CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`761125Orig1s000
`
`
` BEOVU (brolucizumab-dbll) injection for intravitreal
`injection.
`brolucizumab-dbll
`
`Trade Name:
`
`
`
`Generic or Proper
`Name:
`
`
`Sponsor:
`
`Approval Date:
`
`Indication:
`
`
`Novartis Pharmaceuticals Corporation
`October 7, 2019
`indicated for the treatment of Neovascular (Wet) Age-
`Related Macular Degeneration (AMD)
`
`Novartis Exhibit 2294.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`761125Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Clinical Review(s)
`Product Quality Review(s)
`Non-Clinical Review(s)
`Statistical Review(s)
`Clinical Microbiology / Virology Review(s)
`Clinical Pharmacology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`X
`X
`
`
`X
`X
`X
`X
`
`X
`X
`X
`X
`X
`
`Novartis Exhibit 2294.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`761125Orig1s000
`
`
`APPROVAL LETTER
`
`Novartis Exhibit 2294.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`111
`
`U.S. FOOD & DRUG
`
`ADMIN ISTRATION
`
`?"~
`
`f J{(
`~,-::z.f
`
`BLA APPROVAL
`
`BlA 761125
`
`Novartis Pharmaceuticals Corporation
`Attention: Franklin Akomeah, PhD
`Global Regu latory Director
`4800 Overton Plaza
`Suite 300
`Fort Worth, TX 76109
`
`Dear Dr. Akomeah:
`
`Please refer to your biologics license application (BlA) dated and received February 7,
`2019, and your amendments, submitted under section 351 (a) of the Public Health
`Service Act for BEOVU (brolucizumab-dbll) injection for intravitreal injection.
`
`LICENSING
`We are issuing Department of Health and Human Services U.S. License No. 1244 to
`Novartis Pharmaceuticals Corporation, East Hanover, NJ under the provisions of
`section 351 (a) of the Public Health Service Act controlling the manufacture and sale of
`biological products. The license authorizes you to introduce or deliver for introduction
`into interstate commerce, those products for which you r company has demonstrated
`compliance with establishment and product standards.
`
`Under this license, you are authorized to manufacture the product BEOV U
`(brolucizumab-dbll) injection. BEOVU is indicated for the treatment of neovascular
`age-related macular degeneration.
`
`MANUFACTURING LOCATIONS
`4
`Under this license, you are approved to manufacture BEOVU drug substance at
`<b><
`>
`f
`- -.--,~ j The fi nal formulated drug product will be manufactured, filled,
`i abeled, and paci<ageclat Novartis Pharma Stein AG, Stein, Switzerland. Secondary
`·
`<b>,~~
`
`1:
`
`4
`
`Lka in will occur at Novartis Pharma Stein AG, Stein, Switzerland
`---
`
`4~ ou may label your product with the proprietary name, BEOV U, and
`(b)(
`market il in a vial kit includ ing one 6 mg/0.05 ml dosage in a 2 ml single-dose vial of
`BEOV U and a filter needle.
`
`DATING PERIOD
`The dating period for BEOVU shall be 18 months from the date of manufacture when
`stored at 5°C ± 3°C. The date of manufacture shall be defined as the date of fi nal sterile
`fi ltration of the formu lated drug product. The dating period for your drug substance shall
`be l!~ months from the date of manufacture when stored at less than <b><
`410c.
`
`Reference ID 4502977
`
`Novartis Exhibit 2294.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 761125
`Page 2
`
`FDA LOT RELEASE
`You are not currently required to submit samples of future lots of BEOVU and each kit
`component to the Center for Drug Evaluation and Research (CDER) for release by the
`Director, CDER, under 21 CFR 610.2. We will continue to monitor compliance with 21
`CFR 610.1, requiring completion of tests for conformity with standards applicable to
`each product prior to release of each lot.
`
`Any changes in the manufacturing, testing, packaging, or labeling of BEOVU, or in the
`manufacturing facilities, will require the submission of information to your biologics
`license application for our review and written approval, consistent with 21 CFR 601.12.
`
`APPROVAL & LABELING
`We have completed our review of this application, as amended. It is approved, effective
`on the date of this letter, for use as recommended in the enclosed agreed-upon
`labeling, which is identical to the package insert submitted on October 3, 2019.
`
`CONTENT OF LABELING
`As soon as possible, but no later than 14 days from the date of this letter, submit, via
`the FDA automated drug registration and listing system (eLIST), the content of labeling
`[21 CFR 601.14(b)] in structured product labeling (SPL) format, as described at
`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (Prescribing
`Information). Information on submitting SPL files using eLIST may be found in the
`guidance for industry SPL Standard for Content of Labeling Technical Qs and As.2
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND CONTAINER LABELING
`We acknowledge your September 18 and 27, and October 4, 2019, submissions
`containing printed carton and container labeling. Submit final printed carton and
`container labeling that are identical to the enclosed carton and container labeling as
`soon as they are available, but no more than 30 days after they are printed. Please
`submit these labeling electronically according to the guidance for industry Providing
`Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical
`Product Applications and Related Submissions Using the eCTD Specifications. For
`administrative purposes, designate this submission “Final Printed Carton and
`Container Labeling for approved BLA 761125.” Approval of this submission by FDA
`is not required before the labeling is used.
