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`translation of the following document, attached hereto:
`Saishin no shinyal(u_2001
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`CROSSLINGUAL, LLC
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`before me, Q52 S[\.)\$g_ bi ?~J9sUL..
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`ALAMEDACOUNTY
`ConInissionExpiresAPR11,2017
`
`PAGE 1 OF 11
`
`SENJU EXHIBIT 2039
`
`INNOPHARMA v SENJU
`
`IPR20l5-00903
`
`

`
`
`
`Salkln no shin'yaku New drugs in Japan.
`2001
`General Collection
`CW .772 8132
`2001-09-07 13 57 43
`
`.‘
`
`
`
`Negw Eimgg fim1fl@g@@£m
`
`
`
`
`
`" I
`PROPERTY OF THE.
`
`NATIONAL ""
`
`
`LIBRARY or
`‘I’.
`
`
` "1 MEDICIN
`
`
`PAGE 2 OF 11
`
`

`
`Preface to “New Drugs in Japan 2001”
`
`During the half-century since 1949, “New Drugs in Japan” has annually collated, edited and published
`information on newly approved and newly marketed pharmaceuticals (for prescription and non-prescription use) in
`the broadest possible scope.
`On the occasion of the 50th anniversary of the inaugural issue in 2000, the character of a “new drug yearbook”
`introducing pharmaceuticals newly put on the market during the previous year was more sharply defined, and a new
`start was made by updating listing methods, classifications, and appearance, as well as enlarging the format to B5-
`size. “New Drugs in Japan 2001” — the second volume since the relaunch — is an introductory new drug yearbook
`which collects, classifies, and arranges in the broadest possible scope the new drugs (for prescription and non-
`prescription use) that were approved and newly marketed during the previous year (2000) within Japan.
`The editorial guidelines are as follows.
`1. Classification method
`Listed pharmaceuticals are broadly classified into: I. pharmaceuticals containing new active ingredients (new
`substances) (excluding new administration routes and new standards); II. newly marketed prescription drugs
`(excluding the pharmaceuticals containing new active ingredients of I); and III. non-prescription drugs. Prescription
`drugs are arranged by pharmacoefficacy classification in conformity with the Japan Standard Commodity
`Classification (June 1990 Revision), and non-prescription drugs broadly conform to the order of the “Standards for
`manufacturing (importation) approval of non-prescription drugs” with suitable adjustments.
`2. Listing system
`With respect to pharmaceuticals containing new active ingredients, not only are package inserts (including
`reference literature) recorded for the pertinent pharmaceuticals, but also the development background,
`reexamination period, basis for drug price calculation, and so on.
`With respect to other prescription drugs, there is listing of efficacy/effects, usage,/dosage, foreign name of
`pertinent product, regulation, manufacturing (import sales) origin / sales (marketing) origin, approval date, sales
`initiation date, date of price listing, price standard listing pharmaceutical code, and packaging, and this is done by
`unit of generic name classified/arranged in the order of pharmacoefficacy classification.
`Beginning with this issue, we have created a page for introducing pharmaceuticals with newly added efficacies
`(prescription drugs that have been given added efficacy during January-December 2000).
`With respect to non-prescription drugs, there is listing of manufacturing (import sales) origin / sales (marketing)
`origin, approval date, sales initiation date, product characteristics, ingredients and quantities, additives, usage/dosage,
`and packaging,
`3. Descriptive content
`“Cautions for use” pertaining to pharmaceuticals containing new active ingredients are in principle recorded as
`in the description of the package insert, and are omitted with respect to other new drugs. The method of referring to
`back issues of this publication was discontinued. The so-called commentary which had been included up to the 50th
`issue is not included in the editing of package insert compliance documentation.
`
`
`As described above, this publication was created as a “new drug yearbook” of what was newly approved and
`marketed over a one-year period, and we await the comments and requests of all our readers with respect to this
`volume.
