`
`EXHIBIT A-2
`
`Invalidity Claim Chart of Boulange, alone or in combination with any of Sigg, 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 2009/030976 to Boulange et al. (“Boulange”), in view of Sigg, 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.
`
`Boulange is an International Patent Application publication that was published on March 12, 2009, and therefore qualifies as prior art
`at least under pre-AIA § 102(b).
`
`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 Boulange. 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 2005.001
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`[1.a-pre] A pre-filled . . .
`syringe
`
`Corresponding Disclosure
`Boulange discloses a pre-filled syringe.
`
`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.
`
`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.
`
`
`With reference to figures 1 and 2, the medical device 1 comprises a first and a second
`parts 2 and 3, one being complementary to the other, for example a piston 3 housed in a
`container 2, the piston 3 and the internal surface of the container 2 being in contact with
`one another via a contact region 10. The piston 3 and the container 2 are able to move one
`with respect to the other in a predetermined gliding movement 4, for example
`translationally and/or rotationally. The container 2 is intended to accommodate a medical
`
`
`
`
`
`2
`
`Novartis Exhibit 2005.002
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`product 6 in the liquid, gaseous or fluid phase, the volume of said product 6 varying
`according to the movement of the piston 3 with respect to the container 2. In particular,
`for administering the product 6, the piston 3 is caused to move distally along arrow 4 of
`figure 1 in order to push the product 6 out of the container 2. The piston 3 is designed to
`deform in order to tighten the contact region 10. For example on figure 2, at least part of
`the developed surface of the piston 3, which corresponds to the contact region 10, is
`provided with a coating 8 which is continuous, intrinsically elastic and firmly secured to
`the piston 3.
`
`Boulange at 9:21-35.
`
`
`The following test protocol is performed on a medical device 1 of the syringe type,
`according to the second embodiment depicted in Figure 2 of the present application.
`
`The container 2 is a glass syringe body accommodating a piston 3 able to move
`translationally along arrow 4 of figure 2 inside the container 2.
`
`The piston 3 is made of a viscoelastic material such as bromobutyl rubber commercially
`available at West Company, or chlorobutyl rubber commercially available at West
`Company.
`
`
`Boulange at 13:8-15.
`
`
`
`
`
`
`3
`
`Novartis Exhibit 2005.003
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`
`
`Boulange at Figure 2; see also Boulange at Figure 1.
`
`
`
`
`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.
`
`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, 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-1, A-3–
`A-13, B-1–B-3 and all references cited therein.
`It would have been obvious to terminally sterilize the prefilled syringe disclosed in Boulange. A
`POSITA would have understood and appreciated the benefits of terminal sterilization using H2O2
`or EtO and would have found it obvious to sterilize the syringe in such manner as required by this
`claim limitation.
`
`terminally sterilized syringe
`
`
`
`
`
`4
`
`Novartis Exhibit 2005.004
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Corresponding Disclosure
`
`Boulange alone or in view of Lam, Sigg, Nema, Metzner, Wittland, Hagen, Scypinski, and/or
`D’Souza, disclose a terminally sterilized syringe. A POSITA would have had a reasonable
`expectation of success combining Boulange and Lam, Sigg, Nema, Metzner, Wittland, Hagen,
`Scypinski, and/or D’Souza in a way that would satisfy this limitation.
`
`To the extent this limitation is not expressly and/or inherently disclosed by Boulange, such
`limitation would have been obvious, 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 according to known methods, to achieve predictable results.
`
`In addition, the 631 Patent fails to disclose a new process for terminal sterilization. The 631 Patent
`explains “a careful balancing act is required to ensure that while a suitable level of sterilisation is
`carried out, the syringe remains suitably sealed, such that the therapeutic is not compromised.” 631
`Patent at 1:31-36. The 631 Patent says that the sterilization it discloses may be done via "known"
`methods, such as by using VHP or EtO, but no details are provided regarding the sterilization
`process itself. 631 Patent at 9:49-54 (“As noted above, a terminal sterilisation process may be used
`to sterilise the syringe and such a process may use a known process such as an ethylene oxide
`(EtO) or a hydrogen peroxide (H2O2) sterilisation process. Needles to be used with the syringe
`may be sterilised by the same method, as may kits according to the invention.”) The remaining
`description in the 631 Patent only sets forth desired results – how long the syringe remains sterile,
`the Sterility Assurance Level, the alkylation of the product, and the amount of chemical residue
`remaining – but does not detail the steps to achieving them. See e.g., id. at 9:55-10:22. Because the
`631 Patent does not provide any details regarding the known sterilization methods, it admits that
`those methods were known in the art and thus render this claim limitation obvious.
`
` POSITA would have known that terminal sterilization of prefilled containers in secondary
`packaging is one way to sterilize the device and maintain a low bio-burden and low risk of
`contaminants. A POSITA also would have known that terminal sterilization is applicable to a broad
`range of solutions, including those that are temperature, oxidation, or radiation sensitive.
