`
`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.
`
`———————————
`
`
`Patent Number: 9,220,631
`
`
`———————————
`
`DECLARATION OF HORST KOLLER
`
`
`
`
`
`
`
`
`Regeneron Exhibit 1003.001
`
`

`

`
`
`V. 
`
`I. 
`Introduction ...................................................................................................... 1 
`II. 
`Summary of Opinions ...................................................................................... 1 
`III.  Qualifications and Compensation .................................................................... 3 
`IV.  Relevant Legal Standards ................................................................................ 9 
`A. 
`Claim Construction ............................................................................. 10 
`B. 
`Invalidity ............................................................................................. 11 
`C. 
`Person of Ordinary Skill in the Art ..................................................... 14 
`Background of the Technology ..................................................................... 16 
`A. 
`Intravitreal Administration of VEGF Antagonists .............................. 16 
`B. 
`Pre-filled Syringes ............................................................................... 17 
`C. 
`Syringe Stopper Forces ....................................................................... 23 
`D. 
`Siliconization of Pre-filled Syringe Components ............................... 28 
`1. 
`“Oily” or “Spray-on” Siliconization ......................................... 30 
`2. 
`“Baked-On” Siliconization ....................................................... 33 
`3. 
`Coated, Uncoated, and Siliconized Stoppers ............................ 40 
`E. 
`Sterilization of Pre-filled Syringes ...................................................... 44 
`F. 
`Particulate Content .............................................................................. 53 
`VI.  The ’631 Patent .............................................................................................. 55 
`A. 
`The Claims .......................................................................................... 55 
`B. 
`Overview of Specification ................................................................... 59 
`1. 
`The ’631 patent fails to disclose a process for applying
`the claimed levels of silicone oil ............................................... 59 
`The ’631 patent fails to disclose process details for
`terminal sterilization ................................................................. 61 
`Prosecution History ............................................................................. 64 
`
`2. 
`
`C. 
`
`
`
`1
`
`Regeneron Exhibit 1003.002
`
`

`

`
`
`D. 
`Claim Construction ............................................................................. 68 
`VII.  The Prior Art to the ’631 Patent .................................................................... 70 
`A. 
`“Sigg” – WO 2011/006877 ................................................................. 70 
`B. 
`“Lam” – International Pat. Appl. Pub. No. WO 2008/077155 ........... 76 
`C. 
`“Boulange” – International Pat. Appl. Pub. No. WO
`2009/030976 ........................................................................................ 81 
`2008 Macugen Label ........................................................................... 89 
`“Fries” – A. Fries, Drug Delivery of Sensitive
`Biopharmaceuticals with Prefilled Syringes, Drug Delivery
`Technology, Vol. 9, No. 5 ................................................................... 92 
`F. 
`“Furfine” – WO 2007/149334 ............................................................. 93 
`VIII.  Ground 1: Sigg in View of Boulange Renders Obvious Claims 1-3, 5-
`9, 14-22 .......................................................................................................... 94 
`A.  Motivation to Combine Sigg and Boulange ........................................ 94 
`1. 
`Silicone Oil and Break Loose / Slide Forces ............................ 94 
`2. 
`Particulate Content .................................................................. 101 
`3. 
`Stopper Configurations ........................................................... 103 
`Reasonable Expectation of Success .................................................. 111 
`Claim 1 .............................................................................................. 116 
`1. 
`[1.a] A pre-filled, terminally sterilized syringe for
`intravitreal injection ................................................................ 116 
`[1.b] the syringe comprising a glass body forming a
`barrel, a stopper and a plunger ................................................ 118 
`[1.c] and containing an ophthalmic solution which
`comprises a VEGF-antagonist, wherein: ................................ 120 
`[1.d] the syringe has a nominal maximum fill volume of
`between about 0.5 mL and about 1 mL .................................. 122 
`[1.e] the syringe barrel comprises from about 1 μg to 100
`μg silicone oil .......................................................................... 124 
`[1.f] the VEGF-antagonist solution comprises no more
`than 2 particles > 50 μm in diameter per mL .......................... 127 
`
`6. 
`
`
`
`2
`
`D. 
`E. 
`
`B. 
`C. 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`Regeneron Exhibit 1003.003
`
`

