Kenyon8£Kenyon
`
`Ebbltll J. Holllnll
`
`m212.soa.esov
`
`ohollandakanyuncom
`
`Kenyon 5 Kenyon LLP
`Ono Broadway
`New Yor1(.l~lY 10004-100?
`212.425.7200
`Fax 212.425.5233
`
`May 13, 2014
`
`Via Fednf Prior_rt1' Overn;g'ht Service
`
`Bausch & Lomh, Inc.
`50 Technology Drive
`Irvine, CA 92618
`
`Valeant Pharmaceuticals International, Inc.
`2150 St. Elzéar Blvd. West
`Laval, Quebec I-l7l.. 4A8
`Canada
`
`Senju Pharmaceutical Co., Ltd.
`5-8 l-liranomachi 2—Chorne, Chuo-Ku
`Osaka-Shi, Osaka 541-0046 Japan
`
`mag; cgnrmgmtéy
`
`Re:
`
`Notification of Certification of Invalidity, Unenforceabilily, andfor Noninfringement
`for U.S. Patent No. 8,669,290 Pursuant to § 5l}5(j)(2)(B)(ii) and (iv) of the Federal
`Food, Drug, and Cosmetic Act’
`
`Dear Madam or Sir:
`
`Pursuant to § 505(j)(2)(B)(ii) and (iv) of the Federal Food, Drug, and Cosmetic Act and
`21 CPR. § 314.95, we hereby provide notice on bchalfofLupin Limited (“Lupin”) ofthe
`following information to Bausch & Lomb, Inc- (“Bausch & Lamb”), as the purported holder of
`approved New Drug Application (“NDA”) No. 203168 for Prolensam Bromfenac Ophthalmic
`Solution 0.07%, according to the records of the U.S. Food and Drug Administration (“FDA”).
`addition, Lupin provides notice to Senju Pharmaceutical Co., Ltd. (“Senju”) as the purported
`assignee of U.S. Patent No. 8,669,290, according to the electronic records of the United States
`Patent and Trademark Office (“PTO”).
`
`In
`
`As a courtesy, Lupin also provides a copy of this Notice Letter and detailed statement to
`
`‘
`
`2
`
`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 previousiy provided its notice letter and detailed statement regarding its Paragraph IV
`certification that U.S. Patent No. 8,129,431 is invalid, unenforceable andior not infringed.
`
`Page 1 of 23
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`New‘rork Wasning'lon.DC Silicon Vailey www.I:enyon.com
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`SENJU EXHIBIT 2018
`
`METRICS v. SENJU
`IPR2014-01043
`
`Page 1 of 23
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`SENJU EXHIBIT 2018
`METRICS v. SENJU
`IPR2014-01043
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`

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`"’g"2
`My I3, 2014
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`Kenyon8cKcnyon
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`Valeant Pharmaceuticals International, Inc., which reportedly acquired Bausch & Lornb in 2013.
`
`Pursuant to 21 C.F.R. § 314.9S(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 FeclEx° 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(i)(5)(B)(iii) begins from the receipt ofthis Notice Letter sent via FedEx‘.
`
`Pursuartt to 21 U.S.C. § 355(i)(2)(B}(iv)(I) and 21 CPR. § 3l4.95(c)(l), Lupin
`1.
`advises that FDA has received an Amendment to an Abbreviated New Drug Application
`(“ANDA”) from Lupin for Brcmfenac Ophthalmic Solution 0.07%. The ANDA contains the
`required bioavaiiability andfor bioequivalence data andfor bioequivalence waiver. The
`Amendment to the ANDA was submitted under 21 U.S.C. §§ 355(j)(l) 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 US. Patent No.
`8,669,290, which is listed in the Patent and Exclusivity lnforrnation Addendum of FDA’-5
`publication, Approved Drug Products With Therapeufitr: Equivaience Evaluations (commonly
`known as “the Orange Book”).
`
`Pursuant to 21 C.F.R. § 3 l4.95(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
`Ill.
`the drug product that is the subject of Lupin’s ANDA is Brornfenar: Ophthalmic Solution 0.07%.
