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. 8,846,695 to Dugi
`Issue Date: Sept. 30, 2014
`Title: Treatment for Diabetes in Patients
`with Inadequate Glycemic Control
`Despite Metformin Therapy Comprising a DPP-IV Inhibitor
`
`Inter Partes Review No.: IPR2016-01564
`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,695 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
`
`

`

`TABLE OF CONTENTS
`
`C.
`
`I.
`II.
`III.
`
`Page
`INTRODUCTION ...........................................................................................1
`OVERVIEW....................................................................................................1
`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.
`Judicial Matters...........................................................................5
`2.
`Administrative Matters ...............................................................5
`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)) ....................5
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(a))..........................................6
`THE ’695 PATENT.........................................................................................6
`A.
`CLAIM CONSTRUCTION ..................................................................7
`VII. EXPERT DECLARATION OF MAYER B. DAVIDSON, M.D...................8
`VIII. PERSON OF SKILL IN THE ART (“POSA”)...............................................9
`IX.
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)).................10
`A.
`The Scope and Content of the Prior Art..............................................11
`1.
`Metformin .................................................................................11
`2.
`DPP-IV Inhibitors .....................................................................12
`3.
`The Combination of DPP-IV Inhibitors, Specifically
`Linagliptin, was Known in the Art ...........................................14
`i
`
`V.
`
`VI.
`
`

`

`4.
`
`B.
`
`The Benefits of Administering DPP-IV Inhibitors with
`Metformin in Type II Diabetes Patients with Inadequate
`Glycemic Control Despite Therapy with Metformin
`Were Well-Known....................................................................15
`Ground 1: Claims 1–4 Are Unpatentable Under 35 U.S.C.
`§ 103(a) as Obvious Over Charbonnel or Hughes in View of the
`’940 Publication ..................................................................................16
`1.
`Charbonnel (Ex. 1004)..............................................................16
`2.
`Hughes (Ex. 1005) ....................................................................18
`3.
`The ’940 Publication (Ex. 1003)...............................................19
`4.
`Independent Claims 1 and 2......................................................21
`5.
`Dependent Claims 3 and 4 ........................................................25
`Ground 2: Claims 1–4 Are Unpatentable Under 35 U.S.C.
`§ 103(a) Over the Janumet Label, Nauck, or Ahrén 2008 in
`View of the ’940 Publication ..............................................................26
`1.
`The ’940 Publication (Ex. 1003)...............................................26
`2.
`Janumet Label (Ex. 1007).........................................................26
`3.
`Nauck (Ex. 1006)......................................................................27
`4.
`Ahrén 2008 (Ex. 1022) .............................................................28
`5.
`Independent Claims 1 and 2......................................................31
`6.
`Dependent Claims 3 and 4 ........................................................34
`Objective Indicia of Nonobviousness .................................................35
`D.
`CONCLUSION..............................................................................................36
`
`C.
`
`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.) .............................................5
`Cuozzo Speed Techs., LLC v. Lee,
`136 S.Ct. 2131 (2016)...........................................................................................7
`Daiichi Sankyo, Ltd. v. Apotex, Inc.,
`501 F.3d 1254 (Fed. Cir. 2007) ............................................................................9
`
`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) ..............................................................................................................9
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007)..............................................................................................9
`Novo Nordisk A/S v. Caraco Pharm. Labs., Ltd.,
`719 F.3d 1346 (Fed. Cir. 2013) ........................................................................3, 4
`Richardson-Vicks, Inc. v. Upjohn Co.,
`122 F.3d 1476 (Fed. Cir. 1997) ............................................................................4
`Sinclair & Carroll Co. v. Interchemical Corp.,
`325 U.S. 327 (1945)..............................................................................................4
`Standard Oil Co. v. Am. Cyanamid Co.,
`774 F.2d 448 (Fed. Cir. 1985) ..............................................................................9
`STATUTES
`35 U.S.C. § 102(b) .............................................................................................17, 19
`35 U.S.C. § 103(a) ...................................................................................................16
`
`iii
`
`

