Example 1 and Comparative Examples 1 and 2
`
`EP O 879 611 A2
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`In the following Example and Comparative Examples, a rubber sheet having an excellent gas permeability resist(cid:173)
`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 µm, obtained in the foregoing Reference Examples, were
`placed on a metallic mold for shaping, corresponding to a cross-sectional shape of a stopper shown in Fig. 3 (a),
`pressing at a mold-fastening pressure of 150 kg/cm2 depending on the vulcanization conditions of at 150 to 180 °C,
`vulcanized for 10 minutes, and the whole body of the rubber stopper was laminated with PTFE or ETFE film to prepare
`a sealing stopper with a cross-sectional shape as shown in Fig. 3 (a). The size of the sealing stopper was allowed to
`correspond to that of an injection cylinder used in each test described hereinafter.
`
`Measurement of Sliding Resistance Value
`
`Injection cylinders each having a volume of 5 ml and 100 ml, made of plastic (polypropylene), and sealing stoppers
`having sizes shown in Table 5, corresponding to these injection cylinders were prepared and each of the sealing stop(cid:173)
`pers was th rusted and set into the injection cylinder. The sealing stopper was slowly 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, a commercially available disposable injection needle having a determined size was firmly 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 th rusted into the end side at
`a rate of 100 mm/sec by a compression test disk of spherical seat type of a pressure senser-fitted measurement device
`[Autograph AG-1 KND -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 at the start of sliding, i.e. static friction
`resistance value Ffs was smaller than a value during sliding (kinematic frictionresistance value) Ffd. The results are
`shown in Table 5, from which it is evident that in Comparative Example 3 in which FTFE was laminated, the slidability
`is too low to measure the sliding resistance value and it is difficult to set in the injection cylinder.
`
`Injection Cylinder
`Volume (ml)
`
`Diameter of Sealing
`Stopper (mm)
`
`5
`100
`(Note):* Newton (1 N = 9.8 kg)
`
`12.89
`32.58
`
`Table 5
`
`Example 1
`
`Comparative
`Example 2
`
`3
`
`PTFE Coated
`Sealing Stopper by
`Casting Method
`
`PTFE Coated
`Sealing Stopper by
`Skiving Method
`
`ETFE Coated Seal-
`Stopper by
`Extrusion Method
`
`21.1 N*
`68.8 N
`
`20.4 N
`59.3 N
`
`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 was carried out.
`A plastic injection cylinder (volume 5 ml) having a cross-sectional shape shown in Fig. 1 (c) was washed and dried,
`followed 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 th rusted 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
`taken and the surface thereof was dried for 30 minutes in a desiccator, followed by precisely weighing each sample
`(at least five measurement points). The resulting data of weight change was treated in statistical manner to calculate
`as a regression function and a numerical value corresponding to three years is extrapolated in the time term to estimate
`
`11
`
`Regeneron Exhibit 1002.1141
`
`

`

`EP O 879 611 A2
`
`and assess the sealing property for a long time after formulation of a medicament. In order to correspond to the real
`formulation, seventy samples were respectively 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 lnX, obtained by the above described statistical
`procedure can be represented in Example 1, as follows:
`When fitting a plunger:
`
`When not fitting a plunger:
`
`Y = -1.896 + 1.087 X lnX
`
`Y = -4.200 + 1.594 x lnX
`
`(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 (b) are
`6.31 mg and 0.12 % in two years and 6.96 mg and 0.13 % in three years.
`The similar procedure to that of Example 1 was also carried out as to Comparative Example 1 (D-2) and Compar(cid:173)
`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 shown in 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 laminated is inferior in slidability between the film and inner wall of the injection
`cylinder because of much higher sliding resistance so that 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.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`12
`
`Regeneron Exhibit 1002.1142
`
`

