Attorney Docket No. 2015-GLFLC-0002
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`Patent No. 8,865,688
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
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`GENERICO, LLC
`FLAT LINE CAPITAL, LLC
`Petitioners,
`v.
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`DR. FALK PHARMA GmbH,
`Patent Owner
`
`U.S. Patent No. 8,865,688
`Issue Date: Oct. 21, 2014
`Inventor: William Forbes
`
`Title: COMPOSITIONS AND METHODS FOR TREATMENT OF BOWEL
`DISEASES WITH GRANULATED MESALAMINE
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`
`
`
`Case Number: Unassigned
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO.
`8,865,688 UNDER TO 35 U.S.C. §§ 311 ET SEQ. AND
`37 C.F.R. § 42.100 ET SEQ.
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`Patent No. 8,865,688
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`Attorney Docket No. 2015-GLFLC-0002
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`TABLE OF CONTENTS
`I. NOTICE OF REAL-PARTY-IN-INTEREST UNDER 37 C.F.R. § 42.8(B)(1) ........... 1
`II. NOTICE OF RELATED MATTERS UNDER 37 C.F.R. § 42.8(B)(2) ......................... 1
`III. NOTICE UNDER 37 C.F.R. § 42.8(B)(3) AND (B)(4) ....................................................... 1
`IV. PAYMENT OF FILING FEE UNDER 37 C.F.R. § 42.103 .............................................. 2
`V. GROUNDS FOR STANDING UNDER 37 C.F.R. § 42.104(A) ....................................... 2
`VI. STATEMENT OF PRECISE RELIEF REQUESTED UNDER 37 C.F.R. §
`42.104(B)(1)-(2) ........................................................................................................................... 2
`VII. BACKGROUND ......................................................................................................................... 3
`A. THE ‘688 PATENT ...................................................................................................................... 3
`B. PROSECUTION HISTORY OF THE ‘688 PATENT ....................................................................... 5
`C. BACKGROUND OF THE PRIOR ART ........................................................................................... 7
`1. Ulcerative Colitis ........................................................................................................ 7
`2. Mesalamine (5-Aminosalicylic Acid) .......................................................................... 8
`3. Enteric Coating ......................................................................................................... 11
`4. Polymer Matrix ......................................................................................................... 13
`5. Combinations of Enteric Coatings and Polymer Matrices ....................................... 15
`D. PERSON OF ORDINARY SKILL IN THE ART ............................................................................ 16
`VIII. CLAIM CONSTRUCTION UNDER 37 C.F.R. § 42.104(B)(3) .................................. 17
`A. WITHOUT FOOD ....................................................................................................................... 17
`B. GRANULATED MESALAMINE FORMULATION ....................................................................... 20
`IX. ANALYSIS ................................................................................................................................ 24
`A. GROUND 1: CLAIMS 1 AND 16 ARE RENDERED OBVIOUS UNDER 35 U.S.C. § 103 OVER
`SEPTEMBER 2007 PRESS RELEASE IN VIEW OF ENDONURSE AND DAVIS-1985. ....................... 25
`B. GROUND 2: CLAIMS 1 AND 16 ARE RENDERED OBVIOUS UNDER 35 U.S.C. § 103 OVER
`SEPTEMBER 2007 PRESS RELEASE IN VIEW OF ENDONURSE, DAVIS-1985 AND EP590. .......... 39
`C. GROUND 3: CLAIMS 1 AND 16 ARE RENDERED OBVIOUS UNDER 35 U.S.C. § 103 OVER
`SEPTEMBER 2007 PRESS RELEASE IN VIEW OF ENDONURSE, DAVIS-1985 AND
`MARAKHOUSKI. ............................................................................................................................... 44
`D. GROUND 4: CLAIMS 1 AND 16 ARE RENDERED OBVIOUS UNDER 35 U.S.C. § 103 OVER
`SEPTEMBER 2007 PRESS RELEASE IN VIEW OF ENDONURSE, DAVIS-1985 AND BRUNNER. .... 47
`X. CONCLUSION ......................................................................................................................... 51
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`Attorney Docket No. 2015-GLFLC-0002
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`Patent No. 8,865,688
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`EXHIBIT LIST
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`
`Description
`U.S. Patent No. 8,865,688 (“the ‘688 Patent”)
`Declaration of George A. Digenis, Ph.D. (“Digenis Decl.”)
