`
`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 Owner
`
`
`Case No. IPR2021-00816
`U.S. Patent No. 9,220,631
`
`
`
`DECLARATION OF JAMES AGALLOCO
`
`
`
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`Regeneron Exhibit 1100.001
`Regeneron v. Novartis
`IPR2021-00816
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`TABLE OF CONTENTS
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`Page
`INTRODUCTION ........................................................................................... 1
`I.
`QUALIFICATIONS AND COMPENSATION .............................................. 1
`II.
`III. LEGAL STANDARDS ................................................................................... 5
`IV. A PERSON OF ORDINARY SKILL IN THE ART ...................................... 7
`V. DEFINITION OF “TERMINAL STERILIZATION” IN THE '631
`PATENT .......................................................................................................... 8
`VI. BACKGROUND ............................................................................................. 9
`A.
`Sterilization of Pre-filled Syringes ........................................................ 9
`B.
`Sterility Assurance and Validation ...................................................... 12
`VII. RELEVANT PRIOR ART TO THE '631 PATENT ..................................... 18
`A.
`“Sigg” – WO 2011/006877 ................................................................. 18
`B.
`“Lam” – WO 2008/077155 ................................................................. 19
`VIII. A Person with Specialized Skills in Microbiology Would Be
`Motivated to Use Sigg’s VHP Method to Achieve an SAL of 10-6 and
`Would Have a Reasonable Expectation of Success in so Doing ................... 21
`A.
`Sigg Provides a Motivation to Use its VHP Method .......................... 21
`B.
`A Person with Specialized Skills in Microbiology Would
`Understand that Sigg’s VHP Method Could Be Used to
`Achieve an SAL of 10-6 ....................................................................... 23
`C. A Person with Specialized Skills in Microbiology Would Have
`Reasonably Expected to Succeed in Using Sigg’s VHP Method
`to Achieve an SAL of 10-6 ................................................................... 25
`
`
`
` .................................. 27
`IX. A Person with Specialized Skills in Microbiology Would Have Been
`Motivated to Use Lam’s EtO Method to Achieve a SAL of 10-6, and
`Would Have a Reasonable Expectation of Success ...................................... 29
`X. DECLARATION ........................................................................................... 35
`
`D.
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`i
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`Regeneron Exhibit 1100.002
`Regeneron v. Novartis
`IPR2021-00816
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`I.
`
`INTRODUCTION
`I have been retained by Petitioner Regeneron Pharmaceuticals, Inc.
`1.
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`("Petitioner" or "Regeneron"), as an independent expert witness in the above-
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`captioned inter partes review ("IPR"), in which Regeneron has requested that the
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`U.S. Patent and Trademark Office cancel as unpatentable all claims of U.S. Patent
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`No. 9,220,631 ("the '631 patent") (Ex. 1001).
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`2.
`
`This declaration sets forth my analyses and opinions based on my
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`knowledge, experience, and the materials I have considered.
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`II. QUALIFICATIONS AND COMPENSATION
`I have a M.B.A. in Pharmaceutical Studies from Fairleigh Dickinson
`3.
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`University, a M.S.Ch.E. from the Polytechnic Institute of New York, and a
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`B.E.Ch.E. from Pratt Institute.
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`4.
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`I have over fifty years of management experience in pharmaceutical
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`manufacturing, pharmaceutical process, pharmaceutical process engineering,
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`technical services and research and development. Since 1991, I have been the
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`President of Agalloco & Associates, which provides to the pharmaceutical,
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`biotechnology, and medical device industry a wide range of technical services such
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`as process and product validation, sterilization, aseptic processing, processing,
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`isolation technology, sterility assurance, compliance and facility design.
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`1
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`Regeneron Exhibit 1100.003
`Regeneron v. Novartis
`IPR2021-00816
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`5.
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`Prior to 1991, I was Director of Validation and Technology at Bristol-
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`Myers Squibb; Director of Worldwide Validation and Automated Technology and
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`Pharmaceutical Engineering; Department Manager at Bristol-Myers Squibb, and
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`held a number of other positions, including Engineering Project Manager and
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`Senior Production Supervisor at Pfizer Pharmaceuticals.
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`6.
