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 9,220,631
`
`__________
`
`
`
`DECLARATION OF MICHAEL J. MILLER, PH.D., IN SUPPORT OF
`NOVARTIS’S PATENT OWNER RESPONSE
`
`
`
`
`Novartis Exhibit 2203.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`TABLE OF CONTENTS
`Introduction ........................................................................................................ 1
`I.
`II. Qualifications ..................................................................................................... 1
`III. Scope of Study ................................................................................................... 7
`IV. Summary of Opinions ........................................................................................ 7
`V. Person of Ordinary Skill in the Art .................................................................... 8
`VI. Claim Construction .......................................................................................... 10
`
`VII. Background on Sterile Products and Sterilization Techniques .................... 10
` Development of a Sterilization Cycle .......................................................... 10
`A.
` Sterilization Techniques ............................................................................... 11
`B.
` Sterility Assurance Level ............................................................................. 13
`C.
` Labeling of Sterile Products ......................................................................... 21
`D.
`VIII. Sigg ............................................................................................................... 22
` A Microbiologist Would Not Have Been Motivated to Use Sigg’s VHP
`A.
`Method to Terminally Sterilize a PFS and Would Not Have a Reasonable
`Expectation That a PFS Would be Successfully Sterilized With This Method .. 22
` A Microbiologist Would Not Have Been Motivated to Use Sigg’s VHP
`B.
`Method to Terminally Sterilize a PFS Filled With a VEGF Antagonist to an SAL
`of 10-6 as Required by Claim 21, and Would Not Have Had a Reasonable
`Expectation of Success in Doing So ................................................................... 26
`
`IX. Lam .................................................................................................................. 29
` A Microbiologist Would Not Have Been Motivated to Use Lam’s EtO
`A.
`Method to Terminally Sterilize a PFS Filled With a VEGF Antagonist, and
`Would Not Have a Reasonable Expectation of Success in Doing So ................. 29
` Lam Does Not Disclose an SAL of 10-6 as Required by Claim 21 .............. 35
`B.
` A Microbiologist Would Not Have Been Motivated to Use Lam’s EtO
`C.
`Method to Terminally Sterilize a PFS Filled With a VEGF Antagonist to an SAL
`of 10-6 as Recited in Claim 21 of the ’631 Patent, and Would Not Have Had a
`Reasonable Expectation of Success in Doing So ................................................ 36
`
`i
`
`Novartis Exhibit 2203.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`X. Macugen .......................................................................................................... 37
`XI. Declaration ....................................................................................................... 41
`
`
`ii
`
`Novartis Exhibit 2203.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`I.
`
`Introduction
`
`1.
`
`I, Michael J. Miller, have been retained to provide expert opinions in
`
`the above captioned proceeding, which I understand was initiated by Regeneron
`
`Pharmaceuticals, Inc. (“Petitioner”) by filing a Petition seeking cancellation of all
`
`claims of U.S. Patent No. 9,220,631 (“the ’631 patent”). I submit this declaration
`
`on behalf of Novartis Pharma AG, Novartis Technology LLC, and Novartis
`
`Pharmaceuticals Corporation (collectively, “Patent Owner” or “Novartis”).
`
`II. Qualifications
`
`2.
`
`I am a microbiologist and an expert in, among other things, the
`
`sterilization of medical devices, pharmaceutical and ophthalmic preparations.
`
`3.
`
`I have over 30 years of experience in the fields of microbiology,
`
`sterilization, manufacturing, regulatory and quality assurance for the
`
`pharmaceutical, biopharmaceutical, ophthalmic/contact lens care and medical
`
`device industries.
`
`4.
`
`I received a Ph.D. in Microbiology and Biochemistry from Georgia
`
`State University (GSU) in 1988. My Ph.D. focused on the bacterial contamination
`
`of contact lenses, which was a significant clinical issue during the time of my
`
`studies. My studies resulted in the publication of my research in several peer-
`
`reviewed clinical microbiology and ophthalmology journals.
`
`1
`
`Novartis Exhibit 2203.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`5.
`
`Concurrent with my Ph.D. work at GSU, I performed research studies
`
`associated with bacterial endophthalmitis (an inflammatory condition of the
`
`intraocular cavities, i.e., the aqueous and/or vitreous humor, usually caused by
`
`infection) at the Department of Ophthalmology at Emory University School of
`
`Medicine. My research was published in two peer-reviewed ophthalmology
`
`journals.
