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. 8,853,156 to Dugi et al.
`Issue Date: Oct. 7, 2014
`Title: Treatment for Diabetes in Patients
`Inappropriate for Metformin Therapy
`
`Inter Partes Review No.: IPR2016-01565
`
`Petition for Inter Partes Review of U.S. Patent No. 8,853,156 Under
`35 U.S.C. §§ 311–319 and 37 C.F.R. §§ 42.1–.80, 42.100–.123
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`

`

`I.
`II.
`III.
`
`Page
`INTRODUCTION ...........................................................................................1
`OVERVIEW....................................................................................................1
`STANDING (37 C.F.R. § 42.104(a); PROCEDURAL
`STATEMENTS)..............................................................................................2
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))......................................3
`A.
`Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) ...........................3
`B.
`Notice of Related Matters (37 C.F.R. § 42.8(b)(2))..............................3
`1.
`Judicial Matters...........................................................................3
`2.
`Administrative Matters ...............................................................3
`Designation of Lead and Back-Up Counsel and Service (37
`C.F.R. §§ 42.8(b)(3), 42.8(b)(4), 42.10(a), and 42.10(b)) ....................3
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(a))..........................................4
`THE ’156 PATENT.........................................................................................4
`A.
`CLAIM CONSTRUCTION ..................................................................6
`VII. EXPERT DECLARATION OF MAYER B. DAVIDSON, M.D...................7
`VIII. PERSON OF ORDINARY SKILL IN THE ART (“POSA”).........................8
`IX.
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))...................9
`A.
`The Scope and Content of the Prior Art Pertinent to the
`Claimed Subject Matter of the ’156 Patent.........................................10
`Ground 1: Claims 1, 2, 4, 5, and 23 are Anticipated Under 35
`U.S.C. § 102(a) by Mikhail.................................................................15
`1.
`Mikhail (Ex. 1003)....................................................................15
`
`C.
`
`B.
`
`TABLE OF CONTENTS
`
`i
`
`V.
`
`VI.
`
`

`

`C.
`
`Mikhail Anticipates Independent Claims 1 and 23...................17
`2.
`Mikhail Anticipates Dependent Claims 2, 4, and 5..................18
`3.
`Ground 2: Claims 1–2, 4–8, and 10–18, and 23–25 Would
`Have Been Obvious Under 35 U.S.C. § 103(a) Over the Januvia
`Label in View of Huettner together with either the Knowledge
`of a POSA or Mikhail..........................................................................19
`1.
`Mikhail (1003) ..........................................................................19
`2.
`Januvia Label (Ex. 1006) ..........................................................19
`3.
`Huettner (Ex. 1004)...................................................................21
`4.
`Eckhardt 2007 (Ex. 1005).........................................................22
`5.
`Independent Claims 1 and 23–25 Are Obvious........................22
`6.
`Dependent Claims 2, 4–8 and 10–18 Are Obvious ..................26
`Objective Indicia of Nonobviousness .................................................31
`D.
`CONCLUSION..............................................................................................31
`
`X.
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`Boehringer Ingelheim Pharmaceuticals Inc., et al. v. HEC Pharm Group, et
`al., Civ. Action No. 3:15-cv-05982-PGS-TJB (D.N.J.) .......................................3
`Cuozzo Speed Techs., LLC v. Lee,
`136 S.Ct. 2131 (2016)...........................................................................................6
`Daiichi Sankyo, Ltd. v. Apotex, Inc.,
`501 F.3d 1254 (Fed. Cir. 2007) ............................................................................8
`In the Matter of Mahurkar Double Lumen Hemodialysis Catheter Patent
`Litig., 831 F. Supp. 1354 (N.D. Ill. 1993), aff'd sub nom., In re Mahurkar
`Double Lumen Hemodialysis Catheter Patent Litig., 71 F.3d 1573 (Fed.
