`
`EXHIBIT A-3
`
`Invalidity Claim Chart of Lam, alone or in combination with any of Sigg, Boulange, Reuter, Scypinski, Fries, Chacornac,
`Nema, D’Souza, Furfine, Badkar, Macugen, Eylea, Lucentis, Stewart, USP789, Liu, Hioki, DC365, Khandke, and/or Dixon
`against U.S. Patent No. 9,220,631.
`
`
`
`Charted Reference:
`
`PCT Patent Publication No. WO 2008/077155 to Lam et al. (“Lam”), in view of Sigg, Boulange, Reuter, Scypinski, Fries, Chacornac,
`Nema, D’Souza, Furfine, Badkar, Macugen, Eylea, Lucentis, Stewart, USP789, Liu, Hioki, DC365, Khandke, and/or Dixon., 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 Lam. 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 2045.001
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`[1.a-pre] A pre-filled,
`terminally sterilized syringe
`for intravitreal injection
`
`Corresponding Disclosure
`Lam 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:
`
`
`Objects used in medical applications are generally sterilized before use. Sterilization can
`be accomplished by a variety of methods including, e.g., steam sterilization, radiation
`sterilization, gas sterilization (e.g. with ethylene oxide), and chemical sterilization.
`However, these treatments cannot be used for objects containing pharmaceutical
`compositions because their active ingredients are typically sensitive to them. For example,
`steam and gas sterilization are generally performed at high temperatures (approx. 45 0 C
`to 55 0 C or higher) that damage certain active ingredients in pharmaceutical
`compositions. Similarly, the agents used for radiation or chemical sterilization generally
`cause chemical damage to the active ingredients. Consequently, pharmaceutical
`compositions are generally sterilized by an alternative method, e.g. by filtration, and then
`packaged into separately sterilized objects. Because of the complexity of this process, it is
`difficult to also ensure the sterility of the surfaces of the objects.
`
`In many circumstances it would be advantageous to sterilize the surfaces of these objects
`in order to reduce the risk of contamination during subsequent handling. For example,
`there is an increased risk of endophthalmitis after intraocular injection if the surface of the
`syringe used for injection is not sterilized. Thus, there remains a need for efficient and
`cost-effective methods of surface-sterilizing objects containing ethylene-oxide-sensitive,
`temperature-sensitive compounds, such as biological molecules, without a significant
`adverse effect on their activity or integrity.
`
`
`Lam at 1:14-32.
`
`
`The invention relates to methods for surface-sterilizing objects containing ethylene-
`oxide-sensitive, temperature-sensitive compounds, such as biological molecules. The
`invention is based, in part, on the surprising discovery of ethylene-oxide -based
`sterilization conditions that will effectively sterilize the surface of an object but which do
`
`
`
`2
`
`Novartis Exhibit 2045.002
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`not significantly damage ethylene-oxide-sensitive, temperature-sensitive compounds
`contained inside.
`
`
`
`
`
`
`
`In one aspect, the invention provides a method for surface-sterilizing an object having an
`ethylene-oxide(EtO)-impermeable interior space containing a compound with a
`temperature-sensitive and EtO-sensitive activity by exposing the object to EtO under
`conditions such that the object is surface-sterilized and the compound retains at least 50%
`of said activity. In some embodiments, the conditions comprise: a) temperature between
`25 0 C and 35 0 C; b) EtO concentration of between 300 mg/L and 800 mg/L; and c)
`relative humidity between 45% and 60%; for between 1 and 6 hours. In some
`embodiments, the conditions comprise: a) temperature between 27 0 C and 33 0 C; b) EtO
`concentration of between 300 mg/L and 600 mg/L; and c) relative humidity between 48%
`and 52%; for between 1 and 6 hours. In some embodiments, the conditions comprise: a)
`temperature of 3O 0 C; b) EtO concentration of 600 mg/L; and c) relative humidity of
`50%; for 1, 1.5 or 2 hours.
