In the United States Patent and Trademark Office
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`Before the Patent Trial and Appeal Board
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`FOHILL CAPITAL PARTNERS
`MYCONOVO, INC.,
`Petitioner
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`v.
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`DR. FALK PHARMA GmbH,
`Patent Owner
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`
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`U.S. Patent No. 8,865,688
`Issue Date: October 21, 2014
`Inventor: William Forbes
`
`Title: COMPOSITIONS AND METHODS FOR TREATMENT OF BOWEL
`DISEASES WITH GRANULATED MESALAMINE
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`Inter Partes Review No.: Unassigned
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`Petition for Inter Partes Review of U.S. Patent No. 8,865,688 Under
`35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.1-42.80, 42.100-42.123
`
`
`
`
`
`

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`TABLE OF CONTENTS
`TABLE OF CONTENTS .................................................................................................................. i
`LISTING OF EXHIBITS PURSUANT TO 37 C.F.R. § 42.63(e) .................................................... iii
`I.
`MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) ............................................................ 1
`A.
`Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1) ---------------------------------------- 1
`
`Page
`
`II.
`III.
`IV.
`
`V.
`VI.
`
`B.
`
`Related Matters Under 37 C.F.R. § 42.8(b)(2) ----------------------------------------------- 2
`
`Lead And Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3) --------------------------------- 2
`C.
`Service Information Under 37 C.F.R. § 42.8(b)(4) ------------------------------------------ 3
`D.
`GROUNDS FOR STANDING (37 C.F.R. §§ 42.101 and 42.104) ........................................ 3
`PAYMENT OF FEES (37 C.F.R. § 42.103) ......................................................................... 3
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE REASONS
`THEREFOR (37 C.F.R. § 42.22(a)) ...................................................................................... 3
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) ......................................... 4
`BACKGROUND ................................................................................................................... 5
`A.
`The ‘688 Patent ----------------------------------------------------------------------------------- 5
`B.
`Prosecution History of the ‘688 Patent -------------------------------------------------------- 7
`
`C.
`
`Background of the Prior Art --------------------------------------------------------------------- 9
`1. ULCERATIVE COLITIS ............................................................................................................................... 9
`
`2. MESALAMINE (5-AMINOSALICYLIC ACID) ............................................................................................. 10
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`3. ENTERIC COATING ................................................................................................................................. 13
`
`4. POLYMER MATRIX ................................................................................................................................. 15
`
`5. COMBINATIONS OF ENTERIC COATINGS AND POLYMER MATRICES ....................................................... 17
`Person of Ordinary Skill in the Art ------------------------------------------------------------- 19
`D.
`VII. CLAIM CONSTRUCTION (37 C.F.R. § 42.104(b)(3)) ....................................................... 19
`A.
`Without Food -------------------------------------------------------------------------------------- 19
`
`Granulated Mesalamine Formulation --------------------------------------------------------- 22
`B.
`VIII. ANALYSIS ........................................................................................................................... 27
`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. ------------------ 27
`
`B.
`
`C.
`
`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.--------- 42
`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. -------------------------------------------------------------------------------------- 46
`
`i
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`

`
`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. ------- 49
`CONCLUSION ..................................................................................................................... 52
`IX.
`CERTIFICATE OF SERVICE .......................................................................................................... 53
`
`
`
`ii
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`

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`LISTING OF EXHIBITS PURSUANT TO 37 C.F.R. § 42.63(e)
`
`Description
`Exhibit
`1001 U.S. Patent No. 8,865,688 (“the ‘688 Patent”)
`1002 Declaration of George A. Digenis, Ph.D. (“Digenis Decl.”)
`1003 U.S. Patent No. 6,004,581 (“the ‘581 Patent”)
`
`Stephen Hanauer et al., Mesalamine Capsules for Treatment of Active
`
`1004
`
`Ulcerative Colitis: Results of A Controlled Trial, 88 AMERICAN J.
