`
`Journal name: Clinical Ophthalmology
`Article Designation: Review
`Year: 2019
`Volume: 13
`Running head verso: Sassalos and Paulus
`Running head recto: Sassalos and Paulus
`DOI: 169044
`
`Dovepress
`
`R e v i e w
`
`Prefilled syringes for intravitreal drug delivery
`
`This article was published in the following Dove Medical Press journal:
`Clinical Ophthalmology
`
`Thérèse M Sassalos1
`Yannis M Paulus1,2
`1Department of Ophthalmology
`and visual Sciences, w.K. Kellogg
`eye Center, University of Michigan,
`Ann Arbor, Mi, USA; 2Department of
`Biomedical engineering, University
`of Michigan, Ann Arbor, Mi, USA
`
`video abstract
`
`Point your SmartPhone at the code above. If you have a
`QR code reader the video abstract will appear. Or use:
`http://youtu.be/0bnNXtfi44Y
`
`Correspondence: Yannis M Paulus
`Department of Ophthalmology and visual
`Sciences, w.K. Kellogg eye Center,
`University of Michigan, 1000 wall Street,
`Ann Arbor, Mi 48105, USA
`Tel +1 734 764 4182
`Fax +1 734 936 3815
`email ypaulus@med.umich.edu
`
`Abstract: Intravitreal injections of anti-vascular endothelial growth factor (VEGF) medications
`play an increasingly critical role in numerous retinal vascular diseases. Initially, anti-VEGF
`medications came in vials that had to be drawn up by the physician into a syringe for adminis-
`tration. In 2018, the US Food and Drug Administration (US FDA) approved the ranibizumab
`0.3 mg prefilled syringe (PFS), and in October 2016, the US FDA approved the ranibizumab
`0.5 mg PFS. This article discusses the advantages of the PFS, including reduced injection time,
`possible reduced risk of endophthalmitis, reduction in intraocular air bubbles and silicone oil
`droplets, and improved precision in the volume and dose of intravitreal ranibizumab administered,
`along with possible disadvantages. Implications of the innovation of the PFS on intravitreal
`injection technique and clinical practice pattern are discussed and reviewed.
`Keywords: intravitreal injection, intravitreous injection, anti-VEGF, ranibizumab, prefilled
`syringe, diabetic retinopathy
`
`Introduction
`The advent and ubiquity of anti-vascular endothelial growth factor (anti-VEGF)
`injections have led intravitreal injections to become an increasingly common and
`effective method of delivering many types of medications into the vitreous cavity.1
`Anti-VEGF medications are designed to bind to and inhibit VEGF, which is thought
`to play a critical role in the formation of new blood vessels and vascular permeability
`of these vessels. The number of intravitreal injections being performed is increasing
`at epidemic proportions, with over 4 million intravitreal injections performed in the
`USA in 2013 and rising to an estimated 5.9 million patients receiving intravitreal
`injections in 2016 in the USA.2 Anti-VEGF injections have become a cornerstone in
`the treatment of retinal diseases.
`Furthermore, randomized clinical trials have demonstrated the efficacy of anti-
`VEGF intravitreal injections in the treatment of retinal diseases including exudative
`age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions.3–7
`In these studies, patients demonstrated the efficacy of anti-VEGF therapy not only in
`avoiding visual loss but also in improving visual acuity.8–11
`There are currently three anti-VEGF agents commonly used in retina practices
`in the USA: Avastin® (bevacizumab; Genentech, Inc., South San Francisco, CA,
`USA), Lucentis® (ranibizumab; Genentech, Inc.), and Eylea® (aflibercept; Regeneron,
`Tarrytown, NY, USA). In March 2018, the US Food and Drug Administration (US
`FDA) approved the ranibizumab 0.3 mg prefilled syringe (PFS) as a new method of
`administering intravitreal injections for the treatment of diabetic retinopathy and dia-
`betic macular edema.12,13 The ranibizumab 0.5 mg PFS was cleared by the US FDA in
`2016. This PFS (Figure 1) is packaged in a single-use, sealed sterile tray, thus allow-
`ing physicians to eliminate a number of steps in the preparation and administration
`
`submit your manuscript | www.dovepress.com
`Dovepress
`http://dx.doi.org/10.2147/OPTH.S169044
`
`701
`Clinical Ophthalmology 2019:13 701–706
`© 2019 Sassalos and Paulus. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php
`and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you
`hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission
`for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
`
`Open Access Full Text Article
`
`open access to scientific and medical research
`
`Novartis Exhibit 2015.001
`Regeneron v. Novartis, IPR2020-01317
`
`
`
`Sassalos and Paulus
`
`Dovepress
`
`to administration. Retina specialists and ophthalmic medical
`personnel have successfully performed both simulated-use
`and actual-use usability studies (with the PFS) with reported
`ease and without any critical errors.14 Reduction in these steps
`in the administration of intravitreal injections comes with
`some advantages which are detailed in the following sections.
