Photocoagulation Treatment of
`Proliferative Diabetic Retinopathy
`
`Clinical Application of Diabetic Retinopathy Study
`(DRS) Findings, DRS Report Number 8
`
`THE DIABETIC RETINOPATHY STUDY RESEARCH GROUP
`
`Abstract: Additional follow-up confirms previous reports'~* from the
`Diabetic Retinopathy Study (DRS) that photocoagulation, as used in the
`study, reducestherisk of severe visual loss by 50% or more. Decreases
`of visual acuity of one or more lines and constriction of peripheral visual
`field due to treatment were also observed in some eyes. These harmful
`effects were more frequent and more severe following the DRS xenon
`technique.** The two-year risk of severe visual
`loss without treatment
`outweighsthe risk of harmful treatment effects for two groupsof eyes: (1)
`eyes with new vessels and preretinal or vitreous hemorrhage; and (2)
`eyes with new vessels on or within one disc diameter of the optic disc
`(NVD) equaling or exceeding 1/4 to 1/3 disc area in extent, (Fig 1), even
`in the absence ofpreretinal or vitreous hemorrhage. For eyes with these
`characteristics, prompt treatment is usually advisable. For eyes with less
`severe retinopathy, DRS findings do not provide a clear choice between
`prompt treatment or deferral unless progression to these more severe
`stages occurs. [Key words: clinical trial, diabetic retinopathy, photo-
`coagulation.] Ophthalmology 88:583-—600, 1981
`
`
`The Diabetic Retinopathy Study (DRS) is a ran-
`domized controlled clinical trial sponsored by the Na-
`tional Eye Institute to evaluate photocoagulation
`treatment for proliferative diabetic retinopathy. Sev-
`€nteen hundred fifty-eight patients were enrolled in
`the study between 1972 and 1975. On thebasis of data
`demonstrating a strong beneficial treatmenteffect, the
`Protocol was changed in 1976 to allow photocoagula-
`
`
`
`From the DRS Coordinating Center, Department of Epidemiology
`and Preventive Medicine, University of Maryland, 600 Wyndhurst
`Avenue, Baltimore, Maryland 21210
`Presented at
`the Eighty-Fifth Annual Meeting of the American
`Academy of Ophthalmology, Chicago, November 2--7, 1980.
`The DRSis supported by contracts with the National EyeInstitute,
`Nationa! Institutes of Health, US Department of Health and Human
`Services,
`
`tion treatment of eyes initially assigned to the un-
`treated control group in which the risk of severe visual
`loss without treatment clearly outweighed the risk of
`harmful effects from treatment. Patient follow-up was
`completed on June 30, 1979.
`
`MATERIALS AND METHODS
`
`Eligible patients had proliferative diabetic reti-
`nopathyin at least one eye or severe nonproliferative
`retinopathyin both eyes, and visual acuity of 20/100 or
`better in each eye. One eye of each patient was ran-
`domly assigned to immediate photocoagulation and the
`other to follow-up without treatment regardless of the
`course followed by either eye. The eye chosen for
`photocoagulation was randomly assigned to either of
`
`9161-6420/81/0700/0583/$1.40 © American Academy of Ophthalmology
`
`583
`
`IPR2023-00884
`Samsunget al. v. Regeneron
`Regeneron Pharmaceuticals, Inc.
`Exhibit 2122
`Page 1
`
`

`

`@ VOLUME 88 ® NUMBER 7
`
`the vortex vein ampulae and often completed in a
`single sitting. The argon treatment technique specified
`800 to 1600 500-micron scatter burns of 0.1 seconds
`duration and focal treatment of new vessels whether
`on or within one disc diameter of the optic disc (NVD)
`or outside this area (‘‘elsewhere,’’ NVE). This focal
`treatment was applied both for new vessels on the
`surface of the retina and for elevated new vessels.
`Focal treatment was also applied to microaneurysms
`or otherlesions thought to be causing macular edema.
