23_11_2012-01-00003-00000030
`
`23_11_2012-01-—00003-—G0G0C032
`
`-7-
`
`
`
`In one
`solution comprises no more than 50 particles >10um in diameter per ml.
`embodiment, the ophthalmic solution comprises no more than 2 particles >50yum in
`diameter per mi, no more than 5 particles >25um in diameter per mi and no more than 50
`particles >10um in diameter per mi.
`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
`
`Antibody VEGFantagonists
`
`10
`
`15
`
`20
`
`25
`
`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
`In one aspect of the invention, the non-antibody VEGFantagonist is an immunoadhesin.
`One such immuoadhesin is aflibercept (Eylea®), which has recently been approved for
`human use andis also known as VEGF-trap (Holash etal. (2002) PNAS USA 99:11393-
`
`98; Riely & Miller (2007) Clin 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 VEGFreceptors 1
`and 2 extracellular domains fused to the Fe portion of human IgG71. It is a dimeric
`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 havethe following amino
`acid sequence (SEQ ID NO:1):
`
`SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTILKKFPLDTLIPDGKRIIWDSRK
`GFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNC
`TARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVIRSDQGLY
`TCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP
`
`EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
`NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY
`
`30
`
`PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE
`
`ALHNHYTQKSLSLSPG
`
`.
`
`and disulfide bridges can be formed between residues 30-79, 124-185, 246-306 and
`352-410 within each monomer, and betweenresidues 211-211 and 214-214 between the
`monomers.
`
`35
`
`Regeneron Exhibit 1002.0381
`
`

`

`23114_2012-01-00003-00000031
`
`23_11_2012-01-—-00003-00060031
`
`
`
`-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/Fit-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-C. The molecule is prepared using twodifferent 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
`havethe following amino acid sequence (SEQ ID NO:2):
`,
`
`10
`
`MVSYWDTGVLLCALLSCLLLTGSSSGGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNIT
`VTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNT
`
`IIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSG
`
`SEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGSGMESLVE
`ATVGERVRLPAKYLGYPPPEIKWYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVILTN
`
`15
`
`PISKEKQSHVVSLVVYVPPGPGDKTHTCPLCPAPELLGGPSVFLFPPKPKDTLMISRTPE
`VTICVVWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN
`
`GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP
`SDIAVEWESNGQPENNYKATPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
`LHNHYTQKSLSLSPGK
`oo
`|
`
`20
`
`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,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 preventsit from binding to VEGFR-2. One
`example for such a molecule its DARPin® MP0112. The ankyrin binding domain may
`havethe following amino acid sequence (SEQ ID NO: 3):
`
`25
`
`GSDLGKKLLEAARAGQDDEVRILMANGADVNTADSTGWTPLHLAVPWGHLEIVEVLLK
`
`YGADVNAKDFQGWTPLHLAAAIGHQEIVEVLLKNGADVNAQDKFGKTAFDISIDNGNED
`
`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
`
`W0O2010/060748 and WO2011/135067.
`
`Further specific antibody mimetics with VEGF antagonist activity are the 40 kD pegylated
`
`35
`
`anticalin PRS-050 and the monobody angiocept (CT-322).
`
`Regeneron Exhibit 1002.0382
`
`
`
`

`

`231 1_2012-01-00003-00000032
`
`23.3 1_2012-01-p9003-00G00032
`
`
`
`-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
`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 sequencevariants will have an amino acid sequence having
`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
`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 sequenceidentity, and not considering any conservative substitutions
`as part of the sequenceidentity.
`
`Sequenceidentity 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
`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 caiculated 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 numberof gaps introduced into the
`longer sequencesin orderto 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
`proteinaceous, but may include modifications
`that are non-proteinaceous
`(e.g.,
`pegylation, glycosylation).
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Regeneron Exhibit 1002.0383
`
`

