Example 1 and Comparative Examples 1 and 2
`
`EP 0 879 611 A2
`
`In the following Example and Comparative Examples, a rubber sheet having an excellent gas permeability resist-
`ance of Compounding Example 2 in Table 3 was used. According to the compounding formulation, the mixture was
`kneaded using an open roll, aged for 24 hours and heated to obtain an unvulcanized rubber sheet. The resulting rubber
`sheet and D-1, D-2 and D-3 films with a thickness of 20 um, obtained in the foregoing Reference Examples, were
`placed on a metallic mold for shaping, corresponding to a cross-sectional shape of a stopper shownin Fig. 3 (a),
`pressing at a mold-fastening pressure of 150 kg/cm? depending on the vulcanization conditions of at 150 to 180 °C,
`vulcanized for 10 minutes, and the whole bodyof the rubber stopper was laminated with PTFE or ETFE film to prepare
`a sealing stopper with a cross-sectional shape as shownin Fig. 3 (a). The size of the sealing stopper was allowed to
`correspondto that of an injection cylinder used in each test described hereinafter.
`
`Measurementof Sliding Resistance Value
`
`Injection cylinders each having a volume of 5 ml and 100 ml, made of plastic (polypropylene), and sealing stoppers
`having sizes shownin Table 5, corresponding to these injection cylinders were prepared and eachofthe sealing stop-
`pers wasthrusted andsetinto the injection cylinder. The sealing stopper wasslowly thrusted therein in such a manner
`that the end of the sealing stopper reached a position for defining a specified volume, thus preparing a sample injection
`cylinder. Then, acommercially available disposable injection needle having a determined size wasfirmly inserted into
`the end of the sample injection cylinder. Using a commercially available syringe fitted with an injection needle, on the
`other hand, distilled water with the specified volume of the injection cylinder was charged in the end of the sample
`injection cylinder, during which care was taken so that air was not allowed to enter therein. The end of the injection
`cylinder was directed downwards, inserted in a metallic jig and the sealing stopper was thrusted into the end side at
`a rate of 100 mm/sec by a compressiontest disk of spherical seat type of a pressure senser-fitted measurement device
`[Autograph AG-1KND -commercial name- manufactured by Shimazu Seisakujo KK], during which a sliding resistance
`value was measured. The maximum value was read from the thus resulting sliding measured chart to define this as
`the sliding resistance value. In general, there was a tendency such that a value atthe startof sliding, i.e. static friction
`resistance value Ffs was smaller than a value during sliding (kinematic frictionresistance value) Ffd. The results are
`
`shownin Table 5. from which it is evident that in Comparative Example 3 in which FTFE was laminated, the slidability
`is too low to measurethe sliding resistance value andit is difficult to set in the injection cylinder.
`
`Table 5
`
`Example1
`
`Comparative
`Example 2
`
`3
`
`Injection Cylinder
`Volume (ml)
`
`Diameter of Sealing
`Stopper (mm)
`
`5
`100
`(Note): * Newton (1 N = 9.8 kg)
`
`12.89
`32.58
`
`PTFE Coated
`Sealing Stopper by
`Casting Method
`21.1 N*
`68.8 N
`
`PTFE Coated
`Sealing Stopper by
`Skiving Method
`20.4 N
`59.3 N
`
`ETFE Coated Seal-
`Stopper by
`Extrusion Method
`not measurable
`not measurable
`
`
`
`
`Test for Estimation of Sealing Property for Long time
`
`Alternative Test for Estimation of Presence or Absence of Invasion of Microorganisms)
`
`Using sealing stoppers of Example 1 and Comparative Examples 2 and 3 each having a size corresponding to an
`injection cylinder with a volume of 5 ml, the following procedure wascarried out.
`1 (¢) was washed and dried,
`A plastic injection cylinder (volume 5 ml) having a cross-sectional shape shownin Fig.
`ollowed by sealing the end thereof by a rubber cap. Water with a predetermined volume was then poured therein and
`each of the above described sealing stoppers was slowly inserted into the opening part.
`In the case of Comparative
`Example 2, the sealing stopper was forcedly thrusted therein. The whole weight (initial weight) of the sample cylinder
`was precisely weighed and then subjected to storage under an accelerating condition of a temperature of 40 °C and
`relative humidity of 75 % for at least 6 months, during which every one month, each sample injection cylinder was
`aken and the surface thereof was dried for 30 minutes in a desiccator, followed by precisely weighing each sample
`at least five measurementpoints). The resulting data of weight change wastreated in statistical manner to calculate
`as aregression function and a numerical value corresponding to three years is extrapolatedin the time term to estimate
`
`10
`
`16
`
`20
`
`256
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`11
`
`Regeneron Exhibit 1002.1141
`
`

