PQRI Workshop on Thresholds and Best Practices for Parenteral and Ophthalmic
`
`Bethesda, MD, February 22-23, 2011
`
`Drug Products (PODP)
`
`Division of Therapeutic Proteins
`Office of Biotechnology Products
`
`Center for Drug Evaluation and Research
`
`U.S. Food and Drug Administration
`
`Expert Review Scientist
`
`Ingrid Markovic, Ph.D.
`
`Extractables and Leachables
`
`Safety Qualification of
`
`Regulatory Perspective on
`
`Novartis Exhibit 2179.001
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Bethesda, MD, February 22-23, 2011
`
`Drug Products (PODP)
`
`Division of Therapeutic Proteins
`Office of Biotechnology Products
`
`Center for Drug Evaluation and Research
`
`U.S. Food and Drug Administration
`
`Expert Review Scientist
`
`Ingrid Markovic, Ph.D.
`
`Extractables and Leachables
`
`Safety Qualification of
`
`Regulatory Perspective on
`
`Novartis Exhibit 2179.001
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`manufacturing process, product stability, etc.)
`
`•Quality considerations(e.g., impact on the
`
`development of neutralizing activity via NAb
`
`a product → loss of activity; L may induce
`
`•Efficacy considerations(e.g., L interacting with
`
`formation)
`
`immunogenicity, etc.)
`
`•Safety considerations(e.g., toxicity,
`
`E&L
`
`Risk-based Approach in Evaluating
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.002
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`May promote non-specific inflammation
`
`Altering the PK of the drug
`
`-thrombocytopenia)
`
`endogenous protein (e.g., erythropoietin -anemia/PRCA; thrombopoietin
`
`May be life-threatening if NAbs are developed against a non-redundant
`A decrease or loss of efficacy due to development of neutralizing activity
`
`May promote development of anti-drug antibodies
`
`may be a serious safety concern for therapeutic proteins
`
`In contrast to vaccines where adjuvant effect is a desired effect, this
`
`system without having any specific antigenic effect
`
`Adjuvants are substances that increase the activity of the immune
`
`•Adjuvant effects:
`
`endocrine dysregulation, etc.)
`
`•Toxicity (e.g., acute, chronic, synergistic, additive, carcinogenicity,
`
`Safety considerations
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.003
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`therapy)
`be tolerated if drug is considered a part of essential
`•Therapeutic necessity of the drug (higher levels may
`
`•Prior clinical exposure to leachables may enhance
`
`sensitivity in case of re-exposure
`
`exposure)
`(e.g., SC vs. IV, life-time dosing and chronic
`
`•Drug dose, mode and frequency of administration
`
`Safety considerations (cont.)
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.004
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`•Risks often assessed on a case-by-case basis
`
`phosphate buffer)
`
`•Formulation/choice of excipients; (e.g., liquid vs. lyophilized; pH;
`
`ethylhexyl)phthalate, which is linked to various toxicities)
`
`•Type of polymeric material (e.g., PVC at risk for leaching di(2-
`
`•Contact time
`
`•Surface-to-volume ratio
`
`•Storage temperature (e.g., freezing vs. 2-8C)
`
`final product)
`
`•Type of the processed/stored material (e.g., purification buffer vs.
`
`finished product)
`typically risks are greater as production moves closer to the
`•Place in the process stream (e.g., upstream vs. downstream;
`
`Manufacturing considerations
`
`www.fda.gov
`
`Fli)~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.005
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`•Leachables studies are often omitted
`
`over time
`
`stability studies, which monitor changes in product quality
`
`•Analysis of extractables is done in conjunction with
`
`extraction medium (role of excipients important)
`
`Note: Drug Product vehicle may or may not be used as an
`
`Alternatively, the drug manufacturer may rely on the E
`
`studies done by the vendor
`
`conditions (organic solvents, accelerated T°, pH, etc.)
