Ranibizumab 0.5mg
`Q4
`
`IAI (EYLEA, VEGF
`TrapmEye) 2.0mg Q4
`
`IAI (EYLEA1 VEGF
`TrapmEye) 0.5mg Q4
`
`IAI (EYLEAI VEGF
`Trap-Eye) 2.0mg Q8
`
`306
`
`304
`
`304
`
`269
`
`284
`
`22
`
`4
`
`3
`
`0
`
`1
`
`1
`
`3
`
`10
`
`Started
`
`Patients Received Treatment (SAF)
`
`Full Analysis Set (FAS) Population
`
`Per Protocol Set (PPS) Population
`
`Completed
`
`Not Completed
`
`Adverse Event
`
`Death
`
`Lack of Efficacy
`
`Lost to Follow~up
`
`OTHER
`
`Protocol Violation
`
`Withdrawal by Subject
`
`Baseline Characteristics ......
`
`Reporting Groups
`
`304
`
`304
`
`304
`
`285
`
`293
`
`11
`
`3
`
`1
`
`0
`
`2
`
`0
`
`0
`
`5
`
`304
`
`304
`
`301
`
`270
`
`277
`
`27
`
`5
`
`2
`
`2
`
`4
`
`4
`
`3
`
`7
`
`303
`
`303
`
`301
`
`265
`
`276
`
`27
`
`4
`
`7
`
`2
`
`4
`
`1
`
`1
`
`8
`
`Description
`
`Ranibizumab 0.5mg Q4
`
`Patients received a 0.5mg dose of ranibizumab via IVT injection every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF Trap~Eye)
`2.0mg Q4
`
`Patients received a 2.0mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA, VEGF TrapnEye)
`every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF Trap-Eye)
`0.5mg Q4
`
`Patients received a 0.5mg dose of lntravitreal Aflibercept Injection (IAl 1 EYLEA VEGF Trap-Eye)
`every 4 weeks for the first year.
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2396
`
`

`

`IAI (EYLEA, VEGF Trap-Eye)
`2.0mg Q8
`
`Patients received a 2.0mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA1 VEGF Trap-Eye)
`every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year and were to
`receive sham injections at interim monthly visits.
`
`Baseline Measures
`
`Ranibizumab
`0.5mg Q4
`
`IAI (EYLEA,
`IAI (EYLEA,
`IAI (EYLEA,
`VEGF Trap-
`VEGF Trap-
`VEGF Trap-
`Eye) 2.0mg Q4 Eye) 0.5mg Q4 Eye) 2.0mg Q8
`
`Total
`
`Overall Number of Participants
`
`304
`
`304
`
`304
`
`303
`
`1215
`
`Age Continuous [1]
`Mean (Standard Deviation)
`Unit of measure: years
`
`Number
`Analyzed
`
`Sex: Female, Male
`Measure type: Count of
`Participants
`Unit of measure: Participants
`
`Number
`Analyzed
`
`Female
`
`Male
`
`304 Participants
`
`304 Participants
`
`304 Participants
`
`303 Participants
`
`1215 Participants
`
`78.2 (0 to 0)
`
`77.7 (0 to 0)
`
`78.3 (0 to 0)
`
`77.9 (0 to 0)
`
`78.0 (8.00)
`
`[1] Measure Description: SAF population used for analysis.
`
`304 Participants
`
`304 Participants
`
`304 Participants
`
`303 Participants
`
`1215 Participants
`
`172 56.58%
`
`194 63.82%
`
`169 55.59%
`
`179 59.08%
`
`714 58.77%
`
`132 43.42%
`
`110 36.18%
`
`135 44.41 %
`
`124 40.92%
`
`501
`
`41.23%
`
`304 Participants
`
`304 Participants
`
`Number
`Analyzed
`
`Ethnicity (NIH/OMB) [1]
`Measure type: Count of
`Participants
`Unit of measure: Participants Hispanic or 7 2.3% (0 to 0) 11
`Latino
`
`304 Participants
`
`303 Participants
`
`1215 Participants
`
`11
`
`3.62% (0 to
`0)
`
`3.62% (0 to 12 3.96% (0 to
`0)
`0)
`
`41
`
`3.37%
`
`Not Hispanic
`or Latino
`
`Unknown or
`Not Reported
`
`297 97.7%
`
`293 96,38%
`
`293 96.38%
`
`291
`
`96.04%
`
`1174 96,63%
`
`0 0%
`
`0 0%
`
`0 0%
`
`0 0%
`
`0 0%
`
`[1] Measure Description: SAF population used for analysis.
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2397
`
`

