EuropllJ<het
`Patentamt
`European
`Patent Office
`Office eu~en
`desb,.,,,..ts
`
`Bescheinigung
`
`Certificate
`
`Attestation·
`
`Die angehefteten
`Unterlagen stimmen mit der
`als ursprOnglich eingereicht
`geltenden Fassung der auf
`dem nachsten Blatt
`bezeichneten europaischen
`Patentanmeldung uberein.
`
`The attached documents. are
`exact copies of the text in
`which the European patent
`application described on the
`following page is deemed to
`have been filed.
`
`Les documents joints a la
`presente attestation sont
`conformes au texte,
`considere comme
`initialement depose, de la
`demande de brevet
`europeen qui est specifiee a
`la page suivante.
`
`Patentanmeldung Nr.
`
`Patent application No.
`
`Demande de brevet n°
`
`12189649.2 / EP12189649
`
`The organization code and number of your priority application, to be used for filing abroad under the Paris
`Convention, is EP12189649.
`
`Der Prasident des Europaischen Patentamts;
`Im Auftrag
`
`For the President of the European Patent Office
`
`Le President de l'Office europeen des brevets
`p.o.
`
`U. lngmann
`
`MV03101
`
`EPA/EPO/OEB Form 1014
`
`05.12
`
`Novartis Exhibit 2023.001
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`Anmeldung Nr:
`Application no.:
`Demande no:
`
`12189649.2
`
`Anmelder I Applicant(s) I Demandeur(s):
`
`Novartis AG
`Lichtstrasse 35
`4056 Basel/CH
`
`Anmeldetag:
`Date of filing:
`Date de depc)t :
`
`23.10.12
`
`Bezeichnung der Erfindung I Title of the invention I Titre de !'invention:
`(Falls die Bezeichnung der Erfindung nicht angegeben ist, oder falls die Anmeldung in einer Nicht-Amtssprache des EPA eingereicht
`wurde, siehe Beschreibung bezuglich ursprunglicher Bezeichnung.
`If no title is shown, or if the application has been filed in a non-EPO language, please refer to the description for the original title.
`Si aucun titre n'est indique, ou si la demande a ete deposee dans une langue autre qu'une langue officielle de l'OEB, se referer a la
`description pour le titre original.)
`
`Syringe
`
`In Anspruch genommene Prioritat{en) I Priority{Priorities) claimed I Priorite(s) revendiquee{s)
`Staat/Tag/Aktenzeichen I State/Date/File no. I Pays/Date/Numero de depc)t:
`
`Am Anmeldetag benannte Vertragstaaten I Contracting States designated at date of filing I Etats contractants designees lors
`du dep6t:
`
`AL AT BE BG CH CYCZ DE DK EE ES Fl FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL
`PT RO RS SE SI SK SM TR
`
`EPA/EPO/OEB Form 1014
`
`05.12
`
`2
`
`Novartis Exhibit 2023.002
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`PAT055157-EP-EPA
`
`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 content-. 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 0.1 ml 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.
`
`There is therefore a need for a new syringe construct which provides a robust seal for its content,
`
`but which maintains ease of use.
`
`25 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 define a variable volume chamber
`
`from which a fluid can be expelled though the outlet, the plunger comprising a plunger contact
`
`30
`
`surface at a first end and a rod extending between the plunger contact surface and a rear portion,
`
`-1-
`
`Novartis Exhibit 2023.003
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`PAT055157-EP-EPA
`
`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, characterised in that the fluid comprises an ophthalmic solution. In one embodiment,
`
`the ophthalmic solution comprises a VEGF-antagonist.
`
`5
`
`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 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
`
`10
`
`standard 789 (USP789).
`
`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
`
`15
`
`of said chamber is reduced. The outlet may comprise a 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
`
`20
`
`connection of 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 a" an injection guide. In one embodiment the
`body may comprise a priming mark. This allows the physician to align a pre-determined part of
`
`25
`
`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.
`
`The stopper may be made from rubber, silicone or other suitable resiliently deformable material.
`
`30
`
`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
`
`-2-
`
`Novartis Exhibit 2023.004
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`PAT055157-EP-EPA
`
`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, for example
`
`substantially planar, substantially conical or of a domed shape. The rear surface of the stopper
`
`may include a substantially central recess. Such a central recess could be used to connect a
`
`5
`
`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.