`
`•Extractables studiesare performed using exaggerated
`
`What’s done in practice…
`
`Novartis Exhibit 2179.006
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Inappropriate sample size that is needed to understand the true variability
`
`in the C/C system (e.g., tungsten and PFS syringes)
`
`scenario risk assessment)
`
`manufacturing, storage and transportation conditions (no worst case
`
`Differences in the levels of leachables at the extremes of the
`
`inorganic leachables such as tungsten, Fe, Al, etc., are never evaluated
`
`Stability studies are often not geared to detect leachable impurities (e.g.,
`
`and organic leachables may be missed)
`
`
`
`
`
`
`
`Product Quality considerations:
`
`•
`
`Product that is at the end of its dating period is rarely evaluated in clinic
`
`Mode of administration (e.g., SC is often more immunogenic than IV)
`
`Potential for adjuvant effect and immunogenicity is not addressed
`
`Toxicity studies are usually acute studies that do not measure chronic
`
`exposure to potential leachables
`
`
`
`
`
`
`
`
`
`regard to leachables studies
`
`Risk assessment and risk reduction with
`
`Safety considerations:
`
`•
`
`Novartis Exhibit 2179.007
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`properties throughout the expiry period
`and product physico-chemical and biological
`
`•Perform stability studies, which monitor impurities
`
`•Ideally, Drug Product material that is at the end of its
`
`shelf-life should be tested in clinic
`
`Without the product (i.e., in placebo alone)
`
`In the presence of product
`
`product
`measuring leachables over the entire shelf-life of the
`
`•Monitor the clinical outcome in conjunction with
`
`Leachables studies
`
`Novartis Exhibit 2179.008
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Some support in the literature
`
`immunomodulatory factors
`
`Leachables as adjuvant and/or
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.009
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`I
`I
`CH a
`
`CH3
`
`C"3
`
`I
`
`
`II
`
`CH a
`
`-Si-O-Sii-0-91-0-Sii-
`
`CH a
`
`I
`
`J
`CH a
`
`CHa
`
`l
`
`
`.I
`
`CH9
`
`PDMS
`
`D4
`
`Locatelli et al., 2004, Nephrol Dial Transplant, 19:288-293
`
`Naim et al., 2000, Clin Diagnostic Lab Immunol, 7:366-370
`
`Naim et al., 1995, Immunol Invest, 24:537-547
`
`•Silicone oil –polydimethylsiloxane and octamethyl-
`
`cyclotetrasiloxane (D4)
`
`immunomodulatory factors
`
`Leachables as adjuvant and/or
`
`Novartis Exhibit 2179.0010
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Nilsen et al., 1997, Toxicology, 124:225-232
`
`Lovik et al., 1997, Toxicology, 121:165-78
`
`•Polycyclic aromatic hydrocarbons (PAH)
`
`Larsen et al., 2007, Tox Letters, 170:223-228
`
`Larsen et al., 2001, Toxicology, 169:37-51
`
`Larsen et al., 2001, Tox Letters, 125:11-18
`
`Mono-2-ethylhexyl phthalate (MEHP)
`
`•Di-(2-ethylhexyl) phthalate (DEHP) and
`
`immunomodulatory factors (cont.)
`
`Leachables as adjuvant and/or
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0011
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Yano et al., 2003, J Health Sci, 49:195-204
`
`•Alkyl phenols
`
`Schmidt et al., 2010, Nature Immunology, 11:814-820
`
`•Nickel
`
`386
`
`Marth et al., 2001, Inter J Occupational Med and Environ Health, 14:375-
`
`Beck-Speier et al., 2009, Particle and Fibre Toxicology, 6: 34-46
`
`•Soluble iron
`
`•Cadmium
`
`immunomodulatory factors (cont.)
`
`Leachables as adjuvant and/or
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0012
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Known's and Unknown’s
`
`leachables in biologics:
`
`Establishing threshold levels for
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0013
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`approach be applied to biologics?