`

`Ranibizumab
`0.5mg Q4
`
`IAI (EYLEA1
`IAI (EYLEA,
`IAI (EYLEA,
`VEGF Trapa
`VEGF Trapa
`VEGF Trapa
`Eye) 2.0mg Q4 Eye) 0.5mg Q4 Eye) 2.0mg Q8
`
`Total
`
`304 Participants
`
`304 Participants
`
`304 Participants
`
`303 Pa1iicipants
`
`1215 Participants
`
`2 o.66% (0 to O 0% (0 to 0) 2 o.66% (0 to 1 o.33% (0 to
`0)
`0)
`0)
`
`5 0.41%
`
`Number
`Analyzed
`
`Race (NIH/OMB} [1l
`Measure type: Count of
`Participants
`Unit of measure: Pa1iicipants American
`Indian or
`Alaska Native
`
`Asian
`
`O 0% (0 to 0) 3 o.99% (0 to 5 1.64% (0 to 4 1.32% (0 to
`0)
`0)
`0)
`
`1 o.33% (0 to 0 0% (0 to 0) 0 0% (0 to 0) 1 o.33% (0 to
`0)
`0)
`
`12 0.99%
`
`2 0.16%
`
`Native
`Hawaiian or
`Other Pacific
`Islander
`
`Black or
`African
`American
`
`White
`
`1 o.33% (0 to 1 o.33% (0 to 0 0% (0 to 0) 1 o.33% (0 to
`0)
`0)
`0)
`
`3 0.25%
`
`296 97.37% (0 295 97.04% (0 294 96.71% (0 289 95.38% (0
`to 0)
`to 0)
`to 0)
`to 0)
`
`1174 96.63%
`
`More than
`one race
`
`0 0% (0 to 0) 0 0% (0 to 0) 0 0% (0 to 0) 1 o.33% (0 to
`0)
`
`Unknown or 4 1.32% (0 to 5 ·1,64% (0 to 3 o.99% (0 to 6 1.98% (0 to
`0)
`0)
`0)
`Not Reported
`0)
`
`1 0.08%
`
`18 1.48%
`
`['1] Measure Description: SAF population used for analysis.
`
`304 Participants
`
`304 Participants
`
`304 Participants
`
`303 Participants
`
`1215 Participants
`
`Number
`Analyzed
`
`Baseline National Eye
`Institute 25-item Visual
`Function Questionnaire
`(NEI VFQ-25) total score [11
`Mean (Standard Deviation)
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2398
`
`

`

`Ranibizumab
`0.5mg Q4
`
`IAI (EYLEA,
`IAI (EYLEA,
`IAI (EYLEA,
`VEGF Trapa
`VEGF Trapa
`VEGF Trapa
`Eye) 2.0mg Q4 Eye) 0.5mg Q4 Eye) 2.0mg Q8
`
`Total
`
`71.7 (0 to 0)
`
`70.4 (0 to 0)
`
`71.1 (0to0)
`
`69.5 (0 to 0)
`
`70.7 (17.11)
`
`r11 Measure Description: SAF population used for analysis. The NEI VFQ-25 total
`score ranges from OR 100 with a score of O being the worst outcome and 100
`being the best outcome. The NEI VFQ questionnaire is organized as a collection
`of subscales which are all scored from OR 100. To reach the overall composite
`score, each sub-scale score is averaged in order to give each subascale equal
`weight.
`
`304 Participants
`
`304 Participants
`
`304 Participants
`
`303 Participants
`
`1215 Participants
`
`6.52 (0 to 0)
`
`6.59 (0 to 0)
`
`6.49 (0 to 0)
`
`6.56 (0 to 0)
`
`6,54 (4.968)
`
`[11 Measure Description: SAF population used for analysis.
`
`304 Participants
`
`304 Participants
`
`304 Participants
`
`303 Participants
`
`1215 Participants
`
`Unit of measure: scores on a
`scale
`
`Baseline Area of Choroidal Number
`Neovascularization (CNV) Analyzed
`[1]
`
`Mean (Standard Deviation)
`Unit of measure: mmA2
`
`Baseline lesion Type [i]
`Measure type: Number
`Unit of measure: patients
`
`Number
`Analyzed
`
`Occult
`
`115 (0 to 0)
`
`110 (0to0)
`
`123 (0to0)
`
`118 (0 to 0)
`
`466 38.35%
`
`Minimally Classic
`
`101 (0 to 0)
`
`105 (0 to 0)
`
`97 (0 to 0)
`
`112 (0to0)
`
`415 34.16%
`
`Predominantly Classic
`
`82 (0 to 0)
`
`87 (0 to 0)
`
`82 (0 to 0)
`
`71 (0 to 0)
`
`322
`
`26.5%
`
`Missing
`
`6 (0 to 0)
`
`2 (0 to 0)
`
`2 (0 to 0)
`
`2 (0 to 0)
`
`12 0.99%
`
`{1] Measure Description: SAF population used for analysis.
`
`304 Participants
`
`304 Participants
`
`304 Participants
`
`303 Participants
`
`1215 Participants
`
`1[_ _ _ ____..._6_.9_9 (_0 t_o o_) ........._6_.98_(_0 t_o o_) ........._6_.96_(_0 t_o o_) ........_6_.88_(_0 t_o o_) .....___6_.95_(5_.2_02_,)
`
`Baseline Total Lesion I Number
`
`Analyzed
`
`Size [·1]
`Mean (Standard Deviation)
`Unit of measure: mmA2
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2399
`
`