`Follow-up treatment was applied as needed at four-
`month intervals. The xenon technique was similar, but
`scatter burns were generally of longer duration and
`stronger and focal treatment was not applied to NVD
`or elevated NVE. Figs 2 and 3, which are montages of
`24-hour post-treatment photographs,
`illustrate the
`seven standard photographic fields used in the DRS
`and the two treatment techniques employed. Further
`details regarding methods are described elsewhere.®
`
`
`RESULTS
`
`As in previous DRSreports, ‘‘severe visual loss”’ is
`defined as visual acuity of less than 5/200 at two or
`more consecutively completed follow-up visits (visits
`scheduled at four-month intervals). The difference
`between the rates of occurrenceof severe visual loss in
`eyes assigned to the control and treated groups pro-
`vides the major measure of treatment effect. Cumula-
`tive incidencerates of this event, calculated by a life-
`table method,® are presented in Table 2. In this table,
`eyes are classified by the treatment group to which
`they were randomly assigned at entry. No exceptions
`have been made, even for contro} group eyesthat were
`treated after the 1976 protocol change. All follow-up
`observations collected prior to termination of patient
`follow-up in June 1979 are includedin this analysis. In
`Table 2, Z is the difference between the rates for con-
`trol and treated eyes measured in standard errors.'*
`Therates. in the ‘‘both groups combined”’ section of
`Table 2 are plotted in Fig 4, together with the compa-
`rable rates from an analysis which excludes observa-
`tions made after the 1976 protocol change. The two
`curves for control group eyesare very similar over the
`first 20 months of follow-up and those for treated eyes
`are similar overat least the first 28 months. The differ-
`ence between the two control group curvesis probably
`due, at least in part, to the beneficial effect of treat-
`ment experienced by someof these eyes after the 1976
`protocol change. A rough estimate of the extent to
`which the curve which includes post-change-of-
`protocol observations may be influenced by treatment
`may be obtained from Table 3, which presentsthe total
`numberof patients completing specified follow-up vis-
`its, the percentage of these visits completed after the
`1976 protocol changed, and the cumulative per-
`centages of control group eyes that had been treated
`prior to each visit. In each of the analyses presented in
`Figure 4, the incidence of severe visual loss in eyes
`
`OPHTHALMOLOGY @ JULY 1981
`
`
`
`Fig 1. Standard Photograph No. 10A, Modified Airlie House
`Classification of Diabetic Retinopathy. New vessels cover about 1/4
`the area of this disc, which is a little larger than average. New
`vessels equaling these might cover 1/3 the area of a smaller disc.
`New vessels equaling or exceeding those in this photograph are
`sufficient to place an eye in the “*high-risk”’ category (without regard
`to the size of the disc).
`
`two treatment techniques, one using the argon laser
`and the other the xenon arc photocoagulator. Patients
`were followed at four-month intervals according to a
`protocol which provided for measurementofbest cor-
`rected visual acuity by examiners who did not know
`the identity of the treated eye and who attempted to
`reduce patient bias by urging the patient to read as far
`down the chart as possible with each eye, guessing at
`letters until more than one in a line was missed. All
`patients gave written informed consent and under-
`stood that the information being collected would be
`analyzedat frequentintervals and used, if possible, for
`their benefit.
`Key features of the argon and xenon photo-
`coagulation techniques used in the DRS are summa-
`rized in Table 1. Both techniques included ‘‘scatter’’
`(panretinal) photocoagulation extending to or beyond
`
`Table 1. DRS Photocoagulation Techniques
`
`Argon
`
`Xenon
`
`400-800 (3°)
`800-1600 (500 ~m)
`or 500-1000 (1000 nm) or 200-400 (4.5°)
`0.1 second
`not specified
`of
`
`++
`
`+ettt
`
`Scatter
`No. of Burns
`
`Exposure time
`Focal
`Surface NVE
`Elevated NVE
`NVD
`Macular Edema
`Follow-up
`
`584
`
`IPR2023-00884
`Samsunget al. v. Regeneron
`Regeneron Pharmaceuticals, Inc.
`Exhibit 2122
`Page 2
`
`

`

`Fig 2. Twenty-four-hour
`post-treatment —photo-
`graphs of an eye treated
`with the DRS argon tech-
`nique. Note extensive 500
`pm scatter burns, con-
`fluent focal treatment of
`two small patches of NVE
`along the inferior temporal
`artery inferotemporal to
`the macula, and focal
`treatment of NVD adjacent
`to the disc.
`
`Fig 3. Twenty-four-hour
`post-treatment
`photo-
`graphs of an eye treated
`with the DRS xenon tech-
`nique. Scatter burns were
`Made with the 4.5° field
`stop and are less evenly
`Spaced than the argon
`burns in Fig 2. Confluent
`focal treatment has been
`applied to four patches of
`surface NVE. The NVE
`superotemporal to the disc
`are Congested and a small
`Preretinal hemorrhage has
`occurred since treatment.
