UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________________
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner
`
`v.
`
`BOEHRINGER INGELHEIM INTERNATIONAL GMBH,
`
`Patent Owner
`
`____________________________
`
`IPR2016-01564
`
`U.S. Patent No. 8,846,695
`
`____________________________
`
`
`
`PATENT OWNER'S PRELIMINARY RESPONSE UNDER 37 C.F.R. § 42.107
`
`
`
`
`
`____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________________
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner
`
`v.
`
`BOEHRINGER INGELHEIM INTERNATIONAL GMBH,
`
`Patent Owner
`
`____________________________
`
`IPR2016-01564
`
`U.S. Patent No. 8,846,695
`
`____________________________
`
`
`
`PATENT OWNER'S PRELIMINARY RESPONSE UNDER 37 C.F.R. § 42.107
`
`
`
`
`
`IPR2016-01564
`U.S. Patent No. 8,846,695
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ......................................................................................... 1
`
`TECHNICAL OVERVIEW OF THE INVENTION ................................. 3
`
`III. GROUND 2: MYLAN FALLS FAR SHORT OF
`ESTABLISHING THAT THE JANUMET LABEL IS A
`PRINTED PUBLICATION .......................................................................... 9
`A. A Reference Must Have Been “Publicly Accessible” To be A
`Printed Publication .............................................................................. 10
`
`B.
`
`The Janumet Label (Exhibit 1007) Is Not A Section 102(b)
`Printed Publication Because There Is No Evidence That It Was
`Publicly Accessible ............................................................................. 11
`
`IV. GROUNDS 1 & 2: MYLAN FAILS TO ESTABLISH A
`REASON TO COMBINE THE TEACHING OF PRIOR ART
`REFERENCES OR REASONABLE EXPECTATION OF
`SUCCESS ..................................................................................................... 13
`A. A Person of Skill in the Art Would Have Had No Reason To
`Select Linagliptin Of All Available DPP-IV Inhibitors ...................... 14
`
`B.
`
`C.
`
`A Person of Skill in the Art Would Have Had No Reason To
`Select Metformin as a Combination Partner for Linagliptin In
`Patients With Inadequate Glycemic Control Despite Therapy
`With Metformin ................................................................................... 16
`
`A Person of Skill In The Art Would Have Had No Reason To
`Modify the Teachings of the Cited Art to Arrive at the Claimed
`Linagliptin Dosages In Combination Therapy .................................... 22
`
`V. CONCLUSION ............................................................................................ 27
`
`
`i
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`
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`IPR2016-01564
`U.S. Patent No. 8,846,695
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Amneal Pharm., LLC, Petitioner,
`IPR2014-00360, 2014 WL 3735722 (P.T.A.B. July 25, 2014) .................... 23, 26
`
`Apple Inc. v. DSS Tech. Mgmt., Inc.,
`Case IPR2015-00369, Paper 14 (P.T.A.B. Aug. 12, 2015) ................................ 13
`
`Coal. for Affordable Drugs IV LLC v. Pharmacyclics, Inc.,
`IPR2015-01076, 2015 WL 7303857 (P.T.A.B. Oct. 19, 2015) .......................... 13
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 14
`
`Frontier Therapeutics, LLC v. Medac Gesellschaft Fur Klinische
`Spezialpraparate MBH,
`Case IPR2016-00649, Paper 10 (P.T.A.B. September 1, 2016) ............. 11, 12, 13
`
`Janssen Pharma., Inc. v. Watson Labs., Inc.,
`Case No. 08-5103, 2012 WL 3990221 (D.N.J. 2012) ........................................ 23
`
`Northern Telecom, Inc. v. Datapoint Corp.,
`908 F.2d 931 (Fed. Cir. 1990) ............................................................................ 10
`
`SRI Int’l, Inc. v. Internet Sec. Sys., Inc.,
`511 F.3d 1186 (Fed. Cir. 2008) .......................................................................... 10
`
`Statutes
`35 U.S.C. §102 ..................................................................................................... 2, 13
`
`35 U.S.C. § 102(b) ............................................................................................. 10, 11
`
`35 U.S.C. §311(b) ................................................................................................ 9, 13
`
`i
`
`
`
`
`
`Exhibit
`No.
