`
`SCORE Placeholder Sheet for IFW Content
`
`Application Number: 13750352
`
`Document Date: 01/25/2013
`
`The presence of this form in the IFW record indicates that the following document type was
`received in electronic format on the date identified above. This content is stored in the SCORE
`database.
`
`-
`
`Sequence Listing
`
`Since this was an electronic submission, there is no physical artifact folder, no artifact folder is
`recorded in PALM, and no paper documents or physical media exist. The TIFF images in the
`IFW record were created from the original documents that are stored in SCORE.
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`Form Revision Date: February 8, 2006
`
`Regeneron Exhibit 1002.0001
`
`
`
`"""""""":1
`
`li
`
`
`PAT£355157~U3va
`WWW*
`agma fl‘f “EXPRE§S MASL” UNDER 37 6333353
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`3
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`Mun“...
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313~MSG
`
`QTiLi‘W PATENT APPUQATSQN TRANSMWTMN 9WD FEEE $§~§EET
`
`Transmiited harewiih for fiiing under 3‘? CFR 331.53%» is the utéiity patent appiicatien of
`
`Appiicant (or identifier):
`
`53mg, Juergen et ai.
`
`Tiiie:
`
`SYRENGE
`
`Enciased are:
`
`m&wm&
`
`“(Om‘dffi
`
`.2. 9’.
`
`mama
`
`BBB
`QQXQE
`
`Specification (inciuding Ciaims and Abstract) » 27 gages;
`Drawings; * 1 sheets
`Executed Seciarmion and F’Qwer of Attorney (originai 0? copy}
`Micmfiche Campuier Fragram (appendix)
`Nucieatide ande’or Amino Acid Sequence Submissim
`3:! Computer Readabie Copy
`[:1 Paper Copy
`:3 giatament Verifying iden‘iity of Abcwe Copies;
`Preiiminary Amendment
`Assignment Papas {Cover Sheet & Bocumenfisi}
`Engiish Transiaiiafi 0?
`information Disciosure Statement
`
`Certified Copy of Priority Documentis)
`Return Receipt Postcard
`Appiicatim Daia Sheet
`Other: 8) Submission of Sequence Listing including Staiemem of Verifieaiien {1
`Sheet)
`b} Unexecutad {)saciaraiion for Uiiiity Appiicafiion using an Appiicaiion Dam
`Sheet {5 $89.33)
`c} Transmittal for Pawer 0f Niamey it) one or mam regissi‘ered Pmcti‘iimess
`and meer of Attorney by Appiicani {2 shears)
`
`Fiiing fee caicuia‘iion:
`
`{:1
`C]
`
`Before caicuiating the fiiing fee, please enter the enciosed Praiéminary Amendment.
`Before caicuia‘iing ihss fiiing fee, piease cancel ciaims
`
`
`
`Regeneron Exhibit 1002.0002
`
`w
`Date cf Deposit
`Express Mai! Labia: Number
`W.....................»..-..“WWW«_«.._.H........‘...._..
`
`u.¢_.W.W
`
`M‘muw‘uu
`
`
`
`“HIM-um
`
`
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`Peach Fee
`
`Examinaiion gee
`
`\
`
`m______________________________*
`
`For
`
`
`
`
`
`andegi‘endém“
`{Ck-aims
`________
`
`Aggfigafign Size Fee
`
` 50 or fraction thereof
`
`Sheets;
`{gyflgd ”E to a whoie number}
`
`Lhfigjfiggfie enden’: Ciaim Fee 1%
`Fareign Language Sgrgfigggga £915.».
`
`E s
`
`E
`
`
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`TQTAL HUNG FEE i
`35
`19.3?{3
`
`{XE F’kaase charge Degosét Assam: No. $943134 in the name ca” Nevams in {he ammuni of
`$19?0. An addétionai cup}! 0‘? this gamer is amzmsed. The Cammissisner is hereby
`authofized to charge any additionai fees under 37‘ CPR €311.38 mud §’i .1? wi'zim'; may he:-
`requéred in connection wiih ihis appiicatian, or credit my averpay‘mem. it“; Demgii
`Account Nu 19~0134 m the name of Novartis».
`
`Piease address 33% carresmndence to we address asaociai'ea‘ wiih flusmmer Na. 30%0957
`which is currentiy:
`
`Novafiis Phas‘maaeuticaig Commaiion
`One Health Piazza, Bidg, ’30?
`East Hanover, NJ 03936
`
`Please direct afi teiephme cans in the undefsigned at the number gfiven bemw; and all
`teiafaxeas to +1 8?3?8£8265.
`
`Novartés Pharmaceuticais Corporaééon
`One Heaith Piazza, Bidg. 3'0?
`E332 Hammer, NJ {37336
`+1 862?7858’38
`
`Date: January 25, 2033
`
`Regpecfiufiy submitted,
`
`lAadmw fimmes i
`
`Andrew Mamas.
