Bass IPR - Pozen ($POZN)

Paper 1 Date: May 21, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE

BEFORE THE PATENT TRIAL AND APPEAL BOARD

COALITION FOR AFFORDABLE DRUGS VII LLC, Petitioner,

v.

POZEN INC., Patent Owner.

IPR2015-01241 Patent 6,926,907

PETITION FOR INTER PARTES REVIEW

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TABLE OF CONTENTS

I. Introduction .................................................................................................... 1

II. Mandatory Notices Per 37 C.F.R. 42.8 ..................................................... 1

A. Real Party-In-Interest ............................................................................ 1

B. Notice of Related Matters ..................................................................... 2

C. Lead and Back-Up Counsel and Service Information .......................... 3

III. Payment of Fees ............................................................................................. 3

IV. Requirements Per 37 C.F.R. 42.104 .......................................................... 4

A. Grounds for Standing ............................................................................ 4

B. Identification of Challenge and Precise Relief Requested .................... 4

C. Evidence Relied Upon to Support the Challenge .................................. 5

V. Background .................................................................................................... 5

A. State of the Art ...................................................................................... 5

B. Person of Ordinary Skill in the Art (POSA) ......................................... 9

VI. Claim Construction ..................................................................................... 10

A. Unit Dosage Form ............................................................................ 10

B. Acid Inhibitor ................................................................................... 10

C. Coordinated Release ........................................................................ 11

D. All Remaining Terms .......................................................................... 11

VII. Ground 1: Gimet in View of Chiverton Renders Obvious Claims 1, 7, 8, 12, 13, 22, and 23 .............................................................................. 12

A. A POSA Would Have Combined Chiverton with Gimet ................... 12

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B. Claim 1: ............................................................................................... 12

1. A pharmaceutical composition in unit dosage form suitable for oral administration to a patient, comprising: ......... 12

2. (a) an acid inhibitor present in an amount effective to raise the gastric pH of said patient to at least 3.5 upon the administration of one or more of said unit dosage forms; ........ 13

3. (b) a non-steroidal anti-inflammatory drug (NSAID) in an amount effective to reduce or eliminate pain or inflammation in said patient upon administration of one or more of said unit dosage forms; ........................................... 14

4. and wherein said unit dosage form provides for coordinated release such that: i) said NSAID is surrounded by a coating that, upon ingestion of said unit dosage form by said patient, prevents the release of essentially any NSAID from said dosage form unless the pH of the surrounding medium is 3.5 or higher; ...................... 14

5. ii) at least a portion of said acid inhibitor is not surrounded by an enteric coating and, upon ingestion of said unit dosage form by said patient, is released regardless of whether the pH of the surrounding medium is below 3.5 or above 3.5. ......................................................... 15

C. Claim 7: The pharmaceutical composition of claim 1, wherein said NSAID is a cyclooxygenese-2 (COX-2) inhibitor. ..................... 17

D. Claim 8: The pharmaceutical composition of claim 7, wherein said COX-2 inhibitor is selected from the group consisting of celecoxib; rofecoxib; meloxicam; piroxicam; valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522; L-745,337; and NS398. ................................................................................................. 17

E. Claim 12: ............................................................................................. 17

1. The pharmaceutical composition of claim 1 wherein said unit dosage form is a multilayer tablet comprising .................. 17

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2. a single core and one or more layers outside of said single core, wherein: ................................................................. 18

3. i) said NSAID is present in said core; ....................................... 18

4. ii) said coating that does not release said NSAID unless the pH of the surrounding medium is 3.5 or higher surrounds said core; and ............................................................ 18

5. iii) said acid inhibitor is in said one more layers outside said core. ................................................................................... 19

F. Claim 13: The pharmaceutical composition of claim 12, wherein said one or more layers outside of said core do not contain NSAID and are not surrounded by an enteric coating. .......... 19

G. Claim 22: ............................................................................................. 19

1. A method of treating a patient for pain or inflammation, comprising ................................................................................. 20

2. administering to said patient the pharmaceutical composition of any one of claims 1-14. .................................... 20

H. Claim 23: The method of claim 22, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis. ................................................................................................ 20

VIII. Ground 2: Gimet in View of Goldman in Further View of Remington Renders Obvious Claims 1-5 and 7-23................................... 21

A. A POSA Would Have Combined Goldman, Remington and Gimet ................................................................................................... 21

B. Claim 1: ............................................................................................... 22


2. (a) an acid inhibitor present in an amount effective to raise the gastric pH of said patient to at least 3.5 upon the

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administration of one or more of said unit dosage forms; ........ 22




C. Claim 2: The pharmaceutical composition of claim 1, wherein said acid inhibitor is an H2 blocker. .................................................... 24

D. Claim 3: The pharmaceutical composition of claim 2, wherein said H2 blocker is selected from the group consisting of: cimetidine; ranitidine; ebrotidine; pabutidine; lafutidine; loxtidine and famotidine. ..................................................................... 24

E. Claim 4: The pharmaceutical composition of claim 3, wherein said H2 blocker is famotidine, present in said unit dosage form in an amount of between 5 mg and 100 mg. ....................................... 25

F. Claim 5: The pharmaceutical composition of claim 1, wherein said acid inhibitor is a proton pump inhibitor selected from the group consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole. ............................................................. 26

G. Claim 7: The pharmaceutical composition of claim 1, wherein said NSAID is a cyclooxygenese-2 (COX-2) inhibitor. ..................... 26

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H. Claim 8: The pharmaceutical composition of claim 7, wherein said COX-2 inhibitor is selected from the group consisting of celecoxib; rofecoxib; meloxicam; piroxicam; valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522; L-745,337; and NS398. ................................................................................................. 26

I. Claim 9: The pharmaceutical composition of claim 1, wherein said NSAID is selected from the group consisting of: aspirin; acetaminophen; ibuprofen; flurbiprofen; ketoprofen; lornoxicam; naproxen; oxaprozin; etodolac; indomethacin; ketorolac; and nabumetone. ................................................................. 27

J. Claim 10: The pharmaceutical composition of claim 9, wherein said NSAID is naproxen present in an amount of between 50 mg and 1500 mg. ................................................................................. 27

K. Claim 11: The pharmaceutical composition of claim 10, wherein said naproxen is present in an amount of between 200 mg and 600 mg. ................................................................................... 28

L. Claim 12: ............................................................................................. 29






M. Claim 13: The pharmaceutical composition of claim 12, wherein said one or more layers outside of said core do not contain NSAID and are not surrounded by an enteric coating. .......... 29

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N. Claim 14: ............................................................................................. 30

1. The pharmaceutical composition of claim 13, wherein said unit dosage form is a bilayer tablet having an outer layer of said acid inhibitor and an inner core of said NSAID and ................................................................................ 30

2. wherein said outer layer of said tablet is surrounded by a non-enteric film coating that releases said acid inhibitor upon ingestion by patient. ......................................................... 31

O. Claim 15: The pharmaceutical composition of any one of claims 1 or 7-14, wherein said acid inhibitor is a proton pump inhibitor. .............................................................................................. 31

P. Claim 16: ............................................................................................. 32

1. The pharmaceutical composition of any one of claims 12-14, wherein said acid inhibitor is a proton pump inhibitor and ............................................................................................. 32

2. wherein said coating surrounding said core does not dissolve unless the pH of the surrounding medium is 4 or greater. ....................................................................................... 33

Q. Claim 17: ............................................................................................. 33



R. Claim 18: The pharmaceutical composition of any one of claims 7-14, wherein said acid inhibitor is an H2 blocker. ................. 35

S. Claim 19: ............................................................................................. 35

1. The pharmaceutical composition of any one of claims 12-

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14, wherein said acid inhibitor is an H2 blocker and ............... 35

2. wherein said tablet has an inner core of said NSAID surrounded by a barrier coating that dissolves at a rate such that said NSAID is not released until the pH of the surrounding medium is 4 or greater. ......................................... 36

T. Claim 20: ............................................................................................. 36

1. The pharmaceutical composition of any one of claims 12-14, wherein said acid inhibitor is an H2 blocker and ............... 37

2. wherein said tablet has an inner core of said NSAID surrounded by a barrier coating that dissolves at a rate such that said NSAID is not released until the pH of the surrounding medium is 5 or greater. ......................................... 37

U. Claim 21: The pharmaceutical composition of claim 1, wherein said unit dosage form is a capsule. ...................................................... 38

V. Claim 22: ............................................................................................. 38



W. Claim 23: The method of claim 22, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis. ................................................................................................ 39

