UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________
`
`
`REGENERON PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`NOVARTIS PHARMA AG,
`NOVARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owners
`
`__________
`
`
`Case IPR2021-00816
`Patent No. 9,220,631
`
`__________
`
`
`DECLARATION OF JOHN E. DILLBERGER, DVM, PH.D.,
`IN SUPPORT OF NOVARTIS’S PATENT OWNER RESPONSE
`
`
`
`
`
`
`Novartis Exhibit 2202.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`TABLE OF CONTENTS
`
` 
`B.
`
`Introduction ...................................................................................................... 1 
` 
`I.
`Background and Qualifications ....................................................................... 1 
` 
`II.
`Summary of Opinions ...................................................................................... 4 
` 
`III.
`  Person Of Ordinary Skill In The Art ............................................................... 5 
`IV.
`  Materials for Primary Packaging of Ophthalmic Injectable Biologic
`V.
`Products Were Subject to Numerous Toxicological Concerns ....................... 7 
`Container/closure toxicology considerations for pre-filled
` 
`A.
`syringes .................................................................................................. 7 
`Requirements for development of packaging for a PFS for
`intravitreal injection of an ophthalmic biologic drug .......................... 11 
`Extensive evaluation and comprehensive study would
` 
`1.
`have been necessary to validate a new stopper coating
`material ...................................................................................... 12 
`Ophthalmic injectable biologic drugs required heightened
`attention to toxicology concerns ............................................... 24 
`  Significant Barriers Existed to Using Parylene C as a Pharmaceutical
`VI.
`Packaging Material ........................................................................................ 28 
`Parylene C was unvalidated as coating material on a PFS
` 
`A.
`stopper for use with a highly sensitive biologic drug product ............ 28 
`Extensive evaluation and validation would have been required
`to use Parylene C in a PFS .................................................................. 32 
`Parlyene C has known properties that would have discouraged
`its use as a primary packaging material for PFSs containing an
`ophthalmic injectable drug .................................................................. 36 
`Parylene C was known to have high protein adsorption,
` 
`1.
`which would have discouraged its use as a primary
`packaging material for PFSs containing a protein-based
`drug ........................................................................................... 36 
`Parylene C was known to potentially generate harmful
`leachables, which would discourage its use as a primary
`packaging material for injectables ............................................ 39 
`  One would not have reasonably expected that Parlyene C would be
`VII.
`suitable for use with a terminally sterilized PFS with a VEGF
`antagonist for intravitreal injection ................................................................ 40 
`  Declaration ..................................................................................................... 45 
`VIII.
`
`
`
` 
`B.
`
` 
`2.
`
` 
`2.
`
` 
`C.
`
`ii
`
`Novartis Exhibit 2202.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`
`I.
`
`INTRODUCTION
`
`1.
`
`I, John E. Dillberger, DVM, Ph.D., submit this declaration on behalf
`
`of Novartis Pharma AG, Novartis Technology LLC, and Novartis Pharmaceuticals
`
`Corp. (collectively, “Novartis”), regarding IPR2021-00816. I understand that
`
`Regeneron Pharmaceuticals, Inc., (“Petitioner”) submitted its petition in IPR2021-
`
`00816 (“Petition”) challenging the patentability of all claims of U.S. Patent No.
`
`9,220,631 (“the ’631 patent”).
`
`2.
`
`This declaration is the result of my review and analysis of the Petition,
`
`the declaration of Mr. Horst Koller (Ex. 1003), and other exhibits submitted in the
`
`above referenced IPR proceeding, as well as additional materials relied on herein.
`
` BACKGROUND AND QUALIFICATIONS
`II.
`
`3.
`
`I received a B.S. in Biology from the University of Georgia in 1975
`
`and a D.V.M. degree from Iowa State University in 1979, completed a 3-year
`
`residency in Comparative Pathology at the University of Miami School of
`
`Medicine and Papanicolaou Cancer Research Institute in 1986, and received a
`
`Ph.D. degree in Pathology and Environmental Toxicology from Michigan State
`
`University in 1989 for research into the molecular mechanisms of carcinogenesis.
