`Carter, eta!.
`Application Under 35 U.S.C. § 156
`
`Page 11
`
`Exemption under FDCA § 505(i)
`became effective
`
`Patent was granted
`
`Biologics License Application (BLA)
`under PHSA § 351 was filed
`
`BLA was approved
`
`October 7, 1999
`
`June 18, 2002
`
`December 29,2005
`
`June 30, 2006
`
`(ii)
`
`(iii)
`
`(iv)
`
`The '213 patent was granted during the period specified in
`§ 156(g)( 1 )(B)(i) (i.e., the period from the date of the grant of the
`exemption under § 505(i) of the FDCA until the date of submission of the
`BLA). Pursuant to§ 156(b) and (c)(2), the calculated regulatory review
`period therefore includes a component of time between when the patent
`was granted and when the BLA was submitted (1/2 of 1289 days or 644
`days).
`
`The patent was granted prior to the start of the period specified in
`§ 156(g)(l)(B)(ii) (i.e., the period from the date of submission ofthe BLA
`until the date of approval). The regulatory review period under § 156(b)
`therefore includes a component equal to the total number of days in that
`period that are after the BLA was submitted (184 days).
`
`The period determined according to § 156(b ), ( c )(2), and (g)( 1) for the
`approved product (i.e., the number of days following the date of issue of
`the patent between the dates of submission and of approval of the BLA for
`LUCENTIS™) is 828 days.
`
`( v)
`
`The '213 patent will expire on June 18, 2019.
`
`(vi)
`
`The date of approval of the approved product is June 30, 2006.
`
`(vii) The date that is fourteen years from the date of approval of the approved
`product is June 30, 2020.
`
`(viii) The period measured from the date the patent expires (i.e., June 18, 2019)
`until the end of the fourteen-year period specified in §156 (c)(3) (i.e., June
`30, 2020) is approximately 1 year and 13 days or 378 days.
`
`(ix)
`
`The number of days in the regulatory review period determined pursuant
`to § 156(g)( 1 )(B)(ii) (i.e., 828 days) exceeds the number of days that the
`
`PFIZER EX. 1502
`Page 4501
`
`
`
`U.S. Patent No. 6,407,213
`Carter, eta/.
`Application Under 35 U.S.C. § 156
`
`Page 12
`
`patent may be extended pursuant to § 156( c )(3). As such, the period by
`which the patent may be extended is limited by the fourteen-year rule of
`§156(c)(3) to 378 days.
`
`(x)
`
`The '213 patent issued after the effective date of Public Law No. 98-417.
`As such, the two- or three-year limit of 35 U.S.C. § 156(g)(6)(C) does not
`apply.
`
`13.
`
`Statement Pursuant to 37 C.F.R. § 1. 740(a)(13)
`
`Pursuant to 37 C.F.R. § 1.740(a)(13), Applicant acknowledges its duty to disclose to the
`Director of the PTO and to the Secretary ofHealth and Human Services any information which
`is material to the determination of entitlement to the extension sought, particularly as that duty is
`defined in 37 C.F.R. § 1.765.
`
`14.
`
`Applicable Fee[§ 1.740(a)(14)}
`
`Our check in payment of the fee prescribed in 37 C.F.R. § 1.200) for a patent term
`extension application under 35 U.S.C. § 156 accompanies this application. Please deduct any
`additional required fees from, or credit any overpayments to our deposit account no. 18-1260.
`
`15.
`
`Name and Address for Correspondence[§ 1.740(a)(14)]
`
`Please direct all inquiries, questions, and communications regarding this application for
`term extension to:
`
`Jeffrey P. Kushan
`SIDLEY AUSTIN LLP
`1501 K Street, N.W.
`Washington, D.C. 20005
`Phone:202-736-8914
`Fax:
`202-736-8111
`email: jkushan@sidley.com
`
`The correspondence address for U.S. Patent No. 6,407,213 is unchanged for all other purposes. A
`Power of Attorney granted to the undersigned by the patent assignee, a copy of which is included
`with this application as Attachment K, accompanies this communication.
`
`PFIZER EX. 1502
`Page 4502
`
`
`
`U.S. Patent No. 6,407,213
`Carter, et al.
`Application Under 35 U.S.C. § 156
`
`Page 13
`
`Two additional copies of this application are enclosed, in compliance with 37 C.F.R.
`§ 1.740(b). Applicant also provides herewith two further copies of the application for the
`convenience of the Office, pursuant to M.P.E.P. § 2763.