`

`
`
`Therapy
`
`-10-
`
`The syringe of the invention may be usedto 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 mneovascularisation, 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 the step of administering an ophthalmic solution to
`the patient using a pre-filled syringe of the invention. This method preferably further
`comprises aninitial priming step in which the physician depresses the plungerof the pre-
`filled syringe to align the pre-determined part of the stopper with the priming mark.
`
`5
`
`10
`
`15
`
`@
`ll
`
`
`
`1
`
`the invention provides a method of treating an ocular disease
`In one embodiment,
`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
`myopia (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.
`
`O)
`
`.
`
`25
`
`Kits
`
`In one
`Also provided are kits comprising the pre-filled syringes of the invention.
`embodiment, such a kit comprises a pre-filled syringe of the invention in a blister pack.
`The blister pack mayitself 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 terminalsterilisation.
`
`Such a kit may further comprise a needle for administration of the VEGF antagonist. If
`the VEGF antagonistis to be administered intravitreally, it is typical to use a 30-gauge x
`% inch needle, though 31-gauge and 32-gauge needles may be used. Forintravitreal
`administration, 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
`
`35
`
`Regeneron Exhibit 1002.0384
`
`

`

`23_11_2012-01-00003-00000034
`
`23_11_2012-01—-0G003-80008934
`
`
`
`a
`
`containing a pre-filled syringe according to the invention contained within a blister pack, a
`needle and optionally instructions for administration.
`
`-11-
`
`Sterilisation
`
`As noted above,a terminalsterilisation process may be usedto sterilise the syringe and
`such a process may use a known process such as an ethylene oxide or a hydrogen
`peroxide sterilisation process. Needies to be used with the syringe may be sterilised by
`the same method, as may kits according to the invention.
`
`The packageis exposed to thesterilising gas until the outside of the syringe is sterile.
`Following 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 beensterilised using EtO with a Sterility Assurance Level of at
`least 10°. In one embodiment, the pre-filled syringe has been sterilised using hydrogen
`peroxide with a Sterility Assurance Level of at least 10°. Of course,it is a requirement
`that significant amounts of the sterilising gas should not enter the variable volume
`chamberof 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
`<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 <O.2ppm EtO residue. In one embodiment, the pre-
`filled syringe has beensterilised using hydrogen peroxide, but the outer surface of the
`syringe has <1ppm, preferably <0.2ppm hydrogen peroxide residue.
`In another
`embodiment,
`the pre-filled syringe has been sterilised using EtO, and the total EtO
`residue found on the outside of the syringe and inside of the blister pack is <0.1mg. In
`another embodiment, the pre-filled 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.
`
`10
`
`15
`
`20
`
`25
`
`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%.
`
`Regeneron Exhibit 1002.0385
`
`

`

`23_11_2012-01-00003-00000035
`
`23_11_2012-01—06003-B0G86035
`
`-12-
`
`References to a percentage sequence identity between two amino acid sequences
`meansthat, when aligned, that percentage of amino acids are the same in comparing the
`two sequences. This alignment and the percent homology or sequence identity can be
`determined using software programs knownin the art, for example those described in
`section 7.7.18 of Current Protocols in Molecular Biology (F.M. Ausubel et al., eds., 1987)
`Supplement 30. A preferred alignment is determined by the Smith-Waterman homology
`search algorithm using an affine gap search with a gap open penalty of 12 and a gap
`extension penalty of 2, BLOSUM matrix of 62. The Smith-Waterman homology search
`algorithm is disclosed in Smith & Waterman (1981) Adv. Appi. Math. 2: 482-489
`
`10
`
`' BRIEF DESCRIPTION OF THE FIGURES
`
`Figure 1 showsa side view of a syringe
`
`Figure 2 showsa cross section of a top down view of a syringe
`
`Figure 3 showsa view of a plunger
`
`Figure 4 showsa cross section though a plunger
`
`15
`
`Figure 5 shows a stopper
`
`
`
`MODES FOR CARRYING OUT THE INVENTION |
`
`The invention will now be further described, by way of example only, with reference to
`the drawings.
`
`20
`
`Figure 1 shows a view from a side of a syringe 1 comprising a body 2, plunger 4,
`backstop 6 and a sealing device 8.
`
`1?
`
`Figure 2 shows a cross section through the syringe 1 of Figure 1 from above. The
`syringe 1
`is suitable for use in an ophthalmic injection. The syringe 1 comprises a body
`2, a stopper 10 and a plunger 4. The syringe 1 extends alongafirst axis A. The body 2
`25
`
`comprises an outlet 12 at an outlet end 14 and the stopper 10 is arranged within the
`
`30
`
`body 2 such that a front surface 16 of the stopper 10 and the body 2 define a variable
`
`volume chamber 18.
`
`The variable volume chamber 18 contains an injectable
`
`medicament 20 comprising an ophthalmic solution comprising a VEGF antagonist such
`
`as ranibizumab. The injectable fluid 20 can be expelled though the outlet 12 by
`movement of the stopper 10 towards the outlet end 14 thereby reducing the volume of
`the variable volume chamber 18. The plunger 4 comprises a plunger contact surface 22
`at a first end 24 and a rod 26 extending between theplunger contact surface 22 and a
`rear portion 25. The plunger contact surface 22 is arranged to contact the stopper 10,
`such that the plunger 4 can be used to move the stopper 10 towards the outlet end 14 of
`
`Regeneron Exhibit 1002.0386
`
`

