UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`REGENERON PHARMACEUTICALS, INC.,
`Petitioner,
`
`V.
`
`NOVARTIS PHARMA AG,
`NOV ARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owners
`
`Patent Number: 9,220,631
`
`DECLARATION OF JAMES AGALLOCO
`
`Regeneron Exhibit 1005.001
`
`

`

`I.
`
`Introduction ...................................................................................................... I
`
`II. Qualifications and Compensation .................................................................... I
`
`III. Relevant Legal Standards ................................................................................ 5
`
`A.
`
`B.
`
`C.
`
`Claim Construction ............................................................................... 5
`
`Invalidity ............................................................................................... 6
`
`Person of Ordinary Skill in the Art ....................................................... 8
`
`IV.
`
`Sterilization of Pre-filled Syringes .................................................................. 9
`
`V.
`
`The '631 Patent .............................................................................................. 17
`
`A.
`
`B.
`
`The Claims .......................................................................................... I 7
`
`Specification of the '631 Patent Regarding Terminal
`Sterilization ......................................................................................... 18
`
`C. Meaning of the Claim Term "Terminally Sterilized" ......................... 19
`
`VI. Relevant Prior Art to the '631 Patent ............................................................ 20
`
`A.
`
`B.
`
`"Sigg" - WO 2011/006877 ................................................................. 20
`
`"Lam" - WO 2008/077155 ................................................................. 24
`
`VII. Sigg and Lam Disclose a "Terminally Sterilized Pre-filled Syringe" as
`Required by Claims I and 17-21 of the '631 Patent ..................................... 27
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Claim I ................................................................................................ 27
`
`Claim I 7 .............................................................................................. 31
`
`Claims 18 and 19 ................................................................................. 33
`
`Claim 20 .............................................................................................. 36
`
`Claim 21 .............................................................................................. 39
`
`VIII. Declaration ..................................................................................................... 43
`
`Regeneron Exhibit 1005.002
`
`

`

`I.
`
`Introduction
`
`1.
`
`I have been retained by Petitioner Regeneron Pharmaceuticals, Inc.
`
`("Petitioner" or "Regeneron"), as an independent expert witness in the above(cid:173)
`
`captioned inter partes review ("IPR"), in which Regeneron has requested that the
`
`U.S. Patent and Trademark Office cancel as unpatentable all claims of U.S. Patent
`
`No. 9,220,631 ("the '631 patent") (Ex. 1001).
`
`2.
`
`This declaration sets forth my analyses and opinions based on my
`
`knowledge, experience, and the materials I have considered.
`
`II. Qualifications and Compensation
`
`3.
`
`I have an M.B.A. in Pharmaceutical Studies from Fairleigh Dickinson
`
`University, a M.S.Ch.E. from the Polytechnic Institute of New York, and a
`
`B.E.Ch.E. from Pratt Institute.
`
`4.
`
`I have over forty years of management experience in pharmaceutical
`
`manufacturing, pharmaceutical process, pharmaceutical process engineering,
`
`technical services and research and development. Since 1991, I have been the
`
`President of Agalloco & Associates, which provides to the pharmaceutical,
`
`biotechnology, and medical device industry a wide range of technical services such
`
`as process and product validation, sterilization, aseptic processing, processing,
`
`isolation technology, sterility assurance, compliance and facility design.
`
`Regeneron Exhibit 1005.003
`
`

