`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`_________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_________________
`
`PROLLENIUM US INC.,
`Petitioner,
`
`v.
`
`ALLERGAN INDUSTRIE, SAS,
`Patent Owner.
`
`_________________
`
`IPR2019-01505, Patent 8,450,475 B2
`IPR2019-01506, Patent 8,357,795 B2
`IPR2019-01508, Patent 9,238,013 B2
`IPR2019-01509, Patent 9,358,322 B2
`IPR2019-01617, Patent 8,822,676 B2
`IPR2019-01632, Patent 8,357,795 B2
`IPR2020-00084, Patent 9,089,519 B2
`
`
`_________________
`
`
`
`DECLARATION OF GLENN PRESTWICH, PH.D.
`
`
`
`1
`
`
`Prollenium Exhibit 1105
`Prollenium v. Allergan
`IPR2019-01505 et al.
`
`
`
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 4
`I.
`EDUCATION, EXPERIENCE, QUALIFICATIONS, AND AWARDS ....... 5
`II.
`SUMMARY OF OPINIONS .........................................................................13
`III.
`IV. TECHNICAL BACKGROUND ...................................................................17
`V.
`PERSON OF ORDINARY SKILL IN THE ART (POSITA) ......................18
`VI. CONSTRUCTION OF CLAIM TERMS IN THE CHALLENGED
`PATENTS 19
`A. “freely released” and “freely released in vivo” ............................................ 20
`VII. THE POSITA WOULD BE MOTIVATED TO MAKE A BDDE-
`CROSSLINKED HA GEL WITH LIDOCAINE ..........................................21
`VIII. BERKLAND MISCHARACTERIZES THE ART TO INCORRECTLY
`CONCLUDE THE POSITA WOULD NOT EXPECT SUCCESS ..............22
`A. Crosslinker selection and chemistry was not unpredictable ......................... 22
`B. Post-crosslinking processing was routine ..................................................... 24
`C. Chemical degradation of HA from lidocaine is overstated and based on false
`premises ........................................................................................................ 26
`1. HA is stable at pH levels around neutrality ..............................................26
`2. pH adjustment does not unpredictably alter rheological properties .........30
`D. Lidocaine does not interact in any chemically meaningful way with either
`crosslinked or free HA .................................................................................. 38
`IX. ANALYSIS OF GROUNDS .........................................................................43
`A. Lebreton and Sadozai ................................................................................... 43
`1. Motivation to Combine .............................................................................43
`2. Expectation of Success .............................................................................44
`3. Design choices for dermal fillers ..............................................................56
`B. Kinney and Zhao ........................................................................................... 60
`1. Motivation to Combine .............................................................................60
`
`
`
`2
`
`
`
`
`
`
`
`
`
`
`2. A POSITA Would Have Had a Reasonable Expectation of Success When
`Combining Kinney and Zhao ...................................................................61
`3. A POSITA would have been able to combine Kinney and Zhao to obtain
`a filler ........................................................................................................73
`X. DETAILED DISCUSSION OF CHEMICAL MODIFICATION AND
`CROSSLINKING OF HA AND FILLERS ..................................................75
`A. HA-based dermal fillers were known and in rapid development ................. 76
`B. Methods of preparing HA-based dermal fillers were well known ............... 76
`1. Hyaluronan ...............................................................................................76
`2. Chemical Modification and Crosslinking of HA .....................................79
`3. Crosslinking of HA with divinyl sulfone (“DVS”) ..................................86
`4. Crosslinking of HA with 1,4-butanediol diglycidyl ether (“BDDE”) .....88
`5. Crosslinking of HA with 1,2,7,8-diepoxyoctane (“DEO”) ......................91
`6. Crosslinking of HA with p-Phenylene Biscarbodiimide (pBCDI, or
`BCDI) .......................................................................................................93
`7. Soft tissue fillers containing both water insoluble crosslinked HA and
`water-soluble HA were known .................................................................94
`8. HA-based dermal fillers containing lidocaine were known .....................97
`9. Heat sterilization of HA preparations .....................................................100
`10. Stability of HA-based dermal fillers ......................................................103
`11. Lidocaine was known to stabilize HA compositions .............................104
`XI. CONCLUSION ............................................................................................109
`
`
`
`
`
`
`
`3
`
`
`
`
`
`
`
`
`
`
`I, Glenn D. Prestwich, Ph.D., declare as follows:
`
`I.
