UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`ACTAVIS LLC,
`Petitioner
`
`v.
`
`ABRAXIS BIOSCIENCE, LLC,
`Patent Owner
`
`
`Case IPR2017-01100
`Patent 8,853,260 B2
`
`DECLARATION OF EDMUND J. ELDER, Jr., Ph.D., R.Ph.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
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`Actavis - IPR2017-01100, Ex. 1034, p. 1 of 31
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`ACTAVIS LLC,
`Petitioner
`
`v.
`
`ABRAXIS BIOSCIENCE, LLC,
`Patent Owner
`
`
`Case IPR2017-01100
`Patent 8,853,260 B2
`
`DECLARATION OF EDMUND J. ELDER, Jr., Ph.D., R.Ph.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
`
`
`
`
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`Actavis - IPR2017-01100, Ex. 1034, p. 1 of 31
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`TABLE OF CONTENTS
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`Page
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`I.
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`II.
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`INTRODUCTION ........................................................................................... 1
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`BACKGROUND AND QUALIFICATIONS ................................................. 2
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`III. LEGAL STANDARDS USED IN MY ANALYSIS ...................................... 6
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`A.
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`B.
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`C.
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`Prior art .................................................................................................. 6
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`Person of ordinary skill in the art .......................................................... 7
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`Obviousness ........................................................................................... 8
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`IV. OBVIOUSNESS ............................................................................................ 11
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`A.
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`B.
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`C.
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`D.
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`Increasing the concentration of active drug in pharmaceutical
`formulations was generally obvious and routine as of June 1997. ..... 13
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`Reducing the particle size of pharmaceutical formulations was
`generally obvious and routine as of June 1997. .................................. 15
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`Optimizing the physical stability of pharmaceutical suspensions
`was generally obvious and routine as of June 1997. ........................... 17
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`The allegedly “unexpected” results asserted by Patent Owner
`regarding stability would have been expected as of June 1997. ......... 20
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`V.
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`CONCLUSION .............................................................................................. 22
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`Actavis - IPR2017-01100, Ex. 1034, p. 2 of 31
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`EXHIBITS CITED
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`Description
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`Desai et al., U.S. Patent No. 8,853,260 B2, “Formulations of Phar-
`macological Agents, Methods for the Preparation thereof and Meth-
`ods for the Use thereof” (issued Oct. 7, 2014) (the “(cid:1932)260 patent”)
`Declaration of Cory J. Berkland, Ph.D.
`in Support of Petition for Inter Partes Review
`Desai et al., U.S. Patent No. 5,439,686, “Methods for In Vivo Deliv-
`ery of Substantially Water Insoluble Pharmacologically Active
`Agents and Compositions Useful therefor” (issued Aug. 8, 1995)
`(“Desai”)
`Shively, U.S. Patent No. 5,407,683, “Pharmaceutical Solutions and
`Emulsions Containing Taxol” (issued Apr. 18, 1995) (“Shively”)
`Liversidge et al., U.S. Patent No. 5,399,363, “Surface Modified An-
`ticancer Nanoparticles” (issued Mar. 21, 1995) (“Liversidge”)
`Remington’s Pharmaceutical Sciences (18th ed. 1990), Chapt. 19,
`“Disperse Systems,” and Chapt. 78, “Sterilization” (“Remington’s”)
`U.S. Application No. 11/520,479, Supplemental Declaration of Neil
`P. Desai Pursuant to 37 C.F.R. § 1.132 (dated Nov. 1, 2013)
`(“Second Inventor Declaration”)
`List et al., U.S. Patent No. 5,389,382, “Hydrosols of Pharmacologi-
`cally Active Agents and their Pharmaceutical Compositions Com-
`prising Them” (issued Feb. 14, 1995) (“List”)
`
`
`
`EX
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`1001
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`1002
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`1003
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`1004
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`1005
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`1006
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`1024
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`1027
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`Actavis - IPR2017-01100, Ex. 1034, p. 3 of 31
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`I, Edmund J. Elder, Jr., Ph.D., R.Ph., hereby declare as follows:
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`I.
