`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`____________________________
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner
`
`v.
`
`BOEHRINGER INGELHEIM INTERNATIONAL GMBH,
`
`Patent Owner
`
`____________________________
`
`IPR2016-01565
`
`U.S. Patent No. 8,853,156
`
`____________________________
`
`
`
`PATENT OWNER'S PRELIMINARY RESPONSE UNDER 37 C.F.R. § 42.107
`
`
`
`
`
`

`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ......................................................................................... 1
`
`TECHNICAL OVERVIEW OF THE INVENTION ................................. 3
`
`III. GROUNDS 1 AND 2: MIKHAIL IS NOT PRIOR ART TO THE
`‘156 PATENT ................................................................................................. 9
`
`IV. MYLAN FALLS FAR SHORT OF ESTABLISHING THAT THE
`JANUVIA LABEL AND HUETTNER ARE PRINTED
`PUBLICATIONS ......................................................................................... 11
`A. A Reference Must Have Been “Publicly Accessible” To be A
`Printed Publication .............................................................................. 11
`
`B.
`
`C.
`
`The Januvia Label (Exhibit 1006) Is Not A Section 102(b)
`Printed Publication Because There Is No Evidence That It Was
`Publicly Accessible ............................................................................. 12
`
`Huettner (Exhibit 1004) Is Not A Section 102(b) Printed
`Publication Because There Is No Evidence That It Was Publicly
`Accessible ............................................................................................ 17
`
`D. Mylan Has Not Presented Any Competent Expert Testimony
`Indicating that the Januvia Label and Huettner Are “Printed
`Publications” ....................................................................................... 19
`
`V. MYLAN FAILS TO ESTABLISH A REASON TO COMBINE
`THE TEACHING OF PRIOR ART REFERENCES OR
`REASONABLE EXPECTATION OF SUCCESS .................................... 20
`A. A Person of Skill in the Art Would Have Had No Reason To
`Select Linagliptin Of All Available DPP-IV Inhibitors ...................... 21
`
`1.
`
`2.
`
`3.
`
`Renal Impairment Affects Hepatic Drug Metabolism .............. 21
`
`Huettner Would Not Have Led a Person of Skill in the
`Art to Linagliptin ...................................................................... 25
`
`The Knowledge of a Person of Skill in the Art Would
`Not Have Led a Person of Skill in the Art to Linagliptin ......... 26
`
`i
`
`

`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`
`
`A Skilled Artisan Would Not Have Looked to Other
`DPP-IV Inhibitors To Determine the Suitable Uses For
`Linagliptin ................................................................................. 27
`
`4.
`
`B.
`
`A Person of Skill in the Art Would Have Had No Reason To
`Administer DPP-IV Inhibitors to Patients For Whom
`Metformin Therapy Is Inappropriate Due to at Least One
`Contraindication .................................................................................. 30
`
`VI. CONCLUSION ............................................................................................ 31
`
`
`
`
`ii
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`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Apple Inc. v. DSS Tech. Mgmt., Inc.,
`IPR2015-00369, Paper No. 14 (P.T.A.B. Aug. 12, 2015) .................................. 20
`
`Cisco Sys. v. Constellation Techs.,
`IPR2014-01085, Paper 11 (P.T.A.B. Jan. 9, 2015) ............................................ 17
`
`Coal. for Affordable Drugs IV LLC v. Pharmacyclics, Inc.,
`No. IPR2015-01076, 2015 WL 7303857 (P.T.A.B. Oct. 19, 2015) ................... 19
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 21
`
`Frontier Therapeutics, LLC v. Medac Gesellschaft Fur Klinische
`Spezialpraparate MBH,
`Case IPR2016-00649, Paper 10 (P.T.A.B. September 1, 2016) ....... 13, 14, 19, 20
`
`In Re Klopfenstein,
`380 F.3d 1345 (Fed. Cir. 2004) .......................................................................... 18
`
`Northern Telecom, Inc. v. Datapoint Corp.,
`908 F.2d 931 (Fed. Cir. 1990) ............................................................................ 12
`
`SRI Int’l, Inc. v. Internet Sec. Sys., Inc.,
`511 F.3d 1186 (Fed. Cir. 2008) .......................................................................... 12
`
`Statutes
`35 U.S.C. § 102 .................................................................................................... 3, 20
`
`35 U.S.C. § 102(b) ....................................................................................... 12, 17, 19
`
`35 U.S.C. §311(b) .............................................................................................. 11, 20
`
`
`
`
`
`iii
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`

`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`
`
`INDEX OF EXHIBITS
`
`Description
`
`Exhibit
`No.