`Focal treatment has been
`applied temporal to the
`Macula to microaneurysms
`thought to be the cause of
`mild macular edema.
`
`DRS RESEARCH GROUP @ DIABETIC RETINOPATHY SYMPOSIUM
`
`
`IPR2023-00884
`Samsung et al. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2122
`Page3
`
`

`

`Table 2. Cumulative Event Rates of Severe Visual Loss, Z Values of Control-treated Differences, Number of Eyes at Risk in
`Each Four-month Interval and Standard Errors by Months of Follow-up and Treatment Group
`
`Argon Group
`Follow-up
`Months
`Control
`Treated
`
`
`Z
`
`Control
`
`
`
`Both Groups CombinedXenon Group
`Treated
`Z
`Control
`Treated
`Z
`
`8
`12
`
`16
`20
`24
`
`28
`32
`36
`
`40
`44
`48
`
`§2
`56
`60
`
`64
`68
`72
`
`4-8
`8-12
`
`1.0
`3.4
`
`6.6
`10.3
`13.6
`
`16.5
`19.2
`21.1
`
`23.6
`25.4
`27.4
`
`29.2
`31.1
`32.1
`
`32.5
`34.2
`34.2
`
`834
`812
`
`A. Cumulative Event Rates Per 100 Eyes at Risk
`1.5
`1.5
`9
`1.1
`2.0
`3.9
`2.9
`1.2
`
`3.1
`4.0
`4.7
`
`5.2
`5.8
`5.9
`
`6.4
`7.0
`7.2
`
`6.8
`7.4
`7.3
`
`7.4
`6.8
`5.9
`
`6.9
`10.9
`14.3
`
`17.0
`19.1
`22.4
`
`24.7
`26.3
`28.2
`
`30.2
`32.3
`33.8
`
`35.9
`35.9
`39.3
`
`3.7
`5.1
`5.8
`
`6.6
`7.4
`7.9
`
`9.1
`9.9
`10.7
`
`11.4
`12.4
`12.7
`
`13.4
`13.4
`15.9
`
`2.9
`4.4
`5.7
`
`6.5
`6.9
`8.1
`
`8.3
`8.4
`8.7
`
`9.0
`9.0
`9.3
`
`9.2
`9.2
`6.6
`
`0.4
`1.8
`
`3.3
`5.1
`6.6
`
`7.9
`9.0
`10.2
`
`11.2
`11.5
`12.6
`
`14.4
`14.6
`15.2
`
`15.2
`16.3
`17.5
`
`1.2
`3.6
`
`6.8
`10.6
`14.0
`
`16.7
`19.1
`21.7
`
`24.1
`25.9
`27.8
`
`29.7
`31.7
`33.0
`
`34.2
`35.1
`36.7
`
`1681
`1624
`
`1.8
`2.2
`
`4.3
`5.9
`7.4
`
`8.3
`9.0
`9.9
`
`10.4
`10.9
`11.2
`
`11.2
`11.6
`11.8
`
`11.8
`11.3
`9.0
`
`0.7
`2.3
`
`3.5
`5.1
`6.2
`
`7.2
`8.2
`9.0
`
`10.1
`10.7
`11.6
`
`12.9
`13.5
`13.9
`
`14.3
`14.8
`16.6
`
`1682
`1634
`
`B. Numberof Eyes at Risk in Each Four-monthInterval
`835
`847
`847
`818
`812
`816
`
`12-16
`16-20
`20-24
`
`24-28
`28-32
`32-36
`
`36-40
`40-44
`44-48
`
`48-52
`52-56
`56-60
`
`60-64
`64-68
`68-72
`
`8
`12
`
`16
`20
`24
`
`28
`32
`36
`
`40
`44
`48
`
`767
`734
`692
`
`656
`614
`589
`
`557
`531
`477
`
`407
`329
`259
`
`190
`118
`65
`
`0.3
`0.6
`
`0.9
`1.1
`1.2
`
`1.3
`1.4
`1.5
`
`1.5
`1.6
`1.6
`
`786
`763
`738
`
`711
`680
`658
`
`633
`617
`560
`
`480
`391
`310
`
`224
`142
`74
`
`0.2
`0.5
`
`0.6
`0.8
`0.9
`
`1.0
`1.0
`11
`
`1.1
`1.1
`1.2
`
`781
`741
`689
`
`655
`628
`§98
`
`571
`539
`483
`
`406
`335
`260
`
`186
`117
`55
`
`797
`777
`754
`
`734
`715
`700
`
`684
`651
`597
`
`516
`429
`341
`
`244
`154
`67
`
`C.
