`
`Elizabeth J. Holland
`Direct 212.908.6307
`eholland@kenyon.com
`
`Kenyon & Kenyon LLP
`One Broadway
`New York, NY 10004-1007
`212.425.7200
`Fax 212.425.5288
`
`July 3, 2014
`
`Via FedEx® Priority Overnight Service
`
`Bausch & Lomb, Inc.
`50 Technology Drive
`Irvine, CA 92618
`
`Valeant Pharmaceuticals International, Inc.
`2150 St. Elzear Blvd. West
`Laval, Quebec H7L 4A8
`Canada
`
`Senju Pharmaceutical Co., Ltd.
`5-8 Hiranomachi 2-Chome, Chuo-Ku
`Osaka-Shi, Osaka 541-0046 Japan
`
`HIGHLY CONFIDENTIAL1
`
`Re: Notification of Certification of Invalidity, Unenforceability, and/or Noninfringement
`for U.S. Patent No. 8,754,131 Pursuant to§ 505U)(2)(B)(ii) and (iv) of the Federal
`Food, Drug, and Cosmetic Act2
`
`Dear Madam or Sir:
`
`Pursuant to§ 505G)(2)(B)(ii) and (iv) of the Federal Food, Drug, and Cosmetic Act and
`21 C.P.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. 8,754, 131, according to the electronic records of the United States
`Patent and Trademark Office ("PTO").
`
`As a courtesy, Lupin also provides a copy of this Notice Letter and detailed statement to
`
`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 and 8,669,290 are invalid, unenforceable and/or not infringed.
`
`New York Washington, DC Silicon Valley www.kenyon .com
`
`Page 1 of 44
`
`SENJU EXHIBIT 2004
`LUPIN v. SENJU
`IPR2015-01097
`
`
`
`Page 2
`Jul 3, 2014
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`Kenyon&Kenyon
`
`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. § 355U)(5)(B)(iii) begins from the receipt ofthis Notice Letter sent via FedEx®.
`
`I.
`Pursuant to 21 U.S.C. § 355U)(2)(B)(iv)(I) and 21 C.F.R. § 314.95(c)(1), Lupin
`advises 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. §§ 3550)(1) and (2)(A), and contains
`a Paragraph IV certification to obtain approval to engage in the commercial manufacture, use or
`sale ofBromfenac Ophthalmic Solution 0.07%, before the expiration of U.S. Patent No.
`8,754,131, which is listed in the Patent and Exclusivity Information Addendum ofFDA'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
`II.
`Lupin is assigned the number 206027 by FDA.
`
`Pursuant to 21 C.F.R. § 314.95(c)(3), Lupin advises that the established name of
`III.
`the drug 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
`IV.
`the 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.
`
`V.
`Pursuant to 21 C.F.R. § 314.95(c)(5), Lupin advises that the patent alleged to be
`invalid, unenforceable and/or not infringed in the Paragraph IV certification is Senju's U.S.
`Patent No. 8, 754,131 , 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, 754,131 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
`VI.
`its knowledge, U.S. Patent No. 8, 754,131 is invalid, unenforceable and/or will not be infringed
`by the commercial manufacture, use or sale ofthe drug products described in Lupin's ANDA.
`Therefore, pursuant to 21 U.S.C. § 355U)(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 hereto and made part hereof. Lupin reserves the right to demonstrate
`
`Page 2 of 44
`
`
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`July 3, 2014
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`additional grounds, reasons and authorities that the claims of U.S. Patent No. 8, 754,131 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
`KENYON & KENYON LLP
`One Broadway
`New York, NY 10004-1007
`eholland@kenyon.com
`
`VIII. Pursuant to 21 U.S.C. § 355U)(5)(C), this Notice Letter includes an Offer of
`Confidential Access to Application. As required by § 355U)(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:
`
`(I)
`Lupin will permit confidential access to certain information from its
`proprietary 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 &
`(2)
`Lomb 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.
`
`(3)
`As provided by § 355(j)(5)(C)(i)(III), the designated outside law firm
`representing 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
`
`Page 3 of 44
`
`
`
`Page4
`Jul 3, 2014
`
`Kenyon&Kenyon
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`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
`(4)
`property of 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
`(5)
`Senju shall, 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 ofBausch & 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
`(6)
`admission 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, 754,131, or to the validity or enforceability of that patent.