`

`EP 0 879 611 A2
`
`and assessthe sealing property for a long time after formulation of a medicament. In order to correspond to the real
`formulation, seventy samples were respéctively prepared and investigated as to both plunger fitted- and plunger-free
`sealing stoppers.
`A reduction curve Y for the time term X of each sample, Y = -K + a InX, obtained by the above describedstatistical
`procedure can be represented in Example 1, as follows:
`When fitting a plunger:
`
`When notfitting a plunger:
`
`Y = -1.896 + 1.087 x Inx
`
`Y = -4.200 + 1.594 x InX
`
`(a)
`
`(b)
`
`When into the time term X of the above described regression function formulas (a) and (b) are extrapolated two
`years (17,520 hours) and three years (26,280 hours) to estimate weight reductions after two years and three years
`under normal state of water for injection in each sample, the weight reductions are 5.27 mg after two years and 5.71
`mg after three years in the case of (a). The reduction ratios when the initial weight is 100 % are 0.11 % in two years
`and 0.11 %in three years. Similarly, the estimated values of the reduction and reduction ratio in the case of (4) are
`6.31 mg and 0.12 % in two years and 6.96 mg and 0.13 % in three years.
`The similar procedureto that of Example 1 wasalso carried out as to Comparative Example 1 (D-2) and Compar-
`ative Example 2 (D-3) to obtain reduction curves, and reductions and reduction ratios after two years and three years,
`obtained by extrapolation of the reduction curves. The results are shownin Table 6.
`As shown in Table 6, the sealing property of the film (ETFE) of D-3 is more excellent, but the sealing stopper of
`Comparative Example 2 having this film laminatedis inferior in slidability between the film and inner wall of the injection
`cylinder because of much higher sliding resistance sothat it cannot be put to practical use. Even when using the same
`PTFE film, Example 1,
`in which the film by the casting method was laminated, is more excellent in slidable property
`and sealing property than Comparative Example 1,
`in which the film by the skiving method was laminated.
`
`10
`
`16
`
`20
`
`256
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`12
`
`Regeneron Exhibit 1002.1142
`
`

`

`10
`
`16
`
`20
`
`256
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`99198]
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`EP 0 879 611 A2
`
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`13
`
`Regeneron Exhibit 1002.1143
`
`