`
`Standard Errors
`0.4
`0.3
`0.7
`0.6
`
`0.9
`1.1
`1.2
`
`1.3
`1.4
`1.5
`
`1.5
`1.6
`1.6
`
`0.7
`0.8
`0.8
`
`0.9
`0.9
`0.9
`
`1.0
`1.1
`1.1
`
`1547
`1475
`1381
`
`1311
`1243
`1187
`
`1127
`1071
`960
`
`813
`664
`519
`
`376
`235
`120
`
`0.3
`0.5
`
`0.6
`0.8
`0.9
`
`0.9
`1.0
`1.0
`
`1.1
`1.4
`1.1
`
`1584
`1539
`1492
`
`1445
`1394
`1358
`
`1317
`1269
`1157
`
`997
`820
`650
`
`469
`297
`141
`
`0.2
`0.4
`
`0.5
`0.5
`0.6
`
`0.6
`0.7
`0.7
`
`0.8
`0.8
`0.8
`
`0.9
`1.2
`1.2
`1.7
`1.3
`1.7
`52
`0.9
`1.2
`1.2
`1.8
`1.3
`1.8
`56
`0.9
`1.3
`1.2
`1.8
`1.4
`1.8
`60
`1.0
`1.3
`1.3
`2.0
`1.4
`1.8
`64
`68
`2.0
`1.6
`2.0
`1.3
`1.4
`1.0
`72
`2.0
`1.9
`2.7
`2.2
`1.7
`1.4
`
`
`586
`
`IPR2023-00884
`Samsung et al. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit 2122
`Page 4
`
`

`

`DRS RESEARCH GROUP e DIABETIC RETINOPATHY SYMPOSIUM
`
`40
`
`W Oo
`
`nm Oo
`
`Oo
`
`
`
`EVENTRATES/IOO
`
`Fig 4. Cumulative rates of
`severe visual loss,
`includ-
`ing and excluding obser-
`vations madeafter the 1976
`protocol change, argon and
`xenon groups combined.
`
`CONTROL
`(allvisits)
`
`CONTROL
`(original protocol)
`
`oe” TREATED
`“” (original protocol) ~§Leas"
`--~ TREATED
`(all visits)
`
`
`
`0 4 8 I2 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
`
`MONTHS OF FOLLOW-UP
`
`Table 3. Number of Patients Who Had Completed Specified Visits as of July 1, 1979, Percentages of Visits Completed After 1976
`Protocol Change, and Percentage of Control Group Eyes Which Had Received Photocoagulation Priorto the Visit
`
`Percentage of Visits
`Numberof Patients
`Percentage of Control
`After 1976 Protocol
`
`
` Visit Who CompletedVisit Change Eyes Previously Treated
`
`
`
`0.0
`0.0
`1742*
`Pre-treatment
`0.0
`0.0
`1673
`FV01 (6 weeks)
`2.4
`8.3
`1570
`FV04 (1 year)
`11.9
`44.3
`1468
`FVO07 (2 years)
`24.2
`89.1
`1342
`FV10 (3 years)
`34.4
`100.0
`1176
`FV13 (4 years)
`
`FV16 (5 years) 39.6 673 100.0
`
`
`
`* Sixteen patients assigned to the combined argon-xenon treatment group, which was discontinued shortly after recruitment began, have been excluded
`all analyses in this report.
`
`assigned to immediate treatment is reduced by 50% or
`More in comparison to control group eyes, and this
`reduction persists throughout the follow-up period.