`

`OTHER AUTHORITIES
`
`35 U.S.C. §§ 311 – 319..............................................................................................1
`35 U.S.C.§§311—319 ............................................................................................ ..1
`OTHER AUTHORITIES
`37 C.F.R. § 42 ............................................................................................................1
`37 C.F.R. § 42 .......................................................................................................... ..1
`37 C.F.R. § 42(a)(1)...................................................................................................5
`37 C.F.R. § 42(a)(1) ................................................................................................. ..5
`37 C.F.R. § 42.6(c)...................................................................................................10
`37 C.F.R. § 42.6(c) ................................................................................................. ..10
`37 C.F.R. § 42.8(b)(1)................................................................................................5
`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)(2) .............................................................................................. ..5
`37 C.F.R. § 42.8(b)(3)................................................................................................5
`37 C.F.R. § 42.8(b)(3) .............................................................................................. ..5
`37 C.F.R. § 42.10(b) ..............................................................................................1, 5
`37 C.F.R. § 42.10(b) ............................................................................................ ..1, 5
`37 C.F.R. §42.63(e)....................................................................................................5
`37 C.F.R. §42.63(e) .................................................................................................. ..5
`37 C.F.R. § 42.100(b) ................................................................................................7
`37 C.F.R. § 42.100(b) .............................................................................................. ..7
`37 C.F.R. § 42.103 .....................................................................................................1
`37 C.F.R. § 42.103 ................................................................................................... ..1
`37 C.F.R. § 42.104(a).................................................................................................4
`37 C.F.R. § 42.104(a) ............................................................................................... ..4
`37 C.F.R. § 42.104(b) ..............................................................................................10
`37 C.F.R. § 42.104(b) ............................................................................................ ..10
`37 C.F.R. § 42.106(a).................................................................................................4
`37 C.F.R. § 42.106(a) ............................................................................................... ..4
`
`iv
`
`iv
`
`

`

`Mylan
`Exhibit #
`1001
`
`1002
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`1010
`
`1011
`
`1012
`
`Petitioner’s Exhibit List
`
`Description
`Dugi et al., U.S. Patent No. 8,846,695, “Treatment for Diabetes in
`Patients with Inadequate Glycemic Control Despite Metformin
`Therapy Comprising a DPP-IV Inhibitor”
`Declaration of Mayer B. Davidson, M.D.
`Dugi et al., U.S. Patent Publication No. 2007/0281940, “Uses of
`DPP-IV Inhibitors” (the “’940 Publication”)
`Charbonnel et al., “Efficacy and Safety of the Dipeptidyl
`Peptidase-4 Inhibitor Sitagliptin Added to Ongoing Metformin
`Therapy in Patients With Type 2 Diabetes Inadequately Controlled
`with Metformin Alone,” Diabetes Care, 29:2638-2643 (2006)
`(“Charbonnel”)
`Hughes, International Patent No. WO 2005/117861, “Use of
`Organic Compounds” (“Hughes”)
`Nauck et al., “Efficacy and safety of the dipeptidyl peptidase-4
`inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in
`patients with type 2 diabetes inadequately controlled on metformin
`alone: a randomized, double-blind, non-inferiority trial Diabetes,”
`Obesity and Metabolism, 9:194-205 (2007) (“Nauck”)
`Janumet® (sitagliptin and metformin HCL tablets) Prescribing
`Information (rev. 2/2008) (“Janumet”)
`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 2004”)
`Curriculum Vitae of Mayer B. Davidson, M.D.
`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”)
`Kohlrausch et al., U.S. Patent Publication No. 2008/0107731,
`“DPP IV Inhibitor Formulations” (the “’731 Publication”)
`Himmelsbach et al., U.S. Patent Publication No. 2004/0097510,
`“8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and
`v
`
`