`

`5.
`
`Prior to 1991, I was Director, Validation and Technology at Bristol-
`
`Myers Squibb; Director, Worldwide Validation and Automated Technology and
`
`Pharmaceutical Engineering; Department Manager at Bristol-Myers Squibb, and
`
`held a number of positions, including Engineering Project Manager and Senior
`
`Production Supervisor at Pfizer Pharmaceuticals.
`
`6.
`
`As Director of Validation and Technology at Bristol-Myers Squibb, I
`
`directed validation, automation and technical documentation activities and served as
`
`an important technical resource for worldwide pharmaceutical manufacturing. I was
`
`an active participant on product introduction and facility upgrade task forces. As
`
`Director of Worldwide Validation and Automated Technology at Bristol-Myers
`
`Squibb, I was responsible for facilities in 27 countries around the world and served
`
`as a major technical resource for facility design, facility start-up, sterilization, aseptic
`
`processing, validation and automation. I participated actively on major product,
`
`process, facility and equipment projects, directed the validation and automation
`
`phases of a $25 million expansion of existing parenteral facility in New Brunswick,
`
`and provided major support to sterile bulk manufacturing.
`
`7.
`
`In previous positions, I provided validation expertise for sterile
`
`facilities, acted as a spokesperson for validation to
`
`the Food and Drug
`
`Administration ("FDA") and other regulatory agencies, managed production
`
`operations for sterile and oral liquid and powder products, and had major areas of
`
`2
`
`Regeneron Exhibit 1005.004
`
`

`

`responsibility including cost control, cost reduction, CGMP compliance, scheduling,
`
`equipment selection, and process trouble shooting.
`
`8.
`
`In addition to my work experience, I have many years of experience
`
`participating in professional organizations, standards settings organizations, and
`
`pharmacopoeias relating to sterilization and sterility assurance for pharmaceuticals
`
`and medical devices. For example, I have led and participated in the development of
`
`numerous sterilization and aseptic processing industry guidance documents as a
`
`member of the Parenteral Drug Association. In addition, I have been an active
`
`member of the United States Pharmacopoeia ("USP") Microbiology and Sterility
`
`Assurance Expert Committee since 2005, and the lead author on the comprehensive
`
`revision of USP <1211> Sterilization & Sterility Assurance of Compendia! Items.
`
`The new USP content (Chapters <1211> Sterility Assurance and <1229>
`
`Sterilization) include substantially expanded content addressing the full range of
`
`sterilization processes and means for the aseptic processing for drugs and medical
`
`devices. I have been a member of the Parenteral Drug Association since 1980 and
`
`served as its President in 1988 and 1989. I am also the co-founder and a current
`
`member of the Validation Discussion Group. I have also served on several scientific
`
`and editorial advisory boards.
`
`9.
`
`In addition to the above, I have given numerous presentations at
`
`industry meetings and in-house at pharmaceutical compames, including many
`
`3
`
`Regeneron Exhibit 1005.005
`
`

`

`presentations over the years that relate to aseptic processing, sterilization, and
`
`process validation.
`
`10. My curriculum vitae is attached as Exhibit 1006, and provides further
`
`information about my experience, expertise, and presentations.
`
`I have also co(cid:173)
`
`authored more than 40 book chapters and over 150 technical papers.
`
`11. Through my professional experience, I have gained extensive expertise
`
`in both aseptic processing and terminal sterilization. I have experience in all types
`
`of medical device and pharmaceutical sterilization, including chemical sterilization,
`
`such as by hydrogen peroxide and ethylene oxide. I have also gained knowledge of
`
`sterilization of container closure systems, including aseptic processing and terminal
`
`sterilization of pre-filled syringes.
`
`12.
`
`I am being compensated at my standard rate of $350/hour. My
`
`compensation is in no way contingent upon my opinions or the outcome of the
`
`proceeding.
`
`13.
`
`I may testify on any or all of the opinions expressed in this declaration.
`
`In addition, I will, as needed, explain principles and terminology referred to in this
`
`declaration as well as materials referenced herein. I have read the declaration of
`
`Horst Koller, filed herewith, and agree with the opinions expressed therein as they
`
`relate to the sterilization of medical devices such as pre-filled syringes. I provide
`
`this declaration to provide specific background and explanation regarding
`
`4
`
`Regeneron Exhibit 1005.006
`
`