`Cir. 1995) ..............................................................................................................8
`KSR Int'l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007)..............................................................................................8
`Standard Oil Co. v. Am. Cyanamid Co.,
`774 F.2d 448 (Fed. Cir. 1985) ..............................................................................8
`STATUTES
`35 U.S.C. § 102(a) ...................................................................................................15
`35 U.S.C. §§ 311–319................................................................................................1
`OTHER AUTHORITIES
`37 C.F.R. § 42 ............................................................................................................1
`37 C.F.R. § 42(a)(1)...................................................................................................3
`37 C.F.R. § 42.6(d) ....................................................................................................9
`37 C.F.R. § 42.8(b)(1)................................................................................................3
`37 C.F.R. § 42.8(b)(2)................................................................................................3
`
`iii
`
`

`

`37 C.F.R. § 42.8(b)(3)................................................................................................3
`
`
`37 C.F.R. § 42.8(b)(3) .............................................................................................. ..337 C.F.R. § 42.8(b)(3) ................................................................................................ 337 C.F.R. § 42.8(b)(3) ................................................................................................ 3
`37 C.F.R. § 42.10(b) ..............................................................................................1, 2
`
`
`37 C.F.R. § 42.10(b) ............................................................................................ ..1, 237 C.F.R. § 42.10(b) .............................................................................................. 1, 237 C.F.R. § 42.10(b) .............................................................................................. 1, 2
`37 C.F.R. §42.63(e)....................................................................................................2
`
`
`37 C.F.R. §42.63(e) .................................................................................................. ..237 C.F.R. §42.63(e) .................................................................................................... 237 C.F.R. §42.63(e) .................................................................................................... 2
`37 C.F.R. § 42.100(b) ................................................................................................6
`
`
`37 C.F.R. § 42.100(b) .............................................................................................. ..637 C.F.R. § 42.10003) ................................................................................................ 637 C.F.R. § 42.10003) ................................................................................................ 6
`37 C.F.R. § 42.103 .....................................................................................................1
`37 C.F.R. § 42.103 ................................................................................................... ..1
`
`37 C.F.R. § 42.103 ..................................................................................................... 137 C.F.R. § 42.103 ..................................................................................................... 1
`37 C.F.R. § 42.104(a).................................................................................................2
`
`
`37 C.F.R. § 42.104(a) ............................................................................................... ..237 C.F.R. § 42.104(a) ................................................................................................. 237 C.F.R. § 42.104(a) ................................................................................................. 2
`37 C.F.R. § 42.104(b) ................................................................................................9
`
`
`37 C.F.R. § 42.104(b) .............................................................................................. ..937 C.F.R. § 42.104(b) ................................................................................................ 937 C.F.R. § 42.104(b) ................................................................................................ 9
`37 C.F.R. § 42.106(a).................................................................................................2
`
`
`37 C.F.R. § 42.106(a) ............................................................................................... ..237 C.F.R. § 42.106(a) ................................................................................................. 237 C.F.R. § 42.106(a) ................................................................................................. 2
`
`iv
`
`
`iViV
`iv
`
`

`

`Mylan
`Exhibit #
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`Petitioner’s Exhibit List
`
`Description
`Dugi et al., U.S. Patent No. 8,853,156, “Treatment for Diabetes in
`Patients Inappropriate for Metformin Therapy”
`Declaration of Mayer B. Davidson, M.D.
`Mikhail, “Incretin mimetics and dipeptidyl peptidase 4 inhibitors in
`clinical trials for the treatment of type 2 diabetes,” Expert Opin.
