`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
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`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v .
`
`BOEHRINGER INGELHEIM INTERNATIONAL GMBH,
`Patent Owner.
`
`U.S. Patent No. 9,173,859 to Dugi et al.
`Issue Date: Nov. 3, 2015
`Title: Uses of DPP-IV Inhibitors
`
`
`
`Inter Partes Review No.: IPR2016-01566
`
`
`
`
`
`
`Petition for Inter Partes Review of U.S. Patent No. 9,173,859 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
`
`
`
`
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`INTRODUCTION ........................................................................................... 3
`
`II.
`
`OVERVIEW .................................................................................................... 3
`
`III.
`
`STANDING (37 C.F.R. § 42.104(a); PROCEDURAL
`STATEMENTS) .............................................................................................. 4
`
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) ...................................... 5
`
`A.
`
`Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) ........................... 5
`
`B.
`
`Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) .............................. 5
`
`1.
`
`2.
`
`Judicial Matters ........................................................................... 5
`
`Administrative Matters ............................................................... 5
`
`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)): ................... 6
`
`V.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(a)) .......................................... 6
`
`VI. THE ’859 PATENT ......................................................................................... 6
`
`A.
`
`CLAIM CONSTRUCTION .................................................................. 9
`
`VII. EXPERT DECLARATION OF MAYER B. DAVIDSON, M.D. .................. 9
`
`VIII. PERSON OF SKILL IN THE ART (“POSA”) .............................................10
`
`IX.
`
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) .................12
`
`A.
`
`The Scope and Content of the Prior Art ..............................................12
`
`1. Metformin .................................................................................13
`
`2.
`
`3.
`
`DPP-IV Inhibitors .....................................................................14
`
`The Benefits of Combining DPP-IV Inhibitors With
`Metformin Were Well-Known. .................................................16
`
`
`
`i
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`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
`
`B.
`
`Ground 1: Claims 1–22 Are Unpatentable Under 35 U.S.C.
`§ 103(a) over the ’510 Publication in view of the Glucophage
`Label ....................................................................................................18
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`The ’510 Publication (Ex. 1003) ...............................................18
`
`Glucophage Label (Ex. 1004) ...................................................19
`
`Independent Claims 1, 13, and 16–18 .......................................20
`
`Dependent Claims 2–4 ..............................................................26
`
`Dependent Claims 5, 6, 19, 21, 22 ............................................27
`
`Dependent Claims 7–12 ............................................................28
`
`Independent Claim 14 and Dependent Claims 15 and 20.........29
`
`C.
`
`Ground 2: Claims 14 and 20 Are Unpatentable Under 35
`U.S.C. § 102(b) over the ’510 Publication ..........................................30
`
`1.
`
`2.
`
`’510 Publication (Ex. 1003) ......................................................30
`
`Claims 14 and 20.......................................................................30
`
`D. Ground 3: Claims 1–22 are Unpatentable Under 35 U.S.C.
`§ 103(a) over the ’510 Publication in light of Ahrén, Hughes,
`and/or Brazg ........................................................................................31
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`’510 Publication (Ex. 1003) ......................................................31
`
`Ahrén (Ex. 1005).......................................................................31
`
`Hughes (Ex. 1006) ....................................................................34
`
`Brazg (Ex. 1007) .......................................................................34
`
`Independent Claims 1, 13, and 16–18 .......................................36
`
`Dependent Claims 2–4 ..............................................................40
`
`Dependent Claims 5, 6, 19, 21, and 22 .....................................41
`
`Dependent Claims 7–12 ............................................................42
`
`
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`ii
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`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
`
`9.
`
`Independent Claim 14 and Dependent Claims 15 and 20.........42
`
`E.
`
`Objective Indicia of Nonobviousness .................................................43
`
`CONCLUSION ..............................................................................................45
`
`X.
