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. 8,846,695 to Dugi
`Issue Date: Sept. 30, 2014
`Title: Treatment for Diabetes in Patients
`with Inadequate Glycemic Control
`Despite Metformin Therapy Comprising a DPP-IV Inhibitor
`
`Inter Partes Review No.: IPR2016-01564
`
`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. 8,846,695 to Dugi
`Issue Date: Sept. 30, 2014
`Title: Treatment for Diabetes in Patients
`with Inadequate Glycemic Control
`Despite Metformin Therapy Comprising a DPP-IV Inhibitor
`
`Inter Partes Review No.: IPR2016-01564
`
`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.................................................................1
`IV.
`Person of Ordinary Skill in the Art (POSA)....................................................3
`V.
`The ’695 patent................................................................................................5
`VI.
`State of the Art as of January, 2009 ................................................................6
`1.
`Metformin ...................................................................................6
`2.
`DPP-IV Inhibitors .......................................................................7
`3.
`The Combination of DPP-IV Inhibitors, Specifically
`Linagliptin, was Known in the Art .............................................9
`The Benefits of Administering DPP-IV Inhibitors with
`Metformin in Type II Diabetes Patients with Inadequate
`Glycemic Control Despite Therapy with Metformin
`Were Well-Known....................................................................10
`VII. Obviousness of Claims 1-4 of the ’695 patent ..............................................11
`A.
`The basis of my analysis with respect to obviousness........................11
`B.
`Ground 1: Claims 1–4 are Obvious Over Charbonnel or Hughes
`in View of the ’940 Publication ..........................................................12
`1.
`Charbonnel (Ex. 1004)..............................................................12
`2.
`Hughes (Ex. 1005) ....................................................................14
`3.
`The ’940 Publication (Ex. 1003)...............................................15
`4.
`Independent Claims 1 and 2......................................................17
`5.
`Dependent Claims 3 and 4 ........................................................20
`
`4.
`
`ii
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`MYLAN Ex. 1002, Page 2
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`
`
`C.
`
`Obviousness Ground 2: Janumet Label, Nauck, and Ahrén 2008
`in View of the ’940 Publication ..........................................................20
`1.
`Janumet Label (Ex. 1007).........................................................20
`2.
`Nauck (Ex. 1006)......................................................................21
`3.
`Ahrén 2008 (Ex. 1022) .............................................................22
`4.
`Independent Claims 1 and 2......................................................25
`5.
`Claims 3 and 4...........................................................................28
`VIII. There is no Evidence of Secondary Considerations......................................28
`IX. Conclusion .....................................................................................................29
`
`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. 8,846,695 (the “’695 patent”), Ex. 1001. I have considered references
`
`published prior to January 7, 2009. 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 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. 8,846,695.
`
`I refer herein to the prior art references and other
`
`documents cited herein using the defined terms presented in the Petition.
`
`III. My Background and Qualifications
`
`1
`
`MYLAN Ex. 1002, Page 4
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`
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`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 2009. 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. 1009,
`
`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 completed
`
`my residency at Cornell Medical School, Bellevue Hospital in Internal Medicine in
`
`1963.
`
`I then completed my research fellowship at the University of Washington
`
`King County Hospital in Endocrinology and Metabolism.
`
`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, 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.
`
`1 I refer to “type II diabetes mellitus” as “type II diabetes.”
`
`2
`
`MYLAN Ex. 1002, Page 5
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`
`
`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
`
`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
`
`3
`
`MYLAN Ex. 1002, Page 6
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`
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`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 January 7, 2009
`
`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 2009, I am qualified to
`
`provide an opinion as to what a POSA would have understood, known, or concluded
`
`as of 2009. 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 January 7, 2009.
`
`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.
`
`4
`
`MYLAN Ex. 1002, Page 7
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`
`
`V.
`
`The ’695 patent
`14.
`I have considered the disclosure and file history of the ’695 patent in
`
`light of general knowledge in the relevant field as of January 7, 2009.
`
`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 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. Claim 1 of the ’695 patent is reproduced below.
`
`A method for treating type 2 diabetes mellitus in a patient
`1.
`with inadequate glycemic
`control despite
`therapy with
`metformin, said method comprising orally administering 1-[(4-
`methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-
`(3-(R)-amino-piperidin-1-yl)-xanthine [“linagliptin”]
`to said
`patient in an amount of 5 mg per day in combination with
`metformin.
`(Ex. 1001, ’695 Patent at 27:5–10).