`

`Baseline Best Corrected
`Visual Acuity (BCVA) [il
`Mean (Standard Deviation)
`Unit of measure: letters read
`
`Number
`Analyzed
`
`Ranibizumab
`0.5mg Q4
`
`IAI (EYLEA1
`IAI (EYLEA,
`IAI (EYLEA,
`VEGF Trapa
`VEGF Trapa
`VEGF Trapa
`Eye) 2.0mg Q4 Eye) 0.5mg Q4 Eye) 2.0mg Q8
`
`Total
`
`[1] Measure Description: SAF population used for analysis.
`
`304 Participants
`
`304 Participants
`
`304 Participants
`
`303 Participants
`
`1215 Participants
`
`54.0 (0 to 0)
`
`55.2 (0 to 0)
`
`55.5 (0 to 0)
`
`55.7 (0 to 0)
`
`55.1 (13.14)
`
`[1] Measure Description: SAF population used for analysis. BCVA assessed by
`Early Treatment Diabetic Retinopathy Study (ETDRS) chart. For BCVA tested
`via the 4 meter ETDRS protocol 1 83 letters or more would represent 20/20 vision
`or better which would be considered an excellent outcome. Although 1 the
`ETD RS charts include 100 letters as the maximum possible score. The worst
`outcome is O letters read.
`
`Outcome Measures ............................................................................................................................................................................................................................................................................................................................ .
`
`1. Primary Outcome Measure:
`
`Measure Title
`
`Percentage of Patients Who Maintained Vision at Week 52 R Last Observation Carried Forvvard
`(LOCF)
`
`Measure Description
`
`Defined 11maintenance of vision" as patients who lost fewer than 15 letters in Early Treatment
`Diabetic Retinopathy Study (ETDRS) letter score compared to baseline.
`
`Time Frame
`
`Baseline and at week 52
`
`Analysis Population Description
`
`PPS population used for analysis.
`
`Reporting Groups
`
`Description
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2400
`
`

`

`Ranibizumab 0.5mg Q4
`
`Patients received a 0.5mg dose of ranibizumab via IVT injection every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF Trap~Eye)
`2.0mg Q4
`
`Patients received a 2.0mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA, VEGF TrapDEye)
`every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF Trap 0 Eye)
`0.5mg Q4
`
`Patients received a 0.5mg dose of lntravitreal Aflibercept Injection (IAl 1 EYLEA, VEGF TrapDEye)
`every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF TrapREye)
`2.0mg 08
`
`Patients received a 2.0mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA, VEGF Trap~Eye)
`every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year and were to
`receive sham injections at interim monthly visits.
`
`Total
`
`Measured Values
`
`Overall Number of Participants Analyzed
`
`Percentage of Patients Who Maintained
`Vision at Week 52 ~ Last Observation
`Carried Forward (LOCF)
`Measure Type: Number
`Unit of Measure: percentage of patients
`
`Ranibizumab
`0.5mg Q4
`
`IAI (EYLEA,
`IAI (EYLEA,
`IAI (EYLEAI
`VEGF Trap~
`VEGF Trap•
`VEGF Trap•
`Eye) 2.0mg 04 Eye) 0.5mg 04 Eye) 2.0mg Q8
`
`269
`
`94,4 (0)
`
`285
`
`270
`
`265
`
`95.1 (0)
`
`95.9 (0)
`
`95.1 (0)
`
`Total
`
`1089
`
`95.1 (0)
`
`Statistical Analysis 1 for Percentage of Patients Who Maintained Vision at Week 52 ~ Last Observation Carried Forward (LOCF)
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2401
`
`

`

`Statistical
`Analysis
`Overview
`
`Comparison Groups Ranibizumab 0.5mg Q4, IAI (EYLEA, VEGF TrapuEye) 2.0mg Q4
`
`Comments
`
`The statistical approach included a conditional sequence of calculations of the
`95.1 % Cl using normal approximation of the difference between the proportion of
`patients with maintained vision at Week 52 for the group treated with 0.5 mg
`ranibizumab and the proportion of patients with maintained vision for each of the
`groups treated with IAI.
`
`Type of Statistical Test Non-Inferiority or Equivalence
`
`Comments
`
`The non-inferiority margin was set at 10%. The power is 90% according to the
`sample size estimation of the study protocol. Although not in the analysis plan for
`the study1 in a separate communication! the FDA further explained that, whereas
`the 10% nonminferiority margin would be used to assess non-inferiority, a 5%
`non-inferiority margin would be used to assess clinical equivalence.
`
`Method of
`Estimation
`
`Estimation Parameter Risk Difference (RD)
`
`Estimated Value -0.7
`
`Confidence Interval (2-sided) 95.1 %
`-4.4 to 3.1
`
`Estimation Comments
`
`The difference is calculated as ranibizumab minus IAI. A positive value favors IAI
`2.0Q4. As adjustment of multiple comparisons as conditional sequence of
`statistical hypotheses is used with alpha= 0.049.
`
`Statistical Analysis 2 for Percentage of Patients Who Maintained Vision at Week 52 ~ Last Observation Carried Forward (LOCF)
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2402
`
`

