CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
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`22-228
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`Form Approved: OMB No. 0910-0513
` Department of Health and Human Services
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`Expiration Date: 7/31/10
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`Food and Drug Administration
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`See OMB Statement on Page 3.
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`PATENT INFORMATION SUBMITTED WITH THE FILING
`NDA NUMBER
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`22—288
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`OF AN NDA, AMENDMENT, OR SUPPLEMENT
`NAME OF APPLICANT/NDA HOLDER
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`For Each Patent That Claims a Drug Substance
`ISTA Phamiaceuticals®, Inc,
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`(Active Ingredient), Drug Product (Formulation and Composition)
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`and/or Method of Use
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`The following'Is provided in accordance with Section 505(b) and (c) of the Federal Food, Drug, and Cosmetic Act.
`TRADE NAME (OR PROPOSED TRADE NAME)
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`BepreveTM
`ACTIVE INGREDIENT(S)
`STRENGTH(S)
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`1.5%
`Bepotastine Besilate
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`DOSAGE FORM
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`Ophthalmic solution
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`This patent declaration form is required to be submitted to the Food and Drug Administration (FDA))with an NDA application
`amendment or supplement as required by 21 CFR 314.58 at the address providedIn 21 CFR 314.53(d)(4).
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`Within thirty (30) days after approval of an NDA or supplement. or within thirty (30) days of issuance of a new patent, a new patent
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`declaration must be submitted pursuant to 21 CFR 314.53(c)(2)(ii) with all of the required information based on the approved NDA or
`supplement. The information submitted in the declaration form submitted upon or after approval will be the only information relied
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`upon by FDA for listing a patent in the Orange Book.
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`For hand-written or typewriter versions (only) of this report: If additional space is requiredfor any narrative answer (i.e., one that
`does not require a "Yes" or “No" response), please attach an additional page referencing the question number.
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`FDA will not list patent information if you submit an incomplete patent declaration or the patent declaration indicates the
`patent is not eligible for listing.
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`For each patent submitted for the pending NDA, amendment, or supplement referenced above, you must submit all the
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`information described below. If you are not submitting any patents for this pending NDA, amendment, or supplement,
`complete above section and sections 5 and 6
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`b. issue Date of Patent
`8/24/04
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`0. Expiration Date of Patent
`12/25/17
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`a. United States Patent Number
`6,780,877
`d. Name of Patent Owner
`Address (of Patent Owner)
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`(1) 12-32, Nishihonmachi 1-Chome,Ube-Shi
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`(2) 2-10, Dosho-Machi 3-Chome, Chuo-Ku, Osaka-Ski
`(1) Ube Indusmes’ Ltd
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`City/State
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`(l) Yamaguchi 755-863, Japan (2) Osaka 541—8505, Japan
`(2) Tanabe Seiyaku Co. Ltd.
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`FAX Number (If ave/labIe)
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`Telephone Number
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`(908) 607-1950
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`9. Name of aceni or representative who resides or maintains Address (ofagent or representative namedIn 1. e.)
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`a place of business within the United States authorized to
`ISTA Pharmaceuticals, Inc.
`receive notice of patent certification under section 505(b)(3)
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`and (j)(2)(B) of the Federal Food. Drug, and Cosmetic Act
`1,5295 Alton Parlor» ay
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`. and 21 CFR 314.52 and 314.95 (if patent owner or NDA
`Olly/Stale
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`applicant/holder does not reside or have a place of
`Irvme, CA
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`business within the United States)
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`Telephone Number
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`Vice President Regulatory Affairs, Quality Assurance,
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`EMail Address (ifavailable)
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`FAX Number (If available)
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`E-Mail Address (ifavai/able)
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`g.
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`approved NDA or supplement referenced above?
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`If the patent referenced above has been submitted previous y for listing, is the expiration
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`[:I Yes
`date a new expiration date?
`Z] No
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`Page 1
`FORM FDA 3542a (7/07)
`EF
`PSC Graphics (301) 443—1090
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`[I Yes
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`E No
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`Page 1 of 3
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`For the patent referenced above, provide the following information on the drug substance, drug product and/or method of
`use that is the subject of the pending NDA, amendment, or supplement.