`

`
`
`7. 
`
`D. 
`
`B. 
`
`[1.g] and wherein the syringe has a stopper break loose
`force of less than about 11N. .................................................. 129 
`Claims 2, 3, 5-9, and 14-22 ............................................................... 132 
`1. 
`Claim 2 .................................................................................... 132 
`2. 
`Claims 3 and 22 ....................................................................... 133 
`3. 
`Claims 5 and 6 ......................................................................... 134 
`4. 
`Claims 7, 8, and 9.................................................................... 135 
`5. 
`Claims 14 and 16..................................................................... 136 
`6. 
`Claim 15 .................................................................................. 139 
`7. 
`Claim 17 .................................................................................. 141 
`8. 
`Claims 18 and 19..................................................................... 142 
`9. 
`Claim 20 .................................................................................. 144 
`10.  Claim 21 .................................................................................. 146 
`IX.  Ground 3: Sigg in View of Boulange and Fries Renders Obvious
`Claims 4, 10, and 23 .................................................................................... 148 
`X.  Ground 5: Sigg in view of Boulange and Furfine Renders Obvious
`Claims 11-13 ................................................................................................ 151 
`XI.  Ground 2: Lam in View of Boulange Renders Obvious Claims 1-3, 5-
`9, and 14-22 ................................................................................................. 154 
`A.  Motivation to Combine Lam and Boulange With a Reasonable
`Expectation of Success ...................................................................... 155 
`1. 
`Silicone Oil and Break Loose / Slide Forces .......................... 155 
`2. 
`Particulate Content .................................................................. 157 
`Claim 1 .............................................................................................. 159 
`1. 
`[1.a] A pre-filled, terminally sterilized syringe for
`intravitreal injection ................................................................ 159 
`[1.b] the syringe comprising a glass body forming a
`barrel, a stopper and a plunger ................................................ 160 
`[1.c] and containing an ophthalmic solution which
`comprises a VEGF-antagonist, wherein: ................................ 161 
`[1.d] the syringe has a nominal maximum fill volume of
`between about 0.5 mL and about 1 mL .................................. 162 
`[1.e] the syringe barrel comprises from about 1 μg to 100
`μg silicone oil .......................................................................... 163 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`
`
`3
`
`Regeneron Exhibit 1003.004
`
`

`

`
`
`C. 
`
`6. 
`
`7. 
`
`[1.f] the VEGF-antagonist solution comprises no more
`than 2 particles >50 μm in diameter per mL ........................... 163 
`[1.g] and wherein the syringe has a stopper break loose
`force of less than about 11N. .................................................. 166 
`Claims 2, 3, 5-9, and 14-22 ............................................................... 166 
`1. 
`Claim 2 .................................................................................... 166 
`2. 
`Claims 3 and 22 ....................................................................... 166 
`3. 
`Claims 5 and 6 ......................................................................... 167 
`4. 
`Claims 7, 8, and 9.................................................................... 167 
`5. 
`Claims 14 and 16..................................................................... 168 
`6. 
`Claim 15 .................................................................................. 168 
`7. 
`Claim 17 .................................................................................. 169 
`8. 
`Claims 18 and 19..................................................................... 170 
`9. 
`Claim 20 .................................................................................. 172 
`10.  Claim 21 .................................................................................. 173 
`XII.  Ground 4: Lam in View of Boulange and Fries Renders Obvious
`Claims 4, 10, and 23 .................................................................................... 176 
`XIII.  Ground 6: Lam in view of Boulange and Furfine Renders Obvious
`Claims 11-13 ................................................................................................ 176 
`XIV.  SECONDARY CONSIDERATIONS ......................................................... 177 
`A. 
`Long-Felt Need .................................................................................. 177 
`B. 
`Unexpected Results ........................................................................... 184 
`C. 
`Industry Praise ................................................................................... 189 
`D. 
`Commercial Success.......................................................................... 191 
`E. 
`Failure of Others ................................................................................ 192 
`XV.  Declaration ................................................................................................... 193 
`
`
`
`4
`
`Regeneron Exhibit 1003.005
`
`

