`
`Prioritatsbescheinigung
`DE 20 2012 011 016.0
`Ober die Einreichung einer Gebrauchsmusteranmeldung
`
`Aktenzeichen:
`
`20 2012 011 016.0
`
`Anmeldetag:
`
`16. November 2012
`
`Anmelder/Inhaber:
`
`Novartis AG, Basel, CH
`
`Bezeichnung:
`
`Syringe
`
`Prioritat:
`
`IPC:
`
`23. Oktober 2012; EP; 12189649
`03. Juli 2012; EP; 12174860
`
`A61M 5/178; A61K 38/02
`
`Die angehefteten StOcke sind eine richtige und genaue VViedergabe der Teile der
`am 16.
`November
`2012
`eingereichten
`Unterlagen
`dieser
`Gebrauchsmusteranmeldung unabhangig von gegebenenfalls durch das
`Kopierverfahren bedingten Farbabweichungen.
`
`MOnchen, den 29. Januar 2013
`Deutsches Patent- und Markenamt
`Dio,Präsidentin
`m Auftrag
`
`Bauemfeind
`
`'11 ki ihk
`
`A 9161(P811)/1
`
`Si, IV;
`
`IrA7
`
`REGITC01116474
`Regeneron Exhibit 1129.001
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`16_11_2012-01-00003-00000005
`
`18_ I 1-2012-01-00003-000000 OS
`
`- 1 -
`
`Description
`
`SYRINGE
`
`TECHNICAL FIELD
`
`The present invention relates to a syringe, particularly to a small volume syringe such as
`
`5 a syringe suitable for ophthalmic injections.
`
`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
`
`10 safety and medicament integrity that the syringe and the contents of that syringe are
`
`sufficiently sterile to avoid 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
`15 intended that about 0.1m1 or less of liquid is to be injected the sterilisation can pose
`
`difficulties that are 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.
`
`20 Furthermore, certain therapeutics such as biologic molecules are particularly sensitive to
`
`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.
`
`There is therefore a need for a new syringe construct which provides a robust seal for its
`
`25 content, but which maintains ease of use.
`
`DISCLOSURE OF THE INVENTION
`
`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 the body such that a front surface of the stopper and the body
`
`30 define a variable volume chamber from which a fluid can be expelled though the outlet,
`
`the plunger comprising a plunger contact surface at a first end and a rod extending
`
`between the plunger contact surface and a rear portion, the plunger contact surface
`
`arranged to contact the stopper, such that the plunger can be used to force the stopper
`
`towards the outlet end of the body, reducing the volume of the variable volume chamber,
`
`REGITC01116475
`Regeneron Exhibit 1129.002
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`16_11_2012-01-00003-00006006
`
`18_11_2012-
`
`3--0000000B
`
`- 2 -
`
`characterised in that the fluid comprises an ophthalmic solution. In one embodiment, the
`ophthalmic solution comprises a VEGF-antagonist.
`
`In one embodiment, the syringe is suitable for ophthalmic injections, more particularly
`intravitreal injections, and as such has a suitably small volume. The syringe may also be
`
`5 silicone oil free, or substantially silicone oil free, or may comprise a low level of silicone
`oil as lubricant.
`
`For ophthalmic injections, it is particularly important for the ophthalmic solution to have
`
`particularly low particle content. In one embodiment, the syringe meets US
`
`Pharmacopeia standard 789 (USP789).
`
`10 Syringe
`
`The body of the syringe may be a substantially cylindrical shell, or may include a
`
`substantially cylindrical bore with a non circular outer shape. The outlet end of the body
`includes an outlet through which a fluid housed within the variable volume chamber can
`
`be expelled as the volume of said chamber is reduced. The outlet may comprise a
`
`15 projection from the outlet end through which extends a channel having a smaller
`
`diameter than that of the variable volume chamber. The outlet may be adapted, for
`
`example via a luer lock type connection, for connection to a needle or other accessory
`
`such as a sealing device which is able to seal the variable volume chamber, but can be
`
`operated, or removed, to unseal the variable volume chamber and allow connection of
`
`20 the syringe to another accessory, such as a needle. Such a connection may be made
`
`directly between the syringe and accessory, or via the sealing device. The body extends
`
`along a first axis from the outlet end to a rear end.