`

`sterilization technology, as well as explaining how certain claim limitations of the
`
`'631 patent relating to sterilization are disclosed and rendered obvious by the prior
`
`art.
`
`III. Relevant Legal Standards
`
`14.
`
`I am not an attorney, and therefore my understanding of patent law and
`
`the legal standards set forth in this report was provided to me by counsel. I have
`
`applied these standards in my analysis.
`
`A.
`
`Claim Construction
`
`15.
`
`It is my understanding that the numbered paragraphs at the end of the
`
`disclosure of a U.S. Patent are the patent "claims" that define the metes and bounds
`
`of the alleged invention. I understand that these claims of the '631 patent are what
`
`is being challenged in the present IPR proceeding.
`
`16.
`
`I have been informed that, in this proceeding, the Board must determine
`
`the scope of the claims by giving the claims their ordinary and customary meaning
`
`in light of the specification, as the claims would be interpreted by one of ordinary
`
`skill in the art.
`
`17.
`
`I understand that patent claims generally include a "transitional" term
`
`or phrase, such as "consisting" or "comprising," which may connect the preamble
`
`of the claim to the body of the claim. I have been informed that if a claim uses the
`
`term "consisting" as a transition term, that means that the claim is a "closed" claim,
`
`5
`
`Regeneron Exhibit 1005.007
`
`

`

`which means that the claim is limited to the claim features that follow the transition
`
`term and nothing else. On the other hand, I understand that the transition term
`
`"comprising" denotes an "open" claim, which means that the claim is not limited to
`
`only the features recited in the claim, and could encompass the listed elements as
`
`well as other unrecited elements.
`
`B.
`
`Invalidity
`
`18.
`
`I understand that Regeneron bears the burden of proving that the
`
`challenged claims of the '631 patent are invalid, and must prove this by a
`
`preponderance of the evidence, which means that invalidity must be shown to be
`
`more likely than not.
`
`19.
`
`I understand that the invalidity analysis must be conducted from the
`
`perspective of the person of ordinary skill in the art, and must consider whether the
`
`skilled artisan would consider any differences between the prior art and what is
`
`claimed to have been obvious. To make this assessment, I have been informed that
`
`the concept of patent obviousness involves four factual inquiries: (1) the scope and
`
`content of the prior art; (2) the differences between the claimed invention and the
`
`prior art; (3) the level of ordinary skill in the art; and ( 4) secondary considerations
`
`of non-obviousness. I have been instructed that one must not engage in hindsight.
`
`Rather, the better approach is to consider what the person of ordinary skill in the art
`
`6
`
`Regeneron Exhibit 1005.008
`
`

`

`would have reason to pursue further, and steps that were routinely done, such as in
`
`response to known problems, steps or obstacles.
`
`20.
`
`It is my understanding that some teaching, suggestion, or motivation in
`
`the prior art that would have led one of ordinary skill to modify the prior art reference
`
`or to combine prior art reference teachings to arrive at the claimed invention may
`
`support the obviousness of an invention. Other rationales that may support the
`
`obviousness of the invention include combining prior art elements according to
`
`known methods to yield predictable results, simple substitution of one known
`
`element for another to obtain predictable results, and applying a known technique to
`
`a known device ready for improvement to yield predictable results.
`
`21.
`
`It is my understanding that the motivation to combine pnor art
`
`references may be implicit and may be found in the knowledge of one of ordinary
`
`skill in the art, or in the nature of the problem to be solved. Specifically, it is my
`
`understanding that an implicit motivation to combine exists not only when a
`
`suggestion may be gleaned from the prior art as a whole, but when the
`
`"improvement" is technology-independent and the combination of references results
`
`in a product or process that is more desirable, for example, because it is stronger,
`
`cheaper, cleaner, faster, lighter, smaller, more durable or more efficient. It is my
`
`further understanding that the motivation to combine references may be found in the
`
`7
`
`Regeneron Exhibit 1005.009
`
`