`

`
`
`I.
`
`Introduction
`1.
`I have been retained by Petitioner Regeneron Pharmaceuticals, Inc.
`
`(“Petitioner” or “Regeneron”), as an independent expert witness in the above-
`
`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”).
`
`2.
`
`This declaration sets forth my analyses and opinions based on my
`
`knowledge, experience, and the materials I have considered. As I explain below, it
`
`is my opinion that all claims of the ’631 patent are directed to subject matter that
`
`was routine, conventional, and well known in the art before the ’631 patent priority
`
`date. As would be readily appreciated by one of skill in the art, the ’631 patent is
`
`rendered obvious by the combination of prior art references discussed herein.
`
`3.
`
`I have reviewed the documents referenced in this declaration. I
`
`understand they have been submitted as exhibits in conjunction with Regeneron’s
`
`Petitions for IPR.
`
`II.
`
`Summary of Opinions
`4.
`Based on my knowledge, experience, and the materials that I have
`
`reviewed, it is my opinion that claims 1-23 of the ’631 patent are obvious.
`
`Specifically:
`
`
`
`1
`
`Regeneron Exhibit 1003.006
`
`

`

`
`
`
`
`(i)
`
`Claims 1-3, 5-9, and 14-22 are obvious based on International
`
`Patent Application Publication No. WO 2011/006877 to Sigg et al. (“Sigg”)
`
`(Ex. 1007) in view of International Patent Application Publication No. WO
`
`2009/030976 to Boulange et al. (“Boulange”) (Ex. 1008), and if necessary,
`
`USP Chapter <789>, titled “Particulate Matter in Ophthalmic Solutions.”
`
`(“USP789”) (Ex. 1019);
`
`(ii) Claims 1-3, 5-9, and 14-22 are obvious based on International
`
`Patent Application Publication No. WO 2008/077155 to Lam et al. (“Lam”)
`
`(Ex. 1029) in view of Boulange, and if necessary, USP789;
`
`(iii) Claims 4, 10 and 23 are obvious based on Sigg in view of
`
`Boulange, further in view of A. Fries, Drug Delivery of Sensitive
`
`Biopharmaceuticals with Prefilled Syringes, Drug Delivery Technology, Vol.
`
`9, No. 5 (May 2009) (“Fries”) (Ex. 1012), and if necessary, USP789;
`
`(iv) Claims 4, 10 and 23 are obvious based on Lam in view of
`
`Boulange, further in view of Fries, and if necessary, USP789;
`
`(v) Claims 11-13 are obvious based on Sigg in view of Boulange,
`
`further in view of International Patent Application Publication No.
`
`WO 2007/149334 (“Furfine”) (Ex. 1021), and if necessary, USP789;
`
`(vi) Claims 11-13 are obvious based on the combination of Lam in
`
`view of Boulange, further in view of Furfine, and if necessary, USP789.
`
`2
`
`Regeneron Exhibit 1003.007
`
`

`

`
`
`III. Qualifications and Compensation
`5.
`I have a Diplom-Ingenieur (“Dipl.Ing.”) degree in biotechnology from
`
`Hochschule Mannheim, which I earned in 1993. A Dipl.Ing is considered
`
`equivalent to a master’s engineering degree that would be awarded by a U.S.
`
`university. Prior to that I had several years of apprenticeship and work experience
`
`as a medical technician in Germany.
`
`6.
`
`I am currently the CEO of HK Packaging Consulting, which is a
`
`consulting company that I formed in 2015. In this role, I consult worldwide on
`
`parenteral packaging, which includes consulting on syringe selection and related
`
`primary packaging issues, and consulting on the role of primary and secondary
`
`packaging in dosage form and drug product development.
`
`7. At HK Packaging Consulting, I provide technical and regulatory
`
`support to both primary packaging manufacturers and pharmaceutical companies.
`
`For primary packaging manufacturers, I work on choosing pharmaceutical
`
`container materials and components (vials, cartridges, and syringes), setting
`
`container specifications, ensuring compliance and testing in accordance with
`
`compendia such as the U.S., European Pharmacopeias, and the International
`
`Organization for Standardization (“ISO”), and providing support for regulatory
`
`filings with the U.S. Food and Drug Administration (“FDA”) and the European
`
`Medicines Agency (“EMA” or “EMEA”). For pharmaceutical companies, I work
`
`
`
`3
`
`Regeneron Exhibit 1003.008
`
`