`
`The body may be made from a plastic material (e.g. a cyclic olefin polymer) or from glass
`
`and may include indicia on a surface thereof to act as an injection guide. In one
`
`25 embodiment the body may comprise a priming mark. This allows the physician to align a
`
`pre-determined part of the stopper (such as the tip of the front surface or one of the
`
`circumferential ribs, discussed later) with the mark, thus expelling excess ophthalmic
`
`solution and any air bubbles from the syringe_ The priming process ensures that an
`
`exact, pre-determined dosage is administered to the patient.
`
`30 The stopper may be made from rubber, silicone or other suitable resiliently deformable
`
`material. The stopper may be substantially cylindrical and the stopper may include one
`
`or more circumferential ribs around an outer surface of the stopper, the stopper and ribs
`
`being dimensioned such that the ribs form a substantially fluid tight seal with an internal
`surface of the_syringe body. The front surface of the stopper may be any suitable shape,
`
`35 for example substantially planar, substantially conical or of a domed shape. The rear
`
`REGITC01116476
`Regeneron Exhibit 1129.003
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`16_11_2012-01-00003-00000007
`
`16_11_2012-01.-00003-00f100007
`
`- 3 -
`
`surface of the stopper may include a substantially central recess. Such a central recess
`could be used to connect a plunger to the stopper using a snap 'fit feature or thread
`connection in a known manner. The stopper may be substantially rotationally symmetric
`about an axis through the stopper.
`
`5 The plunger comprises a plunger contact surface and extending from that a rod extends
`
`from the plunger contact surface to a rear portion. The rear portion may include a user
`
`contact portion adapted to be contacted by a user during an injection event. The user
`contact portion may comprise a substantially disc'shaped portion, the radius of the disc
`extending substantially perpendicular to the axis along which the rod extends. The user
`
`10 contact portion could be any suitable shape. The axis along which the rod extends may
`be the first axis, or may be substantially parallel with the first axis.
`
`The syringe may include a backstop arranged at a rear portion of the body. The
`backstop may be removable from the syringe. If the syringe body includes terminal
`flanges at the end opposite the outlet end the backstop may be configured to
`15 substantially sandwich terminal flanges of the body as this prevent movement of the
`backstop in a direction parallel to the first axis.
`
`The rod may comprise at least one rod shoulder directed away from the outlet end and
`the backstop may include a backstop shoulder directed towards the outlet end to
`cooperate with the rod shoulder to substantially prevent movement of the rod away from
`
`20 the outlet end when the backstop shoulder and rod shoulder are in contact. Restriction
`of the movement of the rod away from the outlet end can help to maintain sterility during
`terminal. sterilisatiOn operations, or other operations in which the pressure within the
`variable volume chamber or outside the chamber may change. During such operations
`
`any gas trapped within the variable volume chamber, or bubbles that may form in a liquid
`
`25 therein, may change in volume and thereby cause the stopper to move. Movement of
`
`the stopper away from the outlet could result in the breaching of a sterility zone created
`by the stopper. This is particularly important for low volume syringes where there are
`m uch lower tolerances in the component sizes and less flexibility in the stopper. The
`
`term sterility zone as used herein is used to refer to the area within the syringe that is
`
`30 sealed by the stopper from access from either end of the syringe. This may be the area
`
`between a seal of the stopper, for example a circumferential rib, closest to the outlet and
`
`a seal of the stopper, for example a circumferential rib, furthest from the outlet. The
`distance between these two seals defines the sterility zone of the stopper since the
`stopper is installed into the syringe barrel in a sterile environment.
`
`35 To further assist in maintaining sterility during the operations noted above the stopper
`may comprise at a front circumferential rib and a rear circumferential rib and those ribs
`
`REGITC01116477
`Regeneron Exhibit 1129.004
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`16_11_2012-01-00003-00000008
`
`1E_ -
`
`--00003-000011001t
`
`- 4 -
`
`may be separated in a direction along the first axis by at least 3mm, by at least 3.5 mm,
`
`by at least 3.75mm or by 4mm or more. One or more additional ribs (for example 2, 3, 4
`or 5 additional ribs, or between 1-10, 2-8,3-6 or 4-5 additional ribs) may be arranged
`In one embodiment there are a total of three
`between the front and rear ribs.