`

`Example 2
`
`EP 0 879 611 A2
`
`This Example was carried out as to a sealing stopper having an UHMWPE film laminated within the scope of the
`present invention, prepared by the extrusion method, and another sealing stopper having an UHMWPE film laminated
`(D-4) in an analogous manner to Example 1, Comparative Example 1 or 2, thus obtaining similar good results to
`Example 1.
`From the foregoing tests, it could be confirmed that the present invention was very excellent in sealing property
`as well as slidable property.
`Results of various tests effected as a sealing stopper for a syringe will be shown using the sealing stopper, as a
`typical example, of the type of Example 1 using the film of D-1.
`
`Test for Liquid Sealing Property
`
`(a) Dynamic Loading Conditions
`
`Compressing Test according to Notification No. 442 of the Ministry of Health and Welfare, Standard of Device for
`Medical Treatment, "Standard of Disposal Injection Cylinder", December 28, 1970, and Bitish Standard.
`Ten samplesof clean plastic injection cylinders each having a specified volume were prepared, the end (lure part)
`of the injection cylinder being sealed by applying a rubber cap thereto. An aqueous Methylene Blue solution of 0.1
`weight/volume % concentration in only a determined volume was poured in the injection cylinder. A rubber sealing
`stopper having a resin film laminated on the surface thereof according to the present invention or a comparative rubber
`stopper was slowly thrusted from the flange part of the injection cylinder and while turning up the headof the cylinder,
`the rubber cap wastaken off at the lure part. A plastic plunger was screwedin a threaded part at the opening side of
`the sealing stopper and slowly pushed up upwards in such a manner that the liquid in the cylinder was not leaked, thus
`pushing out air in the end part of the cylinder. A rubber cap was again applied to the lure part and mounted ona
`measurementdevice for pressure test. After a pressure defined for medical treatment as shownin Table 7 was added
`for 10 seconds, the injection cylinder was taken off from the measurement device and an interface between the sealing
`stopper and injection cylinder was observed with magnifying ten times to confirm whether there was a leakage of the
`above described blue aqueous Methylene Blue solution through the interface part or not (Compressing Test@). The
`measured results are shown in Table 8, from which it is apparent that the sealing stopper of the present invention
`exhibits no leakage in any size of injection cylinders. In addition, Table 8 shows simultaneously the compressibility and
`sliding resistance of sealing stoppers, which teachesthat even a sealing stopper having a larger compressibility (higher
`sealing property) has a higher sliding property.
`Whena further larger pressure was addedto investigate presence or absence of leakage in addition to the above
`described defined Compressing Test (Compressing Test@), there was found no leakage as shownin Table 8.
`
`10
`
`16
`
`20
`
`256
`
`30
`
`35
`
`Table 7
`
`
`
`Application Volume for Injection Cylinder|Pressure (10 sec.)
`40
`
`4.0 kg/cm?
`
`General Medical
`Treatment
`
`4.0 kg/cm?
`less than 3 ml
`3.5 kg/em?
`at least 3 ml less than 10 ml
`3.0 kg/cm?
`at least 10 ml less than 20 ml
`2.5 kg/cm?
`at least 20 ml less than 30 ml
`2.0 kg/cm?
`at least 30 ml
`45
`
`Very Small Amount|less than 2 ml 5.0 kg/cm?
`at least 2 ml
`4.0 kg/cm?
`long
`5.0 kg/cm2
`short
`
`Insulin
`
`50
`
`55
`
`14
`
`Regeneron Exhibit 1002.1144
`
`

`

`EP 0 879 611 A2
`
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`RegeneronExhibit 1002.1145
`
`