`

`Statistical
`Analysis
`Overview
`
`Comparison Groups Ranibizumab 0.5mg Q4, IAI (EYLEA, VEGF TrapuEye) 0.5mg Q4
`
`Comments
`
`The statistical approach included a conditional sequence of calculations of the
`95.1 % Cl using normal approximation of the difference between the proportion of
`patients with maintained vision at Week 52 for the group treated with 0.5 mg
`ranibizumab and the proportion of patients with maintained vision for each of the
`groups treated with IAI (EYLEA, VEGF TrapmEye).
`
`Type of Statistical Test Non-Inferiority or Equivalence
`
`Comments
`
`The non-inferiority margin was set at 10%. The power is 90% according to the
`sample size estimation of the study protocol. Although not in the analysis plan for
`the study1 in a separate communication! the FDA further explained that, whereas
`the 10% nonminferiority margin would be used to assess non-inferiority, a 5%
`non-inferiority margin would be used to assess clinical equivalence.
`
`Method of
`Estimation
`
`Estimation Parameter Risk Difference (RD)
`
`Estimated Value -1.5
`
`Confidence Interval (2-sided) 95.1 %
`-5.1 to 2.1
`
`Estimation Comments
`
`The difference is calculated as ranibizumab minus IAI. A negative value favors
`the IAI 0.5Q4 group. As adjustment of multiple comparisons as conditional
`sequence of statistical hypotheses is used with alpha= 0.049.
`
`Statistical Analysis 3 for Percentage of Patients Who Maintained Vision at Week 52 ~ Last Observation Carried Forward (LOCF)
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2403
`
`

`

`Statistical
`Analysis
`Overview
`
`Comparison Groups Ranibizumab 0.5mg Q4, IAI (EYLEA, VEGF TrapuEye) 2.0mg Q8
`
`Comments
`
`The statistical approach included a conditional sequence of calculations of the
`95.1 % Cl using normal approximation of the difference between the proportion of
`patients with maintained vision at Week 52 for the group treated with 0.5 mg
`ranibizumab and the proportion of patients with maintained vision for each of the
`groups treated with IAI (EYLEA, VEGF TrapmEye).
`
`Type of Statistical Test Non-Inferiority or Equivalence
`
`Comments
`
`The non-inferiority margin was set at 10%. The power is 90% according to the
`sample size estimation of the study protocol. Although not in the analysis plan for
`the study1 in a separate communication! the FDA further explained that, whereas
`the 10% nonminferiority margin would be used to assess non-inferiority, a 5%
`non-inferiority margin would be used to assess clinical equivalence.
`
`Method of
`Estimation
`
`Estimation Parameter Risk Difference (RD)
`
`Estimated Value -0.7
`
`Confidence Interval (2-sided) 95.1 %
`-4.5 to 3.1
`
`Estimation Comments
`
`The difference is calculated as ranibizumab minus IAI. A negative value favors
`the IAI 2.0Q8 group. As adjustment of multiple comparisons as conditional
`sequence of statistical hypotheses is used with alpha= 0.049.
`
`2. Secondary Outcome Measure:
`
`Measure Title
`
`Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Early
`Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 -LOCF
`
`Measure Description
`
`Defined study baseline range of ETDRS Best Corrected Visual Acuity of: letter score of 73 to 25
`(20/40 to 20/320) in the study eye; a higher score represents better functioning.
`
`Time Frame
`
`Baseline and at week 52
`
`Analysis Population Description
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2404
`
`

`

`FAS population used for analysis.
`
`Reporting Groups
`
`Description
`
`Ranibizumab 0.5mg Q4
`
`Patients received a 0.5mg dose of ranibizumab via IVT injection every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF TrapuEye)
`2.0mg Q4
`
`Patients received a 2.0mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA, VEGF TrapuEye)
`every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF TrapnEye)
`0.5mg Q4
`
`Patients received a 0.5mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA, VEGF TrapnEye)
`every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF Trap-Eye)
`2.0mg Q8
`
`Patients received a 2.0mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA, VEGF TrapMEye)
`every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year and were to
`receive sham injections at interim monthly visits.
`
`Total
`
`Measured Values
`
`Ranibizumab
`0.5mg Q4
`
`IAI (EYLEA,
`IAI (EYLEA,
`IAI (EYLEA,
`VEGF TrapM
`VEGF Trapu
`VEGF Trapu
`Eye) 2.0mg Q4 Eye) 0.5mg Q4 Eye) 2.0mg Q8
`
`Total
`
`Overall Number of Participants Analyzed
`
`304
`
`304
`
`301
`
`301
`
`1210
`
`8.1 (15.25)
`
`10.9 (13.77)
`
`6.9 (13.41)
`
`7.9 (15.00)
`
`8.5 (14.44)
`
`Mean Change From Baseline in Best
`Corrected Visual Acuity (BCVA) as
`Measured by Early Treatment Diabetic
`Retinopathy Study (ETDRS) Letter Score at
`Week 52 n LOCF
`Measure Type: Mean (Standard Deviation)
`Unit of Measure: letters read
`
`Statistical Analysis 1 for Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Early Treatment
`Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 n LOCF
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2405
`
`