`
`Sincerely,
`
`f!i~
`
`Attorney for Applicant
`Registration No. 43,401
`
`Sidley Austin LLP
`1501 K Street, N.W.
`Washington, D.C. 20005
`
`. .
`
`Dated: August 25"', 2006
`
`PFIZER EX. 1502
`Page 4503
`
`
`
`INDEX OF ATTACHMENTS
`
`Attachment A: Lucentis™ Product Label
`
`Attachment B: Lucentis™ Biologics' License Application Approval
`
`Attachment C: U.S. Patent No. 6,407,213
`
`Attachment D: Certificate of Correction of U.S. Patent No. 6,407,213
`
`Attachment E: Receipt of Maintenance Fee Payment for U.S. Patent No. 6,407,213
`
`Attachment F: Chen et al., "Selection and Analysis of an Optimized Anti-VEGF Antibody:
`Crystal Structure of an Affinity-Matured Fab in Complex with Antigen." J.
`Mol. Bio., 293:865-881 ( 1999).
`
`Attachment G:
`
`Figures IA, IB, lOA and lOB ofWO 98/45331
`
`Attachment H:
`
`10113/99 Letter from FDA to Genentech regarding IND acceptance/effective
`d~e
`
`• •
`
`Attachment 1:
`
`01/27/06 Letter from the FDA to Genentech regarding receipt and acceptance
`of BLA Application
`
`Attachment J:
`
`03/14/06 Letter from the FDA to Genentech regarding 02/28/06 filing ofBLA,
`and 06/30/06 assignation of User Fee Goal Date
`
`Attachment K:
`
`Power of Attorney by Assignee
`
`PFIZER EX. 1502
`Page 4504
`
`
`
`Page 4505
`
`PFIZER EX. 1502
`
`PFIZER EX. 1502
`Page 4505
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed
`to use LUCENTIS safely and effectively. See full
`prescribing information for LUCENTIS.
`
`LUCENTISTM (ranibizumab injection)
`
`Initial U.S. Approval: 2006
`
`--------··-------INDICATIONS AND USAGE-----------------~-
`
`LUCENTIS is indicated for the treatment of patients with
`neovascular (wet) age-related macular degeneration (I).
`
`------------DOSAGE AND ADMINISTRATION---------------
`
`•
`
`•
`•
`
`FOR OPHTHALMIC INTRA VITREAL INJECTION
`ONLY (2.1)
`
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be
`administered by intravitreal injection once a month (2.2).
`Although less effective. treatment may be reduced to one
`injection every three months after the first four injections
`if monthly injections are not feasible. Compared'to
`continued monthly dosing, dosing every 3 months will
`lead to an approximate 5-letter (l-line} loss of visual
`acuity benefit, on average, over the following 9 months.
`Patients should be evaluated regularly(~.::!).
`
`-------------DOSAGE FORMS AND STRENGTHS----···-----
`•
`I 0 mg/mL single-use vial (3)
`
`---------------------CONTRAINDICA TIONS-------------·------
`•
`Ocular or periocular infections ( 4.1)
`•
`Hypersensitivity (4.2)
`
`--------------WARNINGS AND PRECAUTIONS-------·------
`•
`Endophthalmitis and retinal detachments may occur
`following intravitreal injections. Patients should be
`monitored during the week following the injection (5 I).
`Increases in intraocular pressure have been noted wi1hin
`60 minutes of intravitreal injection (5.2).
`
`•
`
`--------------------ADVERSE REACTIONS--------------------(cid:173)
`The most common adverse reactions (reported ~ o'K higher in
`LUCENTIS-treated subjects than control subjects) are
`conjunctival hemorrhage, eye pain. vitreous floaters, increased
`intraocular pressure, and intraocular inllammation (6.~).
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`Genentech at 1-888-835-2555 or FDA at l-800-FDA-1088
`or www.fda.gov/medwatch.
`
`See Section 17 for PATIENT COUNSELING
`INFORMATION.