`

`Mylan
`Exhibit #
`
`1013
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`Description
`their use as pharmaceutical compositions” (the “‘510 Publication”)
`EMEA guidelines on Galvus® (2007) (“EMEA Galvus”)
`Elrishi et al., “The dipeptidyl-peptidase-4 (DPP-4) inhibitors: a
`new class of oral therapy for patients with type 2 diabetes
`mellitus,” 24 Practical Diabetes Int. 9:474–82 (2007) (“Elrishi”)
`Pei, “From the bench to the bedside: Dipeptidyl peptidase IV
`Inhibitors, a new class of oral antihyperglycemic agents,” Current
`11 Opinion in Drug Discovery & Development 4:512-32 (2008)
`(“Pei”)
`EMEA guidelines on Eucreas® (2007) (“EMEA Eucreas”)
`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”)
`Gwaltney et al., “Inhibitors of Dipeptidyl Peptidase 4,” Annual
`Reports in Medicinal Chemistry, 40:149–165 (December 2005)
`(“Gwaltney”)
`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 Diabestes
`Association, Chicago IL (June 22–25, 2007) (“Huettner”)
`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”)
`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”)
`Ahrén et al., “Novel combination treatment of type 2 diabetes
`DPP-4 inhibition + metformin,” Vascular Health and Risk
`Management, 4(2):383–394 (2008) (“Ahrén 2008”)
`
`vi
`
`