`
`INTRODUCTION
`1.
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`I am the Director of the Zeeh Pharmaceutical Experiment Station at
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`the School of Pharmacy at the University of Wisconsin-Madison. I have been re-
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`tained by Petitioner Actavis LLC in connection with its request for inter partes re-
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`view of U.S. Patent No. 8,853,260 (“the ’260 patent”). A copy of the ’260 patent
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`has been marked EX1001. I have reviewed and am familiar with the ’260 patent.
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`Generally, it describes and claims pharmaceutical compositions comprising the an-
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`ticancer drug paclitaxel bound to the protein albumin and formulated as nanoparti-
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`cles, and methods of using such compositions to treat diseases including cancer.
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`2.
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`I have been asked to provide my independent opinions regarding the
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`patentability of claims 1–27 of the ’260 patent (the “challenged claims”) and to re-
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`view the Declaration of Cory J. Berkland in Support of Petition for Inter Partes
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`Review, which has been marked EX1002. This declaration includes a discussion
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`of my background and qualifications, the legal standards used in my analysis, and
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`my opinions and relevant experiences as a person of ordinary skill in the art as of
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`June 1997 (a “skilled artisan”) regarding the subject matter of the (cid:1932)260 patent.
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`3.
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`I am being compensated for my work in this proceeding at my stand-
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`ard hourly consulting rate of $500.00 per hour. My compensation is in no way
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`contingent on the substance of my opinions or the outcome of this proceeding.
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`Actavis - IPR2017-01100, Ex. 1034, p. 4 of 31
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`4.
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`As set forth more fully below, it is my opinion that the challenged
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`claims are unpatentable because they would have been obvious to a skilled artisan
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`as of June 1997 in view of U.S. Patent No. 5,439,686 to Desai et al. (“Desai”)
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`(EX1003), U.S. Patent No. 5,407,683 to Shively (“Shively”) (EX1004), U.S. Pa-
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`tent No. 5,399,363 to Liversidge et al. (“Liversidge”) (EX1005), and Remington’s
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`Pharmaceutical Sciences (18th ed. 1990) (“Remington’s”) (EX1006). The bases
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`for my opinions are set forth in this declaration.
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`II. BACKGROUND AND QUALIFICATIONS
`5.
`I obtained my Bachelor of Science degree in Pharmacy, and my Doc-
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`tor of Philosophy (Ph.D.) degree in Pharmaceutical Sciences, from the Medical
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`University of South Carolina in 1985 and 1989, respectively. I have over 30 years
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`of experience characterizing materials used in the preparation of pharmaceutical
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`products, formulating pharmaceutical products, and testing such formulations.
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`6. My current responsibilities as Director of the Zeeh Pharmaceutical
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`Experiment Station at the University of Wisconsin-Madison (“the Station”) include
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`overseeing all aspects of our services, including providing pharmaceutical pre-for-
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`mulation and formulation expertise to support pharmaceutical and biopharmaceuti-
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`cal development collaborations across the University of Wisconsin system cam-
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`puses and for clients outside the University. The Station works for both academia
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`and pharmaceutical industry clients in developing and characterizing drugs and
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`Actavis - IPR2017-01100, Ex. 1034, p. 5 of 31
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`pharmaceutical formulations, and providing technical expertise regarding issues
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`arising during pharmaceutical formulation development and manufacture.
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`7.
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`I actively participate in educational programs sponsored by the Station
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`in collaboration with the Division of Pharmacy Professional Development, a de-
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`partment in the School of Pharmacy at the University of Wisconsin-Madison, in
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`which I teach pharmaceutical industry scientists and others in related fields about
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`the process and science of drug development. I also serve as a guest lecturer for
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`the graduate students in the Pharmaceutical Sciences Division providing lectures
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`on an overview of pharmaceutical development and an introduction to formulation
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`development, with a focus on properties of materials.