`

`2341_2012-01-00003-00000036
`
`>
`
`
`
`23_11_2012-01-86603-00000G36
`
`-13-
`
`the body 2. Such movement reduces the volume of the variable volume chamber 18 and
`
`causesfluid therein to be expelled though the outlet.
`
`The backstop 6 is attached to the body 2 by coupling to a terminal flange 28 of the body
`2. The backstop 6 includes sandwich portion 30 which is adapted to substantially
`sandwich at least some of the terminal flange 28 of the body 2. The backstop 6 is
`adapted to be coupled to the body 2 from the side by leaving one side of the backstop 6
`
`open so that the backstop 6 can befitted to the syringe 2.
`
`The body 2 defines a substantially cylindrical bore 36 which has a bore radius. The rod
`
`26 comprises a rod shoulder 32 directed away from the outlet end 14. The rod shoulder
`
`10
`
`32 extends from to a rod shoulder. radius from the first axis A which is such thatit is
`
`slightly less than the bore radius so that the shoulder fits within the bore 36. The
`
`backstop 6 includes a backstop shoulder 34 directed towards the outlet end 14. The
`
`shoulders 32, 34 are configured to cooperate to substantially prevent movementof the
`rod 26 away from the outlet end 14 when the backstop shoulder 34 and rod shoulder 32
`are in contact. The backstop shoulder 34 extends from outside the bore radius to a
`radius less than the rod shoulder radius so that the rod shoulder 32 cannot pass the
`backstop shoulder 34 by moving along thefirst axis A.
`In this case the rod shoulder 32 is
`substantially disc, or ring, shaped and the backstop shoulder 34 includes an arc around a
`rear end 38 of the body 2.
`
`The backstop 6 also includes two finger projections 40 which extend in opposite
`directions away from the body 2 substantially perpendicularto the first axis A to facilitate
`manual handling of the syringe 1 during use.
`
`In this example the syringe comprises a 0.5ml body 2 filled with between about 0.1 and
`0.3 ml of an injectable medicament 20 comprising a 10mg/m!
`injectable solution
`comprising ranibizumab. The syringe body 2 hasaninternal diameter of about between
`about 4.5mm and 4.8mm, a length of between about 45mm and 50mm.
`
`The plunger 4 and stopper 10 will be described in more detail with reference to later
`
`15
`
`20
`
`25
`
`figures.
`
`Figure 3 shows a perspective view of the plunger 4 of Figure 1 showing the plunger
`
`30
`
`contact surface 22 at the first end 24 of the plunger 4. The rod 26 extendsfrom thefirst
`
`end 24 to the rear portion 25. The rear portion 25 includes a disc shaped flange 42 to
`
`facilitate user handling of the device. The flange 42 provides a larger surface area for
`
`contact by the user than a bare end of the rod 26.
`
`‘ Figure 4 showsa cross section though a syringe body 2 and rod 26. The rod 26 includes
`
`35
`
`four longitudinal ribs 44 and the angle betweentheribs is 90°.
`
`Regeneron Exhibit 1002.0387
`
`