`Cumulative incidence rates of severe visual loss are
`Plotted separately for the argon and xenon treatment
`groups in Fig 5, using the information in Table 2. The
`treatment effect,
`ie, the difference in rates between
`treated and control eyes, appears somewhatgreater in
`the xenon thanin the argon group, but the differencein
`treatment effect between argon and xenon groups is
`Small,
`its statistical significance borderline, and its
`Clinical importance outweighed by the greater harmful
`treatment effects observed following the DRS xenon
`technique.?~4
`Analyses of the occurrence of severe visual loss in
`
`eyes Classified’ according to severity and location of
`new vessels and presenceof vitreous and/or preretinal
`hemorrhage (VH/PRH) in baseline fundus photographs
`allowed documentation in previous DRS reports’ * of
`certain ‘high-risk characteristics.’’ High-risk charac-
`teristics are presence of NVD equaling or exceeding
`those in Fig 1 (which are about 1/4 to 1/3 disc area in
`extent), with or without VH/PRH, or the presence of
`VH/PRH andless extensive new vessels, either NVD
`less than those in Fig 1 or NVE one-half disc area or
`more in extent (in any photographic field). It was for
`eyes with these characteristics that the 1976 protocol
`change was implemented. Fig 6 illustrates the greater
`risk of severe visual loss observedin these eyes than in
`the remaining eyes in the study, which had less severe
`
`587
`
`IPR2023-00884
`Samsunget al. v. Regeneron
`Regeneron Pharmaceuticals, Inc.
`Exhibit 2122
`Page 5
`
`

`

`40
`
`w oO
`
`mM oO
`
`oO
`
`
`
`EVENTRATES/1I00
`
`OPHTHALMOLOGY @ JULY 1981 @ VOLUME 88 e NUMBER 7
`
`XENON CONTROLawe
`"ARGON CONTROL
`
`e ARGON TREATED -—
`
`—
`
`*
`
`ar
`
`O 4 8 [2 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
`
`MONTHS OF FOLLOW-UP
`
`PDR with HRC
`CONTROL -:::-
`TREATED ——
`
`PDR without HRC
`CONTROL
`TREATED =ew=
`NPDR
`CONTROL tosses
`TREATED ------
`
`re “eC
`
`woo
`
`gasenet
`en
`~
`. —
`
`
`
`O
`
`4
`
`8
`
`12
`
`I6 20 24 28 32 36 40 44 48 52 56 60
`MONTHS OF FOLLOW-UP
`
`60r
`
`50
`
`40
`
`30
`
`20
`
`10
`
`
`
`EVENTRATES/100
`
`588
`
`Fig 5. Cumulative rates of
`severe visual loss for argon
`and xenon groups sepa-
`rately.
`
`Fig 6. Cumulative rates of
`severe visual loss for eyes
`classified by presence of
`proliferative retinopathy
`(PDR) and high-risk char-
`acteristics (HRC) in base-
`line fundus photographs,
`argon and xenon groups
`combined. NPDRsignifies
`nonproliferative diabetic
`retinopathy.
`
`IPR2023-00884
`Samsungetal. v. Regeneron
`Regeneron Pharmaceuticals, Inc.
`Exhibit 2122
`Page6
`
`

`

`DRS RESEARCH GROUP @ DIABETIC RETINOPATHY SYMPOSIUM
`
`retinopathy. After 24 monthsof follow-up, the rate for
`control eyes with high-risk characteristics is about
`26% and is reduced to about 11% in treated eyes. After
`24 months offollow-up, a similar 50% treatmenteffect
`can be seen in eyes with proliferative retinopathy
`without high-risk characteristics, but both control and
`treated rates are lower, about 7 and 3%, respectively.
`Only after 36 months of follow-up does the incidence
`of severe visual
`loss in untreated eyes with
`nonproliferative retinopathy reach the 7% level. At
`this point, a similar 50% treatmenteffect is apparent.
`Someeyes with nonproliferative retinopathy are those
`of patients who were eligible for the study because
`severe nonproliferative retinopathy was present in
`both eyes and someare the fellow eyes of patients
`eligible because proliferative retinopathy was present
`in the other eye. In many of the eyes without high-risk
`characteristics at baseline which subsequently devel-
`oped severe visual loss, the development of high-risk
`characteristics presumably preceded the occurrence of
`severe visual loss.
`Harmful effects of treatment were greater in the
`xenon group, as indicated in Table 4, which summa-
`rizes information from previous DRSreports.”*
`Twenty-five percent of xenon-treated eyes suffered a
`modest loss of visual field and an additional 25% a
`more severe loss. In the argon group, 5% of eyes
`showed some constriction of visual field to the large
`test object used (Goldmann IVe4). We estimate that a
`persistent visual acuity decrease of one line may be
`attributed to treatment in 19% of xenon-treated eyes
`and a persistent decrease of two or more lines in an
`additional 11%. Comparable estimates for the argon
`group are 11% and 3%, respectively.