`

`nature of the problem to be solved where prior art references are directed to precisely
`
`the same problem of underpinning slumping foundations.
`
`22.
`
`I also understand that prior art may be relied on for its express
`
`disclosure and teachings. I also understand that the prior art may be relied upon for
`
`a teaching of features that are necessarily present in the prior art reference even if
`
`that specific feature is not expressly or explicitly disclosed.
`
`C.
`
`Person of Ordinary Skill in the Art
`
`23.
`
`I have been asked to review U.S. Patent No. 9,220,631 ("the '631
`
`patent") from the perspective of a person of ordinary skill in the art ("POSIT A"). I
`
`understand that the '631 patent claims an earliest priority date of July 3, 2012. 1
`
`Therefore, I have considered the state of the art as of July 3, 2012 and shortly before
`
`that date, and the level of knowledge that a POSIT A would have possessed at that
`
`time. Unless I state otherwise, whenever I refer to any principle or technical subject
`
`matter as having been known or understood, this is meant to denote the knowledge
`
`and understanding of a POSITA at or prior to July 3, 2012. 2
`
`1 I have been informed that the date of "July 30, 2012" for EP 12174860 listed on
`the face of the '631 patent is typographical error and should be July 3, 2012.
`
`2 I understand that the '631 patent may not be entitled to the July 3, 2012 priority
`date, and that the next earliest priority date claimed by the patent would be October
`23, 2012. For purposes of my opinions, there is no appreciable difference in the
`state of the art between July 3 and October 23, 2012, because the subject matter I
`describe herein as it relates to the '631 patent was well-known and conventional well
`before July 3, 2012.
`
`8
`
`Regeneron Exhibit 1005.010
`
`

`

`24.
`
`I understand that Horst Koller has defined a POSITA relevant to the
`
`'631 patent as someone having at least an advanced degree (Dipl.Ing, M.S., or
`
`Ph.D.), with
`
`research experience
`
`in mechanical engineering, biomedical
`
`engineering, materials science, chemistry, or a related field or at least 2-3 years of
`
`professional experience in one or more of those fields. He has also opined that a
`
`POSITA would have had experience with (i) the design of pre-filled syringes; and
`
`(ii) sterilization of drug delivery devices, including those containing sterilization
`
`sensitive therapeutics, and that such sterilization experience would include
`
`experience with microbiology. I agree with that definition, and I have adopted it for
`
`my analysis presented herein. Based on my education, training and experience, it is
`
`my opinion that I can accurately represent the views of a POSIT A as of the earliest
`
`claimed priority date of July 3, 2012 as to the sterilization-related features of claims
`
`1 and 17-21 of the '631 patent.
`
`IV. Sterilization of Pre-filled Syringes
`
`25.
`
`Sterility is a general requirement for most drug products. See, e.g., Ex.
`
`1029 at 1: 14 ("Objects used in medical applications are generally sterilized before
`
`use."). Regulatory agencies such as the FDA and EMA require all ophthalmic
`
`products, such as pre-filled syringes for intravitreal injection, to be sterile. For
`
`example, the FDA rule relating to sterility of ophthalmic products states: "Informed
`
`medical opinion is in agreement that all preparations offered or intended for
`
`9
`
`Regeneron Exhibit 1005.011
`
`