`
`Reduced injection time
`By eliminating a number of steps in the previous injection
`preparation, reduced injection time is a significant advantage
`to using the ranibizumab PFS. Souied et al15 demonstrated a
`27%–39% reduction in syringe preparation time when using
`the PFS rather than the standard ranibizumab vial. Likewise,
`a previous multicenter study comparing preparation times
`using traditional syringes vs the PFS revealed that the use
`of a PFS saved an average of 25.5 seconds.16 Although this
`figure may appear modest when considering a single injec-
`tion, when taken in the context of a busy retina practice
`performing multiple injections in a day, a physician using
`a PFS could save substantial time using a PFS compared to
`conventional injection vials.
`
`Endophthalmitis
`The most visually devastating risk of intravitreal injections
`is infectious endophthalmitis (Figure 2). Regardless of the
`clinical setting or drug injected, this risk is rare, occurring
`on average in approximately one in 2,000 injected eyes.17–23
`Although there are regional and global differences in aseptic
`intravitreal injection technique, the use of povidone–iodine
`remains a critical agent to reduce bacterial colonization and
`the risk of endophthalmitis.
`The use of PFSs effectively eliminates a number of
`steps in (aseptic) injection preparation, thus decreasing the
`risk of iatrogenic contamination due to suboptimal drug/
`device handling.16,24 Although a recent report on an ongoing
`multicenter study has suggested that the odds of endophthal-
`mitis with conventional intravitreal injections were higher
`than those using ranibizumab PFS, there are currently no
`comparative trials to confirm the validity of this hypothesis.25
`
`Reduction in intraocular air bubbles
`and silicone oil droplets
`The occurrence of intraocular air bubbles during intravitreal
`anti-VEGF injection has been well described.26,27 Although
`intravitreal air bubbles typically resorb spontaneously within
`3 days, they can produce unexpected and disturbing symp-
`toms as well as a risk for patients during air travel.28 Thought
`to be a result of the physician inadvertently drawing up
`
`Figure 1 Photograph of ranibizumab PFS.
`Abbreviation: PFS, prefilled syringe.
`
`of intravitreal ranibizumab. This review summarizes the
`literature on the administration of ranibizumab via the PFS
`and the implications of this innovation on intravitreal injec-
`tion technique and clinical practice pattern (Table 1).
`
`Ranibizumab PFS injection technique
`and ease of administration
`Typical ranibizumab injection setup requires the physician/
`assistant to remove the vial cap, disinfect the drug vial top
`often with an isopropyl alcohol 70% swab, attach a filter
`needle to a sterile syringe, draw the medication into a sterile
`syringe, remove the filter needle, replace this needle with a
`smaller gauge sterile injection needle (often a 30 G or 32 G
`1/2 inch needle), remove air bubbles, and adjust the volume
`of the medication prior to administration. In contrast, the
`ranibizumab 0.3 mg PFS is made of borosilicate glass and
`is packaged in a single-use, sealed sterile tray. Therefore,
`using the PFS, the physician simply removes the syringe
`cap, attaches the injection needle, and adjusts the dose prior
`
`Table 1 Overview of the advantages and disadvantages of the
`PFS for intravitreal drug delivery
`
`Proposed advantages/
`disadvantages
`Reduced injection time
`Reduction in endophthalmitis risk
`Reduction in intraocular air bubbles
`and silicone oil droplets
`Accuracy and precision of intravitreal
`ranibizumab doses
`Disadvantages of a sterile syringe/
`drug assembly
`Abbreviation: PFS, prefilled syringe.