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`As Director of Validation and Technology at Bristol-Myers Squibb, I
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`directed validation, automation and technical documentation activities and served
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`as an important technical resource for worldwide pharmaceutical manufacturing. I
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`was an active participant on product introduction and facility upgrade task forces.
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`As Director of Worldwide Validation and Automated Technology at Bristol-Myers
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`Squibb, I was responsible for facilities in 27 countries around the world and served
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`as a major technical resource for facility design, facility start-up, sterilization,
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`aseptic processing, validation and automation. I participated actively on major
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`product, process, facility and equipment projects, directed the validation and
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`automation phases of a $25 million expansion of existing parenteral facility in New
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`Brunswick, and provided major support to sterile bulk manufacturing. As head of
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`the Validation department at Squibb New Brunswick, I was responsible for
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`validation of all processes at the site including various sterilization processes. I
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`also led the validation effort for a $60 million parenteral facility.
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`2
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`Regeneron Exhibit 1100.004
`Regeneron v. Novartis
`IPR2021-00816
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`7.
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`In previous positions, I provided validation expertise for sterile
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`facilities, acted as a spokesperson for validation to the Food and Drug
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`Administration (“FDA”) and other regulatory agencies, managed production
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`operations for sterile and oral liquid and powder products, and had major areas of
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`responsibility including cost control, cost reduction, Current Good Manufacturing
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`Practice (“CGMP”) compliance, scheduling, equipment selection, and process
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`trouble shooting.
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`8.
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`In addition to my work experience, I have many years of experience
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`participating in professional organizations, and pharmacopoeias relating to
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`sterilization and sterility assurance for pharmaceuticals and medical devices,
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`including microbiology as it relates to sterilization. For example, I have been an
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`active member of the United States Pharmacopoeia (“USP”) Microbiology Expert
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`Committee since 2005, and the lead author on the comprehensive revision of USP
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`<1211> Sterilization & Sterility Assurance of Compendial Items. The new USP
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`content (Chapters <1211> Sterility Assurance and <1229> Sterilization) includes
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`substantially expanded content addressing the full range of sterilization processes
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`and means for the aseptic processing for drugs and medical devices. In addition, I
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`have led and participated in the development of numerous sterilization and aseptic
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`processing industry guidance documents as a member of the Parenteral Drug
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`Association. I have been a member of the Parenteral Drug Association since 1980
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`3
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`Regeneron Exhibit 1100.005
`Regeneron v. Novartis
`IPR2021-00816
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`and served as its President in 1988 and 1989. I am also the co-founder and a
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`current member of the Validation Discussion Group. I have also served on several
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`scientific and editorial advisory boards. I have also co-authored more than 60 book
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`chapters and over 160 technical papers.
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`9.
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`In addition to the above, I have given numerous presentations at
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`industry meetings and in-house at pharmaceutical companies, including many
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`presentations over the years that relate to aseptic processing, sterilization, and
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`process validation.
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`10. Through my professional experience, I have gained extensive
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`expertise in both aseptic processing and terminal sterilization. I have experience in
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`all types of medical device and pharmaceutical sterilization, including chemical
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`sterilization, such as by hydrogen peroxide and ethylene oxide. I have also gained
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`knowledge of sterilization of container closure systems, including aseptic
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`processing and terminal sterilization of pre-filled syringes.
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`11.
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`I am being compensated at my standard rate of $350/hour. My
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`compensation is in no way contingent upon my opinions or the outcome of the
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`proceeding.
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`12.
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`I may testify on any or all of the opinions expressed in this expert
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`report. In addition, I will, as needed, explain principles and terminology referred to
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`in this report as well as materials referenced herein. I provide this declaration to
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`4
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`Regeneron Exhibit 1100.006
`Regeneron v. Novartis
`IPR2021-00816
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`provide specific background and explanation regarding sterilization technology, as
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`well as explaining how certain claim limitations of the ’631 patent relating to
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`sterilization are disclosed and/or rendered obvious by the prior art.
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`13. My curriculum vitae is attached as Attachment A, and provides
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`further information about my experience, expertise, publications, and
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`presentations.
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`III. LEGAL STANDARDS
`I understand that the invalidity analysis must be conducted from the
`14.