`
`In some embodiments, the compound retains at least 90% of said activity. In some
`embodiments, the compound is a polypeptide, e.g. an antibody, which includes
`monoclonal antibodies, chimeric antibodies, humanized antibodies or human antibodies.
`In some embodiments where the compound is a polypeptide, the percent alkylation of the
`polypeptide is not statistically different from a control polypeptide not exposed to EtO. In
`some embodiments, the antibody is an antigen-binding fragment, e.g. a Fab fragment. In
`some embodiments, the Fab fragment binds VEGF, e.g. ranibizumab (LUCENTIS®). In
`some embodiments, the compound is present in an aqueous pharmaceutical composition,
`e.g. a composition comprising at least one of: an amino acid, a disaccharide and a non-
`ionic surfactant. In some embodiments the pharmaceutical composition comprises
`histidine, trehalose and polysorbate 20.
`
`In some embodiments, the object is a syringe. In some embodiments the syringe
`comprises glass and comprises a stopper comprising D777-7 laminated with FluroTec®;
`and a tip cap comprising D777-7 laminated with FluroTec® or D21-7H laminated with
`
`
`
`3
`
`Novartis Exhibit 2045.003
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`FluroTec®. In some embodiments, the object is contained within a package comprising an
`EtO-permeable material, e.g. TYVEK®.
`
`
`Lam at 2:3-33.
`
`
`In some embodiments, the pharmaceutical composition is designed for intraocular
`injection.
`
`
`Lam at 11:30-31.
`
`
`The methods of the invention are typically used to sterilize objects containing
`pharmaceutical formulations. For example, the methods of the invention may be used with
`syringes, vials or cartridges (such as are used in devices designed for multiple injections).
`In addition, the method of the invention may be used with a syringe with or without a
`needle. In the latter case, some sort of cap or needle shield is generally positioned where
`the needle will subsequently be attached. The following example is intended merely to
`illustrate the practice of the present invention and is not provided by way of limitation.
`The disclosures of all patent and scientific literatures cited herein are expressly
`incorporated in their entirety by reference.
`
`
`Lam at 12:31-13:6.
`
`
`We performed experiments to identify whether there were parameters for EtO sterilization
`that would effectively sterilize the surface of an object but which do not damage an
`ethylene-oxide-sensitive, temperature-sensitive compound contained inside. We
`performed EtO sterilization runs on syringes containing a ranibizumab solution (at a
`protein concentration indicated in Table 2 in a solution with 10 mM histidine HCl, 10% α,
`α - trehalose dehydrate, 0.01% polysorbate 20, pH 5.5) where each run had the following
`standard EtO sterilization steps: (1) set temperature; (2) evacuate chamber to about 5.0"
`HgA; (3) leak test; (4) wash twice with nitrogen; (5) humidify chamber and incubate
`about 30 min; (6) inject EtO gas and incubate for dwell time; (7) evacuate chamber to
`about 5.0" HgA; and (8) wash four times with nitrogen (each wash cycle is about 15-20
`
`
`
`4
`
`Novartis Exhibit 2045.004
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`min). In addition to the syringe, each run also included a paper strip with approximately
`1.9 x 10 6 Bacillus subtilis spores, which was used to monitor the sterilization as follows:
`the strip was soaked in media, vortexed vigorously and then serial dilutions were plated
`and grown for one week. We then varied the following sterilization-critical factors as
`indicated in Table 1 : temperature, relative humidity, time of exposure (gas dwell), and
`EtO concentration
`
`
`Lam at 13:12-26.