`Agent far Appiicant
`Reg, No. 5'Lf313
`
`
`
`Regeneron Exhibit 1002.0003
`
`
`
`TECHNICAL FIELD
`
`SYRINGE
`
`The present invention relates to a syringe, particularly to a small volume syringe such as a
`
`syringe suitable for ophthalmic injections.
`
`5
`
`BACKGROUND ART
`
`Many medicaments are delivered to a patient in a syringe from which the user can dispense the
`
`medicament. If medicament is delivered to a patient in a syringe it is often to enable the patient,
`
`or a caregiver, to inject the medicament.
`
`It is important for patient safety and medicament
`
`integrity that the syringe and the contents of that syringe are sufficiently sterile to avoid
`
`10
`
`infection, or other, risks for patients. Sterilisation can be achieved by terminal sterilisation in
`
`which the assembled product, typically already in its associated packaging, is sterilised using
`
`heat or a sterilising gas.
`
`For small volume syringes, for example those for injections into the eye in which it is intended
`
`that about 0.1m] or less of liquid is to be injected the sterilisation can pose difficulties that are
`
`15
`
`not necessarily associated with larger syringes. Changes in pressure, internal or external to the
`syringe, can cause parts of the syringe to move unpredictably, which may alter sealing
`characteristics and potentially compromise sterility.
`Incorrect handling of the syringe can also
`
`pose risks to product sterility.
`
`Furthermore, certain therapeutics such as biologic molecules are particularly sensitive to
`
`20
`
`sterilisation, be it cold gas sterilisation,
`
`thermal sterilisation, or irradiation. Thus, a careful
`
`balancing act is required to ensure that while a suitable level of sterilisation is carried out, the
`
`syringe remains suitably sealed, such that the therapeutic is not compromised. Of course, the
`syringe must also remain easy to use,
`in that the force required to depress the plunger to
`
`administer the medicament must not be too high.
`
`25
`
`There is therefore a need for a new syringe construct which provides a robust seal for its content,
`
`but which maintains ease of use.
`
`DISCLOSURE OF THE H‘IVENTION
`
`The present invention provides a pre—filled syringe, the syringe comprising a body, a stopper and
`
`a plunger, the body comprising an outlet at an outlet end and the stopper being arranged within
`
`30
`
`the body such that a front surface of the stopper and the body define a variable volume chamber
`
`-1-
`
`
`
`Regeneron Exhibit 1002.0004
`
`
`
`from which a fluid cam be expei'ied though the outiet, the Monger comprising a emigre? eootaet
`,
`surface 3‘; a first end and a rod extending bee-{ween the phage? {:emaef surface and
`
`rear portion,
`
`the pionger contact surface arranged to contact the stopper, such that {Le Monger can be used to
`
`force the seopper towards the oufle‘i end of the body, reducing the veitime of the variabie voiume
`
`U2 momma characterised in {hat the fluid comprises an ophthaémie solution. In one embodiment.
`
`the ophthaiimic soiution comprises a VEGFentagonist.
`
`In one embodiment,
`
`the syringe is suitable for ophthaimie mjeetioesy more paz‘tieulariy
`
`inflevitreai injectiona and as such has a suitabiy smai'i vohzme, The syringe may aiso be siiicone
`
`oii foee or su‘estamiafiy siiie me oil free, or may comprise a. §ow Eevei ofsiiieone oii as moment.
`
`10
`
`in one embodiment, despite the E'ow siiicone oii level? the stopper break ioose and slide force is
`
`less {has} 2QN°
`
`‘
`For mkthalmie in'ectionse if.
`
`y
`1
`.
`is mieularlv imoortam for the ee‘mheimie soéution to have
`
`pafiimfiafly iow pefiieie cement.
`
`in one embodiment,
`
`the gorge meets US Pharmawpeia
`
`simdaxéi 3789 (EJSP’i89).
`
`i5
`
`+ yrénge
`
`The body of the syringe may be a substantiafiy cyiindricm Shea 02‘ may ine‘sede a sobetantiaiiy
`
`eyiindricai bore wii‘h a non dream outer shape. The outlet enci of the body includes an outlet
`
`through which a fluid housed wimie the variaer volume chambes‘ can, be expefied es the vofiume
`
`of saéd chamber is reducee. The outlet may comprise a profieefioe from the ou‘dei end through
`
`26
`
`WE ieh extends a chan‘nei having a smafler diameter than that of me variabie voiome chamber.