`U.S. Patent No. 6,004,581 (“the ‘581 Patent”)
`Stephen Hanauer et al., Mesalamine Capsules for Treatment of Active
`Ulcerative Colitis: Results of A Controlled Trial, 88 AMERICAN J.
`GASTROENTEROLOGY 1188 (1993) (“Hanauer”)
`J. N. C. Healey, Gastrointestinal Transit and Release of Mesalazine
`Tablets in Patients with Inflammatory Bowel Disease, 25 SCAND J.
`GASTROENTEROLOGY 47 (Supp. 127 1990) (“Healey”)
`L. M. L. Stolk et al., Dissolution Profiles of Mesalazine Formulations in
`Vitro, 12 PHARMACEUTISCH WEEKBLAD SCIENTIFIC EDITION 200 (1990)
`(“Stolk”)
`European Patent Application No. 0 671 168 A1 (“EP168”)
`PCT Publication No. WO 91/07949 (“PCT949”)
`S. S. Davis, The Design and Evaluation of Controlled Release Systems for
`the Gastrointestinal Tract, 2 J. CONTROLLED RELEASE 27 (1985) (“Davis-
`1985”)
`S. S. Davis et al., Transit of Pharmaceutical Dosage Forms Through the
`Small Intestine, 27 GUT 886 (1986) (“Davis-1986”)
`U.S. Patent No. 6,551,620 (“the ‘620 Patent”)
`Salix Announces Statistically Significant Top-Line Results of a Unique
`Granulated Mesalamine Product Registration Study in Ulcerative Colitis
`(September 2007),
`http://www.sec.gov/Archives/edgar/containers/fix021/1009356/00011931
`2507195530/dex992.htm (“Sept. 2007 Press Release”)
`U.S. Patent Application Publication No. 2010/0035850 A1 (“Meyeroff”)
`XIFAXAN Trials Initiated in C. difficile-Associated Diarrhea, Irritable
`Bowel Syndrome and Hepatic Encelophalopathy. New Article [online]
`EndoNurse, 12 January 2006 (“Endonurse”)
`European Patent Application No. 0 040 590 A2 (“EP590”)
`‘688 Patent File History (“FH688”), Amendment 5/9/2014
`‘688 Patent File History (“FH688”), Amendment 6/20/2014
`‘688 Patent File History (“FH688”), Amendment to the Claims
`‘688 Patent File History (“FH688”), Notice of Allowance
`‘688 Patent File History (“FH688”), Amendment 10/8/2013
`iii
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`Exhibit
`1001
`1002
`1003
`1004
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`1005
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`1006
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`1007
`1008
`1009
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`
`1010
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`1011
`1012
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`1013
`1014
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`1015
`1016
`1017
`1018
`1019
`1020
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`Attorney Docket No. 2015-GLFLC-0002
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`Patent No. 8,865,688
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`1021
`1022
`1023
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`1024
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`1025
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`1026
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`‘688 Patent File History (“FH688”), Amendment 4/24/2013
`European Patent Application No. 0 453 001 A1 (“EP001”)
`P.J. Watts et al., Encapsulation of 5-aminosalicylic Acid into Eudragit RS
`Microspheres and Modulation of Their Release Characteristics by Use of
`Surfactants, 16 J. CONTROLLED RELEASE 311 (1991) (“Watts”)
`Marakhouski et al., “A Double- blind Dose-escalating Trial Comparing
`Novel Mesalazine Pellets with Mesalazine Tablets in Active Ulcerative
`Colitis,” Aliment Pharmacol. Ther. 21:133-140 (2005) (“Marakhouski”)
`Brunner et al., “Gastrointestinal Transit and Release of 5-aminosalicylic
`Acid from 153Sm-labelled Mesalazine Pellets vs. Tablets in Male Healthy
`Volunteers,” Aliment. Pharmacol. Ther. 17:1163-1169 (2003) (“Brunner”)
`Brouwers, J.R.B.J. “Advanced and controlled drug delivery systems in
`clinical disease management,” Pharmacy World & Science: (1996) 18(5),
`153-162 (“Brouwers”)
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`Attorney Docket No. 2015-GLFLC-0002
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`Patent No. 8,865,688
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`This is a petition for Inter Partes Review pursuant to 35 U.S.C. §§ 311 et
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`seq. and 37 C.F.R. §§ 42.100 et seq., of claims 1 and 16 of U.S. Patent No.