`
`5 circumferential ribs.
`
`A stopper with such an enhanced sterility zone can also provide protection for the
`
`injectable medicament during a terminal sterilisation process. More ribs on the stopper,
`
`or a greater distance between the front and rear ribs can reduce the potential exposure
`
`of the medicament to the sterilising agent. However, increasing the number of ribs can
`
`10 increase the friction between the stopper and syringe body, reducing ease of use. While
`
`this may be overcome by increasing the siliconisation of the syringe, such an increase in
`
`silicone oil levels is particularly undesirable for syringes for ophthalmic use.
`
`The rod shoulder may be arranged within the external diameter of the rod, or may be
`
`arranged outside the external diameter of the rod. By providing a shoulder that extends
`
`15 beyond the external diameter of the rod, but still fits within the body, the shoulder can
`
`help to stabilise the movement of the rod within the body by reducing movement of the
`
`rod perpendicular to the first axis. The rod shoulder may comprise any suitable shoulder
`
`forming elements on the rod, but in one embodiment the rod shoulder comprises a
`
`substantially disc shaped portion on the rod.
`
`20 In one embodiment of the syringe, when arranged with the plunger contact surface in
`
`contact with the stopper and the variable volume chamber is at its intended maximum
`
`volume there is a clearance of no more than about 2mm between the rod shoulder and
`backstop shoulder. In some embodiments there is a *clearance of less than about 1_5
`
`m m and in some less than about 1mm. This distance is selected to substantially limit or
`25 prevent excessive rearward (away from the outlet end) movement of the stopper.
`
`In one embodiment the variable volume chamber has an internal diameter greater than
`5mm or 6mm, or less than 3mm or 4mm. The internal diameter may be between 3mm
`
`and 6mm, or between 4mm and 5mm.
`
`I n another embodiment the syringe is dimensioned so as to have a nominal maximum fill'
`30 volume of between about 0.1m1 and about 1.5m1. In certain embodiments the nominal
`maximum fill volume is between about 0.5m1 and about 1mI. In certain embodiments the
`
`nominal maximum fill volume is about 0.5m1 or about 1m1, or about 1.5m1.
`
`The length of the body of the syringe may be less than 70mm, less than 60mm or less
`
`than 50mm. In one embodiment the length of the syringe body is between 45mm and
`
`35 50mm.
`
`REGITC01116478
`Regeneron Exhibit 1129.005
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`16_11_2012-01-00003-00000009
`
`16_11_2012-01-110003-
`
`- 5 -
`
`In one embodiment, the syringe is filled with between about 0.01m1 and about 1.5m1 (for
`
`example between about 0.05m1 and about 1m1, between about 0.1m1 and about 0.5m1,
`
`between about 0.15m1 and about 0.175m1) of a VEGF antagonist solution. In one
`
`embodiment, the syringe is filled with 0.165m1 of a VEGF antagonist solution. Of course,
`
`5 typically a syringe is filled with more than the desired dose to be administered to the
`
`patient, to take into account wastage due to "dead space" within the syringe and needle.
`There may also be a certain amount of wastage when the syringe is primed by the
`physician, so that it is ready to inject the patient.
`
`Thus, in one embodiment, the syringe is filled with a dosage volume (i.e. the volume of
`
`10 medicament intended for delivery to the patent) of between about 0.01m1 and about
`
`1.5m1 (e.g. between about 0.05m1 and about 1m1, between about 0.1m1 and about 0.5m1)
`
`of a VEGF antagonist solution. In-one embodiment, the dosage volume is between about
`
`0.03m1 and about 0.05m1. For example, for Lucentis, the dosage volume is 0.05m1 or
`
`0.03m1 (0.5mg or 0.3mg) of a 10mg/m1 injectable medicament solution; for Eylea, the
`
`15 dosage volume is 0.05m1 of a 40mg/m1 injectable medicament solution.
`
`In one embodiment the length, of the syringe body is between about 45mm and about
`
`50mm, the internal diameter is between about 4mm and about 5mm, the fill volume is
`
`between about 0.12 and about 0.3m1 and the dosage volume is between about 0.03m1
`
`and about 0.05m1.