`
`6.
`
`After receiving my degree, I was employed by Advanced Sterilization
`
`Products (ASP), a Johnson & Johnson company, and Johnson & Johnson Medical,
`
`Inc. in Arlington, Texas from July 1988–July 1991, where I held the position of
`
`Senior Microbiologist and Manager of Microbiology. While at ASP, I was
`
`personally responsible for developing all the microbiology developmental and
`
`validation strategies for the company’s vaporized hydrogen peroxide (“VHP”)
`
`technology. My work encompassed the development of the technology,
`
`demonstrating technical benefits to other sterilization methods, including ethylene
`
`oxide, performance of VHP residual studies and biological indicator challenges to
`
`demonstrate sterility assurance levels. I was also responsible for managing a
`
`laboratory that conducted many of the evaluations, focusing on the sterilization of
`
`surgical and ophthalmic instrumentation and implantable medical devices. During
`
`this time, I also worked on an American National Standard Institute (ANSI)
`
`sterilization technical committee, whose work was used to help create the
`
`2
`
`Novartis Exhibit 2203.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`International Organization for Standardization (ISO) worldwide sterilization
`
`standards. ISO sterilization standards outline the principles for many aspects of
`
`sterilization validation and use, written by global subject matter experts from
`
`numerous countries around the world.
`
`7.
`
`Following my time at Johnson & Johnson, I worked at Bausch & Lomb
`
`from 1991-2002, where I held numerous technical and management positions,
`
`including Manager of Quality Assurance Microbiology, Manager of Research
`
`Microbiology, Director of Biological and Sterilization Sciences, and Director of
`
`External Technology. Within the quality assurance microbiology group, I was
`
`responsible for overseeing all finished product stability, finished product release
`
`and pharmacopoeial microbiology testing for aseptically filled prescription
`
`ophthalmic products, aseptically filled and terminally sterilized (via radiation)
`
`contact lens care solutions, and terminally sterilized (via moist heat) contact lenses.
`
`I was also responsible for developing many of the testing strategies and
`
`validations. Within the research microbiology role, I worked directly with the
`
`Product Development and Development Formulation teams in creating
`
`microbiology strategies in support of those activities and conducted all the
`
`laboratory testing. As the Director of Biological and Sterilization Sciences, I was
`
`responsible for all of the corporate microbiology functions, as well as global
`
`toxicology—the latter focusing on the potential for ophthalmic products to interact
`
`3
`
`Novartis Exhibit 2203.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`with the ocular environment and cause an unintended clinical outcome. This
`
`included the potential for sterilized ophthalmic devices to illicit a toxic response
`
`when the device is placed on or implanted in the eye. When tasked with
`
`developing a global sterilization science group, I was responsible for working with
`
`all the quality and operations organizations at the manufacturing sites when
`
`creating the company’s strategies for the sterilization of commercial
`
`ophthalmology products. I was also responsible for working with external
`
`inventors and other collaborators in bringing new technologies into the company,
`
`which included reviewing new inventor's patents.
`
`8.
`
`From February 2002 to September 2003, I served as Vice President of
`
`Consulting at Pharmaceutical Systems, Inc. in Mundelein, Illinois, where I was
`
`responsible for consulting, developing, and implementing pharmaceutical
`
`manufacturing, QA/QC and regulatory solutions in all areas of medical device and
`
`pharmaceutical operations including sterilization, aseptic and non-sterile
`
`compounding and filling and microbiology. The products I worked with included
`
`sterile injectables and oral dosage forms. I also managed several consultants who
`
`worked primarily at pharmaceutical and biopharmaceutical manufacturing
`
`facilities, helping them resolve their compliance issues with the U. S. Food and
`
`Drug Administration (FDA) and other regulatory agencies.
`
`4
`
`Novartis Exhibit 2203.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`9.