`2001 A Snapshot: Diabetes in the United States, Centers for Disease Control
`and Prevention, (2014)
`2002 American Diabetes Association, Standards of Medical Care in
`Diabetes—2016, Diabetes Care, 39(S1):S1-S98 (2016)
`
`2003
`
`Screening for Type 2 Diabetes – Report of a World Health Organization
`and International Diabetes Federation Meeting, World Health
`Organization, Geneva, Switzerland (2003)
`
`2004
`
`Szablewski, L., Glucose Homeostasis – Mechanism and Defects,
`Diabetes - Damages and Treatments, Prof. Everlon Rigobelo (Ed.),
`ISBN: 978-953-307-652-2, In Tech, 227-256 (2011). Available at:
`http://www.intechopen.com/books/diabetes-damages-and-
`treatments/glucose-homeostasis-mechanism-and-defects
`2005 Boron, W.E. and Boulpaep, E.L., Medical Physiology – A Cellular and
`Molecular Approach, Elsevier Science: Pennsylvania, 1066-1085 (2003)
`2006 Aronoff, S.L., et al., Glucose Metabolism and Regulation: Beyond
`Insulin and Glucagon, Diabetes Spectrum, 17(3):183-190 (2004)
`
`2007
`
`Green, B.D., et al., Inhibition of Dipeptidyl Peptidase IV Activity as a
`Therapy of Type 2 Diabetes, Expert Opin. Emerging Drugs, 11(3):525-
`539 (2006)
`
`2008
`
`Nathan, D.M., et al., Management of Hyperglycemia in Type 2 Diabetes:
`A Consensus Algorithm for the Initiation and Adjustment of Therapy, A
`Consensus Statement From the American Diabetes Association and the
`European Association for the Study of Diabetes, Diabetes Care,
`29(8):1963-1972 (2006)
`
`
`
`iv
`
`

`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`
`
`Description
`
`Nathan, D.M., et al., Medical Management of Hyperglycemia in Type 2
`Diabetes: A Consensus Algorithm for the Initiation and Adjustment of
`Therapy, A Consensus Statement From the American Diabetes
`Association and the European Association for the Study of Diabetes,
`Diabetes Care, 32(1):193-203 (2009)
`
`Dugi, K., Boehringer Ingelheim GmbH Clinical Development Plan for
`Project No. 1218.P1, Long Term Improvement of Glycemic Control in
`Patients with Type 2 Diabetes (as Monotherapy and as Combination
`Therapy) (2004)
`
`Hüttner, S., et al., Boehringer Ingelheim GmbH Clinical Trial No.
`1218.1, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics
`of Single Rising Oral Doses of BI 1356 BS as a Solution at Dose Levels
`2.5 - 5 mg and Tablets at Dose Levels 25 - 600 mg Administered to
`Healthy Mall Subjects (2005)
`
`Hüttner, S., et al., Boehringer Ingelheim GmbH Clinical Trial No.
`1218.7, Investigation of the Metabolism and Pharmacokinetics of 10 mg
`[14C] BI 1356 Administered Orally Compared to 5 mg [14C] BI 1356
`Administered Intravenously in Healthy Male Volunteers in an Open
`Label, Single-Dose and Parallel Study Design (2008)
`
`Exhibit
`No.
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013 Management Summary of BI 1356 for Type 2 Diabetes Mellitus (2006)
`2014 Blech, S., et al., Metabolism of BI 1365 BS in Healthy Male Volunteers
`(2007)
`2015 Boehringer Ingelheim, BI 1356 Draft Communications
`Strategy/Publications Strategy (2007)
`2016 Archive.org, Frequently Asked Questions. Available at:
`https://archive.org/about/faqs.php
`
`
`
`v
`
`

`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`
`
`Description
`
`Touchette, M.A. and Slaughter, R.L., The Effects of Renal Failure on
`Hepatic Drug Clearance, The Annuals of Pharmacotherapy, 25:1214-
`1224 (1991)
`
`Dreisbach, A.W. and Lertora, J.J., The Effect of Chronic Renal Failure
`on Hepatic Drug Metabolism and Drug Disposition, Seminars in
`Dialysis 16(1): 45-50 (2003)
`
`Exhibit
`No.