`
`20 As the syringe contains a medicament solution, the outlet may be reversibly sealed to
`
`m aintain 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 OVSTm system which is available
`
`from Vetter Pharma International GmbH.
`
`It is typical to siliconise the syringe in order to allow ease of use, i.e. to apply silicone oil
`
`25 to the inside of the barrel, which decreases the force required to move the stopper.
`
`However, for ophthalmic use, it is desirable to decrease the likelihood of silicone oil
`droplets being injected into the eye. Furthermore, silicone oil can cause proteins to
`aggregate. A typical 1m1 syringe comprises 100-800pg silicone oil in the barrel. Thus, in
`one embodiment, a syringe according to the invention comprises less than about 800pg
`30 (i.e. about less than about 500pg, less than about 300pg, less than about 200pg, less
`
`than about 100pg, less than about 75pg, less than about 50pg, less than about 25pg,
`
`less than about 15pg, less than about 10pg) silicone oil in the barrel. Methods for
`
`measuring the amount of silicone oil in such a syringe barrel are known in the art and
`
`include, for example, differential weighing methods and quantitation by infrared-
`
`35 spectroscopy of the oil diluted in a suitable solvent. Various types of silicone oil are
`
`available, but typically either DC360 (Dow Coming®; with a viscosity of 1000cP) or
`
`REGITC01116479
`Regeneron Exhibit 1129.006
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`16_11_2012-01 -00003-00000010
`
`1&..1 i_2012—Oi -OUCO3 c OOiD
`
`- 6 -
`
`DC365 emulsion (Dow Corning®; DC360 oil with a viscosity of 350cP) are used for
`
`syringe siliconisation. In one embodiment, the pm-filled syringe of the invention
`
`comprises DC365 emulsion.
`
`During testing it was found that, for syringes having small dimensions, such as those
`5 discussed above, and particularly those described in conjunction with the Figures below,
`the break loose and sliding forces for the stopper within the syringe are substantially
`unaffected by reducing the siliconisation levels far below the current standard to the
`
`levels discussed here. This is in contrast to conventional thinking that would suggest that
`
`if you decrease the silicone oil level, the forces required would increase. Having too great
`10 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. 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 100pg-about 800pg silicone oil.
`15 In one embodiment the glide/slide force for the stopper Within the pre-filled syringe is less
`than about 11N or less than 9N, less than 7N, less than 5N or between about 3N to 5N.
`I n one embodiment, the break loose force is less than about 11N 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
`
`20 stopper travelling speed of 190mm/min. In one embodiment, the syringe has a nominal
`
`maximal full volume of between about 0.5m1 and 1m1, contains less than about 100pg
`
`silicone oil and has a break loose force between about 2N to 5N.
`
`I n 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
`
`25 less, 200nm or less, 100nm or less, 50nm or less, 20nm or less). Methods to measure
`
`the thickness of silicone oil 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.
`
`I n one embodiment, the syringe is silicone oil free, or substantially silicone oil free. Such
`30 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 assembly and fill line.
`
`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
`
`35 >50pm in diameter per ml. In one embodiment, the ophthalmic solution comprises no
`
`more than 5 particles >25pm in diameter per ml. In one embodiment, the ophthalmic
`
`REGITC01116480
`Regeneron Exhibit 1129.007
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`16_11_2012-01-00003-00000011
`• 1'6_11_2012-01- 3
`
`- 7 -
`
`solution comprises no more than 50 particles >10pm in diameter per ml. In one
`embodiment, the ophthalmic solution comprises no more than 2 particles >50pm in
`diameter per ml, no more than 5 particles >25pm in diameter per ml and no more than 50
`
`particles >10pm in diameter per ml. In one embodiment, a syringe according to the
`
`5 invention meets USP789. In one embodiment the syringe has low levels of silicone oil
`sufficient for the syringe to meet USP789.
`
`VEGF Antagonists
`
`Antibody VEGF antagonists
`
`VEGF is a well-characterised signal protein which stimulates angiogenesis. Two antibody
`10 VEGF antagonists have been approved for human use, namely ranibizumab (Lucentise)
`and bevacizumab (Avastin8).
`
`Non-Antibody VEGF antagonists
`
`In one aspect of the invention, the non-antibody VEGF antagonist is an immunoadhesin.