`

`2311_2012-01-00003-00000037
`
`-
`
`
`
`23_11_2012-01-e80G03-e0000037
`
`<4,
`°
`
`10
`
`-14-
`
`Figure 5 shows a detailed view of a stopper 10 showing a conical shaped front surface
`16 and three circumferential ribs 52,54,56 around a substantially cylindrical body 58.
`The axial gap betweenthefirst rib 52 and the fast rib 56 is about 3mm. The rearsurface
`60 of the stopper 10 includes a substantially central recess 62. The central recess 62
`includes an initial bore 64 having a first diameter. The initial bore 64 leading from the
`rear surface 60into the stopper 10 to an inner recess 66 having a second diameter, the
`second diameter being larger than thefirst diameter.
`
`Stopperforces
`
`0.5mi syringes siliconised with <100ygsiliconeoil, filled with Lucentis, comprising one of
`two different stopper designs were tested for maximal and average break out and slide
`force. Prior to testing, 30G.x 0.5” needles were attached to the syringes. The testing was
`carried out at a stopper speed of 190mm/min overa travel length of 10.9mm.
`
`value
`
`loose force
`
`of syringes
`
`individual
`
`value
`
`
`
`Sliding Average of 10|3.1N
`
`force
`
`syringes
`
`Max
`
`individual
`
`For both stopper designs, average and maximum break out force remained below 3N.
`For both stopper designs, average and maximumsliding force remainedbelow 5N.
`
`It will be understood that the invention has been described by way of exampie only and
`modifications may be made whilst remaining within the scope andspirit of the invention.
`
`15
`
`20
`
`Regeneron Exhibit 1002.0388
`
`

`

`23_11_2012-01-00003-00000038
`¢
`
`
`2211_2012-01-08003~000GCEz8
`
`CY)
`
`Claims
`
`-15-
`
`1.
`
`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 chamberfrom whicha 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
`
`10
`
`volume chamber, characterised in that the fluid is an ophthalmic solution which
`_ comprises a VEGF-antagonist, wherein
`
`’ (a) the syringe has a nominal maximum fill volume of between about 0.5ml and
`
`about 1ml,
`
`' (b) the syringeis filled with between about 0.15ml and about 0.175m! of said VEGF
`
`15
`
`antagonist solution which comprises a dosage volume of about 0.05ml of said
`
`VEGF antagonist solution,
`
`(c) the syringe barrel comprises less than about 500ygsilicone oil,
`
`(d) the VEGF antagonist solution comprises no more than 2 particles >50um in
`diameter per mi, and
`
`20
`
`(e) the VEGF antagonist is the antibody VEGF antagonist bevacizumab.
`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 chamberfrom which a fluid can be expelled though the outlet, the plunger
`
`25
`
`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, characterised in that the fluid is an ophthalmic solution which
`
`comprises a VEGF-antagonist, wherein
`(a) the syringe has a nominal maximumfill volume of between about 0.5m! and
`about iml,
`
`30
`
`Regeneron Exhibit 1002.0389
`
`