`
`2017
`
`2018
`
`2019
`
`Pichette, V. and Leblond, F.A., Drug Metabolism in Chronic Renal
`Failure, Current Drug Metabolism, 4(2):91-103 (2003)
`
`2020
`
`Yuan, R. and and Venitz, J., Effect of Chronic Renal Failure on the
`Disposition of Highly Hepatically Metabolized Drugs, International
`Journal of Clinical Pharmacology and Therapeutics, 38(5):245-253
`(2000)
`
`2021
`
`Terao, N. and Shen, D., Reduced Extraction of I-Propranolol by
`Perfused Rat Liver in the Presence of Uremic Blood, The Journal of
`Pharmacology and Experimental Therapeutics, 233(2):277-284 (1985)
`2022 Gibson, T.P., Renal Disease and Drug Metabolism: An Overview,
`American Journal of Kidney Diseases, 8(1):7-17 (1986)
`2023 Reidenberg, M.M. and Drayer, D.E., Drug Metabolism and Active Drug
`Metabolites in Renal Failure, Journal of Dialysis, 1(4):313-318 (1977)
`2024 Yates, M.S., et al., Pharmacokinetics of Indocyanine Green in Rats with
`Chronic Renal Failure, J. Pharm. Pharmacol., 35:593-594 (1983)
`
`2025
`
`Gibbons, J., et al., Phase I and Pharmacokinetics Study of Imatinib
`Mesylate in Patients with Advanced Malignancies and Varying Degrees
`of Renal Dysfunction: A Study by the National Cancer Institute Organ
`Dysfunction Working Group, Journal of Clinical Oncology, 26(4):570-
`576 (2008)
`
`
`
`vi
`
`

`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`
`
`Description
`
`Yates, M.S., et al., Effect of Acute Renal Failure on the Clearance and
`Biliary Excretion of Indocyanine Green in Perfused Rat Liver,
`Biochemical Pharmacology, 33(10):1695-1696 (1984)
`
`Exhibit
`No.
`
`2026
`
`2027
`
`Bowmer, C.J. and Yates, M.S., Pharmacokinetics and Biliary Excretion
`of Bromosulphophthalein, [3H]-ouabain and [3H]-taurocholic Acid in
`Rats with Glycerol-Induced Acute Renal Failure, Br. J. Pharmac.,
`83:773-782 (1984)
`
`2028
`
`Ortiz de Montellano, P.R. and Kunze, K.L., Self-Catalyzed Inactivation
`of Hepatic Cytochrome P-450 by Ethynyl Substrates, The Journal of
`Biological Chemistry, 255(12):5578-5585 (1980)
`2029 Kunze, K.L., et al., The Cytochrome P-450 Active Site, The Journal of
`Biological Chemistry, 258(7):4202-4207 (1983)
`
`2030
`
`Ortiz de Montellano, P.R. and Komives, E.A., Branchpoint for Heme
`Alkylation and Metabolite Formation in the Oxidation of Arylacetylenes
`by Cytochrome P-450, The Journal of Biological Chemistry,
`260(6):3330-3336 (1985)
`2031 Leblond, F.A., et al., Downregulation of Hepatic Cytochrome P450 in
`Chronic Renal Failure, J. Am. Soc. Nephrol., 12:326-332 (2001)
`
`
`
`vii
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`IPR2016-01565
`U.S. Patent No. 8,853,156
`
`I.
`
`INTRODUCTION
`Diabetes is a progressive metabolic disease affecting more than 29 million
`
`Americans. Additionally, another 86 million adults have pre-diabetes—a blood
`
`glucose level that is elevated above normal level but is not high enough to be
`
`classified as type 2 diabetes. About a third of the adults with pre-diabetes will
`
`develop type 2 diabetes in the next few years. (Ex. 2001, A Snapshot: Diabetes in
`
`the United States, Centers for Disease Control and Prevention (2014).