`
`I was next employed by Eli Lilly and Company, Indianapolis, Indiana as
`
`Director, Microbiology Leader and Senior Research Fellow from October 2003–
`
`February 2009. In this role, I worked directly with product development
`
`organizations in providing microbiology strategies for testing, sterilization
`
`(including the validation of vaporized hydrogen peroxide sterilization procedures
`
`to decontaminate aseptic processing areas where pre-filled syringes would be
`
`filled), and stability as they related to contamination control for a wide variety of
`
`products, including sterile injectables, such as insulin, nonsterile products for oral
`
`administration and small molecule and large molecule active pharmaceutical
`
`ingredients that would be used in finished pharmaceutical preparations. During that
`
`time, I also worked directly with the FDA and global regulatory agencies in
`
`defining the future expectations for microbiology testing.
`
`10.
`
`I am currently the President of Microbiology Consultants, LLC,
`
`located in Lutz, Florida, a company specializing in providing expertise in
`
`microbiology and rapid microbiology methods, sterility assurance and sterilization,
`
`isolator technology, Process Analytical Technology (PAT), Good Manufacturing
`
`Practice (GMP) compliance, and quality, manufacturing, and regulatory solutions
`
`for the pharmaceutical, biopharmaceutical and medical device industries. I have
`
`been in this position since February 2009.
`
`5
`
`Novartis Exhibit 2203.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`11.
`
`I have been a member of the Parenteral Drug Association (PDA) for 30
`
`years. I am currently the co-chair of a task force responsible for developing industry
`
`best practices for new microbiology methods. I was also the co-chair for numerous
`
`PDA annual global conferences on pharmaceutical microbiology.
`
`12.
`
`For more than 30 years I have also been an active member of the
`
`American Society for Microbiology (ASM).
`
`13.
`
`Throughout my career, I've been invited to deliver presentations,
`
`keynote addresses, as well as training courses in a wide variety of areas, including
`
`microbiology, contamination control, disinfection, sterilization, aseptic processing,
`
`new microbiology technologies, and quality and regulatory affairs.
`
`14.
`
`I have had the opportunity to author papers published in peer-
`
`reviewed journals and in technical and industry trade journals. I've written
`
`textbook chapters on various microbiology topics and was the editor of the
`
`Encyclopedia of Rapid Microbiological Methods. In total, I have authored over 75
`
`published works.
`
`15.
`
`I am currently a reviewer for the PDA Journal of Pharmaceutical
`
`Science and Technology and am on the editorial boards for American
`
`Pharmaceutical Review and European Pharmaceutical Review.
`
`16. My educational background, work experience, and publications are set
`
`forth in my curriculum vitae, attached to this report as Appendix A.
`
`6
`
`Novartis Exhibit 2203.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`III. Scope of Study
`
`17.
`
`I have been asked by counsel for Patent Owner to provide my
`
`opinions in response to the opinions of Petitioner’s expert Horst Koller as they
`
`relate to sterilization.
`
`IV. Summary of Opinions
`
`18.
`
`A microbiologist who was a member of a product development team1
`
`would not have been motivated to use Sigg’s VHP method to terminally sterilize a
`
`prefilled syringe (“PFS”) filled with a VEGF antagonist as recited in Claims 1 and
`
`17 of the ’631 patent and would not have a reasonable expectation of success in
`
`doing so.
`
`19.
`
`Sigg does not disclose using VHP to achieve a Sterility Assurance
`
`Level (SAL) of 10-6 as recited in Claim 21 of the ’631 patent.
`
`20.
`
`A microbiologist who was a member of a product development team
`
`would not be motivated to use Sigg’s VHP disclosure to terminally sterilize a PFS
`
`filled with a VEGF antagonist to an SAL of 10-6 as recited in Claim 21 of the ’631
`
`patent and would not have a reasonable expectation of success in doing so.
`
`
`As discussed in section V, below, a person of ordinary skill in the art would
`
`1
`
`have been a member of a product development team that also included a
`
`microbiologist.
`
`7
`
`Novartis Exhibit 2203.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`21.
`
`A microbiologist who was a member of a product development team
`
`would not have been motivated to use Lam’s ethylene oxide (EtO) method to
`
`terminally sterilize a PFS filled with a VEGF antagonist as recited in Claims 1 and
`
`17 of the ’631 patent, and would not have a reasonable expectation of success in
`
`doing so.
`
`22.
`
`Lam does not disclose an SAL of 10-6 as recited in Claim 21 of the
`
`’631 patent.
`
`23.
