US 12,048,837 B2Grant

Syringe

Issue Date:2024-07-30

•19 Claims

•3 Drawing Sheets

Abstract

The invention provides a syringe for use in an ophthalmic injection. The syringe comprises a body, a stopper and a plunger. The body comprises an outlet at an outlet end and the stopper is 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 comprises a plunger contact surface at a first end and a rod extends between the plunger contact surface and a rear portion. The plunger contact surface is arranged to contact the stopper but not couple thereto, 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, but not to move the stopper away from the outlet end.

Metadata

Assignee

NOVARTIS AG

Inventors

Andrew Bryant
Heinrich Buettgen
Wolfgang Papst
Marie Picci

Application Information

Application Number:US 18/063,918

Filing Date:2022-12-09

Priority Date:2012-06-01

Art Unit:3783

Classifications

IPC:

A61M5/00A61M5/28A61M5/315A61P27/02A61F9/00A61M5/31

Field of Search:

A61M 5/31511A61M 5/31513A61M 2005/31508A61M 2005/31516A61M 5/31515A61M 5/315A61M 5/5013A61M 5/502

Patent Drawings (3 sheets)

Description

Cross Reference to Related Applications

[0001] This application claims priority to and is a continuation of U.S. application Ser. No. 17/500,174, filed Oct. 13, 2021, which claims priority to and is a continuation of U.S. application Ser. No. 17/335,684, filed Jun. 1, 2021, which claims priority to U.S. application Ser. No. 16/409,291, filed May 10, 2019, which claims priority to and is a continuation of U.S. application Ser. No. 14/403,801, filed Nov. 25, 2014, which is a national stage entry of PCT/EP2013/061215, filed May 30, 2013, which claims priority to EP Appl. No. 12170628.7, filed Jun. 1, 2012. All of the above are hereby incorporated into this application by reference in their entirety.

[0002] The present invention relates to a syringe, particularly to a small volume syringe such as a syringe suitable for ophthalmic injections. The invention also extends to a method of assembling such a syringe.

[0003] 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 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.

[0004] For small volume syringes, for example those for injections into the eye in which it is intended that less than about 0.1 ml of liquid is to be injected, the sterilisation can pose difficulties that are 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, including assembly, of the syringe can also pose risks to product sterility.

[0005] The present invention provides a 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 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 but not couple thereto, 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, but not to move the stopper away from the outlet end.

[0006] Providing a plunger which does not couple to the stopper reduces the chances for incorrect handling of the syringe as the plunger can be withdrawn from the syringe without movement of the stopper away from the outlet end. This prevents a user from accidentally moving the plunger (and therefore a stopper connected thereto) and causing non-sterile air (or other fluid) to be drawn into the syringe, or causing movement of the stopper to a non-sterile area. It has also been found that creating a connection between a plunger to a stopper during assembly, using for example a screwing action or a push-fit action, can distort the stopper in an unpredictable manner which may compromise the sealing and/or sterility of the final product, or may increase pressure in the variable volume chamber which could cause fluid leakage from the outlet end.

[0007] 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 of said chamber is reduced. The outlet may comprise a projection from the outlet end through which extends a channel having a smaller diameter than that of the variable volume chamber. The outlet may be adapted, for example via a luer lock type connection, for connection to a needle or other accessory such as a sealing device which is able to seal the variable volume chamber, but can be operated, or removed, to unseal the variable chamber and allow 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.

[0008] The body may be made from a plastic material or from glass, or from any other suitable material and may include indicia on a surface thereof to act as an injection guide.

[0009] The stopper may be made from rubber, silicone or other suitable resiliently deformable material. The stopper provides a sealing function by defining the rear of the variable volume chamber with a fluid tight seal which also provides a sterility seal. 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 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, or substantially conical.

[0010] The stopper may be substantially solid or may include recesses. The rear surface of the stopper may include a substantially central recess which may be any shape provided the sealing function of the stopper is not compromised. Said central recess may be substantially cylindrical in shape or said central recess may include an initial bore having a first diameter, the initial bore leading from the rear surface into the stopper to an inner recess having a second diameter, the second diameter being larger than the first diameter. Such a central recess could be used to connect a plunger to the stopper using a snap fit feature in a known manner. Such a design allows a substantially standard stopper design to be used and this can reduce the parts cost for the syringe. Also, it is noted that removing material from the central portion of the stopper, where it is not needed for the stopper to function as required, reduces the stopper weight and reduces the amount of material needed to manufacture the stopper. The stopper may be substantially rotationally symmetric about an axis through the stopper.

[0011] 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 comprise a substantially disc shaped portion, the radius of the disc extending substantially perpendicular to the axis along which the rod extends. The user contact portion could be any suitable shape. The axis along which the rod extends may be the first axis, or may be substantially parallel with the first axis.

[0012] The plunger contact surface is adapted to make contact with the rear surface of the stopper, but not couple thereto. The plunger contact surface may be substantially planar and may be substantially circular in shape. The plunger contact surface may be substantially circular with an outer diameter less than the internal diameter of the body. The diameter of the plunger contact surface may be substantially equal to the diameter of the rear surface of the stopper with which it is to make contact. The plunger contact surface may be adapted to present a substantially rotationally symmetrical surface to the rear surface of the stopper as this assists in providing a repeatable and evenly distributed force to the stopper during use which can help to prevent distortions. The plunger contact surface may not be planar and may comprise an annular contact surface to contact the stopper at or adjacent an out edge thereof. The plunger contact surface may comprise a plurality of arms which extend from the plunger rod to make contact with the stopper. The plunger contact surface may be substantially rotationally symmetrical in any of the above, or other, embodiments.

[0013] The rod may have a round or cross-form cross-section. A cross-form cross section may be formed from ribs extending along at least part of the rod. The ribs may extend substantially parallel with the axis along which the rod extends. The cross-form cross section provides rigidity to the rod without significantly increasing manufacturing complexity.

[0014] The rod may be manufactured from any suitable material, or combination of materials, and in one embodiment is made from a plastic material. The rod may be substantially rigid under expected use conditions. Although some flexing of the materials in the plunger is unavoidable in a bulk manufactured product, it is advantageous that the rod cannot flex significantly during use, particularly for low volume, accurate, injections as any flexing could lead to unpredictable dosing results.

[0015] The syringe may include a backstop arranged at a rear portion of the body. The backstop may be removable from the syringe. If the syringe body includes terminal flanges at the end opposite the outlet end the backstop may be configured to substantially sandwich terminal flanges of the body as this prevent movement of the backstop in a direction parallel to the first axis.

[0016] The rod may comprise at least one rod shoulder directed away from the outlet end and the backstop may include a backstop shoulder directed towards the outlet end to cooperate with the rod shoulder to substantially prevent movement of the rod away from the outlet end when the backstop shoulder and rod shoulder are in contact. Restriction of the movement of the rod away from the outlet end can help to maintain sterility during terminal sterilisation operations, or other operations in which the pressure within the variable volume chamber or outside the chamber may change. During such operations any gas trapped within the variable volume chamber, or bubbles that may form in a liquid therein, may change in volume and thereby cause the stopper to move. Movement of the stopper away from the outlet could result in the breaching of a sterility zone created by the stopper. This is particularly important for low volume syringes where there are much lower tolerances in the component sizes and less flexibility in the stopper. The term sterility zone as used herein is used to refer to the area within the syringe that is sealed by the stopper from access from either end of the syringe. This may be the area between a seal of the stopper, for example a circumferential ridge, closest to the outlet and a seal of the stopper, for example a circumferential ridge, furthest from the outlet. The distance between these two seals defines the sterility zone of the stopper since the stopper is installed into the syringe barrel in a sterile environment.