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`perspective of the person of ordinary skill in the art, and must consider whether the
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`skilled artisan would consider any differences between the prior art and what is
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`claimed to have been obvious. To make this assessment, I have been informed that
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`the concept of patent obviousness involves four factual inquiries: (1) the scope and
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`content of the prior art; (2) the differences between the claimed invention and the
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`prior art; (3) the level of ordinary skill in the art; and (4) secondary considerations
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`of non-obviousness. I have been instructed that one must not engage in hindsight.
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`Rather, the better approach is to consider what the person of ordinary skill in the
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`art would have reason to pursue further, and steps that were routinely done, such as
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`in response to known problems, steps or obstacles.
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`15.
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`It is my understanding that some teaching, suggestion, or motivation
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`in the prior art that would have led one of ordinary skill to modify the prior art
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`5
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`Regeneron Exhibit 1100.007
`Regeneron v. Novartis
`IPR2021-00816
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`reference or to combine prior art reference teachings to arrive at the claimed
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`invention may support the obviousness of an invention. Other rationales that may
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`support the obviousness of the invention include combining prior art elements
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`according to known methods to yield predictable results, simple substitution of one
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`known element for another to obtain predictable results, and applying a known
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`technique to a known device ready for improvement to yield predictable results.
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`16.
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`It is my understanding that the motivation to combine prior art
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`references may be implicit and may be found in the knowledge of one of ordinary
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`skill in the art, or in the nature of the problem to be solved. Specifically, it is my
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`understanding that an implicit motivation to combine exists not only when a
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`suggestion may be gleaned from the prior art as a whole, but when the
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`“improvement” is technology-independent and the combination of references
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`results in a product or process that is more desirable, for example, because it is
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`stronger, cheaper, cleaner, faster, lighter, smaller, more durable or more efficient.
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`It is my further understanding that the motivation to combine references may be
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`found in the nature of the problem to be solved where prior art references are
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`directed to precisely the same problem.
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`17.
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`I also understand that prior art may be relied on for its express
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`disclosure and teachings. I also understand that the prior art may be relied upon
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`6
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`Regeneron Exhibit 1100.008
`Regeneron v. Novartis
`IPR2021-00816
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`for a teaching of features that are necessarily present in the prior art reference even
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`if that specific feature is not expressly or explicitly disclosed.
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`IV. A PERSON OF ORDINARY SKILL IN THE ART
`I understand that Novartis has asserted that the following definition of
`18.
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`a person of ordinary skill in the art (POSITA) should apply in this proceeding:
`
`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.
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`Ex. 2203.0011-.0012 at ¶ 26. Dr. Miller further asserts that a person “expected to
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`contribute to a larger team responsible for developing sterile pharmaceuticals,
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`medical devices, or related dosage forms” would be “[a] microbiologist or one
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`who is versed in the scientific principles of sterilization techniques and validation
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`strategies.” Ex. 2203.0014 at ¶ 32 (emphasis added). In my opinion, microbiology
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`is relevant to the '631 patent to the extent it references sterility, terminal
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`sterilization, and sterility assurance. See also Ex. 1210.029-.030 at 29:8-30:11.
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`Furthermore, a person with experience and well-versed in sterilization techniques
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`7
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`Regeneron Exhibit 1100.009
`Regeneron v. Novartis
`IPR2021-00816
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`would be a suitable product development team member with specialized skills in
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`microbiology insofar as that person would be knowledgeable in microbiology as it
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`relates to sterilization processes. See also Ex. 1210.037 at 37:3-12.
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`19. As an expert in terminal sterilization, and a member of the USP
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`Microbiology Expert Committee, I am qualified to opine from the perspective of
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`team member with specialized skills in microbiology as it relates to terminal
`
`sterilization. I have an in-depth knowledge of terminal sterilization concepts that
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`implicate the subject of microbiology, such as bioburden, bioindicators, log-
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`reduction and the calculation of sterility assurance level. Furthermore, I have been
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`a member of numerous product development teams, specifically as one with
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`expertise in microbiology as it relates to the sterilization of medical devices,
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`pharmaceuticals and ophthalmic preparations, as well as one who is versed in the
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`scientific principles of sterilization techniques and validation strategies. Thus, I am
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`able to offer my opinions in this declaration from the perspective of a member of a
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`product development team who has specialized skills in microbiology, and have
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`done so in the sections below.