`
`GASTROENTEROLOGY 1188 (1993) (“Hanauer”)
`
`J. N. C. Healey, Gastrointestinal Transit and Release of Mesalazine
`
`1005
`
`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
`
`1006
`
`in Vitro, 12 PHARMACEUTISCH WEEKBLAD SCIENTIFIC
`
`EDITION 200 (1990) (“Stolk”)
`1007 European Patent Application No. 0 671 168 A1 (“EP168”)
`1008 PCT Publication No. WO 91/07949 (“PCT949”)
`S. S. Davis, The Design and Evaluation of Controlled Release Systems
`
`1009
`
`for the Gastrointestinal Tract, 2 J. CONTROLLED RELEASE 27
`
`(1985) (“Davis-1985”)
`
`1010
`
`S. S. Davis et al., Transit of Pharmaceutical Dosage Forms Through
`
`the Small Intestine, 27 GUT 886 (1986) (“Davis-1986”)
`
`1011 U.S. Patent No. 6,551,620 (“the ‘620 Patent”)
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`iii
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`

`
`Salix Announces Statistically Significant Top-Line Results of a Unique
`
`Granulated Mesalamine Product Registration Study in Ulcerative
`
`1012
`
`Colitis (September 2007), available at
`
`http://www.sec.gov/Archives/edgar/containers/fix021/1009356/000119
`
`312507195530/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
`
`1013
`
`1014
`
`Bowel Syndrome and Hepatic Encephalopathy. New Article [online]
`
`EndoNurse, 12 January 2006 (“Endonurse”)
`1015 European Patent Application No. 0 040 590 A2 (“EP590”)
`
`1016
`
`‘688 Patent File History (“FH688”), Amendment 5/9/2014
`
`‘688 Patent File History (“FH688”), Amendment 6/20/2014
`1017
`‘688 Patent File History (“FH688”), Amendment to the Claims
`1018
`‘688 Patent File History (“FH688”), Notice of Allowance
`1019
`‘688 Patent File History (“FH688”), Amendment 10/8/2013
`1020
`‘688 Patent File History (“FH688”), Amendment 4/24/2013
`1021
`1022 European Patent Application No. 0 453 001 A1 (“EP001”)
`P.J. Watts et al., Encapsulation of 5-aminosalicylic Acid into Eudragit
`
`1023
`
`1024
`
`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”)
`
`iv
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`

`
`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
`
`1025
`
`(2003) (“Brunner”)
`
`Brouwers, J.R.B.J. “Advanced and controlled drug delivery systems in
`
`1026
`
`clinical disease management,” Pharmacy World & Science: (1996)
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`18(5), 153-162 (“Brouwers”)
`
`
`
`v
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`

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`
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`Petition for Inter Partes Review of U.S. Patent No. 8,865,688
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`MycoNovo, Inc. and Foxhill Opportunity Fund, L.P. (“Petitioner”) requests
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`that the Board institute inter partes review (“IPR”) of claims 1 and 16 of U.S.
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`Patent No. 8,865,688 (“the ’688 Patent”) issued to William Forbes (Ex. 1001), and
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`that these claims be canceled as unpatentable over the prior art. Inter partes
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`review of claims 1 and 16 of the ’688 Patent was instituted in IPR2016-00297 on
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`June 10, 2016, based on a petition filed by Generico, LLC and Flat Line Capital,
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`LLC (collectively, “Generico”). For the sake of completeness and efficiency, the
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`present Petition is a practical copy of the petition in IPR2016-00297. Petitioner is
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`requesting however, that the Board institute only on the Grounds instituted in
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`IPR2016-00297, i.e., Grounds 3 and 4 (which the Board determined subsumed
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`Ground 1), as to claims 1 and 16, and not on Grounds 1 and 2. A Motion for
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`Joinder with IPR2016-00297 is being filed concurrently with this Petition.
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`I. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))
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`Petitioner provides the following mandatory notices under 37 C.F.R. §§
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`42.8(a)(1) and 42.8(b).
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`A. Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1)
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`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner hereby certifies that the
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`following persons or entities are the only real parties in interest for this IPR
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`petition: MycoNovo, Inc., (“MycoNovo”), Foxhill Opportunity Fund, L.P.
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`(“Foxhill”); Foxhill Capital Partners, LLC; Foxhill Capital (GP), LLC; Neil
`1
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`
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`Petition for Inter Partes Review of U.S. Patent No. 8,865,688
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`Anthony Weiner; Laura Pollack Weiner; and William D. Hare. No other entities or
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`persons other than Petitioners have authority to direct or control Petitioners’
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`actions or decisions relating to this petition. Petitioners are collectively funding all
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`of the fees and costs of this petition for inter partes review.
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`B. Related Matters Under 37 C.F.R. § 42.8(b)(2)
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`Petitioner identifies the following related matters:
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`District Court and C.A.F.C. Matters: Salix Pharmaceuticals, Inc. et al. v.