`
`Diabetes can be managed through physical activity, diet, and appropriate use
`
`of oral medications to lower blood sugar levels. There are numerous anti-diabetic
`
`agents that can be used in the treatment of type 2 diabetes. One example of a
`
`commonly used oral anti-diabetic agent is metformin. (Ex. 1001, ‘156 Patent, 1:31-
`
`41). However, treatment with metformin can be associated with side effects, such
`
`as gastrointestinal symptoms or lactic acidosis, which although rare, is often fatal.
`
`(Id., 1:51-62). Moreover, metformin is contraindicated in patients with renal
`
`disease or renal impairment. (Id., 1:63-67). Likewise, because of increased
`
`susceptibility to adverse effects, metformin is often used with caution in elderly
`
`patients and is typically not recommended for patients older than 80 years old. (Id.,
`
`3:1-9). Thus, a number of type 2 diabetes patients who might otherwise benefit
`
`from metformin therapy may be ineligible to receive it due to intolerability or
`
`contraindication. (Id., 1:65-67). DPP-IV inhibitors are one class of anti-diabetic
`
`1
`
`

`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`agents used in the treatment of type 2 diabetes that can be administered in
`
`combination with metformin or as monotherapy. (Ex. 2002, Standards of Medical
`
`Care in Diabetes—2016: Approach to Glycemic Treatment, Diabetes Care, 39(S1),
`
`S52-S59 (2016), at S54). The inventors of the ‘156 patent discovered that certain
`
`DPP-IV inhibitors had surprising and particularly advantageous properties which
`
`make them particularly suitable for treating and/or preventing metabolic diseases
`
`such as type 2 diabetes, in patients for whom metformin therapy is inappropriate
`
`due to intolerability or contraindication against metformin. (Ex. 1001, 9:30-42).
`
`The inventions of U.S. Patent No. 8,853,156 concern methods of treating
`
`metabolic diseases such as type 2 diabetes in patients for whom metformin therapy
`
`is inappropriate due to at least one contraindication against metformin, by
`
`administering a DPP-IV inhibitor. Mylan Pharmaceuticals Inc. (“Mylan”) requests
`
`inter partes review of claims 1-2, 4-8, 10-18, and 23-25 of the ‘156 patent. For the
`
`reasons set forth below, the Board should deny Mylan’s request.
`
`As an initial matter, the inventions of the ‘156 patent were conceived and
`
`reduced to practice no later than August 7, 2007. (See, infra, Section III). The
`
`Mikhail reference Mylan relies upon in Grounds 1 and 2, which was published in
`
`June 2008, after the conception and reduction to practice of the ‘156 patent
`
`inventions, is not prior art to the ‘156 patent. As such, Grounds 1 and 2 must fail
`
`on this basis alone. Additionally, Mylan has failed to present any evidence that the
`
`2
`
`

`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`Januvia Label (Ex. 1006) it relies upon in Ground 2 is a prior art “printed
`
`publication” as required by 35 U.S.C. § 102. Ground 2 must fail for this additional
`
`reason. Finally, Mylan and its expert, Dr. Davidson, have failed to point to any
`
`reason that a skilled artisan would have (1) been motivated to select linagliptin as
`
`the DPP-IV inhibitor of choice for the methods claimed by the ‘156 patent; and (2)
`
`would have modified the teachings of the references relied upon in Ground 2 to
`
`arrive at the claimed invention. Mylan and its expert have further failed to show
`
`that a person of skilled in the art would have had a reasonable expectation of
`
`success in modifying the teachings of the prior art to arrive at the claimed
`
`invention.
`
`Mylan’s Petition does not establish a reasonable likelihood of success and
`
`should be denied.
`
`II. TECHNICAL OVERVIEW OF THE INVENTION
`Diabetes mellitus is a metabolic disorder characterized by elevated blood
`
`glucose levels resulting from defects in insulin secretion, insulin resistance, or
`
`both. See Ex. 2003, Screening for Type 2 Diabetes, Report of a World Health
`
`Organization and International Diabetes Federation Meeting, World Health
`
`Organization, Geneva, Switzerland (2003), at 1. Glucose is the primary source of
`
`energy for the cells and must be readily available for cells to function normally.
`
`Therefore, the body tightly regulates blood glucose levels to ensure that the level
`
`3
`
`

`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`of glucose in the blood is high enough for energy production, but is not so high as
`
`to reach a toxic level. This regulatory process is known as glucose homeostasis.