`

`"' "'
`
`"' 0
`
`-IS. "'
`
`-IS.
`0
`
`V)
`
`"'
`
`V)
`0
`
`"' "'
`
`"' 0
`
`;;;
`
`0
`
`"'
`
`Table 6
`
`Example
`
`Laminated Resin
`(Reference Example)
`Production Process
`
`Plunger
`
`Reduction Curve
`(Regression Function)
`Y = - a + K • lnX
`
`Reduction and
`Reduction Ratio
`After 2 Years
`
`Reduct ion und
`Reduction Ratio
`After 3 Years
`
`.....
`c.>
`
`Example 1
`
`PTFE (D-1)
`: Casting Method
`
`Comparative
`Example 1
`
`PTF'E (D-2)
`: Skiving Method
`
`Comparative
`Example 2
`
`ETFE (D-3)
`Extrusion Method
`
`yes
`no
`
`yes
`no
`
`yes
`no
`
`Y = -1.896 + 1.087 lnX
`Y = -4.200 + 1.594 lnX
`
`5. 27 mg o. 11 %
`6.31 mg o. 12 %
`
`5.71 mg 0.11 X
`6.96 ~ 0. l3 X
`
`Y = -6.357 + 3.518 lnX
`Y = -6.676 + 3.617 lnX
`
`16.84 mg 0.32 %
`17.17 mg 0.32 %
`
`17.79 mg 0.34 %
`18.64 mg 0.35 X
`
`Y = -7.379 + 2.683 lnX
`Y = -7.214 + 2.658 lnX
`
`10.31 mg o. 19 %
`10.31 mg o. 19 %
`
`11.40 mg 0.22 %
`11.39 mg 0.21 X
`
`m ,,
`0
`CX>
`.....
`CD
`...
`a,
`......
`)>
`I\)
`
`:::a
`CD
`(C
`CD
`::l
`CD .,
`0
`::l
`m
`><
`::l"
`C"
`;::::;
`
`~
`0
`0
`I\)
`
`~
`
`~ .,:.
`w
`
`

`

`Example 2
`
`EP O 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 samples of 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 head of the cylinder,
`the rubber cap was taken off at the lure part. A plastic plunger was screwed in 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 on a
`measurement device for pressure test. After a pressure defined for medical treatment as shown in 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 TestG). 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 teaches that even a sealing stopper having a larger compressibility (higher
`sealing property) has a higher sliding property.
`When a further larger pressure was added to investigate presence or absence of leakage in addition to the above
`described defined Compressing Test (Compressing Test<:2), there was found no leakage as shown in Table 8.
`
`Application
`
`Volume for Injection Cylinder
`
`Table 7
`
`General Medical
`Treatment
`
`Very Small Amount
`
`Insulin
`
`less than 3 ml
`at least 3 ml less than 10 ml
`at least 1 0 ml less than 20 ml
`at least 20 ml less than 30 ml
`at least 30 ml
`less than 2 ml
`at least 2 ml
`long
`short
`
`Pressure (10 sec.)
`4.0 kg/cm2
`3.5 kg/cm2
`3.0 kg/cm2
`2.5 kg/cm2
`2.0 kg/cm2
`5.0 kg/cm2
`4.0 kg/cm2
`5.0 kg/cm2
`4.0 kg/cm2
`
`s
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`14
`
`Regeneron Exhibit 1002.1144
`
`