`Investig. Drugs, 17(6): 845-853 (2008) (“Mikhail”)
`Huettner et. al., “BI 1356, a novel and selective xanthine based
`DPP-4 inhibitor demonstrates good safety and tolerability with a
`wide therapeutic window (Poster No. 0586P),” American Diabetes
`Association, Chicago IL (June 22-25, 2007) (“Huettner”)
`Eckhardt et. al., “8-(3-(R)-Aminopiperidin-1-yl)-7-but-2-ynyl-3-
`methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-diydropurine-2,6-
`dione (BI 1356), a Highly Potent, Selective, Long-Acting, and
`Orally Bioavailable DPP-4 Inhibitor for the Treatment of Type 2
`Diabetes,” J. Med. Chem., 50:6450–6453 (2007) (“Eckhardt
`2007”)
`Januvia (sitagliptin phosphate tablets) Prescribing Information
`(2006) (“Januvia Label”)
`Curriculum Vitae of Mayer B. Davidson, M.D.
`Glucophage® (metformin hydrochloride tablets) and Glucophage®
`XR (metformin hydrochloride extended-release tablets) prescribing
`information (2001) (“Glucophage”)
`Mathieu et. al., “Antihyperclycaemic therapy in elderly patients
`with type 2 diabetes: potential role of incretin mimetics and DPP-4
`inhibitors,” International Journal of Clinical Practice, 61 (Suppl.
`154):29–37 (2007) (“Mathieu”)
`Vincent et. al., “Metabolism and Excretion of the Dipeptidyl
`Peptidase 4 Inhibitor [14C]Sitagliptin in Humans,” Drug
`Metabolism and Disposition, 35(4):533–538 (2007) (“Vincent”)
`Flatt et. al., “Dipeptidyl peptidase IV (DPP IV) and related
`molecules in type 2 diabetes,” Frontiers in Bioscience, 13:3648–
`3660 (2008) (“Flatt”)
`
`vi
`
`

`

`Mylan
`Exhibit #
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`Description
`Zerilli et. al., “Sitagliptin Phosphate: A DPP-4 Inhibitor for the
`Treatment of Type 2 Diabetes Mellitus,” 29(12):2614–34 (2007)
`(“Zerilli”)
`He et. al., “The influence of hepatic impairment on the
`pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitor
`vildagliptin,” Eur. J. Clin. Pharmacol. 63:677–686 (2007) (“He I”)
`He et. al., “The Influence of Renal Impairment on the
`Pharmacokinetics of Vildagliptin,” Clinical Pharmacology &
`Therapeutics, 81 (Suppl. 1):S113 (2007) (“He II”)
`Himmelsbach et. al., U.S. Patent Publication No. 2004/0097510,
`“8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and
`their use as pharmaceutical compositions” (“the ’510 publication”)
`Dugi, et. al., “Safety, tolerability, pharmacokinetics, and
`pharmacodynamics of BI 1356, a novel DPP-IV Inhibitor with a
`wide therapeutic window,” Diabetic Medicine P821 (2006). (“Dugi
`2006”)
`Dugi et. al., U.S. Patent Publication No. 2007/0281940, “Uses of
`DPP-IV Inhibitors” (“the ’940 publication”)
`Heise T et. al., Treatment with BI 1356, a Novel and Potent DPP-
`IV Inhibitor, Significantly Reduces Glucose Excursions after an
`oGTT in Patients with Type 2 Diabetes, diabetes, A Journal of the
`American Diabetes Association®, 56(Suppl. 1) at A156, abstract
`588-P and Poster No. 0588P (June 2007) (“Heise”)
`Thomas, et. al., “BI 1356, a novel and selective xanthine based
`DPP-IV inhibitor, exhibits a superior profile when compared to
`sitagliptin and vildagliptin,” Diabetologia 50:[Suppl1]S1–S538,
`Abstract 0879 (2007). (“Thomas”)
`Gwaltney et. al., “Inhibitors of Dipeptidyl Peptidase 4,” Annual
`Reports in Medicinal Chemistry, 40:149–165 (December 2005)
`(“Gwaltney”)
`
`vii
`
`

`

`I.
`
`INTRODUCTION
`Pursuant to 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42, Mylan Pharmaceuticals
`
`Inc. (“Petitioner”) petitions for Inter Partes Review (“IPR”) of claims 1–2, 4–8, 10–
`
`18, and 23–25 of U.S. Patent No. 8,853,156 (the “’156 patent,” Ex. 1001).