`
`3
`4
`
`5
`
`6
`
`FULL PRESCRIBING INFORiVIA TION: CONTENTS*
`1
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2
`2.1
`General Dosing Information
`2.2 Dosing
`2.3
`Preparation for Administration
`2.4 Administration
`2.5
`Stability and Storage
`DOSAGEFORMSANDSTRENGTHS
`CONTRA INDICATIONS
`4.1 Ocular or Periocular Infections
`4.2 Hypersensitivity
`WARNINGS AND PRECAUTIONS
`5.1
`Endophthalmitis and Retinal
`Detachments
`Increases in Intraocular Pressure
`5.2
`Thromboembolic Events
`5.3
`ADVERSE REACTIONS
`6.1
`Injection Procedure
`6.2 Clinical Studies Experience -Ocular
`Events
`Clinical Studies Experience- Non(cid:173)
`Ocular Events
`lmmunogenicity
`6.4
`DRUG INTERACTIONS
`7
`USE IN SPECIFIC POPULATIONS
`8
`U.S. BLA (Bl125156) Ranibizumab injection
`
`6.3
`
`10
`11
`12
`
`8.1
`Pregnancy
`8.3 Nursing Mothers
`Pediatric Use
`8.4
`8.5 Geriatric Usc
`8.6
`Patients with Renal Impairment
`8.7
`Patients with Hepatic Dy~function
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`CLINICAL STUDIES
`14.1 Study I and Study 2
`14.2 Study 3
`HOW SUPPLIED/STORAGE AND
`HANDLING
`PATIENT COUNSELING INFORMATION
`17
`* Sections or subsections omitted from the Full Prescribing
`Information are not listed.
`
`13
`
`14
`
`16
`
`Genentech, Inc.
`
`PFIZER EX. 1502
`Page 4506
`
`
`
`FULL PRESCRIBING INFORJ\'IA TION
`
`INDICATIONS AND USAGE
`LUCENTIS is indicated for the treatment of patients with
`neovascular (wet) age-related macular degeneration.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`General Dosing Information
`2.1
`FOR OPHTHALMIC INTRA VITREAL INJECTION ONLY.
`
`Dosing
`2.2
`LUCENTIS 0.5 mg (0.05 mL) is recommended to be
`administered by intravitreal injection once a month.
`
`Although less effective, treatment may be reduced to one
`injection every three months after the first four injections if
`monthly injections are not feasible. Compared to continued
`monthly dosing, dosing every 3 months will lead to an
`approximate 5-letter (!-lim!) loss of visual acuity benefit. on
`average, over the following 9 months. Patients should be
`evaluated regularly [see C/iniwl Swdin· ( /-1.2 )].
`
`Preparation for Administration
`2.3
`Using aseptic technique, all (0.2 mL) of the LUCENTIS vial
`contents are withdrawn through a 5-micron 19-gauge filter
`needle attached to a I-cc tuberculin syringe. The filter needle
`should be discarded after withdrawal of the vial contents and
`should not be used for intravitreal injection. The filter needle
`should be replaced with a sterile 30-gauge x 112-inch needle
`for the intravitreal injection. The contents should be expelled
`until the plunger tip is aligned with the line that marks
`0.05 mL on the syringe.
`
`2.4
`Administration
`The intravitreal injection procedure should be carried out·
`under controlled aseptic conditions, which include the use of
`sterile gloves, a sterile drape, and a sterile eyelid speculum (or
`equivalent). Adequate anesthesia and a broad-spectrum
`microbicide should be given prior to the injection.
`
`Following the intravitreal injection, patients should be
`monitored for elevation in intraocular pressure and for
`endophthalmitis. Monitoring may consist of a check for
`perfusion of the optic nerve head immediately after the
`injection, tonometry within 30 minutes following the injection,
`and biomicroscopy between two and seven days following the
`injection. Patients should be instructed to report any
`symptoms suggestive of endophthalmitis without delay.
`
`Each vial should only be used for the treatment of a single eye.
`If the contralateral eye requires treatment, a new vial should
`be used and the sterile field, syringe, gloves, drapes, eyelid
`speculum, filter, and injection needles should be changed
`before LUCENTIS is administered to the other eye.
`
`No special dosage modification is required for any of the
`populations that have been studied (e.g., gender, elderly).
`
`Stability and Storage
`2.5
`LUCENTIS should be refrigerated at 2°-8°C (36"-46°F). DO
`NOT FREEZE. Do not use beyond the date stamped on the
`label. LUCENTIS vials should be protected from light. Store
`in the original carton until time of use.
`
`3
`DOSAGEFORMSANDSTRENGTHS
`Single-use glass vial designed to deliver 0.05 mL of
`10 mg/mL.
`
`4
`
`CONTRAINDICA TIONS
`
`4.1
`Ocular or Periocular Infections
`LUCENTIS is contraindicated in patients with ocular or
`periocular infections.
`
`4.2
`Hypersensitivity
`LUCENTIS is contraindicated in patients with known
`hypersensitivity to ranibizumab or any of the excipients in
`LUCENTIS.