`
`Pursuant to 21 C.F.R. § 3 l4.95(c)(4), Lupin advises that the active ingredient in
`IV.
`the proposed drug product is bromfenac sodium; the strength ofthe proposed drug product is a
`0.07% solution; and the dosage form ofthe proposed drug product is an ophthalmic solution-
`
`Pursuant to 21 C.I-‘.R. § 314.9S(c)(S), Lupin advises that the parent alleged to be
`V.
`invalid, unenforceable andfor not infiinged in the Paragraph IV certification is Senju’s U.S.
`Patent No. 8,669,290, which is now listed in the Orange Book in connection with Bausch &
`Lomb’s approved NDA No. 203168 for Prolcnsam (Bromfenac Ophthalmic Solution 0.07%).
`
`According to information submitted for listing in the Orange Book, U.S. Patent No.
`8,669,290 wiil 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. 8,669,290 is invalid, imenforceable andfor 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. § 3SS(i)(2)(B)(iv)(Il) and 21 CPR. § 3 l4.95(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 23
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`Kenyon 8cKenyon
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`additional grounds, reasons and authorities that the claims ofthe ’290 patent are invalid,
`unenforceable, andfor not infringed.
`
`Pursuant to 21 C.F.R. § 3l4.95(c)(7), the name and address ofan agent hr the
`VII.
`United States authorized to accept service of process for Lupin, limited to commencement of a
`patent infi-ingement suit based on this notification of certification, is:
`
`Elizabeth J. Holland
`KENYON & KENYON LLP
`
`One Broadway
`New York, NY 10004-1007
`eholland@ltenyon.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 § 35S(j)(S)(C)(i)(IlI), Lupin offers to
`provide confidential access to certain information fiom its ANDA No. 20602? for the sole and
`exclusive purpose of determining whether an infiingement 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 35S(j)(5)(C)(i)(II1) 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 secrem and other confidential
`business infonnation." 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
`(I)
`proprietary ANDA No. 206027 to attorneys fiotn one outside law firm representing Bausch &
`Lomb andfor 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 Senja employees, outside scientific consultants, andlor other
`outside counsel retained by Bausch & Lomb or Senju, without the prior written consent of Lupin.
`
`As provided by § 355(j)(5)(C)(i)(III), the designated outside law firm
`(3)
`representing Bausch & Lomb andfor Senju shall make use of the Confidential Lupin Information
`for the sole and exclusive purpose of determining whether an action refened to in §
`355(j)(S)(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 firture or pending
`
`Page 3 of 23
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`Page 3 of 23
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`;"°f3,,m,
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`Kenyon 8cKcnyon
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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
`andfor Senju agrees to take all measures necessary to prevent unauthorized disclosure or use of
`the Confidential Lupin Information, and that all Confidential Lupin Infonnation 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 andfor their outside law firm any interest in or license for the
`Confidential Lupin Infonnation.
`
`The designated outside law firm representing Bausch & Lomb andfor
`(5)
`Senju shall, within thirty-five (35) days from t]1e 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 andfor Senju shall return all Confidential Lupin Information
`to Lupin before any infringement suit is filed by Bausch & Lomb andfor Senju, if suit is
`commenced before this 35-day period expires. In the event that Bausch & Lomb andfor Senju
`opts to file suit, none ofthe 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 ofany 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 andfor 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
`infi-ingement of U.S. Patent No. 8,669,290, or to the validity or enforceability of that patent.
`
`The attorneys from the designated outside law firm representing Bausch &
`(7)
`Lornb andfor Senju shall acknowledge in writing their receipt ofa copy ofthese 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 andfor Senju to any person not authorized to receive such
`Confidential Lupin Information pursuant to this Offer ofConfidential Access, then the designated
`outside law firm representing Bausch & Lomb andfor 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 Infonnation.