`
`8,865,688 (“the ‘688 Patent”) filed Oct. 2, 2009 and issued to William Forbes
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`(Exhibit 1001).
`
`Notice of Real-Party-In-Interest Under 37 C.F.R. § 42.8(b)(1)
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`The
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`real-parties-in-interest
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`for
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`this Petition are GeneriCo, LLC,
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`I.
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`
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`(“GeneriCo”) and Flat Line Capital, LLC (“FLC”) (collectively, “Petitioners”). No
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`other entities or persons other than Petitioners has authority to direct or control
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`Petitioners’ actions or decisions relating to this petition. Petitioners are collectively
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`funding all of the fees and costs of this petition for inter partes review.
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`II. Notice of Related Matters Under 37 C.F.R. § 42.8(b)(2)
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`
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`Petitioner identifies the following related matters: District Court and
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`C.A.F.C. Matters: Salix Pharmaceuticals, Inc. et al. v. Novel Laboratories, Inc.,
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`1-15-cv-00027 (DED); Salix Pharmaceuticals, Inc. et al. v. Novel Laboratories,
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`Inc., 1-15-cv-00213 (DED); Salix Pharmaceuticals, Inc et al v. Mylan
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`Pharmaceuticals, Inc. et al, 1-15-cv-00109 (N. W.V.). This petition contains
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`arguments regarding the patentability of the ‘688 Patent not previously presented
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`to the United States Patent and Trademark Office.
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`III. Notice Under 37 C.F.R. § 42.8(b)(3) and (b)(4)
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`Lead Counsel
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`Backup Counsel
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`1
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`Attorney Docket No. 2015-GLFLC-0002
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`Patent No. 8,865,688
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`Zachary D. Silbersher
`Kroub, Silbersher & Kolmykov PLLC
`305 Broadway 7th Fl.
`New York, NY 10007
`Tel: (212) 323-7442
`zsilbersher@kskiplaw.com
`(Reg. No. 62,090)
`
`Gaston Kroub
`Kroub, Silbersher & Kolmykov PLLC
`305 Broadway 7th Fl.
`New York, NY 10007
`Tel: (212) 323-7442
`gkroub@kskiplaw.com
`(Reg. No. 51,903)
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`Pursuant to 37 C.F.R. § 42.10(b), a Power of Attorney has been filed with
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`this Petition. Petitioner consents to electronic service by email at:
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`zsilbersher@kskiplaw.com, gkroub@kskiplaw.com, info@kskiplaw.com.
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`IV. Payment of Filing Fee Under 37 C.F.R. § 42.103
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`A fee set forth in 37 C.F.R. § 42.15(a) accompanies this petition.
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`
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`V. Grounds For Standing Under 37 C.F.R. § 42.104(a)
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`Petitioner hereby certifies that the patent for which review is sought is
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`available for inter partes review and that the Petitioner is not barred or estopped
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`from requesting an inter partes review challenging the patent claims on the
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`grounds identified in the petition.
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`VI. Statement of Precise Relief Requested Under 37 C.F.R. § 42.104(b)(1)-
`(2)
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`Petitioner respectfully requests that claims 1 and 16 of the ‘688 Patent be
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`
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`cancelled based upon the following grounds of unpatentability:
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`
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`GROUND 1: Claim 1 and 16 rendered obvious under 35 U.S.C. § 103 over
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`Sept. 2007 Press Release in view of Endonurse and Davis-1985.
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`GROUND 2: Claims 1 and 16 rendered obvious under 35 U.S.C. § 103 over
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`Sept. 2007 Press Release in view of Endonurse, Davis-1985 and EP590.
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`GROUND 3: Claims 1 and 16 rendered obvious under 35 U.S.C. § 103 over
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`Sept. 2007 Press Release in view of Endonurse, Davis-1985 and Marakhouski.
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`GROUND 4: Claims 1 and 16 rendered obvious under 35 U.S.C. § 103 over
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`Sept. 2007 Press Release in view of Endonurse, Davis-1985 and Brunner.