`

`23_11_2012-01-00003-00000039
`
`23_11_2012-01—00063-CGG0CB3S
`
`-16-
`(b) the syringe is filled with between about 0.15ml and about 0.175mlof said VEGF
`antagonist solution which comprises a dosage volume of about 0.05ml of said
`VEGF antagonistsolution,
`
`(c) the syringe barrel comprises less than about 500ugsiliconeoil,
`
`(d) the VEGF antagonist solution comprises no more than 2 particles >50um in
`diameter per ml, and
`
`(e) the VEGF antagonist is the antibody VEGF antagonist bevacizumab at a
`concentration of 25 mg/ml.
`
`A pre-filled syringe according to claim 1 or 2, wherein the syringeis filled with
`about 0.165m! of said VEGF antagonist solution.
`
`A pre-filled syringe according to any previous claim, wherein the syringe barrel has
`
`an internal coating of silicone oil that has an average thickness of about 450nm or
`less.
`
`A pre-filled syringe according to any previous claim, wherein the syringe barrel has
`an internal coating of less than about 500 wgsilicone oil, preferably less than about
`100pg silicone oil, preferably less than about 50g silicone oil, preferably less than
`about 25ygsilicone oil.
`
`A pre-filled syringe according to any previous claim, wherein the silicone oil
`
`is
`
`DC365 emulsion.
`
`@
`
`10
`
`15
`
`20
`
`A pre-filled syringe according to any previous claim, wherein the syringe is silicone
`
`oil free.
`
`A pre-filled syringe according to any previous claim, wherein the VEGF antagonist
`
`solution further comprises one or more of (i) no more than 5 particles >25ym in
`
`diameter per ml, and (ii) no more than 50 particles >10um in diameter per ml.
`
`25
`
`A pre-filled syringe according to any previous claim, wherein the VEGF antagonist
`
`solution meets USP789.
`
`10.
`
`A pre-filled syringe according to any previous claim, wherein the syringe has a
`
`stopper break loose force of less than about 11N.
`
`30
`
`11.
`
`12.
`
`A pre-filled syringe according to claim 10, wherein the syringe has a stopper break
`loose force of less than about 5N.
`
`A pre-filled syringe according to any previous claim, wherein the syringe has a
`stopperslide force of less than about 11N.
`
`Regeneron Exhibit 1002.0390
`
`

`

`23_11_2012-01-00003-00000040
`8
`
`
`23_11_2012-01-C0203-0R00GR4L
`
`-17-
`
`13. A pre-filled syringe according to claim 12, wherein the syringe has a stopper slide
`force of less than about 5N.
`
`14. A pre-filled syringe according to any previous claim, in which the dosage volumeis
`determined by volumeof the variable volume chamber when a predetermined part
`of the stopper orplungeris aligned with a priming mark on the syringe
`
`5
`
`15. A blister pack comprising a pre-filled syringe according to any previous claim,
`wherein the syringe has beensterilised using H2O2 or EtO.
`
`16. A blister pack comprising a pre-filled syringe according to claim 15, wherein the
`outer surface of the syringe has <1ppm EtO or H2O,residue.
`
`10
`
`15
`
`20
`
`17. A blister pack comprising a pre-filled syringe according to claim 15, wherein the
`Syringe has beensterilised using EtO or H202 andthe total EtO or H,O2 residue
`found onthe outside of the syringe and inside of the blister pack is <O.1mg..
`
`18. A blister pack comprising a pre-filled syringe according to any one of claims 15-17,
`wherein <5% of the VEGF antagonistis alkylated.
`
`19. A blister pack comprising a pre-filled syringe according to any of claims 15-18,
`wherein the syringe has beensterilised using EtO or hydrogen peroxide with a
`Sterility Assurance Level ofat least 10°.
`
`20. A kit comprising: (i) a pre-filled syringe according to any one of claims 1-14, or a
`blister pack comprising a pre-filled syringe according to any one of claims 15-19,
`(ii) a needle, and optionally (iii) instructions for administration.
`
`21. Akit according to claim 20, wherein the needle is a 30-gauge x % inch needle.
`
`~e,
`©
`
`ah
`
`22. Apre-filled syringe according to any oneof claims 1-14 for use in therapy.
`
`23. A pre-filled syringe according to any one of claims 1-14 for use in the treatment 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
`
`25
`
`neovascularisation secondary to pathologic myopia (PM), diabetic macular edema
`
`(DME), diabetic retinopathy, and proliferative retinopathy.
`
`Regeneron Exhibit 1002.0391
`
`

