` BLA 125156/S-110
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` Page 4
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` HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use
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` LUCENTIS safely and effectively. See full prescribing information for
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`LUCENTIS.
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` LUCENTIS® (ranibizumab injection)
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`Intravitreal Injection
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`Initial U.S. Approval: 2006
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`--------------------------RECENT MAJOR CHANGES-----------------­
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`Dosage and Administration, Preparation for Administration (2.6) XX/2016
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`Dosage and Administration, Administration (2.7)
`XX/2016
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`--------------------------INDICATIONS AND USAGE------------------­
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`LUCENTIS, a vascular endothelial growth factor (VEGF) inhibitor, is
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`indicated for the treatment of patients with:
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` Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1.1)
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` Macular Edema Following Retinal Vein Occlusion (RVO) (1.2)
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` Diabetic Macular Edema (DME) (1.3)
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` Diabetic Retinopathy in patients with DME (1.4)
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`----------------------DOSAGE AND ADMINISTRATION-------------­
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`For Ophthalmic Intravitreal Injection Only (2.1)
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`Neovascular (Wet) Age-Related Macular Degeneration (AMD) (2.2)
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`LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
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`intravitreal injection once a month (approximately 28 days).
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`Although not as effective, patients may be treated with 3 monthly doses
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`followed by less frequent dosing with regular assessment.
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`Although not as effective, patients may also be treated with one dose every 3
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`months after 4 monthly doses. Patients should be assessed regularly.
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`Macular Edema Following Retinal Vein Occlusion (RVO) (2.3)
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` LUCENTIS 0.5 mg (0.05 mL) is recommended to be administered by
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`intravitreal injection once a month (approximately 28 days).
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`Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) in
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`patients with Diabetic Macular Edema (2.4, 2.5)
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`LUCENTIS 0.3 mg (0.05 mL) is recommended to be administered by
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`
`intravitreal injection once a month (approximately 28 days).
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`---------------------DOSAGE FORMS AND STRENGTHS-----------­
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`Single-use prefilled syringe designed to provide 0.05 mL for intravitreal
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`injections:
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` 10 mg/mL solution (LUCENTIS 0.5 mg) (3)
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`Single-use glass vial designed to provide 0.05 mL for intravitreal injections:
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` 10 mg/mL solution (LUCENTIS 0.5 mg) (3)
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` 6 mg/mL solution (LUCENTIS 0.3 mg) (3)
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`------------------------------CONTRAINDICATIONS-------------------­
` Ocular or periocular infections (4.1)
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` Hypersensitivity (4.2)
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`-----------------------WARNINGS AND PRECAUTIONS-------------­
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` Endophthalmitis and retinal detachments may occur following intravitreal
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`injections. Patients should be monitored following the injection (5.1).
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` Increases in intraocular pressure (IOP) have been noted both pre- and
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`post-intravitreal injection (5.2).
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` There is a potential risk of arterial thromboembolic events following
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`intravitreal use of VEGF inhibitors (5.3).
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` Fatal events occurred more frequently in patients with DME and DR at
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`baseline, who were treated monthly with LUCENTIS compared with
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`control (5.4).
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`------------------------------ADVERSE REACTIONS--------------------­
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` The most common adverse reactions (reported more frequently in
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`LUCENTIS-treated subjects than control subjects) are conjunctival
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`hemorrhage, eye pain, vitreous floaters, and increased IOP (6.2).
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`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
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`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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`See 17 for PATIENT COUNSELING INFORMATION.