`
`18. Claims 2 is similar, but
`
`recites giving linagliptin as “add-on
`
`combination with metformin.” (Ex. 1001, 27:11–17).
`
`5
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`MYLAN Ex. 1002, Page 8
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`
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`19. Dependent claims 3 and 4 recite different dosing frequencies of
`
`linagliptin—respectively, 5 mg once daily and 2.5 mg twice daily. (Ex. 1001, 27:18-
`
`25).
`
`VI.
`
`State of the Art as of January, 2009
`20.
`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. When
`
`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.
`
`1.
`21.
`
`Metformin
`It was well known that metformin, a “first line” treatment for type II
`
`diabetes that has been used worldwide for many years, 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. As a result,
`
`metformin can help the body respond better to its own insulin and decrease blood
`
`glucose levels. Metformin has been available in several forms,
`
`including an
`
`6
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`MYLAN Ex. 1002, Page 9
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`
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`immediate release form (e.g., Glucophage IR in 1994),
`
`long-acting form
`
`(Glucophage XR in 2000), among other forms. Figure 1 below illustrates generally
`
`how metformin reduces blood glucose levels in type II diabetes patients.
`
`Fig. 1: Metformin’s Mechanism of Action.
`
`DPP-IV Inhibitors
`2.
`22. 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 2009. DPP-IV Inhibitors have a completely different mechanism of
`
`7
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`MYLAN Ex. 1002, Page 10
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`
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`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
`
`23. A POSA would have recognized that metformin and linagliptin would
`
`work well concomitantly because they accomplish lowering of blood sugar via
`
`different physiologic pathways.
`
`(Ex. 1010, Brazg at Abstract 11-OR).
`
`8
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`MYLAN Ex. 1002, Page 11
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`
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`3.
`
`The Combination of DPP-IV Inhibitors, Specifically
`Linagliptin, was Known in the Art
`The combination of DPP-IV Inhibitors, such as linagliptin, and
`
`24.
`
`metformin to treat type II diabetes was known in the art. (Ex. 1003, ’940 Publication,
`
`¶¶ [0032], [0060]–[0061], [0091]; Ex. 1012, ’510 publication [245], [298]).
`
`Selection of linagliptin over other known DPP-IV Inhibitors—vildagliptin and
`
`sitagliptin—would have been an obvious choice for the POSA because of
`
`linagliptin’s superior properties. Specifically, prior to the alleged invention, it was
`
`known that linagliptin (also known as BI 1356), was a “long-lasting,” “preferred,”
`
`“potent,” and “selective DPP-IV inhibitor.” (E.g., Ex. 1003 ¶ [0044]; Ex. 1021,
`
`Thomas; Ex. 1011, ’731 publication ¶¶ [0021]-[0022]; Ex. 1017, Heise).
`
`25.
`
`In fact, linagliptin was known to be even longer-lasting DPP-IV
`
`Inhibitor than sitagliptin and vildagliptin.
`
`(Ex. 1021, Thomas (“BI 1356 can be
`
`preclinically differentiated from vildagliptin and sitagliptin by a longer-lasting
`
`inhibition of plasma DPP-IV activity and a longer-lasting improvement of glucose
`
`tolerance at the same doses”).
`
`26.
`
`In addition, it was known prior to the alleged date of invention that 2.5
`
`mg and 5 mg were effective dosages for linagliptin. (Ex. 1019, Huettner at Abstract;
`
`see also, Ex. 1020, Dugi 2006 (disclosing 5 mg as an effective dose)).
`
`27. And, it was well recognized that the combination of a DPP-IV Inhibitor
`
`with metformin was especially useful because each drug utilizes a different
`
`9
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`MYLAN Ex. 1002, Page 12
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`
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`mechanism of action. (Ex. 1010, Brazg at Abstract 11-OR (“Combination treatment
`
`with [sitagliptin] and metformin may be useful since these agents target different
`
`pathophysiologic processes leading to hyperglycemia in [type II diabetes].”); Ex.
`
`1008, Ahrén 2004, at 2874, 2878-9 (“LAF237 [vildagliptin] effectively prevents
`
`deterioration of glycemic control when added to metformin monotherapy in type 2
`
`diabetes.”); see also Ex. 1004, Charbonnel at 2638 (DPP-IV Inhibitor, “Sitagliptin
`
`100 mg once-daily added to ongoing metformin therapy was efficacious and well-
`
`tolerated in patients with type 2 diabetes who had inadequate glycemic control with
`
`metformin alone.”)).