IX. Ground 3: Goldman in View of Remington in Further View of Abe Renders Obvious Claims 1-5, 7-18, 21, and 22.................................. 39

A. A POSA Would Have Combined Remington, Abe, and Goldman .............................................................................................. 39

B. Claim 1: ............................................................................................... 40

1. A pharmaceutical composition in unit dosage form

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suitable for oral administration to a patient, comprising: ......... 40





C. Claim 2: The pharmaceutical composition of claim 1, wherein said acid inhibitor is an H2 blocker. .................................................... 44

D. Claim 3: The pharmaceutical composition of claim 2, wherein said H2 blocker is selected from the group consisting of: cimetidine; ranitidine; ebrotidine; pabutidine; lafutidine; loxtidine and famotidine. ..................................................................... 44

E. Claim 4: The pharmaceutical composition of claim 3, wherein said H2 blocker is famotidine, present in said unit dosage form in an amount of between 5 mg and 100 mg. ....................................... 45

F. Claim 5: The pharmaceutical composition of claim 1, wherein said acid inhibitor is a proton pump inhibitor selected from the group consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole. ............................................................. 45

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G. Claim 7: The pharmaceutical composition of claim 1, wherein said NSAID is a cyclooxygenese-2 (COX-2) inhibitor. ..................... 45

H. Claim 8: The pharmaceutical composition of claim 7, wherein said COX-2 inhibitor is selected from the group consisting of celecoxib; rofecoxib; meloxicam; piroxicam; valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522; L-745,337; and NS398. ................................................................................................. 46

I. Claim 9: The pharmaceutical composition of claim 1, wherein said NSAID is selected from the group consisting of: aspirin; acetaminophen; ibuprofen; flurbiprofen; ketoprofen; lornoxicam; naproxen; oxaprozin; etodolac; indomethacin; ketorolac; and nabumetone. ................................................................. 46

J. Claim 10: The pharmaceutical composition of claim 9, wherein said NSAID is naproxen present in an amount of between 50 mg and 1500 mg. ................................................................................. 46

K. Claim 11: The pharmaceutical composition of claim 10, wherein said naproxen is present in an amount of between 200 mg and 600 mg. ................................................................................... 47

L. Claim 12: ............................................................................................. 47






M. Claim 13: The pharmaceutical composition of claim 12,

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wherein said one or more layers outside of said core do not contain NSAID and are not surrounded by an enteric coating. .......... 50

N. Claim 14: ............................................................................................. 51

1. The pharmaceutical composition of claim 13, wherein said unit dosage form is a bilayer tablet having an outer layer of said acid inhibitor and an inner core of said NSAID and ................................................................................ 51

2. wherein said outer layer of said tablet is surrounded by a non-enteric film coating that releases said acid inhibitor upon ingestion by patient. ......................................................... 51

O. Claim 15: The pharmaceutical composition of any one of claims 1 or 7-14, wherein said acid inhibitor is a proton pump inhibitor. .............................................................................................. 52

P. Claim 16: ............................................................................................. 52



Q. Claim 17: ............................................................................................. 53



R. Claim 18: The pharmaceutical composition of any one of claims 7-14, wherein said acid inhibitor is an H2 blocker. ................. 54

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S. Claim 21: The pharmaceutical composition of claim 1, wherein said unit dosage form is a capsule. ...................................................... 55

T. Claim 22: ............................................................................................. 55



X. Ground 4: Goldman in View of Remington in Further View of Fitton Renders Obvious Claims 1, 5, and 6 ............................................... 56

A. A POSA Would Have Combined Remington, Fitton, and Goldman .............................................................................................. 56

B. Claim 1: ............................................................................................... 57





5. ii) at least a portion of said acid inhibitor is not surrounded by an enteric coating and, upon ingestion of said unit dosage form by said patient, is released

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regardless of whether the pH of the surrounding medium is below 3.5 or above 3.5. ......................................................... 59

C. Claim 5: The pharmaceutical composition of claim 1, wherein said acid inhibitor is a proton pump inhibitor selected from the group consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole. ............................................................. 59

D. Claim 6: The pharmaceutical composition of claim 5, wherein said proton pump inhibitor is pantoprazole, present in said unit dosage form in an amount of between 10 mg and 200 mg. ................ 60

XI. Any Secondary Considerations of Nonobviousness Would Fail ............. 60

XII. Conclusion .................................................................................................... 60

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TABLE OF AUTHORITIES

Statutes

35 U.S.C. 102(b) .................................................................................................4, 5

35 U.S.C. 103(a) .................................................................................................4, 5

35 U.S.C. 311-319 ................................................................................................ 1

Regulations

37 C.F.R. 42.8(b)(3) ................................................................................................... 3

37 C.F.R. 42.10(b) .................................................................................................. 3

37 C.F.R. 42.100 et seq. .......................................................................................... 1

37 C.F.R. 42.104 ..................................................................................................... 4

37 C.F.R. 42.15(a) ................................................................................................... 4

37 C.F.R. 42.6(c) ..................................................................................................... 5

37 C.F.R. 42.63(e) ................................................................................................... 5

37 C.F.R. 42.8 ......................................................................................................... 1

37 C.F.R. 42.8(b)(1) ................................................................................................ 1

37 C.F.R. 42.8(b)(2) ................................................................................................ 2

37 C.F.R. 42.8(b)(4) ................................................................................................ 3

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EXHIBIT LIST

Exhibit No. Description

1001 U.S. Patent No. 6,926,907 (the 907 Patent)

1002 File History of the 907 Patent

1003 Declaration of Leon Shargel, Ph.D., R.Ph.

1004 U.S. Patent No. 5,698,225 (Gimet)

1005 U.S. Patent No. 5,204,118 (Goldman)

1006 Remingtons Pharmaceutical Sciences, Alfonso R. Gennaro, et al., Mack Publg Co., Seventeenth Edition, 1985 (Remington)

1007 Does Misoprostol Given as a Single Large Dose Improve its Antisecretory Effect? S.G. Chiverton, et al., Aliment. Pharmacol. Therap., Vol. 3 (1989) (Chiverton)

1008 U.S. Patent No. 4,757,060 (Lukacsko)

1009 The Mechanism of Action of Aspirin, J.R. Vane, et al., Pergamon (2003)

1010 G.B. Patent No. 1211134

1011 Drug-Induced Peptic Ulcer Disease, Valerie Vella, Journal of the Malta College of Pharmacy Practice (2005)

1012 Goodman & Gilmans The Pharmacological Basis of Therapeutics, Joel G. Hardman, et al., McGraw-Hill Publg Co., Ninth Edition (1996)

1013 U.S. Patent No. 6,365,184 (Depui)

1014 Tagamet: The Discovery of Histamine H2-Receptor Antagonists, SmithKlein Beecham Pharmas., Am. Chem. Soc. (Nov. 24, 1997)

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1015 Inhibition of Gastric (H+ + K+)-ATPase by the Substituted Benzimidazole Picoprazole, B. Wallmark, et al., Biochimica et Biophysica Acta, Vol. 728, at 31-38 (1983)

1016 U.S. Patent No. 4,255,431

1017 Drug Discovery: Practices, Processes, and Perspectives, Jie Jack Li, et al., John Wiley & Sons (Apr. 3, 2013)

1018 U.S. Patent App. Pub. 2002/0045184 (Chen)

1019 Management of NSAID-Related Gastrointestinal Mucosal Injury, A.F. Barrison, et al., Inflammopharmacology 7(3), at 277-86 (1999)

1020 Prevention of NSAID-Induced Gastroduodenal Ulcers, A. Rostom, et al., Cochrane Database of Systematic Reviews (2000)

1021 VIMOVO (Naproxen and Esomeprazole Magnesium) Tablets | Horizon Pharma, http://www.horizonpharma.com/vimovo/ (last visited May 9, 2015)

1022 Horizon Pharma plc 2014 Irish Statutory Accounts, Horizon Pharma Public Limited Company (Apr. 9, 2015)

1023 Nov. 19, 2004 Amendment and Response Under 37 C.F.R. 1.116, File History of the 907 Patent

1024 Pharmaceutical Companies Buy Rivals Drugs, Then Jack Up the Prices, The Wall Street Journal (Apr. 26, 2015)

1025 Oct. 20, 2004 Final Office Action, File History of the 907 Patent

1026 Nov. 19, 2004 Request for Continued Examination, File History of the 907 Patent

1027 Mar. 29, 2005 Notice of Allowance and Fee(s) Due, File History of the 907 Patent

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1028 Dec. 25, 2007 Certificate of Correction, File History of the 907 Patent