[0017] As noted above, a terminal sterilisation process may be used to sterilise the complete article and such a process may use a known process such as an Ethylene Oxide or a Hydrogen Peroxide sterilisation process.

[0018] The inclusion of one or more circumferential ribs on the stopper can alter the force required to cause the stopper to move from a stationary position and can also alter the sealing properties of the stopper. To further assist in maintaining sterility during the operations noted above the stopper may comprise at least a front circumferential rib and a rear circumferential rib and those ribs may be separated in a direction along the first axis by at least 3 mm, by at least 3.5 mm, by at least 3.75 mm or by 4 mm or more. One or more additional ribs (for example 2, 3, 4 or 5 additional ribs, or between 1-10, 2-8, 3-6 or 4-5 additional ribs) may be arranged between the front and rear ribs. In one embodiment there are a total of three circumferential ribs.

[0019] A stopper with such an enhanced sterility zone can also provide protection for the injectable medicament during a terminal sterilisation process. Some medicaments, example a biological medicament, could be damaged by exposure to Ethylene Oxide. More ribs on the stopper, or a greater distance between the front and rear ribs, can reduce the potential exposure of the medicament to the sterilising agent.

[0020] The rod shoulder may be arranged within the external diameter of the rod, or may be arranged outside the external diameter of the rod. By providing a shoulder that extends beyond the external diameter of the rod, but still fits within the body, the shoulder can help to stabilise the movement of the rod within the body by reducing movement of the rod perpendicular to the first axis. The rod shoulder may comprise any suitable shoulder forming elements on the rod, but in one embodiment the rod shoulder comprises a substantially disc shaped portion on the rod.

[0021] In one embodiment of the syringe, when arranged with the plunger contact surface in contact with the stopper and the variable volume chamber is at its intended maximum volume there is a clearance of no more than about 2 mm between the rod shoulder and backstop shoulder. In some embodiments there is a clearance of less than about 1.5 mm and in some less than about 1 mm. This distance is selected to substantially limit or prevent excessive rearward (away from the outlet end) movement of the stopper.

[0022] In one embodiment the variable volume chamber has an internal diameter greater than 5 mm or 6 mm and less than 3 mm or 4 mm. The internal diameter may be between 3 mm and 6 mm, or between 4 mm and 5 mm. In another embodiment the syringe is dimensioned so as to have a nominal maximum fill volume of volume of between about 0.25 ml and 0.75 ml, or between 0.4 ml and 0.6 ml. The length of the body of the syringe may be less than 70 mm, less than 60 mm or less than 50 mm. In one embodiment the length of the syringe body is between 45 mm and 50 mm, the internal diameter is between 4 mm and 5 mm and the fill volume is between 0.1 ml and 0.3 ml of liquid.

[0023] In one embodiment, the syringe is suitable for ophthalmic injections, and as such has a suitably small volume. The syringe may be adapted for ophthalmic injections. The syringe may also be silicone free, or substantially silicone free, or may comprise a low level of silicone as lubricant. In one embodiment, the syringe may meet USP789.

[0024] The variable volume chamber of the syringe may be filled with any suitable injectable liquid or medication, for example an injectable medicament. In one embodiment the variable volume chamber is filled with an injectable medicament comprising an active suitable for the treatment of an ocular disease. Examples of such ocular diseases include choroidal neovascularisation, age-related macular degeneration (both wet and dry forms), macular edema secondary to retinal vein occlusion (RVO) including both branch RVO (bRVO) and central RVO (cRVO), choroidal neovascularisation secondary to pathologic myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and proliferative retinopathy. In one embodiment, the medicament comprises a biologic active. The biologic active may be an antibody (or fragment thereof) or a non-antibody protein. In one embodiment the medicament comprises a VEGF antagonist. Suitable VEGF antagonists include ranibizumab (Lucentis™, bevacizumab (Avastin™), aflibercept (Eylea™, also known as VEGF-Trap Eye), conbercept (KH902 from Chengdu Kanghong Biotechnologies Co. Ltd, described as FP3 in WO2005/121176, the contents of which are hereby incorporated by reference) and the related glycoform KH906 or pazopanib (from GlaxoSmithKline).

[0025] In one embodiment, the syringe is filled with between about 0.01 ml and about 2 ml (for example between about 0.05 ml and about 1 ml, between about 0.1 ml and about 0.5 ml) of an injectable medicament. Of course, typically a syringe is filled with more than the desired dose to be administered to the patient, to take into account wastage due to “dead space” within the syringe and needle. Thus, in one embodiment, the syringe is filled with a dosage volume (i.e. the volume of medicament intended for delivery to the patent) of between about 0.01 ml and about 2 ml (e.g. between about 0.05 ml and about 1 ml, between about 0.1 ml and about 0.5 ml) of an injectable medicament. For example, for Lucentis, the dosage volume is 0.05 ml or 0.03 ml (0.5 mg or 0.3 mg) of a 10 mg/ml injectable medicament solution; for Eylea, the dosage volume is 0.05 ml of a 40 mg/ml injectable medicament solution.

[0026] As noted above, when the syringe contains a medicament solution the outlet may be reversibly sealed to maintain sterility of the medicament. This sealing may be achieved through the use of a sealing device as is known in the art. For example the OVS™ system which is available from Vetter Pharma International GmbH. The sealing of the outlet should be such that that sterility of the contents of the variable volume chamber can be maintained until such time as the stopper is moved to breach the sterility seal or the outlet is unsealed.

[0027] By providing a plunger that does not couple with the stopper a new method of assembly is made possible and so the invention further provides a method of assembling a syringe, the method comprising the steps of:

- [0028] i) providing a body and a stopper, 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 outlet being releasably sealed and the variable volume chamber containing a medicament; and
- [0029] ii) providing a plunger comprising a plunger contact surface at a first end and a rod extending between the plunger contact surface and a rear portion and arranging the plunger contact surface and at least part of the plunger within the body without coupling the plunger to the stopper.

[0030] The method may further comprise an additional step, step iii), of filling the variable volume chamber of the syringe, which may be filled with any suitable injectable medicament. In one embodiment the variable volume chamber is filled with an injectable medicament suitable for the treatment of an ocular disease. Examples of such ocular diseases include choroidal neovascularisation, age-related macular degeneration (both wet and dry forms), macular edema secondary to retinal vein occlusion (RVO) including both branch RVO (bRVO) and central RVO (cRVO), choroidal neovascularisation secondary to pathologic myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and proliferative retinopathy. In one embodiment, the medicament comprises a biologic active. The biologic active may be an antibody (or fragment thereof) or a non-antibody protein. In one embodiment the medicament comprises a VEGF antagonist. Suitable VEGF antagonists include ranibizumab (Lucentis™), bevacizumab (Avastin™), aflibercept (Eylea™, also known as VEGF-Trap Eye), conbercept (KH902 from Chengdu Kanghong Biotechnologies Co. Ltd, described as FP3 in WO2005/121176, the contents of which are hereby incorporated by reference) and the related glycoform KH906 or pazopanib (from GlaxoSmithKline).

[0031] It should be noted that steps ii) and iii) above may be carried out in either order. Thus the method may comprise, in sequence, steps i), ii), iii) or steps i), iii), ii) or steps iii), i), ii).