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`8.
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`Additionally, I am the course coordinator and senior lecturer for the
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`Biotechnology Operations course in the Master of Science in Biotechnology pro-
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`gram in the School of Medicine and Public Health at the University of Wisconsin-
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`Madison. I teach sessions that include an overview of biopharmaceutical develop-
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`ment, regulatory operations, CMC (chemistry, manufacturing, and controls) opera-
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`tions, pre-clinical operations, and clinical operations.
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`9.
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`Prior to my employment at the University of Wisconsin-Madison, I
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`was the Global Pharmaceutical Development Director / Applications Development
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`Leader from April 2004 until April 2006 at Dowpharma, a business unit of the
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`Actavis - IPR2017-01100, Ex. 1034, p. 6 of 31
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`Dow Chemical Company that was dedicated to serving the pharmaceutical and bio-
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`pharmaceutical industries. From August 2000 until April 2004, I was Pharmaceu-
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`tics Director / Technical Leader of the Pharmaceutics Technologies group at The
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`Dow Chemical Company. From February 1997 until August 2000, I was Group
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`Leader, then Senior Group Leader, for formulation and process development at
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`Glaxo Wellcome Inc. (now GlaxoSmithKline, Inc.).
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`10.
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`I began my industrial career in 1989, at the predecessor company,
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`Glaxo Inc. From September 1989 to February 1997, I progressed from Senior Sci-
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`entist, to Research Investigator, to Research Leader for Pharmaceutical Technol-
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`ogy Development, to Research Leader for Liquids Process Development. As of
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`June 27, 1997, I was the Group Leader for formulation development. During my
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`time at Glaxo from 1989 to 1997, I regularly worked directly in formulation and
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`process development, as well as optimization and scale-up of pharmaceutical for-
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`mulations, including formulations of poorly soluble drugs.
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`11.
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`I have at least ten publications, three book contributions, and 68 scien-
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`tific presentations (17 invited).
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`12.
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`I have been licensed as a pharmacist in South Carolina from 1985 to
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`present and in Wisconsin from 2010 to present.
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`Actavis - IPR2017-01100, Ex. 1034, p. 7 of 31
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`13.
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`I am on the Editorial Advisory Board for the journal Drug Develop-
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`ment and Industrial Pharmacy. I have reviewed journal articles in the pharmaceu-
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`tical sciences submitted for publication to AAPS PharmSci Tech; the European
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`Journal of Pharmaceutics and Biopharmaceutics; the Journal of Biomedical Nano-
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`technology; the International Journal of Pharmaceutics; Pharmaceutical Re-
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`search; and Drug Development and Industrial Pharmacy. I have also screened sci-
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`entific papers submitted for annual meetings of the American Association of Phar-
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`maceutical Scientists.
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`14.
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`I have presented lectures and seminars at 20 Schools or Colleges of
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`Pharmacy throughout the United States on drug development, assessment and opti-
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`mization of drug manufacturing processes, formulation development, excipient
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`considerations in formulations, scale-up, technology transfer, and applications of
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`particle engineering to nanotechnologies. I have also been an instructor at continu-
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`ing education Short Courses presented to pharmaceutical industry scientists
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`through the UW-Madison, School of Pharmacy, Division of Pharmacy Professional
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`Development, giving over 180 lectures covering dosage form design, drug solubili-
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`zation, drug delivery, drug stability, and particle engineering/nanotechnology.
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`15.
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`I am a member of the 2015–2020 Compounding Expert Committee of
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`the United States Pharmacopeia (USP), which is responsible for setting global
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`standards for pharmaceuticals. I also served on the USP Compounding Expert
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`Actavis - IPR2017-01100, Ex. 1034, p. 8 of 31
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`Committee for the 2010–2015 review cycle. I have been a member of the Ameri-
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`can Association of Pharmaceutical Scientists since 1987. I am also a member of
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`Sigma Xi, The Scientific Research Society, and a Life Member of the National Ea-
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`gle Scout Association.