`

`ophthalmic use, including preparations for cleansing the eyes, should be sterile. It is
`
`further evident that such preparations purport to be of such purity and quality as to
`
`be suitable for safe use in the eye." 21 C.F.R. § 200.50 (a)(l). A POSITA would
`
`have known and readily appreciated the importance of sterilizing pre-filled syringes
`
`for intravitreal injection, including the outer surface of such syringes, because of the
`
`risk of infection from a non-sterile syringe being held over and used on an exposed
`
`human eye.
`
`See, e.g., Ex. 1029 at 1:28-29 ("there is an increased risk of
`
`endophthalmitis after intraocular injection3 if the surface of the syringe used for
`
`injection is not sterilized").
`
`26.
`
`The FDA, in its guidance on aseptic filling, indicates that "terminal
`
`sterilization" is required when possible. See Ex. 1036.007. "Terminal sterilization"
`
`( outside of the context of the '631 patent) typically refers to a process in which the
`
`drug and container closure system ( which are not already sterile) are sterilized
`
`together in a single process. See id. Thus, for drugs that are not heat sensitive, this
`
`type of one-step terminal sterilization can be accomplished by heating (for example,
`
`in an autoclave) with steam to sterilize the drug in its primary container-closure
`
`system in a single step. See generally Ex. 1029 at 1:14-22.
`
`3 Intraocular injection refers to all injections into the chambers of the eye.
`Intravitreal injection is a subset of intraocular injection, and refers to injection into
`the vitreous cavity specifically. Ex. 1015 at 35.
`
`10
`
`Regeneron Exhibit 1005.012
`
`

`

`27.
`
`The '631 patent use the term "terminal sterilization" in a different
`
`context, specifically stating that "[ t ]he package is exposed to the sterilising gas until
`
`the outside of the syringe is sterile," and also that "it is a requirement that significant
`
`amounts of the sterilising gas should not enter the variable volume chamber of the
`
`syringe." Ex. 1001 at 9:49, 55-6; 10:2-4. Thus, in the context of the '631 Patent,
`
`"terminal sterilization" refers to the sterilization of only the outer surface of the pre(cid:173)
`
`filled syringe after filling, wherein the drug preparation inside the syringe is already
`
`sterile because it was filled into the syringe under aseptic conditions (known as
`
`"aseptic fill"). The exterior of the pre-filled syringe is then sterilized when the pre(cid:173)
`
`filled syringe is in its secondary packaging ( e.g., blister pack), while the already(cid:173)
`
`sterile ( aseptically filled) drug formulation is not exposed directly to the sterilization
`
`conditions.
`
`28.
`
`There are many ways to sterilize medical products, including via "steam
`
`sterilization, radiation sterilization, gas sterilization ( e.g., with ethylene oxide), and
`
`chemical sterilization." Ex. 1029 at 1: 14-16. "When deciding on a sterilization
`
`method, one of the first considerations should be product compatibility." Ex.
`
`1045.001. From a compatibility standpoint, it was already known prior to 2012 that
`
`protein drug formulations can be degraded by high temperature sterilization
`
`processes, which are therefore disfavored for use with protein therapeutics such as
`
`11
`
`Regeneron Exhibit 1005.013
`
`

`

`VEGF-antagonist solutions in pre-filled syringes. See Ex. 1018 at [0010]-[0011],
`
`[0021]-[0022]; Ex. 1007 at 7:29-8:1; Ex. 1029 at 1:18-25.
`
`29. With respect
`
`to sterilization processes
`
`that do not use high
`
`temperatures, several such processes were known, including sterilization using
`
`ethylene oxide ("EtO") gas, and using vaporized hydrogen peroxide (H2O2)
`
`("VHP"), which were both well-known by 2008. See e.g., Ex. 1046.001 ("Until
`
`2008, there were three options for these purposes; ethylene oxide (EO), gas plasma,
`
`and ozone systems."); id. at 002 ("Vaporized hydrogen peroxide (VHP) technology
`
`was originally developed by STERIS Corporation and introduced in the early 1990s.
`
`It soon became a 'gold standard' for pharmaceutical sterilization, in critical
`
`environments where drugs are produced and packaged."). Ethylene oxide (EtO) is
`
`a gas-based sterilization method, and hydrogen peroxide (H2O2) sterilization is a
`
`vapor-based (2-phase system of liquid suspended in a gas) sterilization method.
`
`Both EtO and VHP were used to sterilize medical devices for many years prior to
`
`2012. See id.
`
`30. EtO sterilization has been used since "the 1950s to sterilize heat and
`
`moisture-sensitive medical devices."
`
`Id. at 001; see also Ex. 1050.002 (citing
`
`Phillips, C. R., and S. Kaye, The sterilizing action of gaseous ethylene oxide, L.
`
`Review. Amer. J. Hyg. 50:270-279 (1949)). APOSITA would have been well aware
`
`that EtO was "[t]he most prevalent gas utilized for sterilization" such that
`
`12
`
`Regeneron Exhibit 1005.014
`
`