1029 Clinical Trial: Evaluation of Gastric Acid Suppression with Three Doses of Immediate-Release Esomeprazole in the Fixed-Dose Combination of PN 400 (Naproxen/Esomeprazole Magnesium) Compared with Naproxen 500 mg and Enteric-Coated Esomeprazole 20 mg: A Randomized, Open-Label, Phase I Study in Healthy Volunteers, Miner et al., Alim. Pharmacol. Ther., 32:414-424 (2010) (Miner)

1030 Nexium 24HR Acid Reducer, 42 Capsules Walmart.com, http://www.walmart.com/ip/Nexium-24HR-Acid-Reducer-42-Capsules/35284453 (last visited May 9, 2015)

1031 Effects of Misoprostol on Gastric Acid and Mucus Secretion in Man, Donald E. Wilson, et al., Digestive Diseases and Sciences, Vol. 31, No. 2 (Feb. 1986)

1032 Misoprostol Versus Antacid Titration for Preventing Stress Ulcers in Postoperative Surgical ICU Patients, Michael J. Zinner, MD, et al., Ann. Surg., Vol. 210, No. 5 (Nov. 1989)

1033 COX-2 Inhibitors, Peter M. Brooks, et al., Australian Prescriber (Feb. 1, 2000)

1034 Effect of Orally Administered Prostaglandin E2 and its 15-Methyl Analogues on Gastric Secretion, Karim, et al., British Med. Journal (Jan. 20, 1973)

1035 Effect of Increasing Gastric pH with Famotidine on the Absorption and Oral Pharmacokinetics of the Inotropic Agent Vesnarinone, B. Koneru, et al., J. Clin. Pharmacol. (1998)

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1036 Twenty-Four-Hour Intragastric pH Profiles and Pharmacokinetics Following Single and Repeated Oral Administration of the Proton Pump Inhibitor Pantoprazole in Comparison to Omeprazole, M. Hartmann, et al., Aliment Pharmacol. Ther. (Jan. 3, 1996)

1037 Effects of Famotidine on Gastric pH and Residual Volume in Pediatric Surgery. J.S. Jahr, et al., Acta Aneasthesiol Scand. (1991)

1038 Effect of Preanesthetic Famotidine on Gastric Volume and pH, Takahiko Okuda, et al., Journal of Anesthesia, Vol. 2, Issue 1 (Mar. 1988)

1039 Effect of Oral and Intramuscular Famotidine on pH and Volume of Gastric Contents, Kazuo Abe, M.D., et al., Anesth. Analg. (1989) (Abe)

1040 High-Viscosity HPMC as a Film-Coating Agent, G. Maffione, et al., Drug Dev. & Indus. Pharmacy (1993)

1041 Upper Gastrointestinal (GI) pH in Young, Healthy Men and Women, Jennifer B. Dressman, et al., Pharmaceutical Research, Vol. 7, No. 7, 756-761 (1990)

1042 FDA Response to Horizons Citizen Petition

1043 Notice of Final Determination, In re: Patent Term Extension for U.S. Patent No. 6,143,771

1044 Prevention of the Gastrointestinal Adverse Effects of Nonsteroidal Anti-Inflammatory Drugs, Gregor J.E. Brown, et al., Drug Safety (6): 503-512 (December 21, 1999)

1045 Abolition by Omeprazole of Aspirin Induced Gastric Mucosal Injury in Man, T K Daneshmend et al., Gut, Vol. 31, 514-517 (1990) (Daneshmend)

1046 U.S. Patent No. 6,319,519

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1047 Shargel Walmart Receipts

1048 Pantoprazole A Review of its Pharmacological Properties and Therapeutic Use in Acid-Related Disorders, A. Fitton, et al., Drugs, Vol. 51, Issue 3 (Mar. 1996) (Fitton)

1049 The Pathophysiological and Pharmacological Basis of Peptic Ulcer Therapy, J. Freston, Toxicologic Pathology, Vol, 16, No. 2 (1988)

1050 Measurement of Gastrointestinal pH Profiles in Normal Ambulant Human Subjects, D. F. Evans, et al., Gut, Vol. 29, 1035-1041 (1988) (Evans)

1051 Intragastric pH and Serum Gastrin During Administration of Different Doses of Pantoprazole in Healthy Subjects, H. Koop, et al., European Journal of Gastroenterology & Hepatology (Sept. 1996)

1052 Omeprazole: A Preliminary Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Peptic Ulcer Disease and Zollinger- Ellison Syndrome, Clissold et al., Drugs, 32, 15-47 (1986) (Clissold)

1053 Development of an Oral Formulation of Omeprazole, Pilbrant and Cederberg, Scand. J. Gastroenterol., 20(Suppl. 108):113-120 (1985) (Pilbrant)

1054 Effects of Single and Repeated Doses of Omeprazole in Gastric Acid and Pepsin Secretion in Man, Howden et al., Gut, Vol. 25, 707-710 (1984) (Howden)

1055 Omeprazole: A Study of Its Inhibition of Gastric pH and Oral Pharmacokinetics After Morning or Evening Dosage, Prichard et al., Gastroenterol., 88:64-69 (1985) (Prichard)

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1056 The Effects of Oral Doses of Lansoprazole and Omeprazole on Gastric pH, Tolman et al., J. Clin. Gastroenterol, 24(2):65-70 (1997) (Tolman)

1057 Horizons Citizen Petition (February 4, 2014)

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I. Introduction

The Coalition for Affordable Drugs VII LLC (CFAD or Petitioner)

respectfully requests inter partes review of claims 1-23 of U.S. Patent No.

6,926,907 (the 907 Patent) (Ex. 1001) in accordance with 35 U.S.C. 311-319

and 37 C.F.R. 42.100 et seq. The 907 Patent is assigned to Pozen Inc.

II. Mandatory Notices Per 37 C.F.R. 42.8

A. Real Party-In-Interest

Pursuant to 37 C.F.R. 42.8(b)(1), CFAD certifies that Coalition For

Affordable Drugs VII LLC; Hayman Credes Master Fund, L.P. (Credes);

Hayman Orange Fund SPC Portfolio A (HOF); Hayman Capital Master Fund,

L.P. (HCMF); Hayman Capital Management, L.P. (HCM); Hayman Offshore

Management, Inc. (HOM); Hayman Investments, L.L.C. (HI); nXn Partners,

LLC (nXnP); IP Navigation Group, LLC (IPNav); J Kyle Bass; and Erich

Spangenberg (collectively, RPI) are the real parties-in-interest. The RPI certify

the following: CFAD is a wholly owned subsidiary of Credes. Credes is a limited

partnership. HOF is a segregated portfolio company. HCMF is a limited

partnership. HCM is the general partner and investment manager of Credes and

HCMF. HCM is the investment manager of HOF. HOM is the administrative

general partner of Credes and HCMF. HI is the general partner of HCM. J Kyle

Bass is the sole member of HI and sole shareholder of HOM. CFAD, Credes,

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HOF, and HCMF act, directly or indirectly, through HCM as the general partner

and/or investment manager of Credes, HOF, and HCMF. nXnP is a paid

consultant to HCM. Erich Spangenberg is the Manager and majority member of

nXnP. IPNav is a paid consultant to nXnP. Erich Spangenberg is the Manager and

majority member of IPNav. Other than HCM and J Kyle Bass in his capacity as

the Chief Investment Officer of HCM and nXnP and Erich Spangenberg in his

capacity as the Manager/CEO of nXnP, no other person (including any investor,

limited partner, or member or any other person in any of CFAD, Credes, HOF,

HCMF, HCM, HOM, HI, nXnP, or IPNav) has authority to direct or control (i) the

timing of, filing of, content of, or any decisions or other activities relating to this

petition or (ii) any timing, future filings, content of, or any decisions or other

activities relating to the future proceedings related to this petition. All of the costs

associated with this petition are expected to be borne by HCM, CFAD, Credes,

HOF, and/or HCMF.