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`Revised: XX/2016
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`_____________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
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`6.2 Clinical Studies Experience
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`INDICATIONS AND USAGE
`1
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`Immunogenicity
`6.3
`1.1 Neovascular (Wet) Age-Related Macular Degeneration
`Postmarketing Experience
`6.4
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`7 DRUG INTERACTIONS
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`(AMD)
`8 USE IN SPECIFIC POPULATIONS
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`1.2 Macular Edema Following Retinal Vein Occlusion
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`(RVO)
`Pregnancy
`8.1
`1.3 Diabetic Macular Edema (DME)
`8.3 Nursing Mothers
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`1.4 Diabetic Retinopathy in patients with DME
`Pediatric Use
`8.4
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`2 DOSAGE AND ADMINISTRATION
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`8.5 Geriatric Use
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`10 OVERDOSAGE
`2.1 General Dosing Information
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`11 DESCRIPTION
`2.2 Neovascular (Wet) Age-Related Macular Degeneration
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`12 CLINICAL PHARMACOLOGY
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`(AMD)
`2.3 Macular Edema Following Retinal Vein Occlusion
`12.1 Mechanism of Action
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`(RVO)
`12.2 Pharmacodynamics
`2.4 Diabetic Macular Edema (DME)
`12.3 Pharmacokinetics
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`13 NONCLINICAL TOXICOLOGY
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`2.5 Diabetic Retinopathy in patients with DME
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`Preparation for Administration
`2.6
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`14 CLINICAL STUDIES
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`2.7 Administration
`3 DOSAGE FORMS AND STRENGTHS
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`14.1 Neovascular (Wet) Age-Related Macular Degeneration
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`4 CONTRAINDICATIONS
`(AMD)
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`4.1 Ocular or Periocular Infections
`14.2 Macular Edema Following Retinal Vein Occlusion
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`4.2 Hypersensitivity
`(RVO)
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`5 WARNINGS AND PRECAUTIONS
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`14.3 Diabetic Macular Edema (DME)
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`Endophthalmitis and Retinal Detachments
`5.1
`14.4 Diabetic Retinopathy in patients with DME
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`Increases in Intraocular Pressure
`5.2
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`17 PATIENT COUNSELING INFORMATION
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`Thromboembolic Events
`5.3
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`Fatal Events in Patients with DME and DR at baseline
`5.4
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`6 ADVERSE REACTIONS
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`Injection Procedure
`6.1
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`* Sections or subsections omitted from the Full Prescribing Information are
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`not listed.
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`Reference ID: 3998669
`
`Regeneron Exhibit 1200.001
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-110
`
` Page 5
`
` FULL PRESCRIBING INFORMATION
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`1
` INDICATIONS AND USAGE
` LUCENTIS is indicated for the treatment of patients with:
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` 1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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` 1.2 Macular Edema Following Retinal Vein Occlusion (RVO)
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` 1.3 Diabetic Macular Edema (DME)
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` 1.4 Diabetic Retinopathy (Non Proliferative Diabetic Retinopathy (NPDR), Proliferative Diabetic
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` Retinopathy (PDR)) in patients with Diabetic Macular Edema (DME)
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`2
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` DOSAGE AND ADMINISTRATION
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` 2.1 General Dosing Information
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` FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.
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` 2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
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` LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS solution) is recommended to be administered by
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` intravitreal injection once a month (approximately 28 days).
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` Although not as effective, patients may be treated with 3 monthly doses followed by less frequent dosing with
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` regular assessment. In the nine months after 3 initial monthly doses, less frequent dosing with 4-5 doses on
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` average is expected to maintain visual acuity while monthly dosing may be expected to result in an additional
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` average 1-2 letter gain. Patients should be assessed regularly [see Clinical Studies (14.1)].
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` Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses.
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` Compared with continued monthly dosing, dosing every 3 months over the next 9 months will lead to an
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` approximate 5-letter (1-line) loss of visual acuity benefit, on average. Patients should be assessed regularly [see
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` Clinical Studies (14.1)].
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` 2.3 Macular Edema Following Retinal Vein Occlusion (RVO)
` LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS solution) is recommended to be administered by
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` intravitreal injection once a month (approximately 28 days).
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` In Studies RVO-1 and RVO-2, patients received monthly injections of LUCENTIS for 6 months. In spite of
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` being guided by optical coherence tomography and visual acuity re-treatment criteria, patients who were then
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` not treated at Month 6 experienced on average, a loss of visual acuity at Month 7, whereas patients who were
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` treated at Month 6 did not. Patients should be treated monthly [see Clinical Studies (14.2)].
