`
`EXHIBIT A-1
`
`Invalidity Claim Chart of Sigg, alone or in combination with any of Boulange, Lam, Reuter, Scypinski, Metzner, Shah, Fries,
`Schoenknecht, Chacornac, Nema, D’Souza, Furfine, Badkar, Macugen, Eylea, Lucentis, Stewart, USP789, Liu, Hioki, DC365,
`Hagen, Khandke, Wittland, Shams, Dixon, and/or Cormier against U.S. Patent No. 9,220,631.
`
`
`
`Charted Reference:
`
`PCT Patent Publication No. WO 2011/006877 to Sigg et al. (“Sigg”), alone or in view of Boulange, Lam, Reuter, Scypinski, Metzner,
`Shah, Fries, Schoenknecht, Chacornac, Nema, D’Souza, Furfine, Badkar, Macugen, Eylea, Lucentis, Stewart, USP789, Liu, Hioki,
`DC365, Hagen, Khandke, Wittland, Shams, Dixon, and/or Cormier, render obvious claims 1-26 of U.S. Patent No. 9,220,631.
`
`This claim chart is based on Regeneron’s current understanding of the asserted claims, and Regeneron’s investigation to date.
`Regeneron is not admitting to the accuracy of any particular construction. Regeneron reserves all rights to amend this invalidity claim
`chart in light of any claim construction developments or any amendments to Novartis’s infringement contentions or domestic industry
`contentions, should such developments occur or amendments be allowed. Further, as discovery is ongoing and Regeneron continues to
`seek discovery from third parties regarding the references identified in Regeneron’s invalidity contentions as well as other potential
`prior art, Regeneron reserves the right to revise its invalidity contentions as appropriate in view of any ongoing discovery.
`
`The claim chart below identifies where each limitation of each asserted claim of the 631 Patent can be found in Sigg. The citations
`provided below are exemplary, rather than exhaustive, and Regeneron reserves the right to rely upon any other portion of the cited
`references. Where Regeneron identifies a portion of a reference’s text, the identification should be understood as referencing any
`corresponding figure or diagram, and vice versa.
`
`
`
`
`
`Novartis Exhibit 2004.001
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`[1.a-pre] A pre-filled,
`terminally sterilized syringe
`for intravitreal injection,
`
`Corresponding Disclosure
`Sigg discloses a pre-filled, terminally sterilized syringe for intravitreal injection.
`
`For example, see the following passages and/or figures, as well as all related disclosures:
`
`
`Terminal sterilization of prefilled containers in secondary packaging is one way to provide
`the device to an end user with a low bio-burden and low risk of contaminants, for safe
`application of the product by the end user. Moreover there is a strong market need for
`terminally antimicrobially-treated medical devices, such as prefilled syringes used for
`intravitreal injections.
`
`
`Sigg at 2:15-19.
`
`
`Described herein is a terminal sterilization and surface decontamination treatment of
`prefilled containers, specifically for sterilization of prefilled containers containing
`sensitive solutions, such as a drug product or biological therapeutic, within secondary
`packaging. In one embodiment, terminal sterilization is achieved by treating prefilled
`containers within secondary packaging with controllable vaporized-hydrogen peroxide
`(VHP).
`
`
`Sigg at 3:8-13.
`
`
`The method and system described herein decontaminate or, more preferably render sterile
`an outside surface of primary packaged drug products within a secondary pack, thereby
`improving safety of products for critical administration (e.g. use in a surgical suite or for
`intravitreal injections)
`
`
`Sigg at 4:12-15.
`
`
`In one embodiment, the prefilled container is a syringe. Other suitable prefilled containers
`include vials, bottles, bags and other medical devices capable of containing a sterile
`solution or a solution requiring sterilization.
`
`
`
`2
`
`
`
`Novartis Exhibit 2004.002
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Corresponding Disclosure
`In one embodiment, the syringe is filled with a drug product, such as in the form of liquid,
`solution, powder or solid. In another embodiment the drug product is a solution such as a
`drug solution or protein solution that is otherwise sensitive to exposure to high
`temperatures, such as those used in steam sterilization, and ionizing energy, such as
`gamma or beta rays and oxidizing gasses. In yet another embodiment the drug product is
`one that has been lyophilized, in other words a solid, and requires reconstitution in liquid
`or solution prior to use.