`
`Characterization of
`evidence
`Strongly supportive
`Theoretical
`Theoretical, of possible
`clinical significance
`Supportive
`
`Theoretical
`
`702
`
`submit your manuscript | www.dovepress.com
`Dovepress
`
`Clinical Ophthalmology 2019:13
`
`Novartis Exhibit 2015.002
`Regeneron v. Novartis, IPR2020-01317
`
`
`
`Dovepress
`
`Sassalos and Paulus
`
`Figure 2 endophthalmitis: 66-year-old male with aggressive endophthalmitis resulting in enucleation. (A) external photograph demonstrating conjunctival injection and
`hypopyon. (B) Slit-beam photo demonstrating hypopyon and keratic precipitates.
`
`non-sterile air from the standard drug vial (when preparing a
`drug for injection), air bubbles can prove difficult to eliminate
`once drawn into the syringe and can take significant addi-
`tional physician time to remove, particularly for aflibercept.
`The design features of the ranibizumab PFS include a
`latex-free, nonretractable plunger preventing inadvertent draw-
`ing of non-sterile air. Thus, by eliminating the need to draw
`up the medication and introducing a nonretractable plunger,
`the user is far less likely to inject intraocular air bubbles into
`the vitreous cavity (if proper syringe ventilation is observed).
`In addition to intraocular air bubbles, recent reports have
`shown presumed silicone oil drops associated with intravit-
`real anti-VEGF injections. Specifically, a recent study dem-
`onstrated 1.73% of patients receiving bevacizumab prepared
`with insulin syringes to have a complication of silicone oil
`droplets (Figure 3).29 The culprit for these silicone oil droplets
`
`Figure 3 Silicone oil droplets post intravitreal injection of bevacizumab: 78-year-old
`female with exudative age-related macular degeneration of the right eye who had
`been receiving intravitreal injections of Avastin (bevacizumab) every 1–2 months for
`4 years and 3 months demonstrating silicone oil droplets. visual acuity was 20/60 on
`the initiation of anti-veGF therapy and 20/25 at last follow-up on the acquisition of
`the photograph.
`Abbreviation: veGF, vascular endothelial growth factor.
`
`is thought to be polydimethylsiloxane, a chemical used as
`lubrication to reduce the friction between the syringe barrel
`and plunger. Much like intraocular air bubbles, silicone oil
`droplets are thought to result in symptoms of droplet-related
`floaters. Although not yet substantiated by clinical data, there
`is also a concern for the theoretical development of glaucoma
`due to retained oil droplets.30
`Among the design features of the PFS is included an
`optimized siliconization process whereby a silicone oil-in-
`water emulsion is spray coated to the syringe barrel’s inner
`surface and then heat fixed to minimize oil migration into
`the ranibizumab solution. This “baked silicone” process
`is thought to reduce the incidence of silicone-related
`complications from repeated intravitreal injections.24
`Accuracy and precision of intravitreal
`ranibizumab doses
`The established therapeutic doses of anti-VEGF medications
`are achieved by injecting an intraocular volume of 0.05 mL.
`One ranibizumab PFS contains 0.165 mL of ranibizumab,
`ensuring that one always has adequate volume to administer a
`single dose of 0.05 mL. Several studies have revealed consid-
`erable variability in the accuracy and repeatability achieved
`with typical syringes used for intravitreal injections.31–35
`Most commonly used small-volume syringes tend to over
`deliver their target volume.33,35 Furthermore, all syringes
`have unique surface markings (volume metrics) which can
`also lead to inaccuracies in volume dispensed. Finally, the
`presence of silicone oil and water deposits in the syringe can
`lead to deviations in volume.
`The accuracy of intravitreal injection volumes directly
`influences their therapeutic effect on the eye. Therefore,
`even small deviations from intended volumes can have
`significant implications with regard to therapeutic response,
`
`Clinical Ophthalmology 2019:13
`
`submit your manuscript | www.dovepress.com
`Dovepress
`
`703
`
`Novartis Exhibit 2015.003
`Regeneron v. Novartis, IPR2020-01317
`
`
`
`Sassalos and Paulus
`
`Dovepress
`
`drug toxicity, and IOP changes. Although formal comparative
`studies have yet to be published, the work by Loewenstein
`et al35 postulated that the accuracy of anti-VEGF injection
`volume was better achieved using a PFS compared to their
`conventional counterparts, although this study was not
`masked. They further projected that the ideal design for an
`intravitreal injection would consist of a low-volume, PFS
`with a low dead space plunger.35 The current design of the
`ranibizumab PFS includes a small syringe barrel (0.5 mL)
`which is minimally siliconized with low void volumes. This
`syringe design helps to offer improved dose assurance.