`
`INTRODUCTION
`
`
`
`I have been asked by Meunier Carlin & Curfman LLC, on behalf of
`
`Petitioner Prollenium US Inc. (Prollenium) to provide this declaration related to
`
`the inter partes reviews of several patents owned by Allergan Industrie, SAS
`
`(Allergan or Patent Owner): I will refer to U.S. Patent Nos. 8,357,795 (’795
`
`patent), 8,822,676 (’676 patent), 9,238,013 (’013 patent), 9,089,519 (’519 patent),
`
`8,450,475 (’475 patent), and 9,358,322 (’322 patent) (collectively, the “Challenged
`
`Patents”).
`
`
`
`I have been asked to review the above-mentioned patents, as well as
`
`the Declaration of Dr. Cory J. Berkland, Patent Owner’s expert, submitted with
`
`Patent Owner’s Response to the Inter Partes review petitions. I also reviewed Dr.
`
`Lebreton’s inventor’s declaration regarding the state of the art in August 2008 and
`
`the alleged “unexpected” nature of the effects of adding lidocaine to one of the
`
`Patent Owner’s existing BDDE-crosslinked commercial dermal fillers. In addition,
`
`I have been requested to discuss the technology and concepts relating to the
`
`properties of hyaluronic acid (HA) dermal fillers.
`
`
`
`I have also been asked to provide my opinions of whether a person of
`
`ordinary skill in the art (POSITA) as of August 2008 would have been motivated
`
`to combine the teachings of the prior art identified in the Grounds, and would have
`
`
`
`4
`
`
`
`
`
`
`
`
`
`
`had a reasonable expectation of success in achieving dermal fillers possessing the
`
`characteristics recited in the challenged claims.
`
`
`
`I have also reviewed the Deposition Transcript of Dr. Berkland taken
`
`on October 7-9, 2020 (Exhibit 1200), as well as Dr. Berkland’s Declaration dated
`
`August 31, 2020. Herein I provide my opinions, clarifications, and corrections of
`
`matters represented incompletely or inaccurately by Dr. Berkland in his testimony.
`
`
`
`I have reviewed the Declaration of Dr. Dale P. DeVore and the
`
`Deposition Transcript of Dr. DeVore taken in August 2020 (Exhibit 2100). Herein
`
`I also provide my own opinions and conclusions, based on my own specific
`
`expertise and experience in HA chemical modification reactions, stability of
`
`crosslinked HA, and crosslinked HA product development.
`
`II. EDUCATION, EXPERIENCE, QUALIFICATIONS, AND AWARDS
`
`
`
`I am currently the President’s Distinguished Professor at Washington
`
`State University, Health Sciences Spokane, where I am tasked with developing an
`
`ecosystem of innovation and entrepreneurship in Spokane, including creation of
`
`Spinout Space in Spokane, a.k.a, sp3nw, a life sciences innovation hub. I am also
`
`Presidential Professor of Medicinal Chemistry, Emeritus, at the University of Utah
`
`in Salt Lake City, UT. I also concurrently hold the Emeritus rank for the titles of
`
`Research Professor of Biochemistry, Adjunct Professor of Chemistry, Adjunct
`
`
`
`5
`
`
`
`
`
`
`
`
`
`
`Professor of Bioengineering, and Adjunct Professor of Surgery at the University of
`
`Utah.
`
`
`
`A copy of my CV, which fully describes my qualifications as an
`
`expert in this matter, is submitted as Exhibit 1106. I have set forth my education,
`
`professional qualifications, publications, patents, and awards in the paragraphs that
`
`follow.
`
`
`
`I obtained a Bachelor of Science Degree (Honors) in Chemistry from
`
`the California Institute of Technology in Pasadena, California (1970) and a Ph.D.
`
`degree in Organic Chemistry from Stanford University in Palo Alto, California
`
`(1974).