`
`2001
`
`IPR2016-01564
`U.S. Patent No. 8,846,695
`
`INDEX OF EXHIBITS
`
`Description
`
`A Snapshot: Diabetes in the United States, Centers for Disease Control
`and Prevention (2014)
`
`2002 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)
`
`2003
`
`2004
`
`Screening for Type 2 Diabetes – Report of a World Health Organization
`and International Diabetes Federation Meeting, World Health
`Organization, Geneva, Switzerland (2003)
`
`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., 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)
`
`ii
`
`
`
`
`Exhibit
`No.
`
`Description
`
`IPR2016-01564
`U.S. Patent No. 8,846,695
`
`2009 Kuhn, B., et al., Molecular Recognition of Ligands in Dipeptidyl
`Peptidase IV, Current Topics in Medicinal Chemistry, 7:609-619 (2007)
`
`2010
`
`2011
`
`Feng, J., et al., Discovery of Alogliptin: A Potent, Selective,
`Bioavailable, and Efficacious Inhibitor of Dipeptidyl Peptidase IV, J.
`Med. Chem., 50:2297-2300 (2007)
`
`Szczepankiewicz, B.G., and Kurukulasuriya, R., Aromatic Heterocycle-
`Based DPP-IV Inhibitors: Xanthines and Related Structural Types,
`Current Topics in Medicinal Chemistry, 7:569-578 (2007)
`
`2012 Weber, A.E., and Thornberry, N., Case History: Januvia™ (Sitagliptin),
`a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type
`2 Diabetes, Annual Reports in Medicinal Chemistry, 42:95-109 (2007)
`
`2013 U.S. Patent No. 7,317,109, Issued to Campbell et al.
`
`2014
`
`JanuviaTM (sitagliptin phosphate) Tablets Prescribing Information
`
`2015 Ortiz de Montellano, P., et al., Self-Catalyzed Inactivation of Hepatic
`Cytochrome P-450 by Ethynyl Substrates, The Journal of Biological
`Chemistry 255(12):5578–5585 (1980)
`
`2016 Kunze, K., et al., The Cytochrome P-450 Active Site, The Journal of
`Biological Chemistry 258(7):4202–4207 (1983)
`
`2017 Ortiz de Montellano, P., et al., Branchpoint for Heme Alkylation and
`Metabolite Formation in the Oxidation of Arylacetylenes by Cytochrome
`P-450, The Journal of Biological Chemistry 260(6):3330–3386 (1985)
`
`2018 Brunton, L.L., et al., Goodman & Gilman’s The Pharmacological Basis
`of Therapeutics, 12th Ed., 72-87 (2011)
`
`iii
`
`
`
`
`Exhibit
`No.
`
`Description
`
`IPR2016-01564
`U.S. Patent No. 8,846,695
`
`2019 U.S. Food and Drug Administration, FDA Drug Approval Process.
`Available at
`http://www.fda.gov/downloads/Drugs/ResourcesForYou/Consumers/UC
`M284393.pdf
`
`2020 Manzi, S., et al,. Drug Interactions - A Review, Clinical Pediatric
`Emergency Medicine, 6:93-102 (2005)
`
`2021 Glucophage® and Glucophage® XR Prescribing Information. Available
`at
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020357s031,
`021202s016lbl.pdf
`
`iv
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`U.S. Patent No. 8,846,695
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`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. Ex. 2002, 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. 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. (Id.). When treatment with
`
`a single oral anti-diabetic agent becomes insufficient, other anti-diabetic agents are
`
`added to the treatment regimen. (Id.) DPP-IV inhibitors are one class of anti-
`
`diabetic agents used in the treatment of type 2 diabetes. The inventions of U.S.