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`Endophthalmitis and Retinal Detachments
`5.1
`lntravitreal injections, including those with LUCENTIS. have
`been associated with endophthalmitis and retinal detachments.
`Proper aseptic injection technique should always be used -
`when administering LUCENTIS. In addition, patients should
`be monitored during the week following the injection to
`permit early treatment should an infection occur [see Doxag<'
`and ,\dminislration (2.3. 2.4) and PatienT Counseling
`lnfomrarion ( 17)].
`
`Increases in Intraocular Pressure
`5.2
`Increases in intraocular pressure have been noted within
`60 minutes ofintravitreal injection with LUCENTIS.
`Therefore, intraocular pressure as well as the perfusion of the
`optic nerve head should be monitored and managed
`appropriately [see Dosa.~e and Adminislmrion (2.4 )].
`
`Thromboembolic Even"ts
`5.3
`Although there was a low rate ( <4%) of arterial
`thromboembolic events observed in the LUCENTlS clinical
`trials, there is. a theoretical risk of arterial thromboembolic
`events following intravitreal use of inhibitors of VEGF [see
`:\drerse R£'actions (li.3 )].
`
`6
`
`ADVERSE REACTIONS
`
`lnjection Procedure
`6.1
`Serious adverse events related to the injection procedure have
`occurred in< 0.1% of intravitreal injections, including
`endophthalmitis (see Wamin,!,'s alllll'recuurions (5.1 )J,
`rhegmatogenous retinal detachments, and iatrogenic traumatic
`cataracts.
`
`Clinical Trials Experience- Ocular Events
`6.2
`Other serious ocular adverse events observed among
`LUCENTIS-treated patients occurring in <2% of patients
`
`U.S. BLA (BL125156} Ranibizumab injection
`
`Genentech, Inc.
`
`PFIZER EX. 1502
`Page 4507
`
`
`
`included intraocular inflammation and increased intraocular
`.pressure [see Warnings and l'rccuwi!ou (5.1. 5.1)1.
`
`The available safety data include exposure to LUCENTIS in
`874 patients with neovascular age-related macular
`degeneration in three double-masked, controlled studies with
`dosage regimens of0.3 mg (375 patients) or 0.5 mg
`(379 patients) administered monthly by intravitreal injection
`(Studies I and 2) [see C/iuical Swdics ( 1-1.1 J] and dosage
`regimens of 0.3 mg (59 patients) or 0.5 mg (6 I patients}
`administered once a month for 3 consecutive doses followed
`by a dose administered once every 3 months (Study 3)
`[see Clinicul S1udies { /-1'2)].
`
`Because clinical trials are conduCted under widely varying
`conditions, adverse reaction rates observed in one clinical trial
`of a drug cannot be directly compared with rates in the clinical
`trials of the same or another drug and may not reflect the rates
`observed in practice.
`
`Table I shows the most frequently reported ocular adverse
`events that were reported with LUCENTIS treatment. The
`ranges represent the maximum and minimum rates across all
`three studies for control, and across all three studies and both
`dose groups for LUCENTIS.
`
`Table I
`LUCENTIS
`77%-43%
`37%-17%
`32%-3%
`26%-15%
`24%-8%
`22%-7%
`18%-5%
`19%-4%
`16%-5%
`
`19%-6%
`
`17%-3%
`13%-0%
`14%-0%
`13%-3%
`13%-0%
`10%-5%
`10%-3%
`
`Adverse Event
`Conjunctival hemorrhage
`Eye pain
`Vitreous floaters
`Retinal hemorrhage
`Intraocular pressure increased
`Vitreous detachment
`Intraocular inflammarion
`Eye irritation
`Cataract
`Foreign body sensation in
`eyes
`Lacrimation increased
`Eye pruritis
`Visual disturbance
`Blepharitis
`Subretinal fibrosis
`Ocular hyperemia
`Maculopathy
`Visual acuity
`blurred/decreased
`Detachment of the retinal
`lp_igment epithelium
`Dry eye
`Ocular discomfort
`Conjunctival hyperemia
`Posterior capsule
`opacification
`Retinal exudates
`
`Control
`66%-29%
`33%-11%
`10%-3%
`56%-37%
`7%-3%
`18%-13%
`II %-3%
`20%-6%
`16%-6%
`
`14%-6%
`
`16%-0%
`12%-3%
`9%-2%
`9%-4%
`19%-lO%
`10%-l%
`11%-3%
`
`17%-4%
`
`24%-10%
`
`ll%-1%
`
`10%-3%
`8%-0%
`9%-0%
`
`8%-0%
`
`9%-1%
`
`15%-3%
`
`8%-5%
`5%-0%
`7%-0%
`
`5%-0%
`
`11%-3%
`
`Clinical Trials Experience- Non-Ocular Events
`6.3 ·
`Table 2 shows the most frequently reponed non-ocular
`adverse events with LUCENTIS treatment. The ranges
`represent the maximum and minimum rates across all three
`s!Udies for control, and across all three srudies and both dose
`groups for LUCENTIS.