`
`
`We also tested several different syringe components: where the stopper on the plunger
`comprised D777-7 laminated with a 125 μm coating of FluroTec® barrier film and where
`the tip cap comprised either D777-7 or D21-7H laminated on both the surface in contact
`with the tip of the syringe and the exterior surface with a 125 μm coating of FluroTec®
`barrier film (all components from West Pharmaceutical Services / Daikyo Seiko). We
`measured the residual EtO in the syringe and the stability of ranibizumab by IEC the same
`day as the treatment and at various monthly time points thereafter. For IEC, we measured
`the percentage of protein in the main peak and in the acidic and basic peaks, with the
`protein in the basic peak representative of alkylation which may have been caused by the
`EtO treatment. As shown in Table 3, under all conditions tested the percentage of protein
`in the basic peaks was at most approximately 1% over control. Further, when the
`FluroTec® barrier film was used on the syringe components, the percentage of protein in
`the basic peak was not statistically different from control.
`
`
`Lam at 15:12-24.
`
`
`
`
`5
`
`Novartis Exhibit 2045.005
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`
`
`Lam at Table 3.
`
`
`The above specification, example and data provide a complete description of the
`manufacture and use of the composition of the invention. Since many embodiments of the
`invention can be made without departing from the spirit and scope of the invention, the
`invention includes all such embodiments.
`
`
`
`
`
`6
`
`Novartis Exhibit 2045.006
`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
`This specification contains numerous citations to literature and patents. Each is hereby
`incorporated by reference for all purposes, as if fully set forth.
`
`Lam at 16:3-8.
`
`To the extent Novartis alleges this limitation is not met by any of the disclosures above, it would be
`obvious in view of Sigg, Boulange, Reuter, Scypinski, Metzner, Shah, Fries, Schoenknecht,
`Chacornac, Nema, D’Souza, Furfine, Badkar, Macugen, Eylea, and/or Lucentis. See A-1–A-2, A-
`4–A-13, B-1–B-3 and all references cited therein.
`Lam 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:
`
`
`In some embodiments, the object is a syringe. In some embodiments the syringe
`comprises glass and comprises a stopper comprising D777-7 laminated with FluroTec®;
`and a tip cap comprising D777-7 laminated with FluroTec® or D21-7H laminated with
`FluroTec®. In some embodiments, the object is contained within a package comprising an
`EtO-permeable material, e.g. TYVEK®.
`
`
`Lam at 2:29-33.
`
`
`As used herein, an "ethylene-oxide-impermeable" or "EtO-impermeable" object is one in
`which no more than 0.5 ppm EtO is present inside the object after EtO sterilization. As
`EtO-impermable object may comprise, e.g., glass and/or certain plastics.
`
`
`Lam at 3:17-19.
`
`
`We next tested additional conditions with different dwell times during the EtO cycle,
`different numbers of washes and different container components. We performed EtO
`sterilization runs on syringes containing a ranibizumab solution (at 10.0 mg/ml in a
`solution with 10 mM histidine HCl, 10% α, α -trehalose dehydrate, 0.01% polysorbate 20,
`pH 5.6) where each run had the following standard EtO sterilization steps: (1) set
`
`
`
`7
`
`Novartis Exhibit 2045.007
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`temperature to 3O 0 C; (2) evacuate chamber to about 5.0" HgA; (3) leak test; (4) wash
`twice with nitrogen; (5) humidify chamber and incubate about 30 min; (6) inject EtO gas
`and incubate for dwell time indicated in Table 3; (7) evacuate chamber to about 5.0" HgA;
`and (8) wash with with nitrogen the number of time indicated in Table 3. In addition to the
`syringe, each run also included a paper strip with approximately 1.9 x 10 6 Bacillus
`subtilis spores, which was used to monitor the sterilization as follows: the strip was
`soaked in media, vortexed vigorously and then serial dilutions were plated and grown for
`one week. We also tested several different syringe components: where the stopper on the
`plunger comprised D777-7 laminated with a 125 μm coating of FluroTec® barrier film
`and where the tip cap comprised either D777-7 or D21-7H laminated on both the surface
`in contact with the tip of the syringe and the exterior surface with a 125 μm coating of
`FluroTec® barrier film (all components from West Pharmaceutical Services / Daikyo
`Seiko). We measured the residual EtO in the syringe and the stability of ranibizumab by
`IEC the same day as the treatment and at various monthly time points thereafter. For IEC,
`we measured the percentage of protein in the main peak and in the acidic and basic peaks,
`with the protein in the basic peak representative of alkylation which may have been
`caused by the EtO treatment. As shown in Table 3, under all conditions tested the
`percentage of protein in the basic peaks was at most approximately 1% over control.