`

`Statistical
`Analysis
`Overview
`
`Statistical
`Test of
`Hypothesis
`
`Method of
`Estimation
`
`Comparison Groups Ranibizumab 0.5mg Q4, IAI (EYLEA, VEGF Trap-Eye) 2.0mg Q4
`
`Comments
`
`The pairwise comparison is pertormed as contrast statement in the analysis of
`covariance model with treatment group as fixed factor (all 4 treatment groups)
`and the baseline measure as covariate. The null hypothesis is that both mean
`changes are equal.
`
`Type of Statistical Test Superiority or Other (legacy)
`
`Comments
`
`[Not specified]
`
`P-Value 0.0054
`
`Comments
`
`As adjustment of multiple comparisons! a conditional sequence of statistical
`hypotheses is used with alpha= 0.049
`
`Method ANCOVA
`
`Comments
`
`[Not specified]
`
`Estimation Parameter Differences in Least Squares means
`
`Estimated Value 3.15
`
`Confidence Interval (2-sided) 95.1 %
`0.92 to 5.37
`
`Estimation Comments
`
`Tl1e difference is calculated as IAI minus ranibizumab. A positive value favors IAI
`2.0Q4.
`
`Statistical Analysis 2 for Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Early Treatment
`Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 ~ LOCF
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2406
`
`

`

`Statistical
`Analysis
`Overview
`
`Statistical
`Test of
`Hypothesis
`
`Method of
`Estimation
`
`Comparison Groups Ranibizumab 0.5mg Q4, IAI (EYLEA, VEGF Trap-Eye) 0.5mg Q4
`
`Comments
`
`The pairwise comparison is pertormed as contrast statement in the analysis of
`covariance model with treatment group as fixed factor (all 4 treatment groups)
`and the baseline measure as covariate. The null hypothesis is that both mean
`changes are equal.
`
`Type of Statistical Test Superiority or Other (legacy)
`
`Comments
`
`[Not specified]
`
`P-Value 0.4793
`
`Comments
`
`As adjustment of multiple comparisons! a conditional sequence of statistical
`hypotheses is used with alpha= 0.049
`
`Method ANCOVA
`
`Comments
`
`[Not specified]
`
`Estimation Parameter Differences in Least Squares means
`
`Estimated Value 0.80
`
`Confidence Interval (2-sided) 95.1 %
`-3.03 to 1.43
`
`Estimation Comments
`
`Tl1e difference is calculated as IAI minus ranibizumab. A positive value favors IAI
`0.5Q4.
`
`Statistical Analysis 3 for Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Early Treatment
`Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 ~ LOCF
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2407
`
`

`

`Statistical
`Analysis
`Overview
`
`Statistical
`Test of
`Hypothesis
`
`Method of
`Estimation
`
`Comparison Groups Ranibizumab 0.5mg Q4, IAI (EYLEA, VEGF Trap-Eye) 2.0mg Q8
`
`Comments
`
`The pairwise comparison is pertormed as contrast statement in the analysis of
`covariance model with treatment group as fixed factor (all 4 treatment groups)
`and the baseline measure as covariate. The null hypothesis is that both mean
`changes are equal.
`
`Type of Statistical Test Superiority or Other (legacy)
`
`Comments
`
`[Not specified]
`
`P-Value 0.8179
`
`Comments
`
`As adjustment of multiple comparisons! a conditional sequence of statistical
`hypotheses is used with alpha= 0.049
`
`Method ANCOVA
`
`Comments
`
`[Not specified]
`
`Estimation Parameter Differences in Least Squares Means
`
`Estimated Value 0.26
`
`Confidence Interval (2-sided) 95.1 %
`-1.97 to 2.49
`
`Estimation Comments
`
`Tl1e difference is calculated as IAI minus ranibizumab. A positive value favors IAI
`2.0Q8.
`
`3. Secondary Outcome Measure:
`
`Measure Title
`
`Percentage of Patients Who Gained at Least 15 Letters of Vision in the ETDRS Letter Score in
`the Study Eye at Week 52 -LOCF
`
`Measure Description
`
`Defined study baseline range of ETDRS Best Corrected Visual Acuity of: letter score of 73 to 25
`(20/40 to 20/320) in the study eye; a higher score represents better functioning.
`
`Time Frame
`
`Baseline and at week 52
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2408
`
`