`
`Adverse Event
`Hypertension/elevated
`blood pressure
`Nasopharyngitis
`Arthralgia
`Headache
`Bronchitis
`Cough
`Anemia
`Nausea
`Sinusitis
`Upper respiratory tract
`infection
`Back pain
`Urinary tract infection
`Influenza
`Arthritis
`Dizziness
`Constipation
`
`Table 2
`LUCENTIS
`23%-5%
`
`16%-5%
`11%-3%
`15%-2%
`10%-3%
`10%-3%
`8%-3%
`9%-2%
`8%-2%
`15%-2%
`
`10%-l%
`9%-4%
`10%-2%
`8%-0%
`8%-2%
`7%-3%
`
`Control
`23%-8%
`
`13%-5%
`9%-0%
`10%-3%
`8%-2%
`7%-2%
`8%-0%
`6%-4%
`6%-4%
`10%-4%
`
`9%-0%
`8%-5%
`5%-1%
`8%-2% -
`10%-2%
`8%-2%
`
`The rate of arterial thromboembolic events in the three studies
`in the first year was 2.1 % of patients ( 18 out of 87 4) in the
`combined group of patients treated with 0.3 mg or 0.5 mg
`LUCENTIS compared with I .I% of patients (5 out of 441) in
`the control arms of the studies. In the second year of Study I.
`the rate of arterial thromboembolic events was 3.0% of
`patients ( 14 out of 466) in the combined group of patients
`treated with 0.3 mg or 0.5 mg LUCENTIS compared with
`3.2% of patients (7 out of 216} in the control arm (see
`WamingJ a11d Precalifions (5.3 Jl-
`
`6.4
`lmmunogenicity
`The pre-treatment incidence of immunoreactivity to
`LUCENTIS was 0%-3% across treatment groups. After
`monthly dosing with LUCENTIS for i2 to 24 months, low
`titers of antibodies to LUCENTIS were detected in
`approximately l %-6% of patients. The immunogenicity data
`reflect the percentage of patients whose test results were
`considered positive for antibodies to LUCENTIS in an
`electrochemiluminescence assay and are highly dependent on
`the sensitivity and specificity of the assay. The clinical
`significance of immunoreactivity to LUCENTIS is unclear at
`this time, although some patients with the highest levels of
`immunoreactivity were noted to have iritis or vitritis.
`
`DRUG INTERACTIONS
`7
`Drug interaction studies have not been conducted with
`LUCENTIS.
`
`U.S. BLA (Bl125156) Ranibizumab injection
`
`Genentech,lnc.
`
`PFIZER EX. 1502
`Page 4508
`
`
`
`LUCENTIS intravitreal injection has been used adjunctively
`with verteporfin photodynamic therapy (PDT). Twelve of 105
`(II%) patients developed serious intraocular intlammation; in
`I 0 of the 12 patients, this occurred when LUCENTIS was
`administered 7 days (± 2 days) after verteporfin PDT.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Pregnancy Category C. Animal reproduction studies have not
`been conducted with ranibizumab. It is also not known
`whether ranibizumab can cause fetal harm when administered
`to a pregnant woman or can affect reproduction capacity.
`LUCENTIS should be given to a pregnant woman only if
`clearly needed.
`
`Nursing Mothers
`8.3
`It is not known whether ranibizumab is excreted in human
`milk. Because many drugs are excreted in human milk, and
`because the potential for absorption and harm to infant growth
`and development exists, caution should be exercised when
`LUCENTIS is administered to a nursing woman.
`
`Pediatric Use
`8.4
`The safety and effectiveness of LUCENTIS in pediatric
`patients has not been established.