`
`A microbiologist who was a member of a product development team
`
`would not be motivated to use Lam’s EtO method to terminally sterilize a PFS
`
`filled with a VEGF antagonist to an SAL of 10-6 as recited in Claim 21 of the ’631
`
`patent and would not have a reasonable expectation of success in doing so.
`
`24.
`
` A microbiologist who was a member of a product development team
`
`would not have understood from the Macugen label that the product had been
`
`terminally sterilized or had achieved any particular SAL.
`
`25.
`
`Genentech’s efforts to terminally sterilize the Lucentis PFS with EtO
`
`failed.
`
`V. Person of Ordinary Skill in the Art
`
`26.
`
`I understand that the prior art must be viewed from the perspective of
`
`a person of ordinary skill in the art (“POSA”). I have been informed that Novartis
`
`has offered the following definition of a POSA:
`
`8
`
`Novartis Exhibit 2203.0011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`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 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.
`
`27.
`
`This definition of a POSA aligns with how a PFS product would
`
`actually be developed. I would have been a member of such a product
`
`development team, specifically as a microbiologist with expertise in sterilization of
`
`medical devices, pharmaceuticals and ophthalmic preparations. I offer my
`
`opinions in this declaration from the perspective of such a microbiologist.
`
`28.
`
`I have been asked to assume that the relevant date for assessing the
`
`prior art is July 3, 2012, and my opinions reflect the understanding of a
`
`microbiologist as of that date. I was also asked whether my opinions would
`
`change were the relevant date instead be October 23, 2012, and they would not.
`
`Accordingly, when I refer to the state of the art, I am referring to the state of the art
`
`as of both July 2012 and October 2012, unless I say otherwise.
`
`9
`
`Novartis Exhibit 2203.0012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`VI. Claim Construction
`
`29.
`
`I have been informed that, for purposes of these proceedings, the term
`
`“terminal sterilization” refers to a process whereby the outside of a pre-filled
`
`syringe is sterilized, while contact between the sterilizing agent and the drug
`
`product within the syringe is minimized. I have used this definition in offering my
`
`opinions below.
`
`VII. Background on Sterile Products and Sterilization Techniques
`
` Development of a Sterilization Cycle
`A.
`30.
`
`As of 2012, the development of a sterilization cycle required an
`
`understanding of the item to be sterilized, the intended level of sterility assurance
`
`the sterilization cycle must achieve, and whether the proposed sterilization method
`
`will be compatible with said item (i.e., there is no impact to the item’s safety,
`
`efficacy and/or performance). These considerations would have applied to a
`
`medical device, pharmaceutical injectable product, an ophthalmic product required
`
`to be sterile, and related dosage forms.
`
`31.
`
`Regarding the compatibility of the item to be sterilized, it would have
`
`been considered critical to determine whether a sterilization process would alter the
`
`physical, safety and/or pharmacological properties of the item; otherwise, the item
`
`may fail in its performance, become degraded or provide a dangerous environment
`
`10
`
`Novartis Exhibit 2203.0013
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`where the item is used. For example, an ophthalmic injectable that contains unsafe
`
`levels of EtO residuals would be toxic and detrimental to the ocular environment.
`
`32.
`
`A microbiologist or one who is versed in the scientific principles of
`
`sterilization techniques and validation strategies would have been expected to
`
`contribute to a larger team responsible for developing sterile pharmaceuticals,
`
`medical devices, or related dosage forms.
`
` Sterilization Techniques
`
`Different scientific principles may be used to achieve terminal
`
`B.
`33.
`
`sterilization, including the use of EtO, moist heat (autoclaving) or dry heat,
`
`radiation (gamma irradiation or e-beam) and vaporized hydrogen peroxide (VHP).
`
`The technique used largely depends on the type of pharmaceutical preparation and
`
`its components or ingredients.
`
`34.
`
`In order to be successful, a terminal sterilization process must not only
`
`achieve an appropriate level of sterilization, but it must also avoid (1) degradation
`
`or alteration of the drug product; (2) degradation of the drug product components,
`
`including its packaging; and (3) leaving traces of toxic substances that can render
`
`the drug product unsafe for use. I understand this concept to be at least partially
`
`incorporated in the definition of “terminal sterilization” in these proceedings in that
`
`the purpose of minimizing contact between the sterilizing gases and the drug
`
`11
`
`Novartis Exhibit 2203.0014
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`product is to avoid degradation of the active ingredient which can render the PFS
`
`unusable.