`
`Concurrently filed herewith is a Power of Attorney pursuant to 37 C.F.R. § 42.10(b).
`
`Also, pursuant to 37 C.F.R. § 42.103, the fee set forth in § 42.15(a) accompanies this
`
`Petition.
`
`II. OVERVIEW
`Claims 1–2, 4–8, 10–18, and 23–25 of the ’156 patent (the “Challenged
`
`Claims”) are generally directed to methods for treating type II diabetes in patients
`
`for whom the type II diabetes drug, metformin, is contraindicated due to one or more
`
`medical conditions, the most relevant here being renal impairment. For these
`
`patients, the claims require administering a well-known class of type II diabetes
`
`drugs—dipeptidyl peptidase 4 inhibitors (“DPP-IV Inhibitors”). Other claims
`
`require administering the DPP-IV Inhibitor, linagliptin.
`
`There is nothing unique about the subject matter of the Challenged Claims. At
`
`the time of the invention, it was well-known that DPP-IV Inhibitors, such as
`
`sitagliptin, could be administered as an alternative to metformin therapy to type II
`
`diabetes patients with renal impairment.
`
`In addition, it was well-known that the
`
`DPP-IV Inhibitor, linagliptin, was not excreted renally, and thus standard linagliptin
`
`1
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,853,156
`doses could be safely used in patients with renal impairment. It was further well-
`
`known that linagliptin was more potent and long-lasting than the other DPP-IV
`
`Inhibitors previously used as alternatives to metformin therapy for renally impaired
`
`patients. Thus, the POSA would have readily chosen linagliptin over the other DPP-
`
`IV Inhibitors.
`
`Accordingly, a POSA would have understood that DPP-IV Inhibitors, such
`
`as sitagliptin and linagliptin, could safely and effectively be given to treat type II
`
`diabetes patients with renal impairment for whom metformin is contraindicated.
`
`Claims 1–2, 4–8, 10–18, and 23–25 are therefore unpatentable, as discussed more
`
`fully below.
`
`III.
`
`STANDING (37 C.F.R. § 42.104(a); PROCEDURAL STATEMENTS)
`
`Petitioner certifies that (1) the ’156 patent is available for IPR; and (2)
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the ’156
`
`patent on the grounds identified herein. This Petition is filed in accordance with 37
`
`C.F.R. § 42.106(a). Filed herewith are a Power of Attorney and an Exhibit List
`
`pursuant to § 42.10(b) and § 42.63(e). The required fee is paid through Deposit
`
`Acct. No. 160605, and the Office is authorized to charge any fee deficiencies and
`
`credit overpayments to that account (Customer ID No. 00826).
`
`2
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,853,156
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))
`A.
`Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1))
`The real parties in interest for this petition are Mylan Pharmaceuticals Inc.,
`
`Mylan Laboratories Limited, Mylan Inc., and Mylan N.V.
`
`B.
`
`Notice of Related Matters (37 C.F.R. § 42.8(b)(2))
`1.
`Judicial Matters
`The ’156 patent is currently the subject of the following litigation: Boehringer
`
`Ingelheim Pharmaceuticals Inc., et al. v. HEC Pharm Group, et al., Civ. Action No.
`
`3:15-cv-05982-PGS-TJB (D.N.J.) (consolidated).
`
`Administrative Matters
`2.
`Petitioner has filed, concurrently with this Petition, Petitions for inter partes
`
`review of the following U.S. Patents: U.S. Patent Nos. 9,173,859; 8,673,927; and
`
`8,846,695, which are also asserted in Boehringer Ingelheim Pharmaceuticals Inc.,
`
`et al. v. HEC Pharm Group, et al., Civ. Action No. 3:15-cv-05982-PGS-TJB
`
`(D.N.J.) (consolidated).
`
`C.