`
`I was certified as an expert in Veterinary Pathology by the American College of
`
`Veterinary Pathologists in 1987. I was certified as an expert in Toxicology by the
`
`American Board of Toxicology in 1992 and have been re-certified every five years
`
`1
`
`Novartis Exhibit 2202.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`since then. In 2001, I became one of a handful of toxicologic pathologists
`
`accepted as a fellow in the International Academy of Toxicologic Pathology, and I
`
`served as Treasurer for the organization from 2006 to 2012. I have authored
`
`numerous scientific papers and a book chapter entitled “Nonclinical Development
`
`of Drugs and Biologics: Pharmacology and Toxicology,” served as reviewer for
`
`Antimicrobial Agents and Chemotherapy, and served two terms on the editorial
`
`board of Veterinary Pathology.
`
`4.
`
`I am currently employed full time as president and principal of
`
`J. Dillberger, LLC, a nonclinical development consulting company that I founded
`
`in 2000. I specialize in the application of toxicology, pathology, and
`
`pharmacology expertise to the safety evaluation of drugs, biologics, medical
`
`devices, imaging agents, diagnostic agents, and combination products. My clients
`
`include biopharmaceutical companies in the USA, Canada, UK, Denmark, Korea,
`
`Japan, Italy, Germany, Israel, Australia, and New Zealand; nonprofit foundations;
`
`and investment firms with pharmaceutical company portfolios.
`
`5.
`
`I have over 30 years of product development experience in the
`
`pharmaceutical industry. Over that time, I have held positions of increasing
`
`responsibility at Marion Merrell Dow, GlaxoWellcome, Triangle Pharmaceuticals,
`
`and Charles River Laboratories, Inc. I served as Head of USA Pathology, Director
`
`of Safety Evaluation for USA-Based Development Projects, and Worldwide
`
`2
`
`Novartis Exhibit 2202.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`Specialist in Oncology Drug Projects for GlaxoWellcome, Director of Toxicology
`
`at Triangle Pharmaceuticals, and Senior Director of Research at Charles River
`
`Laboratories, Inc. I have prepared or helped prepare safety evaluation packages for
`
`numerous clinical trial and marketing applications in the USA and Europe,
`
`including the successful NDAs for Coviracil®, Kapvay®, and Northera®,
`
`Triferic®, Auryxia®, Sovaldi®, and Pretomanid and CTDs for Thelin®, Tyvaso®,
`
`and Maxigesic®.
`
`6.
`
`Safety evaluation involves finding existing information and
`
`generating new information about a product’s potential harmful effects, which
`
`might derive from its active ingredient(s), inactive ingredient(s), device
`
`components, or packaging. Preparing a safety evaluation package involves
`
`critically reviewing and synthesizing this information in written form for use by a
`
`company developing the product and by regulatory authorities overseeing such
`
`development. Information about a product’s potential harmful effects can be found
`
`in scientific publications, reviews by expert panels, and reviews by regulatory
`
`authorities of previous products that contained the same ingredient or device
`
`component or that used the same packaging. Information about a product’s
`
`potential harmful effects also can be generated by designing, executing, and
`
`analyzing the results from studies in cells, tissues, and animals in order to discover
`
`and understand the product’s effects before it is tested in human subjects or
`
`3
`
`Novartis Exhibit 2202.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`allowed on the market. Companies use a safety evaluation package to design safe
`
`clinical trials and to decide how to monitor human subjects for side effects during
`
`clinical trials and how to communicate the potential risks to physicians who will
`
`conduct the trials and to subjects who will participate in them. Regulatory
`
`authorities use a safety evaluation package to decide if a product can be safely
`
`tested in human subjects, to decide if a product should be allowed on the market,
`
`and to write the package insert/label for the product.