`
`•What we don’t know: Can the same
`
`etc.) that can be applied across board
`PQRI, ICH Q3C, published literature,
`been proposed and/or established (e.g.,
`
`•Toxicological threshold levels have
`
`What we know
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0014
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`unfolding and aggregation, whereas in another case, it had no effect
`API that had different formulation: in one case tungsten caused
`
`E.g., tungsten oxides had a very different effect on two analogous
`
`protein products, formulation composition and C/C systems
`
`Needs to be assessed on a case-by case basis due to diversity of
`
`•Threshold for product quality
`
`1,000x less sensitive to LPS compared to humans)
`unlikely to be predictive of the clinical outcome (e.g., mice are
`However, the threshold levels identified in animal studies are
`
`after a change in the C/C system) and in identifying potential risks
`Such studies may be useful in looking at relative differences (e.g.,
`
`Adjuvant effects of leachables may be studied in animal models
`
`(e.g., in mice)
`
`•Threshold for the adjuvant effect:
`
`A feasibility exercise
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0015
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`injectables administered frequently at relatively high volumes and doses of mg/ml)
`•Drug dose, mode and frequency of administration (e.g., many biologics are sterile
`
`protein)
`hydrophilic and hydrophobic sites (the latter are usually buried in the interior of the
`Proteins may be more efficient in solubilizing leachables due to abundance of both
`
`of potential sites of interaction
`Large size (e.g., MAb 150 KD) and extensive surface area ensures →high frequency
`
`•
`
`•
`
`function)
`release testing is unlikely to detect areas of protein unfolding unless it impacts the
`
`•Routine analytical testing often doesn’t detect finite changes in the protein (e.g.,
`
`–Changes in glycosylation
`
`–Deamidation and/or oxidation
`
`–Aggregation and/or degradation
`
`environment
`
`–Protein conformation (e.g., secondary, tertiary) is sensitive to external
`
`•Manufacturing and stability issues:
`
`for the following additional reasons…
`
`Biologics may deserve a special consideration
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0016
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Case studies
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0017
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`S.c. route of administration was contraindicated in CRF patients, which
`
`Stricter control of the cold-chain from manufacture to administration
`
`was subsequently reversed
`
`Switch to teflon-coated stoppers
`
`•Resolution:
`
`•Hypothetical MoA: leachables acted as adjuvants leading to formation
`
`of neutralizing Abs to endogenous protein
`
`safety: serious adverse event (pure red cell aplasia, PRCA)
`
`no notable changes in protein physico-chemical properties
`
`storage (e.g., Vultac 2 di, tri, tetra, penta, hexasulfide, etc.)
`
`•Source: Vulcanizing agents leached from the rubber stopper during
`
`•C/c system: pre-filled syringes with uncoated rubber stoppers
`
`Impact:
`
`•
`
`•Change from HSA to polysorbate formulation
`
`Pharm, 5:86-91)
`
`(Casadevall et al., 2002, N Engl J Med, 346:469-475; Sharma et al., 2004, Eur J Hospital
`
`Leachables from the uncoated stoppers
`
`Novartis Exhibit 2179.0018
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`125
`
`115
`
`105
`
`95
`
`85
`
`75
`
`65
`
`55
`
`Time (min)
`
`placebo w/ uncoated rubber stoppers
`
`Leachables
`r15
`
`125 1
`
`Time (min)
`
`105
`
`95
`
`85
`
`75
`
`65
`
`55
`
`C
`
`< 0.05
`.c
`(/)
`0 0.10
`.c
`n,
`g 0.15
`0.20
`
`Q)
`
`/ Drug
`
`uncoated rubber stoppers
`
`B
`
`Time (min)
`
`.c < 0.05
`i 0_10
`g 0.15
`0.20
`
`Q)
`
`(/)
`
`125
`oni=:==:::;====::::::::====:::::::::====:::::====::....._-==:.==-=-.
`
`115
`
`105
`
`95
`
`85
`
`75
`
`65
`
`55
`
`o.