`One such immuoadhesin is aflibercept (Eylea6), which has recently been approved for
`15 human use and is also known as VEGF-trap (Holash etal. (2002) PNAS USA 99:11393-
`
`98; Riely & Miller (2007) CIO Cancer Res 13:4623-7s). 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 dOrnains fused to the Fc portion of human IgG1. It is a dimeric
`20 glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains
`
`glycosylation, constituting an additional 15% of the total 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):
`
`25 SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRK
`
`GFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNC
`
`TARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLY
`
`TCAASSG LMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTP
`
`EVTCVVVDVSH EDPEVKFNVVYVDGVEVH NAKTKPRE EQYNI STYRVVSVLTVLHQ DWL
`
`30 NGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSR DELTKNQVS LTCLVKGFY
`
`PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE
`
`ALHNHYTQKSLSLSPG
`
`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
`35 monomers.
`
`REGITC01116481
`Regeneron Exhibit 1129.008
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`16_11_2012-01-0000 00000012
`
`1 ._1 1_2012-D1 --00003-43
`
`2
`
`- 8 -
`
`Another non-antibody VEGF antagonist immunoadhesin currently in pre-clinical
`development is a recombinant human soluble VEGF receptor fusion protein similar to
`VEGF-trap containing extracellular ligand-binding domains 3 and 4 from VEGFR2/KDR,
`and domain 2 from VEGFR1/Flt-1; these domains are fused to a human IgG Fc protein
`
`5 fragment (Li et al., 2011 Molecular Vision 17:797-803). This antagonist binds to isoforms
`VEGF-A, VEGF-B and VEGF-C. The molecule is prepared using two different production
`processes resulting in different glycosylation patterns on the final proteins. The two
`glycoforms are referred to as KH902 (conbercept) and KH906. The fusion protein can
`have the following amino acid sequence (SEQ ID NO:2):
`
`10 MVSYVVDTGVLLCALLSCL LLTGSSSGG RPFVEMYSEI PE II HMTEG RELVI PCRVTSPN IT
`
`VTLKKFPLDTLIPDGKRI IWDS RKGF I IS NATYKEIGLLTCEATVNG HLYKTNYLTHRQTNT
`
`IIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNVVEYPSSKHQHKKLVNRDLKTQSG
`
`SEMKKFLSTLTI DGVTRSDQGLYTCAASSG LMTKKNSTFVRVHEKPFVAFGS GM ESLVE
`
`ATVGERVRLPAKYLGYPPPEIKVVYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVILTN
`
`15 PI SKEKQSHVVSLVVYVPPGPGDKTHTCPLC PAPELLGGPSVFLFPPKPKDTLMISRTPE
`VTCVVVDVSHEDPEVKFNVVYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN
`
`GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNOVSLTCLVKGFYP
`
`SDIAVEWESNGQPENNYKATPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
`
`LHNHYTQKSLSLSPGK
`
`20 and, like VEGF-trap, can be present as a dimer. This fusion protein and related
`molecules are further characterized in EP1767546.
`
`Other non-antibody VEGF antagonists include antibody mimetics (e.g. Affibodyititi
`
`molecules, affilins, affitins, anticalins, avimers, Kunitz domain peptides, and rnonobodies)
`
`with VEGF antagonist activity. This includes recombinant binding proteins comprising an
`25 ankyrin repeat domain that binds VEGF-A and prevents it from binding to VEGFR-2. One
`example for such a molecule is DARPinal) MP0112. The ankyrin binding domain may
`
`have the following amino acid sequence (SEQ ID NO: 3):
`
`GSDLGKKLLEAARAGQDDEVRILMANGADVNTADSTGVVTPLHLAVPWGHLEIVEVLLK
`
`YGADVNAKDFQGVVTPLHLAAAIGHQEIVEVLLKNGADVNAQDKFGKTAFDISIDNGNED
`
`30 LAEILQKAA
`
`Recombinant binding proteins comprising an ankyrin repeat domain that binds VEGF-A
`
`and prevents it from binding to VEGFR-2 are described in more detail in
`
`W02010/060748 and W02011/135067.
`
`Further specific antibody mimetics with VEGF antagonist activity are the 40 kD pegylated
`35 anticalin PRS-050 and the monobody angiocept (CT-322).