`Partly on the basis of results similar to these, photo-
`coagulation techniques were modified when treatment
`wascarried out in eyes initially assigned to the un-
`treated control groups after the 1976 protocol change.
`Argon treatment waspreferred but the most techni-
`cally difficult features of the original protocol, focal
`treatment of NVD and elevated NVE, were not re-
`
`Table 4. Estimated Percentages of Eyes With Harmful Effects
`Attributable to DRS Treatment
`
`
`
` Argon Xenon
`
`Constriction of visualfield
`(Goldmann !Ve4)
`to an average of
`=45°, >30° per meridian
`<30° per meridian
`Decrease in visual acuity
`19
`11
`1 Line
`
`
`3=2 Lines 1eee
`
`25
`25
`
`5
`0
`
`quired and wererarely used. In the hope of reducing
`the risk of visual acuity decreases, many DRS inves-
`tigators divided scatter treatment into two or more
`episodes, days or weeks apart.
`
`CLINICAL APPLICATION OF DRS
`RESULTS
`
`Clinical application of DRS results to eyes with
`high-risk characteristics is straightforward. The risk of
`severe visual loss without treatment substantially out-
`weighs the risks of photocoagulation, particularly
`those observed following the DRS argon technique,
`and prompt treatment is usually advisable. Figs 7
`through 11 illustrate the course followed by five DRS
`patients who had high-risk characteristics in both eyes.
`The patient presented in Fig 11 illustrates the remark-
`able spontaneous improvement sometimes observedin
`patients with proliferative diabetic retinopathy and
`underscores the need for randomized, controlled trials
`in evaluating treatment.
`For eyes with severe nonproliferative retinopathy or
`with proliferative retinopathy without high-risk char-
`acteristics, prompt photocoagulation is attractive,
`since with it, the 12% two-year risk of severe visual
`loss observed in the high-risk group even with photo-
`coagulation might be avoided. On the other hand, de-
`ferral of photocoagulation unless high-risk character-
`istics develop defers the risks of photocoagulation.
`Eyes followed and treated as soon as high-risk char-
`acteristics develop might be expected to do better than
`did the DRS high-risk group, which included eyes
`which already had moresevere retinopathy at the time
`of treatment. DRS findings do not provide a clear
`choice between prompt photocoagulation and deferral.
`Careful, periodic follow-up is essential for patients
`with diabetic retinopathy. When nonproliferative ret-
`inopathy changes are present, follow-up visits should
`be scheduled at frequent intervals.
`For eyes with nonproliferative retinopathy or prolif-
`erative retinopathy without high-risk characteristics,
`important questions remain unanswered.
`Is early
`photocoagulation preferable to deferral? Is the exten-
`sive scatter treatment used in the DRS necessary, or
`might less extensive treatment retard the progression
`of retinopathy and be attended by fewer harmful side
`effects? Apart from its value for the proliferative fea-
`tures of diabetic retinopathy, whatis the role of photo-
`coagulation in diabetic maculopathy? Might low dose
`aspirin slow the progression of retinopathy? These
`questions are being addressed by another randomized
`controlled clinical trial, the Early Treatment Diabetic
`Retinopathy Study (ETDRS).
`
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`Fig 7A
`
`Fig 7B Fig 7C
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` Fig 7D
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`Figs 7A-D. Twenty-three-year-old white man, diabetes diagnosed at age 4. Decreasedvisionfirst noted in left eye two years ago, withlittle
`change since. This and the remaining figures present stereo pairs. Some observers may require up to 10 diopters prism base out and,if
`presbyopic, sufficient plus powerfor a viewing distance of20 to 25 centimetersin order to obtain a stereoscopic view. 7A. Right eye at entry.
`Visual acuity 20/30. Very severe NVDare present, with preretinal and vitreous hemorrhage. There islittle stereoscopic effect in this photo.
`7B. Right eye four monthsfollowing argon laser photocoagulation. Considerable regression of NVD has occurred and they have been pulled
`forward by vitreous contraction. 7C. Right eye four years following initial photocoagulation. Follow-up photocoagulation was carried out on
`two occasions. NVD have regressed completely. Visual acuity 20/30. 7D. Left eye at entry. Visual acuity 20/40. Very severe NVD.Visual
`acuity four months following entry into the study was less than 5/200 in the left eye, and fundus photography was precluded by vitreous
`hemorrhage. Vitreous hemorrhage failed to clear and two yearslater visual acuity was no light perception. Neovascularization of the iris,
`posterior synechia, and cataract were present.