`

`10
`
`16
`
`20
`
`256
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`EP 0 879 611 A2
`
`Test for Liquid Sealing Property
`
`(b) Accelerated Conditions
`
`Plastic injection cylinders having various volumes ten by ten and sealing stoppers having sizes corresponding
`thereto and end capsten by ten were prepared. In a plastic injection cylinder whose end was covered with a cap was
`poured a 1 % aqueous Methylene Blue solution of a determined volume and then the sealing stopper of the present
`invention and that for comparison were slowly inserted respectively from the opening part of the injection cylinder. After
`passage of at least six months under accelerating conditions of a temperature of 40 °C and a relative humidity of 75
`%, it was confirmed by visual observation whether there was leakage of the above described aqueous Methylene Blue
`solution at the interface between the plastic injection cylinder and sealing stopper. This method wascarried out as a
`test method for proving that in the case of formulation of a liquid injection agent through a sterile formulation step, there
`was no leakage of the liquid medicament nor invasion of a liquid material from the outside.
`
`Test for Liquid Sealing Property
`
`(c) Severer Conditions
`
`Each of samples prepared in an analogous manner to the above described accelerating test was subjected to
`confirmation of the presence or absence of leakage of the above described aqueous Methylene Blue solution at the
`interface between the plastic injection cylinder and sealing stopper by heating at 121 °C for 30 minutes using an
`autoclave. This method is a method for estimating sealing property in a formulation step, which comprises adding a
`stress similar to a formulation step of a part of a liquid injection agent, sterilized after the formulation. The results of
`the foregoing (b) and (c) are shownin Table 9.
`
`Gas Sealing Property Test (Invasion of Steam: Test according to "Moisture Permeability Test of US Pharmacopoeia’,
`22nd Edition)
`
`Injection Cylinders each having a volume of 1 to 100 ml (ten by ten) as shownin Table 8 were precisely weighed,
`a drying agent was charged in the injection cylinder, maintained stood, in such a manner that the thickness (height)
`be 13 mm, and the sealing stopper was fixed at a scale of the injection cylinder, representing a specfified volume. As
`the drying agent, there was preferably used calcium chloride passing through a 4-mesh sieve, dried at 110 °C for 1
`hour and then cooled in a desiccator. After precisely weighing the weight (Ti) of each sample, the sample was preserved
`at a temperature of 20 °C and a humidity of 75 % RH, and after passage of 14 days, the weight (Tf) was precisely
`weighed again. An increment of weight for a period of 14 days (Tf - Ti) was sought. On the other hand, for control, the
`initial weight (Ci) and the weight (Cf) after passage of 14 days were precisely weighed concerning dried glass beads-
`charged samples instead of the calcium chloride to obtain the increment of weight (Cf - Ci) for control for a period of
`14 days. When the volume ofthe injection cylinder is V, the moisture permeability can be given bythe following formula.
`The results are shownin Table 9.
`
`Moisture Permeability = (100/14 V)[(Tf - Ti) - (Cf - Ci)]
`
`Table 9
`
`Liquid Sealing Property
`Test!) Results
`
`Liquid Sealing Property
`Test®) Results
`
`Gas Sealing Property
`Test?) Results (mg/day- |)
`
`
`
`Injection Cylinder Volume
`(ml)
`1
`
`no leakage of MB4
`no leakage of MB
`3
`no leakage of MB
`5
`no leakage of MB
`10
`no leakage of MB
`20
`(Note) 1) accelerating condition: 40 °C, 75 % RH, 6 months
`2) severer condition: 121 °C, 1 hour
`3) moisture permeability test : 20°C, 75 % RH, 14 days
`4) MB: Methylene Blue
`
`)
`
`no leakage of MB
`no leakage of MB
`no leakage of MB
`no leakage of MB
`no leakage of MB
`
`16
`
`Regeneron Exhibit 1002.1146
`
`