`

`1/1
`
`CZs
`
`23_11_2012-01-00003-00000041
`
`23_11_2012-01-G0003-G0060041
`
`@ VA SLLDNmkes Oy aH
`
`Regeneron Exhibit 1002.0392
`
`

`

`SCORE Placeholder Sheet for IFW Content
`
`DocCode — SCORE
`
`Application Number: 13750352
`
`Filing Date: 03/15/2013
`
`The presenceof this form in the IFW record indicates that the following documentis stored
`in the SCORE database
`
`* Certified Copy of Foreign Application with Color Illustrations
`
`To access the documents in the SCORE database, refer to instructions below.
`
`At the time of document entry (noted above):
`¢ Examiners may access SCOREcontent via the eDANinterface.
`¢ Other USPTO employees can bookmark the current SCORE URL
`(http://es/ScoreAccessWeb/).
`¢ External customers may access SCOREcontentvia the Public and Private
`PAIR interfaces.
`
`Regeneron Exhibit 1002.0393
`
`

`

`BUNDESREPUBLIK DEUTSCHLAND
`
`
`
`Aktenzeichen:
`
`20 2013 000 688.9
`
`Anmeldetag:
`Anmelder/inhaber:
`
`|
`
`23. Januar 2013
`Novartis AG, Basel, CH
`
`Bezeichnung:
`
`Glas-Spritze
`
`Prioritat:
`
`_
`
`16. November 2012; AU; 2012101678
`16. November 2012; AU; 2012101677
`
`23. Oktober 2012; EP; 12189649.2
`
`16. November 2012; DE; 20 2012 011 016.0
`
`03. Juli 2012; EP; 12174860.2
`
`03. Dezember 2012; EP; 12195360.8
`
`
`
`Prioritatsbescheinigung
`DE 20 2013 000 688.9
`liber die Einreichung einer Gebrauchsmusteranmeldung
`
`Yh , Farbabweichungen. Munchen, den 28. Eebruar 2013
`
`IPC:
`
`AG1F 9/00: A61M 5/178
`
`Die angehefteten Stiicke sind eine richtige und genaue Wiedergabe der Teile der
`am 23. Januar 2013 eingereichten Unterlagen dieser Gebrauchsmusteranmeldung
`
`
`
`
`
`a unabhangig das_Kopierverfahrenvon gegebenenfalls durch bedingten
`
`Regeneron Exhibit 1002.0394
`
`

`

`23_01_2013-01-00003-00000106
`
`23_01_2013-01-O0003-GBU0001GEB
`
`
`
`Beschreibung
`
`GLAS-SPRITZE
`
`TECHNISCHES GEBIET
`
`Die vorliegende Erfindung betrifft eine Spritze, insbesondere eine kleinvolumige Spritze,
`
`die sich zum Verabreichen ophthalmischer Injektionen eignet.
`
`STAND DER TECHNIK
`
`Patienten werden viele Medikamente mit Hilfe einer Spritze verabreicht, mit der der
`
`Anwender das Medikament anwenden kann. Wird einem Patienten ein Medikamentin
`
`10
`
`einer Spritze verabreicht, geschieht dies oft, um es dem Patienten oder einer
`Pflegeperson zu ermdglichen, das Medikament
`selbst
`zu
`injizieren. Fur
`die
`Patientensicherheit und die Unversehrtheit des Medikaments ist es wichtig, dass die
`Spritze und deren Inhalte ausreichend steri! sind, um Infektionen und andere Risiken fir
`die Patienten zu vermeiden. Die Sterilisation kann durch eine abschlieRende Sterilisation
`
`erreicht werden, bei der das zusammengefigte Produkt, das sich typischerweise bereits
`in der dazugehérigen Verpackung befindet, unter Zuhilfenahme von Hitze oder eines
`
`15
`
`sterilisierenden Gasessterilisiert wird.
`
`im Fall von kleinvolumigen Spritzen, zum Beispiel jenen fir Injektionen in das Auge, bei
`
`denen beabsichtigt ist, dass ungefahr 0,1 ml oder weniger der Flussigkeit injiziert werden
`sollen, kann die Sterilisation zu Problemen fuhren, die bei gréReren Spritzen nicht
`unbedingt auftreten. Druckveranderungen innerhalb oder auRerhalb der Spritze kGnnen
`
`20
`
`dazu
`
`fiihren,
`
`dass
`
`sich Teile
`
`der
`
`Spritze
`
`unvorhersehbar
`
`bewegen, was
`
`Dichteeigenschaften verandern und unter Umstandendie Sterilitat beeintrachtigen kann.
`
`Zudem_
`
`sind
`
`bestimmte Therapeutika, wie
`
`biologische Molekile,
`
`besonders
`
`25
`
`sterilisationsempfindlich, handelt es sich um eine kalte Gassterilisation, eine thermische
`Sterilisation oder eine Bestrahlung. Daherist ein vorsichtiger Balanceakt notwendig, um
`sicherstellen, dass, wahrend ein geeigneter Sterilisationsgrad erreicht wird, die Spritze
`weiterhin entsprechend abgedichtet bleibt, damit das Therapeutikum nicht beeintrachtigt
`wird. Selbstverstandlich muss die Spritze leicht handhabbar bleiben, insofern dass die
`Kraft, die erforderlich ist, um den Kolben herabzudriicken, um das Medikament zu
`
`30
`
`verabreichen, nicht zu hoch sein darf.
`
`Deshalb besteht ein Bedarf nach einer neuen Spritzenkonstruktion, die eine stabile
`Abdichtungfirihre Inhalte bietet, aber eine leichte Handhabung beibehdit.
`
`Regeneron Exhibit 1002.0395
`
`