`ox
`The oofiet may be adapied, for example via a luer lock type connection, we eoeneetion to a
`
`oeed'ie or other aceessow such as a seaiing device which is abée to seafi ti e \Iax‘iable volume
`
`chamber, but can be operated, or removeci,
`
`to uneeai the variaifie voiume (chamber and aflow
`
`connection of the syringe to another accessory; such as a needie,
`
`$11G?! a amneetion may be
`
`25
`
`made directly between the syringe and accessory; or via the seaiing. device. The body extends
`
`aiong a. first axis floor: the oufie‘t end to a rear end,
`
`The body may be made from a piastic materiai {6,52,
`
`:3: cyc'iie oiefie pefiymer) or fmm giass and
`
`may include indieia on a surface thereof to act as an fleeces-n guide. in one embodiment the
`
`body may eomprise a priming mark. This aliows the ehysicia‘n {0 ”we a predetermined part of
`
`30
`
`the stopper (such as the tip of the from surface or one ofthe circumferential ribs, dfiseussed mm}
`
`or pionger with. the mark, thus expefling excess ophthaimic solution and any air buebies from the
`
`
`
`Regeneron Exhibit 1002.0005
`
`
`
`syringe. "I‘he priming process ensures that an exact, prewdetez‘afisized fies-age is adminiszered to the
`
`patient.
`
`The stopper may be made from rubber. siiicose or oiher suitab§e resiiienfiy deiomable material
`
`The stopper may be substantiafiy cylindrical and the stopper may incioée one or more
`
`1)}
`
`circumferentiafi
`
`r».
`ribs around an outer surface of fhe stoppers he stopper and, ribs being
`
`dimensioned such that the ribs form a substantiaiiy fluid tight seal with an infernal surface oft‘he
`
`syringe body,
`
`'81:: from susfaee of the stopper may be any saitabie shape. for example
`
`sobsi‘aotiafiy planar? subsiantiaiiy conical or of a domed sfiape. The rear surfs e of the stopper
`
`may meiosis: a substantiafiy centra§ recess. Such a centre} recess eooid be used to connect a
`
`i 10
`
`piunger to the stopoer using a snag:
`
`131‘, feature or thread connection in a knows. manner. The
`
`stopper may be substantially rotatiooaély symmetric about an axis through she stopper.
`
`'Efise piuager comprises a piunger eontac: surface and extending from that a rod (amends from the
`
`manger comes: surface ‘10 a rear portion. The rear portion may iaciude 21. uses contact portion
`
`adapted to be contacted by a user during an injection event. The user comma oortien may
`
`15
`
`comprise a substantiafiy disc. shaped poflion, the radius of the disc. exteoding substantiaily
`
`perpendicular {o the axis along which the rod extends. The user contact poz’iion could be any
`
`suitabie shape. The axis aiong which the rod extends may he the. first axis, or may be
`
`substamfiaiiy parailei with the first axis.
`
`The syringe may ineiude a backstop arranged at a rear portion of the body. The backstop may be
`
`20
`
`removable from the syringe. ifthe syringe body ineludes temfinai flanges at the end opposite the
`
`cutie? em? 1118 backstop may be c1. nfigured to substantiaily sandwich stamina? flanges ofthe boéy
`
`
`
`as sis seven movemen o e as {so finet? I: tfthblt
`
`
`
`
`
`
`
`ire {ion 321m :6: so so arsaxis.dc E‘itlfi
`
`
`
`1
`
`The rod may comprise at was: one .er shouiéer seemed away from the outiet end and the
`
`backstop may ineiude a backstop shoufider directed towards the cutie? end to cooperate with the
`
`25
`
`red shouider to sobsizmtiafiy prevent movement of she rod away from “the ouiiet end when the
`
`backstop shudder and rod shomcier are in contact. Restriction ofthe movement of the rod away
`
`from the outlet end can help '10 maintain. steriiiiy during, terminai stea‘iiisation oms‘ations, or other
`
`operations in which the pressure within the sariabie voiume assesses or omside {be chamber
`
`may change. During such operations any gas Reopen: within the variabie voiome chamber. or
`
`DJ CD
`
`hobbies shat may form in a fiaoid sherein, may change in voiume amfi {hereby cause the stopper
`
`in move. Movement of the stopper away from the outlet (some resu‘it
`
`in she bteaching of 21
`
`steriiity zone created by the Hopper. This is particoiariy impori‘am for 30w vohmae syringes
`
`52.2
`
`
`
`Regeneron Exhibit 1002.0006
`
`
`
`where there are much tower toierances in the component sizes and iess fiexibitity in the stopper.
`
`The term sterility zone as used herein is used to refer to the area Within the syringe that is sealed
`
`by the stopper from access from eithei end ot‘the syringe, This: may be the area between a seal
`
`of the stopper, for exempie a. circumferentiai rice closest to the ootiet and a seal of‘the stoppen
`
`‘J'x
`
`for example a circumfierential ri‘o, furthest {tort the outlet, The distance between these two seaie
`
`efihes the sterility zone ofthe stopper since the stopper is ihstelieo into the syringe barrel in a
`
`sterile environment.