`
`35.
`
`Gas sterilization is a chemical method of sterilization that uses a
`
`sterilizing gas such as EtO or VHP. Typically, the material to be sterilized is
`
`placed in a specialized chamber under vacuum and exposed to the gas under
`
`specific parameters for relative humidity and temperature. For example, EtO
`
`sterilization is enhanced in environments where the relative humidity is ~60% and
`
`the temperature is between 50-60°C. Ex. 2185, Ansel 1995 at .016.
`
`36.
`
`Gases used in sterilization can penetrate many materials, allowing pre-
`
`packaged materials to be sterilized with this method. Sterilizing gases cannot,
`
`however, penetrate impermeable materials, such as foil. As such, packaging used
`
`in gas sterilization processes must be designed to allow the gas to penetrate the
`
`package.
`
`37.
`
`Sterilizing gases are toxic, and, during sterilization of a PFS, can
`
`adulterate the drug product if the gas is allowed to penetrate the syringe
`
`components, including the plunger and stopper. Sterilizing gases can also adsorb
`
`onto syringe components during sterilization and subsequently leach into the drug
`
`product over time. Once sterilizing gas gets into the drug product, it may be
`
`difficult or even impossible to remove the gas or its by-products.
`
`12
`
`Novartis Exhibit 2203.0015
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`38.
`
`Sterilization by ionizing radiation is accomplished through exposure
`
`to gamma rays from a radioisotope source (e.g., cobalt-60), or beta rays produced
`
`from the mechanical acceleration of electrons (e.g., electron-beam). Ionizing
`
`radiation disrupts cell metabolism by the creation of highly energized, free radicals
`
`such as hydrogen and hydroxyl ions, and destroys microorganisms by stopping
`
`reproduction because of lethal mutations. Ex. 2186, Lachman 1986 at .008. As of
`
`2012, ionizing radiation was used to sterilize both bulk drug substances and final
`
`drug dosage forms.
`
`39.
`
`Aseptic processing is not a sterilization technique but is a procedure
`
`that was frequently used in the compounding and filling of finished drug products
`
`that will not withstand terminal sterilization processes in the final package or
`
`container. During aseptic processing, individual components of a finished drug
`
`product are sterilized, and these components are then aseptically filled into
`
`previously sterilized packages, or containers. Sterility must be maintained
`
`throughout the aseptic processing operation, and it was understood to be necessary
`
`to use sterile equipment and a controlled working environment, such as a clean
`
`room, laminar flow hood or a barrier isolator.
`
` Sterility Assurance Level
`c.
`40.
`
`Sterile products are dosage forms of therapeutic agents that are free of
`
`viable microorganisms. Ex. 2186.018. In a commercial process, an absolute
`
`13
`
`Novartis Exhibit 2203.0016
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`definition of sterility cannot be applied, since each sterile article of a
`
`manufacturing lot would have to be tested and, in the process, destroyed.
`
`Therefore, as of 2012, sterility was defined in probabilistic terms, where the
`
`likelihood of contamination or finding a non-sterile manufactured article is
`
`acceptably remote. This probability was typically referred to as an SAL.
`
`41.
`
`An SAL was normally expressed in quantitative terms of 10-n, where n
`
`represents a negative base 10 logarithmic value. For example, an SAL of 10-3
`
`equals a 1 in 1,000 probability of a nonsterile unit; an SAL of 10-4 equals a 1 in
`
`10,000 probability of a nonsterile unit, an SAL of 10-5 equals a 1 in 100,000
`
`probability of a nonsterile unit, and an SAL of 10-6 equals a 1 in 1,000,000
`
`probability of a nonsterile unit. An SAL of 10-6 therefore represents a more
`
`rigorous sterility level than an SAL between 10-3 and 10-5.
`
`42.
`
`The concept of SAL is derived from the exponential value of
`
`inactivation kinetics. Specifically, SAL is the probability of a survivor per item
`
`determined from first-order death rate kinetics data after exposure to the sterilant
`
`used for the sterilization process. Ex. 2187, ANSI/AAMI ST67:2011 at .017.
`
`43.