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`VII. Background
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`A. The ‘688 Patent
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`
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`The ‘688 Patent is directed to methods for “maintaining the remission of
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`ulcerative colitis” through a “granulated mesalamine formulation.” (Ex. 1001,
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`‘688 Patent col. 34:11-35:17). The ‘688 Patent acknowledges that, at the time it
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`was filed, numerous prior art formulations containing mesalamine existed for
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`treating ulcerative colitis. For instance, the patent identifies prior art formulations
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`that are “related to delivery of the intact molecule to the colonic mucosa without
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`breakdown during digestion.” (Ex. 1001, ‘688 Patent col. 1:60-63). This includes
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`“oral mesalamine treatments [that] are based on 3 types of delivery systems”
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`including “azo-bonded to release drug in the colon once the drug is exposed to
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`colonic bacteria”, polymer-coated “delayed release tables” for “release of drug
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`when the pH in the digestive tract reaches the desired value”, and “time-dependent
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`release mechanisms”. (Ex. 1001, ‘688 Patent col. 1:61-2:3).
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`The ‘688 Patent, however, claims the following problems purportedly
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`existed with prior art mesalamine formulations for treating UC: “variation within
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`formulations in the release of mesalamine, including premature release, the
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`possibility of dose dumping, and sensitivity to conditions that increase gastric pH
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`and cause premature release of mesalamine (e.g., ingestion of a meal).” (Ex. 1001,
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`‘688 Patent col. 2:3-8).
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`The ‘688 Patent, however, is not directed to a novel formulation of
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`mesalamine. Rather, the claims are directed to a method of “maintaining the
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`remission of ulcerative colitis” that comprises administration of “a granulated
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`mesalamine formulation.” (Ex. 1001, ‘688 Patent col. 34:10-13). The ‘688 Patent
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`expressly incorporates embodiments of granulated mesalamine formulations taught
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`in prior patents (to which the ‘688 Patent does not claim priority.) (Ex. 1001, ‘688
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`Patent col. 10:47-53).
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`The ‘688 Patent purports to solve the alleged prior-art problems with the
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`claimed methods for maintaining the remission of ulcerative colitis. (Ex. 1001,
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`‘688 Patent col. 34:10-35:17). During prosecution, the Applicant identified his
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`“discovery that the oral mesalamine formulation was equally effective when
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`administered with or without food.” (Ex. 1017, FH688, Amendment 6/20/14 at 5-
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`6). After a tortured prosecution history, including seven office action rejections
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`and amendment to independent claim 1 on six separate occasions, the issued
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`claims require that administration of the granulated mesalamine is “without food”.
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`(Ex. 1001, ‘688 Patent col. 34:15).
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`B.
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`Prosecution History of the ‘688 Patent
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`The ‘688 Patent issued from U.S. Patent Application No. 12/573,081, filed
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`Oct. 9, 2009, which was purportedly related to U.S. Provisional Application Nos.
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`61/102,807 and 61/109,708, filed Oct. 3, 2008 and Oct. 30, 2008, respectively.
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`Accordingly, the priority date for the ‘688 Patent is not earlier than October 30,
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`2008.
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`The ‘688 Patent underwent a tortured prosecution history before allowance.
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`The claim that eventually issued as claim 1 (claim 14 during prosecution) was
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`amended at least six times. Applicant submitted two additional office-action
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`responses that included unsuccessful attempts to persuade the Examiner to allow
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`the claim without amendment. (See Ex. 1018, FH688 Amendments to the Claims).
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`Independent claims 1 and 16 (which recite substantively similar
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`requirements) were both finally allowed upon Applicant’s amendment that the
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`claimed methods for “maintaining the remission of ulcerative colitis” were
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`“without food.” In support of this amendment, Applicant stated: “unlike other 5-
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`mesalamine drugs available at the time of the invention, Applicant has
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`demonstrated that the claimed methods are equally safe and effective when
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`granulated mesalamine is administered to a subject without food.” (Ex. 1017,
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`FH688, Amendment 6/20/14 at 5).