`
`(Ex. 2004, Szablewski, L., Glucose Homeostasis – Mechanism and Defects,
`
`Diabetes - Damages and Treatments, Prof. Everlon Rigobelo (Ed.), ISBN: 978-
`
`953-307-652-2, (2011) at 227).
`
`When the blood glucose level decreases below a certain threshold—during
`
`physical activity, for example—a process known as glycogenolysis occurs. In
`
`response to the lowered blood glucose level, the pancreas releases glucagon.
`
`Glucagon is a peptide hormone that raises the concentration of glucose in the
`
`bloodstream, and hence, its effect is opposite to that of insulin, which lowers the
`
`glucose concentration. As a result, when glycogenolysis occurs, blood glucose
`
`levels increase. (Ex. 2005, Boron, W.E. and Boulpaep, E.L., Medical Physiology,
`
`(2003) at 1067-68, 1076).
`
`On the other hand, when the blood glucose level is high—after a meal, for
`
`instance—the pancreas releases insulin, promoting the creation and storage of
`
`glycogen polysaccharides in the muscles and liver. (Id. at 1076-77) This process is
`
`known as glycogenesis. Glycogenesis usually begins when the blood glucose level
`
`reaches an upper threshold in the gastrointestinal tract. (Id.) High concentration of
`
`glucose causes nearby cells to secrete incretin hormones, such as glucagon-like
`
`peptide (GLP-1) and the glucose-dependent insulotropic polypeptide (GIP). (Id. at
`
`4
`
`

`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`1073). Once in circulation, GLP-1 and GIP cause the pancreas to increase insulin
`
`secretion and decrease glucagon secretion, leading to a decreased level of glucose
`
`in circulation. (Id.).
`
`Glucose regulation is a complex process involving a delicate balance
`
`between the function of many organs and hormones. A simplified schematic
`
`representation is presented below:
`
`(Ex. 2006, Aronoff, S.L., et al., Glucose Metabolism and Regulation: Beyond
`
`Insulin and Glucagon, Diabetes Spectrum, 17, 183-190 (2004) at 186).
`
`
`
`5
`
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`IPR2016-01565
`U.S. Patent No. 8,853,156
`Dipeptidyl peptidase IV (DPP-IV) enzymes are key players in the
`
`glycogenesis process through their interaction with GLP-1 and GIP. As discussed,
`
`GLP-1 and GIP, which increase insulin secretion and decrease glucagon secretion,
`
`are secreted during glycogenesis leading to decreased levels of glucose in
`
`circulation. DPP-IV enzymes, however, rapidly inactivate GLP-1 and GIP
`
`hormones. In essence, DPP-IV enzymes degrade the hormones responsible for the
`
`release of insulin, thereby depressing the level of insulin in the body. Because
`
`DPP-IV enzymes are expressed in many tissues and are also abundantly present in
`
`plasma, under natural conditions, GLP-1 and GIP are quickly deactivated, with
`
`half-lives on the order of minutes. (Ex. 2007, Green, B.D., et al., Inhibition of
`
`dipeptidyl peptidase IV activity as a therapy of Type 2 diabetes, Expert Opin.
`
`Emerging Drugs, 11, 525-539 (2006) at 525-26).
`
`The methods described in the ‘156 patent alter the above-described natural
`
`process through introducing a foreign compound to the body. DPP-IV inhibitors
`
`are synthetic compounds that bind to DPP-IV enzymes, thereby inactivating them.
`
`The inhibition of DPP-IV enzymes through introducing DPP-IV inhibitors
`
`artificially lengthen the half-lives of GLP-1 and GIP hormones. (Ex. 2009, Nathan,
`
`D.M., et al., Medical Management of Hyperglycemia in Type 2 Diabetes: A
`
`Consensus Algorithm for the Initiation and Adjustment of Therapy, A Consensus
`
`Statement From the American Diabetes Association and the European Association
`
`6
`
`

`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`for the Study of Diabetes, Diabetes Care, 32(1):193-203, at 199)). The resulting
`
`increased levels of GLP-1 and GIP hormones causes the pancreas to increase
`
`insulin secretion and decrease glucagon secretion, in turn leading to a decreased
`
`level of glucose in circulation. (Id.) The end result of this series of reactions is that
`
`the body has a lower blood glucose level. (Id.)