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`V. DEFINITION OF “TERMINAL STERILIZATION” IN THE '631
`PATENT
`20. Although “terminal sterilization” traditionally refers to a process
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`whereby the drug and its container are sterilized within their packaging, I
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`understand that, as used in the '631 patent, the parties have agreed that “terminally
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`8
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`Regeneron Exhibit 1100.010
`Regeneron v. Novartis
`IPR2021-00816
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`sterilized” refers to a process whereby the outside of a pre-filled syringe is
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`sterilized, while contact between the sterilizing agent and the drug product within
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`the syringe is minimized.
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`VI. BACKGROUND
`Sterilization of Pre-filled Syringes
`A.
`21. Regulatory agencies such as the FDA and EMA require all ophthalmic
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`products, such as pre-filled syringes for intravitreal injection, to be sterile. See 21
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`C.F.R. § 200.50(c) (“[D]ispensers intended for ophthalmic use should be sterile….
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`These articles, which are regulated as drugs if packaged with the drugs with which
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`they are to be used, should be packaged so as to maintain sterility until the package
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`is opened.”). Maintaining the sterility of pre-filled syringes for intravitreal
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`injection was known to be important because of the risk of infection from a non-
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`sterile syringe used on an exposed human eye. See, e.g., Ex. 1029.002 at 1:28-29
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`(“[T]here is an increased risk of endophthalmitis after intraocular injection1 if the
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`surface of the syringe used for injection is not sterilized.”).
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`
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`1 Intraocular injection refers to all injections into the chambers of the eye.
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`Intravitreal injection is a subset of intraocular injection, and refers to injection into
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`the vitreous cavity specifically. Ex. 1015.035.
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`9
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`Regeneron Exhibit 1100.011
`Regeneron v. Novartis
`IPR2021-00816
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`22. The FDA, in its guidance on aseptic filling, indicates that “terminal
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`sterilization” is required when possible. See Ex. 1036.007. “Terminal sterilization”
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`(outside of the context of the '631 patent) traditionally refers to a process in which
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`the drug and container closure system (which are not already sterile) are sterilized
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`together in a single process. See id. For drugs that are not heat sensitive, this one-
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`step terminal sterilization can be accomplished by heating (for example, in an
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`autoclave) with steam to sterilize the drug in its primary container-closure system.
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`See generally Ex. 1029.002 at 1:14-22.
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`23. The '631 patent uses the term “terminal sterilization” in a different
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`context, specifically stating that “[t]he package is exposed to the sterilising gas
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`until the outside of the syringe is sterile,” and also that “it is a requirement that
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`significant amounts of the sterilising gas should not enter the variable volume
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`chamber of the syringe.” Ex. 1001.008 at 9:49, 9:55-56; 10:2-4 (emphasis added).
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`Thus, the '631 patent describes “terminal sterilization” of only the outer surface of
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`the syringe after the syringe has been filled with the drug product, generally under
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`aseptic conditions.
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`24. There are many ways to sterilize medical products, including via
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`“steam sterilization, radiation sterilization, gas sterilization (e.g., with ethylene
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`oxide), and chemical sterilization.” Ex. 1029.002 at 1:14-16. It was already known
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`prior to 2012 that protein drug formulations can be degraded by high temperature
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`10
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`Regeneron Exhibit 1100.012
`Regeneron v. Novartis
`IPR2021-00816
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`sterilization processes, which are therefore disfavored for use with protein
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`therapeutics such as VEGF-antagonist solutions in pre-filled syringes. See Ex.
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`1018.003 at [0010]-[0011], [0021]-[0022]; Ex. 1007.008-.009 at 7:29-8:1; Ex.
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`1029.002 at 1:18-25. With respect to sterilization processes that do not use high
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`temperatures, several such processes were known, including sterilization using
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`ethylene oxide (“EtO”) gas, and using vaporized hydrogen peroxide (H2O2)
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`(“VHP”). See e.g., Ex. 1046.001 (describing ethylene oxide sterilization); id. at
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`002 (describing vaporized hydrogen peroxide (VHP) sterilization). Ethylene oxide
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`(EtO) is a gas-based sterilization method, and hydrogen peroxide (H2O2)
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`sterilization is a vapor-based (2-phase system of liquid suspended in a gas)
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`sterilization method. Both EtO and VHP were used to sterilize medical devices for
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`many years prior to 2012. See id.