`
`Patent No. 8,846,695 concern methods of using a novel DPP-IV inhibitor—
`
`linagliptin—in combination with metformin in patients with inadequate glycemic
`
`1
`
`
`
`
`control despite therapy with metformin, where linagliptin is administered in an
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`specific doses.
`
`Mylan Pharmaceuticals Inc. (“Mylan”) requests inter partes review of all of
`
`the claims of the ‘695 patent. For the reasons set forth below, the Board should
`
`deny Mylan’s request.
`
`As an initial matter, Mylan has failed to present any evidence that some of
`
`the publications on which it relies are prior art “printed publications” as required
`
`by 35 U.S.C. §102. Moreover, even if the references are assumed to be prior art
`
`printed publications, with
`
`the exception of U.S. Patent Publication No.
`
`2007/0281940 A1 (“the ‘940 Publication,” Ex. 1003), none of the references cited
`
`by Mylan—Hughes, Janumet, Ahrén 2008, Nauck, and Charbonnel—even discuss
`
`linagliptin at all, and instead pertain to DPP-IV inhibitors that are structurally
`
`unrelated to linagliptin. Mylan relies on these references for the proposition that
`
`because other DPP-IV inhibitors were allegedly known to be useful in combination
`
`with metformin to treat patients with inadequate glycemic control, it would have
`
`been obvious to utilize linagliptin in the same way. But this argument, based on
`
`nothing but hindsight, ignores the structural and chemical differences between the
`
`DPP-IV inhibitors disclosed in these references and linagliptin, and glosses over
`
`the significant unpredictability of the relevant art. Moreover, the only references
`
`disclosing linagliptin that Mylan relies upon in both of its challenge Grounds, the
`
`2
`
`
`
`
`‘940 Publication, discloses a genus of over fifty DPP-IV inhibitors, only one of
`
`IPR2016-01564
`U.S. Patent No. 8,846,695
`
`which is linagliptin. Moreover, the ‘940 Publication does not disclose using
`
`linagliptin in combination with metformin in patients with inadequate glycemic
`
`control despite therapy with metformin, and further fails to specifically disclose or
`
`suggest the linagliptin dosage claimed by the ‘695 patent. Finally, Mylan and its
`
`expert, Dr. Davidson, have failed to point to any reason that a skilled artisan (1)
`
`would have been motivated to select linagliptin from the numerous DPP-IV
`
`inhibitors available in the art generally and the dozens disclosed by the ‘940
`
`Publication specifically, (2) would have combined the teachings of the ‘940
`
`Publication with the other cited references addressing unrelated and structurally
`
`distinct DPP-IV inhibitors, and (3) would have modified those combinations of
`
`teachings to arrive at the claimed invention. Finally, Mylan and its expert have
`
`failed to show that a person of skill 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
`
`3
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`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
`
`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, In Tech, 227-256 (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 –
`
`A Cellular and Molecular Approach, Elsevier Science: Pennsylvania, 1066-1085
`
`(2003) at 1067-68, 1076).
`
`4
`
`
`
`On the other hand, when the blood glucose level is high—after a meal, for
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`
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`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
`
`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:
`
`5
`
`
`
`
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`(Ex. 2006, Aronoff, S.L., et al., Glucose Metabolism and Regulation: Beyond
`
`Insulin and Glucagon, Diabetes Spectrum, 17(3):183-190 (2004) at 186).
`
`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
`
`6
`
`
`
`
`release of insulin, thereby depressing the level of insulin in the body. Because
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`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(3):525-539 (2006) at 525-26).
`
`The methods described in the ‘695 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. 2008, 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): 193-2003, 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.)