`
`As of the priority date of the ‘156 patent, August 6, 2008, the American
`
`Diabetes Association (“ADA”) and the European Association for the Study of
`
`Diabetes (“EASD”) had published a consensus algorithm outlining the consensus
`
`treatment plan of type 2 diabetes. (Ex. 2008, Nathan, D.M., et al., Management of
`
`Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and
`
`Adjustment of Therapy, A Consensus Statement From the American Diabetes
`
`Association and the European Association for the Study of Diabetes, Diabetes
`
`Care, 29(8), 1963-1972 (2006), at 1964-65). According to this ADA algorithm,
`
`type 2 diabetes was initially treated with lifestyle interventions (diet and exercise),
`
`followed by the addition of antidiabetic agents such as, among others, metformin,
`
`insulin, sulfonylureas, and thiazolidinediones (TZDs). Notably, although some
`
`DPP-IV inhibitors were known at the time, they were not commonly accepted for
`
`the treatment of diabetes and were not a part of the ADA Consensus Algorithm. In
`
`point of fact, DPP-IV inhibitors were not added to the algorithm until December
`
`2008, with only one DPP-IV inhibitor, sitagliptin, having been approved in the US
`
`7
`
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`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`and two, sitagliptin and vildagliptin, having been approved in Europe at that time.
`
`(Ex. 2009, at 199.)
`
`Importantly, the DPP-IV inhibitors available at the time were unrelated and
`
`structurally distinct:
`
`
`Boehringer discovered and developed linaglitpin—a novel, structurally
`
`distinct DPP-IV inhibitor, which offered various advantages over pre-existing
`
`DPP-IV inhibitors and further developed methods of treating patients who could
`
`not be treated with metformin with DPP-IV inhibitors:
`
`
`The inventions of the ‘156 patent relate to methods of treating type II
`
`diabetes in patients ineligible for metformin therapy due to a contraindication
`
`against metformin by administering DPP-IV inhibitors such as linagliptin
`
`8
`
`

`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`III. GROUNDS 1 AND 2: MIKHAIL IS NOT PRIOR ART TO THE ‘156
`PATENT
`Soon after linagliptin was selected as a lead compound, a plan was made to
`
`study its properties for applications in patients with renal impairment. (Ex. 2010,
`
`Boehringer Ingelheim Clinical Development Plan for Project No. 1218.P1 at 17-
`
`18.) Specifically, the clinical trials masterplan outlined in this document called for
`
`the evaluation of the PK/PD and safety of linagliptin in patients with renal
`
`insufficiency (Id., at 27 (referencing trial 1218.14)). Moreover, beyond the ability
`
`to treat patients ineligible to take metformin, the ‘156 patent inventors recognized
`
`that their invention would satisfy an unmet clinical need if the compound had
`
`improved safety profile versus metformin, such that it could be a administered in
`
`patients with renal insufficiency for whom metformin is contraindicated. (See id. at
`
`4). Thus, no later than April 20, 2004, the inventors had conceived of a method to
`
`treat type 2 diabetes with linagliptin in patients with renal insufficiency without
`
`dose adjustment.
`
`Soon thereafter, in October 2004, the first phase I trial (1218.1) aimed at
`
`determining
`
`the
`
`safety/tolerability,
`
`the
`
`pharmacokinetics
`
`and
`
`the
`
`pharmacodynamics of single ascending doses of linagliptin in healthy volunteers
`
`was initiated. (Ex. 2011, BI Trial No. 1218.1 Clinical Trial Report). This trial
`
`ended first quarter of 2005 and in the second quarter, a complementary phase Ib
`
`trial (1218.2) evaluating multiple ascending doses was initiated. Follow up trials
`
`9
`
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`

`IPR2016-01565
`U.S. Patent No. 8,853,156
`aiming at determining the starting dose for the efficacy studies were initiated. After
`
`these dose finding trials, a phase IIb trial (1218.7) was specifically designed to
`
`evaluate the excretion pathways and the metabolism of linagliptin in human after
`
`oral administration. This trial ran from June 2006 to November 2006 (Ex. 2012, BI
`
`Trial No. 1218.7 Clinical Trial Report). At the end of this trial, based on the
`
`resulting data, Boehringer scientists concluded that renal excretion of linagliptin
`
`(BI 1356) represents a minor elimination pathway. (Ex. 2013, December 2006
`
`Management Summary for BI1356, at 31). Thus as of December 2006, the
`
`inventors had obtained convincing data to show that linagliptin was not eliminated
`
`via the kidney.