`

`Analysis Population Description
`
`FAS population used for analysis.
`
`Reporting Groups
`
`Description
`
`Ranibizumab 0.5mg Q4
`
`Patients received a 0.5mg dose of ranibizumab via IVT injection every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF TrapMEye)
`2.0mg Q4
`
`Patients received a 2.0mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA, VEGF TrapMEye)
`every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF Trap-Eye)
`0.5mg Q4
`
`Patients received a 0.5mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA1 VEGF Trap-Eye)
`every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF TrapaEye)
`2.0mg Q8
`
`Patients received a 2.0mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA, VEGF TrapaEye)
`every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year and were to
`receive sham injections at interim monthly visits.
`
`Total
`
`Measured Values
`
`Ranibizumab
`0.5mg Q4
`
`IAI (EYLEA,
`IAI (EYLEA
`IAI (EYLEAI
`VEGF Trapa
`VEGF Trapm
`VEGF Trapm
`Eye) 2.0mg Q4 Eye) 0.5mg Q4 Eye) 2.0mg Q8
`
`Overall Number of Participants Analyzed
`
`304
`
`304
`
`301
`
`301
`
`30.9 (0)
`
`37.5 (0)
`
`24.9 (0)
`
`30.6 (0)
`
`Percentage of Patients Who Gained at
`Least 15 Letters of Vision in the ET DRS
`Letter Score in the Study Eye at Week 52 -
`LOCF
`Measure Type: Number
`Unit of Measure: percentage of patients
`
`Total
`
`1210
`
`31.1 (0)
`
`Statistical Analysis 1 for Percentage of Patients Who Gained at Least 15 Letters of Vision in the ETDRS Letter Score in the Study Eye
`at Week 52 R LOCF.
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2409
`
`

`

`Statistical
`Analysis
`Overview
`
`Statistical
`Test of
`Hypothesis
`
`Method of
`Estimation
`
`Comparison Groups Ranibizumab 0.5mg Q4, IAI (EYLEA, VEGF Trap-Eye) 2.0mg Q4
`
`Comments
`
`The null hypothesis is that both percentages are equal.
`
`Type of Statistical Test Superiority or Other (legacy)
`
`Comments
`
`[Not specified]
`
`PM Value 0.1042
`
`Comments
`
`As adjustment of multiple comparisons 1 a conditional sequence of statistical
`hypotheses is used with alpha= 0.049.
`
`Method Chi-squared
`
`Comments
`
`[Not specified]
`
`Estimation Parameter Risk Difference (RD)
`
`Estimated Value 6.6
`
`Confidence Interval (2-sided) 95.1 %
`a 1.0 to 14.1
`
`Estimation Comments
`
`The difference is calculated as IAI minus ranibizumab. A positive value favors IAI
`2.0Q4.
`
`Statistical Analysis 2 for Percentage of Patients Who Gained at Least 15 Letters of Vision in the ETDRS Letter Score in the Study Eye
`at Week 52 n LOCF.
`
`Statistical
`Analysis
`Overview
`
`Comparison Groups Ranibizumab 0.5mg Q4, IAI (EYLEA, VEGF TrapnEye) 0.5mg Q4
`
`Comments
`
`The null hypothesis is that both percentages are equal.
`
`Type of Statistical Test Superiority or Other (legacy)
`
`Comments
`
`[Not specified]
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2410
`
`

`

`Statistical
`Test of
`Hypothesis
`
`Method of
`Estimation
`
`Pm Value 0.1037
`
`Comments
`
`As adjustment of multiple comparisons, a conditional sequence of statistical
`hypotheses is used with alpha= 0.049.
`
`Method ChiMsquared
`
`Comments
`
`[Not specified]
`
`Estimation Parameter Risk Difference (RD)
`
`Estimated Value -6,0
`
`Confidence Interval (2msided) 95.1 %
`~ 13.2 to 1.2
`
`Estimation Comments
`
`The difference is calculated as IAI minus ranibizumab. A positive value favors IAI
`0.5Q4.
`
`Statistical Analysis 3 for Percentage of Patients Who Gained at Least 15 Letters of Vision in the ETDRS Letter Score in the Study Eye
`at Week 52 M LOCF.
`
`Statistical
`Analysis
`Overview
`
`Statistical
`Test of
`Hypothesis
`
`Comparison Groups Ranibizumab 0.5mg Q41 IAI (EYLEA VEGF Trap~Eye) 2.0mg Q8
`
`Comments
`
`The pairwise The null hypothesis is that both percentages are equal.
`
`Type of Statistical Test Superiority or Other (legacy)
`
`Comments
`
`[Not specified]
`
`P-Value 0.93
`
`Comments
`
`As adjustment of multiple comparisons, a conditional sequence of statistical
`hypotheses is used with alpha= 0.049.
`
`Method Chi~squared
`
`Comments
`
`[Not specified]
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2411
`
`