`
`7
`
`
`
`Around the priority date of the ‘695 patent, January 7, 2009, American
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`
`
`Diabetes Association (“ADA”) and the European Association for the Study of
`
`Diabetes (“EASD”) published a consensus algorithm outlining the standard
`
`treatment plan of type 2 diabetes. (Ex. 2008). 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 had not been commonly accepted
`
`for the treatment of diabetes and had not been a part of the ADA Consensus
`
`Algorithm prior to January 2009. In point of fact, only one DPP-IV inhibitor,
`
`sitagliptin, had been approved in the US and two, sitagliptin and vildagliptin, had
`
`been approved in Europe at that time. (Ex. 2008, at 199). Indeed, underscoring the
`
`novelty of this class of anti-diabetic agents and the uncertainty in the field about
`
`their use, the 2009ADA Consensus Algorithm notes, with respect to DPP-IV
`
`inhibitors, that “[t]he potential for this class of compounds to interfere with
`
`immune function is of concern; an increase in upper respiratory infections has been
`
`reported.” (Ex. 2008, at 199.)
`
`Importantly, the DPP-IV inhibitors available at the time were unrelated and
`
`structurally distinct:
`
`8
`
`
`
`
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`Boehringer discovered and developed linagliptin—a novel, structurally
`
`distinct DPP-IV inhibitor, which offered various advantages over pre-existing
`
`DPP-IV inhibitors.
`
`
`
`The inventions of the ‘695 patent relate to methods of treating type II
`
`diabetes in patients with inadequate glycemic control despite therapy with
`
`metformin, by administering metformin in combination with linagliptin in a
`
`specific therapeutic doses.
`
`III. GROUND 2: MYLAN FALLS FAR SHORT OF ESTABLISHING
`THAT THE JANUMET LABEL IS A PRINTED PUBLICATION
`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 Janumet Label—Exhibits 1007—but Mylan has not shown
`
`9
`
`
`
`
`that this document was publically accessible before the priority date of the ‘695
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`patent. Thus, Mylan has not shown that the Janumet Label is a “printed
`
`publication.” The Board should not institute trial on this reference.
`
`A. A Reference Must Have Been “Publicly Accessible” To be A
`Printed Publication
`“‘[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). “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. 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, Ex. 1007 is not a printed publication.
`
`10
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`U.S. Patent No. 8,846,695
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`B.
`
`The Janumet Label (Exhibit 1007) Is Not A Section 102(b) Printed
`Publication Because There Is No Evidence That It Was Publicly
`Accessible
`Mylan provides no evidence that the Janumet Label (Ex. 1007), 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 “[t]he Janumet Label published in February 2008,”
`
`(Paper 2, at 26), but provides no evidence to support this assertion. Such
`
`unfounded and conclusory assertions do not satisfy Mylan’s burden of showing
`
`that the document was published on the alleged date and qualifies as a “printed
`
`publication.”
`
`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.” (Id.). This
`
`11
`
`
`
`
`was so, despite the fact that the first page of the document was entitled “Product
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`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 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. Paper 10 at 22).
`
`Likewise here, Exhibit 1007 provides no publication date on its face. Rather,
`
`the only date on the document is a revision date: “Revised 2/2008.” But a revision
`
`date is not synonymous with a publication date. (IPR2016-00649, Paper 10 at 22).
`
`By its plain terms, the February 2008 date only indicates when the document was
`
`revised, and has no bearing on whether and when it became publically available.
`
`Mylan’s expert declaration likewise only provides conclusory allegations
`
`that the Glucophage Label is prior art, but fails to provide any evidence in this
`
`regard. Dr. Davidson, in his declaration, makes a statement identical to that in
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`Mylan’s brief: “[t]he Janumet Label published in February 2008.” (Ex. 1002, at
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`20). But a conclusory statement by an expert that the reference was publically
`
`available, without more, such as any real evidence, is insufficient to establish
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`12
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`
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`dissemination sufficient to qualify as a printed publication. See, e.g., IPR2016-
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`00649, Paper 10 at 22 (disregarding expert testimony that “present[s] conclusory
`
`assertions without citing sufficient evidence in support.”); Coal. for Affordable
`
`Drugs IV LLC v. Pharmacyclics, Inc., IPR2015-01076, 2015 WL 7303857, at *3
`
`(P.T.A.B. Oct. 19, 2015) (declining to credit expert’s conclusory statements that a
`
`reference is a printed publication, where the expert “has not attested to any
`
`personal knowledge of the public accessibility or dissemination” of the reference at
`
`the relevant time). At the very least, Dr. Davidson would have to establish that he
`
`has specific first-hand knowledge that the publication is prior art. As was the case
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`in Frontier Therapeutics, in the instant Petition, Mylan has failed to meet its
`
`burden of at least a preliminary threshold showing that Ex. 1007 is a printed
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`publication. Apple Inc. v. DSS Tech. Mgmt., Inc., Case IPR2015-00369, Paper 14 at
`
`5 (P.T.A.B. Aug. 12, 2015) (noting that Petitioner has the burden to make a
`
`threshold showing that a reference is “printed publication” prior art under 35
`
`U.S.C. §§ 102 and 311(b)). Mylan has not shown this document to be prior art and
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`the Board should not institute trial on its basis.