`
`To {tether assist in. mainteiniog sterility during the operations rooted above the stopper may
`
`comprise at a from circumferential rib and a rear circumferentiei rib and those ribs may be
`
`it}
`
`Separated in a direction along the first axis by at loco: 3mm, :3 st Reset 3.5 mm by at least
`
`3.75mm or by 4mm or more.
`
`(lee or more additionei ribs {foe example 2, Be it or 5 additional
`
`ribs, or between 34m? 2~8, 3-6 or 4-5 additional ribs) may be arranged between the front and rear
`
`ribs in one embodiment there are a total of three circumferentitti rites.
`
`A stopoer with such an enhartced steriiity zone can atso provide protection for the iojectahle
`
`15
`
`medicament during a terminal sterilisation process. More ribs on the stoooec or a greater
`
`distance between the front and rear ribs can reduce the pot otiai exoosure of the medicament to
`
`the sterilising agent. However, increasing the number of ribs can Ettorease the friction between
`
`the stopper and syringe body, reducing ease of. use. While this may be overcome €33
`
`increasing
`
`the siiiecoisation of the syringe, such an increase in. siiiconc oi? ioveis is particoiariy unéesimble
`
`2.0
`
`for syringes for ophthalmic use.
`
`the rod. shoulder may be arranged within the cxtcmai diameter of the rod, or may be arranged
`
`outside the externat diameter of the rod? 83' providing a shoulticr that extends beyond the
`
`oxtemai diameter of the red, but stilt tits within the body, the shouttler cat: help to stabilise the
`
`movement of‘the rod within the body by reducing movement of the ted perpendicuiar to the first
`
`2133\i'fi The rod shoulder may comprise any soita‘oie shoulder townie}; eiements on the rod, but in
`
`one embodiment the rod shoutder comprises a substantial!3 disc shaped portion on the rod.
`
`in one embodiment of the syricge, when arranged with the phmger contact surface in contact
`
`with the stopper and the variable voiume chamber is at its intended maximum volume there is a
`
`clearance of no xrtore than about 2mm between the rod shooter)? and backstop shoulder,
`
`in some
`
`30
`
`embodiments there is a ciearartce of less than. about 't 3,5 mm and in soc'ie less that} about 3mm.
`
`This distarrcc is selected to etzhstentieiiy iimlt or prevent excusm rearward (away from the
`
`cutie: cod) movement of the stopper.
`
`
`
`Regeneron Exhibit 1002.0007
`
`
`
`in one embodiment the vatiabie voiume (331521333362? has an intomai
`
`iiameter greater than 5mm or
`
`6mm or iess than 3mm or 4mm. The internal {tiameter may be between 3mm and. 63mm, or
`
`between, 4mm and 5mm.
`
`in another embodiment the syringe is dimensioned so as to have a nominal maximum flit volume
`
`5
`
`of between about {Mm} mad about 1.53m. in certain embodimoots the nominati maximum {iii
`
`voiume is between about iifimi and about imi.
`
`is cestain embooimoots the nominal maximum
`
`iii} volume is about 0.5m} oi about imi, or about 151213.
`
`The isngtii of the body of the syringe may be iess than Titiiom, iess than 66mm or iess than
`
`53mm.
`
`in one embodiment the iength oftho syringe body is betweeo 45mm anti 58mm.
`
`-
`1
`in coo embodiment the syringe is tiiied with between about $.0imi anti about swml {for
`
`it)
`
`example between about 8335211} and about imip between about Sinai and about 0.13mi, between
`
`about {iiifimi and about 0.i751ni} of a VERSE antagonist soitttiott
`
`in one embodiment,
`
`the
`
`syringe is fiiied with 0.365121% of a VEGF antagomist soiutioo. Gt‘ course? typically a syringe is
`
`iiiied with more than the desired {lose to be administered to the oatient, to tsite into account
`
`,.,. U:
`
`wastage due to “dead space” Within. the syringe and needio. There may 3130 its a certain, amount
`
`of wastage when the syringe i s primed by the physician, so that it is ready to ioieot the patient.
`
`Thus,
`
`in one embodiment,
`
`the syringe is fiiied with a dosage voiume (to.
`
`the voiumo of
`
`medicament intendeti toy doiivei'y to the patent} of between about {3.91mi and about. 1.53mi (eg.
`
`between about (3.05mi and about
`
`imi, between about {Mm} and about (15ml): of a VEGP
`
`2t)
`
`antagonist soiutiott in one embodiment, the dosage volume is between about Gflffimi and. about
`
`0.05mi. For exampie, for Lueentis, the dosage voiume is OVOSmE 0t GJEBMI (05mg or 3.31119 ofa
`
`iOmg/mi injectahie :metiioameot soiution; for iiyiea, the dosage voitsme is 0.66mi oft: wing/mi
`
`injeotabie mediesment soiution. Aithougio unapproved for ophtitziimic indications, bevacizumab
`
`is used stiliabei in such ophtitaimic indications at a concentration of ZSmg/mi; iypieaiiy at a
`
`i\) ‘J!