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`25. EtO sterilization has been used since “the 1950s to sterilize heat and
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`moisture-sensitive medical devices.” Id. at .001. A POSITA would have been well
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`aware that EtO was “[t]he most prevalent gas utilized for sterilization” such that
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`“sterilization using other agents is based on methods used for ETO.” Ex.
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`1016.260-.261 (describing EtO sterilization).
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`26. Similarly, the use of hydrogen peroxide (H2O2) for decontamination
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`has been around since at least the early 1990s. Ex. 1046.002-.003. There were two
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`well-known methods of H2O2-based sterilization that developed prior to 2012. Id.
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`11
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`Regeneron Exhibit 1100.013
`Regeneron v. Novartis
`IPR2021-00816
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`at .002-.003. The first is sterilization via the creation of a hydrogen peroxide
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`plasma. Id at .002. The second method, vaporized hydrogen peroxide (VHP), is
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`simpler because it does not require formation of a plasma and has a large
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`processing capacity. Id at .002-.003. Prior to 2012, VHP systems were available
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`for “processing packaged, heat and moisture-sensitive instruments for terminal
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`sterilization and storage.” Id. at .002.
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`Sterility Assurance and Validation
`B.
`27. The sterility of a medical product can be measured in terms of the
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`sterility assurance level, or SAL, which was a well-known concept in the art long
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`before 2012, and is a mathematical measure of the probability that a sterilized
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`article may not in fact be sterile. Ex. 1007.008 at 7:8-9 (“‘Sterility’ as used herein
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`is meant to refer to complete absence of microbial life as defined by a probability
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`of nonsterility or a sterility assurance level (SAL).”). An SAL of 10-6, the
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`preferred sterility level for health care products, refers to the probability that only 1
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`in 1,000,000 processed units would be non-sterile. Id. at 7:10-13 (“For example,
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`required SALs for health care products are defined to be at least 10-6, i.e. a chance
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`of less than 1:1 million of a non-sterile product”); Ex. 1049.003.
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`28. Determining the SAL of a sterilization process would be routine and
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`well within the ordinary skill of a POSITA prior to 2012. Because it is not feasible
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`to test millions of products to directly measure the rate of non-sterility, sterilization
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`12
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`Regeneron Exhibit 1100.014
`Regeneron v. Novartis
`IPR2021-00816
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`process validation is used. Ex. 1049.002-.003. This type of process validation
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`utilizes the fact that microbial kill rates from most sterilization techniques are
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`exponential in nature. Id. at .003. When a plot of log population versus time is
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`prepared a line can be drawn indicating the death curve. This allows the calculation
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`of SAL level “based on the extent of exposure to the sterilization modality and the
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`corresponding microbial log reduction,” which ultimately derive from the
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`measured time or dose. The D-value is the time “required to achieve inactivation
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`of 90% of a population of the test microorganism” (that is, each log reduction is a
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`90% reduction —e.g., from 100 to 10 or from 10 to 1). Id. Performing such a
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`calculation would be routine to a POSITA, and indeed the adoption of SAL across
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`multiple industries is due in part to its easily adapted standardized approach.
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`29.
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`In the context of sterilizing a medical product, such as a prefilled
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`syringe, the actual number of microorganisms present on the medical product prior
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`to sterilization is referred to as the “bioburden.” The test organisms acting as a
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`stand-in for the bioburden, which can be used to estimate the microbial log
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`reduction of a sterilization process, are called “bioindicators.” The commonly used
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`bioindicator has about 106 bacterial spores of a species (usually from the genus
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`Bacillus or Geobacillus) that is particularly resistant to the type of sterilization
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`used, and thus can represent the worst-case scenario for the bioburden. Ex. 1016.
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`264, .267. Bioindicators are placed alongside or within the products to be
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`13
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`Regeneron Exhibit 1100.015
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`IPR2021-00816
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`terminally sterilized, and after undergoing a sterilization process, the number of
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`remaining spores on the bioindicator are counted. This final number is then
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`expressed as a log reduction in comparison to the starting population.