`
`7.
`
`As a consultant, I regularly am called upon to evaluate the safety of
`
`materials that are or may be included in packaging of drugs or biologics and the
`
`safety of combination products that consist of a drug or biologic and a medical
`
`device.
`
`8.
`
`A copy of my curriculum vitae, attached as Exhibit A, contains further
`
`details concerning my education, experience, publications, patents, and other
`
`qualifications to render an expert opinion in this matter.
`
` SUMMARY OF OPINIONS
`III.
`
`9.
`
`I was asked to give my opinions concerning the suitability of Parylene
`
`C as a stopper coating in a prefilled syringe intended for intravitreal injection of a
`
`VEGF antagonist solution from the point of view of a toxicologist involved in a
`
`product development team. Based on my knowledge, experience, and reviewed
`
`materials, it is my opinion that:
`
`4
`
`Novartis Exhibit 2202.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`
`
`A stopper coating in a prefilled syringe would have been considered
`
`part of the drug product’s primary packaging, and therefore subject to
`
`
`
`
`
`a number of toxicological concerns;
`
`Alleviating these toxicological concerns would have required
`
`extensive testing of Parylene C as a stopper coating;
`
`The known properties of Parylene C would have suggested that its use
`
`as a stopper coating in a prefilled syringe containing a VEGF
`
`antagonist solution may adversely impact the active ingredient and be
`
`unsafe for patients;
`
`
`
`Parylene C would not have been understood to be safe, non-toxic, or
`
`pharmaceutically acceptable to use as a stopper coating in a prefilled
`
`syringe for intravitreal injection of a VEGF antagonist solution.
`
` PERSON OF ORDINARY SKILL IN THE ART
`TV.
`
`10.
`
`I understand that the prior art must be viewed from the perspective of
`
`a person of ordinary skill in the art (“POSA”), and I have been informed that
`
`Novartis has offered the following definition of a POSA:
`
`A POSA would have an advanced degree (i.e., an M.S., a Ph.D., or
`
`equivalent) in mechanical engineering, biomedical engineering,
`
`materials science, chemistry, chemical engineering, or a related field,
`
`and at least 2–3 years of professional experience, including in the
`
`5
`
`Novartis Exhibit 2202.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`design of a PFS and/or the development of ophthalmologic drug
`
`products or drug delivery devices. Such a person would have been a
`
`member of a product development team and would have drawn upon
`
`not only his or her own skills, but also the specialized skills of team
`
`members in complementary fields including ophthalmology,
`
`microbiology and toxicology.
`
`11. This definition of a POSA comports with how a PFS product would
`
`actually be developed. I would have been a member of such a product
`
`development team with my expertise in toxicology—specifically, evaluating the
`
`safety of materials included in the packaging of drugs, biologics, and medical
`
`devices. It is from the perspective of a toxicologist involved in a product
`
`development team that I offer my opinions in this declaration.
`
`12.
`
`I was asked to assume that the relevant date for assessing the prior art
`
`is July 3, 2012, and my opinions reflect the understanding of a toxicologist as of
`
`that date. I was also asked whether my opinions would change were the relevant
`
`date instead October 23, 2012. They would not. Therefore, when I refer to the
`
`state of the art herein, I am referring to the state of the art as of both July 2012 and
`
`October 2012, unless otherwise specified.
`
`6
`
`Novartis Exhibit 2202.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
` MATERIALS FOR PRIMARY PACKAGING OF OPHTHALMIC
`V.
`INJECTABLE BIOLOGIC PRODUCTS WERE SUBJECT TO
`NUMEROUS TOXICOLOGICAL CONCERNS
` Container/closure toxicology considerations for pre-filled syringes
`A.