`
`
`
`After obtaining my Ph.D., I worked as a research scientist from 1974-
`
`1977 at the International Centre for Insect Physiology and Ecology in Nairobi,
`
`Kenya. I conducted research on insect chemical communication, with the goal of
`
`identifying compounds produced by termites, ticks, tsetse flies, mosquitoes, and
`
`armyworms that could be useful for control of insect agricultural pests and insect
`
`disease vectors. I continued my research on the identification of structure,
`
`function, synthesis, and biochemistry of insect and arthropod natural products,
`
`including defensive secretions, pheromones, hormones, and steroids, during the
`
`years 1977 to 1995.
`
`
`
`6
`
`
`
`
`
`
`
`
`
`
` From 1977 to 1996, I was appointed first as an Assistant Professor
`
`and, subsequently, Associate Professor and then Full Professor of Chemistry at the
`
`State University of New York at Stony Brook, NY. From 1992-1996, I was also
`
`appointed as Professor of Biochemistry and Cellular Biology, and I was the
`
`Director of the New York State Center for Advanced Technology in
`
`Biotechnology, also called the Center for Biotechnology, at SUNY Stony Brook.
`
` From 1996-2002, I was the Chair of the Department of Medicinal
`
`Chemistry at the University of Utah. In addition, from 1997-2002, I directed the
`
`Center for Cell Signaling, a Utah Center of Excellence dedicated to launching new
`
`start-up companies based on faculty technologies in cell signal research; I assisted
`
`in starting three new companies, one of which involved technology from my
`
`research laboratories. From 2002-2006, I directed a second Utah Center of
`
`Excellence, the Center for Therapeutic Biomaterials, from which I helped launch
`
`five new companies, each of which involved technology created in my
`
`laboratories.
`
` My academic duties have included teaching undergraduate and
`
`graduate courses in bioorganic chemistry, structural organic chemistry, medicinal
`
`chemistry, chemical ecology and site-targeted drug delivery. I have also been
`
`active in research directing graduate students, technicians, postdoctoral fellows and
`
`visiting faculty members. My university research and other scholarly duties have
`
`
`
`7
`
`
`
`
`
`
`
`
`
`
`resulted in the publication of over 595 original peer-reviewed scientific papers and
`
`review articles, and 64 book chapters and books. I am also a named inventor on
`
`more than 93 patents and patent applications, of which 48 U.S. and foreign patents
`
`have issued. These inventions cover many areas, including the control of insect
`
`pests, cholesterol lowering agents, labeled phospholipids and phosphoinositides in
`
`drug discovery assays, anti-cancer and anti-angiogenic agents, signal transduction
`
`modifiers, mercury sensing chemicals, wound-healing and regenerative medicine
`
`compositions, anti-inflammatory drugs, as well as the compositions and uses for a
`
`wide variety of chemically modified hyaluronan (aka, hyaluronic acid, HA)
`
`derivatives. Relevant to this matter, approximately 146 of the 595 published papers
`
`(24.5%), 19 of the 60 book chapters (31.6%), 60 of the 93 patent applications
`
`(64.5%) and 36 of the 48 issued patents (75%) pertain to chemically modified HA.
`
`Five of these issued patents teach carbodiimide and biscarbodiimide modifications
`
`of HA.
`
` My entrepreneurial and technology commercialization activities began
`
`during my tenure as Director of the Center for Biotechnology, when I co-founded
`
`my first company, Clear Solutions Biotech, in 1994. Since moving to Utah in
`
`1996, I co-founded and/or served as a Director, Chief Scientific Officer (CSO),
`
`Chief Scientific Advisor, or Chief Executive Officer (CEO) for a number of
`
`
`
`8
`
`
`
`
`
`
`
`
`
`
`companies and consulted for many other faculty startups and biotechnology
`
`companies in the life sciences.
