Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`
`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. 8,673,927 to Dugi et al.
`Issue Date: Mar. 18, 2014
`Title: Uses of DPP-IV Inhibitors
`
`Inter Partes Review No.: IPR2016-01563
`
`Petition for Inter Partes Review of U.S. Patent No. 8,673,927 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
`
`
`of U.S. Patent No. 8,673,927
`
`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. 8,673,927 to Dugi et al.
`Issue Date: Mar. 18, 2014
`Title: Uses of DPP-IV Inhibitors
`
`Inter Partes Review No.: IPR2016-01563
`
`Petition for Inter Partes Review of U.S. Patent No. 8,673,927 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. 8,673,927
`TABLE OF CONTENTS
`
`C.
`
`I.
`II.
`III.
`
`Page
`INTRODUCTION ...........................................................................................1
`OVERVIEW OF GROUNDS FOR UNPATENABILITY.............................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)):...................4
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(a))..........................................4
`THE ’927 PATENT.........................................................................................4
`A.
`CLAIM CONSTRUCTION ..................................................................6
`VII. EXPERT DECLARATION OF MAYER B. DAVIDSON, M.D...................6
`VIII. PERSON OF 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..............................................10
`1.
`Metformin .................................................................................10
`2.
`DPP-IV Inhibitors .....................................................................12
`3.
`The Benefits of Combining DPP-IV Inhibitors With
`Metformin Were Well-Known..................................................14
`i
`
`V.
`
`VI.
`
`
`
`2.
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`Ground 1: Claims 18–26 Are Anticipated Under 35 U.S.C.
`§ 102(b) by the ’510 Publication.........................................................15
`1.
`The ’510 Publication (Ex. 1003) Anticipates Independent
`Claims 18, 19, and 20 ...............................................................16
`The ’510 Publication Anticipates Dependent Claims 21–
`26...............................................................................................20
`Ground 2: Claims 1–26 Are Unpatentable Under 35 U.S.C.
`§ 103(a) as Obvious over the ’510 Publication and the
`Glucophage Label................................................................................21
`1.
`’510 Publication (Ex. 1003)......................................................21
`2.
`Glucophage Label (Ex. 1004)...................................................21
`3.
`Claims 1–9 ................................................................................22
`4.
`Claims 10–17 ............................................................................25
`5.
`Independent Claims 18–20 and Dependent Claims 21–26.......27
`Ground 3: Claims 1–26 Are Unpatentable Under 35 U.S.C.
`§ 103(a) over the ’510 Publication in view of Ahrén, Hughes,
`and/or Brazg ........................................................................................29
`1.
`’510 Publication (Ex. 1003)......................................................29
`2.
`Ahrén (Ex. 1005).......................................................................30
`3.
`Hughes (Ex. 1006) ....................................................................32
`4.
`Brazg (Ex. 1007).......................................................................33
`5.
`Independent Claims 1 and 10....................................................34
`6.
`Dependent Claims 2–9 and 11–17............................................38
`7.
`Independent Claims 18–20 and Dependent Claims 21–26.......39
`Objective Indicia of Nonobviousness .................................................40
`
`B.
`
`C.
`
`D.
`
`E.
`
`ii
`
`
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`CONCLUSION..............................................................................................41
`
`X.