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`bzs’tancefilActii/e Vln'gredientlf
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`2.1 Does the patent claim the drug substance that is the active Ingredient in the dmg product
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`described in the pending NDA, amendment, or supplement?
`[2] Yes
`D No
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` 2.2 Does the patent claim a drug substance that is a different polymorph of the active
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`ingredient described in the pending NDA, amendment. or supplement?
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`2.3 if the answer to question 2.2 is "Yes," do you certify that, as otthe, date of this declaration, you have test
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`data demonstrating that a drug product containing the polymorph will perform the same as the drug product
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`described in the NDA? The type of test data required is described at 21 CFR 314.53(b).
`I] Yes
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` 2.4 Specify the polymorphicform(s) claimed by the patent for which you have the test results described in 2.3.
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`DNo
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`3.1 Does the patent claim the drug product, as defined in 21 CFR 314.3, in the pending NDA, amendment,
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`or supplement?
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`2.5 Does the patent claim only a metabolite of the active ingredient pending in the NDA or supplement?
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`(Complete the information in section 4 below if the patent claims a pending method of using the pending
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`1:] Yes
`Z] No
`drug product to administer the metabolite.)
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`2.6 Does the patent claim only an intermediate?
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`2.7 If the patent referenced in 2.1 is a product—by-process patent, is the product claimed in the
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`patent novel? (An answer is required only it the patent is a product-by-process patent.)
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` 3.2 Does the patent claim only an intermediate?
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` 3.3 If the patent referenced in 3.1 is a product—by-process patent, is the product claimed in the
`patent novel? (An answer is required only if the patent is a product-by-process patent.)
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`Sponsors must submit the information in section 4 for each method of using the pending drug product for which apprcival is being
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`sought that'is claimed by the patent. For each pending method of use claimed by the patent, provide the following information:
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`4.1 Does the patent ciaim one or more methods of use for which approval is being sought in
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`E] Yes
`the pending NDA, amendment, or supplement?
`2] No
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`Does (Do) the patent claim(s) referenced in 4.2 claim a
`4.2 Patent Claim Number(s) {as‘liste'd in the patent)
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`pending method of use for which approval is being sought
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`in the pending NDA, amendment. or supplement?
`D No
`[I Yes
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`4.2a if
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`Use: (Submit indication or method of use information as identified specifically in the proposed labeling.)
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`"Yes," identify with speci-
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`ficity the use with refer-
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`ence to the proposed
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`labeling for the drug
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`product.
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` For this pending NDA, amendment, or supplement, there are no relevant patents that claim the drug substance (active ingredient),
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`drug product (formulation or composition) or method(s) of use, for which the applicant is seeking approval and with respect to which
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`a claim of patent infringement could reasonably be asserted if a person not licensed by the owner ofthe patent engaged in the
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`manufacture, use, or sale of the drug product.
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`FORM FDA 3542a (7/07)
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`Page 2
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`r? (Pertififc’éith
`6.1 The undersigned declares that this is an accurate and complete submission of patent information for the NDA,
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`amendment, or supplement pending under section 505 of the Federal Food, Drug, and Cosmetic Act. This time-
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`sensitive patent information is submitted pursuant to 21 CFR 314.53. lattest that I am familiar with 21 CFR 314.53 and
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`this submission complies with the requirements of the regulation. I verify under penalty of perjury that the foregoing is
`true and correct.
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`Warning: A willfully and knowingly false statement is a criminal offense under 18 U.S.C. 1001.
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`Date Signed
`Authorized Signature of NDA Applicant/Holder or Patent Owner (Attorney, Agent, Representative or
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`holder is authorized to sign the declaration but may not submit it directly to FDA. 21 CFR 314.53(c)(4) and (d)(4).
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`Check applicable box and provide information below.
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`Official
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`otherAuthorized Official) (Provide Information below)
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`E] NDA Applicant/Holder
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` El Patent Owner's Attorney, Agent (Representative) or Other Authorized
`El Patent Owner
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`ISTA Pharmaceuticals®, Inc.