`
` These companies include: Clear Solutions Biotech (Stony Brook, NY)
`
`(1994-2001); Echelon Biosciences, Inc. (Salt Lake City, UT)(CSO, 1997-2003;
`
`Science Advisor 2004 – current); Sentrx Surgical, Inc. (Salt Lake City, UT)(CSO,
`
`2004 – 2005); Carbylan Biosurgery, Inc. (Palo Alto, CA)(Science Advisor, 2005 –
`
`2009); Sentrx Animal Care, Inc. (Salt Lake City, UT)(Science Advisor, 2006 –
`
`current); Glycosan BioSystems, Inc. (Salt Lake City, UT) (CSO, 2006 – 2011);
`
`GlycoMira Therapeutics, Inc. (Salt Lake City) (CSO, 2008 – current);
`
`Metallosensors (Salt Lake City) (CEO, 2011 – 2014); Brickell Biotech (Ft.
`
`Lauderdale, FL) (Director, 2011- 2013); BioTime (Alameda, CA)(now Lineage
`
`Cell Therapeutics)(Scientific Advisor, 2011 – 2014); Organovo (Scientific
`
`Advisory Board (SAB), 2008 – 2018); Modern Meadow (SAB, 2012 – current);
`
`Deuteria Agrochemicals LLC (Manager, 2014-2019); Deuteria Biomaterials LLC
`
`(Manager, 2014 – current) and Matrix Diagnostics Biosystems (President, 2020 –
`
`current). With the exception of Echelon Biosciences, Metallosensors, Inc.,
`
`Organovo, Modern Meadow, and Deuteria Agrochemicals, each of these
`
`companies, currently or in the past, has been engaged in the development of
`
`products based on chemically-modified HA. Echelon recently added a suite of HA
`
`products.
`
`
`
`9
`
`
`
`
`
`
`
`
`
`
` Since 2015, I have held consulting or employment roles with several
`
`companies engaged in developing projects involving chemically modified HA
`
`and/or other glycosaminoglycans. These include Symic Bio (Emeryville, CA)
`
`(SAB 2015-2017; SVP and CSO, 2017 – 2019); Shasqi, Inc. and Tambo, Inc. (San
`
`Francisco, CA) (Consultant, 2018 – current); Valitor (Berkeley, CA) (Consultant,
`
`2018 – current); 109 Therapeutics (Salt Lake City, UT) (Consultant, 2020 –
`
`current); and HTL Biotechnology (Fougeres, France) (Consultant, 2019 – current).
`
`
`
`I have received peer and community recognition and numerous
`
`awards for my work, including the Alfred P. Sloan Research Award (1981-85) and
`
`Camille and Henry Dreyfus Teacher-Scholar Award (1981-86). In 2001, I was
`
`awarded the prestigious Silverstein- Simeone Award of the International Society of
`
`Chemical Ecology, for lifetime research achievements in the chemistry, biology
`
`and biochemistry of insect chemical communication.
`
`
`
`I received both the 1998 Paul Dawson Biotechnology Award and the
`
`2008 Volwiler Research Award of the American Association of Colleges of
`
`Pharmacy. I was elected as a Fellow of the American Institute for Medical and
`
`Biological Engineering in 2005, named one of vSpring’s Top 100 Entrepreneurs in
`
`2005 and 2006, and selected as a recipient of a TIAA-CREF “Greater Good”
`
`award (2006), as a Utah Business Magazine “Health Care Hero” for 2006. I was
`
`awarded the Utah Governor’s Medal for Science and Technology for 2006. In
`
`
`
`10
`
`
`
`
`
`
`
`
`
`
`2010, I received the University of Utah Distinguished Scholarly and Creative
`
`Research Award, and in 2014 I was awarded the University of Utah Distinguished
`
`Innovation and Impact Award. In 2010, I received the “Rooster Prize” of the
`
`International Society for Hyaluronan Science (ISHAS) for outstanding
`
`contributions to HA-derived products; I am currently the Vice President of the
`
`Applied Division of ISHAS. In 2013, I was inducted as a Fellow of the National
`
`Academy of Inventors, and in 2018, I was elected as a Fellow of the American
`
`Association for the Advancement of Science.
`
` During my 41 years as a faculty member at Stony Brook University
`
`(formerly State University of New York at Stony Brook) and University of Utah, I
`
`have trained over 125 graduate and postdoctoral scientists, many undergraduate
`
`students, and mentored over 22 adjunct and visiting faculty members, including
`
`both scientists and physicians.