`
`
`
`
`
`iii
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`

`

`
`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Boehringer Ingelheim Pharmaceuticals Inc., et al. v. HEC Pharm Group, et
`al., Civ. Action No. 3:15-cv-05982-PGS-TJB (D.N.J.) ....................................... 5
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) .......................................................................................... 9
`
`Daiichi Sankyo, Ltd. v. Apotex, Inc.,
`501 F.3d 1254 (Fed. Cir. 2007) .......................................................................... 11
`
`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) ............................................................................................................ 11
`
`KSR Int'l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ........................................................................................ 4, 10
`
`Standard Oil Co. v. Am. Cyanamid Co.,
`774 F.2d 448 (Fed. Cir. 1985) ............................................................................ 10
`
`STATUTES
`
`35 U.S.C. §§ 311-319................................................................................................. 3
`
`OTHER AUTHORITIES
`
`37 C.F.R. § 42 ............................................................................................................ 3
`
`37 C.F.R. § 42(a)(1) ................................................................................................... 5
`
`37 C.F.R. § 42.6(d) .................................................................................................. 12
`
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 5
`
`37 C.F.R. § 42.8(b)(2) ................................................................................................ 5
`
`37 C.F.R. § 42.8(b)(3) ................................................................................................ 6
`
`
`
`iv
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`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
`
`37 C.F.R. § 42.10(b) .............................................................................................. 3, 5
`
`37 C.F.R. §42.63(e) .................................................................................................... 5
`
`37 C.F.R. § 42.100(b) ................................................................................................ 9
`
`37 C.F.R. § 42.103 ..................................................................................................... 3
`
`37 C.F.R. § 42.104(a) ................................................................................................. 4
`
`37 C.F.R. § 42.104(b) .............................................................................................. 12
`
`37 C.F.R. § 42.106(a) ................................................................................................. 5
`
`
`
`
`
`
`
`
`
`v
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`

`

`Mylan
`Exhibit #
`
`Petitioner’s Exhibit List
`
`
`Description
`
`1001
`
`1002
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`Dugi et al., U.S. Patent No. 9,173,859, “Uses of DPP-IV Inhibitors”
`
`Declaration of Mayer B. Davidson, M.D.
`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”)
`
` Glucophage® (metformin hydrochloride tablets) and Glucophage®
`
`XR (metformin hydrochloride extended-release tablets) prescribing
`information (2001) (“Glucophage Label”)
`
`
`Ahrén et al., “Twelve and 52-Week Efficacy of the Dipeptidase IV
`Inhibitor LAF237 in Metformin-Treated Patients with Type 2
`Diabetes,” Diabetes Care 27:2874–2880 (2004) (“Ahrén”)
`
`Hughes, International Patent No. WO 2005/117861, “Use of
`Organic Compounds” (“Hughes”)
`
`Brazg et al., “Effect of Adding MK-0431 to On-going Metformin
`Therapy in Type 2 Diabetic Patients Who Have Inadequate
`Glycemic Control on Metformin,” Diabetes 54 (Suppl. 1):A3
`(2005) (“Brazg”)
`
`Curriculum Vitae of Mayer B. Davidson, M.D.
`
`Demuth et al., “Type 2 diabetes—Therapy with dipeptidyl
`peptidase IV inhibitors,” Biochimica et Biophysica Acta 1751:33-
`44 (2005) (“Demuth”)
`Deacon et al., “Inhibitors of Dipeptidyl Peptidase IV: a Novel
`Approach for the Prevention and Treatment of Type 2 Diabetes?”