`

`Test?) ResultsSs(meicay 50
`
`EP 0 879 611 A2
`
`Table 9
`
`(continued)
`
`Liquid Sealing Property
`Test?) Results
`
`no leakage of MB
`no leakage of MB
`
`Gas Sealing eat
`
`2.8
`
`Injection CylinderVolume
`(ml)
`
`Liquid Sealing Property
`Test!) Results
`
`no leakage of MB
`no leakage of MB
`100
`(Note) 1) accelerating condition: 40 °C, 75 % RH, 6 months
`2) severer condition: 121 °C, 1 hour
`3) moisture permeability test : 20°C, 75 % RH, 14 days
`
`10
`
`16
`
`20
`
`256
`
`In the moisture permeability test, a sealing property to gas (steam) at a setting part of a plastic injection cylinder
`and sealing stopper is estimated, but this test can be considered to be an alternative test for estimating possibility of
`invasion of microorganisms. The results of the moisture permeability within a range of -1 to 30 mg/day- liter according
`to the present invention, as shown in Table 9, teach very high sealing property.
`Substantially similar good results could be obtained in an estimation test as to the sealing stopper having UHMWPE
`laminated in Example 2.
`
`Advantagesof the Invention
`
`Asillustrated above, according to the present invention, there can be obtained a sealing stopper for a syringe,
`which has more improved slidability as well as sealing property, to such a degree that even if the compressibility of a
`ruber stopper is rendered higher, smooth sliding can be obtained, by laminating a PTFE film or UHMWPE film with a
`very excellent surface property. In particular, the sealing property in a formulation step (high temperature or pressure
`condition) as well as the sealing proeprty during storage for a long time are higher and moreover, during use, admin-
`istration of an injection medicamentcan be carried out in easy and rapid manner becauseof the higher sliding property,
`so that requirements in the real medical scenes may be satisfied. The above described advantages can similarly be
`obtained in the case of the prefilled syringe according to the present invention.
`
`30
`
`Claims
`
`1. A sealing stopper for a syringe, in which a surface of the rubber body is laminated with a tetrafluoroethylene resin
`film or ultra-high molecular weight polyethylene film having an average roughness Ra on the central line of the
`surface in a range of at most 0.05 tm and a kinematic friction coefficient of at most 0.2.
`
`2. The sealing stopper for a syringe, as claimed in Claim 1, wherein the tetrafluoroethylene resin film is prepared by
`a casting shaping method comprising using, as a raw material, a suspension coniaining tetrafluoroethylene resin
`powder having a grain diameter of at most 0.01 to 1.0 um, a dispersing agent and a solvent.
`
`3. The sealing stopper for a syringe, as claimed in Claim 1, wherein the ultra-high molecular weight polyethylene film
`is prepared by aninflation shaping method or extrusion shaping method.
`
`4. Aprefilled syringe, in which a medicamentis enclosed and sealedin an injection cylinder or two-componentcylinder
`by the use of the sealing stopper for a syringe, and in which a surface of the rubber body is laminated with a
`tetrafluoroethylene resin film or ultrahigh molecular weight polyethylene film having an average roughness Ra on
`the central line of the surface in a range of at most 0.05 um and a kinematic friction coefficient of at most 0.2.
`
`5. A processfor the production of a sealing stopper for a syringe, which comprises preparing a suspension of poly-
`tetrafluoroethylene fine grains having a maximum grain diameter in a range of 0.01 to 1.0 um with a concentration
`of 40 to 50 %in a suitable solvent containing a dispersing agent, coating the resulting suspension onto a metallic
`belt, heating and drying the coating at a temperature of higher than the melting point of polytetrafluoroethylene to
`forma thin film, repeating this procedure to obtain a sintered castfilm with a suitable thickness and then laminating
`a rubber body with the castfilm.
`
`6. The process for the production of a sealing stopper for a syringe, as claimed in Claim 5, wherein the thin film has
`a thicknessof 5 to 20 rm and the sintered castfilm has a thickness of 10 to 60 um.
`
`35
`
`40
`
`45
`
`50
`
`55
`
`17
`
`Regeneron Exhibit 1002.1147
`
`

`

`EP 0 879 611 A2
`
`CYLINDER
`
` 5 INJECTION
`
`INNER DIAMETER
`
`(b)
`
`(c)
`
`OUTER DIAMETER
`
`- /4s SEALING STOPPER
`ron ZN
`AA ¥ 3 RESIN FILM
`ea
`Y—2 RUBBER STOPPER BODY
`
`a
`
`?
`
`KN
`
`4
`
`Regeneron Exhibit 1002.1148
`
`

`

`
`
`
`
`CUTOFFVALUE(mm)
`
`EP 0 879 611 A2
`
`0-1
`
`PTFE FILM
`
`D-2
`
`(
`
`SKIVING METHOD|
`
`PTFE FILM
`
`
`
`MEASURED LENGTH (mm)
`
`FIG. 2
`
`Regeneron Exhibit 1002.1149
`
`

`

`EP 0 879 611 A2
`
`1 SEALING STOPPER
`
`Ds RESIN FILM
`
`[IK—K&{Z77OROSG
`
`
`ANAS
`on
`
`
`
`CITZehhMondor
`
`
`
`
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`
`
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`
`
`
`20
`
`Regeneron Exhibit 1002.1150
`
`