`
`IV. GROUNDS 1 & 2: MYLAN FAILS TO ESTABLISH A REASON TO
`COMBINE THE TEACHING OF PRIOR ART REFERENCES OR
`REASONABLE EXPECTATION OF SUCCESS
`Mylan asserts that the claims of the ‘695 patent are obvious over Charbonnel
`
`or Hughes in view of the ‘940 Publication (Ground 1) and Janumet, Nauck, or
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`13
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`
`
`
`Ahrén 2008 in view of the ‘940 Publication (Ground 2). To prove obviousness,
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`Mylan must show “that a skilled artisan would have had reason to combine the
`
`teaching of the prior art references to achieve the claimed invention, and that the
`
`skilled artisan would have had a reasonable expectation of success from doing so.”
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676
`
`F.3d 1063, 1068-69 (Fed. Cir. 2012). Mylan has failed to show that such
`
`motivation to combine and reasonable expectation of success existed.
`
`A. A Person of Skill in the Art Would Have Had No Reason To Select
`Linagliptin Of All Available DPP-IV Inhibitors
`To start, Mylan and its expert have not provided any explanation as to why,
`
`as of the priority date, a skilled artisan would have selected linagliptin over
`
`numerous other potential DPP-IV inhibitors for use in combination therapy. Mylan
`
`assumes that a skilled artisan would begin with the teachings of the ‘940
`
`Publication, but does not explain why that would be the case, given the extensive
`
`work on DPP-IV inhibitors in the art. (See, e.g., Ex. 2009, Kuhn, B., et al.,
`
`Molecular Recognition of Ligands in Dipeptidyl Peptidase IV, Current Topics in
`
`Medicinal Chemistry, 7:609-619 (2007); Ex. 2010, Feng, J., et al., Discovery of
`
`Alogliptin: A Potent, Selective, Bioavailable, and Efficacious Inhibitor of
`
`Dipeptidyl Peptidase IV, J. Med. Chem., 50:2297-2300 (2007); Ex. 2011,
`
`Szczepankiewicz, B.G., and Kurukulasuriya, R., Aromatic Heterocycle-Based
`
`DPP-IV Inhibitors: Xanthines and Related Structural Types, Current Topics in
`
`14
`
`
`
`
`Medicinal Chemistry, 7:569-578 (2007); Ex. 2012, Weber, A.E., and Thornberry,
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`N., Case History: Januvia™ (Sitagliptin), a Selective Dipeptidyl Peptidase IV
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`Inhibitor for the Treatment of Type 2 Diabetes, Annual Reports in Medicinal
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`Chemistry, 42:95-109 (2007); Ex. 2013, U.S. Patent No. 7,317,109 to Campbell, et
`
`al.). Moreover, even assuming that a person of skill in the art would be motivated
`
`to start with the ‘940 Publication—the only reference cited by Mylan that discloses
`
`linagliptin—this references discloses a genus of over fifty DPP-IV inhibitors, with
`
`a dozen preferred compounds. Mylan and its expert have not provided any
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`evidence that a person of skill in the art would be motivated to pursue any
`
`particular one of these dozens of compounds. Importantly, the ‘940 Publication
`
`would direct a person of skill in the art to pursue linagliptin specifically. Mylan
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`argues that linagliptin is listed first among the “particularly preferred” DPP-IV
`
`inhibitors, but this argument is unavailing as Mylan and its expert have identified
`
`nothing in the ‘940 Publication suggesting that the order in which the compounds
`
`are listed is anything other than arbitrary and would be of any significance to a
`
`skilled artisan.
