CROSS
`LINGUAL
`
`CROSSLINGUAL, LLC
`3736 Fallon Road, Suite 226
`Dublin, CA 94568
`Tel: 206-851-7932
`
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`
`AFFIDAVIT OF TRANSLATION
`
`I, Alan F. Siegrist, of CROSSLINGUAL, LLC, hereby declare that:
`1.
`I am fluent in Japanese and English.
`2.
`I am an active member of the American Translators Association and a Certified
`
`Translator of Japanese to English.
`
`3. The English translation attached to this declaration is an accurate and correct
`translation of the following document, attached hereto:
`
`2002.6 - 2nd Edition [Bronuck Package Insert]
`
`I declare that the foregoing is true and correct to the best of my knowledge.
`
`Executed on October 29, 2015
`
`Certification #63788
`
`Alan F. Siegrist, CT
`CROSSLINGUAL, LLC
`ATA Member No. 31889
`
`A notary public or other officer completing this certificate verifies only the identity of the individual who signed the
`documents to which this certificate are attached, and not the truthfulness, accuracy, or validity of that document.
`
`
`
`
`
`evidence to be the person whose name is subscribed to the within instrument and acknowledged to me
`that he executed the same in his authorized capacity, and that by his signature on the instrument the
`person, or the entity upon behalf of which the person acted, executed the Instrument.
`
`State of California, County of
`On
`personally appeared alg/l
`
`+f‘& GSTK
`before me,
`gr; 5:‘
`
`‘
`'
`
`i Cr
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`who proved to me on the basis of satisfactory
`
`‘F,
`
`I certify under PENALTY OF PERJURY under the laws of the State of California that the foregoing
`paragraph is true and correct.
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`Witness my hand and fficial seal.
`
`
` JACQUEUNE IILEI counts:
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`COMM. _e2i05_829 g
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`
`
`
`.5 N19
`
`Page 1 of 5
`
`LUPIN v. SENJU
`IPR2015—0l100
`
`SENJU EXHIBIT 2112
`
`

`
`‘June 2002 — Revised (Second Edition)
`May 2000 — Created
`Storage Method: Room temperature storage
`Expirmiui:
`Tobeusedbytheexpirationdatedisplayedontheexteriorpackage
`(even before expiration, tobeusedpromptlyafieropening).
`
`Japan Standard Commodity Classification No. 871319
`2l200AMZ00l68
`
`1997
`
`July 2000
`J
`
`Non-steroidal anti-inflammatory ophthalmic agent
`
`Designated Prescription Drug BRONUCK° OPHTHALMIC SOLUTION
`Bromfenac sodium h
`te o hthalmic solution
`
`The following adverse effects were observed in the foregoing
`o
`
`0.1% to less than 5%
`Blepharitis, eonjtmctival hyperemia, stinging, ocular pain
`(temporary), eorneal inflammation, corneal epithelial abrasion,
`
`S
`
`. K
`
`[Contraindications (do not administer to the following
`patients)]
`Patients with a previous history ofhypersensitivity to the
`'
`- dients ofthis dru
`
`
`
`
`Bmic acid,borax,drysodinmsulfite, sodium
`edetate, povidone, polysorbate 80,
`bennlkonium chloride, sodium h
`
`3. Administration to Pregnant, Parturient, and Nursing
`Women
`
`
`
`Administration is to be 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 lactation
`has not been established.)
`4. Administration to Children
`
`Safety relative to children has not been established (there is
`little experience with use).
`5. Cautions for Use
`
`(1) Administration route: only to be used for ocular instillation
`(2) At time of administration:
`ocular instillation. take
`care so that the lip of the container does not directly contact
`the eye.
`[Pharmaeolrineties]
`(Reference)
`Intraocular Migration <rabbits>1)
`In testing wherein ocular instillation of 0.05 mL of 0.1% “C-
`bromfenac sodium hydrate ophthalmic solution was conducted
`once a day is both eyes of rabbits. and radioactivity was
`measured after 15 minutes. 30 minutes. and l. 2. 4. 8. 32. 24.
`48. and 72 hours. elevated values were observed in the cornea.
`conjunctiva. and anterior scleia.
`At 72 hours after ocular instillation. all ocular tissue except
`for the lens was below the detection limit (0.1 ng eq.:’g or
`.r§&:-gwmli
`Conn
`
` _I 9. I
`
`"Anterior" vitreo'ushumor
`' Blood
`
`
`
`
`
`
`
`Bmmfenacsodiumhydateconcentration
`
`‘_
`
`m [
`
`_
`_
`Eflicaey / Effects]
`Symptomatic treatment of inflammatory ailments of the
`external eye and anterior eye (blepharitis. conjunctivitis.
`scleritis
`(including
`episcleritis).
`and
`postoperative
`inflammation)
`[Usage / Dosage]
`Ordinarily.
`l-2 drops per administration. and 2 ocular
`instillations per day.
`[Cautious for Use]
`1. Important Basie 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 eflects observed with the foreign
`oral agent were due to long-term administration exceeding
`the approved usage and dosage. sales have been volimtarily
`suspended.
`(2) As there is risk that eye infection may become subclinical.
`in case of use on inflammation resulting from infection.
`administration is to be conducted carefully with adequate
`observation.
`2. Adverse Efleets
`
`At the time of approval. adverse eflects 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%).
`2 cases of
`corneal
`inflammation (0.47%).
`1 case of conical epithelial abrasion
`(0.24%). 1 case of superficial punctate keratitis (0.24%). 1 case
`of follicular conjunctivitis (0.24%). 1 case of pruritus (0.24%).
`and 1 case of burning sensation (eyelids) (0.24%) (at the time of
`approval).
`
`Page 2 of 5
`
`