`
`dosage ‘voiume of Cnfifimi { i.25mg), in one embodiment, the extraotabie voiome from the syringe
`
`{that is the amount of product obtainabie from the syringe fi‘iiiowirig iiiiiitg, taking into account
`
`ioss due to dead space in the syringe and neetiie) is about 0.09mi.
`
`in one embodiment the iength of the syringe oody is between about " 5mm and about 50mm, the
`
`intern-3i diameter is Between about 4mm and about 5mm, the tiii voiume is between about 0.12
`
`38‘
`
`and about 0.33mi and the dosage voitime is between about 8.03mi and about Gtiié'mi.
`
`
`
`Regeneron Exhibit 1002.0008
`
`
`
`As the syringe contains a medicament solution, the outlet may be reversibly sealed to maintain
`
`sterility of the medicament. This sealing may be achieved through the use of a sealing device as
`
`is known in the art.
`
`for example the {WSW system which is available from Vettet i’liarma
`
`international Gmbi-i.
`
`a)»
`
`it is typical to siliconise the syringe in order to allow ease oi’use, its. to appiy silicone oil to the
`
`inside oi, the barrel? which rieoreases the three requires to move the stopper. However, for
`
`ophthalmic use it is desirable to decrease the likeiihood of siiieone oil droplets oeing injected
`
`into the eye. With multiple injections? the amount of silicone dropiets can buiid up in the eye,
`
`causing potential adverse elitists, including “floaters” and an increase iri intrasoeuiai’ pressure.
`
`it)
`
`Furthermore, silicone oil eait cause proteins to aggregate. A typical i313 syringe comprises UK)»
`
`800% silicone oil in the barrel, though a survey oi‘mamrtaettirers resorted ti at 50i3nitltlliitg was
`
`typically used in pie—tilled syringes {Badltar at of. 2m. l, AAPS l-‘I-armaSsi'lth, l2(i2}:§64~fi72).
`
`Thus? in one embodiment a syririge according to the im’eetiort comprises iess titer: about 800w;
`
`(Le. about less than about Sillltig, iess than about Blitiiig, less than about ZUOilgp less than about
`
`in
`
`timing? less than about 75% less than. about mag, less than shoot Rfieg, less than alien: lfiiwi
`
`less than about 'lOiig) silicone oil in the barrel. lfthe syringe comprises a low ievel of silicone
`
`oilg this may be mete than about irtg, more than. about Bog; more than about 534g, more than
`
`about his; or more than about lOiig silicone oil it: the barrel. “lites,
`
`in one embodiment, the
`
`syringe may cortiprise about iagnabout Slicing about Sagsaboot :Zitiiiig, about Sitaabout 300mg
`
`20
`
`or about loitgebout Sllgig silicone oil
`
`in the barrel. Methods for measuring the amount. of
`
`silieone oil in such a syringe barrel. are knows in the art and include, fos example, differential
`
`weighing methods and quantitation by ini‘rarewspectroscopy of the oil diluted in a suitable
`
`solvent. Various types of silicone eii are available, but typicaiiy either [X3360 {Dow Corning);
`
`with a viscosity of 18009?) or DCESE emulsion {Dow Corning“; £33360 oil with a viscosity of
`
`25
`
`35%?) are used for syringe siliconisation,
`
`lit one embotiimerig the presiiiled syringe of the
`
`invention comprises DC365 emulsion.
`
`Dating testing it was surprisingly found "that, for swinges having sma
`
`7‘...‘
`
`dimensions, smelt as those
`
`discussed above. and particularly those described in coriitieotioti with the Figures below, the
`
`break loose and sliding forces for the stopper within the syringe are substantially iiiiai‘feeted by
`
`30
`
`reducing the siliconisation leveis far below the current standard to the leveis discussed here. This
`
`is in. contrast to conventional thinking that would suggest that iiT you decrease the siiicoae oil
`
`levei, the forces required would increase (see eg. Sehoeriitiieelit. AAE’S National Biotechnology
`
`Conference 200’? _ Abstract no. NBCG7~00O488, which indicates that wliiie dietitig silicosis: oil is
`
`-5-
`
`
`
`Regeneron Exhibit 1002.0009
`
`
`
`acceptable, usability improves when increased to 800ug). Having too great a force required to
`
`move the stopper can cause problems during use for some users, for example accurate dose
`
`setting or smooth dose delivery may be made more difficult if significant strength is required to
`
`move, and/or keep in motion, the stopper. Smooth administration is particularly important in
`
`5
`
`sensitive tissues such as the eye, where movement of the syringe during administration could
`
`cause local tissue damage. Break loose and slide forces for pre-filled syringes known in the art
`
`are typically in the region of less than 20N, but where the pre—filled syringes contain about
`
`100ug-about 800ug silicone oil. In one embodiment the glide/slide force for the stopper within
`
`the pre-filled syringe is less than about llN or less than 9N, less than 7N,
`
`less than 5N or
`
`10
`
`between about 3N to 5N. In one embodiment, the break loose force is less than about llN or less
`
`than 9N, less than 7N, less than 5N or between about 2N to 5N. Note that such measurements are
`
`for a filled syringe, rather than an empty syringe. The forces are typically measured at a stopper
`
`travelling speed of l90mm/min. In one embodiment, the forces are measured with a 30G x 0.5
`
`inch needle attached to the syringe. In one embodiment, the syringe has a nominal maximal fill
`
`15
`
`volume of between about 0.5ml and 1ml, contains less than about lOOug silicone oil and has a
`
`break loose force between about 2N to 5N.