B. Notice of Related Matters

Per 37 C.F.R. 42.8(b)(2), CFAD is aware of the following judicial matters

involving the 907 Patent: (1) AstraZeneca AB v. Dr. Reddys Labs. Inc., 3:11-cv-

02317 (D.N.J.); (2) AstraZeneca AB v. Dr. Reddys Labs., Inc., 3:13-cv-00091

(D.N.J.); (3) AstraZeneca AB v. Watson Labs., Inc.- Florida, 3:13-cv-03038

(D.N.J.); and (4) AstraZeneca AB v. Mylan Pharmas., 3:13-cv-04022 (D.N.J.). In

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addition, CFAD is aware of the following judicial and administrative matters

involving patents related to the 907 Patent: (1) Dr. Reddys Labs., Inc. v. Pozen

Inc., IPR2015-00802 (P.T.A.B.); (2) Horizon Pharma, Inc. v. Actavis Labs. FL,

Inc., 3:15-cv-03322 (D.N.J.); (3) Horizon Pharma, Inc. v. Dr. Reddys Labs., Inc.,

3:15-cv-03324 (D.N.J.); (4) Horizon Pharma, Inc. v. Lupin Ltd., 3:15-cv-03326

(D.N.J.); and (5) Horizon Pharma, Inc., v. Mylan Pharmas., Inc. 3:15-cv-03327

(D.N.J.).

C. Lead and Back-Up Counsel and Service Information

Per 37 C.F.R. 42.8(b)(3), CFAD designates counsel as follows:

Lead Counsel Back-Up Counsel Amy E. LaValle (Reg. No. 51,092) [email protected] Postal and Hand-Delivery Address: Conley Rose, P.C. 5601 Granite Parkway, Suite 500 Plano, Texas 75024 (972) 731-2288 (phone) (972) 731-2289 (fax)

Jerry C. Harris, Jr. (Reg. No. 66,822) [email protected] Rodney B. Carroll (Reg. No. 39,624) [email protected] Postal and Hand-Delivery Address: Conley Rose, P.C. 5601 Granite Parkway, Suite 500 Plano, Texas 75024 (972) 731-2288 (phone) (972) 731-2289 (fax)

Per 37 C.F.R. 42.8(b)(4), CFAD may be served at the above addresses for Lead

and Back-Up Counsel. CFAD consents to electronic service by e-mail. Per 37

C.F.R. 42.10(b), a Power of Attorney accompanies this Petition.

III. Payment of Fees

The undersigned authorizes the Office to charge the fee required by 37 C.F.R.

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42.15(a) for this Petition to Deposit Account No. 50-1515.

IV. Requirements Per 37 C.F.R. 42.104

A. Grounds for Standing

CFAD certifies that the 907 Patent is available for inter partes review and that

CFAD is not barred or estopped from requesting inter partes review challenging

claims 1-23 of the 907 Patent on the grounds identified in this Petition.

B. Identification of Challenge and Precise Relief Requested

Ground 1: CFAD challenges claims 1, 7, 8, 12, 13, 22, and 23 of the 907

Patent and seeks a ruling that those claims are unpatentable under 35 U.S.C.

103(a) as obvious over Gimet (Ex. 1004) in view Chiverton (Ex. 1007). Gimet

and Chiverton are available as prior art under 35 U.S.C. 102(b).

Ground 2: CFAD challenges claims 1-5 and 7-23 of the 907 Patent and seeks

a ruling that those claims are unpatentable under 35 U.S.C. 103(a) as obvious

over Gimet in view of Goldman (Ex. 1005) and in further view of Remington (Ex.

1006). Gimet, Goldman, and Remington are available as prior art under 35 U.S.C.

102(b).

Ground 3: CFAD challenges claims 1-17, 21, and 22 of the 907 Patent and

seeks a ruling that those claims are unpatentable under 35 U.S.C. 103(a) as

obvious over Goldman in view of Remington and in further view of Abe

(Ex. 1039). Goldman, Remington, and Abe are available as prior art under 35

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5

U.S.C. 102(b).

Ground 4: CFAD challenges claims 1, 5, and 6 of the 907 Patent and seeks a

ruling that those claims are unpatentable under 35 U.S.C. 103(a) as obvious over

Goldman in view of Remington and in further view Fitton (Ex. 1048). Goldman,

Remington, and Fitton are available as prior art under 35 U.S.C. 102(b).

C. Evidence Relied Upon to Support the Challenge

CFAD relies upon the publications cited herein in support of Grounds 1-4.

CFAD also relies upon the Declaration of Leon Shargel, Ph.D., R.Ph. (Ex. 1003)

and the documents cited therein. Filed herewith are an Exhibit List and copies of

the references per 37 C.F.R. 42.63(e) and 37 C.F.R. 42.6(c).

V. Background

A. State of the Art

Non-steroidal anti-inflammatory drugs (NSAIDs) refer to a group of drugs that

reduce pain, inflammation, and fever. (Ex. 1003, 30.) Aspirin is one type of

NSAID. (Id.) Bayer first chemically synthesized aspirin in the 1890s and began

selling aspirin in 1899. (Id.) Since that time, aspirin has become the most widely

used medicine ever. (Id.) Syntex Corporation disclosed its synthesis of naproxen,

another NSAID, in 1968. (Id.) However, since at least 1971, NSAIDs like aspirin

and naproxen have been known to increase gastric acid production and, thus,

increase the incidence of gastric ulcers. (Id.)

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6

Acid inhibitors refer to a group of agents that reduce gastric acid secretion and

gastric acidity. (Ex. 1003, 31.) Prostaglandins, H2 blockers, and proton pump

inhibitors (PPIs) are all types of acid inhibitors. (Id.) Since at least 1973,

prostaglandins have been known to inhibit gastric acid production. (Id.) In 1996,

misoprostol, a prostaglandin, was known to inhibit gastric acid secretion and was

approved for the treatment of gastric ulcer disease induced by NSAIDs. (Id.) In

1970, it was discovered that cimetidine, an H2 blocker, inhibited gastric acid

production. (Id.) Similarly, in the early 1980s, it was discovered that picoprazole,

a PPI, inhibited gastric acid production. (Id.) Omeprazole, another PPI, and its

inhibition of gastric action production, also was discovered in the early 1980s.

(Id.) In 1987, a group led by Gunnel Sundn separated esomeprazole, which is the

enantiopure (S)-isomer of omeprazole. (Id.)

Although NSAIDs provide certain therapeutic benefits, their tendency to

increase the incidence of gastric ulcers may limit their use. (Ex. 1003, 34.) In

order to avoid such limitations, NSAIDs have been used with acid inhibitors at

least as early as 1986. (Id.) For decades before that time, doctors had

recommended that patients take over-the-counter gastric acid neutralizers like

Maalox along with NSAIDs. (Id.) The literature is replete with combination

therapies that include NSAIDs for their therapeutic effects of reducing pain and

inflammation with acid inhibitors to address the side effects of the NSAIDs. (Id.)

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7

However, administration of separate drugs causes various patient compliance

issuespatients may forget or get confused about when to take each drug or how

much to take. (See Chen (Ex. 1018); see also id.)

Acid inhibitors have been combined with NSAIDs in a single tablet at least as

early as 1986. (See, e.g., Lukacsko (Ex. 1008), col. 3 ll. 13-18; see also Ex. 1003,

36.) For example, Dupui discloses a single tablet comprising both an NSAID

and an acid inhibitor. (Dupui (Ex. 1013), col. 1 ll. 11-20, 45-54) Depui recognizes

that such single tablet is [t]he most promising solution to the problem of healing

and preventing NSAID associated upper gastrointestinal problems. (Id. at col. 1

ll. 45-54.) Furthermore, the single tablet addresses the issue of patient compliance.

(Id. at col. 2 ll. 32-41; see also Ex. 1003, 36.)

A combination of an NSAID and an acid inhibitor is just one example of what

is called a combination therapy. (Ex. 1003, 37.) Combination therapy usually

consists of two or more active ingredients combined into a single entity. (Id.)

Through marketing of patented combination drug products, the pharmaceutical

companies can increase their revenue greatly by decreasing or hindering the

consumers access to known, tested, safe, and affordable drugs. (Id.)

Vimovo is a prime example. Vimovo is a combination therapy of naproxen

and esomeprazole magnesium. (Ex. 1003, 39.) Vimovos ingredients,

naproxen and esomeprazole magnesium, are available separately as generic drug

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products. (Id. at 45-51) Pozens affiliates, including Horizon Pharma USA

(Horizon) and AstraZeneca AB (AstraZeneca), currently market and sell

Vimovo. Horizon admits that the active pharmaceutical ingredients (APIs) in

Vimovo have been on the market . . . for many years. (Horizon Pharma plc

2014 Irish Statutory Accounts (Ex. 1022) at 35.) For this reason, Horizon resorts

to sales tactics to convince physicians to prescribeand pharmacists to dispense

Vimovo:

Another key part of our commercial strategy is to encourage physicians to

have their patients agree to fill prescriptions through our Prescriptions-

Made-Easy (PME) [mail-order] specialty pharmacy program . . . .