`

`"' "'
`
`"' 0
`
`-IS. "'
`
`-IS.
`0
`
`V)
`
`"'
`
`V)
`0
`
`"' "'
`
`"' 0
`
`;;;
`
`0
`
`"'
`
`Injection
`Cylinder
`
`Volume (11111)
`
`Injection
`Cylinder
`Inner
`Diameter(mt)
`
`Sea I i ng Stopper
`
`Outer Diameter
`(Rill)
`
`1
`
`3
`5
`
`10
`20
`50
`100
`
`6.8
`8.7
`12.4
`15.0
`20.0
`29.5
`32.2
`
`7. 1
`9. 1
`12.9
`15.5
`21. 0
`30.2
`32.9
`
`Table 8
`
`Compressibilty
`
`SI iding
`Resistance
`
`(%)
`
`4.8
`4.5
`3.8
`3.3
`2. 1
`2.4
`1. 2
`
`(N)
`
`11. 4
`20.7
`21. 1
`16.3
`13.5
`11. 9
`68.1
`
`Compressing Test CD
`Test
`Pressure
`Reselts
`) (Obervation)
`
`(kg/cm2
`
`Compressing Tesl ®
`Test
`Pressure
`Reselts
`) (Obervation)
`
`(kg/cm2
`
`4.0
`3.5
`3.5
`3.0
`2.5
`2.0
`2.0
`
`no leakage
`no leakage
`no leakage
`no leakage
`no Leakage
`no Leakage
`no Leakage
`
`6.9
`5.9
`3. 7
`3.5
`3.5
`2.6
`2.5
`
`no leakage
`no leakage
`no leakage
`no leakage
`no leakage
`no leakage
`no leakage
`
`m ,,
`
`0
`CX>
`......
`CD
`a,
`......
`)>
`I\)
`
`...
`
`[note] Compressibility= [(Stopper Outer Diameter - Cylinder Inner Diameter)/Stopper Outer Diameter)xlOO %
`
`.....
`
`(11
`
`:::a
`CD
`(C
`CD
`::l
`CD .,
`0
`::l
`m
`><
`::l"
`C"
`;::::;
`
`~
`0
`0
`I\)
`
`~
`~
`
`.,:.
`(11
`
`

`

`EP O 879 611 A2
`
`Test for Liquid Sealing Property
`
`(b) Accelerated Conditions
`
`5
`
`Plastic injection cylinders having various volumes ten by ten and sealing stoppers having sizes corresponding
`thereto and end caps ten 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
`10 %, 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 was carried 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.
`
`15
`
`Test for Liquid Sealing Property
`
`(c) Severer Conditions
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`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 shown in 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 shown in 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(cid:173)
`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 of the injection cylinder is V, the moisture permeability can be given by the following formula.
`Tho results arc shown in Table 9.
`
`Moisture Permeability= (100/14 V)[(Tf - Ti) - (Cf - Ci)]
`
`Injection Cylinder Volume
`(ml)
`
`Liquid Sealing Property
`Test1) Results
`
`Liquid Sealing Property
`Test2) Results
`
`Gas Sealing Property
`Test3) Results (mg/day· I)
`
`Table 9
`
`no leakage of MB4)
`1
`no leakage of MB
`3
`no leakage of MB
`5
`no leakage of MB
`10
`no leakage of MB
`20
`..
`(Note) 1) accelerating cond1t1on: 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
`
`-1
`-1
`2
`22
`25
`
`16
`
`Regeneron Exhibit 1002.1146
`
`

`

`EP O 879 611 A2
`
`Table 9
`
`(continued)
`
`5
`
`10
`
`15
`
`20
`
`25
`
`Liquid Sealing Property
`Injection Cylinder Volume
`Test1) Results
`(ml)
`no leakage of MB
`50
`no leakage of MB
`100
`..
`(Note) 1) accelerating cond11lon: 40 °C. 75 % RH. 6 months
`2) severer condition: 121 °C, 1 hour
`3) moisture permeability test: 20°C, 75 % RH, 14 days
`
`Liquid Sealing Property
`Test2) Results
`no leakage of MB
`no leakage of MB
`
`Gas Sealing Property
`Test3) Results (mg/day· I)
`30
`2.8
`
`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.
`
`Advantages of the Invention
`
`As illustrated 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 medicament can be carried out in easy and rapid manner because of 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 ~Lm and a kinematic friction coefficient of at most 0.2.
`
`35
`
`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 containing tetrafluoroethylene resin
`powder having a grain diameter of at most 0.01 to 1.0 µm, a dispersing agent and a solvent.
`
`40
`
`3. The sealing stopper for a syringe, as claimed in Claim 1, wherein the ultra-high molecular weight polyethylene film
`is prepared by an inflation shaping method or extrusion shaping method.
`
`45
`
`50
`
`4. A prefilled syringe, in which a medicament is enclosed and sealed in an injection cylinder or two-component cylinder
`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 µm and a kinematic friction coefficient of at most 0.2.
`
`5. A process for the production of a sealing stopper for a syringe, which comprises preparing a suspension of poly(cid:173)
`tetrafluoroethylene fine grains having a maximum grain diameter in a range of 0.01 to 1.0 µm 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
`form a thin film, repeating this procedure to obtain a sintered cast film with a suitable thickness and then laminating
`a rubber body with the cast film.
`
`55
`
`6. The process for the production of a sealing stopper for a syringe, as claimed in Claim 5, wherein the thin film has
`a thickness of 5 to 20 µm and the sintered cast film has a thickness of 10 to 60 µm.
`
`17
`
`Regeneron Exhibit 1002.1147
`
`