`
`
`
`I have served on more than 16 editorial boards for prominent journals;
`
`my current and past editorial responsibilities most relevant to the Challenged
`
`Patents include: Journal of Biological Chemistry, Bioconjugate Chemistry,
`
`Macromolecular Biosciences, Current Opinion in Chemical Biology, Perspectives
`
`in Medicinal Chemistry, Advanced Therapeutics, and Science Translational
`
`Medicine.
`
`
`
`11
`
`
`
`
`
`
`
`
`
`
` My university research programs for over four decades have focused
`
`in a number of diverse areas: (i) chemistry and biochemistry of insect defensive
`
`compounds, pheromones, and hormones, including natural product structure
`
`determinations using x-ray crystallography; (ii) development of insect-activated
`
`pro-insecticides; (iii) development and use of radiolabeled insect hormone and
`
`growth regulators to study metabolism and mechanism of action in insect pests;
`
`(iv) discovery of cholesterol-lowering drugs by inhibition of key biosynthetic
`
`enzymes; (v) developing chemical and photochemical cross-linking reagents and
`
`protocols for modification and purification of macromolecules, including proteins
`
`and glycosaminoglycans; (vi) chemical synthesis and uses of affinity reagents for
`
`biological studies of phosphoinositides; (vii) new reagents for lipid signaling in
`
`cell biology and cancer treatment; (viii) crosslinked hyaluronan and other
`
`glycosaminoglycan and protein-based biomaterials for wound repair, cartilage
`
`repair, tissue engineering, cell therapy, scar-free healing, and toxicology and tumor
`
`xenograft models; and (ix) sulfated glycosaminoglycan analogues as inflammation
`
`modulators for clinical use.
`
`
`
`In addition to my academic and company background information
`
`above, I have been previously engaged by other parties for the evaluation of the
`
`potential invalidity of the ‘475 and ‘795 patents. In two separate cases in 2014 and
`
`in 2017, I was retained to offer declaration testimony by parties challenging the
`
`
`
`12
`
`
`
`
`
`
`
`
`validity of the ‘475 and ‘795 patents at the PTAB. I have reviewed the contents of
`
`those declarations in preparing this declaration. In a prior district court action
`
`asserting the ‘475 and ‘795 patent, I was retained as an expert to offer opinions on
`
`
`
`the invalidity of those patents.
`
`
`
`III. SUMMARY OF OPINIONS
`
` The Challenged Patents purport to provide a soft tissue filler
`
`containing HA crosslinked with, inter alia, BDDE, uncrosslinked or “free” HA and
`
`lidocaine that has enhanced stability relative to conventional HA-based
`
`compositions “when subjected to sterilization techniques such as autoclaving,
`
`and/or when stored for long periods at ambient temperature. Methods for preparing
`
`such HA-based compositions are also provided as well as products made by such
`
`methods.” (see for example, ‘475 patent, 2:42-49).
`
`
`
`I agree with the Challenged Patents that since the first HA-based filler
`
`was approved by the U.S. Food and Drug Administration (FDA) in December
`
`2003, “this was rapidly followed by the development of other HA-based fillers.”
`
`(see for example, ‘475 patent, 1:63-65). I also agree that by August 2008,
`
`“methods of preparing HA-based soft tissue fillers including both crosslinked and
`
`free HA are well known” (see for example, ‘475 patent, 2:18-19). Similarly, I
`
`agree that “It has been proposed to incorporate certain therapeutic agents, for
`
`
`
`13
`
`
`
`
`
`
`
`
`example, anesthetic agents such as lidocaine, into injectable HA-based
`
`compositions” (‘475 patent, 2:20-22).
`
` However, I disagree with the assertion in the Challenged Patents that,
`
`prior to after August 2008, “HA-based injectable compositions which incorporate
`
`lidocaine during the manufacturing process are prone to partial or almost complete
`
`degradation prior to injection, particularly during high temperature sterilization
`
`steps and/or when placed in storage for any significant length of time” (see for
`
`example, ‘475 patent, 2:22-27). As explained below, it is my opinion, this
`
`statement mischaracterizes relevant prior art, fails to acknowledge other relevant
`
`prior art, and does not accurately describe the expectations of a person of ordinary
`
`skill in the art (POSITA), based on the prior art at that time.