`Further, when the FluroTec® barrier film was used on the syringe components, the
`percentage of protein in the basic peak was not statistically different from control.
`
`
`Lam at 15:1-24.
`
`
`
`Lam at Claim 21.
`
`
`21. The method of claim 20, wherein said syringe comprises glass and comprises:
`(a) a stopper comprising D777-7 laminated with FluroTec®; and
`(b) a tip cap comprising (i) D777-7 laminated with FluroTec® or (ii) D21-7H laminated
`with FluroTec®.
`
`The above specification, example and data provide a complete description of the
`manufacture and use of the composition of the invention. Since many embodiments of the
`
`
`
`8
`
`Novartis Exhibit 2045.008
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`[1.c] and [the syringe]
`containing an ophthalmic
`solution which comprises a
`VEGF-antagonist, wherein
`
`Corresponding Disclosure
`invention can be made without departing from the spirit and scope of the invention, the
`invention includes all such embodiments.
`
`This specification contains numerous citations to literature and patents. Each is hereby
`incorporated by reference for all purposes, as if fully set forth.
`
`Lam at 16:3-8.
`
`To the extent Novartis alleges this limitation is not met by any of the disclosures above, it would
`have been obvious in view of Sigg, Boulange, Reuter, Scypinski, Metzner, Shah, Fries,
`Schoenknecht, Chacornac, Nema, D’Souza, Furfine, Badkar, Macugen, Eylea, and/or Lucentis. See
`A-1–A-2, A-4–A-13, B-1–B-3 and all references cited therein.
`Lam 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 some embodiments, the compound retains at least 90% of said activity. In some
`embodiments, the compound is a polypeptide, e.g. an antibody, which includes
`monoclonal antibodies, chimeric antibodies, humanized antibodies or human antibodies.
`In some embodiments where the compound is a polypeptide, the percent alkylation of the
`polypeptide is not statistically different from a control polypeptide not exposed to EtO. In
`some embodiments, the antibody is an antigen-binding fragment, e.g. a Fab fragment. In
`some embodiments, the Fab fragment binds VEGF, e.g. ranibizumab (LUCENTIS®). In
`some embodiments, the compound is present in an aqueous pharmaceutical composition,
`e.g. a composition comprising at least one of: an amino acid, a disaccharide and a non-
`ionic surfactant. In some embodiments the pharmaceutical composition comprises
`histidine, trehalose and polysorbate 20.
`
`
`Lam at 2:18-24.
`
`
`VEGF or VEGF receptor antibodies including humanized and/or affinity matured VEGF
`antibodies such as the humanized VEGF antibody huA4.6.1 bevacizumab (AVASTIN®)
`
`
`
`9
`
`Novartis Exhibit 2045.009
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`and ranibizumab (LUCENTIS®) (Kim et al., Growth Factors, 7:53-64 (1992),
`International Publication Nos. WO 96/30046 and WO 98/45331)
`
`
`Lam at 7:24-27.
`
`
`In some embodiments, non-polypeptide compounds are used in the methods of the
`invention. These include, e.g., pegaptanib (MACUGEN®; Eyetech Pharmaceuticals),
`steroids, and compounds used for RNA-interference mediated therapy.
`
`
`Lam at 11:9-11.