[P]rescriptions filled through our PME program are . . . less likely to be

subject to the efforts of traditional pharmacies to switch a physicians

intended prescription of our products to a generic or over the counter

brand.

(Ex. 1022 at 5.) Horizon admits that sales of Vimovo may suffer [i]f we are

unsuccessful in convincing physicians to complete prescriptions through our PME

program or otherwise provide prescribing instructions prohibiting the substitution

of . . . generic naproxen and branded Nexium (esomeprazole) as a substitute.

(Ex. 1022, at 17 (emphasis added).) This is a common strategy when APIs are not

themselves patent worthy. (Ex. 1003, 40.) Nonetheless, by virtue of obtaining

the 907 Patent, Pozen and its affiliates have succeeded, thus far, in extending a

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monopoly on a long-known combination that should be available to the public.

(Id.)

The rewards for such an extension are considerable. Indeed, on January 1,

2014, the first day Horizon sold Vimovo, Horizon increased the list price for 60

Vimovo tablets to $959.04, or $15.98 per tablet, a 597% increase. (Wall Street

Journal (Ex. 1024).) On January 1, 2015, Horizon again increased the list price for

60 tablets, this time to $1,678.32, or $27.97 per tablet. (Id.) Currently, Vimovo

can be purchased for $26.46 per tablet. (Ex. 1003, 41.) In contrast, a similar

dosage of the two APIs of Vimovoesomeprazole magnesium and naproxen

can be purchased without a prescription for under $1.00 total. (Id.) In other

words, for the same APIs, the public must pay 30-40 times more for Vimovo.

Despite this enormous pricing disparity, Horizon has announced that it may effect

further price increases for [Vimovo] in 2015 and future periods in response to

future market conditions. (Ex. 1022, at 17.)

B. Person of Ordinary Skill in the Art (POSA)

The field of the 907 Patent is pharmacology. (Ex. 1003, 52-53.) A POSA

in that field at the time of the alleged invention of the 907 Patent, presumably

June 1, 2001, would have been a pharmacist, medical doctor, or pharmaceutical

scientist having a doctor of medicine degree, a doctor of pharmacy degree, or a

Ph.D. degree, or equivalent training or degree, and at least two years of practical

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10

experience or clinical research in pharmaceutical formulations. (Id.)

Alternatively, a POSA at the time of the alleged invention would have been a

pharmacologist or pharmacokineticist having a Ph.D. degree or equivalent training

or degree and at least two years of practical experience or clinical research in

pharmacology or pharmacokinetics. (Id.)

VI. Claim Construction

A. Unit Dosage Form

Claims 1, 4, 6, 12, 14, and 21 include the phrase unit dosage form. (Ex.

1001 col. 20 ll. 9-32, 39-41, 46-49, col. 21 ll. 1-10, 14-19, 39-40.) As issued,

claim 1 uses the phrase unit dose form, but corrects that phrase to unit dosage

form in a Certificate of Correction. (Id. at col. 20 l. 9; Certificate of Correction

(Ex. 1028) at 1.) The specification defines unit dosage form as a single entity

for drug administration. (Ex. 1001 col. 3 ll. 60-61.) Thus, the broadest

reasonable interpretation of unit dosage form in light of the specification of the

907 Patent means a single entity for drug administration. (Ex. 1003, 55.)

B. Acid Inhibitor

Claims 1, 2, 5, 12, 14, 15, and 18 use the phrase acid inhibitor. (Ex. 1001

col. 20 ll. 12, 28, 34, 43, col. 21, ll. 9, 16, 18, 29.) The specification does not

explicitly define acid inhibitor but does state, [t]he term acid inhibitor refers

to agents that inhibit gastric acid secretion and increase gastric pH. (Ex. 1001 col.

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3 ll. 26-28.) In the context of claims 1, 2, 5, 12, 14, 15, and 18, as well as the

specification of the 907 Patent, the broadest reasonable interpretation of acid

inhibitor means an agent that hinders, prevents, or reduces the amount of gastric

acid. (Ex. 1003, 56.) Furthermore, under the broadest reasonable interpretation

in light of the specification of the 907 Patent, the acid inhibitor would include

prostaglandins, H2 blockers, and PPIs. (Id.)

C. Coordinated Release

Claim 1 includes the phrase coordinated release. (Ex. 1001 col. 20 ll. 20-21.)

The specification equates a coordinated release with a sequential release:

All of the dosage forms are designed for oral delivery and provide for the

coordinated release of therapeutic agents, i.e., for the sequential release of

acid inhibitor followed by analgesic.

(Id. at col. 5 ll. 16-19.) Thus, the broadest reasonable interpretation of

coordinated release in light of the specification of the 907 Patent means

sequential release. (Ex. 1003, 57.)

D. All Remaining Terms

Per 37 C.F.R. 42.100(b), all remaining terms in claims 1-23 should be given

[their] broadest reasonable construction in light of the specification.

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12

VII. Ground 1: Gimet in View of Chiverton Renders Obvious Claims 1, 7, 8, 12, 13, 22, and 23

A. A POSA Would Have Combined Chiverton with Gimet

Gimet teaches a unit dosage form suitable for oral administration that

comprises an NSAID and an acid inhibitor (e.g. misoprostol), wherein the NSAID

is present in an enterically-coated core and the acid inhibitor is present in a mantle

coating surrounding the enterically-coated core. (Ex. 1003, 64.) In considering

the dosage and therapeutic effect upon administration of the acid inhibitor (e.g.,

misoprostol) present in the unit dosage form, a known method would be to look to

related literature studying the therapeutic effect of the particular drug (e.g.,

misoprostol) to provide predictable results related to administering the drug. (Id.)

Thus, a POSA would have been motivated to look to clinical studies showing

results of misoprostol on gastric acid pH such as those shown in Chiverton to

provide predictable results of an increase of gastric acid pH associated with the

administration of the known acid inhibitor, misoprostol. (Id.)

B. Claim 1:

Gimet in view of Chiverton discloses each limitation of claim 1 as follows.

1. A pharmaceutical composition in unit dosage form suitable for oral administration to a patient, comprising:

Gimet discloses this limitation. (Ex. 1003, 66.) Specifically, Gimet discloses

[t]he invention herein is directed to a pharmaceutical composition which is a

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core/mantle tablet and [a] method of treating inflammation comprising orally

administering to a patient . . . . (Ex. 1004, col. 3 ll. 8-14, col. 12 ll. 41-44; Ex.

1003, 67-68.)

2. (a) an acid inhibitor present in an amount effective to raise the gastric pH of said patient to at least 3.5 upon the administration of one or more of said unit dosage forms;

Gimet in view of Chiverton discloses this limitation. (Ex. 1003, 69.)

Specifically, Gimet discloses that [s]urrounding the core is a mantle coating

which consists of a prostaglandin. (Ex. 1004, col. 3 ll. 8-14; Ex. 1003, 70.)

Gimet also discloses that the prostaglandin can be administered for its beneficial

therapeutic value in preventing and or inhibiting the incidence of NSAID induced

ulcers. (Ex. 1004, col. 12 ll. 14-19; Ex. 1003, 70.) Gimet further discloses that

the prostaglandin can be misoprostol . . . in an amount from about 50 to about 500

mcg. (Ex. 1004, col. 6 l. 20; Ex. 1003, 70.)

Gimet provides a POSA with a rationale (e.g., a specific teaching, suggestion,

and motivation) for a combination therapy, coordinated release, oral unit dosage

form comprising a prostaglandin as an acid inhibitor, e.g., misoprostol from about

50 to about 500 mcg per dose, and an NSAID, e.g., piroxicam. (Ex. 1003, 71-

72.) A POSA would have understood that a gastric acid inhibitor would be

expected, upon administration, to have a therapeutic effect on gastric pH. (Ex.

1003, 72.) Furthermore, the POSA would have understood that the therapeutic

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14

effect on gastric pH for a dosage of from about 50 to about 500 mcg of misoprostol

could be readily determined by referencing prior art clinical studies such as

Chiverton. (Ex. 1003, 73.) Chiverton discloses that [m]isoprostol is a

prostaglandin E1 analogue that acts primarily through its antisecretory activity.

(Ex. 1007, at 404; Ex. 1003, 71.) Chiverton further discloses that misoprostol

can be dosed in an amount effective to raise gastric pH to at least 3.5. (Ex. 1007,

at 406, Fig. 2, Table 1; Ex. 1003, 71.) A POSA would have known that

misoprostol is a potent inhibitor of gastric acid secretion that can maintain

gastric pH at 4.0 or higher. (Ex. 1003, 74-75.)