`13. For all drug and biologic products, the container in which the product
`
`is provided and stored and the components that close and seal the container (the
`
`“closure”) are integral parts of the drug product. Ex. 1015, Nema Vol. 1 at .064;
`
`Ex. 1041, FDA Guidance for Industry: Container Closure Systems for Packaging
`
`Human and Biologics. As of 2012, there were a number of requirements that a
`
`container/closure (product packaging) must have satisfied, several of which
`
`implicate toxicology concerns. For example, the container/closure system for any
`
`product must adequately protect the product from degradation and contamination
`
`for the entire shelf life, from the time of manufacturing until the time of use. See
`
`Ex. 1015.017; Ex. 1041.010. The packaging of a product must be compatible with
`
`the product as well as its mode of administration and its intended use. Ex.
`
`1015.064–.065, .295.
`
`14. For all products, but especially complex and sensitive products such
`
`as biologics, there was concern that primary packaging—the packaging
`
`components that make direct contact with the dosage form—can interact with the
`
`component-dosage form. See Ex. 2174, WHO Guidelines at .003 (“Interaction
`
`between packaging and [drug or biologic] products is possible due to the
`
`7
`
`Novartis Exhibit 2202.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`combination of a multiplicity of container components and active pharmaceutical
`
`ingredients, excipients and solvents used in a variety of dosage forms.”). When the
`
`drug or biologic product is a protein, then this interaction creates the “potential for
`
`alteration of the structure of the protein through aggregation or chemical
`
`degradation pathways.” Ex. 1015.064; see also Ex. 2175, Akers 2010 at .115–
`
`.116; Ex. 2184, Rathore 2008 at .001–02, .007–.008 . Additionally, the
`
`container/closure may generate leachables—compounds that can leach out of a
`
`packaging material into the product—that can detrimentally impact molecules of
`
`the drug or biologic product or may themselves be toxic or otherwise dangerous if
`
`administered to patients. Ex. 1015.064; see also Ex. 2174.003 (“The kind of
`
`packaging and the materials used must be chosen in such a way that: the packaging
`
`itself does not have an adverse effect on the product (e.g. through chemical
`
`reactions, leaching of packaging materials or absorption).”)
`
`15. Pre-filled syringes (“PFSs”) are pharmaceutical containers that are
`
`also delivery devices. They consist of several components, including a barrel that
`
`is usually made of glass or plastic. Ex. 1015.344. The plunger of a PFS is tipped
`
`with a stopper (plunger), which is usually made of an elastomeric material such as
`
`rubber. The stopper is an “internal” component that “makes a seal on the internal
`
`diameter of the barrel.” Ex. 1015.345. The stopper acts as both a closure and a
`
`mechanical component, i.e., during storage, the syringe functions as a container
`
`8
`
`Novartis Exhibit 2202.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`and the stopper closes the syringe, and during use, the syringe functions as a
`
`delivery device of which the stopper is one component. The stopper “must
`
`maintain an adequate seal” during the shelf life of the syringe, protecting the
`
`syringe contents and maintaining sterility. Id. The stopper closure of a PFS is part
`
`of the primary packaging because it “is in long-term ‘intimate’ contact with the
`
`drug” contained within the PFS after the syringe is filled. Id.
`
`16. Elastomeric closures, including PFS stoppers, can be made from a
`
`variety of compounds with varying elastic properties. The elastomer is the
`
`polymer base of the compound. A rubber compound may either use a single
`
`elastomer or a blend of different elastomers, such as halobutyl compounds,
`
`including bromobutyl rubber and chlorobutyl rubber. See Ex. 1015.348–.349. The
`
`compounds in elastomeric components used for long-term contact with parenterals
`
`(injectable drugs or biologics), such as stoppers in a syringe, are “designed to have
`
`no or the smallest possible level of interaction with the drug.” Ex. 1015.350.