`
`
`We performed experiments to identify whether there were parameters for EtO sterilization
`that would effectively sterilize the surface of an object but which do not damage an
`ethylene-oxide-sensitive, temperature-sensitive compound contained inside. We
`performed EtO sterilization runs on syringes containing a ranibizumab solution (at a
`protein concentration indicated in Table 2 in a solution with 10 mM histidine HCl, 10% α,
`α - trehalose dehydrate, 0.01% polysorbate 20, pH 5.5) where each run had the following
`standard EtO sterilization steps: (1) set temperature; (2) evacuate chamber to about 5.0"
`HgA; (3) leak test; (4) wash twice with nitrogen; (5) humidify chamber and incubate
`about 30 min; (6) inject EtO gas and incubate for dwell time; (7) evacuate chamber to
`about 5.0" HgA; and (8) wash four times with nitrogen (each wash cycle is about 15-20
`min). In addition to the syringe, each run also included a paper strip with approximately
`1.9 x 10 6 Bacillus subtilis spores, which was used to monitor the sterilization as follows:
`the strip was soaked in media, vortexed vigorously and then serial dilutions were plated
`and grown for one week. We then varied the following sterilization-critical factors as
`indicated in Table 1 : temperature, relative humidity, time of exposure (gas dwell), and
`EtO concentration.
`
`
`Lam at 13:12-26.
`
`
`The above specification, example and data provide a complete description of the
`manufacture and use of the composition of the invention. Since many embodiments of the
`
`
`
`10
`
`Novartis Exhibit 2045.010
`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
`invention can be made without departing from the spirit and scope of the invention, the
`invention includes all such embodiments.
`
`This specification contains numerous citations to literature and patents. Each is hereby
`incorporated by reference for all purposes, as if fully set forth.
`
`Lam at 16:3-8.
`
`To the extent Novartis alleges this limitation is not met by any of the disclosures above, it would
`have been obvious in view of Sigg, Boulange, Reuter, Scypinski, Metzner, Shah, Fries,
`Schoenknecht, Chacornac, Nema, D’Souza, Furfine, Badkar, Macugen, Eylea, and/or Lucentis. See
`A-1–A-2, A-4–A-13, B-1–B-3 and all references cited therein.
`Lam discloses pre-filled syringes for intravitreal administration, and therefore, it would have been
`obvious to a POSITA that the syringes are small volume syringes, for example, between 0.5-1 ml
`in volume.
`
`For example, see the following passages and/or figures, as well as all related disclosures:
`
`
`VEGF or VEGF receptor antibodies including humanized and/or affinity matured VEGF
`antibodies such as the humanized VEGF antibody huA4.6.1 bevacizumab (AVASTIN®)
`and ranibizumab (LUCENTIS®) (Kim et al., Growth Factors, 7:53-64 (1992),
`International Publication Nos. WO 96/30046 and WO 98/45331)
`
`
`Lam at 7:24-27.
`
`
`In some embodiments, non-polypeptide compounds are used in the methods of the
`invention. These include, e.g., pegaptanib (MACUGEN®; Eyetech Pharmaceuticals),
`steroids, and compounds used for RNA-interference mediated therapy.
`
`
`Lam at 11:9-11.
`
`
`
`
`11
`
`Novartis Exhibit 2045.011
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`In some embodiments, the pharmaceutical composition is designed for intraocular
`injection.
`
`
`Lam at 11:30-31.
