Emily L. Rapalino
`617.570.1938
`erapalino@goodwinprocter.com
`
`Goodwin Procter LLP
`Counselors at Law
`Exchange Place
`Boston, MA 02109
`T: 617.570.1000
`F: 617.523.1231
`
`
`
`February 19, 2015
`
`VIA FEDEX PRIORITY OVERNIGHT SERVICE
`
`Bausch & Lomb, Inc.
`50 Technology Drive
`Irvine, CA 92618
`
`Valeant Pharmaceuticals International, Inc.
`2150 St. Elzéar Blvd. West HIGHLY CONFIDENTIAL1
`Laval, Quebec H7L 4A8
`Canada
`
`Senju Pharmaceutical Co., Ltd.
`5-8 Hiranomachi 2-Chome, Chuo-Ku
`Osaka-Shi, Osaka 541-0046 Japan
`
`Re: Notification of Certification of Invalidity, Unenforceability, and/or Noninfringement for
`U.S. Patent No. 8,927,606 Pursuant to § 505(j)(2)(B)(ii) and (iv) of the Federal Food, Drug,
`and Cosmetic Act2
`
`
`Dear Madam or Sir:
`
`Pursuant to § 505(j)(2)(B)(ii) and (iv) of the Federal Food, Drug, and Cosmetic Act and 21
`C.F.R. § 314.95, we hereby provide notice on behalf of Lupin Limited (“Lupin”) of the following
`information to Bausch & Lomb, Inc. (“Bausch & Lomb”), as the purported holder of approved New
`Drug Application (“NDA”) No. 203168 for Prolensa® Bromfenac Ophthalmic Solution 0.07%,
`according to the records of the U.S. Food and Drug Administration (“FDA”). In addition, Lupin
`provides notice to Senju Pharmaceutical Co., Ltd. (“Senju”) as the purported assignee of U.S. Patent No.
`8,927,606, according to the electronic records of the United States Patent and Trademark Office
`(“PTO”).
`
`
`1
`You are not authorized to attach this Notice Letter and detailed statement to any court pleading (unless filed under
`seal) or to attach this Notice Letter and detailed statement to any other document that is publicly disclosed.
`
`Lupin Limited previously provided its notice letters and detailed statements regarding its Paragraph IV certifications
`that U.S. Patent Nos. 8,129,431, 8,669,290, 8,754,131, and 8,871,813 are invalid, unenforceable and/or not
`infringed.
`
`2
`
`
`
`
`
`SENJU EXHIBIT 2006
`LUPIN v SENJU
`IPR2015-01100
`
`PAGE 1 OF 78
`
`

`
`
`
`February 19, 2015
`Page 2
`
`
`
`As a courtesy, Lupin also provides a copy of this Notice Letter and detailed statement to Valeant
`
`Pharmaceuticals International, Inc., which reportedly acquired Bausch & Lomb in 2013.
`
`Pursuant to 21 C.F.R. § 314.95(e), permission from FDA to send this Notice Letter by means
`other than registered or certified mail was requested and received. Specifically, permission to send this
`notice by FedEx® was requested. FDA granted this request prior to this notice being sent.
`Consequently, the operative date for determining the start of the 45-day clock under 21 U.S.C. §
`355(j)(5)(B)(iii) begins from the receipt of this Notice Letter sent via FedEx®.
`
`Pursuant to 21 U.S.C. § 355(j)(2)(B)(iv)(I) and 21 C.F.R. § 314.95(c)(1), Lupin advises
`I.
`
`that FDA has received an Amendment to an Abbreviated New Drug Application (“ANDA”) from Lupin
`for Bromfenac Ophthalmic Solution 0.07%. The ANDA contains the required bioavailability and/or
`bioequivalence data and/or bioequivalence waiver. The Amendment to the ANDA was submitted under
`21 U.S.C. §§ 355(j)(1) and (2)(A), and contains a Paragraph IV certification to obtain approval to
`engage in the commercial manufacture, use or sale of Bromfenac Ophthalmic Solution 0.07%, before
`the expiration of U.S. Patent No. 8,927,606, which is listed in the Patent and Exclusivity Information
`Addendum of FDA’s publication, Approved Drug Products With Therapeutic Equivalence Evaluations
`(commonly known as “the Orange Book”).