`
` As explained below, it is my opinion, it would have been obvious to a
`
`POSITA, before August 4, 2008, that the addition of lidocaine to a soft tissue filler
`
`containing HA-BDDE (i.e., HA crosslinked with BDDE) and uncrosslinked HA
`
`would not cause degradation of the filler, either during high temperature
`
`sterilization steps (autoclaving) and/or when placed in storage for any significant
`
`length of time.
`
` Moreover, in my opinion, and for reasons described in detail below, a
`
`skilled artisan, or POSITA, would have been motivated to combine the disclosures
`
`of the prior art identified in the Grounds, and by doing so would have had a
`
`
`
`14
`
`
`
`
`
`
`
`
`
`
`
`
`reasonable expectation of success in achieving a dermal filler with the
`
`characteristics claimed in the Challenged Patents.
`
` As I will explain below, dermal fillers based on chemically
`
`crosslinked hyaluronan (HA) were well known in the art as of August 2008, and
`
`the POSITA would have understood that there were many acceptable and
`
`commercially viable solutions to crosslinking HA and producing a sterile,
`
`injectable dermal filler product. Moreover, the POSITA would also have been
`
`aware of the clinical and commercial motivation to reduce the pain of injection by
`
`the incorporation of a local anesthetic into the sterile HA-based dermal filler
`
`preparation.
`
` Specifically, I explain below, given the successful incorporation of
`
`0.3% lidocaine into sterile, stable HA-based dermal fillers based on three different
`
`crosslinking chemistries, a POSITA would have been motivated to add the same
`
`amount of lidocaine into a dermal filler employing the fourth well-established and
`
`commercially successful crosslinking chemistry. Moreover, the POSITA would
`
`have every reason to expect success in achieving a dermal filler by combining prior
`
`art for crosslinking and formulation protocols, with prior art for the incorporation
`
`of 0.3% lidocaine and then subsequent sterilization.
`
`
`
`I will show that clinically and commercially successful cross-linked
`
`HA dermal fillers can have a wide range of chemical and physical properties, as
`
`
`
`15
`
`
`
`
`
`
`
`
`reflected in the prior art literature, and I will show that the claimed fillers fall
`
`within the properties well-known to a POSITA in August 2008. In addition, the
`
`POSITA was aware that crosslinked HA dermal fillers would have different
`
`physical properties, and could be created with different crosslinking and
`
`formulation chemistries, based in part on their intended clinical applications in
`
`terms of location of injection, depth of injection, desired aesthetic result, and
`
`desired duration of effect.
`
`
`
`I will contrast the breadth of these acceptable ranges with the
`
`relatively small magnitude of the changes in biomaterial properties made in the
`
`Challenged Patents based on the issues raised by Dr. Berkland.
`
` Finally, I will provide a context for the Patent Trial and Appeal Board
`
`(PTAB) to understand why a POSITA would have both the motivation and a
`
`reasonable expectation of success of creating a 0.3% lidocaine-containing HA-
`
`BDDE formulation, in view of the minor changes in physical properties resulting
`
`from addition of lidocaine to an already successful BDDE-crosslinked HA dermal
`
`filler. Moreover, a POSITA would also expect, being aware of other commercial
`
`dermal fillers in syringe formulations, that a 0.3% lidocaine-containing HA-
`
`BDDE formulation could be sterilized by autoclaving and would be a stable
`
`commercial dermal filler product.
`
`
`
`16
`
`
`
`
`
`
`
`
`
`
`IV. TECHNICAL BACKGROUND
`
` The DeVore and Berkland Declarations introduce the bulk of the
`
`technical background on HA with respect to its chemistry and biology. Most of
`
`that background is not in dispute, though the inferences to be drawn and how they
`
`apply to the issues presented have been disputed. With the goal of balancing
`
`completeness with conciseness, I provide my own review of the background of the
`
`chemical modification and crosslinking of HA and related information about HA
`
`fillers in the Detailed Discussion at the end of this declaration. In the main body, I
`
`have noted some disagreements with their testimony.