`
`[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
`[Contact for Requesting Literature]
`Scientific Information Department
`Senju Pharmaceutical Co., Ltd.
`5-8, Hirano-machi 2-chome, Chuo-ku, Osaka-shi, Osaka
`
`Marketed by: Takeda Pharmaceutical Co., Ltd.
`
`1-1, Dosho-machi 4-chome,
`
`Chuo-ku, Osaka
`
`Package 02-075
`
`
`
`
`
`
`
`
`
`Efficacy rate (%) and
`effectiveness
`66.7 (6/9)
`63.2 (60/95)
`63.6 (7/11)
`86.4 (152/176)
`77.3 (225/291)
`
`relative
`
`to
`
`experimental
`
`[Clinical Results]
`A summary of results with respect to 291 cases including
`double-blind comparative testing are shown in the table.
`For the most part, daily dosage and administration period
`were 1 drop per administration and 2 administrations per day
`over a 2-week period.
`Table. Clinical Effects by Ailment
`Name of ailment
`Blepharitis
`Conjunctivitis
`Scleritis (including episcleritis)
`Postoperative inflammation
`Total
`[Pharmacoefficacy and Pharmacology]
`1. Pharmacological Action
`(1) Anti-inflammatory
`action
`conjunctival chemosis in rats2)
`It was observed that Bronuck ophthalmic solution exhibited
`anti-inflammatory action relative to experimental acute
`conjunctival chemosis in rats induced by arachidonic acid
`and carageenin.
`(2) Inhibitory effects relative to increases in aqueous humor
`protein concentration in rabbits after anterior chamber
`paracentesis or after laser irradiation2)
`It was observed that Bronuck ophthalmic solution almost
`completely inhibited increases in aqueous humor protein
`concentration in rabbits after anterior chamber paracentesis
`or after laser irradiation.
`2. Mechanism of Action
`In tests using rabbit iris-ciliary bodies2) and bovine seminal
`vesicles, it was confirmed that inhibitory action was exhibited
`against production of prostaglandin inflammatory mediators via
`cyclooxygenase (in vitro).
`[Physicochemical Findings Relative to Active Ingredients]
`Generic name:
`Bromfenac Sodium Hydrate (JAN)
`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
`
`
`
` Manufactured by: Senju Pharmaceutical Co., Ltd.
`
`
`5-8, Hirano-machi 2-chome,
`
`
`Chuo-ku, Osaka
`
`Page 3 of 5
`
`

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