`
`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
`
`10
`
`comprise a substantially disc shaped portion, the radius of the disc extending substantially
`
`perpendicular to the axis along which the rod extends. The user 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
`
`15
`
`removable from the syringe. If the syringe body includes terminal flanges at the end opposite the
`
`outlet end the backstop may be configured to 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
`
`20
`
`rod shoulder to substantially prevent movement of the rod away from 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 g~s trapped within the variable volume chamber, or
`
`25
`
`bubbles that may form in a liquid 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 much 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 sealed
`
`30
`
`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
`
`-3-
`
`Novartis Exhibit 2023.005
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`PAT055157-EP-EPA
`
`defines the sterility zone of the stopper since the stopper is installed into the syringe barrel in a
`
`sterile environment.
`
`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 tho-se ribs may be
`
`5
`
`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 between the front and rear
`
`ribs. In one embodiment there are a total of three circumferential ribs.
`
`A stopper with such an enhanced sterility zone can also provide protection for the injectable
`
`10 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 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
`
`15
`
`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 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
`
`20
`
`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.
`
`ln 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. ln some
`
`25
`
`embodiments there is a clearance of less than about 1.5 mm and in some less than about l mm.
`
`This distance is selected to substantially limit or 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 5mrn or
`
`6mm, or less than 3mm or 4mm. The internal diameter may be between 3mm and 6mm, or
`
`30
`
`between 4mm and 5mm.
`
`-4-
`
`Novartis Exhibit 2023.006
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`PAT055157-EP-EPA
`
`In another embodiment the syringe is dimensioned so as to have a nominal maximum fill volume
`
`of between about 0.1 ml and about l .5ml. In certain embodiments the nominal maximum fill
`
`volume is between about 0.5ml and about lml. In certain embodiments the nominal maximum
`
`fill volume is about 0.5ml or about lml, or about l.5ml.
`
`5
`
`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 50mm.
`
`In one embodiment, th~ syringe is filled with between about 0.0lml and about 1.5ml (for
`
`example between about 0.05ml and about lml, between about 0.1 ml and about 0.5ml, between
`
`about O. l 5ml and about O. l 75ml) of a VEGF antagonist solution. In one embodiment, the
`
`10
`
`syringe is filled with 0.165ml of a VEGF antagonist solution. Of course, typically a syringe is
`
`fil1ed 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
`
`15 medicament intended for delivery to the patent) of between about 0.01 ml and about l.Sml (e.g.
`
`between about 0.05ml and about lml, between about O. lml and about 0.5ml) of a VEGF
`
`antagonist solution. In one embodiment, the dosage volume is between about 0.03ml and about
`
`0.05ml. For example, for Lucentis, the dosage volume is 0.05ml or 0.03ml (0.5mg or 0.3mg) of a
`
`I Omg/ml injectable medicament solution; for Eylea, the dosage volume is 0.05ml of a 40mg/ml
`
`20
`
`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 0.3ml and the dosage volume is between about 0.03ml and about 0.05mL
`
`As the syringe contains a medicament solution, the outlet may be reversibly sealed to maintain
`
`25
`
`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 OVS™ system which is available from Vetter Pharma
`
`Lntcrnational GmbH.
`
`It is typical to siliconise the syringe in order to allow ease of use, i.e. to apply silicone oil to the
`
`inside of the barrel, which decreases the force required to move the stopper. However, for
`
`30
`
`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 lml syringe
`
`-5-
`
`Novartis Exhibit 2023.007
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`PATOSS 1S7-EP-EPA
`
`comprises 100-800µg silicone oil in the barrel. Thus, in one embodiment, a syringe according to
`
`the invention comprises less than about 800µg (i.e. about less than about SOOµg, less than about
`
`300µg, less than about 200µg, less than about IOOµg, less than about 7Sµg, less than about SOµg,
`
`less than about 25µg, less than about 15µg, less than about lOµg) silicone oil in the barrel.
`
`S 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(cid:173)
`
`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 1 OOOcP) or DC36S emulsion
`
`(Dow Coming'!!); DC360 oil with a viscosity of 350cP) are used for syringe siliconisation. ln one
`
`IO
`
`embodiment, the pre-filled syringe of the invention comprises DC36S emulsion.
