23_1 1_201 2-01 40003-00000030
`
`2.3.1 3. .maa—mdoeeesmcosc
`
`- 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 :50um in
`
`diameter per ml, no more than 5 particles 325pm in diameter per ml and no more than 50
`
`particles 310um 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
`
`Antibody VEGF antagonists
`
`1O
`
`15
`
`20
`
`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 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 13:4623-75). Aflibercept is the preferred non-
`
`antibody VEGF antagonist for use with the invention. Aflibercept is a recombinant human
`
`soluble VEGF receptor fusion protein consisting of portions of human VEGF receptors 1
`
`and 2 extracellular domains fused to the Fc portion of human IgG1.
`
`It
`
`is a 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 Cl-IO K1 cells. Each monomer can have the following amino
`
`acid sequence (SEQ ID NO: 1):
`
`25
`
`SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRK
`
`GFIISNATYKE|GLLTCEATVNGHLYKTNYLTH RQTNTIIDWLSPSHGIELSVGEKLVLNC
`
`TARTELNVGIDFNWEYPS SKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQG LY
`TCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTP
`
`EVTCWVDVSH EDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRWSVLTVLHQDWL
`
`NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQWTLPPSRDELTKNQVSLTCLVKGFY
`
`PSDIAVEWESNGQPENNYK'lTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE
`
`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
`monomers.
`
`30
`
`35
`
`Regeneron Exhibit 1002.0381
`
`

`

`23_11_2o1i-o1poods-oébbo-dm
`
`23-3. 3. .2912—93-460093-W31 .
`
`
`
`- 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 Fc protein
`
`fragment (Li et al., 2011 Molecular Vision 171797-803). 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):
`
`‘
`
`MVSYWDTGVLLCALLSCLLLTGSSSGGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNIT
`
`VTLKKFPLDTLIPDGKRIIWDSRKGFIlSNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNT
`
`llDWLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSG
`
`SEMKKFLSTLTlDGVTRSDQGLYTCAASSGLMTKKN STFVRVHEKPFVAFGSGMESLVE
`
`ATVGERVRLPAKYLGYPPPEIKWYKNGlPLESNHTIKAGHVLTIMEVSERDTGNYTVI LTN
`
`PlSKEKQSHWSLVWVPPGPGDKTHTCPLCPAPELLGGPSVFLFPPKPKDTLMISRTPE
`
`VTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLN
`
`GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP
`
`SDlAVEWESNGQPENNYKATPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
`LHNHYTQKSLSLSPGK
`'
`l
`
`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. _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 prevents it from binding to VEGFR-Z. One
`example for such a molecule is DARPin® MPO112. The ankyrin binding domain may
`
`have the following amino acid sequence (SEQ ID NO: 3):
`
`GSDLGKKLLEAARAGQDDEVRILMANGADVNTADSTGWTPLHLAVPWGHLEIVEVLLK
`
`YGADVNAKDFQGWTPLHLAAAIGHQEIVEVLLKNGADVNAQDKFGKTAFDISIDNGNED
`
`10
`
`15
`
`20
`
`25
`
`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 W0201 1/135067.
`
`Further specific antibody mimetics with VEGF antagonist activity are the 40 kD pegylated
`
`35
`
`anticalin PRS-OSO and the monobody angiocept (CT-322).
`
`v
`
`
`
`Regeneron Exhibit 1002.0382
`
`

`

`s
`23_1 1_201 2-01 -00003-00000032
`
`2 3 i lia1£_101_m93_flgm932
`
`
`
`- g -
`
`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
`
`5
`
`the VEGF antagonist was derived.
`
`Variants of the above-specifiedVEGF 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
`
`i}
`{1.
`
`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
`
`/\
`1.4
`
`25
`
`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 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).
`
`Regeneron Exhibit 1002.0383
`
`

`

`5
`
`
`
`Therapy
`
`_ 1o _
`
`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
`
`5
`
`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
`
`,
`
`4
`
`‘
`
`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 predetermined part of the stopper with the priming mark.
`
`
`
`In 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
`myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and proliferative
`retinopathy, comprising administering a non-antibody VEGF antagonist with a pre-filled
`
`l‘ .
`
`(“i
`
`'
`
`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
`sterilisation, for example terminal sterilisation.
`
`30
`
`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
`
`V: 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
`
`Regeneron Exhibit 1002.0384
`
`

