CROSS
`LINGUAL
`
`CROSSLINGUAL, LLC
`3736 Fallon Road. Suite 226
`Dublin, CA 94568
`Tei: 205-851-7932
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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
`
`Transiator of Japanese to English.
`The English translation attached to this declaration is an accurate and correct
`
`translation of the following document, attached hereto:
`
`2000.5 - 1st Edition [Bronuck Package Insert]
`
`I declare that the foregoing is true and correct to the best of my knowledge.
`
`Executed on October 29, 2015
`
`Alan F. Sie-grist, CT
`CROSSLINGUAL, LLC
`ATA Member No. 31889
`
`Certification #63788
`
`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.
`
`__
`StateofCalifornia, Countyof Q0171 054? g
`afi‘-"&Lf\2F U/l
`On { &OlS
`e,
`before rn
`who proved to me on the basis of satisfactory
`personally appeared
`/l
`, glné
`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.
`
`I certify under PENALTY OF PERJURY under the laws of the State of California that the foregoing
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`paragraph is true and correct.
`
`Witness my hand and official seal.
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`Signature
`
`SENJU EXHIBIT 2 1 1 1
`
`Page 1 of 5
`
`SENJU EXHIBIT 2111
`INNOPHARMA v. SENJU
`IPR2015-00903
`
`

`
`May 2000 – Created (New Format, First Edition)
`
`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).
`
`(cid:45)(cid:68)(cid:83)(cid:68)(cid:81)(cid:3)(cid:54)(cid:87)(cid:68)(cid:81)(cid:71)(cid:68)(cid:85)(cid:71)(cid:3)(cid:38)(cid:82)(cid:80)(cid:80)(cid:82)(cid:71)(cid:76)(cid:87)(cid:92)(cid:3)(cid:38)(cid:79)(cid:68)(cid:86)(cid:86)(cid:76)(cid:191)(cid:70)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:49)o. 871319
`Approval No.
`21200AMZ00168
`Drug price listed
`May 2000
`Sales initiation
`July 2000
`International origin
`July 1997
`
`Non-steroidal anti-(cid:76)(cid:81)(cid:192)(cid:68)(cid:80)(cid:80)(cid:68)(cid:87)(cid:82)(cid:85)(cid:92)(cid:3)ophthalmic agent
`Designated Prescription Drug BRONUCK® OPHTHALMIC SOLUTION
`Bromfenac sodium hydrate ophthalmic solution
`
`The following adverse effects were observed in the foregoing
`study.
`
`0.1% to less than 5%
`Ocular† Blepharitis, conjunctival hyperemia, stinging, ocular pain
`(temporary), corneal (cid:76)(cid:81)(cid:192)(cid:68)(cid:80)(cid:80)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81), corneal epithelial abrasion,
`(cid:86)(cid:88)(cid:83)(cid:72)(cid:85)(cid:191)(cid:70)(cid:76)(cid:68)(cid:79) punctate keratitis, follicular conjunctivitis, pruritus,
`and burning sensation (eyelids)
`†When manifested, administration is suspended.
`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 (cid:69)(cid:72)(cid:81)(cid:72)(cid:191)(cid:87)(cid:86)(cid:3) (cid:82)(cid:73) 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: during ocular instillation, take
`care so that the lip of the container does not directly contact
`the eye.
`[Pharmacokinetics]
`(Reference)
`Intraocular Migration <rabbits>1)
`In testing wherein ocular instillation of 0.05 mL of 0.1% 14C-
`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 1, 2, 4, 8, 32, 24,
`48, and 72 hours, elevated values were observed in the cornea,
`conjunctiva, and anterior sclera.
`At 72 hours after ocular instillation, all ocular tissue except
`for the lens was below the detection limit (0.1 ng eq./g or ml).
`
`Cornea
`Conjunctiva
`Anterior sclera
`Anterior vitreous humor
`Blood
`Below detection limit
`
`Hours after ocular instillation
`
`(hours)
`
`Bromfenac sodium hydrate concentration
`
`Additives
`
`[Contraindications (do not administer to the following
`patients)]
`Patients with a previous history of hypersensitivity to the
`ingredients of this drug
`[Composition / Properties]
`Ingredients / content
`Bromfenac sodium hydrate 1 mg
`(in 1 ml)
`Boric acid, borax, dry sodium sulfite, sodium
`edetate, povidone, polysorbate 80,
`benzalkonium chloride
`Aqueous ophthalmic solution
`Clear yellow
`8.0–8.6
`Aseptic preparation
`
`Form of drug
`Color
`pH
`Other
`[E(cid:73)(cid:191)(cid:70)(cid:68)(cid:70)(cid:92)(cid:3)/ Effects]
`(cid:54)(cid:92)(cid:80)(cid:83)(cid:87)(cid:82)(cid:80)(cid:68)(cid:87)(cid:76)(cid:70)(cid:3) (cid:87)(cid:85)(cid:72)(cid:68)(cid:87)(cid:80)(cid:72)(cid:81)(cid:87)(cid:3) (cid:82)(cid:73)(cid:3) (cid:76)(cid:81)(cid:192)(cid:68)(cid:80)(cid:80)(cid:68)(cid:87)(cid:82)(cid:85)(cid:92)(cid:3) (cid:68)(cid:76)(cid:79)(cid:80)(cid:72)(cid:81)(cid:87)(cid:86)(cid:3) (cid:82)(cid:73) the
`external eye and anterior eye (blepharitis, conjunctivitis,
`scleritis
`(including
`episcleritis),
`and
`postoperative
`(cid:76)(cid:81)(cid:192)(cid:68)(cid:80)(cid:80)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:12)
`[Usage / 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,
`(cid:76)(cid:81)(cid:3) (cid:70)(cid:68)(cid:86)(cid:72)(cid:3) (cid:82)(cid:73)(cid:3) (cid:88)(cid:86)(cid:72)(cid:3) (cid:82)(cid:81)(cid:3) (cid:76)(cid:81)(cid:192)(cid:68)(cid:80)(cid:80)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3) (cid:85)(cid:72)(cid:86)(cid:88)(cid:79)(cid:87)(cid:76)(cid:81)(cid:74) from infection,
`administration is to be conducted carefully with adequate
`observation.
`2. Adverse Effects
`At the time of approval, adverse effects 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 (cid:86)(cid:88)(cid:83)(cid:72)(cid:85)(cid:191)(cid:70)(cid:76)(cid:68)(cid:79)(cid:3)(cid:83)(cid:88)(cid:81)(cid:70)(cid:87)ate keratitis (0.24%), 1 case
`of follicular conjunctivitis (0.24%), 1 case of pruritus (0.24%),
`and l 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
`
`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
`[Pharmaco(cid:72)(cid:73)(cid:191)cacy 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 (cid:76)(cid:81)(cid:192)(cid:68)mmatory 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
`
`Marketed by: Takeda Pharmaceutical Co., Ltd.
`1-1, Dosho-machi 4-chome,
`Chuo-ku, Osaka
`
`Package 00-009
`
`Page 3 of 5
`
`

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`Page 5 of 5