`
` As one preliminary observation, I agree with Dr. Berkland’s
`
`observation that Dr. DeVore included the incorrect structure of the BCDI (or
`
`pBCDI) crosslinking reagent in his declaration, along with an incorrect acronym
`
`transposing two of the letters BDCI vs. BCDI. EX2013 ¶ 68, footnote 8. It does
`
`not appear to me, however, this incorrect structure affected Dr. DeVore’s
`
`explanation or analysis of BCDI-crosslinked HA. Indeed, Dr. DeVore does
`
`correctly depict the crosslinked structure of the bis-N-acylurea crosslinked gel
`
`resulting from reaction of pBCDI and HA, shown below. It appears that Dr.
`
`Berkland agrees as well, as he copies the picture of pBCDI-crosslinked HA
`
`(retaining the transposed letters in BDCI) from Dr. DeVore’s declaration into his
`
`own declaration:
`
`
`
`17
`
`
`
`
`
`
`
`
`
`
`Devore EX1002 ¶ 83
`
`Berkland EX2013 ¶ 68
`
`
`
`
`
`
`
`
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART (POSITA)
`
`
`
`I understand that a person of ordinary skill in the art (POSITA) would
`
`have been one who is presumed to be aware of all pertinent art, thinks along
`
`conventional wisdom in the art, and is a person of ordinary creativity. I have
`
`reviewed both Dr. Berkland and Dr. DeVore’s opinions about the definition of a
`
`POSITA. I understand that Dr. Berkland’s POSITA definition relies on a definition
`
`that “the Board adopted” in “earlier IPR proceedings.” I understand that the
`
`“earlier IPR proceedings” were the cases mentioned above where I offered
`
`testimony on the definition of a POSITA, and the Board appears to have adopted a
`
`paraphrase of my testimony in those cases.
`
`
`
`In my opinion, the only relevant difference between Dr. DeVore’s and
`
`Berkland’s (and my previous) definitions is whether a POSITA would have been
`
`
`
`18
`
`
`
`
`
`
`
`
`
`
`aware of other products and their progress towards FDA approval. Based on my
`
`experience and reviewing the prior art in the case, it is my opinion that a POSITA
`
`would be generally aware of currently marketed dermal fillers and dermal filler
`
`products being publicly tested (e.g., in a clinical trial) by other companies. A
`
`POSITA would also be generally aware of the FDA’s regulatory guidelines, and
`
`that the FDA posted publicly available communications regarding dermal fillers. In
`
`other words, a POSITA would be aware of all the relevant literature on HA-based
`
`dermal fillers. This opinion appears to be consistent with my earlier testimony
`
`(adopted by the Board) because the “pertinent art” and conventional wisdom would
`
`lead a POSITA to the literature generally reflecting clinicians’ needs and technical
`
`specifications and performance of competitors’ products.
`
`VI. CONSTRUCTION OF CLAIM TERMS IN THE CHALLENGED
`PATENTS
`
` Drs. Devore and Berkland generally agree on most issues of claim
`
`construction, including accepting a district Court’s prior claim constructions for
`
`several terms. Some disagreement among the Experts exists on “freely released”
`
`and on “unbound” or “unbound to the HA.” I offer my opinion on the construction
`
`of freely released.
`
`
`
`19
`
`
`
`
`
`
`
`
`
`
`A.
`
`“freely released” and “freely released in vivo”
`
`
`
`I agree with Dr. Berkland Exhibit 2013 at ¶ 208 that the phrase “freely
`
`released” should have its ordinary meaning. While Dr. DeVore does not explicitly
`
`state that the term should have its ordinary meaning, his discussion is consistent
`
`with that interpretation. IPR2019-01506, Exhibit 1002 ¶ 134-137. A POSITA
`
`would understand that in this context lidocaine should be released unhindered from
`
`the HA gel, since the purpose of having lidocaine in the dermal filler formulation is
`
`to reduce pain upon injection. Indeed, Berkland Exhibit 2013 at ¶ 212 points out
`
`the need for the claimed compositions to confer the therapeutic effect of relieving a
`
`patient’s pain upon injection. I agree with his statement that a POSITA “would
`
`have understood that it was the initial puncture and injections into the skin that
`
`caused a patient’s pain. Accordingly, the free release of lidocaine is intended to
`
`effectively reduce a patient’s pain almost immediately. A composition that did not
`
`allow free release of the lidocaine would not provide the required efficacy.”