3. (b) a non-steroidal anti-inflammatory drug (NSAID) in an amount effective to reduce or eliminate pain or inflammation in said patient upon administration of one or more of said unit dosage forms;


[i]f the inner core is piroxicam, the piroxicam can be present in a therapeutically

acceptable amount. (Ex. 1004, col. 4 ll. 34-39; Ex. 1003, 77.) Gimet discloses

that piroxicam is an NSAID. (Ex. 1004, col. 6 ll. 26-27; Ex. 1003, 77.) Gimet

further discloses that [t]he composition . . . provides an ease of delivery of an

NSAID for its therapeutic value such as the alleviation of inflammation. (Ex.

1004, col. 12 ll. 9-14; Ex. 1003, 77.)

4. and wherein said unit dosage form provides for coordinated release such that: i) said NSAID is surrounded by a coating

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15

that, upon ingestion of said unit dosage form by said patient, prevents the release of essentially any NSAID from said dosage form unless the pH of the surrounding medium is 3.5 or higher;


a tablet 16 that includes an NSAID inner core 18 surrounded by an enteric coating

20, the latter of which aids in segregating the NSAID from the prostaglandin and

in directing the dissolution of the NSAID core in the lower G.I. tract as opposed to

the stomach. (Ex. 1004, col. 6 ll. 24-36, Fig. 2; Ex. 1003, 79.)

A POSA would understand that a typical purpose associated with enteric

coatings is to delay release of an enterically-coated drug until after the drug has

exited the stomach. Also, the POSA would know that a typical patient would have

a pH in the small intestine after exiting the stomach of greater than about 3.5. (Ex.

1003, 80.) Thus, the POSA would have a rationale and a reasonable expectation

of success in preparing a combination therapy, coordinated release, unit dosage

form having a delayed release component, for example an enterically-coated drug

(e.g., NSAID) to prevent the release of the drug from the dosage form unless the

pH of the surrounding medium (e.g., portions of the G.I. tract after exiting the

stomach) is 3.5 or higher. (Ex. 1003, 81-82.)

5. ii) at least a portion of said acid inhibitor is not surrounded by an enteric coating and, upon ingestion of said unit dosage form by said patient, is released regardless of whether the pH of the surrounding medium is below 3.5 or above 3.5.


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that the mantle 22 consist[s] of a prostaglandin, which is orally available. (Ex.

1004, col. 1 l. 66 col. 2 l. 3 and col. 6 ll. 24-44; Ex. 1003, 84.)

(Ex. 1004, Fig. 2.) There is nothing, including an enteric coating, surrounding the

prostaglandin. (Ex. 1003, 84.) This means that the prostaglandin (i.e., the acid

inhibitor) is released immediately due to its direct contact with stomach fluids.

(Ex. 1003, 85.) In contrast to enteric coatings, a POSA would have understood

that a given dosage form may employ an uncoated drug and/or a drug coated with

non-enteric coatings, and that, following administration, such formulations may

release their drug quickly upon contact with the surrounding medium (e.g., about

immediate release upon entering the stomach). (Ex. 1003, 86.) Thus, the POSA

would have a rationale and a reasonable expectation of success in preparing a

combination therapy unit dosage form having an immediate release component, for

example an uncoated drug (e.g., acid inhibitor) and/or drug coated with a non-

enteric coating that releases regardless of the pH of the surrounding medium. (Ex.

1003, 87.)

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17

C. Claim 7: The pharmaceutical composition of claim 1, wherein said NSAID is a cyclooxygenese-2 (COX-2) inhibitor.

As discussed above, Gimet in view of Chiverton renders claim 1 obvious.

Gimet further discloses this limitation of claim 7. (Ex. 1003, 88.) Specifically,

Gimet discloses that the inner core is piroxicam. (Ex. 1004, col. 4 ll. 34-39; Ex.

1003, 89.) Gimet discloses that piroxicam is an NSAID. (Ex. 1004, col. 6 ll. 26-

27; Ex. 1003, 89.) Piroxicam is a COX-2 inhibitor. (Ex. 1003, 89.)

Furthermore, claim 8 indicates that piroxicam is a COX-2 inhibitor.

D. Claim 8: The pharmaceutical composition of claim 7, wherein said COX-2 inhibitor is selected from the group consisting of celecoxib; rofecoxib; meloxicam; piroxicam; valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522; L-745,337; and NS398.

As discussed above, Gimet in view of Chiverton renders claim 1 obvious, and

Gimet renders claim 7 obvious. Gimet further discloses this limitation of claim 8.

(Ex. 1003, 90.) Specifically, Gimet discloses that the inner core is piroxicam.

(Ex. 1004, col. 4 ll. 34-39; Ex. 1003, 91.)

E. Claim 12:


Gimet further discloses each limitation of claim 12.

1. The pharmaceutical composition of claim 1 wherein said unit dosage form is a multilayer tablet comprising


that the pharmaceutical composition is a core/mantle tablet. (Ex. 1004, col. 3 ll. 8-

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14; Ex. 1003, 94.)

2. a single core and one or more layers outside of said single core, wherein:


that [s]urrounding the coated inner core is a mantle 22 consisting of a

prostaglandin. (Ex. 1004, col. 6 ll. 24-44, Fig. 2; Ex. 1003, 96.)

3. i) said NSAID is present in said core;


that the inner core is piroxicam. (Ex. 1004, col. 4 ll. 34-49; Ex. 1003, 98.)

4. ii) said coating that does not release said NSAID unless the pH of the surrounding medium is 3.5 or higher surrounds said core; and

As discussed above with respect to claim 1, Gimet discloses this limitation.

(Ex. 1003, 99.) Specifically, Gimet discloses that the enteric coating aids in

segregating the NSAID from the prostaglandin and in directing the dissolution of

the NSAID core in the lower G.I. tract as opposed to the stomach. (Ex. 1004, col.

6 ll. 24-36; Ex. 1003, 100.)

A POSA would understand that a typical purpose associated with enteric

coatings is to delay release of an enterically-coated drug until after the drug has

exited the stomach. Also, the POSA would know that a typical patient would have

a pH in the small intestine after exiting the stomach of greater than about 3.5. (Ex.

1003, 101.) Thus, the POSA would have a rationale and a reasonable expectation

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of success in preparing a combination therapy, coordinated release, unit dosage

form having a delayed release component, for example an enterically-coated drug

(e.g., NSAID) to prevent the release of the drug from the dosage form unless the

pH of the surrounding medium (e.g., portions of the G.I. tract after exiting the

stomach) is 3.5 or higher. (Ex. 1003, 102.)

5. iii) said acid inhibitor is in said one more layers outside said core.

Gimet discloses this limitation. (Ex. 1003, 103.) Specifically, Gimet

discloses that [s]urrounding the coated inner core is a mantle 22 consisting of a

prostaglandin. (Ex. 1004, col. 6 ll. 24-44, Fig. 2; Ex. 1003, 104.)

F. Claim 13: The pharmaceutical composition of claim 12, wherein said one or more layers outside of said core do not contain NSAID and are not surrounded by an enteric coating.

As discussed above, Gimet in view of Chiverton renders claim 1 obvious, and

Gimet discloses each limitation of claim 12. Gimet further discloses this limitation

of claim 13. (Ex. 1003, 105.) Specifically, Gimet discloses that the mantle 22

consist[s] of a prostaglandin, which is orally available. (Ex. 1004, col. 1 ll. 66

col. 2 l. 3 and col. 6 ll. 24-44; Ex. 1003, 106.) There is nothing, including an

enteric coating, surrounding the prostaglandin. (Ex. 1003, 106-07.)

G. Claim 22:

Gimet in view of Chiverton discloses each limitation of claim 22.

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1. A method of treating a patient for pain or inflammation, comprising


discloses [a] method of treating inflammation comprising orally administering to

a patient . . . . (Ex. 1004, 12 ll. 41-44; Ex. 1003, 110.)

2. administering to said patient the pharmaceutical composition of any one of claims 1-14.


discloses [a] method of treating inflammation comprising orally administering to

a patient . . . . (Ex. 1004, 12 ll. 41-44; Ex. 1003, 112.) As discussed above,

Gimet in view of Chiverton discloses and renders obvious the pharmaceutical

composition of claim 1. (Ex. 1003, 112.)

H. Claim 23: The method of claim 22, wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis.


Gimet further discloses this limitation of claim 23. (Ex. 1003, 113.)