`
`
`
`Additionally, the ‘940 Publication does not provide any information
`
`suggesting that a particular compound or a particular set of compounds disclosed
`
`therein are more suitable for use in combination therapy. Rather, the reference
`
`notes that “[t]he DPP IV inhibitors mentioned above may also be used in
`
`15
`
`
`
`
`conjunction with other active substances, by means of which improved treatment
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`results can be obtained.” (Ex. 1003, at [0060]). This statement does not express
`
`preference for linagliptin over any other compounds, but rather suggests that the
`
`potential suitability for combination therapy of the disclosed compounds is generic
`
`and not tied to any particular compound.
`
`Notwithstanding the foregoing, Mylan appears to assert that skilled artisans
`
`would have focused on linagliptin because “the ‘940 Publication disclosed, among
`
`other things, that linagliptin was a longer-lasting and particularly preferred DPP-IV
`
`Inhibitor for combination therapy with metformin.” (Paper 2, at 23 (citing ‘Ex.
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`1003, at [0044])). But the disclosure of Paragraph [0044] upon which Mylan relies
`
`is not specific to linagliptin. Rather, it pertains to no fewer than a dozen DPP-IV
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`inhibitors. Neither does the relied-upon passage suggest that a combination with
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`metformin specifically is particularly favorable. Rather, Paragraph [0044] of the
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`‘940 Publication generically discusses combinations “with other pharmaceutical
`
`active substances.” As such, this disclosure would not have directed a person of
`
`skill in the art to linagliptin specifically, and, as discussed in more detail below,
`
`would also not have directed a person of skill in the art to combine linagliptin with
`
`metformin as opposed to any other active substance.
`
`B. A Person of Skill in the Art Would Have Had No Reason To Select
`Metformin as a Combination Partner for Linagliptin In Patients
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`16
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`With Inadequate Glycemic Control Despite Therapy With
`Metformin
`Mylan appears to argue that a person of skill in the art would have been
`
`motivated to combine linagliptin with metformin because the ‘940 Publication
`
`discloses metformin as a potential combination partner. (Paper 2, at 22-23.) But
`
`Mylan neglects that the ‘940 Publication recites over 50 active agents without
`
`specifying which active agent is optimal for combination therapy in conjunction
`
`with the DPP-IV inhibitors disclosed therein:
`
`
`
`17
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`
`
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`(Ex. 1003, at [0061]). Although the ‘940 Publication provides an example,
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`IPR2016-01564
`U.S. Patent No. 8,846,695
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`Example 13, of combined treatment with DPP-IV inhibitor and metformin, the
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`publication also provides examples of other combination therapies: DPP-IV
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`inhibitor-Glitazone (Example 14), DPP-IV inhibitor-SGLT2 inhibitor (Example
`
`15), DPP-IV inhibitor-antihypertensive Example 16), DPP-IV inhibitor-lipid
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`lowering agent (Example 18), and DPP-IV inhibitor-BNP/BNP-Derived Peptides
`
`or BNP-Fusion Peptides (Example 18). Given this broad disclosure, Mylan’s
`
`assertion that skilled artisans would have automatically chosen metformin as the
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`starting point is not correct, particularly in patients where metformin has already
`
`proven ineffective.
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`Mylan further argues that because other known DPP-IV inhibitors—
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`vildagliptin and sitagliptin—were used in conjunction with metformin in patients
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`with inadequate glycemic control despite therapy with metformin, a person of skill
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`in the art would have used linagliptin in the same way. (Paper 2, at 22). But the
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`references that Mylan cite
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