`
`REGITC01116482
`Regeneron Exhibit 1129.009
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`16_11_2012-01-00003-000-00013
`
`113_1 1_2012-01-00003-0 I300001 3
`
`- 9 -
`
`The afore-mentioned non-antibody VEGF antagonist may be modified to further improve
`their pharmacokinetic properties or bioavailability. For example, a non-antibody VEGF
`antagonist may be chemically modified (e.g., pegylated) to extend its in vivo half-life.
`
`Alternatively or in addition, it may be modified by glycosylation or the addition of further
`
`5 glycosylation sites not present in the protein sequence of the natural protein from which
`
`the VEGF antagonist was derived.
`
`Variants of the above-specified VEGF antagonists that have improved characteristics for
`
`the desired application may be produced by the addition or deletion of amino acids.
`
`Ordinarily, these amino acid sequence variants Will have an amino acid sequence having
`10 at least 60% amino acid sequence identity with the amino acid sequences of SEQ ID
`NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3, preferably at least 80%, more preferably at least
`
`85%, more preferably at least 90%, and most preferably at least 95%, including for
`
`example, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,
`
`93%, 94%, 95%, 96%, 97%, 98%, 99%, and 100%. Identity or homology with respect to
`
`15 this sequence is defined herein as the percentage of amino acid residues in the
`
`candidate sequence that are identical with SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO:
`
`3, after aligning the sequences and introducing gaps, if necessary, to achieve the
`
`maximum percent sequence identity, and not considering any conservative substitutions
`
`as part of the sequence identity.
`
`20 Sequence identity can be determined by standard methods that are commonly used to
`
`compare the similarity in position of the amino acids of two polypeptides.. Using a
`
`computer program such as BLAST or FASTA, two polypeptides are aligned for optimal
`
`matching of their respective amino acids (either along the full length of one or both
`
`sequences or along a pre-determined portion of one or both sequences). The programs
`
`25 provide a default opening penalty and a default gap penalty, and a scoring matrix such
`
`as PAM 250 [a standard scoring matrix; see Dayhoff et al., in Atlas of Protein Sequence
`
`and Structure, vol. 5, supp. 3 (1978)] can be used in conjunction with the computer
`
`program. For example, the percent identity can then be calculated as: the total number
`
`of identical matches multiplied by 100 and then divided by the sum of the length of the
`
`30 longer sequence within the matched span and the number of gaps introduced into the
`
`longer sequences in order to align the two sequences.
`
`Preferably, the non-antibody VEGF antagonist of the invention binds to VEGF via one or
`
`more protein domain(s) that are not derived from the antigen-binding domain of an
`
`antibody. The non-antibody VEGF antagonist of the invention are preferably
`
`35 proteinaceous, but may include modifications that are non-proteinaceous (e.g.,
`
`pegylation, glycosylation).
`
`REGITC01116483
`Regeneron Exhibit 1129.010
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`16_11_2012-01-00003 000014
`
`16_11_20 2-01-00003-00000014
`
`Therapy
`
`- 10 -
`
`The syringe of the invention may be used to treat an ocular disease, including but not
`limited to choroidal neovascularisation, age-related macular degeneration (both wet and
`dry forms), macular edema secondary to retinal vein occlusion (RVO) including both
`
`branch RVO (bRVO) and central RVO (cRVO), choroidal neovascularisation secondary
`to pathologic myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and
`proliferative retinopathy.
`
`Thus the invention provides a method of treating a patient suffering from of an ocular
`
`disease selected from choroidal neovascularisation, wet age-related macular
`10 degeneration, macular edema secondary to retinal vein occlusion (RVO) including both
`
`branch RVO (bRVO) and central RVO (cRVO), choroidal neovascularisation secondary
`to pathologic myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and
`proliferative retinopathy, comprising the step of administering an ophthalmic' solution to
`the patient using a pre-filled syringe of the invention. This method preferably further
`
`15 comprises an initial priming step in which the physician depresses the plunger of the pre-
`
`filled syringe to align the pre-determinedpart of the stopper with the priming mark.