`
`In another embodiment, a solution is any drug product having requirements or desirability
`for sterility of the drug product container surface. In one particular embodiment, the drug
`product is a protein solution, such as ranibizumab (e.g. 6mg/ml or 10 mg/ml) solution for
`intravitreal injection.
`
`
`Sigg at 9:1-14.
`
`
`Example 1
`
`In the following experiment, prefilled syringes were treated with a vaporized- hydrogen
`peroxide sterilization treatment in a chamber, either by a single pass through a VHP
`sterilization procedure or two passes (shown in the table below as 2 x) through a VHP
`sterilization procedure. Syringes containing protein solutions treated by VHP were
`compared to control syringes treated with VHP to determine if the integrity of proteins
`present in solution was maintained.
`
` A
`
` formulation as described in U.S. Patent No. 7,060,269 was tested for protein
`degradation following treatment by VHP.
`
`Approximately 10 mL of solution was filtered through a 0.22 μm syringe filter. (Millex
`GV filter available from Millipore, Billerica, MA USA.) Filling of 0.5 mL syringes was
`performed in a sterile lab for hydrogen peroxide treatment.
`
`
`Claim Language
`
`
`
`3
`
`
`
`Novartis Exhibit 2004.003
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`Analysis after the treatment with VHP revealed the following protein contents, visualized
`by HPLC analysis: byproducts and degradation products by HPLC (IEC) and by-products
`and degradation products by HPLC (SEC).
`
`
`
`
`
`The results seen were within the requirement; there were no differences between the
`results of the untreated syringes and with hydrogen-peroxide treated syringes. Analysis
`can also be carried out at different time points following treatment, such as 1 month, 3
`months and six months following treatment by VHP, or over the shelf-life of the product
`of the prefilled container. Analysis can be carried out to determine continued stability of
`the protein solution, including tests by HPLC for presence of by-products using standard
`HPLC laboratory protocols. Analysis can also be carried out by the presence of physical
`changes, such as measuring the concentration of H2O2 in solution by a fluorescence test
`using an over-the-counter commercially available kit in conjunction with an apparatus
`with fluorescence detection.
`
`Sigg at 20:10-21:11.
`
`
`
`
`4
`
`
`
`Novartis Exhibit 2004.004
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`[1.b] the syringe comprising a
`glass body forming a barrel, a
`stopper and a plunger
`
`Corresponding Disclosure
`To the extent Novartis alleges this limitation is not met by any of the disclosures above, it also
`would have been obvious in view of Boulange, Lam, Reuter, Scypinski, Metzner, Shah, Fries,
`Schoenknecht, Chacornac, Nema, D’Souza, Furfine, Badkar, Macugen, Eylea, Lucentis, Stewart,
`USP789, Liu, Hioki, DC365, Hagen, Khandke, Wittland, Shams, Dixon, and/or Cormier. See
`Exhibits A-2–A-13, B-1–B-3 and all references cited therein.
`Sigg discloses the syringe comprising a glass body forming a barrel, a stopper and a plunger.
`
`For example, see the following passages and/or figures, as well as all related disclosures:
`
`
`Further, sterilizing doses of gamma rays cause a brown discoloration of glass parts of the
`device, and is prone to damage elastomeric materials like plunger stoppers. This
`destruction of the elastomers leads to increased stickiness of the components thus
`impairing the functionality of the system. Thus radiation is not an appropriate means for
`sterilizing prefilled containers, such as syringes, containing a biotech drug product.
`
`Sigg at 2:1-6.
`
`
`Additionally, the oxidative stress exerted on a 0.5% Polysorbate 20 solution in prefilled
`glass syringes (1 mL long, ISO) was investigated by measurement of peroxides according
`to standard protocols. The total amount of peroxides was measured by the Ferrous Oxide
`Oxidation (FOX) test, according to a standard protocol.
`
`Table 3: Peroxide Levels Following Beta Irradiation of Prefilled Containers:
`
`
`
`
`
`
`
`
`
`5
`
`
`
`Novartis Exhibit 2004.005
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`No significant influence of the electron beam treatment on the peroxide content of the
`solution enclosed in glass syringes could be observed. Thus, beta irradiation proved safe
`to solutions within prefilled containers.
`
`
`Sigg at 22:8-17.
`
`
`
`
`Sigg at Figure 1 (annotated).