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` 2.4 Diabetic Macular Edema (DME)
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` LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL LUCENTIS solution) is recommended to be administered by
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` intravitreal injection once a month (approximately 28 days).
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` 2.5 Diabetic Retinopathy in patients with Diabetic Macular Edema
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` LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL LUCENTIS solution) is recommended to be administered by
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` intravitreal injection once a month (approximately 28 days).
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`Reference ID: 3998669
`
`Regeneron Exhibit 1200.002
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-110
`
` Page 6
`
`
`
` 2.6 Preparation for Administration
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` LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL LUCENTIS solution) is recommended to be administered by
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` intravitreal injection once a month (approximately 28 days).
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` 2.6 Preparation for Administration
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` Prefilled Syringe:
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` To prepare LUCENTIS for intravitreal administration, please adhere to
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` these instructions for use. Read all the instructions carefully before using
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` the prefilled syringe.
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` How to store LUCENTIS:
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` LUCENTIS should be refrigerated at 2º-8ºC (36º-46ºF). Do not freeze.
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`  Do not use beyond the expiration date stamped on the label.
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` LUCENTIS prefilled syringes should be protected from light and
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` stored in a dark place.
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`  Do not open the sealed tray until time of use.
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` The prefilled syringe is for single use only. The prefilled syringe is sterile.
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` Do not use the product if the packaging is damaged or has been
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` The opening of the sealed tray and all subsequent steps should be done
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` For the intravitreal injection, a 30-gauge x ½ inch sterile injection needle
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` Note: the dose must be set to 0.05 mL.
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`______________________________________________________________________________
` Device description
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`______________________________________________________________________________
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`______________________________________________________________________________
` Step 1: Prepare
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`______________________________________________________________________________
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` Make sure that your pack contains a sterile prefilled syringe
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`in a sealed tray.
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`Reference ID: 3998669
`
`Regeneron Exhibit 1200.003
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-110
`Page 7
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`  Peel the lid off the syringe tray and, using aseptic technique,
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` remove the syringe.
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`______________________________________________________________________________
` Step 2: Inspect syringe
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`______________________________________________________________________________
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`
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`LUCENTIS should be colorless to pale yellow.
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` Do not use the prefilled syringe if:
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`the syringe cap is detached from the Luer lock.
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`particulates, cloudiness, or discoloration are visible.
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`______________________________________________________________________________
` Step 3: Remove syringe cap
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`______________________________________________________________________________
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`Snap off (do not turn or twist)
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`the syringe cap (see Figure 2).
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`______________________________________________________________________________
` Step 4: Attach needle
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`______________________________________________________________________________
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` Attach a 30G x ½ inch sterile
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`injection needle firmly onto
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`the syringe by screwing it
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`tightly onto the Luer lock (see
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`Figure 3).
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` Carefully remove the needle
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`cap by pulling it straight off.
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`Note: Do not wipe the needle at
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`any time.
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`______________________________________________________________________________
` Step 5: Dislodge air bubbles
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`______________________________________________________________________________
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`  Hold the syringe with the
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` needle pointing up.
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` If there are any air bubbles,
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` gently tap the syringe with
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` rise to the top (see Figure 4).
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`
`Reference ID: 3998669
`
`Regeneron Exhibit 1200.004
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-110
`
` Page 8
`
`______________________________________________________________________________
` Step 6: Expel air and adjust drug dose
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` Hold the syringe at eye
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`level, and carefully push the
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`plunger rod until the edge
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`below the dome of the
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`rubber stopper is aligned
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`with the 0.05 mL dose mark
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`(see Figure 5).
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`Note: The plunger rod is not
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`attached to the rubber
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`stopper – this is to
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`prevent air being drawn
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`into the syringe.
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`______________________________________________________________________________
` Step 7: Inject
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`The injection procedure should be carried out under aseptic
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`Insert the needle into the injection site.