`

`EP O 879 611 A2
`
`5 INJECTION
`CYLINDER
`
`7 INJECTION
`AGENT
`5
`
`<
`
`INNER DIAMETER
`
`( b)
`
`4
`
`(cl
`
`OUTER DIAMETER
`
`t ( j /
`
`1 SEALING STOPPER
`
`3 RESIN FILM
`2 RUBBER STOPPER BODY
`
`4
`
`(a )
`
`FIG. I
`
`18
`
`Regeneron Exhibit 1002.1148
`
`

`

`y
`
`E
`E
`LLJ
`:::J
`..J
`~
`LL.
`LL.
`~
`:::J u
`
`EP O 879 611 A2
`
`0-1
`CASTING METHOD )
`PTFE FILM
`
`(
`
`0-2
`SKIVING METHOD)
`PTFE FILM
`
`(
`
`MEASURED LENGTH(mml
`
`X
`
`FIG. 2
`
`19
`
`Regeneron Exhibit 1002.1149
`
`

`

`EP O 879 611 A2
`
`j 1 SEALING STOPPER
`
`3 RESIN FILM
`
`3
`
`2
`4
`
`2
`
`4
`
`2
`
`4
`
`( b)
`
`3
`
`( d)
`
`3
`
`( f )
`
`3
`
`( h)
`
`2 RUBBER
`STOPPER
`BODY
`
`4 PLUNGER
`FITTING
`PART
`
`2
`
`4
`
`2
`
`4
`
`2
`4
`
`(a)
`
`3
`
`( C)
`
`3
`
`(e)
`
`( g)
`
`FIG. 3
`
`20
`
`Regeneron Exhibit 1002.1150
`
`

`

`PATENT ABSTRACTS OF JAPAN
`
`2002-241264
`(11)Publication number:
`(43)Date of publication of application : 28.08.2002
`
`(51 )Int.Cl.
`
`A61K 9/08
`A61K 38/23
`A61P 3/14
`A61P 19/08
`A61P 19/10
`// A61M 5/28
`
`(21 )Application number : 2001-042590
`19.02.2001
`(22)Date of filing :
`
`(71)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 is 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 ::;;o.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 Acknowledgement Receipt
`
`EFSID:
`
`Application Number:
`
`17242821
`
`13750352
`
`International Application Number:
`
`Confirmation Number:
`
`5306
`
`Title of Invention:
`
`SYRINGE
`
`First Named Inventor/Applicant Name:
`
`Juergen Sigg
`
`Customer Number:
`
`1095
`
`Filer:
`
`James L Lynch/Denise Cooper
`
`Filer Authorized By:
`
`James L Lynch
`
`Attorney Docket Number:
`
`PAT055157-US-NP
`
`Receipt Date:
`
`Filing Date:
`
`Time Stamp:
`
`28-0CT-2013
`
`25-JAN-2013
`
`15:04:49
`
`Application Type:
`
`Utility under 35 USC 111 (a)
`
`Payment information:
`
`Submitted with Payment
`
`I no
`
`File Listing:
`
`Document
`Number
`
`Document Description
`
`File Name
`
`1
`
`Information Disclosure Statement (IDS)
`Form (SB08)
`
`Warnings:
`
`Information:
`
`File Size(Bytes)/
`Message Digest
`
`Multi
`Part /.zip
`
`Pages
`(if appl.)
`
`1730783
`
`PAT055157-US-NP-IDS.pdf
`
`no
`
`3
`
`57d366ea02e39a359a3fdca211 020b7 e578
`b272d
`
`Regeneron Exhibit 1002.1152
`
`