`
`To the extent Novartis alleges this limitation is not met by any of the disclosures above, it also
`would have been obvious in view of Boulange, Lam, Reuter, Scypinski, Metzner, Shah, Fries,
`Schoenknecht, Chacornac, Nema, D’Souza, Furfine, Badkar, Macugen, Eylea, Lucentis, Stewart,
`USP789, Liu, Hioki, DC365, Hagen, Khandke, Wittland, Shams, Dixon, and/or Cormier. See
`Exhibits A-2–A-13, B-1–B-3 and all references cited therein.
`Sigg discloses the syringe contains an ophthalmic solution which comprises a VEGF-antagonist.
`
`For example, see the following passages and/or figures, as well as all related disclosures:
`
`
`In another embodiment, a solution is any drug product having requirements or desirability
`for sterility of the drug product container surface. In one particular embodiment, the drug
`
`[1.c] and [the syringe]
`containing an ophthalmic
`solution which comprises a
`VEGF-antagonist, wherein
`
`
`
`6
`
`
`
`Novartis Exhibit 2004.006
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`[1.d] (a) the syringe has a
`nominal maximum fill
`volume of between about 0.5
`ml and about 1 ml,
`
`Corresponding Disclosure
`product is a protein solution, such as ranibizumab (e.g. 6mg/ml or 10 mg/ml) solution for
`intravitreal injection.
`
`
`Sigg at 9:11-14.
`
`
`A formulation as described in U.S. Patent No. 7,060,269 was tested for protein
`degradation following treatment by VHP. Approximately 10 mL of solution was filtered
`through a 0.22 μm syringe filter. (Millex GV filter available from Millipore, Billerica, MA
`USA.) Filling of 0.5 mL syringes was performed in a sterile lab for hydrogen peroxide
`treatment.
`
`
`Sigg at 20:17-21.
`
`
`3. The method of claim 1 or claim 2, wherein the prefilled container is a syringe
`containing a therapeutically effective amount of ranibizumab.
`
`
`Sigg at Claim 3.
`
`
`12. The method of any one of claims 8-11 , wherein the prefilled container is a syringe
`containing a therapeutically effective amount of ranibizumab.
`
`
`Sigg at Claim 12.
`
`To the extent Novartis alleges this limitation is not met by any of the disclosures above, it also
`would have been obvious in view of Boulange, Lam, Reuter, Scypinski, Metzner, Shah, Fries,
`Schoenknecht, Chacornac, Nema, D’Souza, Furfine, Badkar, Macugen, Eylea, Lucentis, Stewart,
`USP789, Liu, Hioki, DC365, Hagen, Khandke, Wittland, Shams, Dixon, and/or Cormier. See
`Exhibits A-2–A-13, B-1–B-3 and all references cited therein.
`Sigg discloses the syringe has a nominal maximum fill volume of between about 0.5 ml and about
`1 ml.
`
`For example, see the following passages and/or figures, as well as all related disclosures:
`
`
`
`7
`
`
`
`Novartis Exhibit 2004.007
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`[1.e] (b) the syringe barrel
`comprises from about 1 μg to
`100 ug silicone oil,
`
`Corresponding Disclosure
`
`
`Filling of 0.5 mL syringes was performed in a sterile lab for hydrogen peroxide treatment.
`
`
`Sigg at 20:20-21.
`
`
`Additionally, the oxidative stress exerted on a 0.5% Polysorbate 20 solution in prefilled
`glass syringes (1 mL long, ISO) was investigated by measurement of peroxides according
`to standard protocols.
`
`
`Sigg at 22:8-10.
`
`To the extent Novartis alleges this limitation is not met by any of the disclosures above, it also
`would have been obvious in view of Boulange, Lam, Reuter, Scypinski, Metzner, Shah, Fries,
`Schoenknecht, Chacornac, Nema, D’Souza, Furfine, Badkar, Macugen, Eylea, Lucentis, Stewart,
`USP789, Liu, Hioki, DC365, Hagen, Khandke, Wittland, Shams, Dixon, and/or Cormier. See
`Exhibits A-2–A-13, B-1–B-3 and all references cited therein.
`A POSITA would have known and it would have been obvious to use the known baked silicone
`method to siliconize the syringe disclosed in Sigg, which would have resulted in a syringe that
`meets this limitation. Sigg alone or in view of Boulange, Fries, Hioki, Chacornac, D’Souza,
`Reuter, Nema, Khandke, and/or DC365, disclose the syringe barrel comprises from about 1 μg to
`100 ug silicone oil.