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`Applicant further argued that, “[a]t the time of the invention, one of ordinary
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`skill in the art would look to the teachings of the most similar formulation to
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`determine if administration with food is required.” (Ex. 1017, FH688,
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`Amendment 6/20/14 at 6). Applicant distinguished two FDA-approved oral
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`mesalamine formulations, Lialda® and Pentasa®. Applicant argued that Lialda,
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`similar to the “pending claims [which] are directed to methods of administering a
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`delayed and extended-release oral mesalamine formulation, Lialda®” is a “delayed
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`and extended-release oral mesalamine tablet that was approved for inducing the
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`remission of active, mild to moderate ulcerative colitis . . . .” (Id. at 6, emphasis in
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`original). Citing prescribing information for Lialda®, Applicant argued that it is
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`administered as “two to four 1.2 g tablets taken once daily with food.” (Id.,
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`emphasis in original). With respect to Pentasa®, Applicant argued that it is “not a
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`controlled and extended release formulation.” (Id.) Finally, Applicant pointed to
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`two examples in the ‘688 Patent’s specification that purport to describe the results
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`of a clinical trial showing that “there is no decrease in efficacy when granulated
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`mesalamine is administered without food.” (Id. at 7).
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`Upon allowing the application, the Examiner’s “Reasons for Allowance”
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`stated:
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`[t]he cited prior art is silent with respect to whether or not the
`mesalamine formulation is administered with or without food. One
`skilled in the art would reasonably expect the formulation to be
`administered with food, since similar mesalamine formulations are
`directed to be administered with food (see Lialda® information
`pamphlet, submitted by Applicants with response to filed 20 June
`2014).
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`(Ex. 1019, FH688, Notice of Allowance at 3). The Examiner concluded that
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`persons of skill in the art would have been motivated to administer mesalamine
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`formulations with food:
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`Additionally, one skilled in the art would be motivated to administer
`the mesalamine formulation with food, since 5-aminosalicylate
`compounds, including mesalamine, are known to have increased
`bioavailability when administered with food.
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`(Ex. 1019, FH688, Notice of Allowance at 3).
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`C. Background of the Prior Art
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`Ulcerative Colitis
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`1.
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`Inflammatory bowel disease (“IBD”) refers to inflammatory conditions of
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`the gastrointestinal tract, including ulcerative colitis (“UC”), Crohn’s disease
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`(“CD”), as well as other conditions. CD can affect any portion of the
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`gastrointestinal tract, from the mouth to the anus. By contrast, UC is limited to the
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`colon, and often limited to the colonic mucosa (which is the most inner surface of
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`the lumen of the colon.) (Ex. 1002, Digenis Decl. ¶ 26). The prevailing treatment
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`for UC involves management of the symptoms. Management of UC symptoms
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`includes two facets: inducing remission and maintaining remission. Inducement
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`of remission controls an acute attack of UC, whereas maintenance of remission
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`seeks to prevent relapses of acute attacks. (Ex. 1002, Digenis Decl. ¶ 26, citing
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`Ex. 1001, ‘688 Patent col. 1:54-59).
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`2. Mesalamine (5-Aminosalicylic Acid)
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`Beginning in the 1950’s, sulfasalazine became the “the most widely
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`prescribed medication for treatment of inflammatory bowel disease, specifically
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`ulcerative colitis (UC).” (Ex. 1004, Hanauer at 1188). Sulfasalazine is composed
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`of sulfapyridine and 5-aminosalicylic acid (also known as mesalamine or 5-ASA)
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`that is linked by an azo bond. (Ex. 1004, Hanauer at 1188). In the 1970’s, it was
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`discovered that 5-ASA was the therapeutically-active moiety of sulfasalazine.
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`This led to the development of 5-ASA formulations for the treatment of IBD, UC
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`and CD. (Ex. 1004, Hanauer at 1189).
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`Indeed, prior to filing of the ‘688 Patent, it was well-known among persons
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`of ordinary skill that aminosalicylic acid was therapeutically effective for treating
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`UC. (Ex. 1002, Digenis Decl. ¶ 28). “The active compound aminosalicylic acid
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`(in particular 5-ASA) or its derivatives have been used successfully for a relatively
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`long time for the treatment of intestinal disorders, such as, for example, ulcerative
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`colitis and Crohn’s disease.” (Ex. 1011, ‘620 Patent col. 1:15-18).
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`Persons of ordinary skill also knew that aminosalicylic acid works by locally
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`administering the drug at the sites of the lesions within the colon. (Ex. 1002,
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`Digenis Decl. ¶ 29, citing Ex. 1011, ‘620 Patent col. 1:32-39 (“The action of
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`aminosalicylic acid in the treatment of intestinal disorders, or in the prevention of
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`their recurrence . . . takes place by means of the contact of the active compound
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`directly at the site of the disorder in the intestine, the action of aminosalicylic acid,
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`or a derivative thereof, being directly related to its local concentration in the
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`intestinal area to be treated.”); see also id. citing Ex. 1005, Healey at 47 (“[t]he
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`effectiveness of mesalazine in the treatment of inflammatory bowel disease is
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`attributed mainly to a topical action on the intestinal mucosa.” (emphasis added)).