`

`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 1–4 of U.S.
`
`Patent No. 8,846,695 (the “’695 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 1–4 of the ’695 patent (the “Challenged Claims”) are directed to
`
`methods for treating type II diabetes in a patient who, despite receiving metformin
`
`therapy, has inadequate glycemic control. The methods comprise administering to
`
`the patient a combination of linagliptin and metformin. At the time of the alleged
`
`invention, both linagliptin and metformin were known to treat type II diabetes, alone
`
`or in combination.
`
`Metformin is the most commonly prescribed oral agent for the treatment of
`
`type II diabetes. Over time, however, metformin therapy can become less and less
`
`effective, leading to progressive loss of glycemic control in a patient, despite
`
`continued metformin treatment.
`
`Linagliptin is a dipeptidyl peptidase 4 inhibitor (“DPP-IV Inhibitor”). Like
`
`metformin, DPP-IV Inhibitors (e.g., linagliptin, vildagliptin, and sitagliptin) had
`
`been shown to be effective in treating type II diabetes, albeit via a separate
`
`1
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,846,695
`
`mechanism of action.
`
`Because DPP-IV Inhibitors treat
`
`type II diabetes through a different
`
`mechanism of action than metformin, it was known that DPP-IV Inhibitors were
`
`effective in treating type II diabetes even in circumstances when metformin
`
`monotherapy was unable to achieve adequate glycemic control.
`
`Indeed, the prior art indisputably establishes the existence, efficacy, and
`
`safety of using either of two DPP-IV Inhibitors (vildagliptin and sitagliptin) to treat
`
`type II diabetes in those patients who cannot maintain adequate glycemic control
`
`despite treatment with metformin alone.
`
`Prior to the alleged invention, the DPP-IV Inhibitor, linagliptin had been
`
`shown to be an especially potent and long lasting DPP-IV Inhibitor—more potent
`
`and longer-lasting than the other well-known DPP-IV Inhibitors, vildagliptin and
`
`sitagliptin. Moreover, linagliptin was also known to be used in conjunction with
`
`metformin to treat type II diabetes.
`
`Further, nothing is unique or inventive about
`
`the claimed dosages of
`
`linagliptin. In the ’695 patent, the claims require that linagliptin be administered in
`
`its standard monotherapy dosage—which was well-known and used in the prior art.
`
`The same is true of the prior art combinations of other known DPP-IV Inhibitors
`
`(vildagliptin and sitagliptin) when combined with metformin.
`
`There, both
`
`vildagliptin and sitagliptin were each administered in their standard monotherapy
`
`2
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,846,695
`dosages. Accordingly, as of the date of the alleged invention, it would have been
`
`obvious to a person of ordinary skill in the art (“POSA”) to substitute linagliptin for
`
`one of the other two known DPP-IV Inhibitors—vildagliptin and sitagliptin—in
`
`combination with metformin to treat type II diabetes patients who cannot maintain
`
`adequate glycemic control with metformin alone. Not only would such a POSA
`
`have had a reasonable expectation of success, the POSA would have expected that a
`
`combination of linagliptin and metformin would have been better than the known
`
`combinations of vildagliptin with metformin and sitagliptin with metformin. The
`
`superior potency and long-lasting efficacy of linagliptin relative to the other DPP-
`
`IV Inhibitors vildagliptin and sitagliptin, both having the same mechanism of action
`
`as linagliptin, would have been a significant incentive to make the substitution and
`
`arrive at the methods now claimed in the ’695 patent.
`
`Accordingly, the Patent Owner in this case has no more right to withdraw
`
`from the public domain the claimed use of a combination of linagliptin and
`
`metformin than did the patent owner in Novo Nordisk A/S v. Caraco Pharm. Labs.,
`
`Ltd., 719 F.3d 1346 (Fed. Cir. 2013). There, as here, “the closest prior art . . . was
`
`combination therapy” using a small class of drugs that were “well known in the art
`
`to produce beneficial and even synergistic results” when combined with metformin.
`
`Id. at 1351. There, as here, the patentee merely substituted one of the drugs in the
`
`prior art combination—known to have been successfully utilized for the claimed
`
`3
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,846,695
`use—with a newer, more potent, and longer-lasting drug that was “known as . . .
`
`having a similar mechanism of action.” Id. at 1355.
`
`Likewise, in Richardson-Vicks, Inc. v. Upjohn Co., 122 F.3d 1476 (Fed. Cir.
`
`1997), the prior art included similar “combinations” of pseudoephedrine with aspirin
`
`and pseudoephedrine with acetaminophen, and the patentee had claimed the
`
`combination of pseudoephedrine with ibuprofen. There, the Federal Circuit held that
`
`even “substantial evidence” of “unexpected results” could “not overcome the . . .
`
`evidence that the subject matter sought to be patented is obvious.” Id. at 1484.
`
`In this case, where the combinations of vildagliptin/metformin and
`
`sitagliptin/metformin were well known, substituting linagliptin, which would utilize
`
`the same claimed use as vildagliptin or sitagliptin, as the drug to be combined with
`
`metformin is not patentable. See e.g., Sinclair & Carroll Co. v. Interchemical Corp.,
`
`325 U.S. 327, 335 (1945). The claimed invention is simply a combination of known
`
`type II diabetes treatments using known ranges, used for their known purpose to
`
`achieve a predictable result.
`
`III.
`
`STANDING (37 C.F.R. § 42.104(a); PROCEDURAL STATEMENTS)
`
`Petitioner certifies that (1) the ’695 patent is available for IPR; and (2)