`
`To the extent this limitation is not expressly and/or inherently disclosed, such limitation would
`have been, even without resorting to the disclosures of any other reference, because it was within
`the common knowledge of persons of ordinary skill in the art, and was used in the claims according
`to known methods, to achieve predictable results.
`
`For example, it was common knowledge of persons of ordinary skill in the art that the friction
`between the stopper and the barrel of a glass syringe can be reduced by providing an interface
`between their surfaces and such an interface can be created by coating the components of the
`syringe such as the barrel and the stopper with silicone oil, in a process known as “siliconization.”
`Indeed, the 631 Patent acknowledges that “[i]t is typical to siliconise the syringe in order to allow
`
`
`
`8
`
`
`
`Novartis Exhibit 2004.008
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Corresponding Disclosure
`ease of use, i.e. to apply silicone oil to the inside of the barrel, which decreases the force required
`to move the stopper.” 631 Patent at 4:48-50. The 631 Patent further acknowledges that for
`ophthalmic use, “it is desirable to decrease the likelihood of silicone oil droplets being injected into
`the eye. With multiple injections, the amount of silicone droplets can build up in the eye, causing
`potential adverse effects, including “floaters” and an increase in intra-ocular pressure. Furthermore,
`silicone oil can cause proteins to aggregate.” 631 Patent at 4:50-56. Thus, the 631 Patent admitted
`it was known in the prior art that is was desirable to reduce the amount of silicone oil in a pre-filled
`syringe.
`
`Moreover, if Novartis contends that Sigg does not disclose the claimed limitation, then Sigg
`renders this limitation obvious in view of numerous prior art references.
`
` A
`
` person of ordinary skill in the art would have been motivated to combine the teachings of Sigg
`with Boulange, Fries, Hioki, Chacornac, D’Souza, Reuter, Nema, Khandke, and/or DC365, and
`would have had a reasonable expectation of success in doing so, as these references are in the same
`technical field. It further would have been an obvious design choice. Such a person likewise would
`have understood that such combination was merely the application of a known to a known device
`would have led to predictable results.
`
`For example, see the following passages and/or figures, as well as all related disclosures:
`
`
`The present invention relates in general to a medical device, for example a syringe,
`comprising at least one smooth coated part, , for example a container and/or a piston, said
`parts being able to move one relative to the other, for example translationally and/or
`rotationally, when the medical device is operated.
`
`In this application, the term distal means the part furthest from the user's hand, and the
`term proximal means the part closest to the user's hand. Likewise, in this application, the
`term "distal direction" means the direction of administration, i.e., towards the patient, and
`the term "proximal direction" means direction opposite to the direction of administration,
`i.e., away from the patient.
`
`
`Claim Language
`
`
`
`9
`
`
`
`Novartis Exhibit 2004.009
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`Furthermore, the container is intended to accommodate a medical product in the liquid,
`gaseous, fluid, pasty or lyophilized phase, which may have a variable viscosity and is
`therefore able to flow, particularly because of the pressure exerted as a result of the
`movement of the piston relative to the container. The piston is preferably made at least
`partially from a viscoelastic material so as to ensure tightness in the region of contact
`between the container and the piston. At the same time, the volume of the medical product
`contained in the medical device varies, for example decreases, according to the relative
`movement between the two parts of the medical device.
`
`Boulange at 1:3-22.
`
`
`The medical device of the invention allows to have decreased activation, sustainable and
`final forces for moving a first part relative to a second part, for example for moving a
`piston within the container in which it is lodged, without having to add a lubricant and
`while preserving the tightness at the contact region between said two parts. For example,
`in a medical device such as a syringe, the piston must be able to be moved relative to the
`container or syringe body, through a gliding movement, while at the same time ensuring
`the tightness with said container, so that all of the product to be administered escapes only
`via the distal end of the container and does not leak out of said container via the piston at
`the proximal end of the container. The medical device of the invention, thanks to a
`specific coating having a specific roughness range at the contact region between the piston
`and the container, allows the successful completion of these two relatively incompatible
`requirements.
`
`Moreover, with the medical device of the invention, it is possible to decrease the total
`amount of lubricant, for example silicone oil, that is necessary in such a medical device.
