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`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2124 Page 1
`
`

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`Patients With Macular Edema
`and Mild to Moderate Diabetic
`Retinopathy in One or Both Eyes
`(1,122 Bilateral, 754 Unilateral)
`
`
`
`Randomization 1
`
`Immediate
`Photocoagulation
`(1,508 Eyes)
`
`Randomization 2
`
`Panretinal
`Photocoagulation
`Plus Follow-up
`Focal (754 Eyes)
`
`entry into the ETDRS,patients were asked to give written
`informed consentafter receiving written and verbal infor-
`mation concerning their disease and the study.
`
`Study Design
`
`The complete design of the ETDRS has been summa-
`rized previously and is described in detail in the 848-page
`Manual of Operations (available from the US Department
`of Commerce, National Technical Information Service,
`5285 Port Royal Rd, Springfield, VA 22161; Accession No.
`PB85 223006/AS).?7?? The present report is limited to the
`subgroup of eyes in the ETDRS that were identified as
`having mild to moderate nonproliferative diabetic retinop-
`athy and macular edema, as determined by theinitial
`grading of baseline fundus photographs and fluorescein
`angiograms of the ETDRS Fundus Photograph Reading
`Center, Madison, Wis.
`The treatment assignment scheme for these eyes is
`detailed in Fig 1. First, they were randomly assigned to
`immediate photocoagulation or deferral of photocoagula-
`tion until high-risk proliferative retinopathy developed.
`The eyes assigned to immediate photocoagulation were
`then randomly divided into two photocoagulation regi-
`mens. One half (754) of the eyes assigned to immediate
`photocoagulation received only focal treatment for macu-
`lar edemainitially. This report compares these focally
`treated eyes with those randomizedto deferral of photoco-
`agulation (1,490 eyes).
`Excluded from this report are the results for the eyes
`with mild to moderate retinopathy and macular edema
`that were randomly assigned to an initial treatment of
`panretinal photocoagulation and follow-up focal photoco-
`agulation if macular edemapersisted (Fig 1), the eyes with
`moderate nonproliferative retinopathy that did not have
`macular edemaat the time of entry into the ETDRS, and
`all eyes initially graded as having severe nonproliferative
`or early proliferative retinopathy at the time of entry into
`the ETDRS. Follow-up continues for these groups of
`eyes.
`
`Treatment
`
`In the ETDRS, an eye is classified by the Fundus
`Photograph Reading Center as having macular edema
`when there is retinal
`thickening at or within 1 disc
`diameter of the center of the macula or definite hard
`exudates in this region. Macular edema is designated as
`being “clinically significant” if at least one of the charac-
`teristics listed in Table 1 is present.
`An example of an eye with clinically significant macular
`edema and mild to moderate nonproliferative diabetic
`retinopathyis illustrated in Fig 2. Figure 2, middle left,
`shows the appearanceof the retina immediately after focal
`treatment for macular edema, as performed in the ETDRS.
`A pretreatment
`fluorescein angiogram is used during
`photocoagulation to identify “treatable lesions” (Table 2).
`Treatmentis prescribed for all such lesions located within
`2 disc diametersof the center of the macula butat least 500
`microns from the center.
`Microaneurysmsandotherfocal leakagesites receive 50-
`to 100-micron argon blue-green or green-only burns of
`0.1-s duration or less, with adequate power to obtain
`definite whitening around the microaneurysm or leakage
`site. For all microaneurysms greater than 40 microns in
`diameter, an attempt is madeto obtain actual whitening or
`darkening of the microaneurysmitself, which is generally
`accomplished utilizing a 50-micron spot size. Repeated
`burns are sometimes needed. Care is taken to avoid
`rupturing Bruch’s membrane.
`
`Fig 1.—Early Treatment Diabetic Retinopathy Study treatment
`assignment schedule for patients with macular edema and mild
`to moderate diabetic retinopathy in one or both eyes. Random-
`ization 1: All study patients had one eye randomly assigned to
`immediate photocoagulation and other eye to deferral of
`photocoagulation until ‘‘high-risk’’ proliferative retinopathy (as
`described by the Diabetic Retinopathy Study”) developed.