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`16. My curriculum vitae, the Appendix to this Declaration, contains fur-
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`ther details on my education and professional experience, as well as all of my pub-
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`lications for the past 10 years.
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`III. LEGAL STANDARDS USED IN MY ANALYSIS
`17.
`I am not a patent attorney, nor have I independently researched patent
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`law. Counsel for Petitioner have explained certain legal standards to me that I
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`have relied upon in forming my opinions set forth in this Declaration.
`
`A.
`18.
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`Prior art
`
`I have been informed that the law provides certain categories of infor-
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`mation, known as prior art, that may be used to render patent claims anticipated or
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`obvious. The reference materials I discuss in this declaration are prior art at least
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`because they would have been available to members of the public as of June 27,
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`1997, and are relevant to the subject matter of the (cid:1932)260 patent. The references I
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`discuss herein are from the same field of endeavor as the claimed invention (even
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`if they address a different problem), and/or are reasonably pertinent to the problem
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`Actavis - IPR2017-01100, Ex. 1034, p. 9 of 31
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`faced by the inventor (even if they are not in the same field of endeavor as the
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`claimed invention).
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`B.
`19.
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`Person of ordinary skill in the art
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`I understand that U.S. provisional application no. 60/051,021, to
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`which the ’260 patent claims priority, was filed on June 27, 1997, as stated on the
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`front of the patent under the title “Related U.S. Application Data.” For purposes of
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`my analysis, and without offering any opinion as to whether the (cid:1932)260 patent’s
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`claim to priority is valid or appropriate, I have used the June 27, 1997 date as the
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`relevant date for my analysis of the prior art.
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`20.
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`I understand that the assessment of the patentability of the claims of
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`the ’260 patent must be undertaken from the perspective of a hypothetical person
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`of ordinary skill in the art of the earliest priority date of the ’260 patent, i.e., a
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`skilled artisan. The person of ordinary skill in the art is a hypothetical person who
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`is presumed to have known the relevant art as of the effective filing date. Factors
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`that may be considered in determining the level of ordinary skill in the art may in-
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`clude, (i) type of problems encountered in the art, (ii) prior art solutions to those
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`problems, (iii) rapidity with which innovations are made, (iv) sophistication of the
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`technology, and (v) educational level of active workers in the field. I understand
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`that in a given case, every factor may not be present, and one or more factors may
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`predominate.
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`21.
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`I understand that the hypothetical person having ordinary skill in the
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`art to which the claimed subject matter pertains would, of necessity have the capa-
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`bility of understanding the scientific and engineering principles applicable to the
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`pertinent art. I further understand that a person of ordinary skill in the art is also a
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`person of ordinary creativity, not an automaton. In many cases a person of ordi-
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`nary skill will be able to fit the teachings of multiple patents or prior art references
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`together like pieces of a puzzle.
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`22. Based on these factors, my knowledge and expertise, and the prior art
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`to the ’260 patent (i.e., publications before June 27, 1997), I agree with Dr. Berk-
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`land’s opinion that a skilled artisan would include a person with an advanced de-
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`gree in chemistry, chemical engineering, pharmaceutics, pharmacy, or a related
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`discipline, and/or having experience formulating compounds for use in pharmaceu-
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`tical compositions, including nanoparticle suspensions, for several years. Further,
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`it is my opinion that the skilled artisan would know how to evaluate potential drug
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`therapies for in vitro and in vivo activity, including with biological assays.
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`23. Based on my qualifications and experience as of June 27, 1997, I
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`would have qualified as a person of ordinary skill in the art under this definition.
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`C. Obviousness
`24.