[0032] The method may further comprise a step iv) of packaging the assembled syringe in a substantially sealed package. The method may further comprise a terminal sterilisation step, step v), following packaging. The terminal sterilisation step may comprise known techniques such as Ethylene Oxide sterilisation of Hydrogen Peroxide sterilisation.

[0033] The invention also extends to a sealed package containing a sterile pre-filled syringe substantially as described herein.

[0034] If the rod comprises a rod shoulder as described above and the syringe includes a removable backstop as described the backstop may be coupled to the syringe body after the plunger has been arranged in the body and the rod shoulder is arranged between the outlet end and the backstop shoulder. By ensuring that the rod shoulder is arranged between the outlet end and the backstop shoulder when the backstop is coupled to the device a complex mechanism for enabling the movement of the rod shoulder past the backstop shoulder after coupling the backstop to the syringe is avoided.

[0035] In one embodiment step i) and iii) are carried out in a sterile, or substantially sterile, environment. At some point between the filling step and the final assembly being sealed into packaging the syringe is removed from the sterile, or substantially sterile, environment. A terminal sterilisation step can then be conducted on the packaged product.

[0036] In one embodiment of the method the plunger rod is dropped into the syringe body. This is a simple operation and makes use of gravity rather than any automated assembly equipment. This is made possible because the rod does not need to be manipulated or forced to couple with the stopper.

[0037] The invention also provides a plunger suitable for use in the syringe or method described above.

[0038] It should be understood that throughout this specification and in the claims that follow, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, implies the inclusion of the stated integer or step, or group of integers or steps. The term “comprising” encompasses “including” as well as “consisting” e.g. a composition “comprising” X may consist exclusively of X or may include something additional e.g. X+Y. It should also be understood that, unless not physically possible, features described in connection with one embodiment can be used alone, or in combination with one or more features described in connection with the same embodiment or one or more other embodiments. The term “about” in relation to a numerical value x is optional and means, for example, x+/−10%.

[0039] The invention will now be further described, by way of example only, with reference to the following drawings in which:

[0040] FIG. 1 shows a side view of a syringe;

[0041] FIG. 2 shows a cross section of a top down view of a syringe;

[0042] FIG. 3 shows a view of a plunger;

[0043] FIG. 4 shows a cross section though a plunger;

[0044] FIG. 5 shows a stopper; and

[0045] FIG. 6 shows a flowchart of the assembly process.

[0046] FIG. 1 shows a view from a side of a syringe 1 comprising a body 2, plunger 4, backstop 6 and a sealing device 8.

[0047] FIG. 2 shows a cross section through the syringe 1 of FIG. 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 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 but not couple thereto, such that the plunger 4 can be used to move the stopper 10 towards the outlet end 14 of the body 2. Such movement reduces the volume of the variable volume chamber 18 and causes fluid therein to be expelled though the outlet. However, since the plunger 4 is not coupled to the stopper 10 it is not possible to use the plunger 4 to move the stopper 10 away from the outlet end 14.

[0048] 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.

[0049] 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 to a rod shoulder radius from the first axis A which is such that it slightly less than the bore radius so that the shoulder fits within the bore 36. The backstop 6 includes a backstop shoulder 34 directed towards the outlet end 14. The shoulders 32,34 are configured to cooperate to substantially prevent movement of the rod 26 away from the outlet end 14 when the backstop shoulder 34 and rod shoulder 32 are in contact. The backstop shoulder 34 extends from outside the bore radius to a radius less than the rod shoulder radius so that the rod shoulder 32 cannot pass the backstop shoulder 34 by moving along the first axis A. In this case the rod shoulder 32 is substantially disc, or ring, shaped and the backstop shoulder 34 includes an arc around a rear end 38 of the body 2.

[0050] 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.

[0051] In this example the syringe comprises a 0.5 ml body 2, that is a body with a notional maximum fill volume of about 0.5 ml, filled with between about 0.1 and 0.3 ml of an injectable medicament 20 comprising a 10 mg/ml injectable solution comprising ranibizumab. The syringe body 2 has an internal diameter of about between about 4.5 mm and 4.8 mm, a length of between about 45 mm and 50 mm.

[0052] The plunger 4 and stopper 10 will be described in more detail with reference to later figures.

[0053] FIG. 3 shows a perspective view of the plunger 4 of FIG. 1 showing the plunger 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.

[0054] The rod 26 comprises ribs 44 which extend along the rod 26, the ribs forming a cross-form cross section for the rod 26 as shown in more detail in subsequent figures. The rod 26 comprises a disc shaped portion 46, the disc shaped portion 46 extending radially beyond the ribs 44 and also forming the rod shoulder 32.

[0055] The ribs 44 may be substantially solid, or may include gaps 48. The disc portion 46 may be solid, or may include gaps 50. Gaps 48,50 may be used to facilitate gas flow within the body 2 if necessary for sterilization, or other, purposes.

[0056] FIG. 4 shows a cross section though a syringe body 2 and rod 26. The rod 26 includes four longitudinal ribs 44 and the angle between the ribs is 90°.

[0057] FIG. 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 last rib 56 is about 3 mm. The rear surface 60 of the stopper 10 includes a substantially central recess 62. The central recess 62 includes an initial bore 64 having a first diameter. The initial bore 64 leading from the rear surface 60 into the stopper 10 to an inner recess 66 having a second diameter, the second diameter being larger than the first diameter.

[0058] FIG. 6 shows a flow chart for the assembly of a syringe 1. In Step 1 a prefilled body 2 is provided. The prefilled body comprises a body 2 filled with an injectable medicament 20 comprising ranibizumab, although other medicaments could be used in addition or instead, or a placebo solution could be used. A stopper 10 is arranged in the body 2 to form a variable volume chamber 18 and the outlet 12 is sealed with a sealing device 8.

[0059] In Step 2 a plunger 4 is arranged in the body 2. In one embodiment the plunger 4 is dropped into the body 2. This may be by gravity alone, or the plunger may be placed into the body 2 using a machine or human and the body then oriented so that the plunger 4 falls into the body 2 until the plunger contact surface 22 makes contact with the stopper 10.

[0060] In Step 3 a backstop 6 is coupled to the terminal flange 28 of the body. The backstop 6 and rod being arranged such that the rod shoulder 32 is located between the outlet end of the body and the backstop shoulder 34.

[0061] In Step 4 the syringe is sealed into a package and in Step 5 the package and its contents is sterilised in a terminal sterilisation process. The terminal sterilisation process may use known process such as an Ethylene Oxide or a Hydrogen Peroxide sterilisation process.

[0062] It should be understood that the invention has been described above by way of example only and that modifications in detail can be made without departing from the scope of the claims.