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`Novel Laboratories, Inc., 1-15-cv-00027 (DED); Salix Pharmaceuticals, Inc. et al.
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`v. Novel Laboratories, Inc., 1-15-cv-00213 (DED); Salix Pharmaceuticals, Inc et al
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`v. Mylan Pharmaceuticals, Inc. et al, 1-15-cv-00109 (N.D.W.V.).
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`USPTO Matters:
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`GeneriCo, LLC and Flat Line Capital, LLC v. Dr. Falk Pharma GmbH, Case
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`IPR2016-00297 (instituted); and Mylan Pharmaceuticals, Inc. v. Dr. Falk Pharma
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`GmbH, Case IPR2016-01386.
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`C.
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`Lead And Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3)
`
`Lead Counsel
`
`Back-Up Counsel
`
`William Hare (Reg. No. 44,739)
`McNeely Hare & War LLP
`12 Roszel Road, Suite C104,
`Princeton, NJ 08540
`Telephone: (202) 640-1801
`Fax: (202) 478-1813
`bill@miplaw.com
`
`Gabriela Materassi (Reg. No. 47,774)
`McNeely Hare & War LLP
`12 Roszel Road, Suite C104,
`Princeton, NJ 08540
`Telephone: (347) 684-4154
`Fax: (202) 478-1813
`materassi@miplaw.com
`
`
`
`2
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`
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`Petition for Inter Partes Review of U.S. Patent No. 8,865,688
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`D.
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`Service Information Under 37 C.F.R. § 42.8(b)(4)
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`Pursuant to 37 C.F.R. 42.10(b), a Power of Attorney has been filed with this
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`Petition. Documents may be delivered by hand to the addresses of lead and back-
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`up counsel above. Petitioner consents to electronic service by e-mail at the above
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`listed email addresses of Lead and Back-Up Counsel (bill@miplaw.com and
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`materassi@miplaw.com).
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`II. GROUNDS FOR STANDING (37 C.F.R. §§ 42.101 and 42.104)
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`Petitioner hereby certifies that IPR is available for the ’688 Patent and that
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`Petitioner is not barred or estopped from requesting an IPR challenging the patent
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`claims on the instituted grounds identified in this Petition because a motion for
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`joinder has been filed to join IPR2016-00297 no later than one month after
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`institution in accordance with 37 C.F.R. § 42.122(b) and 35 U.S.C. §315(c).
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`III. PAYMENT OF FEES (37 C.F.R. § 42.103)
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`The required fee for this petition are submitted herewith via online payment.
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`The Office is authorized to charge any fee deficiencies and credit overpayments to
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`Deposit Acct. No. 502923, Customer ID No. 32687.
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`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
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`REASONS THEREFOR (37 C.F.R. § 42.22(a))
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`Petitioner requests inter partes review and cancellation of claims 1 and 16.
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`
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`3
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`
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`Petition for Inter Partes Review of U.S. Patent No. 8,865,688
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`Petitioner’s full statement of the reasons for the relief requested is set forth in
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`detail below.
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`V.
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`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))
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`Petitioner respectfully requests inter partes review and cancellation of
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`claims 1 and 16 of the ‘688 Patent based on the grounds set forth in the table
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`below:
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`Ground Challenged Claims Statutory Basis
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`References
`
`1
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`2
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`3
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`4
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`1 and 16
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`§ 103
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`1 and 16
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`§ 103
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`1 and 16
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`§ 103
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`1 and 16
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`§ 103
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`Sept. 2007 Press Release in view
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`of Endonurse and Davis-1985
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`Sept. 2007 Press Release in view
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`of Endonurse, Davis-1985 and
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`EP590
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`Sept. 2007 Press Release in view
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`of Endonurse, Davis-1985 and
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`Marakhouski
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`Sept. 2007 Press Release in view
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`of Endonurse, Davis-1985 and
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`Brunner
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`Grounds 1-4 are practical copies of the grounds presented in the petition in
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`IPR2016-00297, including Grounds 3 and 4 that were instituted by the Board,
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`challenging the same claims over the same prior art and using the same arguments
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`and expert testimony.