Specifically, Gimet discloses that [n]onsteroidal anti-inflammatory drugs

(NSAIDs) . . . have long been recognized as having high therapeutic value

especially for the treatment of inflammatory conditions such as . . . osteoarthritis

(OA) and rheumatoid arthritis (RA). (Ex. 1004, col. 1 ll. 18-23.) Gimet further

discloses piroxicam be administered in a single daily dose of 20 mg for

rheumatoid arthritis and osteoarthritis. (Ex. 1004, col. 4 ll. 34-39; Ex. 1003,

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114.)

VIII. Ground 2: Gimet in View of Goldman in Further View of Remington Renders Obvious Claims 1-5 and 7-23

A. A POSA Would Have Combined Goldman, Remington and Gimet

Both Gimet and Goldman are directed to pharmaceutical compositions

comprising an NSAID and an acid inhibitor, and a POSA tasked with formulating

an NSAID/acid inhibitor combination therapy would have considered their

collective teachings on the subject. (Ex. 1003, 117.) For example, the POSA

would have substituted the NSAIDs and acid inhibitors in Gimet for other known

NSAIDs and acid inhibitors in Goldman to obtain predictable results; alternatively,

it would have been obvious to try Goldmans NSAIDs and acid inhibitors with

Gimets tablets; alternatively, Gimet has a teaching, suggestion, or motivation to

be combined with Goldman. (Id.) A POSA would have substituted Gimets

prostaglandin with Goldmans H2 blockers or PPIs to obtain predictable results of

inhibiting gastric acid, particularly since Gimet discloses that [w]hile

prostaglandins are beneficial compounds and have found therapeutic usage,

prostaglandins are generally considered highly unstable. (Ex. 1004, col. 1 ll. 51-

53; Ex. 1003, 119.) Goldman discloses acid inhibitors other than the unstable

prostaglandins, namely H2 blockers and PPIs, that are more efficacious. (Ex.

1005, col. 5 ll. 64-65; Ex. 1003, 119.) Moreover, a POSA would have

substituted Gimets NSAID, diclofenac, with Goldmans NSAID, naproxen, to

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22

obtain the predictable analgesic effect of said NSAIDs. (Ex. 1003, 120.) It

would have been obvious for a POSA to choose from those identified solutions and

have a reasonable expectation of success in treating pain, inflammation, and other

symptoms with an NSAID while preventing or reducing the undesirable side

effects of the NSAID. (Ex. 1003, 121.) Furthermore, Goldman provides the

POSA with a specific teaching, suggestion, and motivation to look to conventional

techniques for preparing medicament tablets as set forth in Remington and further

incorporates by reference the disclosure of Remington (Ex. 1005, 122.), thereby

providing a design incentive to prepare or improve tablets via known techniques

including enteric and non-enteric coatings to yield predictable results. (Ex. 1005,

col. 6 ll. 26-33; Ex. 1006, at 1604, 1633; Ex. 1003, 122.)

B. Claim 1:

Gimet in view of Goldman in further view of Remington discloses each

limitation of claim 1.

1. A pharmaceutical composition in unit dosage form suitable for oral administration to a patient, comprising:

Gimet discloses this limitation. (Ground 1 at VII(B)(1); Ex. 1003, 124-26.)

2. (a) an acid inhibitor present in an amount effective to raise the gastric pH of said patient to at least 3.5 upon the administration of one or more of said unit dosage forms;


A POSA would know that a typical patient would have a pH in the stomach in a

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23

range of from about 1.5 to about 3.5, and the POSA would know that the typical

therapeutic effect of known acid inhibitors is to increase the gastric pH of the

patient following administration thereof. (Ex. 1003, 130.) Thus, the POSA

would have a rationale and reasonable expectation of success in preparing a

combination therapy unit dosage form having an effective amount of a known acid

inhibitor to raise the gastric pH of a patient to at least 3.5 upon the administration

of one or more unit dosage forms containing the known acid inhibitor. (Ex. 1003,

131.) Further, due to the claim language of one or more of said unit dosage

forms, multiple dosage forms may be administered to achieve the desired effect.

(Ex. 1003, 133.) Thus, the POSA would have a rationale and a reasonable

expectation of success in providing the appropriate dose, including administration

of multiple dosage forms, as needed, to raise the pH to a desired level consistent

with pharmacological effects associated with the known acid inhibitor. (Id.)

3. (b) a non-steroidal anti-inflammatory drug (NSAID) in an amount effective to reduce or eliminate pain or inflammation in said patient upon administration of one or more of said unit dosage forms;


4. and wherein said unit dosage form provides for coordinated release such that: i) said NSAID is surrounded by a coating that, upon ingestion of said unit dosage form by said patient, prevents the release of essentially any NSAID from said dosage form unless the pH of the surrounding medium is 3.5 or higher;


IPR2015-01241 Patent 6,926,907

24

5. ii) at least a portion of said acid inhibitor is not surrounded by an enteric coating and, upon ingestion of said unit dosage form by said patient, is released regardless of whether the pH of the surrounding medium is below 3.5 or above 3.5.


C. Claim 2: The pharmaceutical composition of claim 1, wherein said acid inhibitor is an H2 blocker.

As discussed above, Gimet in view of Goldman in further view of Remington

renders claim 1 obvious. Gimet in view of Goldman further discloses this

limitation of claim 2. (Ex. 1003, 147.) Specifically, Goldman discloses a

composition containing an H2 blocker such as famotidine. (Ex. 1005, col. 5 ll. 25-

30; Ex. 1003, 148.) A POSA would have been motivated to combine Goldman

with Gimet as described above. (Ex. 1003, 149.) Furthermore, a POSA would

have been motivated to replace Gimets prostaglandin with Goldmans H2 blocker

because doing so would be a substitution of one known element for another to

obtain predictable results. (Ex. 1003, 150.)

D. Claim 3: The pharmaceutical composition of claim 2, wherein said H2 blocker is selected from the group consisting of: cimetidine; ranitidine; ebrotidine; pabutidine; lafutidine; loxtidine and famotidine.


renders claim 1 obvious, and Gimet in view of Goldman renders claim 2 obvious.

Gimet in view of Goldman further discloses this limitation of claim 3. (Ex. 1003,

151.) Specifically, Goldman discloses a composition containing an H2 blocker

IPR2015-01241 Patent 6,926,907

25

such as famotidine. (Ex. 1005, col. 5 ll. 9-31; Ex. 1003, 152.) A POSA would

have been motivated to combine Goldman with Gimet as described above. (Ex.

1003, 154.) Furthermore, a POSA would have been motivated to replace

Gimets prostaglandin with Goldmans famotidine because doing so would be a

substitution of one known element for another to obtain predictable results. (Ex.

1003, 155.)

E. Claim 4: The pharmaceutical composition of claim 3, wherein said H2 blocker is famotidine, present in said unit dosage form in an amount of between 5 mg and 100 mg.


renders claim 1 obvious, and Gimet in view of Goldman renders claims 2 and 3

obvious. Gimet in view of Goldman further discloses this limitation of claim 4.

(Ex. 1003, 156.) Specifically, Goldman discloses a composition containing an

H2 blocker such as famotidine from 5 to 40 mg per dose. (Ex. 1005, col. 5 ll.

25-30; Ex. 1003, 157.) A POSA would have been motivated to combine

Goldman with Gimet as described above. (Ex. 1003, 158.) Furthermore, a

POSA would have been motivated to replace Gimets prostaglandin with

Goldmans famotidine in the disclosed amount because doing so would be a

substitution of one known element for another to obtain predictable results and

because, as shown in Goldman, 5 mg to 40 mg was a known therapeutic dosage

range for famotidine. (Ex. 1003, 159.)

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26

F. Claim 5: The pharmaceutical composition of claim 1, wherein said acid inhibitor is a proton pump inhibitor selected from the group consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole.




composition containing a PPI such as omeprazole. (Ex. 1005, col. 5 ll. 29-31; Ex.

1003, 161.) A POSA would have been motivated to combine Goldman with

Gimet as described above. (Ex. 1003, 163.) Furthermore, a POSA would have

been motivated to replace Gimets prostaglandin with Goldmans PPI omeprazole



G. Claim 7: The pharmaceutical composition of claim 1, wherein said NSAID is a cyclooxygenese-2 (COX-2) inhibitor.


renders claim 1 obvious. Gimet further discloses this limitation of claim 7.

(Ground 1 at VII(C); Ex. 1003, 165-66.)