`
`A report dated Aug 7, 2007 discusses the metabolism of linagliptin in
`
`healthy male volunteers and states that linagliptin is mainly excreted unchanged.
`
`(Ex. 2014, Metabolism of BI 1356 in healthy male volunteers, at 9). Thus, no later
`
`than August 7, 2007, the inventors had investigated the metabolism of linagliptin
`
`and were aware that in humans, linagliptin and its metabolites was excreted mainly
`
`unchanged and that renal clearance was a minor clearance pathway. The inventors
`
`had further understood that linagliptin’s metabolites are pharmaceutically inactive.
`
`Based on these characteristics, the inventors concluded that linagliptin can safely
`
`and effectively be used in patients with renal impairment and that no dose
`
`adjustment would be necessary for such patients. (Ex. 2015, BI 1356 Draft
`
`10
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`IPR2016-01565
`U.S. Patent No. 8,853,156
`Communications Strategy/Publications Strategy, at 23). Thus, the inventors were
`
`in possession of the full scope of the claimed inventions of the challenged claims
`
`no later than Aug 7, 2007, prior to the June 2008 publication date of Mikhail. As
`
`such, Mikhail is not prior art to the ‘156 patent, and Grounds 1 and 2 of Mylan’s
`
`challenge must fail for this reason alone.
`
`The evidence presented herein is sufficient to establish conception and
`
`reduction to practice prior to Mikhail. Should trial be instituted on the basis of the
`
`Mikhail reference, Boehringer intends to present additional evidence of prior
`
`conception and reduction to practice.
`
`IV. MYLAN FALLS FAR SHORT OF ESTABLISHING THAT THE
`JANUVIA LABEL AND HUETTNER ARE PRINTED
`PUBLICATIONS
`A patent claim can be challenged in inter partes review “only on the basis of
`
`prior art consisting of patents or printed publications.” 35 U.S.C. §311(b). Mylan’s
`
`petition relies on the Januvia Label and Huettner—Exhibits 1006 and 1004,
`
`respectively—but Mylan has not shown that either of these publications was
`
`publically accessible before the priority date of the ‘156 patent. Thus, Mylan has
`
`not shown that the Januvia Label and Huettner are “printed publications.” The
`
`Board should not institute trial on these references.
`
`A. A Reference Must Have Been “Publicly Accessible” To be A
`Printed Publication
`
`11
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`IPR2016-01565
`U.S. Patent No. 8,853,156
`“‘[P]ublic accessibility’ has been called the touchstone in determining
`
`whether a reference constitutes a ‘printed publication’ bar under 35 U.S.C. §
`
`102(b).” SRI Int’l, Inc. v. Internet Sec. Sys., Inc., 511 F.3d 1186, 1194 (Fed. Cir.
`
`2008) (internal quotations omitted). “A given reference is ‘publicly accessible’
`
`upon a satisfactory showing that such document has been disseminated or
`
`otherwise made available to the extent that persons interested and ordinarily skilled
`
`in the subject matter or art[,] exercising reasonable diligence, can locate it.” Id
`
`(internal quotations omitted). Thus, in order to show that a reference qualifies as a
`
`printed publication, a Petitioner must show that (1) person of skill could have
`
`located the reference; and (2) once the reference was located, a person of skill
`
`would have had access to the reference. See id. at 1196 (“The record . . . does not
`
`show that an anonymous user skilled in the art in 1997 would have gained access
`
`to the FTP server and would have freely navigated through the directory structure
`
`to find the Live Traffic paper.”); Northern Telecom, Inc. v. Datapoint Corp., 908
`
`F.2d 931, 936-37 (Fed. Cir. 1990) (disclosure within a limited group of persons
`
`and organizations does not make a document “generally available”). Measured
`
`under these standards, Exhibits 1006 and 1004 are not printed publications.
`
`B.
`
`The Januvia Label (Exhibit 1006) Is Not A Section 102(b) Printed
`Publication Because There Is No Evidence That It Was Publicly
`Accessible
`
`12
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`IPR2016-01565
`U.S. Patent No. 8,853,156
`Mylan provides no evidence that the Januvia Label (Ex. 1006), on which it
`
`relies in Ground 2, is a prior art, printed publication. Specifically, Mylan offers no
`
`evidence when (or even if) the document was published and publicly available.