`
`iii
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`
`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) ............................................................8
`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)..........................................................................................2, 8
`Perricone v. Medicis Pharma. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) ..........................................................................19
`Standard Oil Co. v. Am. Cyanamid Co.,
`774 F.2d 448 (Fed. Cir. 1985) ..............................................................................8
`STATUTES
`35 U.S.C. § 102(b) .............................................................................................15, 16
`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
`
`iv
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`37 C.F.R. § 42.8(b)(1)................................................................................................3
`37 C.F.R. § 42.8(b)(2)................................................................................................3
`37 C.F.R. § 42.8(b)(3)................................................................................................4
`37 C.F.R. § 42.10(b) ..............................................................................................1, 3
`37 C.F.R. §42.63(e)....................................................................................................3
`37 C.F.R. § 42.100(b) ................................................................................................6
`37 C.F.R. § 42.103 .....................................................................................................1
`37 C.F.R. § 42.104(a).................................................................................................2
`37 C.F.R. § 42.104(b) ................................................................................................9
`37 C.F.R. § 42.106(a).................................................................................................3
`(37 C.F.R. § 42.22(a) .................................................................................................4
`
`v
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`Petitioner’s Exhibit List
`
`Mylan
`Exhibit #
`1001
`1002
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`Description
`
`Dugi et al., U.S. Patent No. 8,673,927, “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”)
`
`vi
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`
`Mylan
`Exhibit #
`
`Description
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`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 April 26, 2013 Response to Nonfinal Office Action
`Dated October 29, 2012 in U.S. Application No. 12/946,193
`
`vii
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`
`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 1–26 of U.S.
`
`Patent No. 8,673,927 (“the ’927 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 OF GROUNDS FOR UNPATENABILITY
`Claims 1–26 of the ’927 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 ’927 patent are
`
`either anticipated and/or obvious. The ’510 Publication specifically teaches the
`
`combination of metformin and linagliptin as an effective combination therapy for
`
`treating patients with type II diabetes. The ’510 Publication also discloses the same
`
`oral 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 18–26, which are not limited to particular amount of
`
`metformin.
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`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 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 ’927 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 ’927 patent is available for IPR; and (2)
`
`2
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`Petitioner is not barred or estopped from requesting IPR of any claim of the ’927
`
`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).
`
`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 ’927 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 herewith, Petitions for inter partes review of
`
`the following: U.S. Patent Nos. 9,173,859; 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 (D.N.J.) (consolidated).
`
`3
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`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)):
`
`C.
`
`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 1–26. Petitioner’s full
`
`statement of the reasons for the relief requested is set forth in detail below.
`
`VI. THE ’927 PATENT
`The ’927 patent, entitled “Uses of DPP-IV Inhibitors,” issued on March 18,
`
`2014. The ’927 patent issued from U.S. patent application 12/946,193, which
`
`ultimately claims priority to EP 06009203 filed on May 4, 2006. This application is
`
`the parent application of 14/161,007, which issued as U.S. Patent No. 9,173,859 and
`
`is the subject of co-pending IPR Petition No. IPR2016-01566. According to records
`
`at the U.S. Patent and Trademark Office, the ’927 patent is assigned to Boehringer
`
`4
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`
`Ingelheim International GmbH.
`
`The Challenged Claims of the ’927 patent are directed to methods of treating
`
`type II diabetes mellitus1 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. (Ex. 1001, ’927 Patent, at 23:45–26:18). The ’927 patent has five
`
`independent claims (claims 1, 10, 18, 19, and 20).
`
`Independent claim 1 reads as
`
`follows:
`
`A method of treating type II diabetes mellitus comprising administering
`to a patient in need thereof a pharmaceutically effective oral amount of
`1-[(4-methyl-quinazolin-2-yl)-methyl]-3-methyl-7-(2-butyn-1-yl)-8-
`a
`(3-(R)-amino-piperidin-1-yl)-xanthine
`[“linagliptin”],
`and
`pharmaceutically effective amount of metformin, which is from 300 mg
`to 1000 mg once or twice a day, or 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.
`
`(Id. at 23:46–54). Independent claim 10 is similar to claim 1, but recites a different
`
`dosage range of metformin/delayed-release metformin, reciting “500 mg, 850 mg or
`
`1000 mg metformin as a single dose with a total daily dose of metformin of 500–
`
`2850 mg, or which is 500 mg, 1000 mg, 1500 mg or 2000 mg metformin in delayed
`
`release form.” (Id. at 24:21–29).
`
`1 Type II diabetes mellitus is referred to herein as “type II diabetes.”