`
`4.
`
`The Benefits of Administering DPP-IV Inhibitors with
`Metformin in Type II Diabetes Patients with Inadequate
`Glycemic Control Despite Therapy with Metformin
`Were Well-Known
`It was also well known that combinations of metformin with other
`
`28.
`
`diabetes drugs, including DPP-IV Inhibitors, such as sitagliptin and vildaglipitin,
`
`were used in addition to metformin when metformin alone provided insufficient
`
`glycemic control for a patient.
`
`(Ex. 1001, 2:35–40; 2:66–3:7; Ex. 1006, Nauck at
`
`194, 203; Ex. 1013, EMEA Galvus at 1, 33; Ex. 1016, EMEA Eucreas at 1, 26–7;
`
`Ex. 1007, Janumet at 1; Ex. 1014, Elrishi at 475-8; Ex. 1015, Pei at 526-8; Ex. 1005,
`
`Hughes at 2–3, 13, 22–23). For example, DPP-IV Inhibitor vildaglipitin “prevents
`
`deterioration of glycemic control when added to metformin monotherapy in type 2
`
`diabetes.” (Ex. 1008, Ahrén 2004, 2874; see also Ex. 1005 Hughes at 2–3, 13, 22–
`
`10
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`MYLAN Ex. 1002, Page 13
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`
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`23). Likewise, DPP-IV Inhibitor “[s]itagliptin 100mg once-daily added to ongoing
`
`metformin therapy was efficacious and well tolerated in patients with type 2 diabetes
`
`who had inadequate glycemic control with metformin alone.” (Ex. 1004, Charbonnel
`
`at 2638; see also Ex. 1006, Nauck at 194, 203).
`
`VII. Obviousness of Claims 1-4 of the ’695 patent
`A.
`The basis of my analysis with respect to obviousness
`29.
`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.
`
`30.
`
`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.
`
`11
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`MYLAN Ex. 1002, Page 14
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`
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`31.
`
`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.
`
`32.
`
`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 1: Claims 1–4 are Obvious Over Charbonnel or Hughes in
`View of the ’940 Publication
`Charbonnel (Ex. 1004)
`1.
`33. Charbonnel was published in 2006. Charbonnel discloses
`
`the
`
`evaluation of the efficacy and safety of the DPP-IV Inhibitor, sitagliptin, added to
`
`ongoing metformin therapy in patients with type II diabetes and inadequate glycemic
`
`control with metformin alone. (Ex. 1004, Charbonnel at 2638).
`
`34.
`
`For example, Charbonnel teaches:
`
`Sitagliptin 100 mg once-daily added to ongoing metformin therapy was
`efficacious and well tolerated in patients with type 2 diabetes who had
`
`12
`
`MYLAN Ex. 1002, Page 15
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`
`
`inadequate glycemic control with metformin alone.
`
`(Ex. 1004, Charbonnel at 2638).
`
`35. Charbonnel discloses that combining oral doses of sitagliptin with
`
`metformin is advantageous “[b]ecause sitagliptin and metformin target potentially
`
`complementary pathways, the addition of sitagliptin for patients with type 2 diabetes
`
`who do not have adequate glycemic control with metformin monotherapy may
`
`provide improved glycemic control.” (Id.). Charbonnel further discloses that
`
`metformin is often unsuccessful in achieving glycemic control in patients with type
`
`II diabetes and many patients require combination therapy. (Id. at 2638, 2642–3).
`
`36. Charbonnel discloses that the HbA1C and other relevant responses
`
`were sustained during the 24-week treatment period and “[n]early half of the patients
`
`receiving sitagliptin 100 mg once-daily achieved the current American Diabetes
`
`Association glycemic goal of A1C ≤ 7% compared with less than one-fifth of
`
`placebo treated patients.” (Ex. 1004, Charbonnel at 2642).
`
`37.
`
`The terms “HbA1c” and “A1c” refer to glycated haemoglobin. By
`
`measuring 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.
`
`38. Charbonnel further discloses that “Sitagliptin 100 mg was well
`
`tolerated in this clinical trial” without any “meaningful differences in the overall
`
`incidence of clinical adverse experiences.” (Id. at 2643). “The addition of sitagliptin
`
`13
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`MYLAN Ex. 1002, Page 16
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`
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`to ongoing metformin therapy did not lead to an increase in the incidence of
`
`gastrointestinal side effects, which are typically associated with metformin treatment
`
`alone.” (Id.).