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`Oral administration of aminosalicylic acid, however, requires the drug to
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`travel through the stomach and the small intestine before reaching the colon.
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`Accordingly, the principal challenge to administering aminosalicylic acid for
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`treatment of UC and other IBD conditions affecting the large intestine is that
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`aminosalicylic acid will be readily absorbed in the small intestine. “A problem in
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`the treatment with aminosalicylic acid is that the active compound is very easily
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`absorbed and can be excreted via the kidney before its action can occur.” (Ex.
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`1011, ‘620 Patent col. 1:45-48). (See also Ex. 1002, Digenis Decl. ¶ 30, citing Ex.
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`1006, Stolk at 200 (“Plain mesalazine is totally absorbed in the upper part of the
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`intestine.”); Ex. 1004, Hanuaer at 1189 (“Oral administration of mesalamine is
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`limited by absorption in the proximal small bowel, necessitating protected delivery
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`systems for distribution to distal sites of enterocolonic inflammation.”)).
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` For this reason, oral administration of 5-ASA has for a long time focused
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`delayed and controlled/sustained release of mesalamine. (Ex. 1002, Digenis Decl.
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`¶ 31, citing Ex. 1005, Healey at 47 (“Because mesalazine is readily absorbed from
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`the small intestine, metabolized, and excreted in the urine, a delayed-release tablet
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`preparation has been developed to prevent release until the drug has reached the
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`terminal ileum and colon.”; marketed as Claversal®); Ex. 1011, ‘620 Patent col.
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`1:49-51 (“[i]n the prior art, tablets and pellets are known which are coated with an
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`enteric coating in order to thus prevent a premature release of the active
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`compounds”; discussing numerous prior art references)). (See also Ex. 1002,
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`Digenis Decl. ¶ 31, citing Ex. 1006, Stolk at 200 (“pharmaceutical formulations
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`[of mesalazine] have been designed, which can transport mesalazine undisturbed
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`through stomach, duodenum and proximal jejunum and deliver high concentrations
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`of mesalazine selectively at the inflammatory sites of the distal small intestine and
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`colon”).
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`In particular, the delayed/controlled release of mesalamine to the lower
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`intestine has commonly been formulated as azo-bonded pro-drugs or non-linked
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`agents. (Ex. 1002, Digenis Decl. ¶ 32, citing Ex. 1009, Hanuaer at 1189). By the
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`early 1990’s, non-linked agents used two mechanisms: (1) pH-dependent enteric
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`coatings (such as acrylic-based resins) that dissolve above pH of approximately 7,
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`after the drug has left the stomach, and (2) pH-independent slow-release that
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`delivers “active drug continuously to the small and large bowel, independent of
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`intestinal pH”). (Ex. 1002, Digenis Decl. ¶ 32, citing Ex. 1009, Hanuaer at 1189).
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`3.
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`Enteric Coating
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`Enteric coating was a well-known means to delay the release mesalamine
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`prior to the filing of the ‘688 Patent. The stomach’s pH is generally lower than the
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`pH of the intestinal tract. (Ex. 1002, Digenis Decl. ¶ 33, citing Ex. 1007, EP168
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`col. 1:27-33 (“it is recognized that the value of pH in the stomach is usually 1.8 to
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`4.5 in a healthy human and that the value of pH in the intestines is 6.5 to 7.5 and
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`the pH does not essentially differ between the small intestine and the large
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`intestine”).
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`Accordingly, a coating that is insoluble at the stomach’s pH range, but
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`soluble at the intestinal tract’s pH range, can delay and control the release of
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`mesalamine until it reaches the lower intestines. Indeed, this was well-known to
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`persons of ordinary skill prior to filing of the ‘688 Patent. (Ex. 1002, Digenis
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`Decl. ¶ 34, citing Ex. 1008, PCT949 at 1:10-18 (“In a medical context, it is
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`particularly advantageous to be able to administer orally a medicament which is
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`coated so that it passes through the stomach and is released only when the coated
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`material reaches the small intestine. Such coatings are called ‘enteric’ coatings
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`and are relatively easy to formulate taking advantage of the fact that the stomach
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`contents are acid and the intestinal contents are neutral to slightly alkaline.”)).