`
`Page 4 of 23
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`Page 4 of 23
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`P5835
`EH:
`,3 2014
`
`Kcnyon&£Kenyon
`
`Section 35S(j}{5)(C)(i)(III} provides that any request for access that Bausch & Lamb
`andfor Senju makes under this Offer of Confidential Access “shall be considered acceptance of
`the ofier 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 andfor Senju requests
`access to Confidential Lupin Information, they necessarily accept the terms and restrictions
`outlined above. Written notice requesting access under this Offer ofConfidential Access should
`be made to:
`
`Elizabeth J. Holland
`KENYON & KENYON LLP
`
`One Broadway
`New York, NY 10004-1007
`ehollgg@genyon.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 er seq., pursuant to
`21 U.S.C. § 355(j)(5)(C).
`
`Very truly yours,
`
`
`
` Elizabeth
`olland
`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. 8,669,290 Is Invalid, Unenforceable andfor Not Infiinged by the Manufacture, Use or Sale
`of Lupin Limited’s Proposed Bromfenac Ophthalmic Solution 0.07%
`
`Page 5 of 23
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`Page 5 of 23
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`
`
`Lupin Limited’s Detailed Statement of the Factual and Legal Bases for Its Opinion That
`U.S. Patent No. 8,669,290 Is Invalid, Unenforceable andfor Not Infringed by the
`Manufacture, Use or Sale of Lupin Limited’s Proposed Bromfenac Ophthalmic Solution
`0.07%
`
`Pursuant to Section 505(i)(2)(B)(ii) of the Food, Drug and Cosmetic Act (codified at 21
`
`U.S.C. § 35S(i)(2)(B)(ii)), and 2] C.F.R. § 314.9S(c), this is the detailed statement ofLupin
`
`Limited (“Lupin”) ofthe factual and legal bases for its opinion that U.S. Patent No. 8,669,290
`
`(“the ’290 patent”) is invalid, unenforceable, andfior 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 8,669,290
`
`The '290 patent, entitled “AQUEOUS LIQUID PREPARATION CONTAINING 2-
`
`AMINO-3-(4-BROMOBENZOYL)PHENYLACETlC ACID,” issued on March I 1_. 2014 from
`
`U.S. Application Serial No. l3X687,242, which was filed on November 28, 2012 as a division of
`
`U.S. Application Serial No. 133353.653 (now U.S. Patent No. 8,497,304), which was filed on
`
`January I9, 2012 as a division of U.S. Application Serial No. l0i'S25,006 (now U.S. Patent No.
`
`8,129,431), which was filed on March 28, 2005 as a U.S. national phase application ofPCT
`
`Application No. PCTlJP2004/000350, which was filed on January 16, 2004, and claims the
`
`benefit ofJapanese Application No. 20034 2427, which was filed on January 2 I, 2003. The
`
`'290 patent lists Shirou Sawa and Shuhei Fujita as inventors, and is assigned on its face to Senju
`
`Pharmaceutical C0,, Ltd. According to the Orange Book listing for Prolensa, the ’290 patent will
`
`expire on January 16, 2024.
`
`A.
`
`Claims of the ’290 Patent
`
`The ‘Z90 patent issued with 30 claims, which are reproduced below:
`
`Page 6 of 23
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`Page 6 of 23
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`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
`pharmacological ly acceptable salt thereof or a hydrate thereof, wherein the hydrate is at least one
`selected from a U2 hydrate, 1 hydrate, and 3E2 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;
`and wherein said stable liquid preparation is formulated for ophthalmic administration.
`
`2. The aqueous liquid preparation according to claim I, further comprising a quaternary
`ammonium salt.
`
`3. The aqueous liquid preparation according to claim I, 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 wfv % to about 0.05 wfv %; 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 wfv %.
`
`5. The aqueous liquid preparation according to claim 4, wherein the concentration of the
`2—arnino-3-(4-brornobenzoyl)phenylacetic acid sodium salt is about 0.1 wlv %.
`
`6. The aqueous liquid preparation according to claim I, wherein the pH is from about 7.5
`to about 8.5.
`
`7. The stable aqueous liquid preparation of claim I, wherein the stable aqueous liquid
`preparation consists essentially of: (a) 2-amino-3-(4-bromobenzoyflphenylacetic acid sodium
`salt, (13) tyloxapol, (c) boric acid, (cl) 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~
`am ino-3-(4-bromoben2:oyl)phenylacetic acid sodium salt is from about 0.02 w./V % to about 0.].