`
`Pursuant to 21 C.F.R. § 314.95(c)(2), we advise you that the ANDA submitted by Lupin
`II.
`
`is assigned the number 206027 by FDA.
`
`Pursuant to 21 C.F.R. § 314.95(c)(3), Lupin advises that the established name of the drug
`III.
`
`product that is the subject of Lupin’s ANDA is Bromfenac Ophthalmic Solution 0.07%.
`
`Pursuant to 21 C.F.R. § 314.95(c)(4), Lupin advises that the active ingredient in the
`IV.
`
`proposed drug product is bromfenac sodium; the strength of the proposed drug product is a 0.07%
`solution; and the dosage form of the proposed drug product is an ophthalmic solution.
`
`Pursuant to 21 C.F.R. § 314.95(c)(5), Lupin advises that the patent alleged to be invalid,
`V.
`
`unenforceable and/or not infringed in the Paragraph IV certification is Senju’s U.S. Patent No.
`8,927,606, which is now listed in the Orange Book in connection with Bausch & Lomb’s approved
`NDA No. 203168 for Prolensa® (Bromfenac Ophthalmic Solution 0.07%).
`
`According to information submitted for listing in the Orange Book, U.S. Patent No. 8,927,606
`
`will purportedly expire on or about January 16, 2024.
`
`Lupin alleges, and has certified to FDA, that in Lupin’s opinion and to the best of its
`VI.
`knowledge, U.S. Patent No. 8,927,606 is invalid, unenforceable and/or will not be infringed by the
`commercial manufacture, use or sale of the drug products described in Lupin’s ANDA. Therefore,
`pursuant to 21 U.S.C. § 355(j)(2)(B)(iv)(II) and 21 C.F.R. § 314.95(c)(6), Lupin’s detailed statement of
`the legal and factual basis for the Paragraph IV certification set forth in Lupin’s ANDA is attached
`
`
`
`PAGE 2 OF 78
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`

`
`
`
`February 19, 2015
`Page 3
`
`
`
`hereto and made part hereof. Lupin reserves the right to demonstrate additional grounds, reasons and
`authorities that the claims of U.S. Patent No. 8,927,606 are invalid, unenforceable, and/or not infringed.
`
`VII. Pursuant to 21 C.F.R. § 314.95(c)(7), the name and address of an agent in the United
`States authorized to accept service of process for Lupin, limited to commencement of a patent
`infringement suit based on this notification of certification, is:
`
`Elizabeth J. Holland
`GOODWIN PROCTER LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018
`eholland@goodwinprocter.com
`
`VIII. Pursuant to 21 U.S.C. § 355(j)(5)(C), this Notice Letter includes an Offer of Confidential
`
`Access to Application. As required by § 355(j)(5)(C)(i)(III), Lupin offers to provide confidential access
`to certain information from its ANDA No. 206027 for the sole and exclusive purpose of determining
`whether an infringement action referred to in §355(j)(5)(B)(iii) for a patent listed in the Orange Book for
`NDA No. 203168 can be brought.
`
`Section 355(j)(5)(C)(i)(III) allows Lupin to impose restrictions “as to persons entitled to access,
`
`and on the use and disposition of any information accessed, as would apply had a protective order been
`entered for the purpose of protecting trade secrets and other confidential business information.” That
`provision also grants Lupin the right to redact its ANDA in response to a request for Confidential
`Access under this offer.
`
`As permitted by statute, Lupin imposes the following terms and restrictions on its Offer of
`
`Confidential Access:
`
`Lupin will permit confidential access to certain information from its proprietary
`(1)
`
`
`ANDA No. 206027 to attorneys from one outside law firm representing Bausch & Lomb and/or Senju;
`provided, however, that such attorneys do not engage, formally or informally, in any patent prosecution
`for Bausch & Lomb or Senju, or any FDA counseling, litigation or other work before or involving FDA.