`
`
` A
`
`Claim Language
`
`
`
`
`
`5
`
`Novartis Exhibit 2005.005
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`Moreover, if Novartis contends that Boulange does not disclose the claimed limitation, then
`Boulange 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 Boulange with
`Lam, Sigg, Nema, Metzner, Wittland, Hagen, Scypinski, and/or D’Souza, and would have had a
`reasonable expectation of success in doing so, at least because these references are in the same
`technical field. Moreover, the references teach the benefits and advantages of applying terminal
`sterilization techniques, as can be seen in the excerpts below. It further would have been an
`obvious design choice. Such a person likewise would have understood that such combination
`would have been nothing more than a simple substitution or combination of known elements and/or
`methods, or an application of known techniques, to achieve predictable results.
`
`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°C to
`55°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,
`
`
`
`
`
`6
`
`Novartis Exhibit 2005.006
`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 1:14-32
`
`
`
`
`
`
`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
`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°C and 35°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°C and 33°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
`30°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
`
`
`
`
`
`7
`
`Novartis Exhibit 2005.007
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`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
`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
`
`
`
`
`
`8
`
`Novartis Exhibit 2005.008
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`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 106 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
`
`
`
`
`
`9
`
`Novartis Exhibit 2005.009
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`
`
`
`Lam at Table 3.
`
`
`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
`
`
`
`
`
`
`
`10
`
`Novartis Exhibit 2005.010
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`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.
`
`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.
`
`
`
`
`
`11
`
`Novartis Exhibit 2005.011
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`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.
`
`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).
`
`
`
`
`
`
`12
`
`Novartis Exhibit 2005.012
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`
`
`
`
`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.
`
`
`GAS STERILIZATION
`
`Gas sterilization is widely used for materials and equipment liable to damage by moist
`heat, dry heat, or radiation processes. Many of the common polymeric materials used in
`medical devices are difficult to sterilize by any other means. When finally packaged for
`delivery into operating and other critical settings, the medical device packaging must be
`sterile as well. The most prevalent gas utilized for sterilization is ETO, and sterilization
`using other agents is based on methods used for ETO. Other commercially available gas
`
`13
`
`
`
`
`
`Novartis Exhibit 2005.013
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`agents for sterilization are ozone and chlorine dioxide. While their use is not widespread,
`they offer the user alternates to ETO. Other gases that have demonstrated sterilization
`capability but almost no commercial support include methyl bromide, propylene oxide,
`helium/ oxygen plasma, and sulfur dioxide (7,8).
`
`
`
`Gases will not condense under typical sterilizing conditions and are highly penetrating.
`The penetrating abilities of the more common gases vary: ETO is superior to ozone, which
`is in turn superior to chlorine dioxide (9). Sterilization efficacy is enhanced when
`prehumidification is provided prior to sterilization. Optimum temperatures vary: ozone
`and chlorine dioxide are typically performed at room temperature, while ETO can be
`effective from ambient temperature to 60T (9).
`
`Gas sterilization process equipment must properly control gas concentration, relative
`humidity, and temperature throughout the process to provide consistent process lethality,
`as changes in the essential process parameters can alter the effectiveness of the gases
`ability to penetrate and react with the microorganisms and thus lethality. Humidification is
`typically accomplished using clean steam injection directly to the sterilizing chamber.
`ETO is highly penetrating through corrugate, polymers, and paper materials, which make
`it well suited for sterilization of medical devices in their final packaging. Ozone and
`chlorine dioxide are less penetrating, and their application for medical devices must be
`considered with some caution. Because each of these agents is a gas and the chamber is
`well mixed, single-point monitoring of gas concentration and RH provides adequate
`process control over the sterilization process. Despite this seemingly minimal monitoring,
`regulatory approval for parametric release for ETO sterilization is widespread.
`
`
`Nema Vol. 2 at pg. 245
`
`
`ETHYLENE OXIDE
`ETO is a powerful oxidizing gas that kills microbes primarily by chemical reaction with
`various sites in microorganisms primarily those with NH2, SH, COOH, and CH2OH
`groups (10). Microbial kill with ETO approximates first-order kinetics and is directly
`related to gas concentration, relative humidity, and process temperature (10). ETO is
`
`
`
`
`
`14
`
`Novartis Exhibit 2005.014
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`widely used for terminal sterilization of medical devices in final packaging. Sterilization
`methods for ETO (and essentially all other sterilizing gases) for the pharmaceutical
`processes follow medical devices practices because of the extensive experience with ETO
`for that application. ETO sterilization is effective across a wide range of conditions: gas
`concentration (300 1000 mg/L); relative humidity (35 85%), and temperature (20 65 'C),
`although the usual processing ranges are somewhat narrower (10). ETO is an extremely
`potent material, has been identified as a mutagenic, carcinogenic, neurotoxic, and highly
`explosive (11). Trace residuals from ETO sterilization are also associated with adverse
`effects, so effective aeration of this is essential for safe use. For these reasons, internal
`usage within pharmaceutical operating companies has decreased. There are a number of
`firms providing contract ETO sterilization that have invested in the necessary controls to
`assure both worker and patient safety, and these offer most of the available industrial
`capacity for ETO sterilization.