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`Inject slowly until rubber stopper reaches the bottom of the
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` After injection, do not recap the needle or detach it from the
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`Vial:
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`Using aseptic technique, all of the LUCENTIS vial contents are withdrawn through a 5-micron, 19-gauge filter
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`needle attached to a 1-cc tuberculin syringe. The filter needle should be discarded after withdrawal of the vial
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`30-gauge x 1/2-inch needle for the intravitreal injection. The contents should be expelled until the plunger tip is
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`2.7 Administration
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`The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include the
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`use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a
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`Prior to and 30 minutes following the intravitreal injection, patients should be monitored for elevation in
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`intraocular pressure using tonometry. Monitoring may also consist of a check for perfusion of the optic nerve
`
`Reference ID: 3998669
`
`Regeneron Exhibit 1200.005
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-110
`
` Page 9
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` Each prefilled syringe or vial should only be used for the treatment of a single eye. If the contralateral eye
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` No special dosage modification is required for any of the populations that have been studied (e.g., gender,
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`3
` DOSAGE FORMS AND STRENGTHS
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` Single-use prefilled syringe designed to provide 0.05 mL for intravitreal injection.
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`  10 mg/mL solution (LUCENTIS 0.5 mg)
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` Single-use glass vial designed to provide 0.05 mL for intravitreal injection.
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`  10 mg/mL solution (LUCENTIS 0.5 mg)
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`  6 mg/mL solution (LUCENTIS 0.3 mg)
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`4
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`CONTRAINDICATIONS
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`4.1 Ocular or Periocular Infections
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`LUCENTIS is contraindicated in patients with ocular or periocular infections.
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`4.2 Hypersensitivity
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`LUCENTIS is contraindicated in patients with known hypersensitivity to ranibizumab or any of the excipients
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`in LUCENTIS. Hypersensitivity reactions may manifest as severe intraocular inflammation.
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Endophthalmitis and Retinal Detachments
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`Intravitreal injections, including those with LUCENTIS, have been associated with endophthalmitis and retinal
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`detachments. Proper aseptic injection technique should always be used when administering LUCENTIS. In
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`addition, patients should be monitored following the injection to permit early treatment should an infection
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`occur [see Dosage and Administration (2.6, 2.7) and Patient Counseling Information (17)].
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`5.2 Increases in Intraocular Pressure
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`Increases in intraocular pressure have been noted both pre-injection and post-injection (at 60 minutes) while
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`being treated with LUCENTIS. Monitor intraocular pressure prior to and following intravitreal injection with
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`LUCENTIS and manage appropriately [see Dosage and Administration (2.7)].
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`5.3 Thromboembolic Events
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`Although there was a low rate of arterial thromboembolic events (ATEs) observed in the LUCENTIS clinical
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`trials, there is a potential risk of ATEs following intravitreal use of VEGF inhibitors. ATEs are defined as
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`nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause).
`
`Reference ID: 3998669
`
`Regeneron Exhibit 1200.006
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-110
`
` Page 10
`
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` Neovascular (Wet) Age-Related Macular Degeneration
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` The ATE rate in the three controlled neovascular AMD studies (AMD-1, AMD-2, AMD-3) during the first year
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` was 1.9% (17 of 874) in the combined group of patients treated with 0.3 mg or 0.5 mg LUCENTIS compared
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` with 1.1% (5 of 441) in patients from the control arms [see Clinical Studies (14.1)]. In the second year of
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` Studies AMD-1 and AMD-2, the ATE rate was 2.6% (19 of 721) in the combined group of LUCENTIS-treated
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` patients compared with 2.9% (10 of 344) in patients from the control arms. In Study AMD-4, the ATE rates
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` observed in the 0.5 mg arms during the first and second year were similar to rates observed in Studies AMD-1,
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` AMD-2, and AMD-3.
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` In a pooled analysis of 2-year controlled studies (AMD-1, AMD-2, and a study of LUCENTIS used
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` stroke) was 2.7% (13 of 484) in patients treated with 0.5 mg LUCENTIS compared to 1.1% (5 of 435) in
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` patients in the control arms (odds ratio 2.2 (95% confidence interval (0.8-7.1))).