`

`This is not an USPTO supplied IDS fillable form
`
`2
`
`Foreign Reference
`
`EP0264273A2.pdf
`
`no
`
`13
`
`616316
`
`Warnings:
`
`Information:
`
`476f4646f8d6bc1 b2b94db68bd 123bb4e2
`47598
`
`1043361
`
`3
`
`Foreign Reference
`
`EP0879611 A2.pdf
`
`no
`
`20
`
`Warnings:
`
`Information:
`
`15b9f1841 ad264fda02238fb642d3b63d38
`7ce3d
`
`306347
`
`4
`
`Foreign Reference
`
`JP2002241264_Abs.pdf
`
`no
`
`1
`
`ae5486bd 2223ef9b5 c6aee 1 bd 9fe4 fbe085 c
`3d50
`
`Warnings:
`
`Information:
`
`Total Files Size (in bytes)
`
`3696807
`
`This Acknowledgement Receipt evidences receipt on the noted date by the USPTO of the 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 A~~lications Under 35 U.S.C. 111
`If a new application is being filed and the application includes the necessary components for a 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 shown on this
`Acknowledgement Receipt will establish the filing date of the application.
`
`National Stage of an International A~~lication 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/E0/903 indicating acceptance of 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.
`
`New International A~~lication 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 181 O), a Notification of the International Application Number
`and of the International Filing Date (Form PCT/R0/1 OS) will be issued in due course, subject to prescriptions concerning
`national security, and the date shown on this Acknowledgement Receipt will establish the international filing date of
`the application.
`
`Regeneron Exhibit 1002.1153
`
`

`

`Europiilsches
`Patentamt
`European
`Patent Office
`Offlr;e europ~en
`des brevets
`
`Bescheinigung
`
`Certificate
`
`Attestation
`
`Die angehefteten
`Unterlagen stimmen mit der
`als ursprunglich eingereicht
`geltenden Fassung der auf
`dem nachsten Blatt
`bezeichneten europaischen
`Patentanmeldung uberein.
`
`The attached documents are
`exact copies of the text in
`which the European patent
`application described on the
`following page is deemed to
`have been filed.
`
`Les documents joints a la
`presente attestation sont
`conformes au texte,
`considers comme
`initialement depose, de la
`demande de brevet
`europeen qui est specifiee a
`la page suivante.
`
`Patentanmeldung Nr.
`
`Patent application No.
`
`Demande de brevet n°
`
`12189649.2 / EP12189649
`
`The organization code and number of your priority application, to be used for filing abroad under the Paris
`Convention, is EP12189649.
`
`EPA/EPO/OEB Form 1014
`
`05.12
`
`Der Priisident des Europiiischen Patentamts;
`Im Auftrag
`
`For the President of the European Patent Office
`
`Le President de l'Office europeen des brevets
`p.o.
`
`U. lngmann
`
`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 of filing:
`Date de depot:
`
`23.10.12
`
`Bezeichnung der Erfindung / Title of the invention / Titre de !'invention:
`(Falls die Bezeichnung der Erfindung nicht angegeben isl, oder falls die Anmeldung in einer Nicht-Amtssprache des EPA eingereicht
`wurde, siehe Beschreibung bezuglich ursprunglicher Bezeichnung.
`If no title is shown, or if the application has been filed in a non-EPO language, please refer to the description for the original title.
`Si aucun titre n'est indique, ou si la demande a ete deposee dans une langue autre qu'une langue officielle de l'OEB, se referer a la
`description pour le titre original.)
`
`Syringe
`
`In Anspruch genommene Prioritat(en) / Priority(Priorities) claimed/ Priorite(s) revendiquee(s)
`Staat/Tag/Aktenzeichen / State/Date/File no. I Pays/Date/Numero de depot:
`
`Am Anmeldetag benannte Vertragstaaten / Contracting States designated at date of filing/ Etats contractants designees lors
`du depot:
`
`AL AT BE BG CH CY CZ DE DK EE ES Fl FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL
`PT RO RS SE SI SK SM TR
`
`EPA/EPO/OEB Form 1014
`
`05.12
`
`2
`
`Regeneron Exhibit 1002.1155
`
`