`
`However, I disagree with his interpretation of the results and the
`
`mischaracterization of the free release of lidocaine occurring in Sadozai Exhibit
`
`1030 and in the Challenged Patents.
`
`
`
`20
`
`
`
`
`
`
`
`
`
`
`VII. THE POSITA WOULD BE MOTIVATED TO MAKE A BDDE-
`CROSSLINKED HA GEL WITH LIDOCAINE
`
` As explained in the Petitions and DeVore declarations, a POSITA
`
`would be aware of four major crosslinking technologies: DVS, BDDE, DEO, and
`
`pBCDI, although additional bisepoxide crosslinkers and crosslinking chemistries
`
`were being explored as research topics. Moreover, product developers recognized
`
`that for HA dermal fillers to be competitive with collagen-based fillers, reducing
`
`the pain of injection was an important product attribute to improve patient
`
`experience and increase patient acceptance. Three out of four primary crosslinkers
`
`used in clinical products – DVS, DEO, and pBCDI – had products approved or in
`
`clinical trials that included 0.3% lidocaine (w/w), in alignment with the lidocaine
`
`concentration in the collagen filler products. In this environment, a POSITA would
`
`view the simple and logical next step to be incorporation of lidocaine into a
`
`BDDE-crosslinked HA dermal filler product.
`
`
`
`I also observe that the crosslinkers used in products were widely
`
`reported in the literature and known to POSITAs before and around the priority
`
`date of the Challenged Patents. E.g., Exhibit 2079, 165 (Table 2); Exhibit 1005,
`
`125 (Table 1); Exhibit 1011, 371-375; Exhibit 1012, 741-742 (discussing BDDE,
`
`DVS, and DEO-crosslinked products); Exhibit 1035, 631 (Table 1); Exhibit 1039,
`
`266 (Table I); Exhibit 1102, 198 (Table 23-4); Exhibit 1216, 154-156 (identifying
`
`
`
`21
`
`
`
`
`
`
`
`
`
`
`various products and crosslinkers, including “Elevess™ crosslinker is p-phenylene
`
`bis(ethyl)carbodimide (BCDI).”). See also Allergan’s 2013 FDA Briefing
`
`document, Exhibit 1103, 24, identifying the three FDA-approved crosslinkers (and
`
`their products) as of that date.
`
`VIII. BERKLAND MISCHARACTERIZES THE ART TO INCORRECTLY
`CONCLUDE THE POSITA WOULD NOT EXPECT SUCCESS
`
`
`
`In order to support his assertions that technology underpinning
`
`crosslinked HA fillers was unpredictable, Dr. Berkland misstates, omits, or
`
`misinterprets the prior art, and he also misrepresents some important aspects of the
`
`science of hyaluronic acid (“HA”) and lidocaine. He and Allergan repeatedly refer
`
`to “the formidable task” and overdramatize the “almost infinite number of
`
`combinations of “many complex factors.” Exhibit 2013 ¶ 63 (quoting Exhibit
`
`2128). However, many of cited references supporting their arguments are taken
`
`out of context, and in many cases, their arguments exaggerate the magnitude of
`
`changes that would be expected. As a result, Dr. Berkland and Allergan reach
`
`numerous incorrect conclusions.
`
`A. Crosslinker selection and chemistry were not unpredictable
`
` Prior to August 2008, a POSITA would have considerable knowledge
`
`of the ranges of useful properties of existing dermal fillers, reflected in the
`
`published literature, issued patents, and public FDA submissions and approvals for
`
`
`
`22
`
`
`
`
`
`
`
`
`
`
`existing dermal fillers and those under development. This is not a case of starting
`
`from scratch to manage an “almost infinite number of combinations,” rather it is a
`
`matter of simply making predictable substitutions in a well-established recipe.
`
`Various references discuss the “well known” or “conventional” means of
`
`crosslinking employed in their disclosures, while at the same time omitting some
`
`minor details or disclosing ranges of acceptable choices. In my opinion, it is
`
`within the level of ordinary skill to modify a specific example in a patent according
`
`to either the general teachings