`
`Designation of Lead and Back-Up Counsel and Service (37 C.F.R.
`§§ 42.8(b)(3), 42.8(b)(4), 42.10(a), and 42.10(b))
`
`Lead Counsel:
`
`Thomas
`
`J.
`
`Parker
`
`(Registration No.
`
`42,062;
`
`thomas.parker@alston.com). Backup Counsel: Christopher L. McArdle (pro hac
`
`vice application to be filed; chris.mcardle@alston.com); Ellen Y. Cheong
`
`(Registration No. 71,852; ellen.cheong@alston.com); and Charles A. Naggar (pro
`
`3
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,853,156
`hac vice application to be filed; charles.naggar@alston.com).
`
`Please direct all correspondence to lead counsel at the following address: 90
`
`Park Avenue, Suite 1200, New York, New York 10016; telephone: (212) 210-9400;
`
`facsimile: (212) 210-9444. Petitioner consents to email service.
`
`V.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(a))
`
`Petitioner requests IPR and cancellation of claims 1–2, 4–8,10–18, and 23–
`
`25. Petitioner’s full statement of the reasons for the relief requested is set forth in
`
`detail below.
`
`VI. THE ’156 PATENT
`The ’156 patent, entitled “Treatment for Diabetes in Patients Inappropriate for
`
`Metformin Therapy.” The ’156 Patent issued on October 7, 2014. The ’156 patent
`
`issued from U.S. patent application 13/057,295, and claims priority to provisional
`
`applications filed August 6, 2008 and October 16, 2008. According to records at the
`
`U.S. Patent and Trademark Office, the ’156 patent is assigned to Boehringer
`
`Ingelheim International GmbH.
`
`The Challenged Claims of the ’156 patent are directed to methods for treating
`
`type II diabetes in patients who cannot tolerate the type II diabetes drug, metformin,
`
`due to one or more medical conditions, including renal insufficiency. For these
`
`patients, the claimed methods require administering other well-known type II
`
`diabetes drugs, namely, DPP-IV Inhibitors, including the prior art DPP-IV Inhibitor,
`
`4
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,853,156
`
`linagliptin.
`
`The ’156 patent has four independent claims (claims 1, 23, 24, and 25).
`
`Independent claim 1 is directed to a method of treating or preventing metabolic
`
`diseases in a patient who has at least one contraindication against metformin,
`
`whereby the method involves orally administering to the patient a DPP-IV Inhibitor.
`
`(Ex. 1001, 29:2–11). The contraindication is selected from the following list: renal
`
`disease, renal impairment or renal dysfunction, among other medical conditions. (Id.
`
`at 29:8–11).
`
`Claims 2, 4–8, and 10–18 depend from claim 1. Dependent claim 2 is directed
`
`to particular patient contraindications against metformin.
`
`(Ex. 1001, 29:12–15).
`
`Dependent claim 4 is limited to a particular metabolic disease: type II diabetes. (Ex.
`
`1001, 29:19–20). Dependent claim 5 is directed to particular contraindications
`
`against renal disease, impairment, or dysfunction. (Ex. 1001, 29:21–23). Dependent
`
`claims 6 through 8 are directed to various DPP-IV Inhibitors, including linagliptin.
`
`(Ex. 1001, 29:24–31:55). Dependent claim 10 is directed to the dose of the DPP-IV
`
`Inhibitor. (Ex. 1001, 31:56–60). Dependent claims 11 through 17 are directed to
`
`characterizations of the metabolites and excretion pathways of the DPP-IV Inhibitors
`
`as they are processed by the human body.
`
`(Ex. 1001, 31:61–32:12). Dependent
`
`claim 18 is directed to the severity of the particular renal contraindication.
`
`(Ex.
`
`1001, 32:13–15).