`Macular edema and mild to moderate retinopathy were present
`in both eyes of 1,122 patients (2,244 eyes), and one eye was
`randomly assigned to immediate photocoagulation or deferral.
`Seven hundredfifty-four patients had macular edema and mild
`to moderate retinopathy in only one eye; these eyes are about
`equally divided between immediate and deferral groups. Ran-
`domization 2: Eyes with macular edema and mild to moderate
`retinopathy assigned to immediate photocoagulation were ran-
`domized to either a combination ofinitial panretina! photocoag-
`ulation and follow-up focal macular photocoagulation if macular
`edema persisted or only focal macular photocoagulation at
`initial
`treatment with panretinal photocoagulation if retinop-
`athy progressed to severe nonproliferative stage or beyond.
`Hatched boxesindicate those groups comparedin this report.
`
`
`
`Table 1.—Clinically Significant Macular Edema (Anyof
`the Foltowing Characteristics)
`
`Thickening of the retina at or within 500 microns of the
`center of the macula
`Hard exudates at or within 500 microns of the center of the
`macula, if associated with thickening of adjacent retina
`
`(not residual hard exudates remaining after disappearance of retinal thickening)
`
`A zone or zones of retinal thickening 1 disc area orlarger,
`any part of which is within 1 disc diameter of the center of
`the macula
`
`Treatment of lesions closer than 500 microns to the
`macula is not required initially. However, if vision is less
`than 20/40, and the retinal edema and leakagepersist,
`treatment of lesions up to 300 microns from the center is
`recommended,unless there is perifoveal capillary dropout,
`which might be worsened by this treatment.
`Areas of diffuse leakage or nonperfusion within 2 disc
`diametersof the center of the macula are treated in a grid
`
`Arch Ophthalmot— Vol 103, Dec 1985
`
`Diabetic Macular Edema—ETORS Research Group
`
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`IPR2023-00884
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`Arch Ophthalmol—Vol 103, Dec 1985
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`Diabetic Macular Edema—ETDRS Research Group
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`IPR2023-00884
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`Regeneron Pharmaceuticals, Inc. Exhibit2124
`Page 3
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`
`
`No. of EyesPaaeeeaes
`Group
`Baseline
`12mo0
`24mo0
`36 mo
`Immediate
`754
`614
`416
`268
`Deferral
`1.490
`1,178
`812
`526
`
`
`
`EyesWithVisualAcuity<20/100,%
`
` No. of Eyes
`
`= 3.29 az
`
`30
`
`
`
`* 196 = Z< 2.58
`$2.58 = 2< 3.29
`
`
`
`
`
`Months of Follow-up
`
`
`
`Group
`Immediate
`Deferral
`
`Baseline
`754
`1,490
`
`12mo
`614
`1,178
`
`24mo
`416
`812
`
`36 mo
`268
`526
`
`* 1.96 = Z2< 2.58
`$2.58 = Z< 3.29
`AZ= 3.29
`
`EyesWithVisionLoss,%
`
`Months of Follow-up
`
`Fig 4.—Comparison of percentage of eyes that experienced
`visual loss of 15 or more letters (equivalent to at least doubling
`ofinitial visual angle or loss of three or more lines) in eyes with
`macular edema and mild to moderate diabetic retinopathy
`assigned to either immediate focal photocoagulation (broken
`line) or deferral of photocoagulation (solid line).
`
`immediate focal photocoagulation re-
`subgroups,
`duced the proportion of eyes that lost 15 or more
`letters compared with deferral of photocoagulation.
`Visual prognosis appears worse for those eyes with
`decreased visual acuity at baseline.
`In eyes with a pretreatmentvisual acuity of 20/40
`or worse, an improvementin visual acuity of six or
`more letters (more than one line on the ETDRS
`visual acuity chart) was much more frequent in
`treated eyes than in eyes assigned to deferral of
`treatment (Fig 7). This improvementin visual acuity
`was uncommon in eyes with good initial visual
`acuities, as might be expected.