`I have been informed that, even if every element of a claim is not
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`found explicitly or implicitly in a single prior art reference, the claim may still be
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`unpatentable if the differences between the claim and the prior art are such that the
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`claim as a whole would have been obvious to a skilled artisan at the time the in-
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`vention was made. For purposes of obviousness, I understand that a skilled artisan
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`may rely on a single prior art reference, or multiple references in combination.
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`25.
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`I have been informed that the following four factors are considered
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`when determining whether a patent claim would have been obvious to a skilled ar-
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`tisan: (a) the level of ordinary skill in the art; (b) the scope and content of the prior
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`art; (c) the differences between the prior art and the claim; and (d) any “secondary
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`considerations” tending to prove nonobviousness. These secondary considerations,
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`which I understand are also called “objective indicia” or “objective evidence,” may
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`include factors such as: (i) the invention’s satisfaction of a long-felt unmet need in
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`the art; (ii) unexpected results of the invention; (iii) skepticism of the invention by
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`experts; (iv) teaching away from the invention in the prior art; (v) commercial suc-
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`cess of an embodiment of the invention; and (vi) praise by others for the invention.
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`I have also been informed that there must be an adequate nexus or connection be-
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`tween the evidence that is the basis for an asserted secondary consideration and the
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`scope of the invention claimed in the patent.
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`26.
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`I understand that when every limitation of a claim is disclosed in the
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`cited prior art references, the question of obviousness turns on whether a hypothet-
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`ical person of ordinary skill in the art would have been motivated to combine those
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`Actavis - IPR2017-01100, Ex. 1034, p. 12 of 31
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`teachings to derive the claimed subject matter with a reasonable expectation of
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`success. Further, I understand that obviousness does not require absolute predicta-
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`bility. Only a reasonable expectation that the beneficial result will be achieved is
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`necessary to show obviousness.
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`27.
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`I have been informed that a claimed invention can be rendered obvi-
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`ous by the combination of teachings in the prior art even if there is no explicit
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`teaching to combine them. Instead, any problem known in the field at the time of
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`the alleged invention can provide a sufficient rationale to combine the elements of
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`the prior art in the manner claimed in the patent.
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`28.
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`I have been informed that examples of sufficient rationales for estab-
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`lishing obviousness include the following:
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`(cid:120) combining prior art elements according to known methods to yield
`predictable results;
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`(cid:120) substituting known elements for other known elements to obtain
`predictable results;
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`(cid:120) using a known technique to improve similar devices, methods, or
`products in the same way;
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`(cid:120) choosing from a finite number of identified, predictable solutions that
`would be obvious to try; and
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`(cid:120) providing some teaching, suggestion, or motivation to modify the
`prior art reference or to combine teachings in prior art references to
`arrive at the claimed invention.
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`29.
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`I understand that where there is a range disclosed in the prior art, and
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`the claimed invention falls within that range, the burden of production falls upon
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`the patentee to come forward with evidence that (1) the prior art taught away from
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`the claimed invention; (2) there were new and unexpected results relative to the
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`prior art; or (3) there are other pertinent secondary considerations. For purposes of
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`this analysis, I understand that a prior art reference does not “teach away” from a
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`claimed invention unless it criticizes, discredits, or otherwise discourages investi-
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`gation into the invention claimed.
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`30.
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`I also understand that even if a claim limitation is missing from the
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`prior art, the missing limitation does not preclude obviousness if it merely recites a
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`latent or inherent characteristic or property of the claimed invention, e.g., a natural
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`result that necessarily flows from the other claim limitations, even if that result was
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`not appreciated by persons of skill in the art at the time of the invention.
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`IV. OBVIOUSNESS
`31.
`I have reviewed the ’260 patent, the exhibits cited herein, and the
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`Declaration of Cory J. Berkland, Ph.D., in Support of Petition for Inter Partes Re-
`
`view, which has been marked as EX1002 in this proceeding. I have also reviewed
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`Actavis - IPR2017-01100, Ex. 1034, p. 14 of 31
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`all of the exhibits cited in Dr. Berkland’s Declaration and listed in the “Exhibits
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`Cited” table at pages 5–6 of EX1002.