`

`23_1 1_2o1 2.01.00003-00000034
`
`23-11:;1532—93-{33363—130006934
`
`
`
`"i
`O
`
`-11-
`
`containing a pre-filled syringe according to the invention contained within a blister pack, a
`
`needle and optionally instructions for administration.
`
`Sterilisatr’on
`
`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 samemethod, 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
`
`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‘. 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
`
`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
`
`_<_10% (preferably _<_5%, 53%, 51%) 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 51ppm, preferably _<_0.2ppm EtO residue. In one embodiment, the pre-
`
`filled syringe has been sterilised using hydrogen peroxide, but the outer surface of the
`
`syringe has 51 ppm, preferably 50.2ppm 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 50.1mg. 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
`I the blister pack is 50.1mg.
`
`General
`
`The term “comprising” means “including" as well as "consisting" eg. a composition
`
`“comprising" X may consist exclusively of X or may include something additional 9.9. X +
`Y.
`
`The term “about” in relation to a numerical value x means, for example, x11 0%.
`
`‘5
`
`10
`
`15
`
`20
`
`3O
`
`35
`
`Regeneron Exhibit 1002.0385
`
`

`

`
`
`23_1 1_201 2-01 —00003-00000035
`
`23.1 1 .213 ifi-fli-fififlflB—W
`
`_ 12 _
`
`References to a percentage sequence identity between two amino acid sequences
`
`means that, 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 known in the art, for example those described in
`
`5
`
`section 7.7.18 cf 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. Appl. Math. 2: 482-489
`
`10'
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`“‘1
`
`Figure 1 shows a side view of a syringe
`
`Figure 2 shows a cross section of a top down view of a syringe
`
`Figure 3 shows a view of a plunger
`
`Figure 4 shows a cross section though a plunger
`
`15
`
`Figure 5 shows a stopper
`
`fl
`‘1.“
`
`MODES FOR CARRYING OUT THE INVENTION '
`
`20
`
`25
`
`30
`
`The invention will now be further described, by way of example only, with reference to
`
`the drawings.
`
`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.
`
`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 along a first axis A. The body 2
`
`comprises an outlet 12 at an outlet end 14 and the stopper 10 is arranged within the
`
`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 the plunger 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
`
`

`

`{3:11_2o12-o1—.60‘oo3—oooooose
`
`'9
`
`23.1 1.30.12-01-W-QGQQGQBS
`
`the body 2. Such movement reduces the volume of the variable volume chamber 18 and
`
`causes fluid therein to be expelled though the outlet.
`
`_ 13 -
`
`
`
`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 be fitted 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
`
`32 extends from to a rod shoulder. radius from the first axis A which is' such that it is
`
`slightly less than the bore radius so that the shoulder fits within the bore 36. The
`
`5 '
`
`10
`
`‘
`
`‘1
`
`backstop 6 includes a backstop shoulder 34 directed towards the outlet end 14. The
`shoulders 32, 34 are configured to cooperate to substantially prevent movement of the
`rod 26 away from the outlet end 14 when the backstop shoulder 34 and rod shoulder 32
`
`15
`
`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 the first axis A.
`
`In this case the rod shoulder 32 is
`
`Substantially disc, or ring, shaped and the backstop shoulder 34 includes an are around a
`rear end 38 of the body 2.
`
`20
`
`The backstop 6 also includes two finger projections 40 which extend in opposite
`
`directions away from the body 2 substantially perpendicular to 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
`
`t."l
`
`injectable solution
`0.3 ml of an injectable medicament 20 comprising a 10mg/ml
`comprising ranibizumab. The syringe body 2 has an internal diameter of about betWeen
`
`25
`
`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
`
`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 extends from the first
`
`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 shows a cross section though a syringe body 2 and rod 26. The rod 26 includes
`
`35
`
`four longitudinal ribs 44 and the angle between the ribs is 90°.
`
`Regeneron Exhibit 1002.0387
`
`