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`Address
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`15295 Alton Parkway
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`Irvine, CA
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`FAX Number (if available)
`E-Mail Address (ifavailable)
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`(949) 727-0833
`mgarrett@istavision.com
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`including the time for reviewing
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`instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send
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`comments regarding this burden estimate or any other aspect of this collection of information. including suggestions for reducing this burden to:
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`Food and Drug Administration '
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` An agency may not conduct or sponsor, and a person it not required to respond to, a collection of
`ilfomiarian unless it displays a currently valid OMB control number.
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`FORM FDA 3542a (7/07)
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`’
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`Page 3
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`Page 3 of3
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`EXCLUSIVITY SUMMARY
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`NDA # 22-288
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`SUPPL #
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`HFD # 520
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`Trade Name Bepreve
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`Generic Name bepotastine besilate ophthalmic solution 1.5%
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`Applicant Name Ista Pharmaceuticals, Inc.
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`Approval Date, If Known
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`PART I
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`IS AN EXCLUSIVITY DETERMINATION NEEDED?
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`1. An exclusivity determination will be made for all original applications, and all efficacy
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`supplements. Complete PARTS II and III of this Exclusivity Summary only if you answer "yes" to
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`one or more of the following questions about the submission.
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`a) Is it a 505(b)(1), 505(b)(2) or efficacy supplement?
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`YES g
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`NO [I
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`Ifyes, what type? Specify 505(b)(1), 505(b)(2), SE1, SE2, SE3,SE4, SE5, SE6, SE7, SE8
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`505(b)(1)
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`0) Did it require the review of clinical data other than to support a safety claim or change in
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`labeling related to safety? (If it required review only of bioavailability or bioequivalence
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`data, answer "no."
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`NOD
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`If your answer is "no" because you believe the study is a bioavailability study and, therefore,
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`7 not eligible for exclusivity, EXPLAIN why it is a bioavailability study, including your
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`reasons for disagreeing with any arguments made by the applicant that the study was not
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`If it is a supplement requiring the review of clinical data but it is not an effectiveness
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`supplement, describe the change or claim that is supported by the clinical data:
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`Page 1
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`d) Did the applicant request exclusivity?
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`YES [I
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`NO g
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`If the answer to (d) is "yes," how many years of exclusivity did the applicant request?
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`6) Has pediatric exclusivity been granted for this Active Moiety?
`YES |:|
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`NO
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`If the answer to the above question in YES, is this approval a result of the studies submitted in
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`response to the Pediatric Written Request?
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`IF YOU HAVE ANSWERED "NO" TO ALL OF THE ABOVE QUESTIONS, GO DIRECTLY TO
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`THE SIGNATURE BLOCKS AT THE END OF THIS DOCUMENT.
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`2. Is this drug product or indication a DESI upgrade?
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`YESlj
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`NOE
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`IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE SIGNATURE BLOCKS
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`ON PAGE 8 (even if a study was required for the upgrade).
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`'
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`FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES
`PART II
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`(Answer either #1 or #2 as appropriate)
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`1. Single active ingredient product.
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`Has FDA previously approved under section 505 of the Act any drug product containing the same
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`esterified forms, salts, complexes, chelates or clathrates) has been previously approved, but this
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`particular form ofthe active moiety, e. g., this particular ester or salt (including salts with hydrogen or
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`coordination bonding) or other non-covalent derivative (such as a complex, chelate, or clathrate) has
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`not been approved. Answer "no” if the compound requires metabolic conversion (other than
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`deesterification of an esterified form of the drug) to produce an already approved active moiety.
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`If "yes," identify the approved drug product(s) containing the active moiety, and, ifknown, the NDA
`- #(s).
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`YES El
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`NO
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`Page 2
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`NDA#
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`NDA#
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`2. Combination product.
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`If the product contains more than one active moiety(as defined in Part II, #1), has FDA previously
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`approved an application under section 505 containing any % of the active moieties in the drug
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`product? If, for example, the combination contains one never-before-approved active moiety'and
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`one previously approved active moiety, ansWer "yes." (An active moiety that is marketed under an
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`OTC monograph, but that was never approved under an NDA, is considered not previously
`approved.)
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`El
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`NO
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`E
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`YES
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`If "yes," identify the approved drug product(s) containing the active moiety, and, ifknown, the NDA
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`#(s).
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`IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART 11 IS "NO," GO DIRECTLY TO THE
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`SIGNATURE BLOCKS ON PAGE 8.