`

`23_01_2013-01-00003-00000107
`
`
`23_01_2013-01-UovU3-BOUUUI U7
`
`OFFENBARUNG DER ERFINDUNG
`
`Die vorliegende Erfindungstellt eine vorgefiillte Spritze bereit, die Spritze umfasst einen
`
`Korper, einen Stopper und einem Kolben, wobei der Kérper an einem Auslass-Ende
`einen Ausiass umfasst und der Stopper im K6rper so angeordnetist, dass die frontale
`5 Oberflache des Stoppers und der K6érper eine Kammer mit variablem Volumen bzw.
`
`variable Volumenkammer beschreiben, aus der eine Flissigkeit durch den Auslass
`
`gedruckt wird, der Kolben umfasst eine Kolbenkontaktflache an einem ersten Ende und
`einen Stab, der sich zwischen der Kolbenkontaktflache und einem hinteren Anteil
`erstreckt, die Kolbenkontaktflache ist derart angeordnet, um den Stopper zu beruhren,
`10 damit der Kolben dazu benutzt werden kann, den Stopper zum Auslass-Ende des
`K6rpers zu driicken, wobei das Volumen der Kammermit variablem Volumen vermindert
`wird, gekennzeichnet dadurch, dass die Filssigkeit eine ophthalmische Lésung umfasst.
`In einer AusfUhrungsform umfasst die ophthalmische L6sung einen VEGF-Antagonisten.
`
`In einer Ausfihrungsform eignet
`
`sich die Spritze fir ophthalmische Injektionen,
`
`15 insbesondere intravitreale Injektionen und verfigt daher Uber ein geeignet geringes
`Volumen. Die Spritze kann auch frei von Silikonéi sein oder nahezu frei von Silikondl
`sein, oder kann eine geringe Menge an Silikonol als Schmiermittel enthalten. Gemak
`einer Ausfihrungsform betragt die Losbrechkratt und Gleitkraft des Stoppers trotz der
`geringen Menge an SitikonGl weniger als 20 N.
`
`@
`
`20 Bei ophthalmischen Injektionen ist es fiir die ophthalmische Lésung von erheblicher
`Bedeutung
`einen
`besonders
`niedrigen
`Partikelgehalt
`aufzuweisen.
`In
`einer
`Ausfihrungsform entspricht die Spritze der Anforderung des Standards 789 (USP 789)
`des US Arzneimittelbuch