`
`
`Boulange at 6:10-25.
`
`
`The container 2 is a glass syringe body accommodating a piston 3 able to move
`translationally. . .
`
`
`
`
`10
`
`
`
`Novartis Exhibit 2004.010
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`Boulange at 13:11-12.
`
`
`Activation Gliding Force (AGF) tests were applied on containers filled with 1 mL of
`demineralised water and each plugged with one piston to be tested (coated or uncoated).
`
`
`Boulange at 14:19-21.
`
`
`Example 5
`
`The protocol of Example 2 was repeated for both of the following scenarios:
`
`Scenario 1: a silicone lubricant was deposited and baked onto the internal surface of the
`syringe body 2, at a rate of 40 μg for a surface area of 10 cm2, but no silicone was used or
`sprayed on the pistons 3.
`
`
`Boulange at 20:11-17.
`
`
`
`
`11
`
`
`
`Novartis Exhibit 2004.011
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`
`
`
`
`Boulange at Table 7 (annotated).
`
`
`
`Boulange at 21:21-22:2.
`
`
`In an alternative form of embodiment that has not been illustrated, the coating according
`to the invention is on the container rather than on the piston. In this configuration, the
`piston may be provided with a coating of silicone to face the coating at the contact region.
`
`Advanced siliconization technology has been developed to lower the level of free (non-
`bound) silicone oil in prefilled syringes. The baked siliconization method uses emulsions
`of silicone oil (e.g., Dow Corning 365, 35% Dimethicone NF Emulsion, diluted to HPW)
`sprayed into syringe barrels followed by heat treatment in a tunnel. Proprietary techniques
`and downstream washing processes vary depending on syringe supplier. Critical quality
`attributes of the siliconization process arc controlled through the settings of siliconization
`pump and nozzle, the volume flow of silicone spray and air, the concentration of the
`
`
`
`12
`
`
`
`Novartis Exhibit 2004.012
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`silicone oil emulsion and tunnel temperature, speed, and length. This technology alters the
`nature of the lubricant in the following way. Heat-induced polymerization reactions
`reduce reactions of low molecular weight form the silicone oil. Removal of water enables
`the lubricant to spread out evenly over the glass surface and creates a thin, uniform film.
`Mono-layers of the lubricant are affixed to the glass surface. The interactions between
`polydimethysiloxane and molecules from the glass surface range from van der Waals
`forces of covalent Si-O bonds. This means thermal fixation processes convert silicone oil
`into Si(R)O coating as illustrated in Figure 4. The thickness of silicone oil layers on the
`glass surface can be measured by reflectometry. A comparative study using cartrdiges as
`glass containers found for oily siliconization a layer thickness with a mean of 232.67 nm
`and for baked siliconization of 76.83 nm.
`
`Fundamental understanding of the design space of baked siliconization allows the syringe
`manufacturer to derive relevant process parameters from the specified quality attributes of
`the syringes. A range of syringes samples are produced through custom engineering
`processes. Quality inspection and initial stability studies with the set of samples determine
`which silicone coating is ideal for purpose. A case study has demonstrated how
`customization of baked silicone coatings facilitates stability of sensitive molecules in
`prefilled syringes (e.g., vaccine candidate for biopharmaceutical development). The study
`has deepened the insight into the relationship between siliconization parameters and
`critical quality attributes. The amount of extractable silicone oil could be reduced below
`the detection limit (0.03 mg) of ICP-AES according to EN ISO 11885. With low levels of
`lubricant quality, the specified syringe functionality was fulfilled (plunger gliding forces
`in the range of 5 to 10 N).
`
`
`Fries at 26.
`
`
`
`Fries at 26-27.
`
`
`Regardless of the material of the barrel, to ensure sufficient slidability between the barrel
`and gasket, a lubricant layer composed of silicone or the like is generally provided on the
`inner peripheral surface of the barrel and/or the outer peripheral surface of the gasket.
`
`
`
`13
`
`
`
`Novartis Exhibit 2004.013
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`
`Hioki at [0005].
`
`
`In the case of conventionally used glass barrels, typically, silicone, in the form of an
`emulsion, is applied to the inner peripheral surface of the barrels and is fixed by baking at
`a high temperature (200 to 300° C.). Silicone in itself is not harmful to the human body,
`but the silicone is fixed to the inner peripheral surface of the barrels to avoid the silicone
`contaminating the drugs.