`(Caution: The questions in part II of the summary should
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`only be answered “NO” for original approvals of new molecular entities.)
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`IF “YES,” GO TO PART III.
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`PART III
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`THREE-YEAR EXCLUSIVITY FOR NDAs AND SUPPLEMENTS
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`To qualify for three years of exclusivity, an application or supplement must contain "reports of new
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`clinical investigations (other than bioavailability studies) essential to the approval ofthe application
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`and conducted or sponsored by the applicant." This section should be completed only ifthe answer
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`to PART II, Question 1 or 2 was "yes."
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`1. Does the application contain reports of clinical investigations? (The Agency interprets "clinical
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`investigations" to mean investigations conducted on humans other than bioavailability studies.) If
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`the application contains clinical investigations only by virtue of a right of reference to clinical
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`investigations in another application, answer "yes," then skip to question 3(a). If the answer to 3(a)
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`is "yes" for any investigation referred to in another application, do not complete remainder of
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`Page 3
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`summary for that investigation.
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`YES D NO [I
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`IF ”NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8.
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`2. A clinical investigation is "essential to the approval" if the Agency could not have approved the
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`application or supplement without relying on that investigation. Thus, the investigation is not
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`essential to the approval if 1) no clinical investigation is necessary to support the supplement or
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`application in light of previously approved applications (i.e., information other than clinical trials,
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`such as bioavailability data, would be sufficient to provide a basis for approval as an ANDA or
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`505(b)(2) application because of what is already known about a previously approved product), or 2)
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`there are published reports of studies (other than those conducted or sponsored by the applicant) or
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`other publicly available data that independently would have been sufficient to support approval of
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`the application, without reference to the clinical investigation submitted in the application.
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`(a) In light of previously approved applications, is a clinical investigation (either conducted
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`by the applicant or available from some other source, including the published literature)
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`necessary to support approval of the application or supplement?
`YES D
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`NO [I
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`If "no," state the basis for your conclusion that a clinical trial is not necessary for approval
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`AND GO DIRECTLY TO SIGNATURE BLOCK ON PAGE 8:
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`(b) Did the applicant submit a list ofpublished studies relevant to the safety and effectiveness
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`ofthis drug product and a statement that the publicly available data would not independently
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`support approval of the application?
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`YES D NO |:]
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`(1) If the answer to 2(b) is "yes," do you personally know of any reason to disagree
`with the applicant's conclusion? If not applicable, answer NO.
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`YES D
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`NO [I
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`If yes, explain:
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`(2) If the answer to 2(b) is ”no," are you aware of published studies not conducted or
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`sponsored by the applicant or other publicly available data that could independently
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`demonstrate the safety and effectiveness of this drug product?
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`YES D
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`NO 1:]
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`Page 4
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`If yes, explain:
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`n/a
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`(0)
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`Ifthe answers to (b)( 1) and (b)(2) were both "no," identify the clinical investigations
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`submitted in the application that are essential to the approval:
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`Studies comparing two products with the same ingredient(s) are consideredto be bioavailability
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`studies for the purpose of this section.
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`3. In addition to being essential, investigations must be "new" to support exclusivity. The agency
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`interprets "new clinical investigation" to mean an investigation that 1) has not been relied on by the
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`agency to demonstrate the effectiveness of a previously approved drug for any indication and 2) does
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`not duplicate the results of another investigation that was relied on by the agency to demonstrate the
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`effectiveness of a previously approved drug product, i.e., does not redemonstrate something the
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`agency considers to have been demonstrated in an already approved application.
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`a) For each investigation identified as "essential to the approval," has the investigation been
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`relied on by the agency to demonstrate the effectiveness of a previously approved drug
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`product? (If the investigation was relied on only to support the safety of a previously
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`approved drug, answer "no."
`
`Investigation #1
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`Investigation #2
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`YES |:]
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`NO |:|
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`YES [:I
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`NO I:
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`If you have answered "yes" for one or more investigations, identify each such investigation
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`and the NDA in which each was relied upon:
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`b) For each investigation identified as "essential to the approva ", does the investigation
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`duplicate the results of another investigation that was relied on by the agency to support the
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`effectiveness of a previously approved drug product?