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the ’695
`
`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
`
`4
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,846,695
`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 deposit 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 ’695 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 have filed concurrently with this Petition, Petitions for inter partes
`
`review of the following: U.S. Patent Nos. 9,173,859; 8,673,927; 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).
`
`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;
`
`5
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,846,695
`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 1–4. Petitioner’s full
`
`statement of the reasons for the relief requested is set forth in detail below.
`
`VI. THE ’695 PATENT
`The ’695 patent, entitled “Treatment for diabetes in patients with inadequate
`
`glycemic control despite metformin therapy comprising a DPP-IV inhibitor,” issued
`
`on September 30, 2014. The ’695 patent issued from U.S. patent application
`
`13/143,370, which is the national stage application of PCT/EP2010/050103, filed
`
`January 7, 2010, and claims priority to EP application 09150159 (filed January 7,
`
`2009). According to records at the U.S. Patent and Trademark Office, the ’695 patent
`
`is assigned to Boehringer Ingelheim International GmbH.
`
`The Challenged Claims of the ’695 patent are directed to methods of treating
`
`type II diabetes in a patient with inadequate glycemic control despite therapy with
`
`6
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,846,695
`metformin using a DPP-IV Inhibitor, 1-[(4-methyl-quinazolin-2-yl)methyl]-3-
`
`methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine
`
`(“linagliptin”).
`
`(Ex. 1001, Abstract, 27:5–25). The ’695 patent has two independent claims, claims
`
`1 and 2.
`
`Independent claim 1 is directed to a method for treating type II diabetes in a
`
`patient with inadequate glycemic control despite therapy with metformin,
`
`comprising orally administering linagliptin to a patient in an amount of 5 mg per day
`
`in combination with metformin. (Ex. 1001, 27:5–10).
`
`Independent claim 2 is directed to a method for treating type II diabetes in a
`
`patient with inadequate glycemic control despite therapy with metformin,
`
`comprising orally administering linagliptin to a patient in an amount of 5 mg per day
`
`as add-on combination with metformin. (Ex. 1001, 27:11–17).
`
`Dependent claims 3 and 4 recite different dosing frequencies of linagliptin—
`
`5 mg once daily and 2.5 mg twice daily, respectively. (Ex. 1001, 27:18–25)
`
`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 ’695 patent. Cuozzo Speed Techs., LLC v. Lee, 136 S.Ct.
`
`2131, 1246 (2016).
`
`7
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 8,846,695
`VII. EXPERT DECLARATION OF MAYER B. DAVIDSON, M.D.
`Filed herewith is the supporting declaration of Mayer B. Davidson, M.D. (Ex.
`
`1002), and a current copy of Dr. Davidson’s curriculum vitae is submitted herewith
`
`as Exhibit 1009. Dr. Davidson is currently a Professor of Medicine at both the David
`
`Geffen School of Medicine at UCLA and Charles Drew University. (Ex. 1009 at 2–
`
`3). He is board certified in Internal Medicine. (Id. at 2). He is also board certified
`
`in the subspecialty of Diabetes, Endocrinology, and Metabolism. (Id.). Dr. Davidson
`
`has been practicing in the field of diabetes, endocrinology, and metabolism for 50
`
`years. (Id. at 1–2).
`
`During his career, Dr. Davidson focused his practice on the diagnosis and
`
`treatment of diabetes. (Ex. 1009). He served as President of the American Diabetes
`
`Association from 1997–1998. (Id. at 6). He has conducted considerable research
`
`on diabetes and spoken on diabetes both nationally and internationally. (Ex. 1009).
`
`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
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`Current Diabetes Reports and the Editor-in-Chief of Diabetes Care, the leading
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`diabetes clinical journal in the world, from 2002 to 2006. (Id.). He has also written
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`168 scientific papers, 31 book chapters, and numerous reviews and editorials as well
`
`as three complete books on diabetes. (Ex. 1009). In 2016, the American Diabetes
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,846,695
`Association presented him with their Outstanding Physician Clinician Award in
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`Diabetes. Dr. Davidson’s declaration explains what the art would have conveyed to
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`a POSA as of January 7, 2009. (Ex. 1002).
`
`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
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`creativity. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). A POSA is not
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`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
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`Hemodialysis Catheter Patent Litig., 71 F.3d 1573 (Fed. Cir. 1995). Factors that may
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`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;
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`rapidity with which 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
`
`omitted).
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,846,695
`Here, a POSA would possess a high level of skill, such as having an advanced