`
`5
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,853,156
`Independent claim 23 is directed to a method of treating type II diabetes in a
`
`patient who has at least one contraindication against metformin, whereby the method
`
`involves orally administering to the patient a DPP-IV Inhibitor. (Ex. 1001, 32:38–
`
`47). The contraindication is selected from the following: renal disease, renal
`
`impairment or renal dysfunction, among other medical conditions. (Id., 32:44–47).
`
`Independent claim 24 is substantively the same as claim 23, except that the treatment
`
`involves orally administering linagliptin. (Ex. 1001, 32:47–57).
`
`Like claim 24, independent claim 25 is directed to a method of treating type
`
`II diabetes in a patient who has at least one contraindication against metformin,
`
`whereby the method involves orally administering linagliptin to the patient. (Ex.
`
`1001, 32:57–65). The contraindication in claim 25, however, is selected from the
`
`following: “mild, moderate, or severe renal impairment or end-stage renal disease.”
`
`(Id., 32:64–65).
`
`CLAIM CONSTRUCTION
`A.
`Petitioner believes that no terms or phrases require specific construction for
`
`the purpose of this IPR. Therefore, in accordance with 37 C.F.R. § 42.100(b), the
`
`challenged claims must be given their broadest reasonable interpretation in light of
`
`the specification of the ’156 patent. Cuozzo Speed Techs., LLC v. Lee, 136 S.Ct.
`
`2131, 1246 (2016).
`
`6
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,853,156
`VII. EXPERT DECLARATION OF MAYER B. DAVIDSON, M.D.
`Filed herewith is the supporting declaration of Mayer B. Davidson, M.D. (Ex.
`
`1002). Dr. Davidson is currently a Professor of Medicine at both the David Geffen
`
`School of Medicine at UCLA and Charles Drew University. (Ex. 1007 at 2-3). He
`
`is board certified in Internal Medicine. He is also board certified in the subspecialty
`
`of Diabetes, Endocrinology, and Metabolism.
`
`(Id. at 2). Dr. Davidson has been
`
`practicing in the field of diabetes, endocrinology and metabolism for 50 years. (See
`
`Id. at 1–2).
`
`During his career, Dr. Davidson focused his practice on the diagnosis and
`
`treatment of diabetes.
`
`(Ex. 1002 ¶ 8; Ex. 1007). He served as President of the
`
`American Diabetes Association from 1997–1998. (Ex. 1007 at 6). He has conducted
`
`considerable research on diabetes and spoken on diabetes both nationally and
`
`internationally. (Id. at 6–40). Dr. Davidson has 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.
`
`(Id. at 3). He was the Founding Editor of Current Diabetes Reports and Editor-in-
`
`Chief of Diabetes Care, the leading diabetes clinical journal in the world, from
`
`2002–2006. (Id. at 3–4). He has also written 168 scientific papers, 31 book chapters,
`
`and numerous reviews and editorials as well as 3 books on diabetes. (Id. at 41–54).
`
`In 2016, the American Diabetes Association gave him their Outstanding Physician
`
`7
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,853,156
`Clinician Award in Diabetes. (Id. at 5–6). Dr. Davidson’s declaration explains what
`
`the art would have conveyed to a POSA as of August 6, 2008. (Ex. 1002). A current
`
`copy of Dr. Davidson’s curriculum vitae is submitted herewith as Exhibit 1007.
`
`VIII. PERSON OF ORDINARY SKILL IN THE ART (“POSA”)
`
`A 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. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). 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. Standard Oil Co. v. Am.
`
`Cyanamid Co., 774 F.2d 448, 454 (Fed. Cir. 1985). “Ordinary skill means at least
`
`the ability to understand the technology and make modest adaptations or advances.”
`
`In the Matter of Mahurkar Double Lumen Hemodialysis Catheter Patent Litig., 831
`
`F. Supp. 1354, 1374 (N.D. Ill. 1993), aff’d sub nom., In re Mahurkar Double Lumen
`
`Hemodialysis Catheter Patent Litig., 71 F.3d 1573 (Fed. Cir. 1995). Factors that
`
`may be considered for determining the level of a skilled practitioner include: the
`
`educational level of the inventor; types of problems encountered in the art; prior art
`
`solutions
`
`to these problems;
`
`rapidity with which innovations are made;
`
`sophistication of the technology; and educational level of active workers in the field.