`
`
`Hioki at [0006].
`
`
`In the case of resin barrels, since the glass transition point of resins is lower than the
`baking temperature of silicone, the same fixing treatment as for glass barrels cannot be
`used. In the case of resin barrels, methods in which a radiation or ultraviolet-curable
`organopolysiloxane is used and methods in which a photopolymerization catalyst such as
`benzophenone is added to silicone have been proposed as examples of methods for fixing
`silicone instead of baking at a high temperature (Patent Document 1).
`
`
`Hioki at [0007].
`
`
`
`Hioki at [0021].
`
`
`That is, the syringe of the present invention is characterized by having a resin barrel, a
`gasket slidably inserted in the barrel, a plunger attached to the gasket, and a silicone film
`formed by applying a silicone oil having a kinematic viscosity of 500 to 100,000 cSt to
`the inner peripheral surface of the above-described barrel in an amount of 5 to 50 μg per 1
`cm2 of area.
`
`Since a silicone oil having a kinematic viscosity of at least 500 cSt is used as the silicone
`constituting the silicone film in this syringe, when spraying the silicone oil, the silicone oil
`is appropriately maintained on the inner peripheral surface of the barrel without running.
`For that reason, even when a small amount of silicone oil is applied, it is possible to
`
`
`
`14
`
`
`
`Novartis Exhibit 2004.014
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`ensure sufficient slidability with the gasket. Additionally, since a silicone oil having a
`kinematic viscosity of at most 100,000 cSt is used, it can be applied to the inner peripheral
`surface of the barrel by spraying, and the silicone oil can be evenly applied in the above
`predetermined application amount per unit area.
`
`
`Hioki at [0022].
`
`
`Further, by using a silicone oil having a kinematic viscosity within that range, it is
`possible to ensure sufficient slidability between the barrel and gasket even when the
`amount of the silicone oil applied is at most 50 μg per 1 cm2 of area on the inner
`peripheral surface of the barrel, and the amount of the silicone oil applied can be
`suppressed to a low amount. As a result thereof, when filling with a drug, even if the
`silicone oil becomes mixed into the drug, the amount of contamination can be kept
`extremely low. As such, the occurrence of turbidity due to contamination by the silicone
`oil can be suppressed, the causes of turbidity in a drug in a prefilled syringe can be limited
`to cases of contamination by impurities other than silicone oil, and accuracy in visual
`inspection to ensure safety can be substantially improved. This is particularly applicable to
`cases where a high viscosity drug which is susceptible to contamination by silicone oil is
`loaded. Further, when the application amount is within this range, as long as observation
`is performed by the naked eye, there is also a low likelihood of glare being detected on the
`inner peripheral surface of the barrel. Moreover, when the amount of the silicone oil
`applied to the inner peripheral surface of the barrel is at least 5 μg per 1 cm2 area,
`sufficient slidability between the barrel and the gasket can be ensured.
`
`
`Hioki at [0023].
`
`
`
`
`While the silicone oil forming silicone film 28 applied to the inner peripheral surface of
`the barrel is basically polydimethylsiloxane, a polydimethylsiloxane with a side chain or
`terminal substitution within a range not impairing lubricity may be used. Specifically, for
`example, polymethylphenylsiloxane and polymethylhydrogen siloxane may be mentioned.
`Various additives may be added to the silicone oil as necessary.
`
`
`
`15
`
`
`
`Novartis Exhibit 2004.015
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`Hioki at [0073].
`
`
`The above-described silicone oil preferably has a kinematic viscosity of 500 to 100,000
`cSt at 25° C., and in particular, one having a kinematic viscosity of 1,000 to 30,000 cSt is
`more preferably used. When the kinematic viscosity is at least 500 cSt, the silicone oil is
`appropriately maintained at the spraying site on the inner peripheral surface of barrel 20
`without running from the inner peripheral surface of barrel 20, so the slidability between
`barrel 20 and gasket 24 can be sufficiently ensured with a small amount of application.
`Moreover, when the kinematic viscosity is at most 100,000 cSt, application to the inner
`peripheral surface of barrel 20 by spraying is possible.
`
`
`Hioki at [0074].
`
`
`The application amount of the silicone oil constituting silicone film 28 is preferably 5 to
`50 μg, and particularly preferably 10 to 30 μg, per 1 cm2 of the inner peripheral surface of
`barrel 20.