Claims

The invention claimed is:

1. A method of terminally sterilizing a packaged, small volume syringe, the method comprising:

sealing a small volume syringe inside a package to form a packaged, small volume syringe, wherein the small volume syringe includes:

a body;

a stopper, wherein:

the body includes an outlet at an outlet end and the stopper is 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 through the outlet,

the stopper includes at least a front circumferential rib and a rear circumferential rib which are separated in a direction along the longitudinal axis of the body by a distance of at least 3 mm to define a sterility zone extending from the front circumferential rib to the rear circumferential rib, and

the syringe is dimensioned to have a nominal maximum fill volume between 0.25 ml and 0.75 ml;

the syringe is filled with a medicament solution; and

a plunger configured to force the stopper towards the outlet end of the body to dispense the medicament solution, wherein the plunger comprises 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 is arranged to contact the stopper but does not couple thereto, such that the plunger can be used to force the stopper towards the outlet end of the body, thereby reducing the volume of the variable volume chamber, but does not to move the stopper away from the outlet end, wherein the rod includes at least one rod shoulder and the syringe includes a backstop arranged at a rear portion of the body, the backstop including a backstop shoulder to cooperate with and contact the rod shoulder to prevent movement of the plunger away from the outlet end to a distance less than the length of the sterility zone;

subjecting the packaged, small volume syringe to a terminal sterilization process that include changing the pressure within the variable volume chamber or changing the pressure outside the variable volume chamber, wherein:

a bubble within the medicament changes in volume during the terminal sterilization process causing the plunger to move away from the outlet end by a distance, as defined by the cooperation between the backstop shoulder and the rod shoulder, that is less than the length of the sterility zone.

2. The method of claim 1, wherein the nominal maximum fill volume is between about 0.4 ml and about 0.6 ml.

3. The method of claim 1, wherein the nominal maximum fill volume is about 0.5 ml.

4. The method of claim 1, which has a body length between 45 mm and 50 mm and a fill volume between 0.1 ml and 0.3 ml.

5. The method of claim 1, wherein the body has an internal diameter between about 4.5 mm and about 4.8 mm.

6. The method of claim 1, wherein the body has a length between 45 mm and 70 mm; and the body has an internal diameter between 3 mm and 6 mm.

7. The method of claim 1, wherein the syringe is filled with between 0.1 ml and 0.3 ml of the medicament solution.

8. The method of claim 1, wherein the stopper further comprises one or more circumferential ribs arranged between the front circumferential rib and the rear circumferential rib.

9. The method of claim 8, wherein the stopper comprises three circumferential ribs.

10. The method of claim 1, wherein the front circumferential rib and the rear circumferential rib are separated in a direction along the first axis of by at least 3.5 mm.

11. The method of claim 1, wherein the front circumferential rib and the rear circumferential rib are separated in a direction along the first axis of by at least 3.75 mm.

12. The method of claim 1, wherein the small volume syringe is substantially silicone free or wherein the body is made out of plastic or glass.

13. The method of claim 1, wherein the medicament solution comprises an active ingredient suitable for ophthalmic injection.

14. The method of claim 1, wherein the medicament solution comprises a VEGF antagonist.

15. The method of claim 14, wherein the VEGF antagonist is an anti-VEGF antibody.

16. The method of claim 14, wherein the VEGF antagonist is bevacizumab.

17. The method of claim 14, wherein the VEGF antagonist is ranibizumab.

18. The method of claim 17, wherein ranibizumab is in a dosage volume of 0.05 or 0.03 ml of a 10 mg/ml injectable medicament solution.

19. The method of claim 14, wherein the VEGF antagonist is aflibercept.

Patent Citations (209)