`
`During testing it was found that, for syringes having small dimensions, such as those 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
`
`l S
`
`to conventional thinking that would suggest that if you decrease the silicone oil level, the forces
`
`required would increase. 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. Break loose and slide forces for pre-filled syringes known in the art arc typically in the
`
`20
`
`region of less than 20N, but where the pre-filled syringes contain about lOOµg-about 800µg
`
`silicone oil. [n one embodiment the glide/slide force for the stopper within the pre-filled syringe
`is less than about l IN or less than 9N, less than 7N, less than SN or between about 3N to SN. [n
`
`one embodiment, the break loose force is less than about l lN or less than 9N. less than 7N, less
`
`than SN or between about 2N to SN. Note that such measurements are for a filled syringe, rather
`
`25
`
`than an empty syringe. The forces are typically measured at a stopper travelling speed of
`
`l 90mrn/min. ln one embodiment, the syringe has a nominal maximal fill volume of between
`
`about 0.5ml and lml, contains less than about lOOµg silicone oil and has a break loose force
`
`between about 2N to SN.
`
`In one embodiment the syringe barrel has an internal coating of silicone oil that has an average
`
`30
`
`thickness of about 450nm or less (i.e. 400nm or less, 3SOnm or less, 300nm or less, 200nm or
`
`less, l OOnm or less, SOnm 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.lD Layer Explorer<© Application, which can
`
`also be used to measure the ma~s of silicone oil inside a syringe barrel.
`
`-6-
`
`Novartis Exhibit 2023.008
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`PAT055157-EP-EPA
`
`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
`
`assembly and fill line.
`
`5
`
`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 ::::_50µm
`
`in diameter per ml. In one embodiment, the ophthalmic solution comprises no more than 5
`
`particles 2:,25µm in diameter per ml. In one embodiment, the ophthalmic solution comprises no
`
`more than 50 particles 2:,IOµm in diameter per ml. In one embodiment, the ophthalmic solution
`
`lO
`
`comprises no more than 2 particles 2:50µm in diameter per ml, no more than 5 particles 2:25µm
`
`in diameter per ml and no more than 50 particles 2:1 Oµm in diameter per ml. In one embodiment,
`
`a syringe according to the invention meets USP789.
`
`In one embodiment the syringe has low
`
`levels of silicone oil sufficient for the syringe to meet USP789.
`
`VEGF Antagonists
`
`15
`
`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
`
`bevacizumab (Avastin®).
`
`Non-Antibody VEGF antagonists
`
`20
`
`· 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 al. (2002) PNAS USA 99: 11393-98; Riely & Miller
`
`(2007) Clin Cancer Res l3:4623-7s). Atlibercept is the preferred non-antibody VEGF antagonist
`
`for use with the invention. Aflibercept is a recombinant human soluble VEGF receptor fusion
`
`25
`
`protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to
`
`the Fe portion of human IgGl. It is a dimeric glycoprotein with a protein molecular weight of97
`
`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 Kl cells. Each monomer can have the
`
`30
`
`following amino acid sequence (SEQ ID NO: 1):
`
`-7-
`
`j
`
`Novartis Exhibit 2023.009
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`PAT055157-EP-EPA
`
`SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATY
`
`KEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPS
`
`SKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPP
`
`CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
`
`5
`
`YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK
`GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL
`
`SLSPG
`
`and disulfide bridges can be formed between residues 30-79, 124-185, 246-306 and 352-410
`
`within each monomer, and between residues 211-211and214-214 between the monomers.
`
`10 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
`
`VEGFRl/Flt-1; these domains are fused to a human IgG Fe protein fragment (Li et al., 2011
`
`Molecular Vision 17:797-803). This antagonist binds to isoforms VEGF-A, VEGF-B and VEGF-
`
`15
`
`C. The molecule is prepared using two different production processes resulting in different
`
`glycosylation patterns on the final proteins. The two glycofonns are referred to as KH902
`
`(conbercept) and KH906. The fusion protein can have the following amino acid sequence (SEQ
`
`IDN0:2):
`
`20
`
`25
`
`MVSYWDTGVLLCALLSCLLLTGSSSGGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDT
`LIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEK
`
`LVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSG
`
`LMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRLPAKYLGYPPPEIKWYKNGIPLESNHTIKAGHVL
`TIMEVSERDTGNYTVILTNPISKEKQSHVVSLVVYVPPGPGDKTHTCPLCPAPELLGGPSVFLFPPKPKDT
`
`LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC
`
`KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
`ATPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
`
`and, like VEGF-trap, can be present as a dimer. This fusion protein and related molecules are
`
`further characterized in EP 1767546.