`Such information (hereinafter, “Confidential Lupin Information”) shall be marked with the legend
`“CONFIDENTIAL.”
`
`The attorneys from the designated outside law firm representing Bausch & Lomb
`(2)
`
`
`and/or Senju shall not disclose any Confidential Lupin Information to any other person or entity,
`including Bausch & Lomb or Senju employees, outside scientific consultants, and/or other outside
`counsel retained by Bausch & Lomb or Senju, without the prior written consent of Lupin.
`
`
`
`PAGE 3 OF 78
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`

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`
`
`February 19, 2015
`Page 4
`
`
`
`As provided by § 355(j)(5)(C)(i)(III), the designated outside law firm representing
`(3)
`
`
`Bausch & Lomb and/or Senju shall make use of the Confidential Lupin Information for the sole and
`exclusive purpose of determining whether an action referred to in § 355(j)(5)(B)(iii) can be brought and
`for no other purpose. By way of example only, the Confidential Lupin Information shall not be used to
`prepare or prosecute any future or pending patent applications by Bausch & Lomb or Senju, or in
`connection with any filing to, or communication with, FDA or the United States Pharmacopeia or any
`similar or related organization relating to Lupin’s ANDA No. 206027. The outside law firm for Bausch
`& Lomb and/or Senju agrees to take all measures necessary to prevent unauthorized disclosure or use of
`the Confidential Lupin Information, and that all Confidential Lupin Information shall be kept
`confidential and not disclosed in any manner inconsistent with this Offer of Confidential Access.
`
`The Confidential Lupin Information disclosed is, and remains, the property of
`(4)
`
`
`Lupin. By providing the Confidential Lupin Information, Lupin does not grant Bausch & Lomb, Senju
`and/or their outside law firm any interest in or license for the Confidential Lupin Information.
`
`The designated outside law firm representing Bausch & Lomb and/or Senju shall,
`(5)
`
`
`within thirty-five (35) days from the date that it first receives the Confidential Lupin Information, return
`to Lupin all Confidential Lupin Information and any copies thereof. The outside law firm of Bausch &
`Lomb and/or Senju shall return all Confidential Lupin Information to Lupin before any infringement suit
`is filed by Bausch & Lomb and/or Senju, if suit is commenced before this 35-day period expires. In the
`event that Bausch & Lomb and/or Senju opts to file suit, none of the information contained in or
`obtained from any Confidential Lupin Information that Lupin provides shall be included in any publicly-
`available complaint or other pleading.
`
`Nothing in this Offer of Confidential Access shall be construed as an admission
`(6)
`
`
`by Lupin regarding the validity, enforceability, and/or infringement of any U.S. patent. Further, nothing
`herein shall be construed as an agreement or admission by Lupin with respect to the competency,
`relevance, or materiality of any such Confidential Lupin Information, document, or thing. The fact that
`Lupin provides Confidential Lupin Information upon request of Bausch & Lomb and/or Senju shall not
`be construed as an admission by Lupin that such Confidential Lupin Information is relevant to the
`disposition of any issue relating to any alleged infringement of U.S. Patent No. 8,927,606, or to the
`validity or enforceability of that patent.
`
`The attorneys from the designated outside law firm representing Bausch & Lomb
`(7)
`
`
`and/or Senju shall acknowledge in writing their receipt of a copy of these terms and restrictions prior to
`production of any Confidential Lupin Information. Such written acknowledgement shall be provided to
`Lupin.
`
`If Confidential Lupin Information is disclosed by the designated outside law firm
`(8)
`
`
`representing Bausch & Lomb and/or Senju to any person not authorized to receive such Confidential
`Lupin Information pursuant to this Offer of Confidential Access, then the designated outside law firm
`
`
`
`PAGE 4 OF 78
`
`

`
`GOODWINIPROCTER
`
`February 19, 2015
`Page 5
`
`representing Bausch & Lomb and/or Senju must immediately bring all pertinent facts relating to such
`disclosure to the attention of Lupin and, without prejudice to other rights and remedies of Lupin, make
`every effort to prevent further disclosure by it or by the person who was the recipient of such
`Confidential Lupin Information.