`

`23_11_2o12-o1-ooooa-ooooooar
`
`fixation—s 1—36993-68890937
`
`if.
`Q
`
`_ 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 between the first 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
`
`5
`
`includes an initial bore 64 having a first diameter. The initial bore 64 leading from the
`rear surface 60 into the stopper 10 to an inner recess 66 having a second diameter, the
`
`second diameter being larger than the first diameter.
`
`Stopper forces
`
`E
`.
`
`10
`
`0.5ml syringes siliconised with <100pg silicone oil, 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 over a travel length of 10.9mm.
`
`,_
`
`f
`
`Stopper design 1
`
`.
`
`Stopper design 2
`
`'
`
`syringes
`
`
`
`on
`~
`
`_
`
`
`
`Average Of 10““-
` loose force
`
` of syringes
`".fl
`individual
`
`
`value
`
`
`
`Average of 10
`-“
`
`syringes
`‘
`
`Max
`
`3.5N
`
`.5N
`
`3
`
`3.6N
`
`4.7N
`
`
`
`individual
`
`value
`
`15
`
`For both stopper designs, average and maximum break out force remained below 3N.
`
`For both stopper designs, average and maximum sliding force remained below 5N.
`
`It will be understood that the invention has been described by way of example only and
`
`modifications may be made whilst remaining within the scope and spirit of the invention.
`
`20
`
`Regeneron Exhibit 1002.0388
`
`

`

`23__1 1_2012-01 -00003-00000038
`0
`
`23.11 jozwa—ww3~mw%
`
`‘
`
`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
`
`5
`
`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
`
` \
`
`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 syringe is filled with between about 0.15mi and about 0.175ml 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 SOOpg silicone oil,
`
`(d) the VEGF antagonist solution comprises no more than 2 particles z50pm in
`
`diameter per ml, and
`
`20
`
`(e) the VEGF antagonist is the antibody VEGF antagonist bevacizumab.
`
`6,
`
`2.
`
`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
`
`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
`
`30
`
`comprises a VEGF-antagonist, wherein
`
`(a) the syringe has a nominal maximum fill volume of between about 0.5ml and
`about 1ml,
`
`Regeneron Exhibit 1002.0389
`
`

`

`23_1 1_2012-01-00003-00000039
`
`23.11.2612—91-m3-99WS
`
`_ 15 _
`
`(b) the syringe is filled with between about 0.15mi and about 0.175ml of said VEGF
`antagonist solution which comprises a dosage volume of about 0.05mi of said
`
`VEGF antagonist solution.-
`
`(c) the syringe barrel comprises less than about 500519 silicone oil,
`
`(d) the VEGF antagonist solution comprises no more than 2 particles 350pm 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 syringe is filled with
`
`about 0.165ml 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 pg silicone oil, preferably less than about
`
`100519 silicone oil, preferably less than about 501.19 silicone oil, preferably less than
`
`about 25119 silicone oil.
`
`A pre-filled syringe according to any previous claim, wherein the silicone oil
`
`is
`
`D0365 emulsion.
`
`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 325um in
`
`diameter per ml, and (ii) no more than 50 particles :10um in diameter per ml.
`
`A pre-filled syringe according to any previous claim, wherein the VEGF antagonist
`
`solution meets USP789.
`
`10.
`
`11.
`
`12.
`
`A pre-filled syringe according to any previous claim, wherein the syringe has a
`
`stopper break loose force of less than about 11N.
`
`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
`
`stopper slide force of less than about 11N.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Regeneron Exhibit 1002.0390
`
`