`Expert Opin. Investig. Drugs, 13(9):1091-1102 (September 2004)
`(“Deacon”)
`
`Gwaltney et al., “Inhibitors of Dipeptidyl Peptidase 4,” Annual
`Reports in Medicinal Chemistry, 40:149-165 (December 2005)
`(“Gwaltney”)
`
`
`
`
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
`
`Mylan
`Exhibit #
`
`Description
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`Chiasson et al., “The Synergistic Effect of Migitol Plus Metformin
`Combination Therapy in the Treatment of Type 2 Diabetes,”
`Diabetes Care 24:989-994 (2001) (“Chiasson”)
`
`Yasuda et al., “Metformin Causes Reduction of Food Intake and
`Body Weight Gain and Improvement of Glucose Intolerance in
`Combination with Dipeptidyl Peptidase IV Inhibitor in Zucker fa/fa
`Rats,” The Journal of Pharmacology and Experimental
`Therapeutics 310:614-619 (2004) (“Yasuda”)
`Nielson “Incretin mimetics and DPP-IV Inhibitors for the treatment
`of type 2 diabetes,” Drug Discovery Today 10(10):703-710 (2005)
`(“Nielson”)
`
`Kirpichnikov et al., “Metformin: An Update,” Ann. Int. Med.
`137(1):25-33 (2002) (“Kirpichnikov”)
`
`Patent Owner’s February 18, 2015 Response to Nonfinal Office
`Action Dated November 19, 2014 in U.S. Application No.
`14/161,007
`Patent Owner’s July 10, 2015 Response to Nonfinal Office Action
`Dated April 15, 2015 in U.S. Application No. 14/161,007
`
`
`
`
`
`
`
`
`
`
`
`
`
`2
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
`
`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 1–22 of U.S.
`
`Patent No. 9,173,859 (“the ’859 patent,” Ex. 1001). Concurrently filed herewith is
`
`a Power of Attorney pursuant to 37 C.F.R. § 42.10(b). Pursuant to 37 C.F.R.
`
`§ 42.103, the fee set forth in § 42.15(a) accompanies this Petition.
`
`II. OVERVIEW
`
`Claims 1–22 of the ’859 patent (the “Challenged Claims”) are directed to
`
`methods for treating type II diabetes by administering a combination of metformin
`
`and oral doses of linagliptin—two drugs that, at the time of the alleged invention,
`
`were known to treat type II diabetes, but through separate and independent
`
`mechanisms of action.
`
`The prior art indisputably demonstrates that the claims of the ’859 patent are
`
`either anticipated and/or obvious. The ’510 Publication specifically teaches the
`
`combination of metformin and oral doses of linagliptin as an effective combination
`
`therapy for treating patients with type II diabetes. The ’510 Publication also
`
`discloses the same linagliptin doses recited in the Challenged Claims. While the
`
`’510 Publication does not disclose a particular amount of metformin, that reference
`
`nonetheless anticipates at least claims 19 and 20, which are not limited to particular
`
`metformin doses.
`
`
`
`3
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
`
`The remaining claims would have been obvious in view of the prior art
`
`because they require nothing more than using known oral doses of linagliptin as
`
`disclosed in the ’510 Publication, together with known standard doses for metformin
`
`monotherapy—which, at the time of the alleged invention, were the same doses of
`
`metformin used in combination with other well-known antidiabetic drugs in the
`
`same class as linagliptin and having the same mechanism of action as linagliptin—
`
`dipeptidyl peptidase IV Inhibitors (DPP-IV Inhibitors). This class of compounds
`
`also includes sitagliptin and vildagliptin.
`
`In sum, the claimed subject matter simply entails using known combinations
`
`of two antidiabetic medications—metformin and DPP-IV Inhibitors—in their
`
`known effective amounts and for their known purposes to achieve a predictable
`
`result, namely, treating type II diabetes. Because the claimed combination “‘simply
`
`arranges old elements with each performing the same function it had been known to
`
`perform’ and yields no more than one would expect from such an arrangement, the
`
`combination is obvious.” KSR Int’l Co. Teleflex Inc., 550 U.S. 398, 417 (2007)
`
`(citation omitted).
`
`As discussed more fully herein, the Challenged Claims of the ’859 patent are
`
`either anticipated and/or obvious in view of the prior art.
`
`III. STANDING (37 C.F.R. § 42.104(a); PROCEDURAL STATEMENTS)
`
`Petitioner certifies that (1) the ’859 patent is available for IPR; and (2)
`
`
`
`4
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the ’859
`
`patent on the grounds identified herein. This Petition is filed in accordance with 37
`
`C.F.R. § 42.106(a). 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).