`
`Section 355(j)(5)(C)(i)(IIl) provides that any request for access that Bausch & Lomb and/or
`Senju makes under this Offer of Confidential Access “shall be considered acceptance of the offer of
`confidential access with the restrictions as to persons entitled to access, and on the use and disposition of
`any information accessed, contained in [this] offer of confidential access” and that the “restrictions and
`other terms of [this] offer of confidential access shall be considered terms of an enforceable contract.”
`Thus, to the extent that Bausch & Lomb and/or Senju requests access to Confidential Lupin Information,
`they necessarily accept the terms and restrictions outlined above. Written notice requesting access under
`this Offer of Confidential Access should be made to:
`
`Elizabeth J. Holland
`
`GOODWIN PROCTER LLP
`
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018
`
`eholland@goodwinprocter.com
`
`By providing this Offer of Confidential Access, Lupin maintains the right and ability to bring
`and maintain a Declaratory Judgment action under 28 U.S.C. §§ 2201 et seq., pursuant to 21 U.S.C. §
`355(i)(5)(C)-
`
`Very truly yours,
`
`
`Emily/‘L. Rapalino
`GOODWIN PROCTER LLP
`
`Exchange Place
`Boston, MA 02109
`(617) 570-1000
`(617) 523-1231 (facsimile)
`
`Counsel for Lupin Limited
`
`Enclosure: Lupin Limited’s Detailed Factual and Legal Bases for Its Opinion That U.S. Patent No.
`8,927,606 Is Invalid, Unenforceable and/or Not Infringed by the Manufacture, Use or Sale of Lupin
`Limited’s Proposed Bromfenac Ophthalmic Solution 0.07%
`
`PAGE 5 OF 78
`
`PAGE 5 OF 78
`
`

`
`
`
`Lupin Limited’s Detailed Statement of the Factual and Legal Bases for Its Opinion That
`U.S. Patent No. 8,927,606 Is Invalid, Unenforceable and/or Not Infringed by the
`Manufacture, Use or Sale of Lupin Limited’s Proposed Bromfenac Ophthalmic Solution
`0.07%
`
`Pursuant to Section 505(j)(2)(B)(ii) of the Food, Drug and Cosmetic Act (codified at 21
`
`U.S.C. § 355(j)(2)(B)(ii)), and 21 C.F.R. § 314.95(c), this is the detailed statement of Lupin
`
`Limited (“Lupin”) of the factual and legal bases for its opinion that U.S. Patent No. 8,927,606
`
`(“the ’606 patent”) is invalid, unenforceable, and/or not infringed by the manufacture, use or sale
`
`of Lupin’s proposed bromfenac ophthalmic solution 0.07% described in ANDA No. 206027
`
`(“Lupin’s proposed product”). The bases for Lupin’s opinion follow.
`
`I.
`
`U.S. PATENT 8,927,606
`
`The ’606 patent, entitled “AQUEOUS LIQUID PREPARATION CONTAINING 2-
`
`AMINO-3-(4-BROMOBENZOYL)PHENYLACETIC ACID,” issued on January 6, 2015 from
`
`U.S. Application Serial No. 14/493,903, which was filed on September 23, 2014 as a division of
`
`U.S. Application Serial No. 14/261,720 (now U.S. Patent No. 8,871,813), which was filed on
`
`April 25, 2014 as a division of U.S. Application Serial No. 14/165,976 (now U.S. Patent No.
`
`8,754,131), which was filed on January 28, 2014 as a division of U.S. Application Serial No.
`
`13/687,242 (now U.S. Patent No. 8,669,290), which was filed on November 28, 2012 as a
`
`division of U.S. Application Serial No. 13/353,653 (now U.S. Patent No. 8,497,304), which was
`
`filed on January 19, 2012 as a division of U.S. Application Serial No. 10/525,006 (now U.S.