`

`"sterilization using other agents is based on methods used for ETO." Ex. 1016.260-
`
`261 (describing EtO sterilization).
`
`31.
`
`Similarly, hydrogen peroxide (H2O2) sterilization has been around since
`
`at least the early 1990s, and, because it produces non-toxic by-products, is generally
`
`considered safer to utilize than EtO. Ex. 1046.002-003. There were two well-known
`
`methods ofH2O2-based sterilization. Id. at 002-003; Ex. 1051.001-002. The first is
`
`sterilization via the creation of a hydrogen peroxide plasma. Ex. 1046.002. This
`
`method is rapid but can be very parameter-dependent, and can leave residuals if not
`
`performed correctly. Id. The second method, vaporized hydrogen peroxide (VHP),
`
`is easier to handle because it does not require formation of a plasma and has a large
`
`processing capacity. Id at 002-003. Prior to 2012, VHP systems were available for
`
`"processing packaged, heat and moisture-sensitive instruments for terminal
`
`sterilization and storage." Id. at 002. VHP sterilization methods can often be done
`
`in-house at pharmaceutical companies producing sterile medical devices or drug
`
`products such as pre-filled syringes.
`
`32. Both EtO and VHP work as sterilization agents in part through the
`
`oxidation of functional groups in the biological molecules of microorganisms and
`
`because both react irreversibly with many chemical moieties on biological molecules
`
`bywayofanalkylationreaction. SeeEx.1016.260-263;Ex.1052.004. Whilethese
`
`characteristics are beneficial for killing microorganisms, they also make it important
`
`13
`
`Regeneron Exhibit 1005.015
`
`

`

`that biologic drug products are not exposed to the sterilizing agents during
`
`sterilization treatment so as not affect the stability of such drug products. Thus, for
`
`medical devices such as pre-filled syringes, it would have been understood by a
`
`POSITA that the syringe itself would have to be sufficiently sealed to prevent
`
`substantial amounts of the sterilizing agent from coming into contact with the drug
`
`formulation within.
`
`33.
`
`Several prior art references teach "terminal sterilization" of a pre-filled
`
`syringe as described and claimed the '631 Patent. For example, Lam teaches the
`
`EtO sterilization of the outer surface of a pre-filled syringe containing a VEGF
`
`antagonist solution where the syringe is in secondary packaging ( e.g., TYVEK®
`
`blister pack). Ex. 1029 at 2: 1-33. Lam discloses that interaction of the EtO with the
`
`VEGF antagonist protein contained in the syringe is avoided, and further shows that
`
`the protein solution substantially maintains its stability throughout the sterilization
`
`process. Id. at 13: 10-16: 3. Similarly, Sigg teaches the VHP sterilization of the outer
`
`surface of a pre-filled syringe containing a VEGF antagonist while in secondary
`
`packaging (e.g., blister pack). See Ex. 1007 at 7:21-8:29, 9:11-26. Metzner, U.S.
`
`Pat. Appl. Pub. No. 2003/0003014, also describes a sterilization procedure that
`
`"permits sensitive biological and therapeutic products to be sterilized externally in
`
`14
`
`Regeneron Exhibit 1005.016
`
`

