, however, are not relevant to Ground 2.
`
`46.
`
`The ’510 Publication discloses administering an oral dose of
`
`linagliptin in combination with metformin as a treatment for patients with type II
`
`diabetes, as recited in claim 1.
`
`(see supra Table 1 at 18(i)-(iv)). The ’510
`
`21
`
`MYLAN Ex. 1002, Page 24
`
`

`
`Publication does not disclose the claimed dosages of metformin combined with
`
`linagliptin.
`
`47.
`
`However, the Glucophage Label discloses the use of metformin in
`
`single oral dose of 500 mg to 1500 mg and 850 mg to 2550 mg. (Ex. 1004 at 2, 6).
`
`These standard metformin dosage disclosed in the Glucophage Label encompass
`
`the claimed metformin ranges recited in claim 1.
`
`48. Moreover, the metformin dosages disclosed in the Glucophage Label
`
`are pharmaceutically effective amounts because they are suitable for a medical use,
`
`namely to treat type II diabetes. A “therapeutically” effective amount would
`
`include a “pharmaceutically” effective amount. See ¶ 36, supra.
`
`49. 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).
`
`50.
`
`In my opinion, A POSA would have also had a reasonable expectation
`
`that administering standard monotherapy doses of metformin with oral doses of
`
`22
`
`MYLAN Ex. 1002, Page 25
`
`

`
`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
`
`my opinion, the alleged claimed 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 DPP-IV Inhibitors—which were already known as effective
`
`combination therapies for treating type II diabetes and have the same mechanism
`
`of action as