`
`This ground must fail. See, e.g., Frontier Therapeutics, LLC v. Medac Gesellschaft
`
`Fur Klinische Spezialpraparate MBH, Case IPR2016-00649, Paper 10 at 22
`
`(P.T.A.B. September 1, 2016) (finding that an alleged “printed package insert” is
`
`not a printed publication).
`
`Mylan simply states that “Januvia® (sitagliptin phosphate) tablets were first
`
`approved by the FDA on October 16, 2006.” and that “[t]he Januvia Label
`
`published 2006.” (Paper 2, at 19). But Mylan provides no evidence to support these
`
`conclusory assertions. In Frontier Therapeutics, LLC, the Petitioner attempted to
`
`introduce an alleged “printed package insert . . . which is dated November 22,
`
`2005” as a printed publication invalidating the challenged claims. (IPR2016-
`
`00649, Paper 10 at 22). The Board, however, found that the Petitioner had not
`
`presented sufficient evidence indicating that the exhibit presented was, in fact, a
`
`printed package label and that “[t]he first page of Hospira . . . is insufficient in this
`
`regard.” This was so, despite the fact that the first page of the document was
`
`entitled “Product Summary.” (IPR2016-00649, Ex. 1009 at 1). Similarly, the Board
`
`noted that “dates presented on the last page of that document . . . are inadequate” to
`
`establish when the document was publically available even though the last page
`
`13
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`

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`IPR2016-01565
`U.S. Patent No. 8,853,156
`provided the “Date of First Authorisation/Renewal of Authorisation” and “Date of
`
`Revision of the Text.” (IPR2016-00649, Paper 10 at 22; IPR2016-00649, Ex. 1009
`
`at 14). The Board further rejected Petitioner’s expert declaration asserting that the
`
`reference in question was prior art, noting that it presented “conclusory assertions
`
`without citing sufficient evidence in support.” (Id. at 22).
`
`Likewise here, Mylan has not in any way shown that Ex. 1006 is the Januvia
`
`label as-approved. The document, on its face, is labeled “Highlights of Prescribing
`
`Information” but contains no source-identifying information. Indeed, the front page
`
`notes that “[t]hese highlights do not include all the information needed to use
`
`JANUVIA safely and effectively” and direct the reader to “[s]ee full prescribing
`
`information.” (Ex. 1006 at 1). As such, Mylan has failed to provide sufficient
`
`evidence that the document is the JANUVIA printed label. Moreover, Exhibit 1006
`
`contains no information identifying when it became publically available. Even
`
`assuming the document to be the label that the FDA approved for JANUVIA in
`
`2006, Mylan has provided no evidence that it became publically available at the
`
`same time as approval. The only date on the document appears on the first page,
`
`noting that it was “Revised: 10/2006.” (Ex. 1006 at 1). But as the Board recognized
`
`in Frontier Therapeutics, a revision date is not synonymous with a publication
`
`date. (IPR2016-00649, Paper 10 at 22). By its plain terms, the 10/2006 date only
`
`14
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`IPR2016-01565
`U.S. Patent No. 8,853,156
`indicates when the document was revised, and has no bearing on whether and
`
`when it became publically available.
`
`Mylan has included as the last page of the exhibit a page from The Internet
`
`Archive, also known as the Wayback Machine. (Ex. 1006 at 14). But Mylan does
`
`not address the significance of this page in its Petition, and does not point to it as
`
`supporting the publication date of the Januvia label, in a tacit acknowledgement
`
`that this page adds nothing to the information on the face of the reference itself.
`
`Specifically, the Wayback Machine printout attached to Exhibit 1006 indicates that
`
`the
`
`website
`
`http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf was saved
`
`47 times between November 8, 2006 and March 16, 2015. Nothing on the page,
`
`however, evidences that the document that is attached as Ex. 1006 is the document
`
`or webpage as it appeared in 2006. In fact, it is the March 16, 2015 update that is
`
`highlighted, suggesting that it is this latest version of the document that was
`
`downloaded:
`
`15
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`IPR2016-01565
`U.S. Patent No. 8,853,156
`
`
` Mylan has provided no evidence of how this update co