`wfv %.
`
`3. 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 U2 hydrate, 1 hydrate, and 3.32 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;
`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.
`
`9. The aqueous liquid preparation according to claim 8, further comprising a quaternary
`ammonium salt.
`
`Page 7 of 23
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`Page 7 of 23
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`10. The stable aqueous liquid preparation of claim 8, 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.
`
`I I . The aqueous liquid preparation according to claim 8, wherein the concentration of
`tyloxapol is from about 0.01 wfv % to about 0.05 wfv %; 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 wlv %.
`
`12. The aqueous liquid preparation according to claim I I, wherein the pH is from about
`7.5 to about 8.5.
`
`13. The stable aqueous liquid preparation of claim 8, wherein the stable aqueous liquid
`preparation consists essentially of: (a) 2-arnino-3-(4-bromobenzoy|)phenylacetic acid or a
`pharmacologically acceptable salt thereof or a hydrate thereof, wherein the hydrate is at least one
`selected from a U2 hydrate, l hydrate, and 3f2 hydrate; (b) tyloxapol; (c) boric acid; (d) sodium
`tetraborate; (e) EDTA sodium salt; (0 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 wfv % to about 0.] wfv %.
`
`14. 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 IE2 hydrate, 1 hydrate, and 3,52 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.
`
`15. The aqueous liquid preparation according to claim 14, further comprising a
`quaternary ammonium salt.
`
`16. The aqueous liquid preparation according to claim 14, wherein the first component is
`a 2-amino-3-(4-bromobenzoyI)phenyIacetic acid sodium salt.
`
`I7. The aqueous liquid preparation according to claim 16, wherein the concentration of
`tyloxapol is from about 0.01 wfv % 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 wfv %.
`
`18. The aqueous liquid preparation according to claim 17, wherein the pH is from about
`7.5 to about 8.5.
`
`19. The stable aqueous liquid preparation of claim 14; 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 112 hydrate, 1 hydrate, and 322 hydrate; (b) tyloxapol; (c) boric acid; (d) sodium
`tetraborate; (e) EDTA sodium salt; (i) benzalkonium chloride; (g) polyvinylpyrrolidone; and (h)
`sodium sultite; wherein the concentration of the 2-amino-3-(4-bromobenzoyl)phenylaeetic acid
`sodium salt is fiom about 0.02 wfv % to about 0.] wfv %.
`
`3
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`Page 8 of 23
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`Page 8 of 23
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`20. The stable aqueous liquid preparation of claim l4, 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.
`
`21. The aqueous liquid preparation according to claim 20. fimher comprising a
`quaternary ammonium salt.
`
`22. The stable aqueous liquid preparation of claim 20; 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.
`
`23. The aqueous liquid preparation according to claim 20, wherein the concentration of
`tyloxapol is from about 0.0] wfv % to about 0.05 wfv %; and wherein the first component is a 2-
`amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt, wherein the concentration of the 2-
`arnino-3-(4-bromobenzoyDphenylacetic acid sodium salt is from about 0.0] to about 0.2 wiv %.
`
`24. The aqueous liquid preparation according to claim 23, wherein the pH is from about
`7.5 to about 8.5.
`
`25. The stable aqueous liquid preparation of claim 20, wherein the stable aqueous liquid
`preparation consists essentially of: (a) 2-amino-3-(4—bromobenzoyl)phenylacetic acid or a
`phannacologically acceptable salt thereof or a hydrate thereof, wherein the hydrate is at least one
`selected from a IE2 hydrate, I hydrate, and 3!}! hydrate; (b) tyloxapol; (c) boric acid; (d) sodium
`tetraborate; (e) EDTA sodium salt; (D 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.] wfv %.
`
`26. The aqueous liquid preparation of claim 1, wherein the aqueous liquid preparation
`further satisfies the preservative efficacy standard of EP—criteria B of the European
`Phannacopoeia as follows: viable cell counts of bacteria (S. aureus, P. aeruginosa) 24 hours and
`7 days after inoculation decrease to not more than III 0 and not more than H1000, respectively,
`and thereafter, the cell count levels off or decreases; and viable cell count of fimgi (C. aIb:’can.r,
`A. niger) 14 days after inoculation decreases to not more than Ill 0, and thereafter, the cell count
`keeps the same level as that of I 4 days after inoculation.