`
`Investigation #1
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`Investigation #2
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`YES El
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`NO El
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`YES [I
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`No [I
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`
`Page 5
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`

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`If you have answered "yes" for one or more investigation, identify the NBA in which a
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`similar investigation was relied on:
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`c) If the answers to 3(a) and 3(b) are no, identify each "new" investigation in the application
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`or supplement that is essential to the approval (i.e., the investigations listed in #2(c), less any
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`that are not ”new" :
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`4. To be eligible for exclusivity, a new investigation that is essential to approval must also have
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`been conducted or sponsored by the applicant. An investigation was "conducted or sponsored by"
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`the applicant if, before or during the conduct ofthe investigation, 1) the applicant was the sponsor of
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`the IND named in the form FDA 1571 filed with the Agency, or 2) the applicant (or its predecessor
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`in interest) provided substantial support for the study. Ordinarily, substantial support will mean
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`providing 50 percent or more of the cost of the study.
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`a) For each investigation identified in response to question 3(c): if the investigation was
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`carried out under an IND, was the applicant identified on the FDA 1571 as the sponsor?
`
`!I
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`! NO D
`! Explain:
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`NO [I
`Explain:
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`Investigation #1
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`IND #
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`YES |:|
`
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`Investigation #2
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`IND#
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`YES El
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`(b) For each investigation not carried out under an IND or for which the applicant was not
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`identified as the sponsor, did the applicant certify that it or the applicant's predecessor in
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`interest provided substantial support for the study?
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`Page 6
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`Investigation #1
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`_
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`!
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`YEslj
`Explain:
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`‘!NOD
`! Explain:
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`Investigation #2
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`YEs|:|
`Explain:
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`!
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`!NO|:l
`! Explain:
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`(c) Notwithstandingvan answer of "yes" to (a) or (b), are there other reasons to believe that
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`the applicant should not be credited with having "conducted or sponsored" the study?
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`(Purchased studies may not be used as the basis for exclusivity. However, if all rights to the
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`drug are purchased (not just studies on the drug), the applicant may be considered to have
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`sponsored or conducted the studies sponsored or conducted by its predecessor in interest.)
`
`YES D
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`NO
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`If yes, explain:
`
`n/a
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`Name of person completing form: Raphael Rodriguez & William Boyd, M.D.
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`Title: Regulatory Project Manager & Clinical Team Leader
`Date:
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`Name of Office/Division Director signing form: Wiley A. Chambers, M.D.
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`Title: Acting Director, DAIOP, HFD-520
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`Form OGD-011347; Revised 05/10/2004; formatted 2/15/05
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`Page 7
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`

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`This is a representation of an electronic record that was signed
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`electronically and this page is the manifestation of the electronic
`signature.
`
`
`
`RAPHAEL R RODRIGUEZ
`09/17/2009
`
`
`
`WILEY A CHAMBERS
`09/22/2009
`
`

`

`
`PEDIATRIC PAGE .
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`(Complete for all filed original applications and efficacy supplements)
`
`Supplement Number.
`NDA Supplement Type (e.g. SE5):
`)A/BLA#: 22-288
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`PDUFA Goal Date: 9/12/09
`Stamp Date: 11/12/2008
`Division Name:DAIOP
`
`
`Proprietary Name:
`
`Established/Generic Name:
`
`
`
`
`
`be otastine besilate o hthalmic solution 1.5%
`
`Bepreve
`
`
`'
`
`
`Dosage Form:
`
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`Applicant/Sponsor:
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`topical ophthalmic solution
`
`ISTA Pharmaceuticals Inc.
`
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`'
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`|ndication(s) previously approved (please complete this question for supplements and Type 6 NDAs only):
`
`(1)
`-
`
`(2) __
`(3) __
`
`(4)
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`Q1: Is this application in response to a PREA PMC?
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`No
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`Yes |:I Continue
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`Please proceed to Question 2.
`
`Supplement #:___
`PMC #:—
`If Yes, NDA/BLA#:
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`Does the division agree that this is a complete response to the PMC?
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`|:] Yes. Skip to signature block.
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`|:I No. Please proceed to Question 2 and complete the Pediatric Page, as applicable.