`
`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 ’859 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).
`
`2.
`
`Administrative Matters
`
`Petitioner has filed concurrently with this Petition, Petitions for inter partes
`
`review of the following U.S. Patents: U.S. Patent Nos. 8,673,927; 8,846,695; and
`
`8,853,156, 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
`
`
`
`5
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
`
`(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
`
`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 1–22. Petitioner’s full
`
`statement of the reasons for the relief requested is set forth in detail below.
`
`VI. THE ’859 PATENT
`
`The ’859 patent, entitled “Uses of DPP-IV Inhibitors,” issued on Nov. 3, 2015.
`
`The ’859 patent issued from U.S. patent application 14/161,007, which ultimately
`
`claims priority to EP 06009203 filed on May 4, 2006. This application is a
`
`continuation of 12/946,193, which issued as U.S. patent no. 8,673,927 and is the
`
`subject of co-pending IPR Petition No. IPR2016-01563. According to records at the
`
`
`
`6
`
`

`

`U.S. Patent and Trademark Office, the ’859 patent is assigned to Boehringer
`
`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
`
`Ingelheim International GmbH.
`
`The Challenged Claims of the ’859 patent are directed to methods of treating
`
`type II diabetes mellitus by administering 1-[(4-methyl-quinazolin-2-yl)-methyl]-3-
`
`methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine
`
`(“linagliptin”)
`
`and metformin and to oral tablet formulations comprising linagliptin and optionally
`
`metformin. (Ex. 1001, ’859 Patent, 23:27–24:66).
`
`The ’859 patent has seven independent claims (claims 1, 13, 14, 16–18, and
`
`20). Independent claim 1 is directed to a method of treating type II diabetes mellitus
`
`by administering 2.5 mg or 5 mg of linagliptin in combination with metformin
`
`“wherein the dose of metformin is 100 mg to 500 mg or 200 mg to 850 mg
`
`(1–3 times a day), or 300 mg to 1000 mg once or twice a day, or as delayed-
`
`release metformin in a dose of 500 mg to 1000 mg once or twice a day, or 500
`
`mg to 2000 mg once a day, or wherein the dose of metformin is 500 mg, 850
`
`mg or 1000 mg as a single dose with a total daily dose of metformin of 500–
`
`2850 mg, or 500 mg, 1000 mg, 1500 mg or 2000 mg metformin in delayed
`
`release form, or wherein the dose of metformin is 500 mg to 1000 mg.”
`
`(Ex. 1001, ’859 Patent, 23:27–43).
`
`Independent claims 13 and 16–18 are similar to claim 1, but recite in a fixed
`
`combination different specified amounts of linagliptin and metformin that fall within
`
`the doses or dosage ranges specified in claim 1. Independent claim 13 recites 2.5
`
`mg of linagliptin in a fixed combination with 500 mg to 1000 mg of metformin. (Ex.
`
`
`
`7
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
`
`1001, ’859 Patent, 24:9–14). Independent claim 16 recites 5 mg of linagliptin in a
`
`fixed combination with 100 mg to 500 mg or 200 mg to 850 mg (1–3 times a day),
`
`or 300 mg to 1000 mg once or twice a day of metformin or 500 mg to 1000 mg once
`
`or twice a day or 500 mg to 2000 mg once a day of delayed-release metformin. (Ex.
`
`1001, ’859 Patent, 24: 23–32). Independent claim 17 recites 5 mg of linagliptin, in
`
`a fixed combination with 500 mg, 850 mg, or 1000 mg as a single dose of metformin
`
`with a total daily dose of metformin of 500–2850 mg, or 500 mg, 1000 mg, 1500 mg
`
`or 2000 mg metformin in delayed released form. (Ex. 1001, ’859 patent, 24:33–42).
`
`Independent claim 18 recites 5 mg of linagliptin in a fixed combination with 500 mg
`
`to 1000 mg of metformin. (Ex. 1001, ’859 Patent, 24:43–48).