`
`27. The aqueous liquid preparation of claim 8, wherein the aqueous liquid preparation
`fimher satisfies the preservative efficacy standard of EP—criteria B of the European
`Pharmacopoeia as follows: viable cell counts of bacteria (3. oureus, P. aeruginosa) 24 hours and
`7 days after inoculation decrease to not more than U10 and not more than H1000, 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 14, 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/ I 000, respectively,
`4
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`Page 9 of 23
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`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 H10, and thereaiter, the cell count
`keeps the same level as that of 14 days after inoculation.
`
`29. The aqueous liquid preparation of claim 20, wherein the aqueous liquid preparation
`fimher satisfies the preservative efficacy standard of EP-criteria B of the European
`Pharmacopoeia as follows: viable cell counts of bacteria (S. aureus, P. aerugfnosa) 24 hours and
`7 days after inoculation decrease to not more than H10 and not more than H1000, respectively,
`and thereafter, the cell count levels off or decreases; and viable cell count of fungi (C. albicans,
`A. nfger) 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 aiter inoculation.
`
`30. The aqueous liquid preparation of claim 22, 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. aareus, P. aerugfnosa) 24 hours and
`7 days after inoculation decrease to not more than 1:’ I 0 and not more than 1! I 000, respectively,
`and thereafter, the cell count levels off or decreases; and viable cell count of fimgi (C. afbfcans,
`A. nfger) l4 days after inoculation decreases to not more than 1:’ l 0, and thereafter, the cell count
`keeps the same level as that of 14 days after inoculation-
`
`B.
`
`Specification of the ‘Z90 Patent
`
`The specification of the '290 patent acknowledges that ophthalmic solutions containing
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`bromfenac were described in the prior art. (‘Z90 patent, col. 1, ll. 26-49.) The specification
`
`quotes a prior art reference (Japanese Patent No. 2,954,356, corresponding to U.S. Patent Nos.
`
`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
`
`considered to be incompatible” with non~steroidal anti-inflammatory drugs (NSAIDS) with
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`acidic groups (e.g., 3 —COOH group) because “[t]hese preservatives lose their ability to fimction
`
`as they form complexes with the charged drug compounds.“ (’290 patent, col. 1, l. 64 — col. 2, 1.
`
`5.) Brom fenac is an NSAID with a —COOH group. Thus, the specification presents the problem
`
`to 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 fonn a complex (:'.e., with improved
`
`stability).
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`Page 10 of 23
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`Page 10 of 23
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`
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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
`
`such as polyethylene glycol monostearate (especially polyoxyl 40 stearate) in the ophthalmic
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`solution. (’290 patent, col. 2, II. 35-49 and col. 5, ll. 22-29.) The specification describes an
`
`experiment (Experimental Example I) in which formulations containing bromfenac, BAC and
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`three different surfactants (polysorbate 80, polyoxyl 40 stearate, and tyloxapol) were prepared
`
`and tested for stability. (‘290 patent, col. 7, l. 8 — col. 8, l. 2.) Two formulations containing
`
`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
`
`considered to be part of the invention, as indicated by the fact that it was referred to as
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`“Comparison Example I."
`
`C.
`
`Prosecution History of the ’290 Patent
`
`As noted above, there are three U.S. applications in the chain leading to the ’290 patent.