`

`23_1 1_2012-01 40003410000040
`h
`
`2 3 1 1'2012_fl 5-90%..ng
`
`
`
`-17-
`
`13. A pre-filled syringe according to claim 12. wherein the syringe has a stopper slide
`
`force of less than about SN.
`
`14. ‘ A pre—filled syringe according to any previous claim, in which the dosage volume is
`
`5
`
`determined by volume of the variable volume chamber when a predetermined part
`of the stopper or plunger is aligned with a priming mark on the syringe
`
`15. A blister pack comprising a pre-filled syringe according to any previous claim,
`wherein the syringe has been sterilised using H202 or Etc.
`
`16. A blister pack comprising a pre-filled syringe according to claim 15, wherein the
`
`outer surface of the syringe has 51 ppm EtO or H202 residue.
`
`10
`
`17. A blister pack comprising a pre-filled syringe according to claim 15, wherein the
`
`x2,
`. .
`
`!
`
`syringe has been sterilised using EtO or H202 and. the total EtO or H202 residue
`found on the outside of the syringe and inside of the blister pack is 50.1mg._
`
`18. A blister pack comprising a pre-filled syringe according to any one of claims 15-17,
`
`wherein _<_5% of the VEGF antagonist is a'lkylated.
`
`15
`
`19. A blister pack comprising a pre-filled syringe according to any of claims 15-18,
`
`wherein the syringe has been sterilised using BC or hydrogen peroxide with a
`
`Sterility Assurance Level of at 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,
`
`20
`
`(ii) a needle, and optionally'(iii) instructions for administration.
`
`21. A kit according to claim 20, wherein the needle is a 30-gauge x ‘/2 inch needle.
`
`/r ,
`
`6
`
`22. A pre—filled syringe according to any one of 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
`
`25
`
`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.
`
`Regeneron Exhibit 1002.0391
`
`

`

`23—_11_2o12-o1_oooos-oooooo41
`
`"23.1 3.2012-91—139393‘00091394}!
`
`6 r
`
`26
`
`“93»
`o.
`
`llA
`
`' “‘L-V‘VAmn“““.‘“‘““l“ w 36‘
`\\\\\\\}fi|
`l\\"_{"\\'\§|‘
`
`-=
`k‘E“..-__ __ ._.__.._____
`
`“““‘“‘“7‘““‘“““““\ '0 ‘JP8?"
`
`o‘..
`f.
`I
`p
`1
`’0’.
`
`.»
`
`Regeneron Exhibit 1002.0392
`
`

`

`DocCode — SCORE
`
`SCORE Placeholder Sheet for lFW Content
`
`Application Number: 13750352
`
`Filing Date: 03l15l2013
`
`The presence of this form in the IFW record indicates that the following document is stored
`in the SCORE database
`
`0 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 SCORE content via the eDAN interface.
`- Other USPTO employees can bookmark the current SCORE URL
`(http://es/ScoreAccessWeb/).
`- External customers may access SCORE content via the Public and Private
`PAIR interfaces.
`
`Regeneron Exhibit 1002.0393
`
`

`

`BUNDESREPUBLIK DEUTSCHLAND
`
`
`
`Prioritétsbescheinigung
`
`DE 20 2013 000 688.9
`
`fiber die Einreichung einer Gebrauchsmusteranmeldung
`
`Aktenzeichen:
`
`20 2013 000 688.9
`
`Anmeldetag:
`
`23. Januar 2013
`
`
`
`ruar 2013
`
`Farbabweichungen. __.
`
`Anmelderllnhaber:
`
`Novartis AG, Basel, CH
`
`Bezeichnung:
`
`GIas-Spritze
`
`Prioritfit:
`
`_
`
`16. November 2012; AU; 2012101678
`
`16. November 2012; AU; 2012101677
`
`23. Oktober 2012; EP; 121896492
`
`16. November 2012; DE; 20 2012 011 016.0
`
`03. Juli 2012; EP; 121748602
`
`IPC:
`
`'
`
`A61F 9/00; A61M 5/178
`
`03. Dezember 2012; EP; 121953608
`
`Die angehefteten Stficke sind eine richtige und genaue Wledergabe der Teile der
`am 23. Januar 2013 eingereichten Unterlagen dieser Gebrauchsmusteranmeldung
`. unabhéingig
`von
`gegebenenfalls
`durch
`das Kopierverfahren
`bedingten
`
`Mflnchen, den 28. F
`
`
`
`Regeneron Exhibit 1002.0394
`
`

