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