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` Macular Edema Following Retinal Vein Occlusion
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` The ATE rate in the two controlled RVO studies during the first 6 months was 0.8% in both the LUCENTIS
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` and control arms of the studies (4 of 525 in the combined group of patients treated with 0.3 mg or 0.5 mg
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` LUCENTIS and 2 of 260 in the control arms) [see Clinical Studies (14.2)]. The stroke rate was 0.2% (1 of 525)
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` in the combined group of LUCENTIS-treated patients compared to 0.4% (1 of 260) in the control arms.
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` Diabetic Macular Edema and Diabetic Retinopathy
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` Safety data are derived from studies D-1 and D-2. All enrolled patients had DME and DR at baseline [see
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` Clinical Studies (14.3, 14.4)].
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` In a pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3)], the ATE rate at 2 years was 7.2% (18
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` of 250) with 0.5 mg LUCENTIS, 5.6% (14 of 250) with 0.3 mg LUCENTIS, and 5.2% (13 of 250) with control.
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` The stroke rate at 2 years was 3.2% (8 of 250) with 0.5 mg LUCENTIS, 1.2% (3 of 250) with 0.3 mg
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` LUCENTIS, and 1.6% (4 of 250) with control. At 3 years, the ATE rate was 10.4% (26 of 249) with 0.5 mg
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` LUCENTIS and 10.8% (27 of 250) with 0.3 mg LUCENTIS; the stroke rate was 4.8% (12 of 249) with 0.5 mg
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` LUCENTIS and 2.0% (5 of 250) with 0.3 mg LUCENTIS.
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` 5.4 Fatal Events in Patients with DME and DR at baseline
` Diabetic Macular Edema and Diabetic Retinopathy
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` Safety data are derived from studies D-1 and D-2. All enrolled patients had DME and DR at baseline [see
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` Clinical Studies (14.3, 14.4)].
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` A pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3)], showed that fatalities in the first 2 years
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` occurred in 4.4% (11 of 250) of patients treated with 0.5 mg LUCENTIS, in 2.8% (7 of 250) of patients treated
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` with 0.3 mg LUCENTIS, and in 1.2% (3 of 250) of control patients. Over 3 years, fatalities occurred in 6.4%
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` (16 of 249) of patients treated with 0.5 mg LUCENTIS and in 4.4% (11 of 250) of patients treated with 0.3 mg
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` LUCENTIS. Although the rate of fatal events was low and included causes of death typical of patients with
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` advanced diabetic complications, a potential relationship between these events and intravitreal use of VEGF
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` inhibitors cannot be excluded.
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` 6 ADVERSE REACTIONS
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` The following adverse reactions are discussed in greater detail in the Warnings and Precautions (5) section of
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` the label:
`
`  Endophthalmitis and Retinal Detachments
`
`
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`
`
`Reference ID: 3998669
`
`Regeneron Exhibit 1200.007
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-110
`
` Page 11
`
`  Increases in Intraocular Pressure
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`  Thromboembolic Events
`  Fatal Events in patients with DME and DR at baseline
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` 6.1 Injection Procedure
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` Serious adverse reactions related to the injection procedure have occurred in < 0.1% of intravitreal injections,
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` including endophthalmitis [see Warnings and Precautions (5.1)], rhegmatogenous retinal detachment, and
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` iatrogenic traumatic cataract.
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` 6.2 Clinical Studies Experience
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` Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one
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` clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug
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` and may not reflect the rates observed in practice.
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` The data below reflect exposure to 0.5 mg LUCENTIS in 440 patients with neovascular AMD in Studies AMD­
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` 1, AMD-2, and AMD-3, and 259 patients with macular edema following RVO. The data also reflect exposure
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` to 0.3 mg LUCENTIS in 250 patients with DME and DR at baseline [see Clinical Studies (14)].
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` Safety data observed in Study AMD-4 were consistent with these results. On average, the rates and types of
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` adverse reactions in patients were not significantly affected by dosing regimen.
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` Ocular Reactions
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` Table 1 shows frequently reported ocular adverse reactions in LUCENTIS-treated patients compared with the
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` control group.