`5
`
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`Independent claims 18–20 are also directed to combinations of linagliptin and
`
`metformin. These claims, however, require administering a particular oral dose of
`
`linagliptin together with an effective amount of metformin. Independent claim 18
`
`recites an oral daily dose of linagliptin from 2.5 mg to 10 mg. (Id. at 24:58–64).
`
`Independent claim 19 recites an oral daily dose of linagliptin of 5 mg. (Id. at 24:65–
`
`25:3). Finally, independent claim 20 recites an oral dosage of linagliptin from 0.5
`
`mg to 50 mg. (Id. at 25:4–12).
`
`The remaining claims 2–9, 11–17, and 21–26 are dependent from either of the
`
`independent claims 1, 10, 18, 19, and 20. These dependent claims recite various
`
`amounts of linagliptin.
`
`CLAIM CONSTRUCTION
`A.
`The claim terms in the ’927 Patent are presumed to take on their ordinary and
`
`customary meaning based on the broadest reasonable interpretation 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 ’927 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.
`
`6
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`1002). Also, a current copy of Dr. Davidson’s curriculum vitae is submitted with
`
`this petition as Ex. 1008. 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 ¶ 8; Ex. 1008). He served as President of the
`
`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,
`
`7
`
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`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`among other things, what the relevant art would have conveyed to a POSA as of
`
`May 4, 2006.
`
`VIII. PERSON OF 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). The 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).
`
`Here, a POSA would possess a relatively high level of skill, such as having an
`
`8
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`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 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 POSA would easily have
`
`understood the prior art references referred to herein, and would have the capability
`
`to draw inferences from them. (Ex. 1002 ¶ 11).
`
`IX.
`
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))
`IPR of claims 1–26 is respectfully requested on the following grounds of
`
`unpatentability:
`
`Ground
`1
`2
`
`3
`
`Prior Art References
`’510 Publication
`’510 Publication in view of the
`Glucophage Label
`’510 Publication in view of Ahrén,
`Hughes, and/or Brazg
`
`Basis Claims Challenged
`102
`18–26
`103
`1–26
`
`103
`
`1–26
`
`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 also filed
`
`herewith and 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 person of skill in the art would have a reasonable expectation of success in
`
`combining the teachings of the references to arrive at the methods recited in the
`9
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`
`Challenged Claims.
`
`The Scope and Content of the Prior Art
`A.
`Type II
`diabetes, once known as adult-onset or noninsulin-dependent
`
`diabetes, is a chronic condition that affects the way the body metabolizes sugar
`
`(glucose)—the body's important source of fuel.
`
`(Ex. 1002 ¶ 26). With type II
`
`diabetes, the body either resists the effects of insulin—a hormone secreted by the
`
`pancreas that regulates the movement of sugar into cells—or does not produce
`
`enough insulin to maintain a normal glucose level. (Id.). While there is no cure for
`
`type II diabetes, it can be managed by eating well, exercising, and maintaining a
`
`healthy weight. (Id.). If diet and exercise are not enough to adequately manage a
`
`diabetic’s blood sugar, then he or she will require diabetes medications, insulin
`
`therapy, or both. (Id.).
`
`1. Metformin
`First discovered in the 1920’s, metformin is considered “first line” treatment
`
`for type II diabetes and has been used worldwide for many years. (Ex. 1002 ¶ 28;
`
`Ex. 1006, Hughes at 3; Ex. 1007, Brazg at A3; Ex. 1012, Chiasson at 989).
`
`Specifically, metformin is a known biguanide that was first approved by the U.S.
`
`Food & Drug Administration for the therapeutic treatment of diabetes in 1994. (Ex
`
`1002 at ¶ 27; See Ex. 1004, Glucophage Label).
`
`10
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`Metformin has been available in several forms, including an immediate
`
`release form (e.g., Glucophage IR in 1994), and long-acting form (e.g., Glucophage
`
`XR in 2000), among other forms. (Ex. 1002 ¶ 28; See Ex. 1004, Glucophage Label).