`
`I n one embodiment, the invention provides a method of treating an ocular disease
`
`selected from choroidal neovascularisation, wet age-related macular degeneration,
`macular edema secondary to retinal vein occlusion (RVO) including both branch RVO
`20 (bRVO) and central RVO (cRVO), choroidal neovascularisation secondary to pathologic
`m yopia (PM), diabetic macular edema (DME), diabetic retinopathy, and proliferative
`
`retinopathy, comprising administering a non-antibody VEGF antagonist with a pre-filled
`
`syringe of the invention, wherein the patient has previously received treatment with an
`antibody VEGF antagonist.
`
`25 Kits
`
`Also provided are kits comprising the pre-filled syringes of the invention. In one
`
`embodiment, such a kit comprises a pre-filled syringe of the invention in a blister pack.
`
`The blister pack may itself be sterile on the inside. In one embodiment, syringes
`
`according to the invention may be placed inside such blister packs prior to undergoing
`
`30 sterilisation, for example terminal sterilisation.
`
`Such a kit may further comprise a needle for administration of the VEGF antagonist. if
`
`the VEGF antagonist is to be administered intravitreally, it is typical to use a 30-gauge x
`1/2 inch needle, though 31-gauge and 32-gauge needles may be used. For intravitreal
`administration, 33-gauge or 34-gauge needles could alternatively be used. Such kits may
`35 further comprise instructions for use. In one embodiment, the invention provides a carton
`
`REGITC01116484
`Regeneron Exhibit 1129.011
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`16_11_2012-01-00003-00000015
`
`_11_2012— —00
`
`00015
`
`- 11 -
`
`containing a pre-filled syringe according to the invention contained within a blister pack, a
`needle and optionally instructions for administration.
`
`Sterilisation
`
`As noted above; a terminal sterilisation process may be used to sterilise the syringe and
`
`5 such a process may use a known process such as an ethylene oxide or a hydrogen
`peroxide sterilisation process. Needles to be used with the syringe may be sterilised by
`
`the same method, as may kits according to the invention.
`
`The package is exposed to the sterilising gas until the outside of the syringe is sterile.
`
`Following such a process, the outer surface of the syringe may remain sterile (whilst in
`
`10 its blister pack) for up to 6 months, 9 months, 12 months, 15 months, 18 months or
`
`longer. In one embodiment, less than one syringe in a million has detectable microbial
`
`presence on the outside of the syringe after 18 months of storage. In one embodiment,
`
`the pre-filled syringe has been sterilised using Et0 with a Sterility Assurance Level of at
`
`least 10-6. In one embodiment, the pre-filled syringe has been sterilised using hydrogen
`
`15 peroxide with a Sterility Assurance Level of at least 10-6. Of course, it is a requirement
`
`that significant amounts of the sterilising gas should not enter the variable volume
`
`chamber of the syringe. The term "significant amounts" as used herein refers to an
`
`amount of gas that would cause unacceptable modification of the ophthalmic solution
`
`within the variable volume chamber. In one embodiment, the sterilisation process causes
`
`20 <10% (preferably <5%, <3%, <1%) alkylation of the VEGF antagonist. In one
`embodiment, the pre-filled syringe has been sterilised using EtO, but the outer surface of
`the syringe has <1ppm, preferably <0.2ppm Et0 residue. In one embodiment, the pre-
`
`filled syringe has been sterilised using hydrogen peroxide, but the outer surface of the
`
`syringe has <1ppm, preferably <0.2ppm hydrogen peroxide residue. In another
`
`25 embodiment, the pre-filled syringe has been sterilised using Et°, and the total Et0
`residue found on the outside of the syringe and inside of the blister pack is <0.1mg. In
`another embodiment, the pre7filled syringe has been sterilised using hydrogen peroxide,
`and the total hydrogen peroxide residue found on the outside of the syringe and inside of
`
`the blister pack is <0.1mg.
`
`30
`
`General
`
`The term "comprising" means 'including" as well as "consisting" e.g. a composition
`
`"comprising" X may consist exclusively of X or may include something additional e.g. X +
`
`Y.
`
`35 The term 'about" in relation to a numerical value x means, for example, x+10%.
`
`REGITC01116485
`Regeneron Exhibit 1129.012
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`16_11_2012-01-00003-00000016
`
`1_203.2-01—000r3—soce001€
`
`- 12 -
`
`References to a percentage sequence identity between two amino acid s