`
`Geriatric Use
`8.5
`ln the controlled clinical studies, approximately 94%
`(822/879) of the patients randomized to treatment with
`LUCENTIS were~ 65 years of age and approximately 68%
`(60 l/879) were 2 75 years of age. No notable difference in
`treatment effect was seen with increasing age in any of the
`studies. Age did not have a significant effect on systemic
`exposure in a population pharmacokinetic analysis after
`correcting for creatinine clearance.
`
`8.6
`Patients with Renal Impairment
`No formal studies have been conducted to examine the
`pharmacokinetics of ranibizumab in patients with renal
`impairment. Sixty-eight percent of patients ( 136 of 200) in the
`population pharmacokinetic analysis had renal impairment
`(46.5% mild, 20% moderate, and 1.5% severe). Reduction in
`ranibizumab clearance is minimal in patients with renal
`impairment and is considered clinically insignificant. Dose
`adjustment is not expected to be needed for patients with renal
`impairmem.
`
`8.7
`Patients with Hepatic Dysfunction
`No formal studies have been conducted to examine the
`pharmacokinetics of ranibizumab in patients with hepatic
`impairment. Dose adjustment is not expected to be needed for
`patients with hepatic dysfunction.
`
`10
`OVERDOSAGE
`Planned initial single doses of ranibizumab injection 1.0 mg
`were associated with clinically significant intraocular
`inflammation in 2 of 2 patients injected. With an escalating
`regimen of doses beginning with initial doses of ranibizumab
`
`injection 0.3 mg. doses as high as 2.0 mg were tolerated in
`I 5 of 20 patients.
`
`DESCRIPTION
`II
`LUCENTIS™ (ranibizumab injection) is a recombinant
`humanized lgG I kappa isotype monoclonal antibody fragment
`designed for intraocular use. Ranibizumab binds to and
`·
`inhibits the biologic activity of human vascular endothelial
`growth factor A (VEGF-A). Ranibizumab has a molecular
`weight of approximately 48 kilodaltons and is produced by an
`E. coli expression system in a nutrient medium containing the
`antibiotic tetracycline. Tetracycline is not detectable in the
`final product.
`
`LUCENTIS is a sterile, colorless to pale yellow solution in a
`single-use glass vial. LUCENTIS is supplied as a
`preservative-free, sterile solution in a single-use glass vial
`designed to deliver 0.05 mL of I 0 mg/mL LUCENT IS
`aqueous solution with 10 mM histidine HCI.
`10% a, a-trehalose dihydrate. 0.01% polysorbate 20. pH 5.5.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`12.1
`Ranibizumab binds to the receptor binding site of active forms
`of VEGF-A, including the biologically active. cleaved form of
`this molecule, VEGF 1.10• VEGF-A has been shown to cau~e
`neovascularization and leakage in models of ocular
`angiogenesis and is thought to contribute to the progression of
`the neova5cular form of age-related macular degeneration
`(AMD). The binding of ranibizumab to VEGF-A prevents the
`interaction of VEGF-A with its receptors (VEGFR l and
`VEGFR2) on the surface of endothelial cells, reducing
`endothelial cell proliferation, vascular leakage, and new blood
`vessel formation.
`
`12.2
`Pharmacodynamics
`Neovascular AMD is associated with foveal retinal thickening
`as assessed by optical coherence tomography (OCT) and
`leakage from CNV as assessed by fluorescein angiography.
`
`In Study 3, foveal retinal thickness was assessed by OCT in
`I I 8/184 patients. OCT measurements were collected at
`baseline, Months I, 2, 3, 5, 8. and I 2. In patients treated with
`LUCENTIS. foveal retinal thickness decreased. on average,
`more than the sham group from baseline through Month 12.
`Retinal thickness decreased by Month I and decreased further
`at Month 3, on average. Foveal retinal thickness data did not
`provide information useful in influencing treatment decisions
`[see Cli11ical Studie.,· ( /4.1)1.
`
`In patients treated with LUCENTIS, the area of vascular
`leakage, on average. decreased by Month 3 as assessed by
`fluorescein angiography. The area of vascular leakage for an
`individual patient was not correlated with visual acuity.
`
`Pharmac(lkinetics
`12.3
`In animal studies, following intravitreal injection, ranibizumab
`was cleared from the vitreous with a half-life of approximately
`3 days. After reaching a maximum at approximately I day,
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`Study 2 received a mean of 12 total treatments out of a
`possible 13 from Day 0 through Month 12.
`
`In both studies, the primary efficacy endpoint was the
`proportion of patients who maintained vision, defined as
`losing fewer than 15 letters of visual acuity at 12 months
`compared with baseline. Almost all LUCENTIS-treated
`patients (approximately 95%) maintained their visual acuity.