`
`/Drug
`
`coated rubber stoppers
`
`A
`
`profile of the drug + leachables
`
`(Sharma et al., 2004, Eur J Hospital Pharm, 5:86-91)
`
`.c < 0.05
`0 0.10
`.c
`n,
`g 0.15
`
`(/)
`
`Q)
`
`0.20
`
`Novartis Exhibit 2179.0019
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Eventually, the problematic presentation was removed from the market
`
`Conduct additional studies to determine the impact on product Q and S
`
`Implement Teflon coated stoppers
`
`Return to the original dating period of 15 months
`
`•Resolution:
`
`•Action: >10 DP lots were recalled due to OOS results
`
`–moderate decrease in potency
`–OOS result for protein content (e.g., >50% of the product was modified)
`
`Several sites on the protein were modified primarily at the N-terminus (primary
`
`targets were peptides with –OH, –NH3and –SH groups)
`
`Fe catalyzed oxidation of the preservative + additional excipient triggering
`
`formation of the protein-preservative adducts
`
`•Critical excipients: preservative and other components
`
`•Source: uncoated rubber stoppers released iron at levels <1 ppm
`
`•Change: extension of the expiry period from 15 to 18 months
`
`preservative adducts
`
`Impact:
`
`•
`
`Fe leachables cause formation of protein-
`=--
`
`Novartis Exhibit 2179.0020
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`~ Truncated
`
`product
`
`~ product
`Original
`
`coated stoppers implemented
`and replaced with the original one; Teflon
`in PK values; it was withdrawn from the market
`cardiovascular adverse events and a change
`
`• Adverse outcome: new formulation led to
`
`• Resolution: chelator (EDTA) added to DP
`
`formulation buffer
`
`Impact: product truncation at the N-terminus
`
`•
`
`(process-related impurity co-eluted with API)
`• Mechanism: activation of a metalloprotease
`
`• Uncovered during stability study under
`
`inverted conditions
`
`• Source: rubber stopper released divalent metal
`
`cations
`
`Metal leachables cause product truncation via
`
`metalloprotease activation
`
`• Change: from lyophilized to a liquid
`
`formulation
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0021
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`PFS
`development in vials and discontinue
`
`•Resolution: Continue product
`
`protein
`neutralizing Abs to the endogenous
`
`•Clinical outcome: Patients developed
`
`aggregation of the protein
`Impact: tungsten caused unfolding and
`
`•
`
`liquid
`into the product when contacted with
`oxides are deposited on the glass and
`
`•Source: tungsten salts and tungsten
`
`needle is attached
`perforate syringe barrel onto which a
`
`Tungsten filaments are used to
`
`•Container closure system: prefilled
`
`syringes
`
`Tungsten leachables from PFS barrels #1
`
`Novartis Exhibit 2179.0022
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`overlay process, special washing procedure, etc.
`
`Alternative -establish tungsten specifications, nitrogen
`
`Optimal -switch to platinum instead of tungsten filaments
`
`•Resolution (different approaches were used by different
`
`Sponsors):
`
`Up to 1% PFS tested positive for aggregates
`
`Up to 60% of aggregated product found in some syringes
`
`aggregation
`Impact: tungsten salts caused protein oxidation followed by
`
`•
`
`•Container closure system: prefilled syringes
`
`Tungsten leachables from PFS barrels #2
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0023
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Reduce product dating period
`
`Switch to lower risk formulation (e.g., pH, buffers, etc.)
`
`temperature control (leads to lower surface alkalinity)
`
`Switch to a different vial manufacturing process with more stringent
`
`Switch to highly resistant glass (high coefficient of thermal expansion)
`
`Contact time (delamination is a time-dependent process) and temperature
`
`•Risk mitigation strategies include the following:
`
`High ionic strength
`
`Certain buffers
`
`Drug solutions formulated at alkaline pH
`
`Specific vial manufacturing process
`
`Glass vials with high surface alkalinity have higher propensity for delmination
`
`•Risk factors promoting delamination (not listed in the order of importance):
`
`solution interface causing breaking of Si-O bonds and weakening of the surface layer
`
`•Glass pitting and surface delamination is initiated by ion exchange at the glass-
`
`•Container closure system: Type I borosilicate glass vials
`
`glass vials
`
`Alkali oxide extractables cause delamination of
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0024
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`New glass vials are coated using a baked-on siliconization process
`
`Recall of lots that failed the particulate spec
`
`•Resolution:
`
`Impact: visible particles (up to 150 μm diam)observed in stability samples
`
`•
`
`over 12 month of age with no other OOS results
`