Patent	Date	Inventor	Cited By
US1704924(A)	1929-03-01	Rehm	Applicant
US2236727(A)	1941-04-01	Dewees	Applicant
US2602447(A)	1952-07-01	Paul	Applicant
US3148772(A)	1964-09-01	Saffir	Applicant
US3248950(A)	1966-05-01	Urselli et al.	Applicant
US3618603(A)	1971-11-01	Levenson	Applicant
US4184593(A)	1980-01-01	Dorr	Applicant
US4252118(A)	1981-02-01	Richard et al.	Applicant
US4507113(A)	1985-03-01	Dunlap	Applicant
US4543093(A)	1985-09-01	Christinger	Applicant
US4946441(A)	1990-08-01	Laderoute	Applicant
US5009646(A)	1991-04-01	Sudo et al.	Applicant
US5173258(A)	1992-12-01	Childers	Applicant
US5405326(A)	1995-04-01	Haber et al.	Applicant
US5597530(A)	1997-01-01	Smith et al.	Applicant
US5607399(A)	1997-03-01	Grimard et al.	Applicant
US5607400(A)	1997-03-01	Thibault et al.	Applicant
US5620423(A)	1997-04-01	Eykmann et al.	Applicant
US5667495(A)	1997-09-01	Bitdinger et al.	Applicant
US5688252(A)	1997-11-01	Matsuda et al.	Applicant
US5795337(A)	1998-08-01	Grimard	Applicant
US6090081(A)	2000-07-01	Sudo et al.	Applicant
USD430015(S)	2000-08-01	Himbert	Applicant
US7060269(B1)	2006-06-01	Baca et al.	Applicant
US7077826(B1)	2006-07-01	Gray	Applicant
US7141042(B2)	2006-11-01	Lubrecht	Applicant
US7303748(B2)	2007-12-01	Wiegand	Applicant
US7678078(B1)	2010-03-01	Peyman et al.	Applicant
US8075535(B2)	2011-12-01	Carrel et al.	Applicant
US8137324(B2)	2012-03-01	Bobst	Applicant
US9116148(B2)	2015-08-01	Linder et al.	Applicant
US9192725(B2)	2015-11-01	Kawamura	Applicant
US9561329(B2)	2017-02-01	Kawamura	Applicant
US20010056264(A1)	2001-12-01	Sayama et al.	Applicant
US20020065239(A1)	2002-05-01	Caplan et al.	Applicant
US20020193778(A1)	2002-12-01	Alchas et al.	Applicant
US20030032928(A1)	2003-02-01	Sudo et al.	Applicant
US20030034264(A1)	2003-02-01	Hamai et al.	Applicant
US20040099994(A1)	2004-05-01	Brinkhues	Applicant
US20050010175(A1)	2005-01-01	Beedon et al.	Applicant
US20050129569(A1)	2005-06-01	Zhao et al.	Applicant
US20050148947(A1)	2005-07-01	Kadziauskas	Applicant
US20050154354(A1)	2005-07-01	Kawasaki et al.	Applicant
US20050182370(A1)	2005-08-01	Hato	Applicant
US20050192544(A1)	2005-09-01	Wolbring et al.	Applicant
US20060172944(A1)	2006-08-01	Wiegand et al.	Applicant
US20060264967(A1)	2006-11-01	Ferreyro et al.	Applicant
US20060293270(A1)	2006-12-01	Adamis et al.	Applicant
US20070179452(A1)	2007-08-01	Kosinski et al.	Applicant
US20070190058(A1)	2007-08-01	Shams	Applicant
US20070250017(A1)	2007-10-01	Carred et al.	Applicant
US20080154213(A1)	2008-06-01	Kiehne	Applicant
US20080114306(A1)	2008-08-01	Bare	Applicant
US20080262435(A1)	2008-10-01	Erickson et al.	Applicant
US20080312607(A1)	2008-12-01	Delmotte et al.	Applicant
US20090131869(A1)	2009-05-01	Caizza et al.	Applicant
US20090247957(A1)	2009-10-01	Heutschi	Applicant
US20090326458(A1)	2009-12-01	Chong et al.	Applicant
US20100087796(A1)	2010-04-01	Baggs	Applicant
US20100093648(A1)	2010-04-01	Cruz	Applicant
US20100100054(A1)	2010-04-01	Cormier et al.	Applicant
US20100152646(A1)	2010-06-01	Girijavallabhan et al.	Applicant
US20100181218(A1)	2010-07-01	Beccaro et al.	Applicant
US20100288393(A1)	2010-11-01	Malmstrom et al.	Applicant
US20100310309(A1)	2010-12-01	Abendroth et al.	Applicant
US20110088493(A1)	2011-04-01	Blumentritt et al.	Applicant
US20110137263(A1)	2011-06-01	Ashmead et al.	Applicant
US20110190709(A1)	2011-08-01	Mitsuno et al.	Applicant
US20110257601(A1)	2011-10-01	Furfine et al.	Applicant
US20110276005(A1)	2011-11-01	Hioki et al.	Applicant
US20120078219(A1)	2012-03-01	Preis	Applicant
US20120078224(A1)	2012-03-01	Lerner et al.	Applicant
US20120091026(A1)	2012-04-01	Chacornac et al.	Applicant
US20120109072(A1)	2012-05-01	Tabata et al.	Applicant
US20120271245(A1)	2012-10-01	Achan, Jr.	Applicant
US20130012918(A1)	2013-01-01	Foster	Applicant
US20130079729(A1)	2013-03-01	Yokota et al.	Applicant
US20140249484(A1)	2014-09-01	Jones et al.	Applicant
CA1123697(A)	1982-05-01		Applicant
CA2689922(A1)	2008-12-01		Applicant
CN201578690(U)	2010-09-01		Applicant
DE12008005938(A1)	2009-07-01		Applicant
EP264273(A2)	1988-04-01		Applicant
EP264273(B1)	1992-03-01		Applicant
EP375778(B1)	1993-09-01		Applicant
EP738517(A1)	1996-10-01		Applicant
EP764450(A1)	1997-03-01		Applicant
EP879611(A2)	1998-11-01		Applicant
EP764450(B1)	2002-08-01		Applicant
EP971749(B1)	2004-07-01		Applicant
EP1455865(B1)	2004-09-01		Applicant
EP1488818(A1)	2004-12-01		Applicant
EP1767546(A1)	2007-03-01		Applicant
EP2047877(A1)	2009-04-01		Applicant
EP1488818(B1)	2010-03-01		Applicant
EP2298392(A1)	2011-03-01		Applicant
EP2371406(A1)	2011-10-01		Applicant
EP2436413(A1)	2012-04-01		Applicant
EP2682145(A1)	2014-01-01		Applicant
EP2470243(B1)	2019-10-01		Applicant
FR2855413(A1)	2004-12-01		Applicant
GB2245173(A)	1992-01-01		Applicant
JP6449569(A)	1989-02-01		Applicant
JP1138454(U)	1989-09-01		Applicant
JP666689(A)	1994-09-01		Applicant
JP1995-025953(Y)	1995-06-01		Applicant
JPH07163587(A)	1995-06-01		Applicant
JP8504352(A)	1996-05-01		Applicant
JP8-317975(A)	1996-12-01		Applicant
JP9308689(A)	1997-12-01		Applicant
JP2814982(B2)	1998-10-01		Applicant
JP11193010	1999-07-01		Applicant
JP2000-14779(A)	2000-01-01		Applicant
JP2001104480(A)	2001-04-01		Applicant
JP2001-340455(A)	2001-12-01		Applicant
JP2002-515268(A)	2002-05-01		Applicant
JP2002-177388(A)	2002-06-01		Applicant
JP2002241264(A)	2002-08-01		Applicant
JP2003052819(A)	2003-02-01		Applicant
JP2003-250889(A)	2003-09-01		Applicant
JP2003-265607(A)	2003-09-01		Applicant
JP2003-339865(A)	2003-12-01		Applicant
JP2004121344(A)	2004-04-01		Applicant
JP2004-313369(A)	2004-11-01		Applicant
JP2005511158(A)	2005-04-01		Applicant
JP2006-016053(A)	2006-01-01		Applicant
JP2006-528044(A)	2006-12-01		Applicant
JP2007-14619(A)	2007-01-01		Applicant
JP2007-155086(A)	2007-06-01		Applicant
JP2007517613(A)	2007-07-01		Applicant
JP2007202822(A)	2007-08-01		Applicant
JPU3134991(U)	2007-08-01		Applicant
JP2007528825(A)	2007-10-01		Applicant
JP2008307237(A)	2008-12-01		Applicant
JP2009-508593(A)	2009-03-01		Applicant
JP2009-183768(A)	2009-08-01		Applicant
JP2009-534064(A)	2009-09-01		Applicant
JP2009540001(A)	2009-11-01		Applicant
JP2009284951(A)	2009-12-01		Applicant
JP2010-377(A)	2010-01-01		Applicant
JP2010036970(A)	2010-02-01		Applicant
JP2010057597(A)	2010-03-01		Applicant
JP2010103919(A)	2010-05-01		Applicant
JP2010-136981(A)	2010-06-01		Applicant
JP2010523162(A)	2010-07-01		Applicant
JP2010528773(A)	2010-08-01		Applicant
JP2011501812(A)	2011-01-01		Applicant
JP2012532715(A)	2011-01-01		Applicant
JP4675537(B2)	2011-02-01		Applicant
JP4698613(B2)	2011-03-01		Applicant
JP2011519347(A)	2011-07-01		Applicant
JP2011522668(A)	2011-08-01		Applicant
JP4848784(B2)	2011-10-01		Applicant
JP2012-045046(A)	2012-03-01		Applicant
JP2012509736(A)	2012-04-01		Applicant
JP5492185(B2)	2014-03-01		Applicant
KR20050004800(A)	2005-01-01		Applicant
KR20060126998(A)	2006-12-01		Applicant
KR20090064525(A)	2009-06-01		Applicant
KR101538532(B1)	2015-07-01		Applicant
KR101704883(B1)	2017-02-01		Applicant
WO9413339(A1)	1994-06-01		Applicant
WO9413345(A1)	1994-06-01		Applicant
WO9744068(A1)	1997-11-01		Applicant
WO9918994(A1)	1999-04-01		Applicant
WO9927971(A2)	1999-06-01		Applicant
WO1999/45984(A1)	1999-09-01		Applicant
WO99/55402(A)	1999-11-01		Applicant
WO1999/055402(A1)	1999-11-01		Applicant
WO164266(A1)	2001-09-01		Applicant
WO2072157(A1)	2002-09-01		Applicant
WO3047668(A1)	2003-06-01		Applicant
WO2004/033018(A1)	2004-04-01		Applicant
WO2004/091700(A1)	2004-10-01		Applicant
WO2005121176(A1)	2005-12-01		Applicant
WO2006047325(A1)	2006-05-01		Applicant
WO2006128564(A1)	2006-12-01		Applicant
WO2007035621(A1)	2007-03-01		Applicant
WO2007121915(A1)	2007-11-01		Applicant
WO2007149334(A2)	2007-12-01		Applicant
WO2008077155(A1)	2008-06-01		Applicant
WO2008151239(A2)	2008-12-01		Applicant
WO2008154630(A2)	2008-12-01		Applicant
WO2009030976(A1)	2009-03-01		Applicant
WO2009055427(A2)	2009-04-01		Applicant
WO2009099641(A2)	2009-08-01		Applicant
WO2009151472(A1)	2009-12-01		Applicant
WO2010060748(A1)	2010-06-01		Applicant
WO2010064667(A1)	2010-06-01		Applicant
WO2010/081838(A2)	2010-07-01		Applicant
WO2010/103919(A1)	2010-09-01		Applicant
WO2010136492(A2)	2010-12-01		Applicant
WO2011/006877(A1)	2011-01-01		Applicant
WO2011023738(A1)	2011-03-01		Applicant
WO2011059823(A1)	2011-05-01		Applicant
WO2011/122574(A1)	2011-10-01		Applicant
WO2011/125475(A1)	2011-10-01		Applicant
WO2011122221(A1)	2011-10-01		Applicant
WO2011123722(A1)	2011-10-01		Applicant
WO2011135067(A1)	2011-11-01		Applicant
WO2012019047(A2)	2012-02-01		Applicant
WO2012019176(A2)	2012-02-01		Applicant
WO2012117837(A1)	2012-09-01		Applicant
WO2012134528(A1)	2012-10-01		Applicant
WO2012149040(A2)	2012-11-01		Applicant
WO2013151904(A1)	2013-10-01		Applicant
WO2013184270(A1)	2013-12-01		Applicant
WO2014005728(A1)	2014-01-01		Applicant
WO2019005072(A1)	2019-01-01		Applicant