H. Claim 8: The pharmaceutical composition of claim 7, wherein said COX-2 inhibitor is selected from the group consisting of celecoxib; rofecoxib; meloxicam; piroxicam; valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522; L-745,337; and NS398.


renders claims 1 and 7 obvious. Gimet further discloses this limitation of claim 8.

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27

(Ground 1 at VII(D); Ex. 1003, 167-69.)

I. Claim 9: The pharmaceutical composition of claim 1, wherein said NSAID is selected from the group consisting of: aspirin; acetaminophen; ibuprofen; flurbiprofen; ketoprofen; lornoxicam; naproxen; oxaprozin; etodolac; indomethacin; ketorolac; and nabumetone.




composition containing an NSAID such as naproxen. (Ex. 1005, col. 5 ll. 17-20;

Ex. 1003, 171.) A POSA would have been motivated to combine Goldman with

Gimet as described above. (Ex. 1003, 173.) Furthermore, a POSA would have

been motivated to replace Gimets NSAID with Goldmans NSAID, naproxen,


obtain predictable results. (Ex. 1003, 173-74.)

J. Claim 10: The pharmaceutical composition of claim 9, wherein said NSAID is naproxen present in an amount of between 50 mg and 1500 mg.




175.) Specifically, Goldman discloses a composition containing an NSAID such

as naproxen from 200 to 500 mg per dose. (Ex. 1005, col. 5 ll. 17-20; Ex. 1003,

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176.) A POSA would have been motivated to combine Goldman with Gimet as

described above. (Ex. 1003, 177.) Furthermore, a POSA would have been

motivated to replace Gimets NSAID with Goldmans NSAID, naproxen, in the

disclosed amount because doing so would be a substitution of one known element

for another to obtain predictable results and because, as shown in Goldman, 200

mg to 500 mg was a known therapeutic dosage range for naproxen. (Ex. 1003,

178.)

K. Claim 11: The pharmaceutical composition of claim 10, wherein said naproxen is present in an amount of between 200 mg and 600 mg.


renders claim 1 obvious, and Gimet in view of Goldman renders claims 9 and 10

obvious. Gimet in view of Goldman further discloses this limitation of claim 11.

(Ex. 1003, 179.) Specifically, Goldman discloses a composition containing an

NSAID such as naproxen from 200 to 500 mg per dose. (Ex. 1005, col. 5 ll. 17-

20; Ex. 1003, 180.) A POSA would have been motivated to combine Goldman


have been motivated to replace Gimets NSAID with Goldmans NSAID,

naproxen, in the disclosed amount because doing so would be a substitution of one

known element for another to obtain predictable results and because, as shown in

Goldman, 200 mg to 500 mg was a known therapeutic dosage range for naproxen.

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29

(Ex. 1003, 182.)

L. Claim 12:


renders claim 1 obvious. Gimet further discloses each limitation of claim 12.

1. The pharmaceutical composition of claim 1 wherein said unit dosage form is a multilayer tablet comprising

Gimet discloses this limitation. (Ground 1 at VII(E)(1); Ex. 1003, 184-85.)

2. a single core and one or more layers outside of said single core, wherein:


3. i) said NSAID is present in said core;


4. ii) said coating that does not release said NSAID unless the pH of the surrounding medium is 3.5 or higher surrounds said core; and


5. iii) said acid inhibitor is in said one more layers outside said core.


M. Claim 13: The pharmaceutical composition of claim 12, wherein said one or more layers outside of said core do not contain NSAID and are not surrounded by an enteric coating.


renders claims 1 and 12 obvious. Gimet further discloses this limitation of claim

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13. (Ground 1 at VII(F); Ex. 1003, 197-99.)

N. Claim 14:


renders claims 1, 12, and 13 obvious. Gimet in view of Remington further

discloses each limitation of claim 14.

1. The pharmaceutical composition of claim 13, wherein said unit dosage form is a bilayer tablet having an outer layer of said acid inhibitor and an inner core of said NSAID and

Remington discloses this limitation. (Ex. 1003, 201.) Specifically,

Remington discloses various conventional techniques for preparing medicament

tablets or caplets. (Ex. 1006, at 1603-32; Ex. 1003, 202.) Remington discloses

that the tablets can be used to give a simple repeat-action effect where

unprotected drug coated over the enteric coat is released in the stomach, while the

remainder, being protected by the coating, is released further down the

gastrointestinal tract. (Ex. 1006, at 1637; Ex. 1003, 202.) A POSA would

understand Remingtons quoted description to refer to a bilayer tablet. (Ex. 1003,

203.) A POSA faced with a common task such as manufacturing a combination

therapy oral dosage form comprising known ingredients would have a rationale

(e.g. motivation) and a reasonable expectation of success in consulting one or more

reputable reference publications, such as Remington, providing conventional

techniques to perform the task. (Ex. 1003, 204.) Furthermore, Goldman

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provides a POSA with a rationale, e.g., a specific teaching, suggestion and

motivation, to look to conventional techniques for preparing medicament tablets as

set forth in Remington and further incorporates by reference the disclosure of

Remington. (Ex. 1003, 202.)

2. wherein said outer layer of said tablet is surrounded by a non-enteric film coating that releases said acid inhibitor upon ingestion by patient.


Remington discloses that the tablets can include film coating that imparts the

same general characteristics as sugar coating, namely to protect the drug from its

surrounding environment and increase the ease by means of which the product

can be ingested. (Ex. 1006, at 1604; Ex. 1003, 206.) Furthermore, a POSA

would understand Remingtons cited description to refer to a non-enteric film

coating that releases said acid inhibitor upon ingestion by the patient. (Ex. 1003,

207.) In addition, a POSA would have been motivated to prepare Gimets tablets

as described in Remington for the reasons described above, including to protect

Gimets tablets from the environment. (Ex. 1003, 208.)

O. Claim 15: The pharmaceutical composition of any one of claims 1 or 7-14, wherein said acid inhibitor is a proton pump inhibitor.




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209.) Specifically, Goldman discloses a composition containing a PPI such as

omeprazole. (Ex. 1005, col. 5 ll. 9-31; Ex. 1003, 210.) A POSA would have

been motivated to combine Goldman with Gimet as described above. (Ex. 1003,

211.) Furthermore, a POSA would have been motivated to replace Gimets

prostaglandin with Goldmans PPI because doing so would be a substitution of one

known element for another to obtain predictable results. (Ex. 1003, 212.)

P. Claim 16:


renders claims 1 and 12 obvious. Gimet in view of Goldman and in further view of

Remington further discloses each limitation of claim 16.

1. The pharmaceutical composition of any one of claims 12-14, wherein said acid inhibitor is a proton pump inhibitor and

Goldman discloses this limitation. (Ex. 1003, 214.) Specifically, Goldman

discloses a composition containing a PPI such as omeprazole. (Ex. 1005, col. 5 ll.

9-31; Ex. 1003, 215.) A POSA would have been motivated to combine Goldman


have been motivated to replace Gimets prostaglandin with Goldmans PPI



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33

2. wherein said coating surrounding said core does not dissolve unless the pH of the surrounding medium is 4 or greater.


Remington discloses the following:

By definition, enteric coatings are those which remain intact in the stomach

. . . to delay the release of drugs which . . . may cause nausea or bleeding

by irritating the gastric mucosa . . . Thus, many modern enteric coatings are

those which remain undissociated in the low pH environment of the

stomach, but readily ionize when the pH rises to about 4 or 5.

(Ex. 1006, at 1637; Ex. 1003, 219.) A POSA would understand this to mean that

enteric coating surrounding the NSAID does not ionize until it is subjected to an

environment having a pH of about 4 or 5. (Ex. 1003, 220.) Furthermore, a

POSA would have been motivated to prepare Gimets tablets as described in order

to allow release of the acid inhibitor in the small intestine, where acid inhibitors are

more effectively absorbed. (Ex. 1003, 221-22.)

Q. Claim 17:


renders claims 1 and 12 obvious. Gimet in view of Goldman and in further view of

Remington further discloses each limitation of claim 17.

1. The pharmaceutical composition of any one of claims 12-14, wherein said acid inhibitor is a proton pump inhibitor and

Goldman discloses this limitation. (Ex. 1003, 224.) Specifically, Goldman

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34

discloses a composition containing a PPI such as omeprazole. (Ex. 1005, col. 5 ll.

9-31; Ex. 1003, 225.) A POSA would have been motivated to combine Goldman


have been motivated to replace Gimets prostaglandin with Goldmans PPI


obtain predictable results.

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