`Improvement of
`visual acuity by 15 letters (three lines or one half of
`the initial visual angle) was uncommon (<3%).
`Visual Acuity Results in Eyes Classified by the Pres-
`ence or Absence of Clinically Significant Macular Ede-
`ma.—Figure 8, top, demonstrates the clear beneficial
`effect of immediate focal treatment in eyes with
`clinically significant macular edema (see also Table
`4). In those eyes, the differences in rates of visual
`loss between the immediate focal photocoagulation
`and deferral of photocoagulation groups werestatis-
`tically significant at the eight-month follow-upvisit
`and thereafter.
`Eyes in which macular edema wasnotclinically
`significant at baseline had low rates of visual loss,
`especially during the first year of follow-up, in both
`the immediate and deferral of photocoagulation
`groups (Fig 8, bottom). At baseline, these eyes had
`only limited areas of retinal
`thickening or hard
`exudates and had none of the characteristics of
`clinically significant macular edema. Clinically sig-
`nificant macular edema developed in both the imme-
`diate and deferral of photocoagulation groups during
`follow-up. When clinically significant macular ede-
`ma developed during follow-up, the eyes assigned to
`immediate treatment received additional focal pho-
`tocoagulation, but the eyes assigned to deferral of
`treatment did not receive photocoagulation. Differ-
`
`Fig 5.—Comparison of percentage of eyes with visual acuity
`score less than 50 (equivalent to a visual acuity of less than
`20/100) in eyes with macular edema and mild to moderate
`diabetic retinopathy assigned to either immediate focal photo-
`coagulation (broken line) or deferral of photocoagulation (solid
`line).
`
`ences in visual loss between the immediate photoco-
`agulation and deferral of photocoagulation groups
`are small in the first two years of follow-up. After
`this time, the differences become somewhatlarger.
`These larger differences can be explained, at least in
`part, by the demonstrated beneficial effect of focal
`photocoagulation for eyes in whichclinically signifi-
`cant macular edema developed during follow-up.
`Visual Acuity Results in Eyes Classified by Severity of
`Retinopathy.—Figure 9 shows the results when eyes
`are categorized according to the severity of retinopa-
`thy, as determined by detailed grading of baseline
`fundus photographs (see also Table 5). Eyes classi-
`fied as having “mild nonproliferative diabetic reti-
`nopathy” were free of soft exudates, intraretinal
`microvascular abnormalities, and venous beading,
`and they had no more than moderate intraretinal
`hemorrhages or microaneurysms. Eyes designated
`as having “moderate nonproliferative diabetic reti-
`nopathy”were subdivided into levels 1 and 2. In level
`1, at least one of the above lesions waspresent, while
`in level 2 there was increased severity of one or more
`of these lesions but less than that in those eyes
`designated as having “severe nonproliferative reti-
`nopathy.” Eyes in the latter category had at least
`three of these lesions present (the same definition of
`severe nonproliferative diabetic retinopathy was
`used in the Diabetic Retinopathy Study).”*
`The ETDRSwasnot designed to assess the effect
`of initial focal treatment without panretinal photo-
`coagulation in eyes with severe nonproliferative or
`early proliferative retinopathy. However, a subgroup
`of eyes with this severity of retinopathy wereinitial-
`ly graded as having only mild to moderate nonprolif-
`erative retinopathy and were treated, according to
`the study protocol, with only focal photocoagulation.
`When more detailed fundus photograph evaluation
`was completed, it was determined that these eyes,
`which had already received focal treatment, actually
`had severe nonproliferative or early proliferative
`diabetic retinopathy. The results of focal photocoag-
`ulation in this small subgroup of eyes are shown in
`Fig 9, bottom.
`
`Arch Ophthalmol—Vol 103, Dec 1985
`
`Diabetic Macular Edema—ETDRS Research Group
`
`1801
`
`Downloaded from jamanetwork.com by Jillian Saucier on 01/22/2024
`
`IPR2023-00884
`Samsungetal. v. Regeneron
`Regeneron Pharmaceuticals,Inc.