`

`25:31_2o13-o1-ooooa-ooooo1oe
`
`?
`
`23.61.20 1 3‘01“UUW3-‘UUUUUIQB
`
`
`
`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 Medikament in
`
`einer Spritze verabreicht, geschieht dies oft, um es dem Patienten oder einer
`
`Pflegeperson zu erméglichen, das Medikament
`selbst
`zu
`injizieren.
`Fflr
`die
`Patientensicherheit und die Unvelsehrtheit des Medikaments ist es wichtig, dass die
`
`Spritze und deren lnhalte ausreichend steril sind, um lnfektionen und andere Risiken fijr
`
`die Patienten zu vermeiden. Die Sterilisation kann durch eine abschlielsende Sterilisation
`
`erreicht werden, bei der das zusammengefljgte Produkt, das sich typischenlveise bereits
`
`in der dazugehérigen Verpaclsung befindet, unter Zuhllfenahme von Hitze oder eines
`
`sterilisierenden Gases sterilisiert wird.
`
`lm Fall von kleinvolumigen Spritzen, zum Beispiel jenen fl'Jr Injektionen in das Auge, bei
`
`denen beabsichtigt ist, dass ungeféihr 0.1 ml oder weniger der Flfisslgkeit injiziert werden
`sollen, kann dié Sterilisation zu Problemen fflhren, die bei gréfieren Spritzen nicht
`
`unbedingt auflreten. Druckveranderungen innerhalb oder aufSerhalb der Spritze k6nnen
`
`dazu
`
`ffihren,
`
`dass
`
`sich Teile
`
`der
`
`Spritze
`
`unvorhersehbar
`
`bewegen, was
`
`Dichteeigenschaften verandern und unter Umstanden die Sterilitat beeintrachtigen kann.
`
`10
`
`15
`
`20
`
`Zudem sind
`
`bestimmte Therapeutika, wie
`
`biologische Molekflle,
`
`besonders
`
`25
`
`sterilisationsempfindlich, handelt es sich um eine kalte Gassterllisation, eine thermische
`Sterilisation oder eine Bestrahlung. Daher ist ein Vorsichtiger Balanceakt notwendig, um
`sicherstellen. dass, wahrend ein geeigneter Sterilisatibnsgrad erreicht wird. die Spritze
`
`weiterhin entsprechend abgedichtet blelbt, damit das Therapeutikum nicht beeintr'a'chtigt
`wird. Selbstverstandlich muss die Spritze Ieicht handhabbar bleibe.n, insofem dass die
`Kraft, die erforderlich ist, um den Kolben herabzudrljcken, um das Medikament zu
`
`30
`
`verabreichen, nicht zu hoch sein darf.
`
`Deshalb besteht ein Bedarf nach einer neuen Spritzenkonstruktion, die eine stabile
`
`Abdichtung filr ihre Inhalte bietet, aber eine leichte Handhabung beibeh'a‘lt.
`
`Regeneron Exhibit 1002.0395
`
`

`

`23-°1—2°‘3'°"°°°.°3‘°°°°°1°7
`
`
`23.m.;2013-m-m5~uouumu7
`
`OFFENBARUNG DER ERFINDUNG
`
`Die vorliegende Erfindung stellt eine vorgefiillte Spritze bereit, die Spritze umfasst einen
`
`Kdrper, einen Stopper und einem Kolben, 'wobei der Kbrper an einem Auslass-Ende
`
`einen Auslass umfasst und der Stopper im K6rper so angeordnet ist, dass die frontale
`
`Oberfléche des Stoppers und der Kérper eine Kammer mit variablem Volumen bzw.
`
`variable Volumenkammer beschreiben, aus der eine Fliissigkeit durch den Auslass
`
`gedrfickt wird, der Kolben umfasst eine Kolbenkontaktfléche 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 ben‘Jhren.
`damit der Kolben dazu benutzt werden kann. den Stopper zum Auslass-Ende des
`Kérpers zu drijcken. wobei das Volumen der Kammer mit variablem Volumen vermindert
`
`wird. gekennzeichnet dadurch, dass die Fitissigkeit eine ophthalmische Losung umfasst.
`
`In einer Ausfflhrungsform umfasst die ophthalmische Losung einen VEGF-Antagonisten.
`
`In einer Ausfiihrungsform eign