`
`
`Hioki at [0075].
`
`
`If the application amount of the silicone oil is at least 5 μg per 1 cm2of the inner
`peripheral surface of the barrel, a sufficient slidability between barrel 20 and gasket 24
`can be ensured. Moreover, if the application amount is at most 50 μg per 1 cm2 of the
`inner peripheral surface of the barrel, even if the silicone oil is mixed into the drug when
`loading drug 27, the amount of contamination can be kept extremely small. Further, as
`long as observation is performed by the naked eye, glare will not be detected on the inner
`peripheral surface of barrel 20.
`
`
`Hioki at [0076].
`
`
`When the device is used not only to close the container but also to deliver the composition
`contained in the container, such as by sliding the plunger of a syringe, it is recommended
`to siliconize the inner surface of the container.
`
`
`
`16
`
`
`
`Novartis Exhibit 2004.016
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`
`Chacornac at [0023].
`
`
`However, it has been observed that silicone may in some cases be detrimental to
`adsorption. Indeed, the desorption rate observed in compositions stored in syringes
`conventionally siliconized by mere surface-treatment with a silicone-in-water emulsion
`may be higher than the desorption rate observed in compositions stored in non-siliconized
`containers. We postulate that although the silicone adheres to the inner surface of the
`container, it remains in free form and, upon shaking or stirring, can flow away from the
`inner surface and pass into the container's content (the vaccine composition).
`
`
`Chacornac at [0024].
`
`
`We have now found that this latter problem can be solved by using a container wherein
`the inner surfaces are coated with polymerized silicone. Such a container can be obtained
`by treating the inner surface of the container with a silicone-in-water emulsion, followed
`by heating the container, for example at a temperature of 270 to 330° C. for 30 min. Upon
`heating, the silicone polymerizes on the inner surface of the container and is therefore no
`longer capable of mixing with the composition. Polymerizing the silicone makes it
`possible to reduce the surface energy of the silicone to which the vaccine composition
`may be sensitive.
`
`
`Chacornac at [0025].
`
`
`Additionally, the siliconizing operation comprising a polymerization step (i) is more
`precise and more homogeneous that a simple standard siliconizing operation; and (ii)
`makes it possible to reduce the amount of silicone that is used (that is, loaded on the inner
`surface of the container) by about a factor of 10 without any loss of lubricating effect. For
`example, according to a standard siliconizing process, from 400 to 1000 μg of silicone are
`deposited in a syringe intended to contain doses of 0.5-1 ml (the total inner surface of the
`0.5-1 ml syringe reservoir is about 8 cm2; in this example this surface corresponds to an
`amount of silicone of from about 50 to 125 μg/cm2), whereas from 40 to 100 μg of
`
`
`
`17
`
`
`
`Novartis Exhibit 2004.017
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`silicone are sufficient for the same syringe (about 5 to 12 μg/cm2) if silicone is deposited
`on the inner surfaces of the container and then polymerized, for example by heating. The
`fact that the inner surface of the syringe is coated with a low amount of polymerized
`silicone in a more homogenous manner than with a low amount of free silicone allows
`non-siliconized plungers to slide smoothly, whereas such plungers are inoperative with
`syringes coated with low amount of free silicone.
`
`
`Chacornac at [0026].
`
`
`The coating 15 may be of any convenient thickness. The thickness will be determined by
`such factors as the quantity applied, viscosity of the lubricant, and the temperature of
`application. For reasons of economy, the coating preferably is applied as thinly as
`practical, since no significant advantage is gained by thicker coatings. The exact thickness
`of the coating 15 does not appear to be critical and very thin coatings, i.e., less than one or
`two microns, can exhibit effective lubricating properties. While not necessary for
`operability, it is desirable that the thickness of the coating be substantially uniform
`throughout. The thickness of the coating layer can range from about 50 nm to about 2 μm,
`or about 500 nm to about 1000 nm, or about 1000 nm to about 2 μm.
`
`
`D'Souza at [0079].
`
`
`The siliconization of the syringe barrel is an extremely important aspect of the production
`of sterile, prefillable glass syringes because the functional interaction of the glass barrel
`siliconization and the plunger stopper siliconization is crucial to the efficiency of the
`entire system. Both inadequate and excessive siliconization can cause problems in this
`connection. Th