`
`39. Charbonnel concludes that “in patients with type 2 diabetes who had
`
`inadequate glycemic control with metformin alone, the addition of [oral doses of]
`
`sitagliptin 100 mg once-daily was well
`
`tolerated and provided effective and
`
`sustained improvement” in various measures related to the treatment of type II
`
`diabetes. (Ex. 1004, Charbonnel at 2643).
`
`Hughes (Ex. 1005)
`2.
`40. Hughes published December 15, 2005.
`
`41. Hughes teaches that a problem with single-agent
`
`therapy for
`
`maintaining glycemic control, including metformin, is that it eventually fails to
`
`maintain adequate glycemic control over time. (Ex. 1005, Hughes at 2). Hughes
`
`discloses that this limitation may be overcome by combining multiple oral drugs to
`
`achieve reductions in blood glucose that cannot be sustained during long-term
`
`therapy with single agents. (Ex. 1005, Hughes at 2).
`
`42. Hughes teaches that it was known to add a DPP-IV Inhibitor to the
`
`standard diabetes treatment in patients whose disease was not adequately controlled
`
`by metformin alone (Ex. 1005 at 2–3, 13). Hughes also teaches that oral doses of
`
`14
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`MYLAN Ex. 1002, Page 17
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`
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`DPP-IV Inhibitors such as LAF237 (i.e., vildagliptin), can be administered in doses
`
`from about 1 to 100 mg daily. (Ex. 1005 at 22).
`
`3.
`43.
`
`44.
`
`The ’940 Publication (Ex. 1003)
`The ’940 Publication published December 6, 2007.
`
`The ’940 Publication states that DPP-IV Inhibitors are useful for
`
`treating patients diagnosed with disorders including type II diabetes. (E.g., Ex. 1003
`
`¶¶ [0025]–[0026], [0076]–[0078]). In the ’940 Publication linagliptin is listed first
`
`among a list of 12 “particularly preferred” DPP-IV Inhibitors. (Ex. 1003 ¶¶ [0031],
`
`[0032], and [0046]).
`
`45.
`
`The ’940 Publication teaches that the disclosed DPP-IV Inhibitors are
`
`especially potent, effective, long-lasting, and bring about “unexpected therapeutic
`
`advantages or improvements when combined with other” pharmaceuticals. (Ex.
`
`1003 ¶ [0044]); see also Ex. 1021, Thomas). Specifically, the ’940 Publication
`
`discloses DPP-IV Inhibitors in combination with other active substances including
`
`metformin. (See e.g., Ex. 1003 ¶¶ [0060], [0061], [0068], and [0091]). In particular,
`
`the ’940 Publication discloses that a particularly preferred example of an antidiabetic
`
`combination partner with DPP-IV Inhibitors is metformin “in doses of about 100 mg
`
`to 500 mg or 200 mg to 850 mg (1–3 times a day), or about 300 mg to 1000 mg once
`
`or twice a day, or delayed-release metformin in doses of about 100 mg to 1000 mg
`
`15
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`MYLAN Ex. 1002, Page 18
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`
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`or preferably 500 mg to 1000 mg once or twice a day or about 500 mg to 2000 mg
`
`once a day.” (Ex. 1003 ¶ [0068]).
`
`46.
`
`The ’940 Publication also teaches that the combination of DPP-IV
`
`Inhibitors and metformin is better than administration of metformin alone. (e.g., Ex.
`
`1003 ¶ [0091]). The ’940 Publication refers to combinations of DPP-IV Inhibitors
`
`with metformin as being “particularly preferred.” (Ex. 1003 ¶ [0068]).
`
`47.
`
`The ’940 Publication teaches oral administration of the DPP-IV
`
`Inhibitor in amounts of 0.5–100 mg, preferably 2.5–50 mg, administered 1–4 times
`
`a day. (Ex. 1003 ¶ [0046]). This is more precisely taught in Example 11, which
`
`discloses oral tablets comprising DPP-IV Inhibitor dosages of 0.500 mg, 1.000 mg,
`
`2.500 mg, 5.000 mg, and 10.000 mg. (Ex. 1003, Table in paragraph ¶ [0088]).
`
`48.
`
`Example 13 of the ’940 Publication is particularly relevant.
`
`It is
`
`directed to treating type II diabetes with a DPP-IV Inhibitor and metformin. (Ex.
`
`1003 ¶ [0091]).
`
`49.