`
`In one embodiment the syringe barrel has an internal coating of silicone oil that has an average
`
`thickness of about 450nm or less (i.e. 400nm or less, 350nm or less, 300nm or less, 200nm or
`
`less, 100nm or less, 50nm or less, 20mm or less). Methods to measure the thickness of silicone oil
`
`20
`
`in a syringe are known in the art and include the rap.ID Layer Explorer® Application, which can
`
`also be used to measure the mass of silicone oil inside a syringe barrel.
`
`In one embodiment, the syringe is silicone oil free, or substantially silicone oil free. Such low
`
`silicone oil levels can be achieved by using uncoated syringe barrels and/or by avoiding the use
`
`of silicone oil as a lubricant for product contacting machine parts, or pumps in the syringe
`
`25
`
`assembly and fill line. A further way to reduce silicone oil and inorganic silica levels in a pre-
`
`filledsyringe is to avoid the use of silicone tubing in filling lines, for example between storage
`
`tanks and pumps.
`
`The syringe according to the invention may also meet certain requirements for particulate
`
`content. In one embodiment, the ophthalmic solution comprises no more than 2 particles 250nm
`
`30
`
`in diameter per ml. In one embodiment, the ophthalmic solution comprises no more than 5
`
`particles 225um in diameter per ml. In one embodiment, the ophthalmic solution comprises no
`
`more than 50 particles ZlOum in diameter per ml. In one embodiment, the ophthalmic solution
`
`-7-
`
`
`
`Regeneron Exhibit 1002.0010
`
`
`
`comprises no more than 2 particles ZSOum in diameter per ml, no more than 5 particles 325nm
`
`in diameter per ml and no more than 50 particles 210nm in diameter per ml. In one embodiment,
`
`a syringe according to the invention meets USP789 (United States Pharmacopoeia: Particulate
`
`Matter in Ophthalmic Solutions).
`
`In one embodiment the syringe has low levels of silicone oil
`
`5
`
`sufficient for the syringe to meet USP789.
`
`VEGF Antagonists
`
`Antibody VEGF antagonists
`
`VEGF is a well-characterised signal protein which stimulates angiogenesis. Two antibody VEGF
`
`antagonists have been approved for human use, namely ranibizumab (Lucentis®) and
`
`10
`
`bevacizumab (Avastin®).
`
`Non-Antibody VEGF antagonists
`
`In one aspect of the invention, the non-antibody VEGF antagonist is an immunoadhesin. One
`
`such immuoadhesin is aflibercept (Eylea®), which has recently been approved for human use
`
`and is also known as VEGF—trap (Holash et a1. (2002) PNAS USA 99:11393-98; Riely & Miller
`
`15
`
`(2007) Clin Cancer Res 13:4623-75). Aflibercept is the preferred non-antibody VEGF antagonist
`
`for use with the invention. Aflibercept is a recombinant human soluble VEGF receptor fusion
`
`protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to
`
`the Fc portion of human IgG1. It is a dirneric glycoprotein with a protein molecular weight of 97
`
`kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total
`
`20 molecular mass, resulting in a total molecular weight of 115 kDa. It is conveniently produced as
`
`a glycoprotein by expression in recombinant CHO K1 cells. Each monomer can have the
`
`following amino acid sequence (SEQ ID NO: 1):
`
`SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATY
`
`KEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPS
`
`25
`
`SKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPP
`
`CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
`
`YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK
`
`GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL
`
`SLSPG
`
`
`
`30
`
`and disulfide bridges can be formed between residues 30-79, 124-185, 246-306 and 352-410
`
`Within each monomer, and between residues 211-211 and 214-214 between the monomers.