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`32. Based on my independent review, I agree with Dr. Berkland’s conclu-
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`sion that claims 1–27 of the (cid:1932)260 patent would have been obvious to a skilled arti-
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`san as of June 27, 1997, in view of the combined teachings of Desai (EX1003),
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`Shively (EX1005), Liversidge (EX1005), and Remington’s (EX1006). As I ex-
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`plain below, Dr. Berkland’s analysis and conclusions regarding the obviousness of
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`claims 1–27 of the (cid:1932)260 patent from the perspective of a hypothetical skilled arti-
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`san as of June 27, 1997, comport with my view of what a hypothetical skilled arti-
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`san would have known and done at the time and the actual practices and problem-
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`solving approaches of real-life skilled artisans who were working in the pharma-
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`ceutical industry as of that time.
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`33. Claim 1 of the (cid:1932)260 patent is generally directed to a pharmaceutical
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`formulation that “comprises nanoparticles comprising a solid core of paclitaxel and
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`an albumin coating,” and that further meets certain requirements regarding the
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`paclitaxel concentration, particle size, and stability of the albumin-paclitaxel nano-
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`particle formulation. EX1001, 67:32–42. I agree with Dr. Berkland that, as of
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`June 1997, albumin-paclitaxel nanoparticle formulations including the formulation
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`of claim 1 of the (cid:1932)260 patent were generally disclosed and covered by Desai, which
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`taught that a “method of delivering a poorly water-soluble drug such as taxol [i.e.,
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`paclitaxel] within a polymeric shell is to prepare a shell of polymeric material
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`around a solid drug core,” wherein the “preferred protein for use in the formation
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`of the polymeric shell is albumin.” EX1003, 15:53–55, 16:14–15.
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`34. The only differences between the broad disclosure of albumin-coated,
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`solid-core paclitaxel particles in Desai and claim 1 of the (cid:1932)260 patent is that the lat-
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`ter recites the specific requirements that the formulation (a) have a paclitaxel con-
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`centration of about 5 mg/ml to about 15 mg/ml, (b) have a particle size less than
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`400 nm, and (c) remain stable for at least three days under at least one of room
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`temperature or refrigerated conditions. EX1001, 67:32–42. As of June 1997,
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`based on my experience at a major pharmaceutical company, a skilled pharmaceu-
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`tical formulator looking to design, make, or optimize an aqueous suspension for-
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`mulation would have been aware that these parameters—(a) active drug concentra-
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`tion, (b) particle size, and (c) stability—had substantial and important effects on
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`the final formulation, and would have been motivated with a reasonable expecta-
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`tion of success to favorably adjust each of these parameters.
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`A.
`
`Increasing the concentration of active drug in pharmaceutical for-
`mulations was generally obvious and routine as of June 1997.
`35. First, as of June 1997, I and my pharmaceutical industry colleagues
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`frequently undertook projects to adjust and raise the concentration of active drug in
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`existing pharmaceutical formulations. It was generally considered desirable to in-
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`crease the concentration of active drug in a pharmaceutical preparation in order to
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`Actavis - IPR2017-01100, Ex. 1034, p. 16 of 31
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`reduce the volume that needs to be administered to a patient. Accordingly, I and
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`other formulators as of June 1997 agreed with the teaching in Desai that “the deliv-
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`ery of high doses of the pharmacologically active agent in relatively small vol-
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`umes” is generally desirable—including for injectable dosage forms, because
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`“[t]his minimizes patient discomfort at receiving large volumes of fluid.” EX1003,
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`5:22–27.