`34%-40% of LUCENT IS-treated patients experienced a
`clinically significant improvement in vision, defined as
`gaining 15 or more letters at 12 months. The size of the lesion
`did not significantly affect the results. Detailed results arc
`shown in the tables below.
`
`Table 3
`h ?4. S d
`h 12
`d M
`0 utcomes at M
`an
`ont
`tu ly I
`ont ~ tn
`LUCENTIS
`Estimated
`0.5 mg
`Difference
`(95% co·
`n=240
`32%
`95%
`(26%, 39%)
`37%
`(29%, 44%)
`
`Month
`Month .12
`
`Sham
`n = 238
`62%
`
`Outcome
`Measure
`Loss of
`< 15
`letters in Month 24
`visual
`acuity
`(%)b
`Gain of
`2:15
`letters in
`visual
`acuity
`(%)b
`Mean
`change in
`visual
`acuity
`(letters)
`(SD)n
`• Adjusted estimate based on the strat1fied model.
`b p<O.OI.
`
`53%
`
`90%
`
`Month 12
`
`Month 24
`
`5%
`
`4%
`
`34%
`
`33%
`
`Month 12
`
`Month 24
`
`-10.5
`( 16.6)
`-14.9
`(18.7)
`
`+7.2 (!4.4)
`
`+6.6 ( 16.5)
`
`29%
`(22%,-35%)
`29%
`(23%, 35%)
`
`17.5
`(14.8. 20.2)
`21.1
`( 18.1. 24.2)
`
`the serum concentration of ranibizumab declined in parallel
`with the vitreous concentration. In these animal studies,
`systemic exposure of ranibizumab is more than 2000-fold
`lower than in the vitreous.
`
`In patients with neovascular AMD, following monthly
`intravitreal administration, maximum ranibizumab serum
`concentrations were low (0.3 ng/mL to 2.36 ng/mL). These
`levels were below the concentration of ranibizumab (II ng/mL
`to 27 ng/mL) thought to be necessary to inhibit the biological
`activity of VEGF-A by 50%, as measured in an in vitro cellular
`proliferation assay. The·maximum observed serum
`concentration was dose proportional over the dose range of
`0.05 to 1.0 mg/eye, Based on a population pharmacokinetic
`analysis, maximum serum concentrations of 1.5 ng/mL are
`predicted to be reached at approximately I day after monthly
`intravitreal administration of LUCENTIS 0.5 mg/eye. Based
`on the disappearance of ranibizumab from serum, the estimated
`average vitreous elimination half-life was approximately
`9 days. Steady-state minimum concentration is predicted to be
`0.22 ng/mL with a monthly dosing regimen. In humans, serum
`ranibizumab concentrations are predicted to be approximately
`90,000-fold lower than vitreal concentrations.
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`13.1
`
`Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`No carcinogenicity or mutagenicity data are available for
`ranibizumab injection in animals or humans.
`
`No studies on the effects of ranibizumab on fertility have been
`conducted.
`
`CLINICAL STUDIES
`14
`The safety and efficacy of LUCENTIS were assessed in three
`randomized, double-masked, sham- or active-controlled
`studies in patients with neovascular AMD. A total of
`1323 patients (LUCENTIS 879, Control 444) were enrolled in
`the three studies.
`
`14.1
`
`Study 1 and Study 2
`
`In Study I, patients with minimally classic or occult (without
`classic) CNV lesions received monthly LUCENTIS 0.3 mg or
`0.5 mg intravitreal injections or monthly sham injections.
`Data are available through Month 24. Patients treated with
`LUCENTIS in Study I received a mean of 22 total treatments
`out of a possible 24 from Oay 0 to Month 24.
`
`In Study 2, patients with predominantly classic CNV lesions
`received one of the following: I) monthly LUCENTIS 0.3 mg
`intravitreal injections and sham PDT; 2) monthly LUCENTIS
`0.5 mg intravitreal injections and sham PDT; or 3) sham
`intravitreal injections and active verteporfin PDT. Sham PDT
`(or active verteporfin PDT) was given with the initial
`LUCENTIS (or sham) intravitreal injection and every
`3 months thereafter if fluorescein angiography showed
`persistence or recurrence of leakage. Data are available
`through Month 12. Patients treated with LUCENTIS in
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`;\dminisfr(l/ion (~.4)). VIALS ARE FOR SINGLE EYE USE
`ONLY.