`
`As a practical matter, it is not possible to directly prove an SAL
`
`of 10-6. As such, model situations have been created that healthcare industries
`
`have used for decades. By 2012, biological indicators were used to verify that a
`
`sterilization process has the ability to inactivate microorganisms that have a known
`
`14
`
`Novartis Exhibit 2203.0017
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`resistance to a referenced sterilization process. Ex. 2188, ISO 141612 at .011.
`
`They were typically paper strips or similar carriers containing extremely large
`
`concentrations of representative test organisms with a maximum resistance to the
`
`sterilization procedure, typically ≥106 bacterial spores per test object. Ex. 2200,
`
`Von Woedtke and Kramer at .003.
`
`44.
`
`The resistance of biological indicators to a sterilization process could
`
`be quantified in terms of a log reduction, which is a reduction in the number of
`
`viable microorganisms, expressed in log10 units, after fractional exposure to a
`
`sterilization process. Ex. 2188.009. The following table illustrates the relationship
`
`between microorganism number, its exponential equivalent and log10 value.
`
`Number Exponential
`Expression
`106
`1,000,000
`105
`100,000
`104
`10,000
`
`2 ISO 14161. Sterilization of health care products - Biological indicators -
`
`Log10 Value
`6
`5
`4
`
`Guidance for the selection, use and interpretation of results. 2000. ISO 14161
`
`“provides guidance for the selection, use and interpretation of results from
`
`application of biological indicators when used in the development, validation and
`
`routine monitoring of sterilization processes,” and would have been relied upon by
`
`microbiologists as of 2012 to develop and evaluate sterilization processes.
`
`15
`
`Novartis Exhibit 2203.0018
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`1,000
`100
`10
`1
`
`103
`102
`101
`100
`
`3
`2
`1
`0
`
`
`
`45.
`
`Log reductions may be used to calculate an SAL, but the terms “log
`
`reduction” and “SAL” mean two distinct things. A log reduction is a measure of
`
`the number of microorganisms eliminated after a sterilization process, while an
`
`SAL is a probability of the number of nonsterile units after a sterilization process,
`
`as I previously explained.
`
`46.
`
`For example, if a biological indicator with 106 (6 logs)
`
`microorganisms is subjected to a sterilization process and the population is reduced
`
`to 102 microorganisms (2 logs), the log reduction is calculated by subtracting the
`
`initial log value from the final log value. In this case, 6 logs - 2 logs = a 4-log
`
`reduction. The following illustration provides a graphical representation of this
`
`example.
`
`16
`
`Novartis Exhibit 2203.0019
`Regeneron v. Novartis, IPR2021-00816
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`

`

`(g
`
`-0
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`Ill
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`Ill
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`0
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`1,000,000
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`100,000
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`10,000
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`1,000
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`100
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`10
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`1
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`4LogR duction
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`47.
`
`As of 2012, pharmaceutical companies often used what is referred to
`
`as a “half-cycle” or “overkill” sterilization method to validate a terminal
`
`sterilization process. In this method, the company defines a sterilization cycle as
`
`described above. The drug product together with the biological indicators,
`
`typically containing 106 test organisms, would then be exposed to one-half of the
`
`normal holding time for the sterilization cycle. Ex. 2188.017. A six-log reduction
`
`in the population of organisms should be demonstrated within that time period. Id.
`
`It could then be assumed that if the product were subjected to the full holding time
`
`for the sterilization cycle (i.e., double the time used for the validation), there would
`
`be an additional six-log reduction, in other words a twelve-log reduction in total.
`
`Ex. 2200.003.
`
`48.
`
`In terms of SAL, because the initial microorganism challenge was 106,
`
`reducing the population by six logs using a half-cycle would provide an SAL of
`
`17
`
`Novartis Exhibit 2203.0020
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`100; reducing another six logs by using the whole cycle (for a total reduction of
`
`twelve logs) would provide an SAL of 10-6. The following illustration summarizes
`
`these concepts:
`
`106
`
`- 104
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`105
`
`103
`
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`
`101
`
`10°
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`10·1
`
`10·2
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`10·3
`
`10·4
`
`10·5
`
`10·6
`
`~ " "-"' ' "-· - '
`"' ' ' "
`'
`
`12 Log I educ tion
`Half Cycle 't
`
`Full Cycle 't
`
`6 Log I ledu, tion
`
`6
`s
`4
`
`3
`
`2
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`0
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`.1
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`.01
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`.001
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`.000001
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`
`49.