`
`1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
`2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
`Documents Database at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4502977
`
`Novartis Exhibit 2294.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 761125
`Page 3
`
`ADVISORY COMMITTEE
`Your application for BEOVU was not referred to an FDA advisory committee because
`this biologic was not the first product licensed for this indication and the evaluation of
`the safety and efficacy data in the treatment of neovascular age-related macular
`degeneration did not raise significant safety or efficacy issues that were unexpected for
`a biologic of this class.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
`new active ingredients (which includes new salts and new fixed combinations), new
`indications, new dosage forms, new dosing regimens, or new routes of administration
`are required to contain an assessment of the safety and effectiveness of the product for
`the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable. We are waiving the pediatric study requirement for this
`application because neovascular age-related macular degeneration does not occur in
`pediatric patients.
`
`POSTMARKETING COMMITMENTS NOT SUBJECT TO THE REPORTING
`REQUIREMENTS UNDER SECTION 506B
`We remind you of your post-marketing commitments, as agreed in the timetable
`submitted on August 13, 2019:
`
`-
`
`
`3691-1 Complete method development and implement a method
` for a drug substance in-process
`
`control.
`
`Method development completed: 12/31/2019
`Evidence of implementation of testing: 04/30/2020
`Limit of
` test results: First Annual Report
`
`3691-2 Complete an accelerated leachables study using the final container
`closure system with both brolucizumab drug product and the most
`appropriate representative buffer.
`
`Final Report Submission: 09/30/2020
`
`3691-3 Use samples from three drug substance lots manufactured using the
`commercial process at
` to qualify the drug substance in
`process and release methods for the bioburden test and drug substance in
`process method for the endotoxin test.
`
`Final Report Submission: 01/31/2020
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4502977
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`Novartis Exhibit 2294.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 761125
`Page 4
`
`3691-4 Develop an endotoxin detection method capable of detecting endotoxin
`from the drug product.
`
`Final report submission: 12/31/2019
`Implementation of the testing method: 04/30/2020
`
`Submit nonclinical and chemistry, manufacturing, and controls protocols and all
`post-marketing final reports to this BLA. In addition, under 21 CFR 601.70 you should
`include a status summary of each commitment in your annual progress report of
`post-marketing studies to this BLA. 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/trials, number of patients entered into each
`study/trial. All submissions, including supplements, relating to these post-marketing
`commitments should be prominently labeled “Post-marketing Commitment Protocol,”
`“Post-marketing Commitment Final Report,” or “Post-marketing Commitment
`Correspondence.”
`
`PROMOTIONAL MATERIALS
`You may request advisory comments on proposed introductory advertising and
`promotional labeling. To do so, submit, in triplicate, a cover letter requesting advisory
`comments, the proposed materials in draft or mock-up form with annotated references,
`and the Prescribing Information, Medication Guide, and Patient Package Insert (as
`applicable) to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`As required under 21 CFR 601.12(f)(4), you must submit final promotional materials,
`and the Patient Package Insert, at the time of initial dissemination or publication,
`accompanied by a Form FDA 2253. Form FDA 2253 is available at FDA.gov.3
`Information and Instructions for completing the form can be found at FDA.gov.4 For
`more information about submission of promotional materials to the Office of Prescription
`Drug Promotion (OPDP), see FDA.gov.5
`
`REPORTING REQUIREMENTS
`You must submit adverse experience reports under the adverse experience reporting
`requirements for licensed biological products (21 CFR 600.80).
`
`3 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`5 http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4502977
`
`Novartis Exhibit 2294.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 761125
`Page 5
`
`Prominently identify all adverse experience reports as described in 21 CFR 600.80.
`
`You must submit distribution reports under the distribution reporting requirements for
`licensed biological products (21 CFR 600.81).
`
`You must submit reports of biological product deviations under 21 CFR 600.14. You
`should promptly identify and investigate all manufacturing deviations, including those
`associated with processing, testing, packing, labeling, storage, holding and distribution.
`If the deviation involves a distributed product, may affect the safety, purity, or potency of
`the product, and meets the other criteria in the regulation, you must submit a report on
`Form FDA 3486 to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Compliance Risk Management and Surveillance
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`Biological product deviations, sent by courier or overnight mail, should be addressed to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Compliance Risk Management and Surveillance
`10903 New Hampshire Avenue, Bldg. 51, Room 4207
`Silver Spring, MD 20903
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`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 FDA.gov.6
`
`6 http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4502977
`
`Novartis Exhibit 2294.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BLA 761125
`Page 6
`
`POST APPROVAL FEEDBACK MEETING
`New molecular entities and new biological products qualify for a post approval feedback
`meeting. Such meetings are used to discuss the quality of the application and to
`evaluate the communication process during drug development and marketing
`application review. The purpose is to learn from successful aspects of the review
`process and to identify areas that could benefit from improvement. If you would like to
`have such a meeting with us, call the Regulatory Project Manager for this application.
`
`If you have any questions, call Dheera Semidey, Regulatory Project Manager, at
`301-796-3009.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Peter P. Stein, MD
`Director
`Office of New Drugs
`Center for Drug Evaluation and Research
`
`ENCLOSURE(S):
` Content of Labeling
`o Prescribing Information
`o Outer Carton (Trade)
`o Outer Carton (Sample)
`o Inner Carton (Trade)
`o Inner Carton (Sample)
`o Vial Label (Trade)
`o Vial Label (Sample)
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4502977
`
`Novartis Exhibit 2294.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`PETER P STEIN
`10/07/2019 05:49:20 PM
`
`Reference ID: 4502977
`
`Novartis Exhibit 2294.0010
`Regeneron v. Novartis, IPR2021-00816
`
`