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`02: Does this application provide for (If yes, please check all categories that apply and proceed to the next
`'estion):
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`, NEW active ingredient(s)'; I:l indication(s); El dosage form; C] dosing regimen; or [I route of
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`administration?*
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`(b) I:I No. PREA does not apply. Skip to signature block.
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`* Note for CDER: SE5, SE6, and SE7 submissions may also trigger PREA.
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`Pediatric use for each pediatric subpopulation must be addressed for each indication covered by current
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`application under review. A Pediatric Page must be completed for each indication.
`Number of indications for this pending application(s):l
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`(Attach a completed Pediatric Page for ich indication in current application.)
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`Indication: Treatment of itching associated with allergic coniunctivits
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`Q3: Does this indication have orphan designation?
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`[:1 Yes. PREA does not apply. Skip to signature block.
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`El No. Please proceed to the next question.
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`Q4: Is there a full waiver for all pediatric age groups for this indication (check one)?
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`[:I Yes: (Complete Section A.)
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`El No: Please check all that apply
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`Partial Waiver for selected pediatric subpopulations (Complete Sections B)
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`E] Deferred for the remaining pediatric subpopulations (Complete Sections C)
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`Completed for some or all pediatricsubpopulations (Complete Sections D)
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`[I Appropriately Labeled for some or all pediatric subpopulations (Complete Sections E)
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`[I Extrapolation in One or More Pediatric Age Groups (Complete Section F)
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`(Please note that Section F may be used alone or in addition to Sections C, D, and/or E.)
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`IF THERE ARE QUESTIONS, PLEASE CONTACT THE CDER PMHS VIA EMAIL OR AT 301-796-0700.
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`NDA/BLA# 22-28822-28822-288224-2‘8822-288—
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`Page 2
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`Section A: Fully Waived Studies (for all pediatric age groups)
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`Reason(s) for full waiver: (check, and attach a brief justification)
`El Necessary studies would be impossible or highly impracticable because:
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`El Disease/condition does not exist in children
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`CI Too few children with disease/condition to study
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`C] Other (e.g., patients geographically dispersed): __
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`'EI Product does not represent a meaningful therapeutic benefit over existing therapies for pediatric
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`patients AND is not likely to be used in a substantial numberof pediatric patients.
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`El Evidence strongly suggests that product would be ineffective or unsafe in all pediatric
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`subpopulations (Note: if studies are fully waived on this ground, this information must be included in
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`the labeling.)
`|:| Justification attached.
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`If there is another
`If studies are fully waived, then pediatric information is complete for this indication.
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`indication, please complete another Pediatric Page for each indication. Otherwise, this Pediatric Page is
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`complete and should be signed and entered into DFS.
` Section B: Partially Waived Studies (for selected pediatric subpopulations)
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`Check subpopulation(s) and reason for which studies are being partially waived (fill in applicable criteria below):
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`Note: If Neonate includes premature infants, list minimum and maximum age in “gestational age” (in weeks).
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`Reason (see below for further detail):
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`Not meaningful
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`Formulation
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`E No; [I Yes.
`Are the indicated age ranges (above) based on weight (kg)?
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`No; |:I Yes.
`Are the indicated age ranges (above) based on Tanner Stage?
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`Reason(s) for partial waiver (check reason corresponding to the category checked above, and attach a brief
`justification):
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`# Not feasible:
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`[:1 Necessary studies would be impossible or highly impracticable because:
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`[I Disease/condition does not exist in children
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`IXI Too few children with disease/condition to study
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`[I Other (e.g., patients geographically dispersed): __
`* Not meaningful therapeutic benefit:
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`[I Product does not represent a meaningful therapeutic benefit over existing therapies for pediatric
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`patients in this/these pediatric subpopulation(s) AND is not likely to be used in a substantial numberof
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`pediatric patients in this/these pediatric subpopulation(s).
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`1' Ineffective or unsafe:
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`I:l Evidence strongly suggests that product would be ineffective or unsafe in this/these pediatric
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`population(s) (Note: if studies are partially waived on this ground, this information must be included in
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`the labeling.)
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`IF THERE ARE QUESTIONS, PLEASE CONTACT THE CDER PNIHS VIA EMAIL OR AT 301-796-0700.
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`

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`NDA/BLA# 2228822488223882278822288“
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`Page 3
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`A Formulation fail