`
`Daiichi Sankyo, Ltd. v. Apotex, Inc., 501 F.3d 1254, 1256 (Fed. Cir. 2007) (citations
`
`omitted).
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`8
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,853,156
`Here, a POSA would possess a high level of skill, such as having an advanced
`
`degree in the field of medicine, pharmaceuticals, medicinal chemistry, and/or a
`
`related discipline. A POSA would also have at least 5 years of clinical experience
`
`treating type II diabetes and related disorders as well as experience with the
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`pharmaceutical and clinical properties of DPP-IV Inhibitors. A POSA would also
`
`preferably have some experience investigating pharmaceutical compositions for
`
`treating diabetes and diabetes-related disorders. A person of ordinary skill in the art
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`would easily have understood the prior art references referred to herein, and would
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`have the capability to draw inferences therefrom. (Ex. 1002 ¶ 13).
`
`IX.
`
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))
`IPR of claims 1–2, 4–8, 10–18, and 23–25 is respectfully requested on the
`
`following grounds of unpatentability:
`
`Ground
`1
`2
`
`References
`
`Mikhail
`Januvia Label in View of Huettner
`together with either the Knowledge
`of a POSA or Mikhail
`
`Basis Claims Challenged
`102
`1, 2, 4, 5, and 23
`1–2, 4–8, and 10–18,
`and 23–25
`
`103
`
`Pursuant to 37 C.F.R. § 42.6(d), copies of the prior art references supporting
`
`each ground are filed herewith. Additional prior art references are discussed herein
`
`to provide further background in the art, further motivation to combine the teachings
`
`of these references, and/or further support for why a POSA would have a reasonable
`
`expectation of success in combining the teachings of the references to arrive at the
`
`9
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,853,156
`methods recited in the Challenged Claims. Copies of these additional references are
`
`filed herewith.
`
`A.
`
`The Scope and Content of the Prior Art Pertinent to the Claimed
`Subject Matter of the ’156 Patent
`As of the earliest claimed priority date (i.e., August 6, 2008), it was known to
`
`those skilled in the art that DPP-IV Inhibitors, including sitagliptin and linagliptin,
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`could be used as monotherapy to treat type II diabetes in patients contraindicated
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`against metformin.
`
`Type II diabetes, once known as adult-onset or noninsulin-dependent diabetes,
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`is a chronic condition that affects the way the body metabolizes sugar (glucose).
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`(Ex. 1002 ¶ 27). With type II diabetes, the body both resists the effects of insulin—
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`a hormone secreted by the pancreas that regulates the movement of sugar into cells—
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`and does not produce enough insulin to maintain a normal glucose level.
`
`(Id.).
`
`While there is no cure for type II diabetes, it can initially be managed by eating well,
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`exercising, and maintaining a healthy weight. (Id.). When diet and exercise are not
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`enough to adequately manage a diabetic’s blood sugar, then he or she may require
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`non-insulin diabetes medications, insulin therapy, or both. (Id.).
`
`First discovered in the 1920’s, metformin is considered “first line” treatment
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`for type II diabetes and has been used worldwide for many years. (Ex. 1002 ¶ 28).
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`It works mainly by decreasing the amount of glucose made by the liver, and some
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`studies suggest that it also increases the amount of glucose utilized by certain body
`10
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,853,156
`tissues. (Id.). As a result, metformin can help the body respond better to its own
`
`insulin and decrease blood glucose levels. (Id.). Metformin has been available in
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`several forms, including an immediate release form (e.g., Glucophage IR in 1994),
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`and long-acting form (e.g., Glucophage XR in 2000), among others. (Id.). Figure 1
`
`below illustrates generally how metformin reduces blood glucose levels in type II
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`diabetes patients.