`
`Disadvantages of a sterile syringe/
`drug assembly
`Although there are several advantages to the syringe/drug
`complex in the PFS, one theoretical disadvantage would
`include the risk of drug loss due to a break in the sterile
`procedure. This includes the incidence of syringes which
`fall off the sterile injection tray or are contaminated prior to
`intravitreal injection. With the standard intravitreal injection
`procedure, the loss or contamination of a syringe (prior to
`drug aspiration) would simply involve replacement with a
`sterile syringe. A provider could incur financial loss (drug
`loss/replacement) from a PFS that is lost or contaminated
`prior to delivery to a patient.
`
`Is the PFS a compelling leap forward?
`With the advent of anti-VEGF treatment in the early 21st
`century, several landmark trials came which demonstrated
`not only the prevention of visual loss but also the significant
`increase in visual acuity of patients in response to treatment for
`retinal diseases ranging from exudative macular degeneration,
`diabetic macular edema, to retinal vein occlusions.36–40 Despite
`the marked success and widespread application of anti-VEGF
`treatment, there are a significant number of patients with
`macular edema and/or retinopathy who fail to respond to
`anti-VEGF treatment.41,42 Furthermore, these treatments are
`invasive and often require frequent administration for thera-
`peutic effect. This has led to the evolution of novel treatments
`including corticosteroid-releasing implants, treatments target-
`ing the kinin–kallikrein system, NSAIDs, vitrectomy surgery,
`laser therapies, immunosuppressants, and antibiotics targeting
`the inflammatory characteristics of early disease.43 So, while
`not a great leap forward, the PFS represents an incremental
`step that significantly reduces injection preparation time
`and the risk of endophthalmitis, silicone oil droplets, and
`air injection while improving the accuracy of drug delivery.
`
`Conclusion
`The ranibizumab PFS represents a novel method of admin-
`istering intravitreal anti-VEGF therapy for the treatment of
`retinal diseases including exudative macular degeneration,
`diabetic retinopathy, and retinal vein occlusions. The PFS
`features a small syringe barrel which is minimally siliconized
`with low void volumes. In addition, the PFS totes a latex-
`free, nonretractable plunger and is packaged in a single-use
`sterile tray. This syringe design helps to offer improved dose
`assurance, while eliminating a number of steps in the previ-
`ous injection preparation thus reducing injection times, risk
`of endophthalmitis, and administration of air or silicone oil
`droplets. In conclusion, the ranibizumab PFS improves the
`ease of administration to physicians for this very common
`intravitreal injection procedure.
`
`Acknowledgments
`This research was supported by a grant from the National
`Eye Institute 1K08EY027458 (YMP), unrestricted depart-
`mental support from Research to Prevent Blindness, and
`the Department of Ophthalmology and Visual Sciences,
`University of Michigan. The authors would like to thank
`Dr. Mark Johnson for generously allowing them to use
`photography from his patient for this article. Figures 1–3
`are original photographs performed at the Department of
`Ophthalmology and Visual Sciences, Kellogg Eye Center,
`University of Michigan, which have not been reproduced
`from any other published source. Written informed consent
`was obtained from the patients depicted in Figures 2 and 3
`to publish the content included in this manuscript.
`
`Author contributions
`TMS and YMP, contributed substantially to the conception
`and design of the manuscript. TMS wrote the initial draft of
`the manuscript, and YMP performed the critical revision of
`the manuscript for intellectual content. Both authors contrib-
`uted to data analysis, drafting and revising the article, gave
`final approval of the version to be published, and agree to be
`accountable for all aspects of the work.
`
`Disclosure
`The authors report no conflicts of interest in this work.
`
`References
`
`1. Peyman GA, Lad EM, Moshfeghi DM. Intravitreal injection of
`therapeutic agents. Retina. 2009;29(7):875–912. doi:10.1097/IAE.
`0b013e3181a94f01
`2. Grzybowski A, Told R, Sacu S, et al. 2018 update on intravitreal injec-
`tions: euretina expert consensus recommendations. Ophthalmologica.