`vaccines, although at concentration leached, it is unlikely to exert
`
`Aluminum phosphate (i.e., alum) is widely used as adjuvant in
`
`such an effect
`
`formulation forming aluminum phosphate crystals
`
`•Mechanism: aluminum interacted with sodium phosphate in the
`
`•Source: aluminum oxide leached from the new glass vials
`
`•Change: change from molded to tubing glass vials
`
`form particulates
`
`Aluminum leachables from glass
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0025
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`data for 10 new vial lots
`established with commitment to generate stability
`
`•Resolution: acceptance limit for barium
`
`stability samples with no other OOS results
`
`•Impact: visible particles observed in 18 month
`
`crystals
`sulfate in the formulation forming barium sulfate
`
`•Mechanism: barium interacted with sodium
`
`•Source: barium leached from new glass vials
`
`•Change: vendor for glass vials
`
`form particulates
`
`Barium leachables from glass
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0026
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`• Resolution: product now packaged in non(cid:173)
`
`siliconized syringes
`
`• Outcome: formation of amorphous polymers
`
`visible by the naked eye
`
`(J Pharm Sci, 2005, 94:918-927)
`denaturation and aggregation
`interact with proteins and cause protein
`
`• Silicone oil forms micelles in solution, which can
`
`effect) from the syringe barrel into the product
`• Observation: silicone oil was shed (break-loose
`
`lubricating agent to coat prefilled syringes
`
`• Source: silicone oil spray was used as a
`
`Silicone
`
`oil
`
`Silicone oil leachables cause
`
`product aggregation
`
`Novartis Exhibit 2179.0027
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`use) systems
`
`•Consideration of E&L for disposable (i.e., single
`
`standardization of E&L testing
`
`•Consideration for the improvement and
`
`minimize patients’ exposure to unnecessary risks
`mining, in order to reduce clinical uncertainty and
`leachables testing, in conjunction with clinical data
`
`•Greater emphasis should be placed on the
`Points to consider…
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0028
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`uncontrolled risk(Barry Cherney)
`its safety & efficacy doesn’t reduce risk, it’s simply,
`
`•Lack of transparency between a product quality attribute and
`
`as it relates to safety and efficacy
`resolve a problem while minimizing changes to product quality
`
`•Corrective actions should employ a simplest approach to
`
`included)
`time points reflective of product dating period should be
`It’s important to monitor leachables over time (e.g., extended
`
`•
`
`leachables acting as adjuvants triggering NAb response)
`significant impact on clinical safety and efficacy (e.g.,
`
`•Undetected differences in product impurities may have a
`
`changes in the C/C system and/or formulation
`
`•Biologic products can be sensitive to minor impurities and
`
`Summary
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0029
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`All of OBP
`
`DanielaVerthelyi
`
`Emily Shacter
`
`Amy Rosenberg
`
`Dov Pluznik
`
`Mike Norcross
`
`Steven Kozlowski
`
`Barry Cherney
`
`Acknowledgments
`
`Novartis Exhibit 2179.0030
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Questions? Comments?
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0031
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`generally poorly described in submissions
`
`•Justification of selected extraction conditions is
`
`Ensures that methods with appropriate specificity and
`
`Highlights immediate safety concerns (if any)
`
`sensitivity are used
`
`conditions)
`
`extractables (depends on the specific extraction
`
`Determines chemical profile and maximal levels of
`
`•Appropriate extraction procedure is relevant
`
`Extractables analysis
`
`=--
`
`www.fda.gov
`
`flu~ U.S. Food and Drug Administration
`
`Protecting and Promoting Public Health
`
`Novartis Exhibit 2179.0032
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`•Cleaning agents
`•Antistatic agents
`•Polycyclic aromatic hydrocarbons
`•Antioxidants (e.g., BHT, Irganox, Irgafos, etc.)
`
`dithiocarbamate, etc.)
`
`•Accelerators (e.g., thiuram, sulfenamide, guanidine,
`
`•Vulcanizing agents (e.g., Vultac 2, etc.)
`•Nitrosamines (e.g., diphenylnitrosamines, etc.)
`•Organic solvents (e.g., acetone, isopropanol, etc.)
`•Silicone oil (e.g., polydimethylsiloxane)
`•Cyclic esters (from polyurethane adhesives)
`•Fatty acids (e.g., stearic, plamitic myristic, etc.)
`•Metals (e.g., Zn, Fe, Ba, Ca, Al, Ni, etc.)
`•Phthalates (e.g., Di(2-ethylhexyl) phthalate -DEHP)
`
`Examples of more common E&L
`
`Novartis Exhibit 2179.0033
`Regeneron v. Novartis, IPR2021-00816
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