`Exhibit2124
`Page6
`
`

`

` Table 3,—Numbers of Eyes in Visual Acuity Subgroups
`
`
`“| indicates immediate focal photocoagulation group; D, deferral of
`photocoagulation group.
`tOne baseline visual acuity score was missing at the time this
`analysis was performed.
`
`Group
`immediate
`Deferral
`
`Baseline
`114
`226
`
`No. of Eyes
`12mo0
`24mo
`92
`65
`182
`125
`
`* 196 = Z< 2.58
`
`36mo
`50
`87
`
`27< 3.29
`42.58 =
`AZ= 3.29
`
`6
`
`404
`
`re
`
`oo
`
`Se,
`
`*
`
`’
`
`Months of Follow-up
`
`a Baseline Visual Acuity Score of 100 to 90 (20/ 15 or Better)
`
`
`
`og2°ta
`¢S
`9>
`
`£=v
`
`eo>w
`
`* 1.96 = Z< 2.58
`$2.58 = Z< 3.29
`No. of Eyes*
`eae>
`AZ= 3.29
`Base-
`12 mo
`linet
`Baseline Visual ——--_ ——-——__
`Acuity Score
`
`36 mo
`24 mo
` ——— ———.
`|
`D
`l
`D
`
`|
`2
`|
`’
`>
`
`
`oo2
`w
`
`
` 1= STeeLSCeTeReet= 204
`
`
`
`_, Baseline Visual Acuity Score <60 (Worse Than 20/60)
`
` T
`24
`
`Fig 6.—Comparison of percentage of eyes that experienced
`visual loss of 15 or moreletters (equivalent to at least doubling
`ofinitial visual angle or loss of three or more lines) in eyes with
`macular edema and mild to moderate diabetic retinopathy
`classified by baseline visual acuity score and assignedto either
`immediate focal photocoagulation (broken line) or deferral of
`photocoagulation (solid line).
`
`The treatment effect appears similar in all four
`subgroups butis statistically significant only in the
`two moderate nonproliferative retinopathy groups,
`evidently because of the larger sample sizes of these
`two groups.
`Results Based on Retinal Thickening
`Involving the Center of the Macula
`Reading Center grading of baseline photographs
`identified 74% of all the eyes withclinically signifi-
`
`Monthsof Follow-up
`
`Fig 7.—Comparison of percentage of eyes that experienced
`visual gain of six or more letters (equivalent to more than
`one-line gain) in eyes with macular edema and mild to moderate
`diabetic retinopathy assigned to either immediate focal photo-
`coagulation (broken line) or deferral of photocoagulation (solid
`line).
`
`cant macular edema as having retinal thickening,
`with the center of the macula involved (Table 6). At
`one year, 35% of these eyes assigned to immediate
`focal
`treatment had retinal
`thickening with the
`center of the macula involved compared with 63% of
`eyes assigned to deferred photocoagulation. This
`difference wasstatistically significant, as it also was
`at three years. None of the eyes without clinically
`significant macular edema had retinal
`thickening
`with the center of the macula involved before entry
`into the study. Small differences in the occurrence of
`retinal thickening with the center of the macula
`involved were noted during follow-up in this latter
`group.
`
`Results Based on Other Visual Function
`Assessment (Visual Fields, Color
`Vision, and Patients’ Impressions of Changein Visual
`Function)
`Adverseeffects of treatment also were assessed by
`considering changes from baseline to follow-up visits
`
`1802
`
`Arch Ophthalmol—Vol 103, Dec 1985
`
`Diabetic Macular Edema—ETDRS Research Group
`
`Downloaded from jamanetwork.com by Jillian Saucier on 01/22/2024
`
`IPR2023-00884
`Samsung etal. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2124
`Page 7
`
`

`

`* 196 @2Z2< 2.58
`166 * 1.96 = Z7< 2.58
`$2.58=Z< 3.29
`167 $2.58 = Z< 3.29
`AZ>=3.29
`168 AZ= 3.29
`
`Months of Follow-up
`
`Mild Nonproliferative Retinopathy
`_ and Macular Edema
`
`Moderate Nonproliferative Retinopathy
`+ (Level 1) and Macular Edema
`
`Moderate Nonproliferative Retinopathy
`(Level 2) and Macular Edema
`
`EyesWithVisionLoss,
`
`Severe Nonproliferative or Early Proliferative
`Retinopathy and Macular Edema
`
`
`
`Fig 9.—Comparison of percentage of eyes that experienced
`visual loss of 15 or moreletters (equivalent to at least doubling
`of initial visual angle or loss of three or more lines) in eyes
`with macular edema classified by severity of retinopathy at
`baseline and assigned to either immediate focal photocoagula-
`tion (broken line) or deferral of photocoagulation (solid line).