`
`
`We next tested additional conditions with different dwell times during the EtO cycle,
`different numbers of washes and different container components. We performed EtO
`sterilization runs on syringes containing a ranibizumab solution (at 10.0 mg/ml in a
`solution with 10 mM histidine HCl, 10% α, α -trehalose dehydrate, 0.01% polysorbate 20,
`pH 5.6) where each run had the following standard EtO sterilization steps: (1) set
`temperature to 3O 0 C; (2) evacuate chamber to about 5.0" HgA; (3) leak test; (4) wash
`twice with nitrogen; (5) humidify chamber and incubate about 30 min; (6) inject EtO gas
`and incubate for dwell time indicated in Table 3; (7) evacuate chamber to about 5.0" HgA;
`and (8) wash with with nitrogen the number of time indicated in Table 3. In addition to the
`syringe, each run also included a paper strip with approximately 1.9 x 10 6 Bacillus
`subtilis spores, which was used to monitor the sterilization as follows: the strip was
`soaked in media, vortexed vigorously and then serial dilutions were plated and grown for
`one week. We also tested several different syringe components: where the stopper on the
`plunger comprised D777-7 laminated with a 125 μm coating of FluroTec® barrier film
`and where the tip cap comprised either D777-7 or D21-7H laminated on both the surface
`in contact with the tip of the syringe and the exterior surface with a 125 μm coating of
`FluroTec® barrier film (all components from West Pharmaceutical Services / Daikyo
`Seiko). We measured the residual EtO in the syringe and the stability of ranibizumab by
`IEC the same day as the treatment and at various monthly time points thereafter. For IEC,
`we measured the percentage of protein in the main peak and in the acidic and basic peaks,
`with the protein in the basic peak representative of alkylation which may have been
`caused by the EtO treatment. As shown in Table 3, under all conditions tested the
`percentage of protein in the basic peaks was at most approximately 1% over control.
`Further, when the FluroTec® barrier film was used on the syringe components, the
`percentage of protein in the basic peak was not statistically different from control.
`
`
`Lam at 15:1-24.
`
`
`
`12
`
`Novartis Exhibit 2045.012
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`
`
`The above specification, example and data provide a complete description of the
`manufacture and use of the composition of the invention. Since many embodiments of the
`invention can be made without departing from the spirit and scope of the invention, the
`invention includes all such embodiments.
`
`This specification contains numerous citations to literature and patents. Each is hereby
`incorporated by reference for all purposes, as if fully set forth.
`
`Lam at 16:3-8.
`
` A
`
` POSITA would have understood that pre-filled syringes for intravitreal administration disclosed
`would be 0.5 ml or 1 ml, or alternatively it would have been obvious for a POSITA to select the
`claimed syringe sizes for use for intravitreal injection. A POSITA would have had a reasonable
`expectation of success combining Lam and Nema, Chacornac, Furfine, Sigg, and/or Macugen in a
`way that satisfies this limitation.
`
`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 art that pre-filled syringes
`containing an ophthalmic solution for intravitreal administration are generally administered in
`volumes < 0.1 mL. Indeed, the Background Art section of the 631 Patent acknowledges that “[f]or
`small volume syringes, for example those for injections into the eye in which it is intended that
`about 0.1 ml or less of liquid is to be injected. . .” 631 Patent at 1:22-24. A POSITA would have
`understood that the nominal maximum fill volume has to be more than the volume that is desired
`for injection, in order to account for priming and loss of product. Moreover, 0.5 mL and 1 mL are
`standard syringe sizes that are commonly used for intravitreal applications. See, e.g., Macugen
`(VEGF antagonist delivered in a 1 ml prefilled syringe).
`
`
`
`
`13
`
`Novartis Exhibit 2045.013
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`Moreover, if Novartis contends that Lam does not disclose the claimed limitation, then Lam
`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 Lam
`with Nema, Chacornac, Furfine, Sigg, and/or Macugen, 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:
`
`
`
`Nema Vol. 1 at Table 1.
`
`
`
`
`
`
`14
`
`Novartis Exhibit 2045.014
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`
`
`
`Nema Vol. 1 at Figure 9.
`
`
`
`
`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
`
`
`
`15
`
`Novartis Exhibit 2045.015
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`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].
`
`
`Example 4. Stability of 40 mg/ml VEGF Trap Liquid Formulation Stored at 5° C in Pre-
`filled Glass Syringe.
