CROSS
`
`LINGUAL
`
`CROSSLINGUAL, LLC
`3736 Fallon Road, Suite 226
`Dublin, CA 94568
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`AFFIDAVIT OF TRANSLATION
`
`I, Alan F. Siegrist, of CROSSLINGUAL, LLC, hereby declare that:
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`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:
`Saishin no shinyaku_2001
`I declare that the foregoing is true and correct to the best of my knowledge.
`
`Executed on October 26, 2015
`
`Alan F. Siegrist, CT
`CROSSLINGUAL, LLC
`ATA Member No. 31889
`Certification #63788
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`
`State of California, County of ~ CO~
`on __ l_;:;o_/_Jk,..;;_lw__;;__\_r_· ___ before me, ~v\3> ~-rJ~~ ~J?"'t<\'iL"\ ~Jg.l._lc.
`personally appeared A.LA,j Q... StE:.C.~\'\
`who proved to me on the basis of satisfactory
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`SENJU EXHIBIT 2248
`LUPIN v. SENJU
`IPR2015-01099
`
`Page 1 of 11
`
`

`
`Yakuji Nippo Edition
`Year 2001 Edition
`
`
`
`
`
`Yakuji Nippo Limited
`
`
`
`
`
`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
`
`Yakuji Nippo Limited
`
`– i –
`
`
`
`Page 3 of 11
`
`

`
`Acitazanolast Hydrate
`
`(Remarks)
`Product characteristics
`(1) It is an ophthalmic solution of Acitazanolast which is
`an in vivo activating metabolite of the oral anti-
`allergic agent Tazanolast.
`
`
`Bromfenac sodium hydrate
`
`(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).
`
`Drug price listed Drug price code
`May 2, 2000
`1319743Q1025
`
`Approval No.
`21200AMZ00168
`
`[Composition / Properties]
`Ingredients / content
`Bromfenac sodium hydrate 1 mg
`(in 1 ml)
`
`[Contraindications (do not administer to the following
`patients)]
`
`Patients with a previous history of hypersensitivity to the
`ingredients of this drug
`
`– 27 –
`
`Japan Standard Commodity Classification No.
`Non-steroidal anti-inflammatory ophthalmic agent
`871319
`Bronuck ophthalmic solution – Bronuck (Instructions) (Notations) Senju Pharmaceutical. Co. (manufacture) /
`Takeda Pharmaceutical Co. (marketing)
`
`Approval date
`Sales initiation
`
`March 10, 2000
`July 3, 2000
`
`[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
`efficacy 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 powerfully inhibits
`production of prostaglandin which is an inflammatory
`mediator. By modifying bromine at the 4th 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
`
`
`Boric acid, borax, dry sodium
`sulfite, sodium edetate, povidone,
`polysorbate 80, benzalkonium
`chloride
`Aqueous ophthalmic solution
`Clear yellow
`8.0–8.6
`Aseptic preparation
`
`Additives
`
`Form of drug
`Color
`pH
`Other
`
`
`[Efficacy / Effects]
`Symptomatic treatment of inflammatory ailments of
`the external eye and anterior eye
`(blepharitis,
`conjunctivitis, scleritis
`(including episcleritis), and
`postoperative inflammation)
`[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, in case of use on inflammation resulting
`from infection, administration is to be conducted
`carefully with adequate observation.
`
`Page 4 of 11
`
`

`
`Novel Substances ● Drugs Affecting Sensory Organs
`
`Cornea
`Conjunctiva
`Anterior sclera
`Anterior vitreous humor
`Blood
`Below detection limit
`
`Bromfenac sodium hydrate concentration
`
`(hours)
`
`
`Hours after ocular instillation
`[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
`Efficacy rate (%) and
`Name of ailment
`effectiveness
`Blepharitis
`66.7 (6/9)
`Conjunctivitis
`63.2 (60/95)
`Scleritis (including episcleritis)
`63.6 (7/11)
`Postoperative inflammation
`86.4 (152/176)
`Total
`77.3 (225/291)
`[Pharmacoefficacy and Pharmacology]
`1. Pharmacological Action
`(1) Anti-inflammatory action relative to experimental
`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)
`
`
`
`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 superficial
`punctate 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).
`The following adverse effects were observed in the
`foregoing study.
`0.1% to less than 5%
`hyperemia,
`conjunctival
`Ocular*
`blepharitis,
`stinging, ocular pain (temporary), corneal inflammation,
`corneal epithelial abrasion, superficial 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 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
`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).
`
`– 28 –
`
`Page 5 of 11
`
`

`
`Dorzolamide Chloride
`
`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.
`
`
`
`– 29 –
`
`Page 6 of 11
`
`

`
`Saiktn no shin'yaku New drugs in Japan.
`2001
`General Collection
`QV 772 8132
`2001-09-07 1357 43
`
`PROPERTY OF THE I . I
`NATIONAL.-
`LIBRARY OF
`MEDICINE
`
`Page 7 of 11
`
`

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`-28 -
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`Page 10 of 11
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`-29 -
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`Page 11 of 11