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`36. For example, in my own experience, I recall a proprietary project
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`prior to June 1997 in which my task was to increase the concentration of active
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`drug in an existing oral capsule dosage form, in order to reduce the size of the cap-
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`sule, because it was easier and more convenient for patients to ingest smaller cap-
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`sules. There was nothing unusual, surprising, or particularly difficult about this
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`project. On the contrary, it was considered obvious and routine at the time to opti-
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`mize a drug formulation to reduce the volume that was necessary for patients to in-
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`gest, to accomplish that goal by increasing the drug concentration in the dosage
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`form, and to be motivated for various reasons including patient compliance to ac-
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`complish that task. This task of increasing the drug concentration of an oral dos-
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`age form was analogous and conceptually similar in many respects to the increase
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`in drug concentration discussed in Desai and claimed in the (cid:1932)260 patent for an in-
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`jectable dosage form. In either case, the goal was to decrease the amount of phar-
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`maceutical preparation that was needed to deliver a given dose.
`
`
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`Actavis - IPR2017-01100, Ex. 1034, p. 17 of 31
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`
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`37. Similarly, on a number of occasions prior to June 1997, I also worked
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`on increasing the concentration of active drug in injectable dosage forms for toxi-
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`cology studies in animals, which frequently required formulations containing high
`
`doses of active drug in small infusion volumes—i.e., high concentrations of active
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`drug. Increasing the concentration of active drug in such formulations was gener-
`
`ally a routine and predictable task. I and other skilled formulators before June
`
`1997 generally had a reasonable expectation of success in modifying and optimiz-
`
`ing existing drug formulations to accomplish this goal.
`
`38. This motivation and reasonable expectation of success in increasing
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`the concentration of active drug for pharmaceutical compositions in the context of
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`other active ingredients would have applied equally to the albumin-paclitaxel for-
`
`mulation of Desai. Thus, it would have been obvious to a skilled artisan as of June
`
`1997 to optimize the concentration of paclitaxel in Desai’s albumin-paclitaxel for-
`
`mulations, as claimed in claim 1 of the (cid:1932)260 patent.
`
`B. Reducing the particle size of pharmaceutical formulations was gen-
`erally obvious and routine as of June 1997.
`39. Second, as of June 1997, I and my pharmaceutical industry colleagues
`
`routinely reduced the particle size of insoluble and poorly soluble drugs, both in
`
`suspensions and other dosage forms, in order to increase the bioavailability of the
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`insoluble drug. In this respect, my experience in the pharmaceutical industry as of
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`
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`Actavis - IPR2017-01100, Ex. 1034, p. 18 of 31
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`
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`June 1997 was in line with the teaching of Liversidge that “[b]ioavailability” de-
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`pends largely on the “dissolution rate of the drug,” and that “[i]t is known that the
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`rate of dissolution of a particulate drug can increase with increasing surface area,
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`i.e., decreasing particle size.” EX1028, 1:13–30 (incorporated by reference in
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`EX1005, 1:8–11). This teaching and understanding was relevant to paclitaxel,
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`which, as Desai taught, has “poor aqueous solubility.” EX1003, 1:41–46.
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`40.
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`In addition, it was routine for me and my colleagues to decrease the
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`particle size of drugs in colloidal suspensions in order to improve suspension sta-
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`bility. In this respect, my experience in the pharmaceutical industry as of June
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`1997 was in line with the teachings of Remington’s that, “[b]ecause of their small
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`size, colloidal dispersions undergo little or no sedimentation or creaming: Brown-
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`ian motion maintains the disperse particles in suspension.” EX1006, 20. This was
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`well known in the art as of June 1997.
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`41. As a general matter, there was nothing surprising, inventive, or unex-
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`pected about reducing the particle size of a poorly soluble drug in order to improve
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`its bioavailability or its physical stability in an aqueous suspension. On the con-
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`trary, reducing the particle size of such drugs was a routine optimization step, for
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`which I and other skilled formulators at the time generally had a reasonable expec-
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`tation of success. Indeed, a skilled artisan as of June 1997 had several methods
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`Actavis - IPR2017-01100, Ex. 1034, p. 19 of 31
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`available for reducing the particle sizes of pharmaceutical products, including mi-
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`cronization by milling or grinding, sonication, and high-pressure homogenization.