`
`Patent No. 8,129,431), which was filed on March 28, 2005 as a U.S. national phase application
`
`of PCT Application No. PCT/JP2004/000350, which was filed on January 16, 2004, and claims
`
`the benefit of Japanese Application No. 2003-12427, which was filed on January 21, 2003. The
`
`’606 patent lists Shirou Sawa and Shuhei Fujita as inventors, and is assigned on its face to Senju
`
`
`
`1
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`PAGE 6 OF 78
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`
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`Pharmaceutical Co., Ltd. According to the Orange Book listing for Prolensa, the ’606 patent will
`
`expire on January 16, 2024.
`
`A.
`
`Claims of the ’606 Patent
`
`The ’606 patent issued with 30 claims, which are reproduced below:
`
`1. A method for treating an inflammatory disease of an eye, the method comprising
`administering to said eye a stable aqueous liquid preparation that comprises: (a) a first
`component; and (b) a second component; wherein the first component is 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a hydrate
`thereof, wherein the hydrate is at least one selected from a 1/2 hydrate, 1 hydrate, and 3/2
`hydrate; the first component is the sole pharmaceutical active ingredient contained in the
`preparation; the second component is tyloxapol and is present in said liquid preparation in an
`amount sufficient to stabilize said first component; wherein said stable liquid preparation is
`formulated for ophthalmic administration; and wherein said liquid preparation is administered to
`said eye at a dose and a frequency effective to treat said inflammatory disease.
`
`2. The method according to claim 1, wherein said inflammatory disease is a disease of an
`anterior or posterior segment of said eye.
`
`3. The method according to claim 2, wherein said disease is postoperative inflammation.
`
`4. The method according to claim 1, wherein the first component is a 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid sodium salt.
`
`5. The method according to claim 1, wherein the concentration of tyloxapol is from about
`0.01 w/v% to about 0.05 w/v %; and wherein the first component is a 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid sodium salt, wherein the concentration of the 2-amino-3-( 4-
`bromobenzoyl)phenylacetic acid sodium salt is from about 0.01 to about 0.2 w/v %.
`
`6. The method according to claim 5, wherein the concentration of the 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid sodium salt is from about 0.02 w/v% to about 0.1 w/v %.
`
`7. The method according to claim 5, wherein the aqueous liquid preparation further
`comprises a quaternary ammonium salt.
`
`8. The method according to claim 5, wherein the concentration of the 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid sodium salt is about 0.1 w/v %.
`
`9. The method according to claim 1, wherein the stable aqueous liquid preparation
`consists essentially of: (a) 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt, (d)
`sodium tetraborate, (e) EDTA sodium salt, (f) benzalkonium chloride, (g) polyvinylpyrrolidone,
`and (h) sodium sulfite, wherein said liquid preparation is formulated for ophthalmic
`administration, and wherein the concentration of the 2-amino-3-( 4-bromobenzoyl)phenylacetic
`acid sodium salt is from about 0.02 w/v% to about 0.1 w/v %.
`
`
`
`2
`
`PAGE 7 OF 78
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`

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`
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`10. The method according to claim 1, wherein said dose comprises one or two drops.
`
`11. A method for treating an inflammatory disease of an eye, the method comprising
`administering to said eye a stable aqueous liquid preparation that comprises: (a) a first
`component; and (b) a second component; wherein the first component is 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a hydrate
`thereof, wherein the hydrate is at least one selected from a 1/2 hydrate, 1 hydrate, and 3/2
`hydrate; the first component is the sole pharmaceutical active ingredient contained in the
`preparation; the second component is tyloxapol; wherein said stable liquid preparation is
`formulated for ophthalmic administration; wherein the stable aqueous liquid preparation is
`characterized in that greater than about 90% of the original amount of the first component
`remains in the preparation after storage at about 60° C. for 4 weeks; and wherein said liquid
`preparation is administered to said eye at a dose and a frequency effective to treat said
`inflammatory disease.
`
`12. The method according to claim 11, wherein the stable aqueous liquid preparation is
`characterized in that greater than about 92% of the original amount of the first component
`remains in the preparation after storage at about 60° C. for 4 weeks.
`
`13. The method according to claim 11, wherein said inflammatory disease is a disease of
`an anterior or posterior segment of said eye.
`
`14. The method according to claim 13, wherein said disease is postoperative
`inflammation.