`
`17. The closures of some PFSs and other containers can be coated with a
`
`specialized polymer that directly contacts the drug formulation. The polymer
`
`coating may act as a barrier between the drug product and the rubber of the
`
`elastomer closure. See Ex. 1015.350; Ex. 2035, Sacha 2010 at .015–.016. For
`
`instance, “coated vial stoppers and coated syringe plungers” may be used in
`
`situations where exposure of the dosage form directly to the rubber could result in
`
`9
`
`Novartis Exhibit 2202.0011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`unacceptable absorption of the drug compound, such as in “biotech drugs that are
`
`used in very small quantities per dose” and “no absorption” by the stopper is
`
`allowed. Ex. 1015.350. Specialized polymer coatings may also reduce the risk of
`
`contaminants leaching from the rubber closure into the syringe contents and
`
`interacting with the drug or biologic or potentially being injected into the patient.
`
`See Ex. 1015.350; Ex. 2035.015–.016 . As of 2012, these specialized polymer
`
`coatings were predominantly fluoropolymers. See Ex. 1015.350.
`
`18. Because stopper coatings come into direct contact with the drug
`
`formulation contained within the PFS, the coatings are considered “primary
`
`packaging,” (Ex. 1041.005) and would have needed to satisfy all of the
`
`requirements of primary packaging components.
`
`19. Examples of negative interactions between primary packaging
`
`components and drug formulations were well known as of 2012. One well-known
`
`example of such an interaction between a drug formulation and a primary
`
`packaging material involved PFSs containing the biologic Eprex® (epoetin alfa),
`
`which is used for treatment of anemia caused by chemotherapy or renal disease.
`
`See Ex. 2035.022; Ex. 2176, Boven 2005 at .001. Following a change in the
`
`formulation of Eprex®, contaminants leaching from rubber stoppers are believed
`
`to have caused reactions in many patients that led to pure red blood cell aplasia
`
`(PRCA), a severe disorder characterized by sudden onset anemia. Ex. 2176.001,
`
`10
`
`Novartis Exhibit 2202.0012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`.007; see also Ex. 2035.021. The contaminants were not found in Eprex® stored in
`
`syringes with FluroTec-coated stoppers. See Ex. 2176.002, .007.
`
`20.
`
`In another example, loss of therapeutic activity of interleukin-2, a
`
`biologic used to treat cancer, was attributed to interactions between the therapeutic
`
`protein and the surface of the catheter tubing used to administer it, which caused
`
`denaturation (disruption of the three-dimensional structure) of the protein. Ex.
`
`2177, Tzannis 1996 at .001, .005. Silicone oil used as a lubricant in PFSs has also
`
`been shown to cause aggregation of and damage to biologic drugs. See, e.g., Ex.
`
`2253, Jones 2005 at .001; Ex. 1012, Fries 2009 at .006.
`
` Requirements for development of packaging for a PFS for
`B.
`intravitreal injection of an ophthalmic biologic drug
`21. Health agencies such as the U.S. Food and Drug Administration
`
`provide guidance as to their thinking about what is appropriate and/or necessary
`
`for pharmaceutical products and medical devices to be suitable for use in human
`
`patients and acceptable for regulatory approval. People working on developing
`
`these types of products understand that FDA guidances are not merely bureaucratic
`
`requirements that should be followed to get regulatory approval for a product; they
`
`are based on what is actually necessary for products to fulfil their intended use and
`
`be safe for use in human patients. For example, the essential requirements for a
`
`PFS containing a biologic for intravitreal injection are reflected in and confirmed
`
`by FDA guidance regarding primary packaging for pharmaceutical products. See,
`11
`
`Novartis Exhibit 2202.0013
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`e.g., Ex. 1015.064; Ex. 2035.002; Ex. 2175, Akers 2010 at .102–.103; see also, Ex.
`
`1041.004–.007. The FDA “considers the compatibility of container/closure with
`
`product as a key requirement in the development of parenteral products.”
`
`Ex. 1015.064. A polymer coating on the stopper of a PFS directly contacts the
`
`syringe contents, so these coatings are part of the drug’s “primary packaging.”