`

`Method of
`Estimation
`
`Estimation Parameter Risk Difference (RD)
`
`Estimated Value -0.4
`
`Confidence Interval (2-sided) 95.1 %
`-7.7 to 7.0
`
`Estimation Comments
`
`The difference is calculated as VEGF TrapnEye minus ranibizumab. A positive
`value favors VEGF TrapDEye 2.0Q8.
`
`4. Secondary Outcome Measure:
`
`Measure Title
`
`Measure Description
`
`Mean Change From Baseline in National Eye Institute Visual Functioning Questionnaire (NEI
`VFQ-25) Total Score at Week 52 -LOCF
`
`The NEI VFQ~25 total score ranges from 0~ 100 with a score of 0 being the worst outcome and
`100 being the best outcome. The NEI VFQ questionnaire is organized as a collection of
`subscales which are all scored from 0D 100. To reach the overall composite score 1 each sub~scale
`score is averaged in order to give each sub-scale equal weight.
`
`Time Frame
`
`Baseline and at Week 52
`
`Analysis Population Description
`
`FAS population used for analysis.
`
`Reporting Groups
`
`Description
`
`Ranibizumab 0.5mg Q4
`
`Patients received a 0.5mg dose of ranibizumab via IVT injection every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF Trap-Eye)
`2.0mg Q4
`
`Patients received a 2.0mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA VEGF Trap-Eye)
`every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF TrapnEye)
`0.5mg Q4
`
`Patients received a 0.5mg dose of lntravitreal Aflibercept Injection (IN EYLEA, VEGF Trap-Eye)
`every 4 weeks for the first year.
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2412
`
`

`

`IAI (EYLEA, VEGF Trap-Eye)
`2.0mg Q8
`
`Patients received a 2.0mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA1 VEGF Trap-Eye)
`every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year and were to
`receive sham injections at interim monthly visits.
`
`Total
`
`Measured Values
`
`Ranibizumab
`0.5mg Q4
`
`IAI (EYLEA,
`IAI (EYLEA,
`IAI (EYLEA
`VEGF Trap-
`VEGF Trap-
`VEGF Trap-
`Eye) 2.0mg Q4 Eye) 0.5mg Q4 Eye) 2.0mg Q8
`
`Total
`
`Overall Number of Participants Analyzed
`
`304
`
`304
`
`301
`
`301
`
`1210
`
`4,9 (14.01)
`
`6.7(13.50)
`
`4.5 (11.87)
`
`5.1 (14.74)
`
`5.3 (13.59)
`
`Mean Change From Baseline in National
`Eye Institute Visual Functioning
`Questionnaire (NEI VFQ-25) Total Score at
`Week 52 -LOCF
`Measure Type: Mean (Standard Deviation)
`Unit of Measure: scores on a scale
`
`Statistical Analysis 1 for Mean Change From Baseline in National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) Total
`Score at Week 52 n LOCF
`
`Statistical
`Analysis
`Overview
`
`Comparison Groups Ranibizumab 0.5mg Q4, IAI (EYLEA, VEGF Trap-Eye) 2.0mg Q4
`
`Comments
`
`The pairwise comparison is performed as contrast statement in the analysis of
`covariance model with treatment group as fixed factor (all 4 treatment groups)
`and the baseline measure as covariate. The null hypothesis is that both mean
`changes are equal.
`
`Type of Statistical Test Superiority or Other (legacy)
`
`Comments
`
`[Not specified]
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2413
`
`

`

`Statistical
`Test of
`Hypothesis
`
`Method of
`Estimation
`
`Pm Value 0.2090
`
`Comments
`
`As adjustment of multiple comparisons, a conditional sequence of statistical
`hypotheses is used with alpha= 0.049
`
`Method ANCOVA
`
`Comments
`
`[Not specified]
`
`Estimation Parameter Differences Least Squares means
`
`Estimated Value 1.28
`
`Confidence Interval (2msided) 95.1 %
`U0.73 to 3.28
`
`Estimation Comments
`
`The difference is calculated as IAI minus ranibizumab. A positive value favors IAI
`2.0Q4.
`
`Statistical Analysis 2 for Mean Change From Baseline in National Eye Institute Visual Functioning Questionnaire (NEI VFQu25) Total
`Score at Week 52 -LOCF
`
`Statistical
`Analysis
`Overview
`
`Comparison Groups Ranibizumab 0.5mg Q41 IAI (EYLEA VEGF Trap-Eye) 0.5mg Q4
`
`Comments
`
`The pairwise comparison is pertormed as contrast statement in the analysis of
`covariance model with treatment group as fixed factor (all 4 treatment groups)
`and the baseline measure as covariate. The null hypothesis is that both mean
`changes are equal.
`
`Type of Statistical Test Superiority or Other (legacy)
`
`Comments
`
`[Not specified]
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2414
`
`