`
` A
`
` liquid formulation containing 40 mg/ml VEGF trap (SEQ ID NO:4), 10 mM phosphate,
`40 mM NaCI, 0.03% polysorbate 20, 5% sucrose, and pH 6.3, was stored at 5 0 C in 1 ml
`prefilled luer glass syringe with 4023/50 FluroTec coated plunger and samples tested at
`0.5, 1 , 2, 3, and 4 months. Stability results are shown in Table 4. Turbidity, percent
`recovered protein and purity was determined as described above.
`
`
`Furfine at [0059]
`
`
`Example 6. Stability of 40 mg/ml VEGF Trap Liquid Formulation Stored at 5 0 C in 1 ml
`Pre- filled Glass Syringe.
`
` A
`
` liquid formulation containing 40 mg/ml VEGF trap (SEQ ID NO:4), 10 mM phosphate,
`135 mM NaCI, 0.03% polysorbate 20, and pH 6.3, was stored at 5 0 C in 1 ml prefilled
`glass luer syringe with 4023/50 FluroTec coated plunger and samples tested at 0.5, 1, 2, 3,
`4, and 5 months. Stability results are shown in Table 6. Turbidity, percent recovered
`protein and purity was determined as described above.
`
`
`Furfine at [0061]
`
`
`Filling of 0.5 mL syringes was performed in a sterile lab for hydrogen peroxide treatment.
`
`Claim Language
`
`
`
`16
`
`Novartis Exhibit 2045.016
`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
`
`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
`
`Macugen (pegaptanib sodium injection) is supplied in a single use 1 mL glass syringe with a gray
`rubber plunger containing 0.3 mg in a 90 uL deliverable volume. Each syringe is fitted with a fixed
`gauge needle covered with a gray rubber needle shield and a rigid plastic outside sheath. All are
`contained in a foil pouch. The accompanying polystyrene plunger rod and white flange are in a
`separate foil pouch. The two foil pouches are packaged in a carton.
`
`To the extent Novartis alleges this limitation is not met by any of the disclosures above and/or
`obvious based on the knowledge of a POSITA, it would have been obvious in view of Sigg,
`Boulange, Reuter, Scypinski, Metzner, Shah, Fries, Schoenknecht, Chacornac, Nema, D’Souza,
`Furfine, Badkar, Macugen, Eylea, and/or Lucentis. See A-1–A-2, A-4–A-13, B-1–B-3 and all
`references cited therein.
`It would have been obvious to a POSITA to use a known baked silicone method to siliconize the
`syringes disclosed in Lam, which would result in a syringe that meets this limitation. Lam 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.
`
`For example, see the following passages and/or figures, as well as all related disclosures:
`
`
`In many circumstances it would be advantageous to sterilize the surfaces of these objects
`in order to reduce the risk of contamination during subsequent handling. For example,
`there is an increased risk of endophthalmitis after intraocular injection if the surface of the
`syringe used for injection is not sterilized. Thus, there remains a need for efficient and
`cost-effective methods of surface-sterilizing objects containing ethylene-oxide-sensitive,
`
`
`
`17
`
`Novartis Exhibit 2045.017
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`temperature-sensitive compounds, such as biological molecules, without a significant
`adverse effect on their activity or integrity.
`
`
`Lam at 1:26-32.
`
`
`
`
`
`
`The invention relates to methods for surface-sterilizing objects containing ethylene-
`oxide-sensitive, temperature-sensitive compounds, such as biological molecules. The
`invention is based, in part, on the surprising discovery of ethylene-oxide -based
`sterilization conditions that will effectively sterilize the surface of an object but which do
`not significantly damage ethylene-oxide-sensitive, temperature-sensitive compounds
`contained inside.
`
`In one aspect, the invention provides a method for surface-sterilizing an object having an
`ethylene-oxide(EtO)-impermeable interior space containing a compound with a
`temperature-sensitive and EtO-sensitive activity by exposing the object to EtO under
`conditions such that the object is surfac