`
`
`
`Fig 8. Fifty-three-year-old white woman, diabetes diagnosed at age 27. Severe retinopathy noted at routine eye examination. Visual
`acuity 20/30 (RE), 20/15 (LE). 8A. Right eye,initial visit. Severe NVD accompanied byfibrous proliferations extend forward, presumably
`the detached posterior vitreous surface. There are tension lines in the macula. No preretinal or vitreous hemorrhage is present. (Figs
`~Fcontinued on following page.)
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`OPHTHALMOLOGY @ JULY 1981 @ VOLUME 88 e NUMBER 7
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`Fig 8B Fig 8C
`
`Figs 8B-F. Right eye two yearsafter argon laser photocoagulation. New vessels have regressed almost completely and tension lines have
`disappeared. Visual acuity 20/15. 8C. Right eye four years post-treatment. New vessels have not increased and visual acuity remains 20/15.
`8D.Left eye, initial visit. NVD are perhaps slightly less extensive than those in the right eye, without fibrousproliferations and with only
`slight elevation of the temporal edge of the patch. A small preretinal hemorrhage was presentin the lower temporal quadrant. 8E. Left eye
`two years after entry, no treatment. New vessels, fibrous proliferations and posterior vitreous detachment have increased. Fine new vessels
`andfibrous proliferations are present on the surface of the retina superotemporalto the disc and there are faint tension lines in the macula.
`8F. Left eye four years after entry and one and one-half years after argon laser photocoagulation applied following the 1976 protocol change.
`Scatter treatment only was applied. Traction retinal detachment involving the macula occurred following photocoagulation, with decrease in
`visual acuity to 20/70, but resolved spontaneously with recovery of visual acuity to 20/30. New vessels have regressed almost completely.
`Fine tension lines in the macula remain.
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`OPHTHALMOLOGY @ JULY 1981 @ VOLUME 88 @ NUMBER 7
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`Fig 9B
`
`Fig 9A
`
`Figs 9A-E. Thirty-six-year-old white woman, diabetes diagnosed at age 8. Visual acuity 20/20 (RE); 20/20 (LE). 9A. Right eye at entry. A
`large patch of fibrovascular proliferations arises from the disc and extends nasally. The temporal edge of the patch is elevated. Intraretinal
`microvascular abnormalities (IRMA) are present temporal to the disc. A symptomatic vitreous hemorrhage had been notedin this eye two
`years previously and had cleared without recurrence. 9B. Right eye three years following xenon arc photocoagulation. New vessels have
`regressed partially, IRMA more completely. There is narrowing and sheathing of someretinal arterioles. Fresh vitreous hemorrhage is visible
`on and anteriorto the fibrous proliferations. This occurred periodically, apparently arising from elevated NVE in the upper temporal quadrant
`which had not regressed. Visual acuity 20/30. Visual field constricted to 20 degrees in the upper and lower nasal quadrants. 9C. Right eye five
`years following photocoagulation. Disc new vessels remain almost completely regressed. Visual acuity remains 20/30. 9D. Left eye at entry.
`NVDextendstraight forward from the disc, suggesting posterior vitreous detachment. Vitreous hemorrhageis present. 9E. Left eye two years
`after entry. New vessels, fibrous proliferations and IRMA have increased somewhat. Visual acuity has improved to 20/15. This was the
`patient's first visit after the 1976 protocol change. The patient was reluctant to have photocoagulation in this eye because she attributed the
`decrease in visual acuity and visual field in the right eye to treatment. During the next 18 months, several small vitreous hemorrhages occurred
`and argon laser photocoagulation was performed. (Fig 9F continued on following page.)