`This volume was edited based on the studies and information gathering conducted by our company with respect
`to the various pharmaceutical manufacturing / sales (marketing) companies. Hereafter, we will request a still greater
`number of pharmaceutical companies to cooperate with our studies.
`Finally, we would like to express our deep gratitude to all our readers and all the pharmaceutical companies that
`have cooperated with our studies over this past half-century to the present, and to Tohoku University Honorary
`Professor Mitsuru Ozawa who has written for us over the half century since the inaugural issue, and who also
`provided useful advice on the occasion of this edition.
`We appeal for the cooperation and support of everyone as we seek to further enhance this publication.
`
`May 2001
`
`– i –
`
`Yakuji Nippo Limited
`
`PAGE 3 OF 11
`
`

`
`(Remarks)
`Product characteristics
`
`(1) It is an ophthalmic solution of Acitazanolast which is
`an in viva activating metabolite of the oral anti-
`allergic agent Tazanolast.
`
`(2) Improves subjective and objective symptoms such as
`pruritus and conjunctival chemosis due to allergic
`conjunctivitis.
`(3) Inhibits release of platelet-activating factors (PAF).
`histamine. leukotriene B4. leukotriene D4 (in vitro;
`rat. guinea pig).
`
`Bromfenac sodium hydrate
`
`iii
`' N .
`J
`S
`dardC mmodi Cl
`ass canon 0
`apan tan
`Non-steroidal anti-inflammatory ophthalmic agent
`0 871312’
`Bronuck ophthalmic solution — Bronuck (Instructions) (Notations) Senju Pharmaceutical. Co. (manufacture) /
`Takeda Pharmaceutical Co. (marketing)
`- Approval date
`
`roval No. 1 March 10, 2000
`T
`
`July 3,2000
`
`Drug price listed
`May 2.2000
`
`Drug price code
`13l9743Ql025
`
`2l200AMZ00l68
`
`[Development Background]
`With respect to treatment of ocular inflammation.
`both steroidal ophthalmic agents and non-steroidal anti-
`inflammatory drug (NSAID) ophthalmic agents are
`currently in general use. However. compared to steroidal
`ophthalmic agents.
`there are fewer types of NSAID
`ophthalmic agents. and options are limited. Thus.
`development of NSAID ophthalmic agents having broad
`efiicacy and strong anti-inflammatory action relative to
`inflammatory ailments of the external eye and anterior
`eye is desirable.
`Bromfenac sodium hydrate, which is the active
`ingredient of Bronuck
`ophthalmic
`solution, was
`discovered by the A. H. Robins Co. (now the Wyeth-
`Ayerst Co.) as a novel NSAID that powerfirlly inhibits
`production of prostaglandin which is an inflammatory
`mediator. By modifying bromine at the 4"‘ position of the
`benzoyl group of Amfenac. which is the basic skeleton.
`this drug strives to reinforce anti-inflammatory action
`and sustain analgesic action.
`Focusing on this strong prostaglandin production
`inhibiting action. Senju Pharmaceutical Co.. Ltd.
`proceeded with development of this drug from 1987.
`Bronuck ophthalmic solution was approved in March
`2000 as a symptomatic therapeutic agent that is effective
`with two ocular instillations per day with respect to
`blepharitis,
`conjunctivitis,
`scleritis
`(including
`episcleritis), and postoperative inflammation.
`[Reexamination Period] 6 years
`
`
`[Contraindications (do not administer to the following
`patients)]
`
`Patients with a previous history of hypersensitivity to the
`ingredients of this drug
`
`PAGE 4 OF 11
`
`Com n osition / Pro a erties
`
`Ingredients / content Bromfenac sodium hydrate 1 mg
`in 1 ml
`
`Boric acid, borax, dry sodium
`sulfite, sodium edetate, povidone,
`polysorbate 80, benzalkonium
`chloride
`
`33:
`
`[Eflicacy I Effects]
`Symptomatic treatment of inflammatory ailments of
`external
`eye
`and
`anterior
`eye
`(blepharitis.