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`degree in the field of medicine, pharmaceuticals, medicinal chemistry, and/or a
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`related discipline. (Ex. 1002 ¶ 11). A POSA would also have at least 5 years of
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`clinical experience treating type II diabetes and related disorders as well as
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`experience with the pharmaceutical and clinical properties of DPP-IV Inhibitors.
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`(Id. at ¶ 11). A person of ordinary skill in the art would also preferably have some
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`experience investigating pharmaceutical compositions for treating diabetes and
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`diabetes-related disorders. (Id. at ¶ 11). A person of ordinary skill in the art would
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`easily have understood the prior art references referred to herein and in Dr.
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`Davidson’s Declaration, and would have the capability to draw inferences from
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`them. (Id. at ¶ 13).
`
`IX.
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`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))
`IPR of claims 1–4 of the ’695 patent is respectfully requested on the specific
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`grounds of unpatentability outlined below. Per 37 C.F.R. § 42.6(c), copies of the
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`references are filed herewith.
`
`Ground
`1
`
`2
`
`References
`Charbonnel or Hughes in view of the
`’940 Publication
`Janumet, Nauck, or Ahrén 2008 in
`view of the ’940 Publication
`
`Basis Claims Challenged
`
`103
`
`103
`
`1–4
`
`1–4
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`Copies of prior art references, in addition to the primary references listed
`
`above, are filed herewith to provide further background in the art, further motivation
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,846,695
`to combine the teachings of these references, and/or further support for why a POSA
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`would have a reasonable expectation of success in combining the teachings of the
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`references to arrive at the methods recited in the 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 ¶ 20). With type II
`
`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
`
`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.).
`
`1. Metformin
`It was well known that metformin, a “first line” treatment for type II diabetes
`
`that has been used worldwide for many years, works by decreasing the amount of
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`glucose made by the liver and increasing the amount of glucose absorbed into body
`
`tissues. (Ex. 1002 ¶ 21). As a result, metformin can help the body respond better to
`
`its own insulin and decrease blood glucose levels. (Id.). Metformin has been
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,846,695
`available in several forms, including an immediate-release form (e.g., Glucophage
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`IR in 1994), long-acting form (e.g., Glucophage XR in 2000), among other forms.
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`(Id. at ¶ 21). Figure 1 below illustrates generally how metformin reduces blood
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`glucose levels in type II diabetes patients.
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`Fig. 1: Metformin’s Mechanism of Action. (Ex. 1002 ¶ 21).
`
`DPP-IV Inhibitors
`2.
`DPP-IV Inhibitors have also been commonly used to treat type II diabetes
`
`patients. (Ex. 1002 ¶ 22). These drugs were first approved for the treatment of type
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,846,695
`II diabetes in 2006. (Id.). DPP-IV Inhibitors have a completely different mechanism
`
`of action as compared to metformin. (Id.). DPP-IV Inhibitors work to increase the
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`level of insulin in the body by preventing the breakdown of GLP-1, a naturally
`
`occurring substance that helps reduce blood glucose by stimulating the pancreas to
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`produce insulin and by inhibiting the release of glucagon, a substance that causes the
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`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 (Ex. 1002 ¶ 22)
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`Petition for Inter Partes Review
`of U.S. Patent No. 8,846,695
`A POSA would have recognized that metformin and linagliptin would work
`
`well concomitantly because they accomplish lowering of blood sugar via different
`
`physiologic pathways.
`
`(Ex. 1002 ¶ 23; Ex. 1010, Brazg at Abstract 11-OR).
`
`3.
`
`The Combination of DPP-IV Inhibitors, Specifically
`Linagliptin, was Known in the Art
`The combination of metformin and DPP-IV Inhibitors, such as linagliptin to
`
`treat type II diabetes was known in the art. (Ex. 1003, ’940 Publication, ¶¶ [0032],
`
`[0060]–[0061], [0091]; Ex. 1012, ’510 Publication [245], [298]; Ex. 1002 ¶ 24).
`
`Selection of linagliptin over other known DPP-IV Inhibitors—vildagliptin and
`
`sitagliptin—would have been an obvious choice for the POSA because of
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`linagliptin’s superior properties. Specifically, prior to the alleged invention, it was
`
`known that linagliptin (also known as BI 1356), was a “longer-lasting,” “preferred,”
`
`“potent,