`
`Other non-antibody VEGF antagonists include antibody mimetics (e.g. Affibody® molecules,
`
`30
`
`affilins, affitins, anticalins, avimers, Kunitz domain peptides, and monobodies) with VEGF
`
`antagonist activity. This includes recombinant binding proteins comprising an ankyrin repeat
`
`domain that binds VEGF-A and prevents it from binding to VEGFR-2. One example for such a
`
`molecule is DARPin® MPOI 12. The ankyrin binding domain may have the following amino
`
`acid sequence (SEQ ID NO: 3):
`
`-8-
`
`Novartis Exhibit 2023.010
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`PAT055157-EP-EPA
`
`GSDLGKKLLEAARAGQDDEVRILMANGADVNTADSTGWTPLHLAVPWGHLEIVEVLLKYGADVNAKDFQGW
`
`TPLHLAAAIGHQEIVEVLLKNGADVNAQDKFGKTAFDISIDNGNEDLAEILQKAA
`
`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
`
`5 W0201 l/135067.
`
`Further specific antibody mimetics with VEGF antagonist activity are the 40 kD pegylated
`
`anticalin PRS-050 and the monobody angiocept (CT -322).
`
`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
`
`10 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 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
`
`15
`
`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 at least 60% amino acid
`
`sequence identity with the amino acid sequences of SEQ lD NO: 1, SEQ lD 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%,
`
`20
`
`87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 100%. Identity
`
`or homology with respect to 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
`
`25
`
`of the sequence identity.
`
`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 F ASTA, two polypeptide.s are aligned for optimal matching of their
`
`respective amino acids (either along the full length of one or both sequences or along a pre-
`
`30
`
`determined portion of one or both sequences). The programs 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
`
`-9-
`
`Novartis Exhibit 2023.011
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`PAT055157-EP-EPA
`
`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 longer sequence within the matched span and the number of gaps
`
`introduced into the longer sequences in order to align the two sequences.
`
`5
`
`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(cid:173)
`
`antibody VEGF antagonist of the invention are preferably proteinaceous, but may include
`
`modifications that are non-protcinaceous (e.g., pcgylation, glycosylation).
`
`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.
`
`15
`
`Thus the invention provides a method of treating a patient suffering from of an ocular disease
`
`selected from choroidal neovascularisation, wet age-related macular 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
`
`20
`
`the step of administering an ophthalmic solution to the patient using a pre-filled syringe of the
`
`invention. This method preferably further comprises an initial priming step in which the
`
`physician depresses the plunger of the pre-filled syringe to align the pre-determined part of the
`
`stopper with the priming mark.
`
`In one embodiment, the invention provides a method of treating an ocular disease selected from
`
`25
`
`choroidal neovascularisation, wet age-related macular 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 administering a non(cid:173)
`
`antibody VEGF antagonist with a pre-filled syringe of the invention, wherein the patient has
`
`30
`
`previously received treatment with an antibody VEGF antagonist.
`
`-10-
`
`Novartis Exhibit 2023.012
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`PA T055 l57-EP-EPA
`
`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
`
`5
`
`placed inside such blister packs prior to undergoing 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 Y2 inch
`
`needle, though 31-gauge and 3 2-gauge needles may be used. For intravitreal administration,
`
`10
`
`33-gauge or 34-gauge needles could alternatively be used. Such kits may further comprise
`
`instructions for use. In one embodiment, the invention provides a carton containing a pre-filled
`
`syringe according to the invention contained within a blister pack, a needle and optionally
`
`instructions for administration.
`
`Sterilisation
`
`15
`
`As noted above, a terminal sterilisation process may be used to sterilise the syringe and 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
`
`20
`
`such a process, the outer surface of the syringe may remain sterile (whilst in 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 EtO
`with a Sterility Assurance Level of at least 10-6
`. In one embodiment, the pre-filled syringe has
`been sterilised using hydrogen peroxide with a Sterility Assurance Level of at least 10-6
`course, it is a requirement that significant amounts of the sterilising gas should not enter the
`
`. Of
`
`25
`
`variab