`
`15. The method according to claim 11, wherein the concentration of tyloxapol is
`fromabout0.01 w/v % to about 0.05 w/v %; and wherein the first component is a 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid sodium salt, wherein the concentration of the 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid sodium salt is from about 0.01 to about 0.2 w/v %.
`
`16. The method according to claim 15, wherein the concentration of the 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid sodium salt is from about 0.02 w/v % to about 0.1 w/v %.
`
`17. The method according to claim 11, further comprising a quaternary ammonium salt.
`
`18. The method according to claim 11, wherein the stable aqueous liquid preparation
`consists essentially of: (a) 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologically
`acceptable salt thereof or a hydrate thereof, wherein the hydrate is at least one selected from a
`1/2 hydrate, 1 hydrate, and 3/2 hydrate; (b) tyloxapol; (c) boric acid; (d) sodium tetraborate; (e)
`EDTA sodium salt; (f) benzalkonium chloride; (g) polyvinylpyrrolidone; and (h) sodium sulfite;
`and wherein the concentration of the 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt
`is from about 0.02 w/v % to about 0.1 w/v %.
`
`19. A method for treating an inflammatory disease of an eye, the method comprising
`administering to said eye a stable aqueous liquid preparation that comprises: (a) a first
`component; and (b) a second component; wherein the first component is 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof or a hydrate
`thereof, wherein the hydrate is at least one selected from a 1/2 hydrate, 1 hydrate, and 3/2
`
`
`
`3
`
`PAGE 8 OF 78
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`
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`hydrate; the first component is the sole pharmaceutical active ingredient contained in the
`preparation; the second component is tyloxapol; wherein said stable liquid preparation is
`formulated for ophthalmic administration; provided that the liquid preparation does not include
`mannitol; and wherein said liquid preparation is administered to said eye at a dose and a
`frequency effective to treat said inflammatory disease.
`
`20. The method according to claim 19, wherein said inflammatory disease is a disease of
`an anterior or posterior segment of said eye.
`
`21. The method according to claim 20, wherein said disease is postoperative
`inflammation.
`
`22. The method according to claim 19, wherein the first component is a 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid sodium salt.
`
`23. The method according to claim 22, wherein the concentration of tyloxapol is from
`about 0.01 w/v % to about 0.05 w/v % and the concentration of the 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid sodium salt is from about 0.05 to about 0.2 w/v %.
`
`24. The method according to claim 22, wherein the concentration of the 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid sodium salt is from about 0.02 w/v % to about 0.1 w/v %.
`
`25. The method according to claim 20; wherein the stable aqueous liquid preparation
`consists essentially of: (a) 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologically
`acceptable salt thereof or a hydrate thereof, wherein the hydrate is at least one selected from a
`1/2 hydrate, 1 hydrate, and 3/2 hydrate; (b) tyloxapol; (c) boric acid; (d) sodium tetraborate; (e)
`EDTA sodium salt; (f) benzalkonium chloride; (g) polyvinylpyrrolidone; and (h) sodium sulfite;
`wherein the concentration of the 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is
`from about 0.02 w/v % to about 0.1 w/v %.
`
`26. The method according to claim 20, wherein the stable aqueous liquid preparation is
`characterized in that greater than about 90% of the original amount of the first component
`remains in the preparation after storage at about 60° C. for 4 weeks.
`
`27. The method according to claim 20, wherein the concentration of tyloxapol is from
`about 0.01 w/v % to about 0.05 w/v %; and wherein the first component is a 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid sodium salt, wherein the concentration of the 2-amino-3-(4-
`bromobenzoyl)phenylacetic acid sodium salt is from about 0.02 to about 0.1 w/v %.
`
`28. The method according to claim 1, wherein the aqueous liquid preparation further
`satisfies the preservative efficacy standard of EP-criteria B of the European Pharmacopoeia as
`follows: viable cell counts of bacteria (S. aureus, P. aeruginosa) 24 hours and 7 days after
`inoculation decrease to not more than 1/10 and not more than 1/1000, respectively, and
`thereafter, the cell count levels off or decreases; and viable cell count of fungi (C. albicans, A.