`
`Example 13 reads in part:
`
`Combined Treatment with DPP-IV Inhibitor--Metformin
`
`[0091] For treating type 2 diabetes . . . a therapeutically effective dose
`of the DPP IV inhibitor (e.g. a dose of between 0.1 and 100 mg) may
`be combined with different doses of metformin, e.g. with 500 mg, 850
`mg or 1000 mg metformin as a single dose with a total daily dose of
`metformin of 500-2850 mg, or with 500 mg, 1000 mg, 1500 mg, or
`
`16
`
`MYLAN Ex. 1002, Page 19
`
`
`
`2000 mg metformin in delayed-release form . . . . Evidence that the
`combination is appropriate and effective can be found in the fact that
`the combination of a DPP-IV inhibitor with metformin leads to a
`significantly greater reduction in the fasting glucose and/or non-fasting
`glucose and/or the HbA1c value than either the DPP IV inhibitor alone
`or metformin alone.
`
`(Ex. 1003 ¶ [0091]).
`
`4.
`50.
`
`Independent Claims 1 and 2
`The elements of Claims 1 and 2 were taught by the disclosures of
`
`Charbonnel or Hughes in view of the ’940 Publication.
`
`51. Charbonnel discloses that the DPP-IV Inhibitor sitagliptin was effective
`
`in treating type II diabetes when added to the ongoing metformin therapy for patients
`
`with inadequate glycemic control with metformin alone. (Ex. 1004, Charbonnel at
`
`2638, 2642–3).
`
`52.
`
`Likewise, Hughes discloses that
`
`the DPP-IV Inhibitor LAF237
`
`(vildagliptin) was effective in treating type II diabetes when added to the ongoing
`
`metformin therapy for patients with inadequate glycemic control with metformin
`
`alone. (Ex. 1005, Hughes at 2–3, 13).
`
`53.
`
`The ’940 Publication discloses a method for treating type II diabetes by
`
`administering an oral dose of a DPP-IV Inhibitor,
`
`including linagliptin, and
`
`metformin. (Ex. 1003, ¶¶ [0004], [0025], [0031], [0032], and [0046]). Specifically,
`
`the ’940 Publication lists oral administration of linagliptin first among 12
`
`17
`
`MYLAN Ex. 1002, Page 20
`
`
`
`“particularly preferred” DPP IV inhibitors (Ex. 1003 ¶¶ [0031], [0032], [0044],
`
`[0046]) in combination with other substances, including metformin (Ex. 1003 ¶¶
`
`[0060], [0061], [0068], and [0091]). The ’940 Publication also teaches that the
`
`disclosed DPP-IV Inhibitors are especially potent, effective, long-lasting, and bring
`
`about “unexpected therapeutic advantages and improvement when combined with
`
`other” pharmaceuticals, including metformin.
`
`(See Ex. 1003 at ¶ [0004], [0060],
`
`[0061], [0068], and [0091]. The ’940 Publication further teaches that “the
`
`combination of a DPP-IV Inhibitor with metformin leads to a significantly greater
`
`reduction in the fasting glucose and/or non-fasting glucose and/or the HbA1c value
`
`than either the DPP IV inhibitor alone or metformin alone.” (Ex. 1003 ¶ [0091]).
`
`54.
`
`The ’940 Publication discloses orally administering 5 mg of a DPP-IV
`
`Inhibitor, which includes linagliptin. (See, e.g., Ex. 1003, ’940 Publication at
`
`[0088]).
`
`55. Accordingly, a POSA seeking to treat a type II diabetes patient unable
`
`to maintain adequate glycemic control, despite treatment with metformin, would
`
`have been motivated by the prior art to substitute the oral administration of
`
`linagliptin (’940 Publication) for the orally administered DPP-IV Inhibitors
`
`sitagliptin (Charbonnel) or vildagliptin (Hughes).
`
`56.
`
`The motivation to make this substitution is compelling. At the time of
`
`the alleged invention, the ’940 Publication disclosed, among other things, that
`
`18
`
`MYLAN Ex. 1002, Page 21
`
`
`
`linagliptin was a longer-lasting and particularly preferred DPP-IV Inhibitor for
`
`combination therapy with metformin. The known combinations of vildagliptin with
`
`metformin (Charbonnel) and sitagliptin with metformin (Hughes) were already well-
`
`known to improve glycemic control in a patient with inadequate glycemic control
`
`despite metformin therapy. These teachings, together with the knowledge of a
`
`POSA, would have provided a significant
`
`incentive to substitute the oral
`
`administration of linagliptin for vildagliptin or sitagliptin, in combination with
`
`metformin, or as an add-on combination with metformin, and thus arrive at the
`
`methods of claims 1 and 2.