`
`Table 5.—Numbers of Eyes in Retinopathy Subgroups
`
`No. of Eyes*
`
`Base-
`36mo
`24mo
`12mo
`linet
`——S-So
`I
`D
`|
`1
`|
`D
`
`
`
`
`
`. Macular Edema
`
`Clinically Significant
`
`EyesWithVisionLoss,%
`
`Months of Follow-up
`
`Fig 8.—Comparison of percentage of eyes that experienced
`visual loss of 15 or moreletters (equivalent to at least doubling
`of initial visual angle or loss of three or more lines) in eyes
`classified by presence or absence of clinically significant
`macular edema and assigned to either immediate focal photo-
`coagulation (brokenline) or deferral of photocoagulation (solid
`line).
`
`
`
`Table 4.—Numbers of Eyes in Macular Edema Subgroups
`No. of Eyes*EE
`Base-
`36 mo
`24 mo
`12 mo
`linet
`OO oe a eee
`
`Clinically
`Significant
`D
`|
`D
`|
`o
`t
`D
`Macular Edema __|
`Present
`434 853 375 717 249 497 168 311
`Absent
`277 545 235 455 164 311
`100 215
`
`*l indicates immediate focal photocoagulation group; D, deferral of
`photocoagulation group.
`tAll of the gradings for the baseline photographs were not available
`at the time this analysis was performed.
`
`in visual field and color vision scores. Small, not
`statistically significant differences were observed in
`visual field scores and proportions of patients with
`scotomasto the I-2 test object. No treatment differ-
`ences were observed in the Farnsworth-Munsell 100-
`hue test color vision scores.
`In 16 of the 23 clinical centers, patients were asked
`for their impressions of change in visual function.
`They reported more improvement and less worsening
`from baseline for eyes assigned to immediate focal
`treatment
`than for eyes assigned to deferral of
`photocoagulation: for improvement, 36% vs 14% at
`12 months, 43% vs 18% at 24 months, and 57% vs
`11% at 36 months; for worsening, 18% vs 25% at 12
`months, 20% vs 25% at 24 months, and 28% vs 35%
`at 36 months. The results for improvement were
`statistically significant (Z > 2.57).
`COMMENT
`
`These results from the ETDRS show that eyes
`with clinically significant macular edema (Table 1)
`
`295 593 253 482 176 336 107 212
`
`74 119
`
`68 105
`
`46
`
`71
`
`36
`
`43
`
`*| indicates immediate focal photocoagulation group; D, deferral of
`photocoagulation group.
`tAIl of the gradings for the baseline photographs werenot available
`at the time this analysis was performed.
`
`Arch Ophthalmol—Vol 103, Dec 1985
`
`Diabetic Macular Edema—ETDRS Research Group
`
`1803
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`Downloaded from jamanetwork.com by Jillian Saucier on 01/22/2024
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`IPR2023-00884
`Samsung etal. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2124
`Page8
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`
`
`
`
`Severity of
`Retinopathy
`Mild nonproliferative and
`69 150 76 58 131 40 97 28
`macular edema
`Moderate nonproliferative
`(level 1) and macular
`
`edema
`__273 537 231 454 151 304
`97 195
`Moderate nonproliferative
`(level 2) and macular
`edema
`Severe nonproliferative
`or early proliferative
`and macular edema
`
`

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`Samsung et al. v. Regeneron IPR2023-00884
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`Downloaded from jamanetwork.com by Jillian Saucier on 01/22/2024
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`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2124 Page 11
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