`niger) 14 days after inoculation decreases to not more than 1/10, and thereafter, the cell count
`keeps the same level as that of 14 days after inoculation.
`
`
`
`4
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`PAGE 9 OF 78
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`
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`29. The method according to claim 11, wherein the aqueous liquid preparation further
`satisfies the preservative efficacy standard of EP-criteria B of the European Pharmacopoeia as
`follows: viable cell counts of bacteria (S. aureus, P. aeruginosa) 24 hours and 7 days after
`inoculation decrease to not more than 1/10 and not more than 1/1000, respectively, and
`thereafter, the cell count levels off or decreases; and viable cell count of fungi (C. albicans, A.
`niger) 14 days after inoculation decreases to not more than 1/10, and thereafter, the cell count
`keeps the same level as that of 14 days after inoculation.
`
`30. The method according to claim 19, wherein the aqueous liquid preparation further
`satisfies the preservative efficacy standard of EP-criteria B of the European Pharmacopoeia as
`follows: viable cell counts of bacteria (S. aureus, P. aeruginosa) 24 hours and 7 days after
`inoculation decrease to not more than 1/10 and not more than 1/1000, respectively, and
`thereafter, the cell count levels off or decreases; and viable cell count of fungi (C. albicans, A.
`niger) 14 days after inoculation decreases to not more than 1/10, and thereafter, the cell count
`keeps the same level as that of 14 days after inoculation.
`
`B.
`
`Specification of the ’606 Patent
`
`The specification of the ’606 patent acknowledges that ophthalmic solutions containing
`
`bromfenac were described in the prior art, and that such preparations were known to be effective
`
`against inflammatory diseases of the anterior or posterior segment of the eye, such as blepharitis,
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`conjunctivitis, scleritis, and post-operative inflammation. (’606 patent, col. 1, ll. 19-41.) The
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`specification quotes a prior art reference (Japanese Patent No. 2,954,356, corresponding to U.S.
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`Patent Nos. 5,603,929 and 5,653,972) for the teaching that benzalkonium chloride (BAC) (a
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`widely used preservative in ophthalmic solutions) and other quaternary ammonium compounds
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`“are generally considered to be incompatible” with non-steroidal anti-inflammatory drugs
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`(NSAIDs) with acidic groups (e.g., a –COOH group) because “[t]hese preservatives lose their
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`ability to function as they form complexes with the charged drug compounds.” (’606 patent, col.
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`1, ll. 56-63.) Bromfenac is an NSAID with a –COOH group. Thus, the specification presents
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`the problem to be overcome as producing an ophthalmic solution containing an NSAID with a –
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`COOH group and BAC wherein the NSAID and the BAC do not form a complex (i.e., with
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`improved stability).
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`The specification indicates that this problem has been overcome by including an alkyl
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`aryl polyether alcohol type polymer such as tyloxapol or a polyethylene glycol fatty acid ester
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`such as polyethylene glycol monostearate (especially polyoxyl 40 stearate) in the ophthalmic
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`solution. (’606 patent, col. 2, ll. 26-40 and col. 3, l. 28-60.) The specification describes an
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`experiment (Experimental Example 1) in which formulations containing bromfenac, BAC and
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`three different surfactants (polysorbate 80, polyoxyl 40 stearate, and tyloxapol) were prepared
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`and tested for stability. (’606 patent, col. 6, l. 46 – col. 7, l. 22.) Two formulations containing
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`tyloxapol were the most stable, followed by a formulation containing polyoxyl 40 stearate,
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`followed by a formulation containing polysorbate 80. The polysorbate 80 formulation was not
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`considered to be part of the invention, as indicated by the fact that it was referred to as
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`“Comparison Example 1.”
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`The specification also indicates that the liquid preparations described in the specification
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`may be “used for the treatment of inflammatory diseases in anterior or posterior segment of the
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`eye.” (’606 patent, col. 6, l. 29-33.) The specification further states that the liquid preparation
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`contemplated may be used in the form of eye drops to treat conditions such as “blepharitis,
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`conjunctivitis, scleritis, and postoperative inflammation.” (’606 patent, col. 3, l. 61-64; col. 6, l.