`
`Regeneron Exhibit 1002.0011
`
`
`
`Another nomamibody VEGE antagsnist imnmuoadhfisin cm‘mnfiyin muciinii.aE devsiopm em 13
`
`a. s‘cccmbinam human sslubie VEGE receptor fusion premix: simiiar to VEGEutrap cmfiaiming
`
`extracailular Eigamdwbmding domains 3 and 4 {mm VEGPRZ/KBK am} domain 2 from
`
`VEGERi/Eltul; 131656 dcmains are fused to a human igG Fe premix: fragmem {Li e: 2:21, 203.?
`
`5 Mm’eczdw Vision 17:79”?803) This antagonist {finds t0 isoibmm‘v:3A VE'13? B and VEGE-
`
`C. The :ms'iecule is prepared using 'iwo different preduciiam pEOC-SSSSS mthing in different
`
`géycosyiation patterns an the: final protsins. The two giycoferms are mferrad to as KHQOZ
`
`combemep“) andiiiHQOé The fusion plotein can have the foaming amina acid sequence {SEQ
`/~\.
`
`153‘ N052}:
`
`13
`
`MVSYWDmUVILCALLSPQJUboESGCRT{VCMYVEIPQ-LHMTEGRELVIFCRVTSPNITVTLKKFPLDT
`
`LIPDGKRIIWDSRRGFIISNAmVKETuLETCEAGVVGHGYEWNYLGPQQUNTT’PVVL1PSHQ’ SVGSK
`
`LVL*CCARTETNVGLD%NWVPSSKHQHKKLVNRDLKTQSGSEMKKFLSVLTIDEJTSDQGLYTCAASSG
`
`LM’FKKNSTFVRVEEEKPFVAFGSGMBSLVEATVGERVRLPAKYLGYPPPlEIWRKNbTPESNHTIKAGFZVL
`
`TTMBVSERDTDVYmVILTNPISFEKQEFVVE[JVYVPPCP“DRTqI U‘ @}APELLGGPSVFLFPPKPKDT
`
`13
`
`LMlSETPEVTCVVVDVSHEDPEVKPNWVVDCVBVHV\KT(”REEQWNSTERVVQVLT”LPQDWLNKEYKC
`
`KVENflAEDAEIBKTI“KAKGQDREPQx'EVPPuxfiELT{NQVLTC‘VRGEYDSDLA"E.WCQPEFN
`
`ATPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
`
`and, film VEGFatrap, can Es: present as a dimer. This fusion protein and related molecules am
`
`further charactarizad in EPE‘F67546.
`
`20
`
`Other nonvamibody VEGF antagonists include antibsdy mimetics (at. g Affi'body-’IE‘) mt:iacuies
`
`aiming, affiiins, anticaiins, avimers, Kunitz domain pagfiidas, and mombodies} with VEGF
`
`antagonist activity. This; includes recambinam bindifig pm'iains comprising an ankyrin repeat
`
`cicmain that binds VEGEA am? max/ems it from binding to VEGERQ. One axampie for such a
`
`moiecuie is DARPin® MPOMZ, The ankyrin binding damain mag haw the foliowing amino
`
`in} U)
`
`acid sequena: (SEQ ED NO: 3):
`
`SSDLuKKLLIAARAGQDDEVWIYAYGAD‘hTRTquWTPuHEAVPWGbxFTVVVLBKYGAJVVAKDFQGW
`
`VPLBLAAAIGHQEIVEVLLKNGADVNAQDKFGKTAFDISIDNGNEDLARLLQKAA
`
`Recumbimnt binding protcim cemprising an ankyrin rep<1"at domed? that: his(is VEGF A and
`
`prsvenm it from binding ”£0 VEGERQ are fiascribed in mm" {‘26aii in W020i3/96fi748 and
`
`39 WOZOH/BSGET
`
`Further spscific- antibody mimetics with EC:F antagonist 80.1w are the 413 1(1) pegylated
`
`amicalin FEB-€050 and the mano’body angiocept ((337622).
`
`
`
`Regeneron Exhibit 1002.0012
`
`
`
`The 11101311100110.1106 11011311111111011y VEGF antagonist may be 11101111150 10 further 1111131010 1111611
`
`131101111000111110110 properties 01 b10011013001111y. F111 031111111110,
`
`11 11010111011003" VEGF antagonist
`
`may 131: 01101111031131 modified (cg, pfigy‘iated} 10 011101111 115 1‘1: vim 11111111110.
`
`.A11‘e1‘11a’11ve1y 01 111
`
`0611111011,
`
`1‘: may 1:10 11101211111311 11y glycosymtion 01‘ 1:111: 1113111111011 of 10111101 ghee3311311011 $11.03 1101
`
`m
`
`111030111.
`
`111 1.111: 131010111 5111;111:1101: 0171111: 113101111 {11016111 1710111 111311011 11.10 VEGF 11110111011151 was
`
`derived.