`the
`conjunctivitis,
`scleritis
`(including episcleritis),
`and
`postoperative inflammation)
`[Usage I Dosage]
`Ordinarily, 1-2 drops per administration. and 2
`ocular instillations per day.
`[Cautions for Use]
`1. Important Basic Cautions
`(1) Keeping in mind that
`treatment by this drug is
`symptomatic treatment rather than causal treatment.
`and that
`it
`is reported that serious liver damage
`(including death) has been observed in patients
`subjected to long-term administration of 1 month or
`more with the oral agent of bromfenac sodium,
`continuous administration for 4 weeks or more is not
`
`conducted in principle. Although the aforementioned
`adverse effects observed with the foreign oral agent
`were due to long-term administration exceeding the
`approved usage
`and dosage,
`sales have been
`voluntarily suspended.
`(2)As there is risk that eye infection may become
`subclinical, in case of use on inflammation resulting
`fi'om infection. administration is to be conducted
`
`carefully with adequate observation.
`
`

`
`‘.':.°°'"""
`
`3
`
`.
`§ ‘°
`
`e..o :
`
`tlon 6
`Bromfenacsodiumhydrateconcert
`
`
`
`
`2. Adverse Effects
`At the time of approval, adverse eifects had been
`observed in 16 out of a total of 423 cases (3.78%).
`With respect to the content of adverse effects, there
`were
`3 cases of blepharitis
`(0.71%),
`3
`cases of
`conjunctival hyperemia (0.71%), 3 cases of stinging
`(0.71%), 3 cases of ocular pain (temporary) (0.71%).
`Zcases of corneal
`inflammation (0.47%),
`1 case of
`conical epithelial abrasion (0.24%), 1 case of superficial
`plmctate
`keratitis
`(0.24%),
`1
`case of
`follicular
`conjunctivitis (0.24%). 1 case of pruritus (0.24%), and l
`7/-,_
`case of burning sensation (eyelids) (0.24%) (at the time
`A ‘win
`-~ ~‘ ~- ~'
`us-.\\~«~..v .\..:
`ofapproval)‘
`_t2
`:4
`¢8~\(hours)
`'_
`‘ " ‘ o
`The following adverse effects were observed in the
`Hours aflerocular imtrllation
`-
`.
`foregoing study
`[Chum] Results]
`0.1% to less than 5%
`A summary of results with respect to 291 cases
`including double-blind comparative testing are shown in
`hyperemia’
`conjunctiva]
`Ocular’:
`blepharitisi
`stinging, ocular pain (temporary), corneal inflammation, h
`bl
`corneal epithelial abrasion, superficial punctate keratitis,
`t e ta e‘
`follicular conjtmctivitis. pruritus, and burning sensation
`_oI:r the most P3?‘ daily d°Sage_a,nd afiminiggfion
`(eyelids)
`pen
`were
`1
`op per
`administration
`2
`*When manifested, administration is suspended.
`adminislmtions per day over a 2'week period‘
`3. Administration to Pregnant, Parturient, and
`Table‘ Chm“! Effects b Aliment
`Nursing Women
`Administration is to he conducted to pregnant
`woman or women who may have conceived and to
`women who are nursing only when it is judged that the
`benefits of treatment outweigh the risks.
`(The safety of administration during pregnancy and
`
`0 l
`o
`
`\\ \\\\\\».\o:s\\\\.»
`1
`'5‘
`
`lactation has not been established.)