`
`As ETO processes are so extensively utilized for medical devices, the typical process is
`largely tailored to the specific requirements of their sterilization. The typical ETO process
`sequence includes
`
`
`• pre-humidification (to raise internal humidity and performed in a room dedicated for
`that purpose);
`• transfer to the sterilizer (with minimal delay);
`• reconditioning in the chamber (to replace humidity lost in transit); • air removal (to
`enhance gas/humidity penetration);
`• exposure to ETO with humidity adjustment;
`• initial aeration in the sterilizing chamber;
`• transfer to a post-exposure aeration location; and
`• post-conditioning (final aeration to remove residual ETO, ethylene chlorhydrin, and
`ethylene glycol) (6).
`
`
`The preprocess treatments ensure adequate moisture is present on the surface of the
`materials for effective kill. The use of pre-humidification chambers/rooms to raise the
`internal moisture content of medical devices is almost universal for ETO sterilization.
`
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`15
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`Novartis Exhibit 2005.015
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`Post-processing aeration chambers are utilized with ETO to reduce residuals to safe levels
`after exposure. ETO sterilization processes introduce essentially all of the gas at the start
`of the process and minor adjustment during the exposure may be performed to maintain
`pressure. Humidity is commonly introduced using clean steam to the chamber
`preexposure for reconditioning after transfer, and adjustment may be required through the
`end of the exposure period.
`
`ETO process control, like all sterilization processes, relies on a combination of physical
`measurements and biological assessments. Biological indicator kill in conjunction with
`data from the sterilizer instrumentation are utilized in evaluating process effectiveness.
`Recently, a lethality model has been proposed that mimics those utilized for steam and dry
`heat (12). Its broader adoption by ETO practitioners is anticipated as it simplifies lethality
`confirmation.
`
`The extensive experience with ETO in medical devices has allowed many firms to
`implement parametric release in lieu of sterility or biological indicator testing of ETO-
`sterilized materials. Parametric release replaces sterility testing with a defined set of
`requirements derived from the initial validation exercise that must be satisfied in
`conjunction with the execution of each subsequent sterilization cycle (13,14). Submission
`to regulatory agencies is required prior to implementation and must be supported by
`comprehensive data derived from prior practice. Once implemented, the user is obligated
`to utilize parameter evaluation exclusively.
`
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`Nema Vol. 2 at pgs. 245-246
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`HYDROGEN PEROXIDE
`
`Hydrogen peroxide effectiveness as a sterilizing agent is well established (18). Hydrogen
`peroxide is available commercially in aqueous mixtures. Solutions of hydrogen peroxide
`should be kept away from flammable materials and reducing agents for safety reasons.
`Solutions of H2O2 should also be protected from light. Delivery to sterilization chambers
`is accomplished by heating the solution (30 50% H2O2 in H2O mixtures have been used)
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`16
`
`Novartis Exhibit 2005.016
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Claim Language
`
`Corresponding Disclosure
`above the boiling point ( -100'C), simultaneously supplying the sterilizing agent (H2O2)
`and required humidity (H2O). The sterilization process may incorporate an evacuation (or
`drying) step to allow for increased H202 concentration without condensation. Thorough
`mixing of the chamber is recommended as it increases uniformity of all process variables.
`Penetration of H2O2 in the gas phase is likely comparable to that of H2O, while liquid
`penetration is minimal. After exposure the chamber is aerated/ evacuated to remove H2O2
`from the materials. This portion of the cycle may be the longest as re-evaporation of any
`condensed H2O2 typically requires more time than the rest of the process. A slight
`modification of the more common process includes the addition of electrical energy to an
`H2O2-filled chamber, which increases the process effectiveness by the creation of short-
`lived free radicals (19).
`
`
`Nema Vol. 2 at pg. 248.
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`The invention relates to a method for hydrogen peroxide plasma sterilization, wherein the
`chamber temperature is set at less than 39° C. throughout, and containers with
`temperature-sensitive products can be efficiently sterilized without the temperature-
`sensitive products showing a significant loss of activity or degradation.
`
`
`Metzner at Abstract
`
`
`The present invention was based on the object of developing a procedure which permits
`sensitive biological and therapeutic products to be sterilized externally in the solid or
`liquid state in their final container (primary packaging). It was moreover intended that the
`selection of the final container ensure that the