Non-Patent Literature (162)

Avastin, Scientific Discussion, EMEA, 2005. 1-61“Bevacizumab”, Scientific Discussion, EMEA, 2005, pp. 1-61.Applicant
“COPHy Poster List—Group A” (Poster 17), The 5th World congress on Controversies in Ophthalmology (COPHy) Mar. 20-23, 2014, Lisbon, Portugal.Applicant
A Complete Guide to Aseptic Manufacturing, 2023 https://www.pharm-int.com/wp-content/uploads/2021 /08/Pi i-Aseptic-Manufacturing-Ebook-FINALUPDATE-08162021.pdf, retrieved Mar. 3, 2023.Applicant
Akers_Sterile Drug Products Formulation, Packaging, Manufacturing, and Quality_Cover and table of content of a book, 3 pages.Applicant
Announcement published in the Federal Register on May 24, 2011.Applicant
Article of BioPharma-Reporter dated Aug. 20, 2019, Regeneron's pre-filled syringe for eye injection finally approved by FDA.Applicant
Australian Public Assessment Report for Ranibizumab (Lucentis), Nov. 2011, pp. 1-121.Applicant
Ausubel, et al., Computer Manipulation of DNA and UNIT 7.7 Protein Sequences, Current Protocols in Molecular Biology, 7.7.1-7.7.23, Supplement 30, 1995.Applicant
Auxuliary Request 4 of EP2869813, Dec. 2020.Applicant
Badkar, et al., Development of Biotechnology Products in Pre-filled Syringes: Technical Considerations and Approaches, AAPS PharmSciTech, 12(2), 564-572, Jun. 2011.Applicant
Bakri, et al., Intravitreal Silicone Oil Droplets after Intravitreal Drug Injections, Retina, The Journal of Retinal and Vitreous Diseases, 28(7), 996-1001, 2008.Applicant
Biopharmaceuticals—SPE applications http://www.particle-explorer.com/yourapplications/biopharmaceuticals/index.html [16.09.2015 11:23:45].Applicant
Byrn, Analysis of Two Commercially Available Bortezomib Products: Differences in Assay of Active Agent and Impurity Profile, AAPS PharmSciTech, 12(2), 461-467, Jun. 2011.Applicant
Chan, et al., Syringe Siliconization Process Investigation and Optimization, Journal of Pharmaceutical Science and Technology, 66 (2), 136-150, 2012.Applicant
Daikyo Ru Crystal Zenith Insert Needle Syringe System, West Delivering Innovative Solutions, 2010.Applicant
Datwyler, Components for prefilled syringes, Oct. 2011.Applicant
Denyer, et al., Hugo and Russell's Pharmaceutical Microbiology, 337, 350, 2008.Applicant
DIN EN ISO 9626, Mar. 2002.Applicant
Dixon, et al., VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration, Expert Opin. Investig. Drugs, 18(10), 1573-1580, 2009.Applicant
EMA EPAR summary Pegaptanib EMA/671614/2010, 2012.Applicant
Email dated Sep. 9, 2015 from Elizabeth Scuderi, Senior meetings Manager, AAPS to Teresa Homrich re: Inquiry about publication of conference abstract.Applicant
Entry for Ranibizumab in Rote Liste 2009.Applicant
EP2854762 WO ISA.Applicant
Evidence for publication date of TechnoPharm from May 2012.Applicant
Evidence for publication date of TechnoPharm from Sep. 2012.Applicant
Extract of the Website of Jaypee Brothers regarding the Publication Date of Sankara Nethralaya.Applicant
Extract of the website of the International Organization for Standardization concerning the life cycle of ISO Norm 2001 (www.iso.org/stand-ard/33503.html).Applicant
Eylea EPAR 20.09.2012.Applicant
FDA approves Lucentis_2012-08-13_European Pharmaceutical Review. Website-Entry of European Pharmaceutical Review, dated Aug. 13, 2012: https://www.europeanpharmaceuticalreview.com/news/14197/fdaapproves-lucentis-ranibizumabinjection-for-treatment-of-diabetic-macularedema/.Applicant
FDA label of Lucentis, available on Jul. 2, 2012.Applicant
FDA website Wayback machine, dated Jun. 19, 2011.Applicant
Fries, Drug delivery of sensitive biopharmaceuticals with prefilled syringes, Drug Delivery Technology, 9(5), May 22-27, 2009.Applicant
Full list of articles published in TechnoPharm, 2012, (5).Applicant
Gebrauchsinformation: Information tor Anwender—Avastin.Applicant
Glockler, et al., Pathway to Overcome Primary Packaging and Drug Product Manufacturing Challenges, OnDrugDelivery, 80-86, 2021.Applicant
Grounds for the Decision on EP2869813, Apr. 7, 2021.Applicant
Hlobik, Reducing quality risks to drug products and meeting needs of patients with enhanced components for prefilled syringe systems, ONdrugDelivery, 30, 32-34, Jan. 2012.Applicant
Holash, et al., VEGF-Trap: A VEGF blocker with potent antitumor effects, PNAS, 99(17), 11393-11398, Aug. 20, 2002.Applicant
International Standard ISO 11139-2018.Applicant
Intervener's Claim Form sealed Mar. 23, 2022.Applicant
ISO 11139-2006.Applicant
Kinney, et al., Prefilled Syringes A Rational Approach to Determining the Maximum Allowable Gas Bubble Inside a Prefilled Syringe to Minimize Stopper Movement & Protect Product Sterility, Drug Delivery Technology, 9(2), 45-47, Feb. 2009.Applicant
Kiss, Perspectives on intravenous bevacizumab repackaged for intravitreal use, Modern Retina Digital Edition, 2(2), 1-6, Jun. 15, 2022.Applicant
Kocabora, et al., Intravitreal silicone oil droplets following pegaptanib injection, Acta Ophthalmol., 88(2), e44-e45, 2010.Applicant
Lambert, et al., Radiation and Ethylene Oxide Terminal Sterilization Experiences with Drug Eluting Stent Products, AAPS PharmSciTech, 12(4), 1116-1126, Dec. 2011.Applicant
Lankers, et al., The Relationship Between Silicone Layer Thickness, Free Silicone Oil and Protein Aggregation in Prefilled Syringes, AAPS National Biotechnology Conference, 2010.Applicant
Letter of the Director General of Health Services, Office of Drugs Controlller General India, of Aug. 22, 2014 regarding the Approval of the Luccentis Pre-filled Syringe in India.Applicant
Li, et al., KH906, a recombinant human VEGF receptor fusion protein, is a new effective topical treatment for corneal neovascularization, Molecular Vision, 17, 797-803, 2011.Applicant
Lincoff, et al., The perfluorocarbon gases in the treatment of retinal detachment, Ophthalmology, 90(5), 546-551, May 1983.Applicant
Lynch, et al., Bevacizumab for Neovascular Ocular Diseases, The Annals of Pharmacotherapy, 41, 614-625, Apr. 2007.Applicant
Macugen Chemistry review, Dec. 14, 2004.Applicant
Majumdar, et al., Evaluation of the Effect of Syringe Surfaces on Protein Formulations, Journal of Pharmaceutical Science, 100, 2563-2573, Jul. 2011.Applicant
Makwana, et al., Prefilled syringes: An innovation in parenteral packaging, International Journal of Pharmaceutical Investigation, 1(4), 200-206, Oct. 2011.Applicant