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`Enteric coatings, including methacrylic acid copolymer, among others, were
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`known to persons of ordinary skill prior to filing the ‘688 Patent. (Ex. 1002,
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`Digenis Decl. ¶ 35, citing Ex. 1005, Healey at 47). Methacrylic acid copolymer is
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`soluble above pH 6.0. Accordingly, prior to filing the ‘688 Patent, persons of
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`ordinary skill knew to apply enteric coatings of methacrylic acid copolymer to
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`aminosalicylic acid formulations to delay its release so that it was insoluble in the
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`stomach, but soluble within the intestine. (Ex. 1002, Digenis Decl. ¶ 35, citing Ex.
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`1005, Healey at 47 (discussing mesalazine tablets “coated with the enteric-coating
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`polymer methacrylic acid copolymer, type A (Eudragit L). This pH sensitive
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`polymer is resistant to gastric conditions but soluble above pH 6.0 in the intestine .
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`. . . A relatively thick coating is applied to the tablets to delay any release of the
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`drug until they reach the terminal ileum and proximal colon”); citing Ex. 1006,
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`Stolk at 200 (“Asacol® tablets contain 400 mg mesalazine and the tablets are
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`coated with an acrylic resign (Eudragit® S), which dissolves above pH 7.0. Thus
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`in vivo it should be transported intact until it reaches the ascending part of the
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`colon where the intraluminal pH rises above 7 and mesalazine is liberated.”).
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`Enteric coatings comprising methacrylic acid copolymer were sold before
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`the filing of the ‘688 Patent under the brand names Eudragit S and Eudragit L, and
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`were well-known among persons of skill in the art. (Ex. 1002, Digenis Decl. ¶36;
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`Ex. 1022, EP001 at 3:17-18 (“Polymer types for forming pH-dependent membrane
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`include . . . copolymers of methacrylic acid (Eudragit L, Eudragit S)”); Ex. 1005,
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`Healey at 48 (“enteric-coating polymer, methacrylic acid copolymer, type A
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`(Eudragit L)”); Ex. 1006, Stolk at 200 (mesalazine “tablets are coated with an
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`acrylic resin (Eudragit® S)”); Ex. 1013, EP590 at 4:2-3 (“Suitable partly methyl
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`esterified methacrylic acid polymers are sold under the names Eudragit L and
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`Eudragit S.”); Ex. 1007, EP 168 col. 6:3-13 (“poly(methacrylic acid, methyl
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`methacrylate (Eudragit L and Endragit S [sic]) are preferably used as enteric
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`polymer”)).
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`4.
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`Polymer Matrix
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`Polymer matrices were also a well-known means to sustain the release of
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`mesaliamine, and treat IBD, long before the ‘688 Patent. (Ex. 1002, Digenis Decl.
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`¶37). For instance, in 1990, Watts disclosed an investigation regarding “the
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`controlled delivery of drugs to the colon” that included the production of “Eudragit
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`RS microspheres containing 5-aminosalicylic acid (5-ASA), an agent active
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`against inflammatory bowel disease.” (Ex. 1023, Watts at 311). The Eudragit
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`series of polymers “are a family of polymers based on acrylic and methacrylic
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`acids suitable for use in orally-administered drug delivery systems.” (Ex. 1023,
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`Watts at 311). Two grades of the Eudragit series, “Eudragit RL and RS, are
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`insoluble in acqueous media but permeable and as such have been shown to be
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`suitable for use in sustained-release microencapsulated dosage forms.” (Ex. 1023,
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`Watts at 311). Watts explicitly disclosed a “drug polymer matrix” containing 5-
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`ASA with Eudragit RS. (Ex. 1002, Digenis Decl. ¶37, citing Ex. 1023, Watts at
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`312, 317). Watts concluded, “[w]e have demonstrated that 5-ASA can be
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`successfully encapsulated into Eudragit RS to produce microspheres for potential
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`sustained-release oral drug-delivery applications.” (Ex. 1023, Watts at 316-17).