`
`Fig. 1: Metformin’s Mechanism of Action.
`
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`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,853,156
`DPP-IV Inhibitors have also been commonly used to treat type II diabetes
`
`patients. (Ex. 1002 ¶ 29). These drugs were first approved for the treatment of type
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`II diabetes in 2006.
`
`(Ex. 1002 ¶ 29; Ex. 1006 at 1). DPP-IV Inhibitors have a
`
`different mechanism of action as compared to metformin. (Ex. 1002 ¶ 29). DPP-IV
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`Inhibitors work to increase the level of insulin in the body by preventing the
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`breakdown of GLP-1, a naturally occurring substance that helps reduce blood
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`glucose by stimulating the pancreas to produce insulin and by inhibiting the release
`
`of glucagon, a substance that causes the liver to release glucose. (Id.). As a result,
`
`these drugs help prevent the liver from producing an excess amount of glucose. (Id.).
`
`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
`
`12
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`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,853,156
`DPP-IV Inhibitors were known, and widely used, and many were
`
`commercially available, before the alleged earliest priority date of the Challenged
`
`Claims (i.e., August 6, 2008). (Ex. 1001, col. 3–9; Ex. 1002 ¶ 30). Prior to that
`
`time, DPP-IV Inhibitors were used as monotherapy or in combination with other
`
`therapies in treating type II diabetes. (Ex. 1015, ’510 Pub. at ¶ [300]; Ex. 1011, Flatt
`
`at 3654, Ex. 1002 ¶ 30). For example, the DPP-IV Inhibitors sitagliptin and
`
`vildagliptin were used both in monotherapy and in combination therapy with
`
`metformin. (Ex. 1011, Flatt at 3654; Ex. 1002 ¶ 30). It was also known that DPP-
`
`IV Inhibitors can be used as monotherapy for “[p]atients who cannot take metformin
`
`due to adverse effects.” (Ex. 1003, Mikhail 2008 at 851; Ex. 1002 ¶ 30).
`
`Metformin is eliminated through the renal excretion pathway.
`
`(Ex. 1001,
`
`1:62–65; Ex. 1008, Glucophage at Pharmacokinetics; Ex. 1002 ¶ 31). High blood
`
`concentrations of metformin will result if renal excretion of the drug is impaired,
`
`which in turn can lead to severe side effects, such as lactic acidosis, a potentially
`
`life-threatening condition. (Ex. 1008, Glucophage Label at Warnings; Ex. 1002 ¶
`
`31). Thus, metformin has been contraindicated for patients with renal disease or
`
`renal impairment for years prior to the date of the invention. (Ex. 1002 ¶ 31; see
`
`also Ex. 1008, Glucophage label (January 2001) at Contraindications (“Glucophage
`
`[IR] and Glucophage XR are contraindicated in patients with . . . Renal disease or
`
`renal dysfunction . . . .”)). Accordingly, it was understood at the time of the alleged
`
`13
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,853,156
`invention that more preferable diabetic medications suitable for patients with renal
`
`impairment would need to avoid drugs that are excreted by the kidneys. (Id.; Ex.
`
`1002 ¶ 31).
`
`DPP-IV Inhibitors are metabolized differently than metformin, and most
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`DPP-IV Inhibitors, except for linagliptin, are primarily excreted through the kidneys.
`
`(Ex. 1003, Mikhail at 851; Ex. 1004, Huettner at Table 2; Ex. 1018, Heise at Results
`
`- Pharmacokinetics; Ex. 1002 ¶ 32). However, unlike metformin, high levels of
`
`DPP-IV inhibitors will not lead to severe side effects, such as lactic acidosis. For
`
`example, the prior art taught that the DPP-IV Inhibitor sitagliptin is excreted mainly
`
`unchanged through the kidneys; that metabolism of sitagliptin represents a minor
`
`elimination pathway; and that sitagliptin has a safety/tolerability profile that is
`
`comparable t