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`30. For example, if the bioindicator has 106 (that is 1,000,000) spores to
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`start, but 103 (that is, 1,000) spores remain after the sterilization cycle, the number
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`of spores has been reduced by 103 (that is, 1,000-fold), which is 3 logs. If 100
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`spores (that is, one spore), remain, then there has been reduction by106 (that is,
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`1,000,000-fold), or a 6-log reduction. If all 106 spores are killed, such that no
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`spores remain, the estimated log reduction is greater than 6 logs, since fractions of
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`a living spore cannot be recovered. To test for a reduction greater than 6 logs, the
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`starting population of the bioindicator would need to be greater than 106 spores.
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`Thus, to reach higher sterility probabilities, a POSITA would look to use certain
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`validation methods, such as the half-cycle method, first developed for use with
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`EtO, and commonly used for sterilization with gases or vapors. Id. at .264-.265.
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`31. As explained above, the standard goal for sterilization of health care
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`products, such as those intended to come into contact with breached skin or
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`compromised tissue, is a sterility assurance level, or SAL, of 10-6. Ex. 2187.0015.
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`To validate a sterilization process using the half-cycle method, a bioindicator with
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`106 microorganisms would be placed in the sterilization chamber, and the time for
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`killing all of the microorganisms would be determined. For example, if a one hour
`
`14
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`Regeneron Exhibit 1100.016
`Regeneron v. Novartis
`IPR2021-00816
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`sterilization cycle killed all 106 spores of the bioindicator, that one hour cycle
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`would show a 6-log reduction. In order to validate a 12-log reduction, which
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`would result in a SAL of 10-6, the time demonstrated to kill 106 spores would then
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`be doubled. Thus, the initial 6-log reduction is considered a “half-cycle.”2 This is
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`shown on the graph below, taken from Dr. Miller’s declaration.
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`
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`2 Dr. Miller equates the half-cycle method with the overkill method. The overkill
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`method, which is used for sterilization methods other than those utilizing gas or
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`vapor, refers generally to a sterilization methodology in which the destruction of a
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`high concentration of a resistant biological indicator assures the reliable
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`elimination of the bioburden, such that its microbial population and resistance can
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`be ignored. The half-cycle method is one example of an overkill method.
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`15
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`Regeneron Exhibit 1100.017
`Regeneron v. Novartis
`IPR2021-00816
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`Ex. 2203.0021
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`
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`32. Although Dr. Miller points out in his declaration that a lesser SAL, for
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`example 10-3 to 10-5, may be acceptable to regulatory authorities if a SAL of 10-6
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`were not possible, the goal for a POSITA and person with specialized skills in
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`microbiology for an ophthalmic pre-filled syringe would nevertheless be a SAL of
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`10-6. The ANSI source that Dr. Miller cites for the proposition that a SAL of 10-6
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`was not absolutely required, explains that, prior to accepting a less stringent SAL,
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`other validation methods beyond the traditional 6-log half-cycle approach would
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`be attempted. See Ex. 2187.0015 (“For those products that require a 10-6 SAL and
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`are incapable of withstanding the sterilization process chosen, alternative
`
`16
`
`Regeneron Exhibit 1100.018
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
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`sterilization processes and/or validation methods should be investigated before
`
`selecting an alternative SAL (e.g., 10-5, 10-4, or 10-3)”).
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`33. An individual with specialized skills in microbiology as it relates to
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`terminal sterilization would understand that the extent of treatment required to
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`validate an SAL of 10-6 can be reduced if a different validation approach is used.
`
`Id. For example, if the initial bioburden can be controlled, a treatment with a
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`sterilization process that achieves less than a 12-log reduction of the biological
`
`indicator (for example, a sterilization process with a shorter treatment time) can
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`validate a SAL of 10-6 for the bioburden. This is referred to as the combined
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`bioburden-bioindicator approach, and was a well-documented method in the art for
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`achieving an SAL of 10-6 before the '631 patent. Ex. 2188.016-.018, .030-.031.
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`
`
`
`
`
`
`Likewise, it is possible to validate a particular SAL by controlling the initial (pre-
`
`sterilization cycle) bioburden and determine the extent to which the actual
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`bioburden is reduced, which can shorten the treatment time further. This is
`
`referred to as a bioburden-based validation method. Ex. 2187.0015 (“[I]n general, a
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`bioburden-based validation method will give a shorter extent of treatment to
`
`achieve a particular SAL than either a biological indicator-bioburden or an
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`‘overkill’ method.”).