`2018;239(4):181–193. doi:10.1159/000486145
`
`704
`
`submit your manuscript | www.dovepress.com
`Dovepress
`
`Clinical Ophthalmology 2019:13
`
`Novartis Exhibit 2015.004
`Regeneron v. Novartis, IPR2020-01317
`
`
`
`Dovepress
`
`Sassalos and Paulus
`
` 3. Ferrara N, Damico N, Shams M, Lowman H, Kim R. Development of
`ranibizumab, an anti-vascular endothelial growth factor antigen bind-
`ing fragment, as therapy for neovascular age-related macular degen-
`eration. Retina. 2006;26(8):859–870. doi:10.1097/01.iae.0000242842.
`14624.e7
` 4. Haritoglou C, Kook D, Neubauer A, et al. Intravitreal bevacizumab
`(Avastin) therapy for persistent diffuse diabetic macular edema. Retina.
`2006;26(9):999–1005. doi:10.1097/01.iae.0000247165.38655.bf
` 5. Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal bevacizumab
`(Avastin) treatment of macular edema in central retinal vein occlusion:
`a short-term study. Retina. 2006;26(3):279–284.
` 6. Lin RC, Rosenfeld PJ. Antiangiogenic therapy in neovascular age-related
`macular degeneration. Int Ophthalmol Clin. 2007;47(1):117–137.
`doi:10.1097/IIO.0b013e31802bd873
` 7. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ.
`Ranibizumab and bevacizumab for neovascular age-related macular
`degeneration. N Engl J Med. 2011;364(20):1897–1908. doi:10.1056/
`NEJMoa1102673
` 8. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular
`age-related macular degeneration. N Engl J Med. 2006;355(14):
`1419–1431. doi:10.1056/NEJMoa054481
` 9. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE
`study: ranibizumab monotherapy or combined with laser versus laser
`monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4):
`615–625. doi:10.1016/j.ophtha.2011.01.031
` 10. Heier JS, Campochiaro PA, Yau L, et al. Ranibizumab for macular
`edema due to retinal vein occlusions: long-term follow-up in the
`HORIZON trial. Ophthalmology. 2012;119(4):802–809. doi:10.1016/j.
`ophtha.2011.12.005
` 11. Holz FG, Bandello F, Gillies M, et al. Safety of ranibizumab in
`routine clinical practice: 1-year retrospective pooled analysis of
`four European neovascular AMD registries within the LUMINOUS
`programme. Br J Ophthalmol. 2013;97(9):1161–1167. doi:10.1136/
`bjophthalmol-2013-303232
` 12. FDA approves lucentis (ranibizumab injection) prefilled syringe.
`[October 14, 2016]. Available from: https://www.gene.com/media/
`press-releases/14640/2016-10-14/fda-approves-genentechs-lucentis-
`ranibiz. Accessed September 14, 2018.
` 13. FDA approves Genentech’s Lucentis (Ranibizumab injection) 0.3 mg
`prefilled syringe for diabetic macular edema and diabetic retinopathy.
`[March 21, 2018]. Available from: https://www.gene.com/media/press-
`releases/14708/2018-03-21/fda-approves-genentechs-lucentis-ranibiz.
`Accessed September 10, 2018.
` 14. Antoszyk AN, Baker C, Calzada J, et al. Usability of the ranibizumab
`0.5 mg prefilled syringe: human factors studies to evaluate critical task
`completion by healthcare professionals. PDA J Pharm Sci Technol.
`2018;72(4):411–419. doi:10.5731/pdajpst.2017.008342
` 15. Souied E, Nghiem-Buffet S, Leteneux C, et al. Ranibizumab prefilled
`syringes: benefits of reduced syringe preparation times and less com-
`plex preparation procedures. Eur J Ophthalmol. 2015;25(6):529–534.
`doi:10.5301/ejo.5000629
` 16. Subhi Y, Kjer B, Munch IC. Prefilled syringes for intravitreal injection
`reduce preparation time. Dan Med J. 2016;63(4).
` 17. Diago T, McCannel CA, Bakri SJ, Pulido JS, Edwards AO,
`Pach JM. Infectious endophthalmitis after intravitreal injection of
`antiangiogenic agents. Retina. 2009;29(5):601–605. doi:10.1097/IAE.