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`29-33; col. 10, l. 64-66.)
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`C.
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`Prosecution History of the ’606 Patent
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`As noted above, there are six U.S. applications in the chain leading to the ’606 patent.
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`During prosecution of the first of these applications (U.S. Application Serial No. 10/525,006),
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`the PTO Examiner cited prior art describing ophthalmic solutions containing bromfenac, BAC
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`and polysorbate 80 as a surfactant, as well as prior art showing that tyloxapol and polysorbate 80
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`were both known as surfactants in ophthalmic solutions, and rejected the claims on the basis that
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`it would have been obvious to substitute tyloxapol for polysorbate 80. (May 6, 2011 Office
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`Action at 2-3 [“It would have been obvious to one of ordinary skill in the art at the time of the
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`invention to interchange polysorbate 80 and tyloxapol. The motivation comes from the teaching
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`of Guy et al. that both compounds are non-ionic surfactant surface active agents. Hence, a
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`skilled artisan would have had a reasonable expectation of successfully producing a composition
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`with similar efficacy and results.”].) In response, applicants argued that they had discovered that
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`substituting tyloxapol for polysorbate 80 produced unexpected results (i.e., improved stability)
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`and pointed to Experimental Example 1 from the specification to support this assertion. (See
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`September 6, 2011 Amendment at 7-8 [“The present inventors have discovered that tyloxapol
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`has an unexpected property in stabilizing an aqueous solution of bromfenac in comparison with
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`polysorbate 80. Please see the description of Experimental Example 1 and Table 1 on pages 14-
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`16 of the specification.”].) The PTO Examiner accepted this argument, and allowed the claims
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`of that application (U.S. Application Serial No. 10/525,006) on the basis of the alleged
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`unexpected results. (December 23, 2011 Notice of Allowability at 3-4 [“The present inventors
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`have discovered that tyloxapol has an unexpected property in stabilizing an aqueous solution of
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`bromfenac in comparison with polysorbate 80. Please see the description of Experimental
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`Example 1 and Table 1 on pages 14-16 of the specification.”].) This application issued as U.S.
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`Patent No. 8,129,431.
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`The next application in the chain leading to the ’606 patent is U.S. Application Serial No.
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`13/353,653. During the prosecution of this application, applicants pursued claims to aqueous
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`liquid preparations including polyoxyl 40 (as opposed to tyloxapol). The claims were allowed
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`based on a declaration submitted by one of the inventors (Shirou Sawa) that set forth the
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`experiments included as Experimental Examples 1-3 of the specification, including Example 1
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`showing that a specific ophthalmic solution including polyoxyl 40 stearate was more stable than
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`a specific ophthalmic solution containing polysorbate 80. (June 7, 2013 Notice of Allowability
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`at 8-9.) This application issued as U.S. Patent No. 8,497,304.
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`The following application in the chain leading to the ’606 patent is U.S. Application
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`Serial No. 13/687,242. During the prosecution of this application, applicants again pursued
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`claims to aqueous liquid preparations including tyloxapol. In allowing the claims, the PTO
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`Examiner explained how the claims were allowable over U.S. Patent No. 6,383,471 to Chen,
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`which she referred to as the closest prior art of record. (January 15, 2014 Notice of Allowability
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`at 4-6.) However, the Chen reference was not substantively discussed during prosecution of U.S.
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`Application Serial No. 13/687,242. The PTO Examiner also pointed to portions of Experimental
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`Examples 1-3 pertaining to ophthalmic solutions containing polyoxyl 40 stearate, despite the fact
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`that the allowed claims all required the inclusion of tyloxapol, not polyoxyl 40 stearate. (January
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`15, 2014 Notice of Allowability at 6.) This application issued as U.S. Patent No. 8,669,290.
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`The next application in the chain leading to the ’606 patent is U.S. Application Serial No.
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`14/165,976. During prosecution of this application, the applicants similarly pursued claims to
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`aqueous liquid preparations containing bromfenac and tyloxapol. As