`
`Therefore, like any primary packaging material, it would have been understood by
`
`2012 that stopper coatings must be compatible with the drug or biologic product
`
`with which they are in contact, must be non-toxic, must be inert, and must not
`
`generate potentially detrimental or toxic leachable contaminants. See Ex.
`
`1041.010; Ex. 1015.064; Ex. 2174.010; Ex. 2178, Markovic 2009 at .002–.003 .
`
`22. By 2012, there was particular concern about leachable contaminants
`
`and interactions between packaging components and dosage forms for injectable
`
`drugs, especially injectable and/or ophthalmic solutions. See, e.g., Ex. 1041.008–
`
`.009; Ex. 1015.064 (recognizing injections as “products with the greatest level of
`
`concern when accounting for route of administration and risk for packaging
`
`component-dosage form interaction.”); Ex. 1015.295 (“The FDA is highly
`
`sensitive to the presence of extractables and leachables in ophthalmic products.”).
`
`
`l.
`
`Extensive evaluation and comprehensive study would have
`been necessary to validate a new stopper coating material
`23. The FDA Guidance for Industry: Container Closure Systems for
`
`Packaging Human Drugs and Biologics (“FDA Guidance”) outlines FDA’s
`12
`
`Novartis Exhibit 2202.0014
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`expectations for evaluating the safety of container components, including stopper
`
`coatings, as of 2012. The FDA Guidance reflects and confirms product
`
`developers’ understanding of the requirements for evaluating the suitability,
`
`including safety, of container components during product development. See, e.g.,
`
`Ex. 2035.002. The FDA Guidance provides that each component of a closure
`
`system must be “suitable for its intended use.” Ex. 1041.010 (emphasis omitted).
`
`This “requires the evaluation of four attributes to establish suitability of materials
`
`and container-closure systems for pharmaceutical products” for every component:
`
`“protection, compatibility, safety, and performance/drug delivery.” Ex. 2035.002;
`
`see also Ex. 1041.010–.014.
`
`24.
`
` For a PFS, suitable “performance” means functioning as a syringe to
`
`safely and properly deliver its contents. See Ex. 1041.014.
`
`25. For a PFS, suitable “protection” means that the syringe “provide[s]
`
`the dosage form with adequate protection from factors (e.g., temperature, light)
`
`that can cause a degradation in the quality of [the syringe contents] over its shelf
`
`life.” Ex. 1041.010.
`
`26. For a PFS, suitable “compatibility” requires that the “dosage form will
`
`not interact sufficiently [with the packaging components] to cause unacceptable
`
`changes in the quality of either the dosage form or the packaging component.” Ex.
`
`1041.012; see also Ex. 2174.010 (“The compatibility of the packaging with the
`
`13
`
`Novartis Exhibit 2202.0015
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`active pharmaceutical ingredients is very important in maintaining the integrity of
`
`the product.”). There was particular concern about interactions between the
`
`packaging component and dosage form that may cause “loss of potency due to
`
`absorption or adsorption of the active drug substance[,] degradation of the active
`
`drug substance induced by a chemical entity leached from a packaging
`
`component[,] reduction in the concentration of an excipient due to absorption,
`
`adsorption or leachable-induced degradation[.]” Ex. 1041.012; see also Ex.
`
`2174.010 (“For primary packaging, it is necessary to know the possible
`
`interactions between the container and the contents,” because there are “numerous
`
`possibilities of interactions between (primary) packaging materials and
`
`pharmaceutical products, such as: ... the absorption or adsorption of
`
`pharmaceutical components by the packaging materials.”).