`0b013e31819d2591
` 18. Day S, Acquah K, Mruthyunjaya P, Grossman DS, Lee PP, Sloan FA.
`Ocular complications after anti-vascular endothelial growth factor
`therapy in medicare patients with age-related macular degeneration.
`Am J Ophthalmol. 2011;152(2):266–272. doi:10.1016/j.ajo.2011.
`01.053
` 19. McCannel CA. Meta-analysis of endophthalmitis after intravitreal injec-
`tion of anti-vascular endothelial growth factor agents: causative organ-
`isms and possible prevention strategies. Retina. 2011;31(4):654–661.
`doi:10.1097/IAE.0b013e31820a67e4
`
` 20. Moshfeghi AA, Rosenfeld PJ, Flynn HW, et al. Endophthalmitis after
`intravitreal vascular [corrected] endothelial growth factor antagonists:
`a six-year experience at a university referral center. Retina. 2011;31(4):
`662–668. doi:10.1097/IAE.0b013e31821067c4
` 21. Shah CP, Garg SJ, Vander JF, Brown GC, Kaiser RS, Haller JA. Outcomes
`and risk factors associated with endophthalmitis after intravitreal injec-
`tion of anti-vascular endothelial growth factor agents. Ophthalmology.
`2011;118(10):2028–2034. doi:10.1016/j.ophtha.2011.02.034
` 22. Bhavsar AR, Stockdale CR, Ferris FL, Brucker AJ, Bressler NM,
`Glassman AR. Update on risk of endophthalmitis after intravitreal drug
`injections and potential impact of elimination of topical antibiotics. Arch
`Ophthalmol. 2012;130(6):809–810. doi:10.1001/archophthalmol.2012.227
` 23. Brown DM, Nguyen JD, Marcus DM, et al. Long-term outcomes of
`ranibizumab therapy for diabetic macular edema: the 36-month results
`from two phase III trials: RISE and RIDE. Ophthalmology. 2013;
`120(10):2013–2022. doi:10.1016/j.ophtha.2013.02.034
` 24. Michaud J-E, Sigg J, Boado L, et al. Ranibizumab pre-filled syringe
`approved in the European union: innovation to improve dose accuracy,
`reduce potential infection risk, and offer more efficient treatment
`administration. Invest Ophthalmol Vis Sci. 2014;55(13):1949.
` 25. Storey P. Do prefilled syringes decrease the risk of endophthalmitis
`with intravitreal injection? A case-control study. Presented at: Wills
`Eye Conference; March 8–10, 2018; Philadelphia.
` 26. Somner JE, Mansfield D. Inadvertent injection of intravitreal air dur-
`ing intravitreal Lucentis injection for wet age-related macular degen-
`eration: an undescribed complication. Eye (Lond). 2009;23(8):1744.
`doi:10.1038/eye.2008.297
` 27. Sukgen EA, Gunay M, Kocluk Y. Occurrence of intraocular air
`bubbles during intravitreal injections for retinopathy of prematurity.
`Int Ophthalmol. 2017;37(1):215–219. doi:10.1007/s10792-016-0257-9
` 28. Mills MD, Devenyi RG, Lam WC, Berger AR, Beijer CD, Lam SR.
`An assessment of intraocular pressure rise in patients with gas-filled
`eyes during simulated air flight. Ophthalmology. 2001;108(1):40–44.
` 29. Khurana RN, Chang LK, Porco TC. Incidence of presumed silicone
`oil droplets in the vitreous cavity after intravitreal bevacizumab injec-
`tion with insulin syringes. JAMA Ophthalmol. 2017;135(7):800–803.
`doi:10.1001/jamaophthalmol.2017.1815
` 30. Yu JH, Gallemore E, Kim JK, Patel R, Calderon J, Gallemore RP. Sili-
`cone oil droplets following intravitreal bevacizumab injections. Am J
`Ophthalmol Case Rep. 2018;10:142–144. doi:10.1016/j.ajoc.2017.07.009
` 31. Gerding H, Timmermann M. Accuracy and precision of intravitreally
`injected ranibizumab doses: an experimental study. Klin Monbl
`Augenheilkd. 2010;227(4):269–272. doi:10.1055/s-0029-1245183
` 32. Meyer CH, Liu Z, Brinkmann C, Rodrigues EB, Helb HL. Accuracy,
`precision and repeatability in preparing the intravitreal dose with a
`1.0-cc syringe. Acta Ophthalmol. 2012;90(2):e165–e166. doi:10.1111/j.