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`
`Reference ID: 3998669
`
`Regeneron Exhibit 1200.008
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-110
`
` Page 12
`
` Table 1
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`Ocular Reactions in the DME and DR, AMD, and RVO Studies
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` DME
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` and DR
`2-year
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`AMD
`2-year
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`AMD
`1-year
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`RVO
`6-month
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`Control
`0.5 mg
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`LUCENTIS
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`Control
`0.5 mg
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`LUCENTIS
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`Control
`0.5 mg
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`LUCENTIS
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`Control
`0.3 mg
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`LUCENTIS
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`n=250 n=250
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`n=379 n=379
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`n=440 n=441
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`n=259 n=260
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`47% 32% 74% 60% 64% 50% 48% 37%
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`17% 13% 35% 30% 26% 20% 17% 12%
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`10% 4% 27% 8% 19% 5% 7% 2%
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`18% 7% 24% 7% 17% 5% 7% 2%
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`11% 15% 21% 19% 15% 15% 4% 2%
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`4% 3% 18% 8% 13% 7% 1% 3%
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`28% 32% 17% 14% 11% 9% 2% 2%
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`10% 5% 16% 14% 13% 10% 7% 5%
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`8% 5% 15% 15% 13% 12% 7% 6%
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`5% 4% 14% 12% 8% 8% 2% 3%
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`3% 2% 12% 8% 8% 5% 0% 1%
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` Adverse Reaction
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` Conjunctival
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`hemorrhage
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` Eye pain
` Vitreous
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`floaters
` Intraocular
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` pressure
`increased
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` Vitreous
`detachment
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` Intraocular
`inflammation
`Cataract
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` Foreign body
` sensation in
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`eyes
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` Eye irritation
` Lacrimation
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`increased
`Blepharitis
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`5% 3% 12% 7% 7% 7% 3% 3%
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`8% 4% 18% 15% 13% 10% 5% 3%
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`4% 4% 12% 11% 9% 7% 1% 2%
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`9% 9% 11% 8% 7% 4% 5% 3%
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` Dry eye
` Visual
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` disturbance or
` vision blurred
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` Eye pruritis
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` Ocular
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`hyperemia
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` Retinal disorder 2% 2% 10% 7% 8% 4% 2% 1%
`Maculopathy
`5% 7% 9% 9% 6% 6% 11% 7%
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` Retinal
`degeneration
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` Ocular
`discomfort
` Conjunctival
`hyperemia
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` Posterior
`
` capsule
`opacification
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` Injection site
`hemorrhage
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`1% 0% 8% 6% 5% 3% 1% 0%
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`2% 1% 7% 4% 5% 2% 2% 2%
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`1% 2% 7% 6% 5% 4% 0% 0%
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`4% 3% 7% 4% 2% 2% 0% 1%
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`1% 0% 5% 2% 3% 1% 0% 0%
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`Reference ID: 3998669
`
`Regeneron Exhibit 1200.009
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

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` BLA 125156/S-110
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` Page 13
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` Non-Ocular Reactions
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` Non-ocular adverse reactions with an incidence of ≥ 5% in patients receiving LUCENTIS for DR, DME, AMD,
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` and/or RVO and which occurred at a ≥ 1% higher frequency in patients treated with LUCENTIS compared to
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` control are shown in Table 2. Though less common, wound healing complications were also observed in some
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`studies.