`

`
`
`the solid or liquid state in their final container (primary packaging4)." See Ex. 1018
`
`at [0010]-[0011], [0016], [0038]-[0039]. The procedure in Metzner, which makes
`
`use of hydrogen peroxide plasma, is detailed in Examples 2 to 6, and is shown to
`
`achieve sterility of the outer surfaces of glass carpules containing a protein
`
`fibrinogen solution, without affecting the stability of the protein itself. Id.
`
`34. After treating a pre-filled syringe in its secondary packaging with cold
`
`sterilizing gases, 5 the gas must be allowed to sufficiently exit the secondary
`
`packaging of pre-filled syringe. Generally, this process involves vacuum removal
`
`of cold sterilizing gases and re-filling of the air in the decontamination chamber (and
`
`thus in the permeable secondary packaging) a number of times to dilute out the
`
`sterilizing gas or vapor until the concentration of such gas or vapor reaches the
`
`desired level. See, e.g., Ex. 1052.004. For example, the VHP sterilization disclosed
`
`in Sigg includes "applying post-treatment measures, within a decontamination
`
`chamber" that ensure full removal of "all potentially remaining hydrogen peroxide
`
`residues." Ex. 1007 at 10:5-6, 3:22-24. This post-application removal protects the
`
`sensitive biologic product within the syringe and the end-user ( e.g., doctor) from the
`
`4 The syringe is the primary packaging, and the syringe can be enclosed in secondary
`packaging, such as a blister pack. Ex. 1018 at [0012].
`
`5 Cold sterilization refers to processes that sterilize a product without requiring high
`temperatures, which would damage sensitive drug formulations.
`
`15
`
`Regeneron Exhibit 1005.017
`
`

`

`sterilizing agent. Ex. 1007 at 13:3-8, 13:24-26. In order to determine that low
`
`enough levels of sterilizing gas or vapor are present, air samples may be taken from
`
`the sterilization chamber and tested using, for example, a gas chromatograph or
`
`infrared spectrophotometer to test for the presence of the sterilizing agent.
`
`Ex.1052.007-008. These same methods may be used to ensure the appropriate
`
`concentration of the sterilizing agent during the sterilization cycle.
`
`35.
`
`The sterility of a medical product can be measured in terms of the
`
`sterility assurance level, or SAL, which was a well-known concept in the art well
`
`prior to 2012, and is a mathematical measure of the probability that a sterilized article
`
`may not in fact be sterile. Ex. 1007 at 7: 8-9 ("' Sterility' as used herein is meant to
`
`refer to complete absence of microbial life as defined by a probability of non-sterility
`
`or a sterility assurance level (SAL)."). An SAL of 10-6
`
`, the preferred sterility level,
`
`refers to the probability that only 1 in 1,000,000 processed units would be non(cid:173)
`
`sterile. Ex. 1007 at 7: 10-13 ("For example, SALs for health care products are
`
`defined to be at least 1 o-6
`
`, i.e. a chance of less than 1: 1 million of a non-sterile
`
`product"); Ex. 1049.003.
`
`36. Determining the SAL of a sterilization process would be routine and
`
`well within the ordinary skill of a POSITA prior to 2012. Because it is infeasible to
`
`test millions of products to directly measure the rate of non-sterility, terminal
`
`sterilization process validation is used. Ex. 1049.002-003. This type of process
`
`16
`
`Regeneron Exhibit 1005.018
`
`

`

`validation utilizes the fact that microbial kill rates from most sterilization techniques
`
`are exponential in nature. Id. at 003. This allows the calculation of SAL level "based
`
`on the extent of exposure to the sterilization modality and the corresponding
`
`microbial log reduction," which ultimately derive from the measured time or dose
`
`"required to achieve inactivation of 90% of a population of the test microorganism."
`
`Id. Performing such a calculation would be routine to a POSITA, and indeed the
`
`adoption of SAL across multiple industries is due in part to its easily adapted
`
`standardized approach. Thus, determining and optimizing the SAL of a sterilization
`
`process would be well within the ordinary skill of a POSIT A.
`
`V.
`
`The '631 Patent
`
`A.
`
`The Claims
`
`3 7. Claim I is reproduced below:
`
`1. A pre-filled, terminally sterilized synnge for intravitreal
`
`injection, the syringe comprising a glass body forming a barrel,
`
`a stopper and a plunger and containing an ophthalmic solution
`
`which comprises a VEGF-antagonist, wherein:
`
`(a)
`
`the syringe has a nominal maximum fill volume of
`
`between about O. 5 ml and about I ml,
`
`(b)
`
`the syringe barrel comprises from about I µg to I 00 µg
`
`silicone oil,
`
`( c)
`
`the VEGF-antagonist solution comprises no more than 2
`
`particles >50 µmin diameter per ml and wherein the syringe has
`
`a stopper break loose force of less than about I IN.
`
`17
`
`Regeneron Exhibit 1005.019
`
`

