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`Novartis Exhibit 2282.001
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`21-756
`
`Trade Name:
`
`Macugen
`
`Generic Name:
`
`Pegaptanib sodium injection, 0.3 mg
`
`Sponsor:
`
`Eyetech Pharmaceuticals, Inc.
`
`Approval Date:
`
`December 17, 2004
`
`Indications:
`
`Provides for the use of Macugen {pegaptanib sodium
`injection) _for the treatment of neovaxcular (wet)
`age-related macular degeneration.
`
`Novartis Exhibit 2282.002
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-756
`
`CONTENTS
`
`Reviews/ Information Included in this NDA Review.
`
`Approval Letter
`Approvable Letter(s)
`Final Printed Labelin2
`Medical Review(s)
`Chemistry Review(s)
`EA/FONSI
`Pharmacolo2Y Review(s)
`Statistical Review(s)
`Microbiolo2Y Review(s)
`Clinical Pharmacoloev/ Biopharmaceutics Review(s)
`Administrative Document(s) and Correspondence
`
`X
`
`X
`X
`X
`
`X
`
`X
`X
`X
`
`Novartis Exhibit 2282.003
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-756
`
`APPROVAL LETTER(S)
`
`Novartis Exhibit 2282.004
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`/~,
`
`(..-::!f.. DEPARTMENT OF HEALTII & HUMAN SERVICES
`
`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA21-756
`
`Eyetech Pharmaceuticals, Inc.
`Attention: Loni da Silva
`Vice President, Global Regulatory Affairs
`Three Times Square
`12th Floor
`New York, New York 10036
`
`Dear Ms. da Silva:
`
`Please refer to your new drug application (NDA) dated June 17, 2004, received June 17, 2004,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Macugen (pegaptanib
`sodium injection) 0.3 mg.
`
`We acknowledge receipt of your submissions dated March 17, May 12 and 27, June 7, July 14 and 28,
`September 10, 13, 20, 22, 23, and 30, October 4, 5, 7, 15, and 29, November 10 (three), 12, 19, 22, and
`23, and December 1, 6, 8, IO (three), 13, 14 and 16, 2004.
`
`This new drug application provides for the use of Macugen (pegaptanib sodium injection) for the
`treatment of neovascular (wet) age-related macular degeneration.
`
`We completed our review of this application, as amended. It is approved. effective on the date of this
`letter, for use as recommended in the agreed-upon labeling text.
`
`The final printed labeling (FPL) must be identical to the enclosed draft labeling (package insert
`submitted December 10, 2004, carton and container labeling submitted December 16, 2004).
`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
`
`The electronic labeling rule published December 11, 2003, (68 FR 69009) requires submission of
`labeling content in electronic format effective June 8, 2004. For additional information, consult the
`following guidances for industry regarding electronic submissions: Providing Regulatory
`Submissions in Electronic Format -NDAs (January 1999) and Providing Regulatory Submissions in
`Electronic Format - Content of Labeling (February 2004). The guidances specify that labeling is to
`be submitted in pd/ format. To assist in our review, we request that labeling also be submitted in MS
`Word format. If formatted copies of all labeling pieces (i.e .• package insert, container labels, and
`carton labels) are submitted electronically, labeling does not need to be submitted in paper.
`
`Novartis Exhibit 2282.005
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`NDA21-756
`Page2
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessment of the safety and
`effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We are
`waiving the pediatric study requirer:qent for this application.
`
`We remind you of your postmarketing study commitments in your submission dated
`December 10, 2004. These commitments are listed below.
`
`1. Provide clinical information from a 2-year (minimum) clinical study to support that there
`are no degenerative effects on the neurosensory retina following the intravitreal
`administration of Macugen.
`
`Protocol Submission:
`Study Start:
`Final Report Submission:
`
`by June, 2005
`by January, 2007
`by July, 2009
`
`2. Provide clinical information from a 1-year (minimum) clinical study to support that there
`are no adverse effects on the corneal endothelium following the intravitreal administration
`ofMacugen.
`
`Protocol Submission:
`Study Start:
`Final Report Submission:
`
`by June, 2005
`by January, 2007
`by July, 2008
`
`3. Provide safety and efficacy data from a 2-year (minimum) clinical study of at least two
`additional doses ofMacugen below 0.3 mg.
`
`Protocol Submission:
`Study Start:
`Final Report Submission:
`
`by June, 2005
`by January, 2007
`by July, 2009
`
`Submit clinical protocols to your IND for this product. In addition, under 21 CFR 314.81(b)(2)(vii)
`and 314.81(b)(2)(viii), you should include a status summary of each commitment in your annual report
`to this NDA. The status summary should include expected summary completion and final report
`submission dates, any changes in plans since the last annual report, and, for clinical studies, number of
`patients entered into each study. All submissions, including supplements, relating to these
`postmarketing study commitments must be prominently labeled "Postmarketing Study Protocol'',
`.. Postmarketing Study Final Report", or "Postmarketing Study Correspondence."
`
`We remind you of the agreement in your December 10, 2004, submission to (bl c4 J
`by March, 2006.
`(b) (4l
`
`Novartis Exhibit 2282.006
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`NDA21-756
`Page3
`
`We acknowledge the following agreements from our December 17, 2004, teleconference:
`
`a) Provide data by January 14, 2005, to show that the <b> <4>
`sufficiently low.
`
`is
`
`b} Provide initial materials by December 31, 2004, to educate medical providers of the controlled
`aseptic conditions under which the drug product must be administered in order to reduce risk to
`the patient and coordinate with the Division for all subsequent educational materials.
`
`c) Provide continued (b) <4 >
`
`In addition, submit three copies of the introductory promotional and educational materials that you
`propose to use for this product. Submit all proposed materials in draft or mock-up form, not final
`print. Send one copy to the Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products,
`and two copies of both the promotional materials and the package insert directly to:
`
`Division of Drug Marketing, Advertising,
`and Communications, HFD-42
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`
`Please submit one market package of the drug product when it is available.
`
`We have not completed validation of the regulatory methods. However, we expect your continued
`cooperation to resolve any problems that may be identified.
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse event
`reports that are received directly by the FDA. New molecular entities and important new biologics
`qualify for inclusion for three years after approval. Your firm is eligible to receive copies of reports for
`this product. To participate in the program, please see the enrollment instructions and program
`description details at www.fda.gov/medwatch/report/mmp.htm.
`
`If you have any questions, contact Michael Puglisi. Project Manager, at (301) 827-2090.
`
`Sincerely,
`
`{ See appended electronic signature page}
`
`Jonca C. Bull, M.D.
`Director
`Office of Drug Evaluation V
`Center for Drug Evaluation and Research
`
`Enclosure
`
`J
`
`Novartis Exhibit 2282.007
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`This Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Isl
`
`Jonca Bull
`12117104 06:57:56 PM
`
`Novartis Exhibit 2282.008
`Regeneron v. Novartis, IPR2021-00816
`
`