`
`The standard dose of metformin IR was well known to be 500 mg twice a day or 850
`
`mg once a day up to a total of 2,000 mg a day with a maximum of 2,550 mg a day
`
`(Ex. 1002 ¶ 27; Ex. 1004 at 6).
`
`Metformin works by decreasing the amount of glucose made by the liver and
`
`increasing the amount of glucose absorbed into body tissues. (Ex. 1002 ¶ 27; Ex.
`
`1015, Kirpichnikov at E-26-E-27). As a result, metformin can help the body respond
`
`better to its own insulin and decrease blood glucose levels.
`
`(Ex. 1002 ¶ 27;
`
`Kirpichnikov at E-27). Figure 1 below illustrates generally how metformin reduces
`
`blood glucose levels.
`
`11
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`
`Fig. 1: Metformin’s Mechanism of Action.
`
`DPP-IV Inhibitors
`2.
`DPP-IV Inhibitors were also known to be beneficial in treating type II diabetes
`
`patients. (Ex. 1002 ¶ 28; See e.g., ’510 publication ¶¶ [0004], [0297]; Ex. 1010 at
`
`1092). DPP-IV Inhibitors have a completely different mechanism of action as
`
`compared to metformin. (Ex. 1002 ¶ 28; Ex. 1009, Demuth at 40; Ex. 1014, Nielson
`
`at 707-708; Ex. 1015, Kirpichnikov at E-26-E-27). DPP-IV Inhibitors work to
`
`increase the level of insulin in the body by preventing the breakdown of GLP-1, a
`
`12
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`naturally occurring substance that helps reduce blood glucose by stimulating the
`
`pancreas to produce insulin and by inhibiting the release of glucagon, a substance
`
`that causes the liver to release glucose. (Ex. 1002 ¶ 28; See Ex. 1014, Nielson at
`
`708; Ex. 1011 at Gwaltney at 149-150). In addition, these drugs help prevent the
`
`liver from producing an excess amount of sugar.
`
`(Ex. 1002 ¶ 28; See Ex. 1014,
`
`Nielson at 707–708; Ex. 1011 at Gwaltney at 149–150). Figure 2 below illustrates
`
`how DPP-IV Inhibitors reduce blood glucose levels.
`
`Fig. 2: Mechanism of Action of DPP-IV Inhibitors
`
`As of May 4, 2006, the date of alleged invention, treating type II diabetes with
`
`DPP-IV Inhibitors was also well-known. (Ex. 1002 ¶ 29; See e.g., ’510 publication
`
`¶ [0004], [0297]). The development of DPP-IV Inhibitors began in the 1970’s after
`
`13
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`the discovery of DPP IV in the 1960’s as an amino peptidase. (Ex. 1002 ¶ 29; Ex.
`
`1009, Demuth at 34). More than a year before the ’927 patent’s priority date, several
`
`DPP-IV Inhibitors,
`
`including sitagliptin and vildagliptin, were well-known
`
`treatments for type II diabetes. (Ex. 1002 at ¶ 29; See e.g., Ex. 1006, Hughes at 12;
`
`Ex. 1005, Ahrén at 2874; Ex. 1007, Brazg at A3; Ex. 1014, Nielson at 708; Ex. 1009,
`
`Demuth at 40–41).
`
`Moreover, as of the date of the alleged invention, linagliptin was also a known
`
`DPP-IV Inhibitor that was effective in treating type II diabetes. (Ex 1002 at ¶ 29;
`
`Ex. 1003, ’510 Publication at ¶¶ [0004], [0245], and [0297]). In fact, linagliptin had
`
`been reported as more potent than the DPP-IV Inhibitors vildagliptin and sitagliptin.
`
`(Ex 1002 ¶ 29). Specifically, Gwaltney disclosed that vildagliptin and sitagliptin
`
`had higher IC50 values and therefore less potency than linagliptin. (Ex. 1011,
`
`Gwaltney at 158); (Ex. 1002 ¶ 29 (comparing Ex. 1003, ’510 publication at ¶ [0295]
`
`with Ex. 1011, Gwaltney at 158)).