`

`
`
`as a consultant to provide troubleshooting services, including technical support and
`
`test methods relating to primary packaging, design and test manufacturing
`
`processes relating to filling and finishing of pharmaceutical containers including
`
`syringes, selection and optimization of syringe materials and evaluation of
`
`components, and assistance with compendial compliance and testing and
`
`regulatory filings.
`
`8. Prior to my current role, I worked at Schott Pharmaceutical Packaging
`
`(“Schott”) in Germany and Switzerland from 2000 to 2015. Schott is a well-
`
`known manufacturer of both glass and polymer pre-filled syringes. At Schott, I
`
`held the following roles in the Syringe Department: Head of Product Technology
`
`for New Products from 2000-01; Manager for Research & Development and
`
`Quality Management from 2001-03; Head of Scientific and Regulatory Advisory
`
`from 2004-07; Manager of Scientific Advisory from 2007-09; Global Quality
`
`Manager for Regulatory Affairs from 2009-11; and finally, Head of Technical and
`
`Quality Support for the Syringe Business from 2011-15.
`
`9. At Schott, my responsibilities included support of the global syringe
`
`business unit regarding questions of technical product requirements and
`
`specifications, and support of the global packaging development group for primary
`
`and secondary packaging systems with regard to technical, quality and regulatory
`
`requirements. My role also included designing and conducting testing programs
`
`
`
`4
`
`Regeneron Exhibit 1003.009
`
`

`

`
`
`for packaging systems, especially for glass and polymer syringe systems, including
`
`machine packaging and validation. I coordinated test programs with external
`
`partners for extractables and leachables analyses and material testing.
`
`10. After earning my degree and prior to working at Schott, I was the
`
`Engineering Supervisor at Abbott GmbH (“Abbott”) in Germany from 1994 to
`
`1999. At Abbott, I was a Research Technician from 1994-95, and then a
`
`Supervisor in Engineering Processes from 1995-99. At Abbott, my responsibilities
`
`included maintenance and calibration of equipment for manufacturing and research
`
`& development, and optimizing packaging lines for pharmaceutical primary and
`
`secondary packaging, including container filling and blister packaging. I also led
`
`the cleaning and sterilization center for glass equipment at Abbott.
`
`11. During my time at Abbott and Schott I was actively involved in
`
`different types of sterilization validation according to ISO requirements for, e.g.,
`
`steam sterilization, VHP sterilization and decontamination, radiation sterilization
`
`(gamma, ebeam and x-ray), and ETO sterilization. My experience includes cycle
`
`development, PCD-development, and BI positioning studies as well as cycle
`
`confirmation runs. I have performed studies on both empty Container Closure
`
`Systems (“CCS”) at the pre-sterilization step prior to filling and on pre-filled CCS
`
`products for terminal sterilization. My experience includes such studies for pre-
`
`
`
`5
`
`Regeneron Exhibit 1003.010
`
`

`

`
`
`filled syringe systems, for which I monitored the sterile field application (blister),
`
`viscosity adjustments, and sterilization after non-aseptic processes.
`
`12. During my time at Schott and Abbott, I designed and analyzed
`
`sterilization techniques and processes for both empty CCS, i.e., pre-sterilization
`
`prior to filling (i.e., empty syringes), in addition to terminal sterilization with filled
`
`CCS (i.e., sterilization that occurs after the syringe has been filled) depending on
`
`the intended use for the pre-filled syringe system. I gained experience with respect
`
`to pre-filling sterilization because syringe suppliers typically sterilize syringes
`
`before providing them to customers. I also gained extensive experience with
`
`respect to the sterilization of pre-filled syringes because syringe suppliers often
`
`perform testing on such syringes to ensure that a syringe design will satisfy the
`
`downstream needs of customers, including syringes for use with any drug products
`
`that were to be terminally sterilized (i.e., sterilized after filling).
`
`13. In addition to my work experience, I have 13 years of experience
`
`participating in professional organizations, standards setting organizations, and
`
`pharmacopeias relating to pharmaceutical packaging including syringes. For
`
`example, I am an active member of the ISO technical committee, TC 84 on
`
`“Devices for administration of medicinal products and catheters,” wherein I am a
`
`member of several working groups including WG 3 (needle-based injection
`
`systems – injector, container and pen needle) and WG 11 (syringes). I am also an
`
`
`
`6
`
`Regeneron Exhibit 1003.011
`
`