`
`Variama of 1:111: abova—speeified VEGF antagonisis that have111112110111211
`
`12111110013111.111103 11111111:
`
`103116.11 21133111001101: 1111111 be 1310011106 111311110 2111111111111 01 110101101111.1211311.111101101111. 0111111311131.11:11:31:
`
`31111110 210111 3130111011151: 1011211115; 11111 have an 211111110 acid 86111101101: 11311711113, at 101-151 60% 01111110 1111111
`
`193
`
`sequence 11361111131 with 1110 111111110 30101 sequences of S13£111 '1\‘1). SEQ 13;} ND 2131 SEQ 11}
`
`ND: .3, 11105011113132 111: 108.51 36°/0, 111010 preferabiv at 11:11:11 85% 111011: 1310101111111 211 101151 9034131111
`
`111051 {11‘0101‘21011/
`
`111‘. 10031 93/11, 1110111111111 .101 example 811% 8.1/21 82%, 8391 84/0, 85%, 86%,
`
`87%, 88%, 89‘“x11,90%, 91%, 92%, 93‘3“,
`
`4‘30, 95%, 913%, 979/1933: 99%, and 111090 11101111151
`
`01‘ homoiogy with 10511001 10 11119 501311011013 13 (1013111011 11010111 as 1111: 13010011121330 01" 01111110 acid
`
`1:"?
`
`1151111111135 111 111.1: 0011131111110 301311131101: 11101 are 111011110211 with SEQ ED NS: 1, SE(} 1.131110: 2 or SEQ
`
`ID NO: 3,
`
`0.11131 aligning 11313 sequences and 1.111101111121115; gaps .11“ necessary, 10 1101110171:
`w
`11131111111111 per-1.0111 5011111311131: 1110111113 and 110100115161011111: 3111' 1:301:1“10111111110 31.111311111110113 as 13011
`
`1111:
`
`011.111: 51301301100 identity.
`
`801311121100 identify 02111 1:11:
`
`(10101111111011 by 510116111111 111131110115 111111 1110 1:011111101113’ 115011 10 1311111132111:
`‘-
`1
`
`E\)C2
`
`”1111: 31111111111131 111 1103111011 01" 1111:. 01111110 acids 01‘“ 11110 poiympiides.
`
`13 5111g 8.. 01111113111121 131‘0g1‘am
`
`33011 as BLAST 01‘ FA8313 two 13011111011111.3105 arc aiigneo;
`
`11:11
`
`0131111101
`
`11111113111111; of 111011
`
`rsspaciive 111111110 1101115 {011101‘ along 11.10 .1’1111 161113111 of 0111: 01‘ 1301.0 313011611003 01‘ aimg a 13113»
`
`11010111111100. 1101711011 of 0111-: 01‘ 130111 5011110110125). The 11111151111113 111011110“defauit 01101111111 1161131111:
`
`and. 31 (101111111 gap penalty, 111111 a scoring 1111111111 311011 21.1 PAM .2513 {0. 51111111111111 30011113: matrix; sea
`
`‘25
`
`1321111101? 1:1 3.1, 111 Atlas of P1010111 8001101101 and 311110111113, 1101. 51.,.1101: '3 {19113}, 1:21.11 1313 11300 1.11
`
`01.111111111211011
`
`1111111
`
`1:110
`
`013111110101 g31‘0g1‘a111.
`
`For
`
`0113111113111.
`
`1111:
`
`pares-3.111
`
`1111211111)!
`
`01111
`
`111011
`
`1‘10
`
`011110111.1111011 115:1111: 101111 11111111161 0111161111001 1111101163 1111111101106 by 11311 and 1111311 03111111011 by 1116
`
`sum 01‘ 1110 101132111 0f the finger 50111101101: within 1.111: 111111011011
`
`5111.111 and 1111: 11111111101 01“ gaps
`
`11111011110011 11110 1:110 11311g61 sequences 111 011101 1‘0 01ng 111011110 5011110111305.
`
`31}
`
`Prcfismbiy, the 11011011111100}! V1561" antagonist of 11113 1111701111011, 1111111315 10 VE‘GF V111 one 01‘ 111011:
`
`131010111 d:3111ai11(_s} that 8.10 1101 derived from 1.1111 a1111g011~b111di11g 11011111111 of 1111 2111111101131. The 11.011~
`
`
`
`Regeneron Exhibit 1002.0013
`
`
`
`antibody VEGF antagonist of the invention are prefei‘abiy preteioaeeous but may include
`
`modifiestions that are non-preteineeeous (egg pegyiaiion, géyeesytetion}.
`
`flaws-1p}!
`
`The syringe of the invention may be used to meet an ecuiez‘ disease, iiieiuciing but not limited to
`
`UI
`
`choroidai netwaseuiarisatioe, age~releted mewiat degenereiéoe {both wet and dry forms),
`
`maeuiar edema secondary to retina} vein oeoiusion {HMO} ineiuding both branch RVO (‘bRVQa
`
`and oeut