`
`3.
`
`The Benefits of Combining DPP-IV Inhibitors With
`Metformin Were Well-Known.
`Because type II diabetes is a progressive disease, patients who initially
`
`respond well to monotherapy often require increased dosages or combination
`
`therapy with other antidiabetic agents in order to maintain adequate glycemic
`
`control. (Ex. 1002 at ¶ 30; Ex. 1006, Hughes at 2; Ex. 1012, Chiasson at 989). It
`
`was well-known in the art that metformin was commonly combined with other
`14
`
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`antidiabetic agents having separate and distinct mechanisms of action than
`
`metformin’s mechanism of action used to treat type II diabetes, including insulin,
`
`sulfonylureas, thiazolidinediones, and DPP-IV Inhibitors.
`
`(Ex. 1002 at ¶ 30; Ex.
`
`1015, Kirpichnikov at E-25; Ex. 1004, Glucophage Label at 6; Ex. 1006, Hughes at
`
`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
`
`metformin could be combined with the DPP-IV Inhibitors, vildagliptin and
`
`sitagliptin, with such combinations providing a significantly improved patient
`
`outcome than use of metformin or either DPP-IV Inhibitor alone. (Ex. 1002 at ¶ 30;
`
`Ex. 1006, Hughes at 32; Ex. 1005, Ahrén at 2874; Ex. 1007, Brazg at A3).
`
`Moreover, the interactions between the two drug families—metformin and
`
`DPP-IV Inhibitors—were “known to be encouraging and mechanistically
`
`predictable.” (Ex. 1002 at ¶ 31; Ex. 1010, Deacon at 1096; Ex. 1009, Demuth at
`
`40). In fact, the combination of valine-pyrrolidide, another DPP-IV Inhibitor, and
`
`metformin even showed “synergistic” effects compared to either metformin or
`
`valine-pyrrolidide alone. (Ex. 1013, Yasuda at 614–15; Ex. 1002 at ¶ 31).
`
`Finally, the specific combination therapy of linagliptin and metformin was
`
`taught in the ’510 Publication.
`
`(Ex. 1002 at ¶ 33; Ex. 1003, ’510 Publication at
`
`¶ [0298]).
`
`B.
`
`Ground 1: Claims 18–26 Are Anticipated Under 35 U.S.C.
`§ 102(b) by the ’510 Publication
`15
`
`
`
`Petition for Inter Partes Review
`of U.S. Patent No. 8,673,927
`The ’510 Publication (Ex. 1003) published on May 20, 2004, and is thus prior
`
`art to the ʼ927 patent under 35 U.S.C. § 102(b). This publication discloses each
`
`element recited in claims 18–26.
`
`1.
`
`The ’510 Publication (Ex. 1003) Anticipates Independent
`Claims 18, 19, and 20
`Independent claims 18–20 of the ’927 patent each contain four elements: (i) a
`
`method of treatment for type II diabetes comprising; (ii) administering to a patient
`
`in need thereof a pharmaceutically effective oral dose of linagliptin; (iii) a specific
`
`dose of linagliptin; and (iv) a pharmaceutically effective amount of metformin. (Ex.
`
`1001, 24:58–64; Ex. 1002 at ¶ 13).
`
`The ’510 Publication discloses orally administering a combination of
`
`metformin and the DDP-IV Inhibitor, linagliptin, as an effective combination
`
`therapy for treating type II diabetes, and thus anticipates independent claims 18–20.
`
`(Ex. 1003 at ¶ [0004], [0297], and [0298]; Ex. 1002 at ¶ 35). Table 1 below
`
`identifies for representative claim 18 where each respective element (i.e., elements
`
`i–iv) for this claim is disclosed in the ’510 Publication.
`
`16
`
`
`
`Claim 18 of the ’927 Patent
`18[i] A method of treating
`type II diabete
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