`
`17
`
`Regeneron Exhibit 1100.019
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
`VII. RELEVANT PRIOR ART TO THE '631 PATENT
`“Sigg” – WO 2011/006877
`A.
`34. Sigg (Ex. 1007) is a patent publication assigned to Novartis. Sigg
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`teaches terminal sterilization that involves the “treatment of prefilled containers in
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`secondary packaging by an application of vaporized-hydrogen peroxide, in which
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`vapors are controllable by certain post-treatment measures, and exposure to
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`tunable-beta radiation, in which the depth of penetration of beta rays into
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`secondary packaging are controllable.” Ex. 1007.009 at 8:8-12. The VHP method
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`includes “applying post-treatment measures, within a decontamination chamber”
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`that ensure full removal of the VHP from the chamber and, as a result, protection
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`of the sensitive biologic product and future handlers from the VHP. Id. at .011,
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`10:5-6.
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`35. Sigg explains that the disclosed VHP terminal sterilization methods
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`are especially suitable for use on pre-filled syringes. Id. at .003, 2:13-15
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`(“Prefilled syringes, although filled under aseptic conditions, are not packed into
`
`their secondary packaging in an aseptic environment and are therefore likely to be
`
`microbiologically contaminated at their outside.”); id. at .004, 3:8-11 (“Described
`
`herein is a terminal sterilization and surface decontamination treatment of prefilled
`
`containers, specifically for sterilization of prefilled containers containing sensitive
`
`solutions, such as a drug product or biological therapeutic, within secondary
`
`18
`
`Regeneron Exhibit 1100.020
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
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`packaging.”). Sigg notes that “[t]erminal sterilization of prefilled containers in
`
`secondary packaging is one way to provide the device to an end user with a low
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`bio-burden and low risk of contaminants.” Id. at .003, 2:15-17.
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`36. Relevant to the claims of the '631 patent, Sigg teaches the terminal
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`sterilization (surface sterilization) of low volume (0.5 mL) pre-filled syringes for
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`intravitreal injection containing an ophthalmic solution comprising a VEGF-
`
`antagonist. Sigg describes that the VHP sterilization process does not impact the
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`sensitive biologic product contained in the pre-filled glass syringe. Id. at .010,
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`9:16-17 (“the contents of the container are sterile and unaffected by surface
`
`decontamination methods as described herein.”). Example 1 of Sigg describes that
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`the protein concentration of an anti-VEGF antibody in pre-filled syringes was
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`relatively unchanged after sterilization with VHP, which indicates that little or no
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`VHP penetrated the syringe. Id. at .021-.022, 20:18-21:3 (describing syringes
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`comprising a “formulation as described in U.S. Patent No. 7,060,269”); Ex. 1023
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`(U.S. Patent No. 7,060,269 describing Anti-VEGF antibodies).
`
`“Lam” – WO 2008/077155
`B.
`37. Lam (Ex. 1029) is a patent publication that is assigned to Genentech.
`
`Lam discloses the terminal sterilization of pre-filled glass syringes containing a
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`VEGF-antagonist intended for intravitreal injection, using EtO sterilization. Ex.
`
`1029.014 at 13:14-15 (“We performed EtO sterilization runs on syringes
`
`19
`
`Regeneron Exhibit 1100.021
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
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`containing a ranibizumab solution….”). Lam teaches that the EtO sterilization
`
`methods taught therein are especially suitable for drug formulations containing
`
`active ingredients that may be damaged by the high temperatures, radiation, or
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`direct interaction with chemical gases used in some sterilization processes. Id. at
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`.002, 1:18-23.
`
`38. Lam discloses that the surface of the syringe is EtO sterilized after the
`
`syringe has already been filled with drug formulation via aseptic fill, and that
`
`contact between the sterilizing agent and the drug formulation is avoided. See id.
`
`at .002, 1:22-33 (“Consequently, pharmaceutical compositions are generally
`
`sterilized by an alternative method, e.g. by filtration…. Thus, there remains a need
`
`for efficient and cost-effective methods of surface-sterilizing objects containing
`
`ethylene-oxide-sensitive, temperature-sensitive compounds, such as biological
`
`molecules….”).
`
`39. By design, the “surface-steril