`
`During prosecution of the first of these applications (U.S. Application Serial No. 10f525,006),
`
`the PTO Examiner cited prior art describing ophthalmic solutions containing bromfenac, BAC
`
`and polysorbate 80 as a surfactant, as well as prior art showing that tyloxapol and polysorbate 80
`
`were both known as surfactants in ophthalmic solutions, and rejected the claims on the basis that
`
`it would have been obvious to substitute tyloxapol for polysorbate 80. (May 6, 201 1 Office
`
`Action at 2-3 [‘‘It would have been obvious to one of ordinary skill in the art at the time ofthe
`
`invention to interchange polysorbate 80 and tyloxapol. The motivation comes from the teaching
`
`of Guy et al. that both compounds are non-ionic surfactant surface active agents. Hence, a
`
`skilled artisan would have had a reasonable expectation of successfully producing a composition
`
`with similar efficacy and results."].) In response, applicants argued that they had discovered that
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`Page 11 of 23
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`Page 11 of 23
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`
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`substituting tyloxapol for polysorbate 80 produced unexpected results (r'.e., improved stability)
`
`and pointed to Experimental Example I from the specification to support this assertion. (See
`
`September 6, 20] I Amendment at 7-3 [“The present inventors have discovered that tyloxapol
`
`has an unexpected property in stabilizing an aqueous solution of bromfenac in comparison with
`
`polysorbate 80. Please see the description of Experimental Example I and Table 1 on pages 14-
`
`16 of the specification."].) The PTO Examiner accepted this argument, and allowed the claims
`
`of that application (U.S. Application Serial No. l0f52S,006) on the basis of the alleged
`
`unexpected results. (December 23, ml I Notice of Allowability at 3-4 [“The present inventors
`
`have discovered that tyloxapol has an unexpected property in stabilizing an aqueous solution of
`
`bromfenac in comparison with polysorbate 80. Please see the description of Experimental
`
`Example 1 and Table 1 on pages l4—l6 of the specification.’‘].) This application issued as U.S.
`
`Patent No. 8,129,431.
`
`The next application in the chain leading to the ‘Z90 patent is U.S. Application Serial No.
`
`13,853,653. During the prosecution of this application, applicants pursued claims to aqueous
`
`liquid preparations including polyoxyl 40 (as opposed to tyloxapol).
`
`The claims were allowed
`
`based on a declaration submitted by one of the inventors (Shirou Sawa) that set forth the
`
`experiments included as Experimental Examples 1-3 of the specification, including Example 1
`
`showing that a specific ophthalmic solution including polyoxyl 40 stearate was more stable than
`
`a specific ophthalmic solution containing polysorbate 80. (June 7, 2013 Notice of Allowability
`
`at 8-9.) This application issued as US. Patent No. 8,497,304.
`
`The final application in the chain leading to the ‘290 patent is US. Application Serial No.
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`131687.242. During the prosecution of this application, applicants again pursued claims to
`
`aqueous liquid preparations including tyloxapol. In allowing the claims, the PTO Examiner
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`
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`explained how the claims were allowable over U.S. Patent No. 6,383,471 to Chen, which she
`
`referred to as the closest prior art of record. (January I5, 2014 Notice of Allowability at 4-6.)
`
`However, the Chen reference was not substantively discussed during prosecution of U.S.
`
`Application Serial No. l3f687,242. The PTO Examiner also pointed to portions of Experimental
`
`Examples I-3 pertaining to ophthalmic solutions containing polyoxyl 40 stearate, despite the fact
`
`that the allowed claims all required the inclusion of tyloxapol. not polyoxyl 40 stearate. (January
`
`15, 2014 Notice of Allowability at 6.) This application issued as the ’290 patent.
`
`II.
`
`NON-IN FRINGEMENT ANALYSIS
`
`A.
`
`Relevant Law
`
`1.
`
`Claim Construction
`
`To ascertain the meaning of claims, the claims, the specification and the prosecution
`
`history must be considered. Markman v. We.vrv:'ew Instruments, Inc, 52 F.3d 967, 979 (Fed. Cir.
`
`1995) (en banc), aff'd, 517 U.S. 370 (1996); see also Boss Control, Inc. v. Bombardier, Ina, 4l0
`
`F.3d 1372, 1376 (Fed. Cir. 2005).
`
`In interpreting a claim, one looks first to the intrinsic evidence
`
`of record, 1‘. e., the patent itself, including the claims, the specification and the prosecution
`
`history. See Markman, 52 F.3d at 979; see also, Phillips v. AWH Corp, 415 F.3d 1303, l3l2
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`(Fed. Cir. 2005). “Such intrdnsic evidence is the most significant source of the legally operative
`
`me