`
`The attorneys from the designated outside law firm representing Bausch &
`(7)
`Lomb 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
`(8)
`firm 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 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.
`
`Page 4 of 44
`
`
`
`Page 5
`Jul 3, 2014
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`Kenyon&Kenyon
`
`Section 355U)(5)(C)(i)(III) 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
`KENYON & KENYON LLP
`One Broadway
`New York, NY 10004-1007
`eholland@kenyon.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. § 355U)(5)(C).
`
`Very truly yours,
`
`. Holland
`Elizabet
`KENYON & KENYON LLP
`One Broadway
`New York, NY 10004-1007
`(212) 425-7200
`(212) 425-5288 (facsimile)
`
`Counsel for Lupin Limited
`
`Enclosure: Lupin Limited's Detailed Factual and Legal Bases for Its Opinion That U.S. Patent
`No. 8,754,131 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 44
`
`
`
`Lupin Limited’s Detailed Statement of the Factual and Legal Bases for Its Opinion That
`U.S. Patent No. 8,754,131 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. 8,754,131
`
`(“the ’131 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 8,754,131
`
`The ’131 patent, entitled “AQUEOUS LIQUID PREPARATION CONTAINING 2-
`
`AMINO-3-(4-BROMOBENZOYL)PHENYLACETIC ACID,” issued on June 17, 2014 from
`
`U.S. Application Serial No. 14/165,976, 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 ’131 patent lists Shirou Sawa and Shuhei Fujita as inventors, and
`
`is assigned on its face to Senju Pharmaceutical Co., Ltd. According to the Orange Book listing
`
`for Prolensa, the ’131 patent will expire on January 16, 2024.
`
`
`
`1
`
`Page 6 of 44
`
`
`
`A.
`
`Claims of the ’131 Patent
`
`The ’131 patent issued with 30 claims, which are reproduced below:
`
`1. A stable aqueous liquid preparation comprising: (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 and is present in the preparation at
`a concentration from about 0.05 w/v % to about 0.2 w/v %; the second component is tyloxapol
`and is present in said liquid preparation in an amount sufficient to stabilize said first component;
`and wherein said stable liquid preparation is formulated for ophthalmic administration.
`
`2. The aqueous liquid preparation according to claim 1, further comprising a quaternary
`ammonium salt.
`
`3. The aqueous liquid preparation according to claim 1, wherein the first component is a
`2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt.
`
`4. The aqueous liquid preparation according to claim 1, wherein the concentration of
`tyloxapol is from about 0.01 w/v % to about 0.05 w/v %.
`
`5. The aqueous liquid preparation according to claim 1, wherein the pH is from about 7.5
`to about 8.5.
`
`6. The stable aqueous liquid preparation of claim 1; wherein the stable aqueous liquid
`preparation consists essentially of: (a) 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium
`salt, (b) tyloxapol, (c) boric acid, (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, 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 %, and wherein the concentration of tyloxapol is from about 0.01 w/v % to about 0.05 w/v
`%.
`
`7. A stable aqueous liquid preparation comprising: (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 and is present in the preparation at
`a concentration from about 0.05 w/v % to about 0.2 w/v %; the second component is tyloxapol;
`wherein said stable liquid preparation is formulated for ophthalmic administration; and 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.
`
`8. The aqueous liquid preparation according to claim 7, further comprising a quaternary
`ammonium salt.
`
`
`
`2
`
`Page 7 of 44
`
`
`
`9. The stable aqueous liquid preparation of claim 7; 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.
`
`10. The aqueous liquid preparation according to claim 7; 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 0.05 w/v % to about 0.1
`w/v %.
`
`11. The aqueous liquid preparation according to claim 10, wherein the pH is from about
`7.5 to about 8.5.
`
`12. The stable aqueous liquid preparation of claim 7; 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 0.05 w/v % to about 0.1 w/v %, and the concentration of tyloxapol
`is about 0.02 w/v %.
`
`13. A stable aqueous liquid preparation comprising: (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 and is present in the preparation at
`a concentration from about 0.05 w/v % to about 0.2 w/v %; the second component is tyloxapol;
`wherein said stable liquid preparation is formulated for ophthalmic administration; provided that
`the liquid preparation does not include mannitol.