`

`PA T055157-EP-EPA
`
`TECHNICAL FIELD
`
`SYRINGE
`
`The present invention relates to a syrmge, particularly to a small volume syrmge such as a
`
`syringe suitable for ophthalmic injections.
`
`5
`
`BACKGROUND ART
`
`Many medicaments are delivered to a patient in a syringe from which the user can dispense the
`
`medicament. If medicament is delivered to a patient in a syringe it is often to enable the patient,
`
`or a caregiver, to inject the medicament.
`
`It is important for patient safety and medicament
`
`integrity that the syringe and the 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 which it is intended
`
`that about 0.1ml or less of liquid is to be injected the sterilisation can pose difficulties that arc
`
`15
`
`not necessarily associated with larger syringes. Changes in pressure, internal or external to the
`
`syringe, can cause parts of the syringe to move unpredictably, which may alter sealing
`
`characteristics and potentially compromise sterility. Incorrect handling of the syringe can also
`
`pose risks to product sterility.
`
`Furthermore, certain therapeutics such as biologic molecules are particularly sensitive to
`
`20
`
`sterilisation, be it cold gas sterilisation, thermal sterilisation, or irradiation. Thus, a careful
`
`balancing act is required to ensure that while a suitable level of sterilisation is carried out, the
`
`syringe remains suitably sealed, such that the therapeutic is not compromised.
`
`There is therefore a need for a new syringe construct which provides a robust seal for its content,
`
`but which maintains ease of use.
`
`25 DISCLOSURE OF THE INVENTION
`
`The present invention provides a pre-filled syringe, the syringe comprising a body, a stopper and
`
`a plunger, the body comprising an outlet at an outlet end and the stopper being arranged within
`
`the body such that a front surface of the stopper and the body define a variable volume chamber
`
`from which a fluid can be expelled though the outlet, the plunger comprising a plunger contact
`
`30
`
`surface at a first end and a rod extending between the plunger contact surface and a rear portion,
`
`-1-
`
`Regeneron Exhibit 1002.1156
`
`

`

`PA T055157-EP-EPA
`
`the plunger contact surface arranged to contact the stopper, such that the plunger can be used to
`
`force the stopper towards the outlet end of the body, reducing the volume of the variable volume
`
`chamber, characterised in that the fluid comprises an ophthalmic solution. In one embodiment,
`
`the ophthalmic solution comprises a VEGF-antagonist.
`
`5
`
`In one embodiment, the syringe is suitable for ophthalmic injections, more particularly
`
`intravitreal injections, and as such has a suitably small volume. The syringe may also be silicone
`
`oil free, or substantially silicone oil free, or may comprise a low level of silicone oil as lubricant.
`
`For ophthalmic injections, it is particularly important for the ophthalmic solution to have
`
`particularly low particle content. In one embodiment, the syringe meets US Pharmacopeia
`
`10
`
`standard 789 (USP789).
`
`Syringe
`
`The body of the syringe may be a substantially cylindrical shell, or may include a substantially
`
`cylindrical bore with a non circular outer shape. The outlet end of the body includes an outlet
`
`through which a fluid housed within the variable volume chamber can be expelled as the volume
`
`15
`
`of said chamber is reduced. The outlet may comprise a projection from the outlet end through
`
`which extends a channel having a smaller diameter than that of the variable volume chamber.
`
`The outlet may be adapted, for example via a lucr lock type connection, for connection to a
`
`needle or other accessory such as a sealing device which is able to seal the variable vo