Media Report of Mar. 20, 2014 regarding the Launch of Lucentis Pre-filled Syringe in Europe (https://www.pharmtech.com/view/novartis-launches-lucentis-prefilled-syringe-europe).Applicant
Meyer, et al., Steps for a safe intravitreal injection technique, Retinal Physician, Jul. 1, 2009.Applicant
Mintz, et al., Prefilled Syringes: The next “Big Thing”, Bioprocess Online, Aug. 30, 2012.Applicant
Clunas, et al: “Ranibizumab pre-filled syringe: recently approved innovation in the European Union with the potential to reduce infection risk, improve does accuracy, and enhance efficient treatment administration.” Congress on Controversies in Ophthalmology, Abstract 2014.Applicant
Nema, et al., Parenteral dosage forms: introduction and historical perspective, Pharmaceutical Dosage Forms, 3th Edition, vol. 1, 1-50, 2013.Applicant
Nethralaya, Clinical Practice patterns in Ophthalmology, 2nd ed. Preface, 2012.Applicant
Nethralaya, Clinical Practice Patterns in OPHTHALMOLOGY, 2nd ed., 355-361, 2012.Applicant
Office Action for EP3470058A1, Aug. 16, 2022.Applicant
Palmer, et al., Quality of bevacizumab compounded for intravitreal administration, Eye, 27, 1090-1097, 2013.Applicant
Park, et al., Intraocular pharmacokinetics of intravitreal vascular endothelial growth factor-Trap in a rabbit model, Eye, 29, 561-568, 2015.Applicant
PIL of Lucentis filed with the Food and Drug Administration, revised on Oct. 2014.Applicant
Prefilled syringes Part 8: ISO 11040-8, 2016.Applicant
Press Release of Regeneron of Aug. 13, 2019 (FDA Approves EYLEA (aflibercept) Injection Prefilled Syringe).Applicant
Priority document EP12170628.7, Jun. 1, 2012.Applicant
Proprietor's Amended Defence and Counterclaim, re-served on Feb. 10, 2023.Applicant
Proprietor's Defense, served on May 6, 2022.Applicant
Ranibizumab, Scientific Discussion, EMEA_2007, 1-54.Applicant
Riely, et al., Vascular Endothelial Growth Factor Trap in Non-Small Cell Lung Cancer, Clin Cancer Res, 13, 4626s-4627s, Aug. 1, 2007.Applicant
Romacker, et al. and Lahendro, Introduction. The rise of prefilled syringes from niche product to primary container of choice: a short history // The next generation of ready-to-use prefillable syringes: first in silicone-free solutions, OnDrugDelivery, 14, 1-5, 24-27, 2008.Applicant
Rote Liste 2009, entry 67273 (Lucentis®) and 67274 (Macugen®).Applicant
Sacha, et al., Practical fundamentals of glass, rubber, and plastic sterile packaging systems, Pharmaceutical Development and Technology, 15(1), 6-34, 2010.Applicant
Screenshot of result of using web link.Applicant
Shah, et al., Pre-Filled Syringes: A New Concept, Pharma Bio World, 51-57, Aug. 2009.Applicant
Sigma-Aldrich Syringes Brochure, 2007.Applicant
Sivertsen, et al., Pharmaceutical compounding of aflibercept in prefilled syringes does not affect structural integrity, stability or VEGF and Fc binding properties, Scientific Reports, 8(2101), 1-9, Feb. 1, 2018.Applicant
Slocik, et al, Creation of stable water-free antibody based protein liquids, Communications Materials, 2(118), 1-11, 2021.Applicant
Smith, et al., Comparison of Biosequences, Advances in Applied Mathematics, 2, 482-489, 1981.Applicant
Spaeth, et al., Ophthalmic Surgery: Principles and Practice, E-Book, 511-512, 2011.Applicant
Sterile Drug Products_Sterile product packaging systems, Chapter 4, 29-47.Applicant
Sterile Drug Products_Sterile products packaging chemistry, Chapter 7,72-95.Applicant
Summary of Product Characteristics Zaltrap (undated).Applicant
Swissmedic Journal_Macugen_2006-02.Applicant
Technical drawing of FluroTec plunger, 2010.Applicant
TGA Product Information for Eylea, Jun. 6, 2012.Applicant
Von Woedtke, et al., The limits of sterility assurance, GMS Krankenhaushygiene Interdisziplinär, 3(3), 1-10, 2008.Applicant
Vorgefullte Spritzen ISO 11040-4, 1996-DE.Applicant
Wikipedia, Techne, Feb. 3, 2023, XP009542923 https://en.wikipedia.org/wiki/Techne retrieved Feb. 3, 2023, publication date not relevant.Applicant
Product Information Eylea, dated Mar. 7, 2012, 18 pages.Applicant
Beginner guide to particle technology_Particle Measuring Systems, pp. 1-13.Applicant
Genetech, Inc., Highlights of Prescribing Information, LUCENTIS [ranibizumab injection], Intravitreal Injection, Year 2006), STN BLA 12516/053, pp. 5-11.Applicant
Regeron, Eylea(TM) (aflibercept) Injection For Intravitreal Injection, Nov. 2011, FDA. <<https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/1253871bl.pdf>> (Year: 2011).Applicant
Third Party Observation for application No. EP20200156274, submission of observation took place on Nov. 26, 2020 Title: SYRINGE, Publication No. EP3679922, Applicant: Novartis Ag[Ch], Dale to publication: Jul. 15, 2020, Date of filing: May 30, 2013, 94 pages.Applicant
Somner et al. : Inadvertent injections of Intravitreal Air During Intravitreal Lucentis Injection for Wet Age-Related Macular Degeneration: An Undescribed Complication, Oct. 3, 2008, Eye 23, 1744; doi 10. 1038/ eye.2008.297 Year 2008).Applicant
Vietnamese Office Action dated Sep. 9, 2019, issued in Vietnamese patent application No. 1-2014- 03899, filed May 30, 2013.Applicant
Third Party Observation for application No. JP2021-137017, filed May 2, 2022.Applicant
Third Party Observation for application No. JP2021-137017, filed Mar. 10, 2022.Applicant
STELMI: “04 Pre-filled Syringe”, Feb. 2007.Applicant
International Standard, ISO 11040-4: “Prefilled syringes—Part 4: Glass barrels for injectables,” Apr. 15, 1996, pp. 1-6.Applicant
Fachinformation Novartis Pharma Lucentis (Jan. 2007).Applicant
“Brief Package” of Regeneron Pharmaceutical Inc., for a “Division of Transplant and Ophthamology Products Advisory Committee Meeting” (DTOP).Applicant
Website-Entry of the US Food and Drug administration (FDA); http://fda.gov/AdvisoryCommittees/Calendar/ucm256594.htm.Applicant
Website-Entry of the US Food and Drug administration (FDA); http://www.fda.goc/AdvisoryCommitteesMeetingMaterials/Drug/DermatologicandOphthalmicDrugsAdvisoryCommittee/ucm259141.htm.Applicant
Screenshots Wayback Machine Jun. 2011.Applicant
Lucentis Material Safety Data Sheet May 22, 2009.Applicant
Eylea Prescribing Information Nov. 2011.Applicant
Lucentis Prescribing Information Jun. 2010.Applicant