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`OPHTHALMOLOGY @ JULY 1981 @ VOLUME 88 @ NUMBER 7
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`4
`20/30. Occasional vitreous hemorrhages occur from elevated NVE which have not regressed. Fig 10A
`
`Fig 9F
`
`Fig 9F. Left eye five years after entry and two years after argon laser photocoagulation. NVD have regressed completely. Visual acuity
`
`Figs 10A-D. Fifty-two-year-old white man, diabetes diagnosedat age 20, Visual acuity 20/20 (RE); 20/20 (LE). 10A. Right eye at entry. NVD
`of moderate extent are present. There were no NVE norpreretinal or vitreous hemorrhage. 10B. Right eye, three years following xenon arc
`photocoagulation. Complete regression of NVD has occurred. Retinal arterioles are narrow. Visual acuity remains 20/20. Visual field is
`constricted to about 30 degrees in most meridians, 55 degrees temporally. 10C. Left eye at entry. A tiny strand of NVD can be seen near the
`disc margin from 3 to 4 o'clock. Thereis a little preretinal hemorrhage lying over the inferior temporal artery. A small amount of vitreous
`hemorrhage was presentin the inferior nasal quadrant. 10D. Left eye, three years after entry. New vessels have grown superiorly along the
`superior temporal vein. Vitreous detachment has occurred and the new vessels have been pulled forward. Vitreous hemorrhages have
`occurred several times during the past three years. Visual acuity was 20/50 at the three-year visit. but fell to less than 5/200 eight monthslater.
`Photocoagulation could not be carried out following the 1976 protocol change because of vitreous hemorrhage.
`:
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`Fig 10B Fig 10C
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`Fig 10
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`OPHTHALMOLOGY @ JULY 1981 ® VOLUME 88 @ NUMBER 7
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`Fig 11A Fig 11B
`
`Figs 11A-E. Twenty-year-old white man, diabetes diagnosedat age 14. Floaters and decreased vision noted several weeksago in theleft eye,
`and a few dayslater in the right eye. 11A. Right eye at entry, visual acuity 20/15. There are extensive new vessels on and near the disc. The
`disc is swollen. Two flecks of preretinal hemorrhage are presentnasally. 11B. Right eye four months following entry. Remarkable spontane-
`ous regression of new vessels has occurred. Visual acuity 20/15. 11C. Right eye four years following entry. New vessels have not recurred.
`11D. Left eye at entry. Visual acuity 20/30. New vessels, disc swelling, and preretinal hemorrhage similar to right eye. More vitreous
`hemorrhage was presentinferiorly. 11E. Left eye four monthsfollowing argonlaser scatter photocoagulation. Focal photocoagulation was not
`required by DRSprotocol for NVDas severe as those presentat entry in this eye, and such treatment was not carried out. Almost complete
`regression of new vessels has occurred. Visual acuity 20/20. (Fig 11F continued on following page.)
`
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`OPHTHALMOLOGY @ JULY 1981 @ VOLUME 88 @ NUMBER 7
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`Fig 11F
`
`Fig 11F. Left eye three years following photocoagulation. There is complete regression of new vessels.
`
`
`REFERENCES
`
`1,
`
`The Diabetic Retinopathy Study Research Group. Preliminary
`Report on Effects of Photocoagulation Therapy. Am J Ophthal-
`mol 1976; 81:383—96.
`. The Diabetic Retinopathy Study Research Group. Photo-
`coagulation Treatment of Proliferative Diabetic Retinopathy:
`The Second Report of Diabetic Retinopathy Study Findings.
`Ophthaimology 1978; 85:82—105.
`. The Diabetic Retinopathy Study Research Group. Photo-
`coagulation Treatmentof Proliferative Diabetic Retinopathy: A
`Short Report of Long Range Results. DRS Report #4. In: Pro-
`
`ceedings, 10th Congress International Diabetes Federation.
`Amsterdam: Excerpta Medica, in press.
`. The Diabetic Retinopathy Study Research Group. Photo-
`coagulation Treatment of Proliferative Diabetic Retinopathy:
`Relationship of Adverse Treatment Effects to Retinopathy Se-
`verity. DRS Report #5. Dev. Ophthalmol, in press.
`. The Diabetic Retinopathy Study Research Group. Baseline
`Monograph. DRS Report #6. Invest Ophthalmol, in press.
`. Littell AS. Estimation of the T-year survival rate from follow-up
`studies over a limited period of time. Hum Bio! 1952;
`24:87—-116
`. The Diabetic Retinopathy Study Research Group. A Modifica-
`tion of the Airlie House Classification of Diabetic Retinopathy.
`DRS Report #7 (to be published).
`
`s
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`Samsunget al. v. Regeneron
`IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit2122
`Page 18
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