`

`38. Claims 17-21 include additional limitations relating to sterilization: the
`
`syringe is sterilized using H2O2 or EtO; the outer surface of the syringe has :::::; 1 ppm
`
`H2O2 or EtO residue; the total H2O2 or EtO residue is:::::; 0.1 mg; less than or equal to
`
`5% of the VEGF-antagonist is alkylated; and the syringe is sterilized with a Sterility
`
`Assurance Level of at least 10-6
`
`. As I explain in this Declaration, the sterilization(cid:173)
`
`related features added by these dependent claims were well-known at or prior to
`
`2012, and a POSIT A would have understood that there was nothing novel or
`
`inventive about the features recited in these claims and the application of these
`
`features to the claimed pre-filled syringe.
`
`B.
`
`Specification of the '631 Patent Regarding Terminal Sterilization
`
`39.
`
`The '631 patent does not teach or describe how sterilization of the outer
`
`surface of the pre-filled syringe is carried out, and instead merely states that such
`
`sterilization may be done via "known" methods, such as VHP or EtO. Ex. 1001 at
`
`9:49-52. The '631 patent discloses no examples of terminally sterilized pre-filled
`
`syringes that are alleged to meet the limitations recited in the patent claims. 6 In my
`
`opinion, the '631 patent disclosure adds nothing new to the art of sterilization, and
`
`6 This is in contrast to Sigg and Lam, for example, which each disclose specific
`examples and procedures for sterilizing the outer surface of a pre-filled syringe
`containing a VEGF-antagonist. Ex. 1007 at 12:15-16:21, 20:10-21:11; Ex. 1029 at
`13: 10-16:3.
`
`18
`
`Regeneron Exhibit 1005.020
`
`

`

`does not teach one of ordinary skill in the art how to sterilize the outer surface of a
`
`pre-filled syringe containing a VEGF -antagonist.
`
`Instead, the '631 patent only
`
`discloses the desired goals of sterilization efforts, in terms of how long the syringe
`
`remains sterile, the Sterility Assurance Level, the alkylation of the product, and the
`
`amount of chemical residue remaining. Ex. 1001 at 9:55-10:22.
`
`C. Meaning of the Claim Term "Terminally Sterilized"
`
`40. As explained above in Section IV, while a POSITA would understand
`
`that terminal sterilization typically refers to the sterilization of both the drug product
`
`and its container in a single process, the '631 patent claims use the term "terminally
`
`sterilized" to include a process for sterilizing the outer surface of a container while
`
`avoiding contact between the sterilization medium and drug product inside the
`
`container. Ex. 1001 at 9:49, 9:55-56 ("The package is exposed to the sterilising gas
`
`until the outside of the syringe is sterile." (emphasis added)); id. at 10:2-4 ("Of
`
`course, it is a requirement that significant amounts of the sterilising gas should not
`
`enter the variable volume chamber of the syringe.").
`
`41.
`
`In the context of the pre-filled syringe recited in the '631 patent claims,
`
`which contains a VEGF-antagonist solution (i.e., a protein therapeutic that is
`
`sensitive to degradation from contact with sterilizing gases), contact between the
`
`drug formulation and the gases should be avoided, and as such the cold sterilization
`
`techniques to be applied would only sterilize the outer surface of the pre-filled
`
`19
`
`Regeneron Exhibit 1005.021
`
`

`

`syringe, optionall