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` Table 2
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` Non-Ocular Reactions in the DME and DR, AMD and RVO Studies
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`DME
`and DR
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`2-year
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`AMD
`2-year
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`AMD
`1-year
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`RVO
`6-month
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`Control
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`0.5 mg
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`LUCENTIS
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`Control
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`0.5 mg
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`LUCENTIS
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`Control
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`0.5 mg
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`LUCENTIS
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`Control
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`0.3 mg
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`LUCENTIS
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`n=250 n=250
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`n=379 n=379
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`n=440 n=441
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`n=259 n=260
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` Adverse Reaction
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`Nasopharyngitis
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`Anemia
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`12%
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`11%
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`6%
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`10%
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`16%
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`13%
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`8%
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`7%
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`8%
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`4%
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`9%
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`3%
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`5%
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`1%
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`1%
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`4%
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`1%
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`2%
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`Nausea
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`Cough
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`Constipation
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` Seasonal allergy
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`Hypercholesterolemia
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`Influenza
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`10%
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`9%
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`8%
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`8%
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`7%
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`7%
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`7%
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`9%
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`4%
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`4%
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`4%
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`5%
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`3%
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`6%
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`9%
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`9%
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`5%
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`4%
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`5%
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`7%
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`1%
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`6%
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`8%
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`7%
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`4%
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`5%
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`5%
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`1%
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`5%
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`5%
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`3%
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`2%
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`3%
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`3%
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`0%
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`5%
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`4%
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`4%
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`2%
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`2%
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`2%
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`0%
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`1%
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`0%
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`0%
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`1%
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`3%
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`0%
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`2%
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`1%
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`2%
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`1%
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`2%
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`0%
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` Renal failure
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` Upper respiratory tract
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`infection
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` Gastroesophageal
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` reflux disease
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`Headache
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` Edema peripheral
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` Renal failure chronic
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`7%
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`7%
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`9%
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`8%
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`5%
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`5%
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`2%
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`2%
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`6%
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`6%
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`6%
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`6%
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`5%
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`4%
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`8%
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`4%
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`2%
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`3%
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`4%
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`12%
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`3%
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`0%
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`1%
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`6%
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`9%
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`5%
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`1%
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`1%
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`3%
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`6%
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`2%
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`0%
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`1%
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`4%
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`5%
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`3%
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`0%
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`0%
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`1%
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`3%
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`0%
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`0%
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`0%
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`0%
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`3%
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`1%
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`0%
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`0%
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` Neuropathy peripheral
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`Sinusitis
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`Bronchitis
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` Atrial fibrillation
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`Arthralgia
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` Chronic obstructive
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` pulmonary disease
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` Wound healing
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`complications
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`5%
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`4%
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`3%
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`3%
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`1%
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`8%
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`4%
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`3%
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`3%
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`1%
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`8%
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`11%
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`5%
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`11%
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`6%
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`7%
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`9%
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`4%
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`9%
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`3%
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`5%
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`6%
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`2%
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`5%
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`3%
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`5%
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`5%
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`2%
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`5%
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`1%
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`3%
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`0%
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`1%
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`2%
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`0%
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`2%
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`2%
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`0%
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`1%
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`0%
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`1%
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`0%
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`1%
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`1%
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`1%
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`0%
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`0%
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`0%
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`Reference ID: 3998669
`
`Regeneron Exhibit 1200.010
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
` BLA 125156/S-110
`
` Page 14
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`6.3 Immunogenicity
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`As with all therapeutic proteins, there is the potential for an immune response in patients treated with
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`LUCENTIS. The immunogenicity data reflect the percentage of patients whose test results were considered
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`positive for antibodies to LUCENTIS in immunoassays and are highly dependent on the sensitivity and
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`specificity of the assays.
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`The pre-treatment incidence of immunoreactivity to LUCENTIS was 0%-5% across treatment groups. After
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`monthly dosing with LUCENTIS for 6 to 24 months, antibodies to LUCENTIS were detected in approximately
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`1%-9% of patients.
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`The clinical significance of immunoreactivity to LUCENTIS is unclear at this time. Among neovascular AMD
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`patients with the highest levels of immunoreactivity, some were noted to have iritis or vitritis. Intraocular
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`inflammation was not observed in patients with DME and DR at baseline, or RVO patients with the highest
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`levels of immunoreactivity.
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`6.4 Postmarketing Experience
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`The following adverse reactions have been identified during post-approval use of LUCENTIS. Because these
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`reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
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`estimate their frequency or establish a causal relationship to drug exposure.
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` Ocular: Tear of retinal pigment epithelium among patients with neovascular AMD
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`7
`DRUG INTERACTIO