`
`14. The aqueous liquid preparation according to claim 13, further comprising a
`quaternary ammonium salt.
`
`15. The aqueous liquid preparation according to claim 13, wherein the first component is
`a 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt.
`
`16. The aqueous liquid preparation according to claim 13, 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 0.1 w/v %.
`
`17. The aqueous liquid preparation according to claim 13, wherein the pH is from about
`7.5 to about 8.5.
`
`18. The stable aqueous liquid preparation of claim 13; 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
`
`
`
`3
`
`Page 8 of 44
`
`
`
`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 %, and the concentration of tyloxapol is
`from about 0.02 w/v % to about 0.05 w/v %.
`
`19. The stable aqueous liquid preparation of claim 13; 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.
`
`20. The stable aqueous liquid preparation according to claim 19, further comprising a
`quaternary ammonium salt.
`
`21. The stable aqueous liquid preparation of claim 19; 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.
`
`22. The stable aqueous liquid preparation according to claim 21, 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
`0.05 w/v % to about 0.1 w/v %.
`
`23. The aqueous liquid preparation according to claim 22, wherein the pH is from about
`7.5 to about 8.5.
`
`24. The stable aqueous liquid preparation of claim 13; 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 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 0.05 w/v % to about 0.1 w/v %.
`
`25. The aqueous liquid preparation of claim 1, wherein the aqueous liquid preparation
`further satisfies the preservative efficacy standard of US 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.
`
`26. The aqueous liquid preparation of claim 4, wherein the aqueous liquid preparation
`further satisfies the preservative efficacy standard of US 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
`
`
`
`4
`
`Page 9 of 44
`
`
`
`decreases to not more than 1/10, and thereafter, the cell count keeps the same level as that of 14
`days after inoculation.
`
`27. The aqueous liquid preparation of claim 7, wherein the aqueous liquid preparation
`further satisfies the preservative efficacy standard of US 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.
`
`28. The aqueous liquid preparation of claim 9, wherein the aqueous liquid preparation
`further satisfies the preservative efficacy standard of US 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.
`
`29. The aqueous liquid preparation of claim 13, wherein the aqueous liquid preparation
`further satisfies the preservative efficacy standard of US 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 aqueous liquid preparation according to claim 1, further comprising one or more
`additives selected from the group consisting of a preservative, buffer, thickener, stabilizer,
`chelating agent, and pH controlling agent.
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`B.
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`Specification of the ’131 Patent
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`The specification of the ’131 patent acknowledges that ophthalmic solutions containing
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`bromfenac were described in the prior art. (’131 patent, col. 1, ll. 21-44.) The specification
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`quotes a prior art reference (Japanese Patent No. 2,954,356, corresponding to U.S. Patent Nos.
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`5,603,929 and 5,653,972) for the teaching that benzalkonium chloride (BAC) (a widely used
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`preservative in ophthalmic solutions) and other quaternary ammonium compounds “are generally
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`considered to be incompatible” with non-steroidal anti-inflammatory drugs (NSAIDs) with
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`acidic groups (e.g., a –COOH group) because “[t]hese preservatives lose their ability to function
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`5
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`Page 10 of 44
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`as they form complexes with the charged drug compounds.” (’131 patent, col. 1, ll. 59-67.)
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`Bromfenac is an NSAID with a –COOH group. Thus, the specification presents the problem to
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`be overcome as producing an ophthalmic solution containing an NSAID with a –COOH group
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`and BAC wherein the NSAID and the BAC do not form a complex (i.e., with improved
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`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. (’131 patent, col. 2, ll. 30-44 and col. 5, ll. 22-29.) 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. (’131 patent, col. 7, ll. 67.) Two formulations containing tyloxapol were
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`the most stable, followed by a formulation containing polyoxyl 40 stearate, followed by a
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`formulation containing polysorbate 80. The polysorbate 80 formulation was not considered to be
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`part of the invention, as indicated by the fact that it was referred to as “Comparison Example 1.”
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`C.
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`Prosecution History of the ’131 Patent
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`As noted above, there are four U.S. applications in the chain leading to the ’131 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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`6
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`Page 11 of 44
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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 ’131 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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`7
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`Page 12 of 44
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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 ’131 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 final application in the chain leading to the ’131 patent is U.S. Application Serial No.
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`14/165,976. Duri