Macugen Prescribing Information Jul. 2011.Applicant
Third Party Observation for application No. JP2021-137017, filed Mar. 7, 2022.Applicant
International Standard, ISO 11040-5: “Prefilled syringes—Part 5: Plunger stoppers for injectables,” Jan. 15, 2012, pp. 1-9.Applicant
Third Party Observation for application No. JP2021-137017, filed Apr. 1, 2022.Applicant
International Standard, ISO 11040-4: “Prefilled syringes—Part 4: Glass barrels for injectables”, Feb. 1, 2007, pp. 1-4.Applicant
International Standard, ISO 11040-5: “Prefilled syringes—Part 5: Plungers for injectables”, Dec. 15, 2001, pp. 1-4.Applicant
International Standard, ISO 11040-6: “Prefilled syringes—Part 6: Plastic barrels for injectables”, Apr. 1, 2012, pp. 1-15.Applicant
Third Party Observation for application No. JP2021-137017, filed Mar. 17, 2022.Applicant
Third Party Observation filed by Anonymous for application No. EP20200198921 dated Apr. 14, 2021, 5 pages.Applicant
Relevance of Third-Party Observation dated Nov. 26, 2021 considered not relevant by Examiner Jun. 21, 2021, 2 pages.Applicant
Extended European Search Report for Application No. 21164847.2 dated Jul. 1, 2021, 8 pages.Applicant
Third Party Observation filed by Anonymous for Application No. JP2020-043041 dated Apr. 27, 2021, 22 pages (English translation attached).Applicant
Third Party Observation filed by Anonymous for Application No. JP2020-043041 dated May 6, 2021, 30 pages (English translation attached).Applicant
Office Action issued in Japanese Patent Application No. 2020-043041, dated Jan. 5, 20221 (English Machine Translation attached).Applicant
English Translation of Office Action issued in Korean Patent Application No. 10-2020-7035156, dated Jan. 5, 2021.Applicant
Jurgen, S., “RF B002 0.5MG/0.5ML Liquid in (pre-filled) syringe,” PFS Development Report, Novartis (2013), pp. 1-5.Applicant
Azad, et al., To Compare Photodynamic Therapy with Ranibizumab vs. Photodynamic Therapy with Pegaptanib for Subfoveal Choroidal Neovascularization in Age-related Macular Degeneration, World Journal of Retina and Vitreous, May-Aug. 2012, 23-27, 2(2).Applicant
Gerding et al., Accuracy and Precision of Intravitreally Injected Panibizumab Doses: An Experimental Study, Klin Monatsbl Augenheilkd, Apr. 20, 2010, 269-272, 227.Applicant
Gerresheimer, Readyject Syringe Systems.Applicant
Guidance for Industry for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products, Nov. 1994, 23 pgs.Applicant
ISO 110410, Part 5: Plungers for injectables (Second edition dated Dec. 15, 2001), 10 pgs.Applicant
ISO 110410, Prefilled syringes, Part 4: Glass barrels for injectables (Second edition dated Feb. 1, 2007), 16 pgs.Applicant
ISO, Sterilization of health care products—Vocabulary of terms used in sterilization and related equipment and process standards, International Standard, Aug. 2018, 1-15, First edition.Applicant
Kim, et al., Short-term Intraocular Pressure Changes Immediately After Intravitreal Injections of Anti-Vascular Endothelial Growth Factor Agents, American Journal of Ophthalmology, Jul. 1, 2008, 930-934, 146(6).Applicant
Reuter, et al., Syringe Siliconization, TechnoPharm, 2012, 1-6, 2(4).Applicant
Schoenknecht, Requirements on pre-fillable glass syringes, AAPS National Biotechnology, 1 page.Applicant
The Catt Research Group, Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration, The New England Journal of Medicine, May 19, 2011, 1897-1908, 364(20).Applicant
Third-party observation for JP2022-021374, Jul. 15 2022_with English translation.Applicant
Third-party observation for JP2022-021374, Jul. 25 2022_with English translation.Applicant
US Pharmacopeia National Formulary, 2011, p. 328-329., vol. 1.Applicant
Wagner Andrea, Advances in Prefilled Syringe Technology, ITP, 2007, pp. 73-75., vol. 24.Applicant
Third Party Observation of JP2021-137017, Oct. 18, 2022, with an English translation.Applicant
Cancellation Petition of KR2386843, Oct. 17, 2022, with an English translation.Applicant
Written Opposition of JP Patent No. 7026991, Sep. 1, 2022, with an English translation.Applicant
Written Opposition of JP7042954, Sep. 28, 2022, with an English translation.Applicant
Revocation Notice of JP7026991, Jan. 6, 2023, with an English translation.Applicant
Revocation Notice of JP7042954, Jan. 4, 2023, with an English translation.Applicant
Third Party Opposition of JP2021-137017, Oct. 28, 2022, with an English translation.Applicant
Third Party Opposition of JP2021-137017, Oct. 14, 2022, with an English translation.Applicant
Nullity Action Bioeq for EP3777834, EP3679922, EP3536310 dated Jan. 10, 2023.Applicant
Opposition from Hamm Wittkopp for EP3679922, dated Apr. 28, 2022.Applicant
Opposition from Wolfgang Wess for EP3679922, dated Apr. 28, 2022.Applicant
Opposition from Keil for EP3679922, dated Apr. 26, 2022.Applicant
Opposition from Hamm Wittkopp for EP3536310, dated Jan. 28, 2022.Applicant
Opposition from Wolfgang Wess for EP3536310, dated Jan. 28, 2022.Applicant
Opposition from Keil for EP3536310, dated Jan. 26, 2022.Applicant
Nullity Action Stada for EP3777834, dated Sep. 20, 2022.Applicant
Opposition from Keil for EP3777834 dated Nov. 14, 2022.Applicant
Opposition from Hamm Wittkopp for EP3777834, dated Nov. 16, 2022.Applicant
Opposition from Wolfgan Wess for EP3777834, dated Nov. 16, 2022.Applicant
Opposition from Strawman Limited for EP3777834, dated Nov. 15, 2022.Applicant
Opposition from Jochen Ehlers for EP3777834, dated Nov. 15, 2022.Applicant
Opposition from Teva for EP3777834, dated Nov. 4, 2022.Applicant

Abstract

Description

Cross Reference to Related Applications

[0008] The body may be made from a plastic material or from glass, or from any other suitable material and may include indicia on a surface thereof to act as an injection guide.

- [0028] i) providing a body and a stopper, 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 outlet being releasably sealed and the variable volume chamber containing a medicament; and
- [0029] ii) providing a plunger comprising a plunger contact surface at a first end and a rod extending between the plunger contact surface and a rear portion and arranging the plunger contact surface and at least part of the plunger within the body without coupling the plunger to the stopper.