`1755-3768.2010.02072.x
` 33. Sampat KM, Wolfe JD, Shah MK, Garg SJ. Accuracy and reproducibil-
`ity of seven brands of small-volume syringes used for intraocular drug
`delivery. Ophthalmic Surg Lasers Imaging Retina. 2013;44(4):385–389.
`doi:10.3928/23258160-20130601-02
` 34. Moisseiev E, Rudell J, Tieu EV, Yiu G. Effect of syringe design on the
`accuracy and precision of intravitreal injections of anti-VEGF agents.
`Curr Eye Res. 2017;42(7):1059–1063. doi:10.1080/02713683.2016.1
`276195
` 35. Loewenstein I, Goldstein M, Moisseiev J, Moisseiev E. Accuracy and
`precision of intravitreal injection of anti-vascular endothelial growth
`factor agents in real life: what is actually in the syringe? Retina. Epub
`2018 Apr 13.
` 36. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic
`macular edema: results from 2 phase III randomized trials: RISE
`and RIDE. Ophthalmology. 2012;119(4):789–801. doi:10.1016/j.
`ophtha.2011.12.039
` 37. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verte-
`porfin for neovascular age-related macular degeneration. N Engl J Med.
`2006;355:1432–1444. doi:10.1056/NEJMoa062655
`
`Clinical Ophthalmology 2019:13
`
`submit your manuscript | www.dovepress.com
`Dovepress
`
`705
`
`Novartis Exhibit 2015.005
`Regeneron v. Novartis, IPR2020-01317
`
`
`
`Sassalos and Paulus
`
`Dovepress
`
` 38. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T. Ranibi-
`zumab versus verteporfin photodynamic therapy for neovascular age-
`related macular degeneration: two-year results of the ANCHOR study.
`Ophthalmology. 2009;116:57–65.e5. doi:10.1016/j.ophtha.2008.10.018
` 39. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF
`trap-eye) in wet age-related macular degeneration. Ophthalmology.
`2012;119:2537–2548. doi:10.1016/j.ophtha.2012.09.006
` 40. Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevaci-
`zumab for treatment of neovascular age-related macular degeneration:
`two-year results. Ophthalmology. 2012;119:1388–1398. doi:10.1016/j.
`ophtha.2012.03.053
`
` 41. Simo-Servat O, Hernandez C, Simo R. Usefulness of the vitreous fluid
`analysis in the translational research of diabetic retinopathy. Mediators
`Inflamm. 2012;2012:872978.
` 42. Dabir SS, Das D, Nallathambi J, Mangalesh S, Yadav NK, Schouten JS.
`Differential systemic gene expression profile in patients with diabetic
`macular edema: responders versus nonresponders to standard treatment.
`Indian J Ophthalmol. 2014;62(1):66–73. doi:10.4103/0301-4738.
`126186
` 43. Bolinger MT, Antonetti DA. Moving past anti-VEGF: novel therapies
`for treating diabetic retinopathy. Int J Mol Sci. 2016;17(9):1498.
`doi:10.3390/ijms17091498
`
`Clinical Ophthalmology
`Publish your work in this journal
`Clinical Ophthalmology is an international, peer-reviewed journal
`covering all subspecialties within ophthalmology. Key topics include:
`Optometry; Visual science; Pharmacology and drug therapy in eye
`diseases; Basic Sciences; Primary and Secondary eye care; Patient
`Safety and Quality of Care Improvements. This journal is indexed on
`
`Submit your manuscript here: http://www.dovepress.com/clinical-ophthalmology-journal
`
`Dovepress
`
`PubMed Central and CAS, and is the official journal of The Society of
`Clinical Ophthalmology (SCO). The manuscript management system
`is completely online and includes a very quick and fair peer-review
`system, which is all easy to use. Visit http://www.dovepress.com/
`testimonials.php to read real quotes from published authors.
`
`706
`
`submit your manuscript | www.dovepress.com
`Dovepress
`
`Clinical Ophthalmology 2019:13
`
`Novartis Exhibit 2015.006
`Regeneron v. Novartis, IPR2020-01317
`
`