`

`PATENT ABSTRACTS OF JAPAN
`
`2002-241264
`(11)Publication number:
`(43)Date of publication of application : 28.08.2002
`
`(514 )Int.cl.
`
`AGIK 9/08
`AGIK 38/23
`AGiP 3/14
`AGIP 19/08
`AGIP 19/10
`// ABIM 5/28
`
`(21)Application number : 2001-042590
`(22)Date offiling :
`19.02.2001
`
`(7)Applicant : ASAHI KASEI CORP
`(72)Inventor : HITOMI KOJI
`ENDO TAKESHI
`
`(54) PREFILLED SYRINGE PHARMACEUTICAL PREPARATION OF ELCATONIN
`(57)Abstract:
`PROBLEM TO BE SOLVED:To obtain a prefilled syringe pharmaceutical preparation of
`elcatonin having stability and safe for human bodies.
`SOLUTION: This prefilled syringe pharmaceutical preparation of the elcatonin its filled with an
`aqueous solution containing the elcatonin as an active ingredient and is characterized in that
`the amount of elution into the aqueous solution is <2% expressed in terms of area ratio
`measured by high-performance liquid chromatography. The prefilled syringe pharmaceutical
`preparation of the elcatonin is filled with the aqueous solution containing the elcatonin as the
`active ingredient and is characterized in that the volume of a gap part is <0.2 when the volume
`occupied by the aqueous solution is 1. The prefilled syringe pharmaceutical preparation of the
`elcatonin comprises the syringe having a silicone at <3 wt./vol.% concentration applied to the
`inner surface and filled with the aqueous solution containing the elcatonin as the active
`ingredient.
`
`Regeneron Exhibit 1002.1151
`
`

`

`Electronic AcknowledgementReceipt
`
`ee
`
`itn
`
`
`
`Title of Invention:
`
`SYRINGE
`
`ee
`
`Paymentinformation:
`
`°°
`
`File Listing:
`
`Document
`
`i
`Information
`
`gs
`
`File Size(Bytes)/
`
`Multi
`
`Pages
`
`Information Disclosure Statement (IDS)
`Form (SBO8)
`
`PAT055157-US-NP-IDS.pdf
`
`1730783
`
`57d366ea02e39a359a3fdca211020b7e578
`b272d
`
`Regeneron Exhibit 1002.1152
`
`

`

`This is not an USPTO supplied IDS fillable form
`
`Foreign Reference
`
`EP0264273A2.pdf
`
`Information:
`
`Information:
`
`Information:
`
`Foreign Reference
`
`EP0879611A2.pdf
`
`Foreign Reference
`
`JP2002241264_Abs.pdf
`
`616316
`
`476f4646f8d6bc1b2b94db68bd123bb4e2.
`47598
`
`1043361
`
`15b9f1841ad264fda02238fb642d3b63d38)
`7ce3d
`
`306347
`
`ae5486bd2223ef9b5cbaeel bd9fedfbedssd
`3d50
`
`the application.
`
`New International Application Filed with the USPTO as a Receiving Office
`If a new international application is being filed and the international application includes the necessary components for
`an international filing date (see PCT Article 11 and MPEP 1810), a Notification of the International Application Number
`and of the International Filing Date (Form PCT/RO/105)will be issued in due course, subject to prescriptions concerning
`national security, and the date shownon this AcknowledgementReceiptwill establish the international filing date of
`
`This AcknowledgementReceipt evidences receipt on the noted date by the USPTOofthe indicated documents,
`characterized by the applicant, and including page counts, where applicable.It serves as evidence of receipt similar to a
`Post Card, as described in MPEP 503.
`
`New Applications Under 35 U.S.C. 111
`If a new application is being filed and the application includes the necessary componentsfora filing date (see 37 CFR
`1.53(b)-(d) and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shownonthis
`AcknowledgementReceiptwill establish thefiling date of the application.
`
`National Stage of an International Application under 35 U.S.C. 371
`If a timely submission to enter the national stage of an international application is compliant with the conditions of 35
`U.S.C. 371 and other applicable requirements a Form PCT/DO/EO/903indicating acceptanceof the application as a
`national stage submission under 35 U.S.C. 371 will be issued in addition to the Filing Receipt, in due course.
`
`Regeneron Exhibit 1002.1153
`
`