`
`efl-ecnveness
`
`[Pharmacoeflicacy and Pharmacology]
`4. Administration to Children
`Safety relative to children has not been established 1. Pharmacological Action
`(there is little experience with use)_
`(1) Anti-inflammatory action relative to experimental
`5, Cautions for Use
`conjunctiva] chemosis in ratsz)
`(1) Administration route; only to be used for ocular
`It was observed that Bronuck ophthahnic solution
`instillation
`exhibited
`anti-inflammatory
`action
`relative
`to
`(2) At time of administration: during ocular instillation,
`experimental acute conjunctiva] chemosis in rats
`take care so that the lip of the container does not
`induced by arachidonic acid and ca1’ageenin-
`directly contact the eye,
`(2) Inhibitory effects relative to increases in aqueous
`[Phat-rnacokint-tics]
`humor protein concentration in rabbits after anterior
`(Reference)
`chamber paracentesis or after laser irradiation”
`Intraocular Migration <rabbits>')
`It was observed that Bronuck ophthalmic solution almost
`In testing wherein ocular instillation of 0_05 nil, of completely inhibited increases in aqueous humor protein
`0.1% "C-bromfenac sodium hydrate ophthalmic solution concentration
`in
`rabbits
`after
`anterior
`chamber
`was conducted once a day is both eyes of rabbits, and paracentesis or afier laser irradiation.
`radioactivity was measured after 15 minutes, 30 minutes, 2. Mechanism of Action
`and 1. 2, 4, 8, 32. 24, 48. and 72 hours, elevated values In tests using rabbit
`iris-ciliary bodies” and bovine
`were observed in the cornea, conjunctiva, and anterior Seminal Vesicles. it Was coniinlled that inhibitory action
`sc1era_
`was
`exhibited against production of prostaglandin
`At 72 hours after ocular instillation, all ocular tissue inflammatory mediators via cyclooxygenase (in ritro).
`except for the lens was below the detection limit (0.1 ng [Physicochemical
`Findings Relative
`to Active
`eq./g or ml).
`Ingredients]
`Generic name: Bromfenac Sodium Hydrate (JAN)
`
`PAGE 5 OF 11
`
`

`
`Chemical name: sodium 2-amino-3-(4-bromobenzoyl)
`phenylacetate sesquihydrate
`Molecular formula: C15H11BrNNaO3 · 1½ H2O
`Molecular weight: 383.17
`Structural formula:
`
`
`Properties: Bromfenac Sodium Hydrate is an odorless
`crystalline powder of yellow-orange color.
`It is freely soluble in water, soluble in methanol, slightly
`soluble in ethanol anhydride, and practically insoluble in
`acetonitrile or ether.
`[Packaging]
`5 mL × 10, 5 mL × 50
`[Principal Literature]
`1) Mitsuyoshi Isaka et al : Pharmacokinetics, 14 (1) 32, 1999
`2) Takahiro Ogawa et al : Journal of Japan Ophthalmology Society, 99, 406, 1995
`[Storage Method] Room temperature storage
`[Expiration] To be used by the expiration date displayed
`on the exterior package (even before expiration, to be
`used promptly after opening).
`
`
`
`●According to package insert prepared in May 2000
`[Drug Price] 0.1% 1 mL 139.00 yen, price
`determination by comparable drug (comparable drug:
`Niflan ophthalmic solution (Pranoprofen))
`[Comments]
`Product Characteristics
`to
`respect
`(l) Efficacy has been confirmed with
`inflammatory ailments of the external eye and the
`anterior eye (efficacy rate 77.3%)
`(2) Anti-inflammatory action is exhibited against post-
`operative inflammation, and it inhibits occurrence of
`aqueous humor protein (flare).
`(3) Remission of symptoms is observed by the third day
`of administration with respect
`to
`inflammatory
`ailments of the external eye.
`(4) Anti-inflammatory action is exhibited with respect to
`experimental conjunctival chemosis
`(rats) end
`experimental post-operative inflammation (rabbits).
`(5) Cyclooxygenase is blocked, and production of PG
`inflammatory mediators beginning with prostaglandin
`(PG) E2 is inhibited (rabbit, bovine in vitro).
`(6) Efficacy is observed with 2 ocular instillations per
`day.
`
`
`
`PAGE 6 OF 11
`
`

`
`Saiknn no shin'yaku New drugs in Japan.
`2001
`General Collection
`QV 772 8132
`2001-09-07 13:57 43
`
`
`
`PROPERTY OFHTHEH}
`NATIONAL
`LIBRARY OF
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