`
`In short, demonstrating a six-log reduction of sterilization-resistant
`
`microorganisms does not equate to an SAL of 10-6; rather, the same sterilizing
`
`conditions would have to be doubled; in other words, there would have to be a
`
`twelve-log reduction to achieve this level of lethality. Of course, additional work
`
`must be performed to demonstrate that a drug product subjected to an SAL of 10-6
`
`would not be degraded or otherwise rendered unsuitable or unsafe for use.
`
`50.
`
`Generally, an SAL of 10-6 has been used for terminal sterilization, but
`
`this was not an absolute requirement. SALs between 10-3 and 10-5 have been used
`
`18
`
`Novartis Exhibit 2203.0021
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`and approved for medical devices that, for example, are unable to withstand a
`
`terminal sterilization process that provides an SAL of 10-6. Ex. 2187.014. The
`
`choice of a sterilization process and SAL would be addressed during the
`
`development of the product, and the FDA considered alternate SALs less stringent
`
`than 10-6 on a case-by-case basis. Ex. 2187.014, .019.
`
`51.
`
`I note that the fact that an SAL of 10-6 was not always required and
`
`that FDA considered alternate SALs when a product cannot withstand a
`
`sterilization process is supported
`
`52.
`
`.
`
`19
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`.
`
`Novartis Exhibit 2203.0022
`Regeneron v. Novartis, IPR2021-00816
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`

`

`53.
`Ww
`
`54.
`
`raNn
`
`55.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
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`20
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`Novartis Exhibit 2203.0023
`Regeneron v. Novartis, IPR202 1-008 16
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`Novartis Exhibit 2203.0023
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`
`
` Labeling of Sterile Products
`D.
`
`56.
`
`The US Code of Federal Regulations (CFR) requires sterile
`
`pharmaceuticals to be labeled as such. For example, 21 CFR 201.57 provides
`
`specific requirements on content and format of labeling for human prescription
`
`drug and biological products. Ex. 2193, CFR 2021.3 Under the section that
`
`specifies the requirements for full prescribing information, section 21 CFR
`
`201.57(c)(12)(i)(D) requires that the label description include a statement that the
`
`product is sterile. Ex. 2193.010. Specifically, 21 CFR 201.57(c)(12)(i)(D) states,
`
`“[i]f the product is sterile, a statement of that fact.” Ex. 2193.010.
`
`
`3 Ex. 2193 is available at https://www.ecfr.gov/current/title-21/chapter-I/subchapter-
`
`C/part-201/subpart-B/section-201.57#p-201.57(c)(12) (accessed December 28,
`
`2021).
`
`21
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`Novartis Exhibit 2203.0024
`Regeneron v. Novartis, IPR2021-00816
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`

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`57.
`
`The same sterile labeling requirement was in place by 2012. See
`
`Ex. 2192, CFR 2008 at .00134; see also Ex. 2191, CFR 2004 at .0015.
`
`58.
`
`It is important to note that in both the current CFR and the CFR as of
`
`2012, there is no requirement to state what sterilization method was used to render
`
`the product sterile, whether the method was a terminal sterilization or an aseptic
`
`process, or the achieved SAL. In each case, the CFR only requires a statement the
`
`product is sterile.
`
`VIII. Sigg
`
` A Microbiologist Would Not Have Been Motivated to Use Sigg’s
`A.
`VHP Method to Terminally Sterilize a PFS and Would Not Have a
`Reasonable Expectation That a PFS Would be Successfully Sterilized
`With This Method
`
`59. Mr. Koller provides a description of Sigg’s disclosure with respect to
`
`VHP, but Sigg actually discloses two terminal sterilization methods, VHP and beta
`
`radiation. Ex. 1007, Sigg at 3:7–4:18. In my opinion, a microbiologist would have
`
`been more motivated to use Sigg’s beta radiation method than its VHP method and
`
`would not have had a reasonable expectation of success using the VHP method.
`
`
`4 Ex. 2192 is available at https://www.govinfo.gov/content/pkg/CFR-2008-title21-
`
`vol4/pdf/CFR-2008-title21-vol4-sec201-57.pdf (acce