`
`Independent claim 14 is directed to an oral tablet formulation comprising 2.5
`
`mg or 5 mg of linagliptin optionally in combination with metformin and a
`
`pharmaceutically acceptable carrier or diluent. (Ex. 1001, ’859 patent, 24:16–20).
`
`Independent claim 20 is directed to a method of treatment, but specifies the
`
`administration of the formulation in independent claim 14 and an amount of 5 mg of
`
`linagliptin. (Ex. 1001, ’859 Patent, 24:53–58).
`
`The remaining method claims 2–12 and 19–22 are ultimately dependent from
`
`either of the independent claims 1 or 14. These dependent claims recite various oral
`
`doses of linagliptin and metformin within the doses or dosage ranges of the
`
`independent claims. Dependent claim 15 recites the oral dosage form of claim 14
`
`
`
`8
`
`

`

`with a particular dosage range of metformin within the dosage range stated in claim
`
`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
`
`1.
`
`A. CLAIM CONSTRUCTION
`
`The claim terms in the ’859 patent are presumed to take on their ordinary and
`
`customary meaning based on the broadest reasonable interpretation (“BRI”) of the
`
`claim language. 37 C.F.R. § 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S.
`
`Ct. 2131, 2142 (2016). Petitioner does not believe that any special meanings apply
`
`to the claim terms in the ’859 patent. Petitioner’s position regarding the scope of the
`
`claims should not be taken as an assertion regarding the appropriate claim scope in
`
`other adjudicative forums where a different claim interpretation standard may apply.
`
`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 R. Drew University. (Ex. 1008 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 has focused his practice on the diagnosis and
`
`treatment of diabetes. (Ex. 1002 ¶ 7; Ex. 1008). He served as President of the
`
`
`
`9
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`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
`
`American Diabetes Association from 1997–1998. (Ex. 1008 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,
`
`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
`
`Clinician Award in Diabetes. (Id. at 5–6). Dr. Davidson’s declaration explains,
`
`among other things, what the relevant art would have conveyed to a POSA as of
`
`May 4, 2006 (Ex. 1002). A current copy of Dr. Davidson’s curriculum vitae is
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`submitted with this petition as Ex. 1008.
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`VIII. PERSON OF SKILL IN THE ART (“POSA”)
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`A POSA is a hypothetical person who is presumed to be aware of all pertinent
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`art, thinks along conventional wisdom in the art, and is a person of ordinary
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`creativity. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). The POSA is
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`not an extraordinarily innovative person, but is a person who thinks conventionally
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`in matters affecting the art in which he or she is skilled. Standard Oil Co. v. Am.
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`Cyanamid Co., 774 F.2d 448, 454 (Fed. Cir. 1985). “Ordinary skill means at least
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`the ability to understand the technology and make modest adaptations or advances.”
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`In the Matter of Mahurkar Double Lumen Hemodialysis Catheter Patent Litig., 831
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`F. Supp. 1354, 1374 (N.D. Ill. 1993), aff'd sub nom., In re Mahurkar Double Lumen
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`Hemodialysis Catheter Patent Litig., 71 F.3d 1573 (Fed. Cir. 1995). Factors that
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`may be considered for determining the level of a skilled practitioner include: the
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`educational level of the inventor; types of problems encountered in the art; prior art
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`solutions
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`to these problems; rapidity with which
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`innovations are made;
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`sophistication of the technology; and educational level of active workers in the field.
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`Daiichi Sankyo, Ltd. v. Apotex, Inc., 501 F.3d 1254, 1256 (Fed. Cir. 2007) (citations
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`omitted).
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`Here, a POSA would possess a relatively high level of skill, such as having an
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`advanced degree in the field of medicine, pharmaceuticals, medicinal chemistry,
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`and/or a related discipline. A POSA would also have at least 5 years of clinical
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`experience treating type II diabetes and related disorders as well as experience with
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`the pharmaceutical and clinical properties of DPP-IV Inhibitors. A POSA would
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`also preferably have some experience investigating pharmaceutical compositions for
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`treating diabetes and diabetes-related disorders. A POSA would easily have
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`understood the prior art references referred to herein, and would have the capability
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`to draw inferences from them. (Ex. 1002 ¶ 12).