`PATIENT COUNSELING INFORMATION
`17
`In the days following LUCENTIS administration, patients are
`at risk of developing endophthalmitis. If the eye becomes red.
`sensitive to light, painful, or develops a change in vision, the
`patient should seek immediate care from an ophthalmologist
`[see Wamings i/1/{/ Precalllion> (5.1 )).
`
`LUCENTISTM {ranibizumab injection]
`Manufactured by:
`Genentech, Inc.
`I DNA Way
`South San Francisco, CA 94080-4990
`
`8277700
`LL1404
`4833801
`FDA Approval Date:
`June 2006
`c2006 Genentech,
`Inc.
`
`U.S_ BLA (Bl125156) Ranibizumab injection
`
`Genentech,lnc_
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`(·-~ DEPARTMENT OF HEALTH & HUMAN SERVICES
`'•,,,~~L_
`
`Public Health Service
`
`Food and Drug Administration
`Rockville. MD 20852
`
`BLA 125156
`
`Genentech, Inc.
`Attention: Robert L. Gamick, Ph.D.
`Senior Vice President, Regulatory Affairs, Quality & Compliance
`1 DNA Way
`South San Francisco, California 94080-4990
`
`Dear Dr. Gamick:
`
`We have approved your biologics' license application for Lucentis (ranibizumab injection)
`effective this date. You are hereby authorized to introduce or deliver for introduction into
`interstate commerce, ranibizumab injection under your existing Department of Health and
`Human Services U.S. License No. I 048. Lucentis (ranibizumab injection) is indicated for the
`treatment of patients with neovascular (wet) age-related macular degeneration.
`
`Under this license, you are approved to manufacture ranibizumab drug substance at Genentech,
`Inc., South San Francisco, California; fill the final formulated product at !Chi l 41----------- _,. ... ____ I
`,·------------------- t and label and package filled vials at Genentech, Inc., South San
`14
`I lhl
`Francisco, California. You may label your product with the proprietary name Lucentis and
`market it in I 0 mg/mL single use glass vials.
`
`We acknowledge receipt of your submissions dated December 29, 2005, and January 31,
`February I 0, 17, 21, and 24, March 17, 23, and 31, April I 0, and 28, May 5, 10, 25 (2),
`26 (2), and 31, and June I, 5 (2), 6, 9, 13, 16, 23, 26, 27, 28 (3), and 29, 2006.
`
`The final printed labeling (FPL) must be identical in content to the enclosed labeling text for
`the package insert, submitted June 28, 2006; the immediate vial container submitted
`March 31, 2006; and the carton labels submitted June 5, 2006. The statement "No U.S. standard
`of potency" should be added with the next printing of carton labels. Marketing this product with
`FPL that is not identical in content to the approved labeling text may render the product
`misbranded and an unapproved new drug.
`
`The dating period for formulated drug product shall be 18 months from the date of manufacture
`when stored at 2° -8°C (36° -46°F). The date of manufacture shall be defined as the date of final
`sterile filtration of the formulated drug product. The dating period for ranibizumab drug
`substance shall be ltbMq '----1! when stored at -20 oc.
`
`You currently are not required to submit samples of future lots of Lucentis to the Center for
`Drug Evaluation and Research (COER) for release by the Director, COER, under 21 CFR 610.2.
`We will continue to monitor compliance with 21 CFR 610.1 requiring completion oftests for
`conformity with standards applicable to each product prior to release of each lot.
`
`PFIZER EX. 1502
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`BLA 125156
`Page 2
`
`You must submit information to your biologics license application for our review and written
`approval under 21 CFR 601.12 for any changes in the manufacturing, testing, packaging or
`labeling of Lucentis, or in the manufacturing facilities.
`
`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 requirement for this application.
`
`The following are Postmarketing Studies that are subject to reporting requirements of
`21 CFR 601.70:
`
`1. Submit the final Clinical Study Report from Study FVF3689g by June 30, 2008.
`
`2. Provide safety and efficacy data from a 2-year adequate and well-controlled clinical trial
`of a mutually acceptable design exploring multiple dosing frequencies of Lucentis.
`
`Date of submission ofprotocol: November 14,2008.
`
`Date of start of study: September 21, 2009.
`
`Date of final clinical study report: April 1, 2013.
`
`3. To detect and characterize immune responses to ranibizumab:.
`
`a. Develop and validate a confirmatory assay capable of detecting both IgG and lgM
`isotype responses.
`
`b. Develop and validate an assay to detect neutralizing anti-ranibizumab an