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`42. This general motivation and reasonable expectation of success in de-
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`creasing the particle size of a poorly soluble pharmaceutical composition in order
`
`to improve its bioavailability and suspension stability would have applied equally
`
`to the albumin-paclitaxel formulation of Desai. Thus, it would have been obvious
`
`to a skilled artisan as of June 1997 to optimize the particle size of Desai’s albumin-
`
`paclitaxel nanoparticle formulations, as claimed in claim 1 of the (cid:1932)260 patent.
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`C. Optimizing the physical stability of pharmaceutical suspensions
`was generally obvious and routine as of June 1997.
`43. Third, it was routine for me and my colleagues in the pharmaceutical
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`industry as of June 1997 to optimize drug formulations to remain stable for given
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`periods of time. Physical stability was and is an important part of a pharmaceutical
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`formulation, because it is desirable that pharmaceutical preparations remain usable
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`for longer, rather than shorter, periods of time. In my work on preparing concen-
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`trated drug formulations for injection in toxicology studies, for example, my task
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`was frequently to formulate suspensions with a given drug concentration that
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`would remain stable in suspension for a given number of days, or even multiple
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`weeks, in order to allow the toxicology study to be completed with the same batch
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`of pharmaceutical preparation, or for extended studies, to reduce the frequency at
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`which batch preparation was required.
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`Actavis - IPR2017-01100, Ex. 1034, p. 20 of 31
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`44.
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`I and other skilled formulators in the pharmaceutical industry as of
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`June 1997 were highly familiar with the concepts of stability discussed in Dr.
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`Berkland’s declaration, including the sedimentation or creaming of particles sus-
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`pended in aqueous media according to Stokes’ law; the displacement of such parti-
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`cles due to Brownian motion; and the use of surfactants or other surface modifiers
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`(including polymers such as albumin) to stabilize colloidal suspensions against
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`particle size changes due to phenomena such as Ostwald ripening. In this respect,
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`the knowledge and level of skill of a skilled artisan as of June 1997 was in line
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`with the teachings of these basic concepts in Remington’s, which was considered a
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`standard pharmaceutical textbook at the time. See EX1006, 30.
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`45.
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`I and my colleagues before June 1997 frequently stabilized colloidal
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`suspensions by a process of routine experimentation. For example, if I needed to
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`prepare a suspension that would remain stable for a given period of time, one tech-
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`nique I frequently used before June 1997 was to prepare multiple formulation
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`batches with progressively smaller particle sizes until I reached a size that allowed
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`the particles to remain in suspension for the desired period of time. For instance, I
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`would micronize a powdered drug product using a milling technique several times,
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`and set aside an equal amount of micronized product after each milling, which
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`would produce batches with progressively smaller particles. If needed, I would
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`also experiment with various well-known surfactants or surface modifiers. I would
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`Actavis - IPR2017-01100, Ex. 1034, p. 21 of 31
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`
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`then use routine stability tests to determine which batches provided the desired
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`level of physical stability—i.e., substantially no precipitation and substantially no
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`change in particle size—for the desired amount of time.
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`46. With respect to the three-day stability claimed by claim 1 of the (cid:1932)260
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`patent, I agree with Dr. Berkland’s opinions that such stability is an inherent prop-
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`erty of the claimed composition, and also would have been expected to a skilled ar-
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`tisan as of June 1997—even before he or she conducted any stability testing—
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`based on simple mathematical calculations using Stokes’ law and other well-
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`known equations outlined in Remington’s. EX1006, 30.
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`47.
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`Independently, however, it is also my opinion that a skilled artisan as
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`of June 1997 would have been motivated and able to obtain the three-day stability
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`claimed by claim 1 of the (cid:1
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