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`IX.
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`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))
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`IPR of claims 1–22 is respectfully requested on the following grounds of
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`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
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`unpatentability:
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`Ground
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`References
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`Basis Claims Challenged
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`1
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`2
`3
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`’510 Publication in view of the
`Glucophage Label
`’510 Publication
`’510 Publication in view of Ahrén,
`Hughes, and/or Brazg
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`103
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`102
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`103
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`1–22
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`14, 20
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`1–22
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`Pursuant to 37 C.F.R. § 42.6(d), copies of the prior art references supporting
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`each ground are filed herewith. Additional prior art references are also filed
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`herewith and discussed herein to provide further background in the art, further
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`motivation to combine the teachings of these references, and/or further support for
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`why a person of skill in the art would have a reasonable expectation of success in
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`combining the teachings of the references to arrive at the methods recited in the
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`challenged claims.
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`A. The Scope and Content of the Prior Art
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`Type II diabetes, once known as adult-onset or noninsulin-dependent
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`diabetes, is a chronic condition that affects the way the body metabolizes sugar
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`(glucose)—the body's important source of fuel. (Ex. 1002 ¶ 27). With type II
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`diabetes, the body either resists the effects of insulin—a hormone secreted by the
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`pancreas that regulates the movement of sugar into cells—or does not produce
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`enough insulin to maintain a normal glucose level. (Id.). While there is no cure for
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`type II diabetes, it can be managed by eating well, exercising, and maintaining a
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`healthy weight. (Id.). If diet and exercise are not enough to adequately manage a
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`diabetic’s blood sugar, then he or she will require diabetes medications, insulin
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`therapy, or both. (Id.).
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`1. Metformin
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`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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`Ex. 1006, Hughes at 3; Ex. 1007, Brazg at A3; Ex. 1012, Chiasson at 989).
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`Specifically, metformin is a known biguanide that was first approved by the U.S.
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`Food & Drug Administration for the therapeutic treatment of diabetes in 1994. (Ex
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`1002, at ¶ 28; See Ex. 1004, Glucophage Label).
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`Metformin has been available in several forms, including an immediate
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`release form (e.g., Glucophage IR in 1994), and long-acting form (e.g., Glucophage
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`XR in 2000), among other forms. (Ex. 1002 ¶ 28; See Ex. 1004, Glucophage Label).
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`The standard dose of metformin IR was well known to be 500 mg twice a day or 850
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`mg once a day up to a total of 2,000 mg a day with a maximum of 2,550 mg a day
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`(Ex. 1002 ¶ 29; Ex. 1004 at 6).
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`Metformin works by decreasing the amount of glucose made by the liver and
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`increasing the amount of glucose absorbed into body tissues. (Ex. 1002 ¶ 30; Ex.
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`1015, Kirpichnikov at E-26-E-27). As a result, metformin can help the body respond
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`better to its own insulin and decrease blood glucose levels. (Ex. 1002 ¶ 30;
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`Kirpichnikov at E-27). Figure 1 below illustrates generally how metformin reduces
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`Petition for Inter Partes Review
`of U.S. Patent No. 9,173,859
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`blood glucose levels.
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`Fig. 1: Metformin’s Mechanism of Action.
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`2.