`

`
`
`active member of the ISO technical committee, TC 76 on “Transfusion, infusion
`
`and injection, and blood processing equipment for medical and pharmaceutical
`
`use,” wherein I am a member of several working groups including: WG 2 (rigid
`
`container system and related accessories for parenterals and injectables) of which I
`
`am the Convenor1, WG 4 (elastomeric parts and components and related secondary
`
`packaging), and WG 6 (primary packaging systems for medicinal products). I was
`
`ad hoc group leader for the WG 2 ISO committee that developed standard 11040-4
`
`for glass syringes and 11040-6 for polymer syringes. I am also the Swiss Medic
`
`Delegate for the European Directorate for the Quality of Medicines (EDQM)
`
`working group WG 16 on the European Pharmacopoeia Chapter 3 relating to
`
`plastics. In addition, I am the faculty head for the area: Transfusion, Infusion and
`
`Injection within the German Standardization Body (DIN) for NA 063 Medicine.
`
`This faculty leads 6 subgroups related to Injection systems, Transfusion and
`
`Infusion container including single use container for IVD, Packaging Systems for
`
`filling and application of medicinal products, Fridges and Freezers for medicinal
`
`
`1 As convenor, I lead the WG experts participating from 22 member countries
`
`(TC76) which have been delegated from national standardization bodies, e.g. ANSI
`
`(USA), AFNOR (France), DIN (Germany), for that group.
`
`
`
`7
`
`Regeneron Exhibit 1003.012
`
`

`

`
`
`products, Quality Management for Primary Packaging and Elastomers for Primary
`
`Packaging.
`
`14. In addition to the above, I have given numerous presentations at
`
`symposiums, conferences, and other professional organizational meetings,
`
`including many presentations over the years that relate to parenteral
`
`manufacturing, pre-filled syringes, extractables, leachables, the packaging of
`
`syringe systems, and regulatory (FDA/EMEA) requirements for the packaging of
`
`parenterals.
`
`15. My curriculum vitae is attached as Appendix 1 to my report, and
`
`provides further information about my experience, expertise, and presentations.
`
`16. Through my professional experience, I have gained extensive expertise
`
`in syringe and syringe materials and components, including their manufacturing,
`
`testing, siliconization, characterization, regulatory compliance, sales, and have a
`
`deep understanding of the worldwide syringe market. I also have gained
`
`knowledge and experience relating to pre-filled syringes, the characterization of
`
`syringe stopper movement forces within a syringe, issues relating to syringe
`
`component leachables and extractables, issues relating to siliconization, regulatory
`
`requirements on particulate matter for parenterals, and sterilization of container
`
`closure systems.
`
`
`
`8
`
`Regeneron Exhibit 1003.013
`
`

`

`
`
`17. I am being compensated at my standard rate of $450/hour. My
`
`compensation is in no way contingent upon my opinions or the outcome of the
`
`proceeding.
`
`IV. Relevant Legal Standards
`18.
`I am not an attorney, and therefore my understanding of patent law
`
`and the legal standards set forth in this report is based on explanations provided to
`
`me by counsel.
`
`19.
`
`I understand that for any claim of a patent to claim priority to an
`
`earlier application (i.e., to benefit from the earlier application’s filing date), the
`
`claims of the later patent must be fully supported by the disclosure of the earlier
`
`patent application to which priority is claimed. I understand that in order for the
`
`claims to be supported, the earlier application’s disclosure must be sufficient to
`
`allow a person of ordinary skill in the art to reasonably conclude that the inventors
`
`were in possession of the claimed invention.
`
`20.
`
`I understand that the ’631 patent claims priority to a number of patent
`
`applications, the earliest of which are European Patent Application No.
`
`EP12174860, filed on July 3, 2012, and European Patent Application No.
`
`EP12189649, filed on October 23, 2012. However, as I explain in Section VI.A
`
`below, the July 3, 2012 Application No. EP12174860 filing does not support the
`
`issued claims of the ’631 patent, and therefore the patent claims are not entitled to
`
`
`
`9
`
`Regeneron Exhibit 1003.014
`
`

`

`
`
`that priority date, and instead should have a priority date of no earlier than October
`
`23, 2012. Nevertheless, for the purposes of my opinions, I have considered the
`
`state of the art as of and shortly before July 3, 2012, and the level of knowledge
`
`that a POSITA 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
`
`A. Claim Construction
`21.
`It is my further 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 the claims of the ’631 patent are
`
`what is being challenged in the present IPR proceeding.
`
`22.
`
`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.
`
`
`2 It is my opinion that there is no appreciable difference between the state of the art
`as of July 3, 2012 and as of October 23, 2012, as it relates to the subject matter
`claimed in the ’631 patent.
`
`
`
`10
`
`Regeneron Exhibit 1003.015
`
`