`

` Europaisches
`
`Patentamt
`European
`Patent Office
`Office européen
`des brevets
`
`Bescheinigung
`
`Certificate
`
`Attestation
`
`Die angehefteten
`Unterlagen stinmen mit der
`als urspriinglich eingereicht
`geltenden Fassung der auf
`dem nachsten Blatt
`bezeichneten europaischen
`Patentanmeldung Uberein.
`
`The attached documents are
`exact copiesof the text in
`which the European patent
`application described on the
`following page is deemed to
`have been filed.
`
`Les documentsjoints a la
`présente attestation sont
`conformes au texte,
`considéré comme
`initialement déposé, de la
`demandede brevet
`européen qui est spécifice a
`la page suivante.
`
`PatentanmeldungNr.
`
`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.
`
`EPA/EPO/OEB Form 1014
`
`3905.12
`
`Der Prasident des Europaischen Patentamts;
`Im Auftrag
`For the President of the European Patent Office
`
`Le President de I'Office européen des brevets
`
`Javits
`
`U. Ingmann
`
`Looea
`
`MV03101
`
`Regeneron Exhibit 1002.1154
`
`

`

`
`
`Anmeldung Nr:
`Application no.:
`Demande no :
`
`12189649.2
`
`Anmelder/ Applicant(s) / Demandeur(s):
`
`Novartis AG
`Lichtstrasse 35
`4056 Basel/CH
`
`Anmeldetag:
`Date offiling:
`Date de dépét:
`
`23.10.12
`
`Bezeichnung der Erfindung / Title of the invention / Titre de I'invention:
`(Falls die Bezeichnung der Erfindung nicht angegeben ist, oder falls die Anmeldung in einer Nicht-Amtssprache des EPA eingereicht
`wurde, siehe Beschreibung beztiglich urspriinglicher Bezeichnung.
`If no title is shown, orif the application has beenfiled in a non-EPO language, please refer to the description for the originaltitle.
`Si aucun titre n'est indiqué, ou si la demande a été déposée dans une langue autre qu'une langue officielle de |'OEB, se référer a la
`description pour letitre original.)
`
`Syringe
`
`In Anspruch genommenePrioritat(en) / Priority(Priorities) claimed / Priorité(s) revendiquée(s)
`Staat/Tag/Aktenzeichen / State/Date/File no. / Pays/Date/Numéro de dépét:
`
`Am Anmeldetag benannte Vertragstaaten / Contracting States designated at date offiling / Etats contractants désignées lors
`du dépét:
`
`AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LILT LU LV MC MK MT NL NO PL
`PT RO RS SE SI SK SM TR
`
`EPA/EPO/OEB Form 1014
`
`3905.12
`
`2
`
`Regeneron Exhibit 1002.1155
`
`

`

`PATO55157-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.
`
`BACKGROUND ART
`
`Many medicaments are delivered to a patient in a syringe from which the user can dispense the
`
`medicament. If medicament is delivered to a patient in a syringe it is often to enable the patient,
`
`or a caregiver, to inject the medicament.
`
`It is important for patient safety and medicament
`
`integrity that the syringe and the contents of that syringe are sufficiently sterile to avoid
`
`10
`
`infection, or other, risks for patients. Sterilisation can be achieved by terminal sterilisation in
`
`which the assembled product, typically already in its associated packaging, is sterilised using
`
`heat or a sterilising gas.
`
`For small volume syringes, for example those for injections into the eye in whichit is intended
`
`that about 0.1ml 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 compromisesterility.
`
`Incorrect handling of the syringe can also
`
`pose risks to productsterility.
`
`Furthermore, certain therapeutics such as biclogic 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
`
`DISCLOSUREOF 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 suchthat 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-
`
`Regeneron Exhibit 1002.1156
`
`

`

`PATO55157-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.
`
`In one embodiment,
`
`the syringe is suitable for ophthalmic injections, more particularly
`
`intravitreal injections, and as such has a suitably small volume. The syringe mayalso besilicone
`
`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 chambercan 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 lucr 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 (c.g. a cyclic olefin polymer) or from glass and
`
`may include indicia on a surface thereof to act as an injection guide. In one embodiment the
`
`25
`
`body may comprise a priming mark. This allows the physician to align a pre-determined part of
`
`the stopper (such as the tip of the front surface or one of the circumferential ribs, discussed later)
`
`with the mark, thus expelling excess ophthalmic solution and any air bubbles from the syringe.
`
`The priming process ensures that an exact, pre-determined dosage is administered to the patient.
`
`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.
`
`Regeneron Exhibit 1002.1157
`
`

`

`PATO55157-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
`
`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 dis