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`DPP-IV Inhibitors
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`
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`DPP-IV Inhibitors were also known to be beneficial in treating type II diabetes
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`patients. (Ex. 1002 ¶ 31; See e.g., ’510 publication ¶¶ [0004], [0297]; Ex. 1010 at
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`1092). DPP-IV Inhibitors have a completely different mechanism of action as
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`compared to metformin. (Ex. 1002 ¶ 31; Ex. 1009, Demuth at 40; Ex. 1014, Nielson
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`at 707-708; Ex. 1015, Kirpichnikov at E-26-E-27). DPP-IV Inhibitors work to
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`increase the level of insulin in the body by preventing the breakdown of GLP-1, a
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`naturally occurring substance that helps reduce blood glucose by stimulating the
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`pancreas to produce insulin and by inhibiting the release of glucagon, a substance
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`that causes the liver to release glucose. (Ex. 1002 ¶ 31; See Ex. 1014, Nielson at
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`708; Ex. 1011 at Gwaltney at 149-150). In addition, these drugs help prevent the
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`liver from producing an excess amount of sugar. (Ex. 1002 ¶ 31; See Ex. 1014,
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`Nielson at 707–708; Ex. 1011 at Gwaltney at 149–150). Figure 2 below illustrates
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`how DPP-IV Inhibitors reduce blood glucose levels.
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`Fig. 2: Mechanism of Action of DPP-IV Inhibitors
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`As of May 4, 2006, the date of alleged invention, treating type II diabetes with
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`DPP-IV Inhibitors was also well-known. (Ex. 1002 ¶ 32; See e.g., ’510 publication
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`¶ [0004], [0297]). The development of DPP-IV Inhibitors began in the 1970’s after
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`the discovery of DPP IV in the 1960’s as an amino peptidase. (Ex. 1002 ¶ 32; Ex.
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`1009, Demuth at 34). More than a year before the ’927 patent’s priority date, several
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`DPP-IV Inhibitors, including sitagliptin and vildagliptin, were well-known
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`treatments for type II diabetes. (Ex. 1002 at ¶ 32; See e.g., Ex. 1006, Hughes at 12;
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`Ex. 1005, Ahrén at 2874; Ex. 1007, Brazg at A3; Ex. 1014, Nielson at 708; Ex. 1009,
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`Demuth at 40–41).
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`Moreover, as of the date of the alleged invention, linagliptin was also a known
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`DPP-IV Inhibitor that was effective in treating type II diabetes. (Ex 1002 at ¶ 33;
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`Ex. 1003, ’510 Publication at ¶¶ [0004], [0245], and [0297]). In fact, linagliptin had
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`been reported as more potent than the DPP-IV Inhibitors vildagliptin and sitagliptin.
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`(Ex 1002 ¶ 33). Specifically, Gwaltney disclosed that vildagliptin and sitagliptin
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`had higher IC50 values and therefore less potency than linagliptin. (Ex. 1011,
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`Gwaltney at 158); (Ex. 1002 ¶ 33 (comparing Ex. 1003, ’510 publication at ¶ [0295]
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`with Ex. 1011, Gwaltney at 158)).
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`3.
`
`The Benefits of Combining DPP-IV Inhibitors With
`Metformin Were Well-Known.
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`Because type II diabetes is a progressive disease, patients who initially
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`respond well to monotherapy often require increased dosages or combination
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`therapy with other antidiabetic agents in order to maintain adequate glycemic
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`control. (Ex. 1002 at ¶ 34; Ex. 1006, Hughes at 2; Ex. 1012, Chiasson at 989). It
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`was well-known in the art that metformin was commonly combined with other
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`antidiabetic agents having separate and distinct mechanisms of action than
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`metformin’s mechanism of action used to treat type II diabetes, including insulin,
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`sulfonylureas, thiazolidinediones, and DPP-IV Inhibitors. (Ex. 1002 at ¶ 34; Ex.
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`1015, Kirpichnikov at E-25; Ex. 1004, Glucophage Label at 6; Ex. 1006, Hughes at
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`12–13; Ex. 1005, Ahrén at 2874; Ex. 1007, Brazg at A3). For instance, taking
`
`advantage of these different mechanism of action, it had been demonstrated that
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`metformin could be combined with the DPP-IV Inhibitors, vildagliptin and
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`sitagliptin, with such combinations providing a significantly improved patient
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`outcome than use of metformin or either DPP-IV Inhibitor alone.