`

`Statistical
`Test of
`Hypothesis
`
`Method of
`Estimation
`
`Pm Value 0.5128
`
`Comments
`
`As adjustment of multiple comparisons, a conditional sequence of statistical
`hypotheses is used with alpha= 0.049
`
`Method ANCOVA
`
`Comments
`
`[Not specified]
`
`Estimation Parameter Differences in Least Squares means
`
`Estimated Value -0.67
`
`Confidence Interval (2msided) 95.1 %
`u2.69 to 1.35
`
`Estimation Comments
`
`The difference is calculated as IAI minus ranibizumab. A positive value favors IAI
`0.5Q4.
`
`Statistical Analysis 3 for Mean Change From Baseline in National Eye Institute Visual Functioning Questionnaire (NEI VFQu25) Total
`Score at Week 52 -LOCF
`
`Statistical
`Analysis
`Overview
`
`Comparison Groups Ranibizumab 0.5mg Q41 IAI (EYLEA VEGF Trap-Eye) 2.0mg Q8
`
`Comments
`
`The pairwise comparison is pertormed as contrast statement in the analysis of
`covariance model with treatment group as fixed factor (all 4 treatment groups)
`and the baseline measure as covariate. The null hypothesis is that both mean
`changes are equal.
`
`Type of Statistical Test Superiority or Other (legacy)
`
`Comments
`
`[Not specified]
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2415
`
`

`

`Statistical
`Test of
`Hypothesis
`
`Method of
`Estimation
`
`Pm Value 0.5579
`
`Comments
`
`As adjustment of multiple comparisons, a conditional sequence of statistical
`hypotheses is used with alpha= 0.049
`
`Method ANCOVA
`
`Comments
`
`[Not specified]
`
`Estimation Parameter Differences in Least Squares means
`
`Estimated Value -0.60
`
`Confidence Interval (2msided) 95.1 %
`~2.61 to 1.42
`
`Estimation Comments
`
`The difference is calculated as IAI minus ranibizumab. A positive value favors IAI
`2.0Q8.
`
`5. Secondary Outcome Measure:
`
`Measure Title
`
`Mean Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 52 (LOCF)
`
`Measure Description
`
`CNV area values measured in square millimeters (mmA2); lower values represent better
`outcomes.
`
`Time Frame
`
`Baseline and at week 52
`
`Analysis Population Description
`
`FAS population used for analysis.
`
`Reporting Groups
`
`Description
`
`Ranibizumab 0.5mg Q4
`
`Patients received a 0,5mg dose of ranibizumab via IVT injection every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF Trap~Eye)
`2.0mg 04
`
`Patients received a 2.0mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA, VEGF Trap~Eye)
`every 4 weeks for the first year.
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2416
`
`

`

`IAI (EYLEA, VEGF Trap-Eye)
`0.5mg Q4
`
`Patients received a 0.5mg dose of lntravitreal Aflibercept Injection (IAI, EYLEA1 VEGF Trap-Eye)
`every 4 weeks for the first year.
`
`IAI (EYLEA, VEGF TrapnEye)
`2.0mg Q8
`
`Patients received a 2.0mg dose of lntravitreal Aflibercept Injection (IN EYLEA, VEGF TrapnEye)
`every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year and were to
`receive sham injections at interim monthly visits.
`
`Total
`
`Measured Values
`
`Ranibizumab
`0.5mg Q4
`
`IAI (EYLEA,
`IAI (EYLEA
`IAI (EYLEA
`VEGF Trapn
`VEGF Trap-
`VEGF Trap-
`Eye) 2.0mg Q4 Eye) 0.5mg Q4 Eye) 2.0mg Q8
`
`Total
`
`Overall Number of Participants Analyzed
`
`304
`
`304
`
`301
`
`301
`
`1210
`
`-4.2 (5.59)
`
`-4.6 (5.47)
`
`-3.5 (5.27)
`
`-3.4 (6.02)
`
`-3.9 (5.61)
`
`Mean Change From Baseline in Choroidal
`Neovascularization (CNV) Area at Week 52
`(LOCF)
`Measure Type: Mean (Standard Deviation)
`Unit of Measure: mmA2
`
`Statistical Analysis 1 for Mean Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 52 (LOCF)
`
`Statistical
`Analysis
`Overview
`
`Comparison Groups Ranibizumab 0.5mg Q4 1 IAI (EYLEA, VEGF Trap-Eye) 2.0mg Q4
`
`Comments
`
`The pairwise comparison is pertormed as contrast statement in the analysis of
`covariance model with treatment group as fixed factor (all 4 treatment groups)
`and the baseline measure as covariate. The null hypothesis is that both mean
`changes are equal.
`
`Type of Statistical Test Superiority or Other (legacy)
`
`Comments
`
`[Not specified]
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 2417
`
`

`

`Statistical
`Test of
`Hypot