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`Importantly, the ‘620 Patent (which long preceded the ‘688 Patent) identifies
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`Eudragit RS as a non-gel forming polymer, i.e., one that is “insoluble in the
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`intestinal tract and permeable to intestinal fluids.” (Ex. 1011, ‘620 Patent at col.
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`3:47-55).
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`Similarly, EP477 disclosed combining mesalamine in a non gel-forming
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`polymer matrix comprising Eudragit RS. (Ex. 1002, Digenis Decl. ¶38; Ex. 1015,
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`EP477 at 8:1-14 (disclosing “[e]ncapsulation of 5-amino-salicylic acid in
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`EUDRAGIT®RS” in a polymer matrix, including through stirring); EP477 at
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`2:14-17 (disclosing “[t]he products [of encapsulation] may also be ‘homogeneous
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`microspheres’, wherein the bioactive substance [5-ASA] is dispersed in the
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`polymer [Eudragit RS].”).
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`Watts further explained that the motivation for investigating controlled
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`delivery of 5-ASA was the same as that of the ‘688 Patent: “[s]ince 5-ASA largely
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`is absorbed from the upper intestine, selective delivery into the colon is required
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`for it to be therapeutically effective.” (Ex. 1023, Watts at 312).
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`5.
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`Combinations of Enteric Coatings and Polymer Matrices
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`Delayed and controlled dosage formulations for treating IBD was not a quiet
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`art before the ‘688 Patent. On the contrary, long before, persons of skill in the art
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`had been actively investigating alternative dosage formulations to adequately
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`delay/control/sustain release of mesalamine for the treatment of IBD. (Ex. 1002,
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`Digenis Decl. ¶40, citing Ex. 1023, Watts at 312 (“colon-specific delivery of 5-
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`ASA is currently receiving considerable research interest [as of 1990]”, listing
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`numerous existing approaches); see Ex. 1004, Hanauer at 1189).
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`Indeed, existing drugs before the ‘620 Patent (which long preceded the ‘688
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`Patent) employed variations of soluble enteric coatings as well as permeable
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`polymers: Asacol® (enteric coating of Eudragit S), Claversal® (enteric coating of
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`Eudragit L), Pentasa® (semi-permeable polymer coating). (See Ex. 1002, Digenis
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`Decl. ¶41, citing Ex. 1006, Stolk at 200; Ex. 1005, Healey at 47; see also Ex.
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`1023, Watts at 312 (citing other approaches)).
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`Persons of skill also experimented with combinations of enteric coatings and
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`insoluble permeable polymers. (Ex. 1002, Digenis Decl. ¶42). For instance,
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`Salofalk® comprised an outer-coating of semi-permeable ethylcellulose, and an
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`inner enteric coating of Eudragit L. (Ex. 1006, Stolk at 200). EP001 disclosed a
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`pharmaceutical composition for “targeted controlled release . . . within the
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`intestine” comprising “two membranes, one of pH-dependent solubility and the
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`other insoluble but permeable to the intestinal fluids.” (Ex. 1022, EP001 at 1).
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`EP590 disclosed pharmaceutical formulations for treatment of IBD comprising a
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`coating of both “acrylic polymer soluble only above pH 5.5” and a “water
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`insoluble [sic] polymer” such as Eudragit RS/RL. (Ex. 1015, EP590 at 3:11-20).
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`Persons of ordinary skill also combined 5-ASA in a polymer matrix
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`surrounded by an enteric coating. (Ex. 1002, Digenis Decl. ¶42). Marakhouski
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`disclosed pellets “coated with Eudragit-L” that contained 5-ASA “located in the
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`core embedded in a matrix polymer responsible for prolonged release of the drug.”
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`(Ex. 1024, Marakhouski at 135). Brunner (published in 2003—5 years before
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`earliest priority date of the ‘688 Patent) disclosed pellets provided by Dr Falk
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`Pharma GmbH, the patent owner of the ‘688 Patent. (Ex. 1025, Brunner at 1164).
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`The pellets contained 500 mg of mesalamine, “coated with Eudragit L” and “with
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`an additional polymer in the pellet core providing prolonged release after removal
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`of the Eudragit L coating.” (Id.).
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`D.
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`Person of Ordinary Skill in the Art
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`In view of the subject matter of the ‘688 Patent, a person of ordinary skill in
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`the art as of the patent’s filing date would typically hold an advanced degree in the
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`chemical or pharmaceutical