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`
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`4
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`
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`Petition for Inter Partes Review of U.S. Patent No. 8,865,688
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`Petitioner supports its challenges with the Declaration of George A. Digenis,
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`Ph.D. (“Digenis Decl.”) (Ex. 1002). The Digenis Declaration is an exact copy of
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`Dr. Digenis’ declaration from IPR2016-00297, which was relied upon by the
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`Board in that proceeding. Dr. Digenis’ IPR2016-00297 Declaration is cited in this
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`Petition to avoid unnecessary cost and to advance efficiency in this instance. As
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`mentioned above, this Petition is presented along with a motion to join IPR2016-
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`00297, and, by using the same Declaration, Petitioner has eliminated the need for
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`analysis of another declaration or the addition of a new expert.
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`VI. BACKGROUND
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`A. The ‘688 Patent
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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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`Petition for Inter Partes Review of U.S. Patent No. 8,865,688
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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).
`
`The ’688 Patent, however, is not directed to a novel formulation of
`
`mesalamine. Rather, the claims are directed to a method of “maintaining the
`
`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
`
`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
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`Petition for Inter Partes Review of U.S. Patent No. 8,865,688
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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 claims
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`require that administration of the granulated mesalamine is “without food.” (Ex.
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`1001, ’688 Patent col. 34:15).
`
`B.
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`Prosecution History of the ‘688 Patent
`
`The ’688 Patent issued from U.S. Patent Application No. 12/573,081, filed
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`October 9, 2009, which was purportedly related to U.S. Provisional Application
`
`Nos. 61/102,807 and 61/109,708, filed October 3, 2008 and October 30, 2008,
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`respectively. Accordingly, the priority date for the ’688 Patent is not earlier than
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`October 30, 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-
`
`mesalamine drugs available at the time of the invention, Applicant has
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`Petition for Inter Partes Review of U.S. Patent No. 8,865,688
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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
`
`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, Amendment
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`6/20/14 at 6). Applicant distinguished two FDA-approved oral mesalamine
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`formulations, Lialda® and Pentasa®. Applicant argued that Lialda® was, similar
`
`to the “pending claims [which] are directed to methods of administering a delayed
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`and extended-release oral mesalamine formulation, Lialda®” is a “delayed and
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`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
`
`original). Citing prescribing information for Lialda®, Applicant argued that it is
`
`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
`
`mesalamine is administered without food.” (Id. at 7).
`
`Upon allowing the application, the Examiner’s “Reasons for Allowance”
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`
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`8
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`
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`stated:
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`Petition for Inter Partes Review of U.S. Patent No. 8,865,688
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`[t]he cited prior art is silent with respect to whether or not the
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`mesalamine formulation is administered with or without food. One
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`skilled in the art would reasonably expect the formulation to be
`
`administered with food, since similar mesalamine formulations are
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`directed to be administered with food (see Lialda® information
`
`pamphlet, submitted by Applicants with response to filed 20 June
`
`2014).
`
`(Ex. 1019, FH688, Notice of Allowance at 3). The Examiner concluded that
`
`persons of skill in the art would have been motivated to administer mesalamine
`
`formulations with food:
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`Additionally, one skilled in the art would be motivated to administer
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`the mesalamine formulation with food, since 5-aminosalicylate
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`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).
`
`C.
`
`Background of the Prior Art
`
`1.
`
`Ulcerative Colitis
`
`Inflammatory bowel disease (“IBD”) refers to inflammatory conditions of
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`9
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`Petition for Inter Partes Review of U.S. Patent No. 8,865,688
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`the gastrointestinal tract, including ulcerative colitis (“UC”), Crohn’s disease
`
`(“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 Ex.
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`1001, ’688 Patent col. 1:54-59).
`
`2. Mesalamine (5-Aminosalicylic Acid)
`
`Beginning in the 1950s, sulfasalazine became the “the most widely
`
`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 1970s, it was
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`discovered that 5-ASA was the therapeutically-active moiety of sulfasalazine. This
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`led to the development of 5-ASA formulations for the treatment of IBD, UC and
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`CD. (Ex. 1004, Hanauer at 1189).
`
`Indeed, prior to filing of the ’688 Patent, it was well-known among persons
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`10
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`Petition for Inter Partes Review of U.S. Patent No. 8,865,688
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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
`
`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, Hanauer 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 [of
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`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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`Petition for Inter Partes Review of U.S. Patent No. 8,865,688
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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, Hanauer at 1189). By the
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`early 1990s, 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, Hanauer 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 of 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 and
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`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 resin (Eudragit® S), which dissolves above pH 7.0. Thus in
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`vivo it should be transported intact until it reaches the ascending part of the colon
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`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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`mesalamine, 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 aqueous 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 2:14-
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`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 abso