`

`
`
`23.
`
`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, 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.
`24.
`
`Invalidity
`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.
`
`25.
`
`I have been asked to consider the question of whether the claims of
`
`the ’631 patent would have been obvious. I understand that this analysis must be
`
`conducted from the perspective of the person of ordinary skill in the art, and
`
`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)
`
`
`
`11
`
`Regeneron Exhibit 1003.016
`
`

`

`
`
`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, I understand that one should instead consider what
`
`the person of ordinary skill in the art would have reason to pursue further, and
`
`steps that were routinely done, such as in response to known problems, steps or
`
`obstacles.
`
`26.
`
`It is my understanding that the following is a non-exhaustive list of
`
`rationales that may support the obviousness of an invention: combining prior art
`
`elements according to known methods to yield predictable results; simple
`
`substitution of one known element for another to obtain predictable results; use of
`
`a known technique to improve a similar device (method, or product) in the same
`
`way; applying a known technique to a known device (method, or product) ready
`
`for improvement to yield predictable results; choosing from a finite number of
`
`identified, predictable solutions, with a reasonable expectation of success; and
`
`some teaching, suggestion, or motivation in the prior art that would have led a
`
`POSITA to modify the prior art reference or to combine prior art reference
`
`teachings to arrive at the claimed invention.
`
`27.
`
`It is my understanding that the motivation to combine prior art
`
`references may be implicit and may be found in the knowledge of one of ordinary
`
`
`
`12
`
`Regeneron Exhibit 1003.017
`
`

`

`
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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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`28.
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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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`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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`29.
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`I understand that before reaching any final conclusion on obviousness,
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`the obviousness analysis requires consideration of objective indicia of non-
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`obviousness, if any such indicia are offered. These must be considered to ensure
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`that, for example, there were not some unanticipated problems, obstacles or
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`hurdles that may seem easy to overcome in hindsight, but which were not readily
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`overcome prior to the relevant invention date of the patents/claims at issue here. I
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`understand that these objective indicia are also known as “secondary
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`
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`13
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`Regeneron Exhibit 1003.018
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`

`

`
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`considerations of non-obviousness,” and may include long-felt but unmet need and
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`unexpected results, among others. I also understand, however, that any offered
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`evidence of secondary considerations of non-obviousness must be commensurate
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`with the scope of the challenged claims. This means that for any offered evidence
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`of secondary considerations of non-obviousness to be given substantial weight, I
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`understand the proponent of that evidence must establish a “nexus” or a sufficient
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`connection or tie between that evidence and the merits of the claimed invention,
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`which I understand specifically incorporates any novel element(s) of the claimed
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`invention. If the secondary consideration evidence offered actually results from
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`something other than the merits of the claim, then I understand that there is no
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`nexus or tie to the claimed invention. I also understand it is the Patent Owner who
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`has the burden of proving that a nexus exists, and I understand that secondary
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`considerations will not overcome a strong showing of obviousness.
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`C.
`30.
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`Person of Ordinary Skill in the Art
`I have been asked to review the ’631 patent from the perspective of a
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`person of ordinary skill in the art (“POSITA”) as of the earliest claimed priority
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`date for the patent—July 3, 2012. I have been asked to evaluate the disclosure and
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`claims of the ’631 patent. I have been further asked to consider whether the prior
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`art renders obvious the pre-filled syringe covered by claims 1-23 of the ’631
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`patent.
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`14
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`Regeneron Exhibit 1003.019
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`31.
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`It is my opinion that a POSITA relevant to the ’631 patent would have
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`had at least an advanced degree (Dipl.Ing, M.S., or Ph.D.), with research
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`experience in mechanical engineering, biomedical engineering, materials science,
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`chemistry, or a related field, or at least 2-3 years of professional experience in one
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`or more of those fields. Furthermore, it is my opinion that a POSITA would have
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`had experience with (i) the design of pre-filled syringes; and (ii) sterilization of
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`drug delivery devices, including those containing sterilization sensitive
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`therapeutics. Such sterilization experience would include experience with
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`microbiology. Based on my education, training