`
`27. For a PFS, suitable “safety” requires that the syringe be “composed of
`
`materials that are considered safe for use with the dosage form and the route of
`
`administration,” (Ex. 1041.010 (emphasis omitted)), which means the packaging
`
`components/materials “will not leach harmful or undesirable amounts of
`
`substances to which a patient will be exposed when being treated with the drug
`
`product.” Ex. 1041.012. Toxicologists understood that “[t]his consideration is
`
`especially important for those packaging components which may be in direct
`
`contact with the dosage form,” such as stopper coatings. See id.
`
`14
`
`Novartis Exhibit 2202.0016
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`28. With respect to safety, it was understood by 2012 that for particular
`
`categories of drug products, including ophthalmic drugs and injectable drugs, it “is
`
`appropriate” to perform a “comprehensive study” of the safety of any new
`
`packaging material. Id. “Comprehensive study” was understood to be an
`
`extensive, thorough, time-consuming, and expensive process to determine whether
`
`any new material used in packaging would likely be safe for human use. See, e.g.,
`
`Ex. 1041.021 (“To establish safety and to ensure consistency, the complete
`
`chemical composition should be provided for every material used in the
`
`manufacture of a packaging component ... To address safety and compatibility, the
`
`results of extraction/toxicological evaluation studies should be provided for drug
`
`products that are likely to interact with the packaging components and introduce
`
`extracted substances into the patient.”).
`
`29.
`
`“Comprehensive study” of the safety of a new material used in
`
`packaging as of 2012 would have involved, at the least, a series of studies using
`
`various solvents and temperature conditions to understand what contaminants, if
`
`any, can be extracted from the material (extraction studies). See Ex. 1041.012–013.
`
`One or more studies would also be required to evaluate what, if any, contaminants
`
`actually leach from the material when the product is stored as directed (leachable
`
`studies), as well as a toxicological evaluation of any potential or actual
`
`contaminants identified in these studies (risk assessment). See Ex. 1041.009.
`
`15
`
`Novartis Exhibit 2202.0017
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`30. The series of activities undertaken to evaluate the safety of a new
`
`material used in product packaging as of 2012 are summarized in the diagram
`
`below.
`
`Figure 1
`
`F lgul't.1, Multl,tler ed apjll"OOCh to Blt al)'ZlngE&L
`
`Incorporate E&L as critical quaJlcy at.tributes whu definina
`a desiin spac.e
`
`Initiate evaluation of
`extractables
`
`Identify, characterize
`and quantihlte
`i.ndividual ext,·acttbles
`
`- - -►
`
`Perfor m supportive t<txicoloa:y stu,die.s
`111d identify extl'actables ,ttth
`
`Correlate Co toxic threshold Jevels1 if
`.._ _ _ _ _ _ .;•;.v .. ailaa· •a.b.l.,•------•
`
`r carclnogeni, and/or to:<lc poUmlEal.
`'
`
`lde.1Hified extrattables are
`
`No toxicity detected
`
`,----- -- - --,
`
`1
`1
`I
`
`Assw the following:
`1 •Volatile compounds
`I •Semi-volatile
`I -Non-volatile
`I •Residual metals
`I -Inoreimir compounds
`I 'PH
`I •TOC
`1 _!C!n!_uc!!'"! _ _ __ _
`,-- -- --- --.
`
`J
`I Establid1 the limit of
`quanl!toliou (LOQ) and 1
`1
`I limit. of detection (I.OD) I
`_ !!_ft_!le .!,.ns~'U~e!!!a.Uo!!. .,
`
`Proceed with the
`leachables study
`
`Identify, rltaracteriu and
`• quant:iry indiv\dual
`lea.chablu in stbr~2e
`
`- - ►
`
`._ ___________ _.
`
`Assess tJ,e i"'pact~on product quality
`(e.g .. oxidation, aggrea:ation,
`degradatlo111 etc.) b, ttorage
`
`/
`
`Cha111,tes in produc1
`quality identified
`
`No tha11geh1
`product quality
`and no saff!ty
`concerns
`
`,.. - - - - - - - -
`
`I
`Correlate lead,ables
`levels to the threshold f
`levels published in
`I
`toxicoloaical
`I
`.!a':b~e.J-
`- I
`
`1
`I -
`
`-
`
`-
`
`Ex. 2178.003.