`
`57.
`
`The POSA would also have had a reasonable expectation of success
`
`that a combination of linagliptin and metformin would have been at least as effective
`
`as the known combination disclosed in Charbonnel or Hughes, particularly in light
`
`of the properties of linagliptin, as disclosed in the ’940 Publication, and the fact that
`
`linagliptin has the same mechanism of action as vildagliptin and sitagliptin.
`
`Moreover, the POSA would have reasonably expected that co-administering 5 mg
`
`of linagliptin each day in combination with metformin or as an add-on combination
`
`with metformin as taught by the ’940 Publication, (Ex. 1003 ¶¶ [0031], [0032],
`
`[0046], [0061], [0068], [0091]) would be an effective method for treating type II
`
`diabetes patients for whom metformin therapy alone was inadequate to control their
`
`glycemic blood levels, as accomplished with the DPP-IV Inhibitors, vildgliptin and
`
`19
`
`MYLAN Ex. 1002, Page 22
`
`
`
`sitagliptin when either drug is combined with metformin. Therefore, Claims 1 and
`
`2 would have been obvious.
`
`5.
`58.
`
`Dependent Claims 3 and 4
`The ’940 Publication teaches that one of the recommended oral dosages
`
`of linagliptin for the treatment of type II diabetes is 5 mg per day. (Ex. 1003, ’940
`
`Publication ¶¶ [0046], [0088]).
`
`59.
`
`The ’940 Publication also teaches orally administering 2.5 mg of
`
`linagliptin twice daily, yielding a total amount of 5 mg per day, for the treatment of
`
`type II diabetes. (Ex. 1003, ’940 Publication ¶¶ [0046], [0088]).
`
`C.
`
`60.
`
`Obviousness Ground 2: Janumet Label, Nauck, and Ahrén 2008 in
`View of the ’940 Publication
`1.
`Janumet Label (Ex. 1007)
`The label for Janumet® discloses a fixed-dose combination product
`
`comprising sitagliptin (another DPP-IV Inhibitor) and metformin. (Ex. 1007).
`
`61.
`
`The Janumet Label published in February 2008. The Janumet Label
`
`states that sitagliptin add-on therapy was efficacious in achieving glycemic control
`
`in patients not adequately controlled on metformin alone:
`
`Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes
`Inadequately Controlled on Metformin Alone
`
`A total of 701 patients with type 2 diabetes participated in a 24-week,
`randomized, double-blind, placebo-controlled study to assess the
`
`20
`
`MYLAN Ex. 1002, Page 23
`
`
`
`efficacy of sitagliptin in combination with metformin. Patients already
`on metformin . . . In combination with metformin, sitagliptin provided
`significant improvements in A1C, FPG, and 2-hour PPG PPG [i.e.,
`blood glucose levels] compared to placebo with metformin.
`
`(Ex. 1007, Janumet Label, at section 14).
`
`Nauck (Ex. 1006)
`2.
`62. Nauck published in 2007. Nauck discloses a clinical study in which
`
`patients with type II diabetes with inadequate control despite metformin
`
`monotherapy, were randomized to the addition of either sitagliptin or glipizide. (Ex.
`
`1006).
`
`63. Nauck explains that metformin is the most commonly prescribed oral
`
`antihyperglycaemic agent, but that defective β-cell function “continues to deteriorate
`
`over time in patients with type 2 diabetes, leading to progressive failure of insulin
`
`secretion.” (Ex. 1006 at 194–195). According to Nauck, “[t]his progressive loss of
`
`β-cell function may explain why many patients who initially achieve glycaemic
`
`control [using metformin] fail to maintain control at levels consistent with current
`
`guidelines [e.g. haemoglobin A1c (HbA1c) < 7 or <6.5%] and hence require
`
`additional therapies” (Ex. 1006 at 195). Nauck states that sulfonylureas are the
`
`typical next drug for addition to ongoing metformin therapy.
`
`(Id.) However,
`
`suflonylureas “are associated with hypoglycaemia because of continued stimulation
`
`of insulin secretion with falling glucose concentrations.” (Id.). According to Nauck,
`
`21
`
`MYLAN Ex. 1002, Page 24
`
`
`
`“An agent that can provide efficacy similar to a sulfonylurea but with a better safety
`
`profile could provide a useful alternative” for type II diabetes patients incapable of
`
`maintaining adequate glycemic control despite therapy w
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