`
`
`
`16
`
`Novartis Exhibit 2202.0018
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`31. Extraction studies on a packaging material were performed to
`
`“determine which chemical species may migrate into the dosage form (and at what
`
`concentration).” Ex. 1041.013; see also Ex. 2175.377 (“Extensive extractable
`
`studies should be performed as part of the qualification of container-closure
`
`components ... Use various solvents, elevated temps, and prolonged extraction
`
`times in conducting these studies.”).
`
`32. Extraction studies were performed by “selecting appropriate
`
`exaggerated and/or exhaustive conditions not stipulated for manufacture, storage
`
`and/or use in order to isolate chemicals from relevant material components.” Ex.
`
`Ex. 2178.002–.003. The extraction studies should “employ worst-case conditions
`
`with regards to pH, ionic strength, contact time, temperature, surface area-to-
`
`volume ratio and, if applicable, with organic solvents of varying polarity” and may
`
`include the “[u]se of detergent (i.e., polysorbate 20).” Ex. 2178.003. In addition to
`
`the worst-case conditions, “fluid representative of the actual process (e.g., cell
`
`culture media, Drug Product formulation buffer, etc.) should be used as a
`
`representative extraction solution ... for accurate prediction of extractables.” Id.
`
`The study “may be performed using a soaking or a recycling method for a given
`
`contact time (e.g., 180 days).” Id.
`
`33. Extraction studies typically further involved analyzing the extract
`
`solutions of the new material for “non-volatile, semi-volatile, and highly volatile
`
`17
`
`Novartis Exhibit 2202.0019
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`organic compounds as well as analysis of trace light and heavy metals.” Id.
`
`“Highly selective analytical techniques should be employed” for this analysis,
`
`which can include “High Performance Liquid Chromatography coupled with Mass
`
`Spectroscopy (HPLC-MS), Gas Chromatography coupled with Mass Spectroscopy
`
`(GC-MS), Inductively Coupled Plasma with Mass Spectroscopy (ICP-MS), Proton
`
`Nuclear Magnetic Resonance (1H-NMR), Fourier Transform Infrared (FTIR)
`
`Spectroscopy, and Atomic Spectroscopy (e.g., atomic absorption, atomic emission
`
`spectroscopy).” Id.
`
`34. Leachable studies on a packaging material should be performed “over
`
`the entire shelf-life of the product.” Ex. 2179, Markovic 2011 at .008.
`
`35. Besides identifying and quantifying extractable and leachable
`
`contaminants and evaluating their impact on product quality, it was understood that
`
`“a toxicological evaluation of those substances which are extracted [should be
`
`done] to determine the safe level of exposure via the label specified route of
`
`administration.” Ex. 1041.013. This risk assessment should consider “the specific
`
`container closure system, drug product formulation, dosage form, route of
`
`administration, and dose regimen.” Id. For many injectable and ophthalmic drug
`
`products, USP Biological Reactivity Tests and USP Elastomeric Closures for
`
`Injections tests were used to ascertain safety of new materials used in packaging.
`
`Id. Among other tests, it was understood that extractable/leachable contaminants
`
`18
`
`Novartis Exhibit 2202.0020
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`“should be assessed for their cytotoxicity (e.g., USP chapter <87>), acute toxicity
`
`in animals (e.g., USP chapter <88>) as well as chronic toxicity.” Ex. 2178.004.
`
`36. When performing a risk assessment on extractable/leachable
`
`contaminants for a biologic product, protein therapeutics had additional
`
`considerations because, unlike small molecule drug products
`
` proteins’ secondary and tertiary conformations are sensitive to the external
`
`environment;
`
` proteins are susceptible to aggregation;
`
` proteins are susceptible to degradation, deam