UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`CIPLA LTD.,
`Petitioner
`
`v.
`
`ABRAXIS BIOSCIENCE, LLC,
`Patent Owner
`
`
`
`Case IPR2018-00162
`Patent 7,820,788 B2
`
`
`
`DECLARATION OF CORY J. BERKLAND, Ph.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
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`I.
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`II.
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`TABLE OF CONTENTS
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`Page
`INTRODUCTION ........................................................................................ 7
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`BACKGROUND AND QUALIFICATIONS ............................................... 8
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`III. LEGAL STANDARDS USED IN MY ANALYSIS ................................... 11
`
`A.
`
`B.
`
`C.
`
`Prior art ............................................................................................. 12
`
`Person of ordinary skill in the art ...................................................... 12
`
`Anticipation ...................................................................................... 14
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`D. Obviousness ...................................................................................... 14
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`IV. THE ʼ788 PATENT .................................................................................... 17
`
`A.
`
`B.
`
`C.
`
`The alleged invention ........................................................................ 17
`
`Challenged claims ............................................................................. 22
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`Claim construction ............................................................................ 24
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`V.
`
`THE PRIOR ART ....................................................................................... 25
`
`A. Desai (EX1006) ................................................................................ 25
`
`B.
`
`C.
`
`Kadima (EX1004) ............................................................................. 34
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`Liversidge (EX1005) ........................................................................ 35
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`VI. ANTICIPATION ........................................................................................ 37
`
`A.
`
`Claims 1–9 and 11–12 of the ʼ788 patent are anticipated. ................. 37
`
`1.
`
`Claim 1 is anticipated by Desai. .............................................. 37
`
`a.
`
`b.
`
`c.
`
`Albumin-paclitaxel combination ................................... 38
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`Particle size of less than about 200 nm .......................... 38
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`Albumin-paclitaxel ratio of about 1:1 to 9:1.................. 40
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`2.
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`Claims 2–9 and 11–12 are anticipated by Desai. ..................... 40
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`B.
`
`The “starting” ratio of albumin to paclitaxel does not change. .......... 43
`
`VII. OBVIOUSNESS ......................................................................................... 47
`
`A.
`
`Claim 1 of the ʼ788 patent would have been obvious. ....................... 47
`
`1.
`
`Obviousness over Desai alone................................................. 47
`
`a.
`
`b.
`
`c.
`
`The albumin-paclitaxel ratio of about 9:1 falls
`within a range disclosed by Desai. ................................ 50
`
`A skilled artisan would have been motivated to
`lower Capxol’s 13.3:1 albumin-paclitaxel ratio. ............ 52
`
`A skilled artisan would have reasonably expected
`an albumin-paclitaxel ratio of 9:1 to retain
`stability. ........................................................................ 54
`
`2.
`
`Obviousness over Desai, Kadima, and Liversidge................... 58
`
`a.
`
`b.
`
`Kadima and Liversidge also disclose ranges of
`albumin-paclitaxel ratios, including about 9:1. .............. 58
`
`Kadima teaches additional reasons to lower a
`13.3:1 ratio of albumin to paclitaxel to about 9:1. ......... 60
`
`B.
`
`C.
`
`The other challenged claims would have been obvious. .................... 63
`
`There are no relevant secondary considerations indicating that
`the challenged claims would not have been obvious. ........................ 66
`
`1.
`
`2.
`
`The allegedly “unexpected” cell-binding results lack a
`nexus to the ʼ788 patent and would have been expected.......... 68
`
`The allegedly “unexpected” clinical data did not
`compare the closest prior art and would have been
`expected. ................................................................................. 71
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`VIII. CONCLUSION .......................................................................................... 75
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`1001
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`1004
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`1005
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`1006
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`1007
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`1009
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`1010
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`1011
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`1017
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`1018
`
`EXHIBITS CITED
`
`EX
`
`Description
`
`Desai et al., U.S. Patent No. 7,820,788 B2, “Compositions and
`Methods of Delivery of Pharmacological Agents” (issued Oct. 26,
`2010) (the “ʼ788 patent”)
`
`Kadima et al., WO 00/06152, “Pharmaceutically Acceptable
`Composition Comprising an Aqueous Solution of Paclitaxel and
`Albumin” (published Feb. 10, 2000) (“Kadima”)
`
`Liversidge et al., U.S. Patent No. 5,399,363, “Surface Modified
`Anticancer Nanoparticles” (issued Mar. 21, 1995) (“Liversidge”)
`
`Desai et al., WO 1999/000113, “Novel Formulations of
`Pharmacological Agents, Methods for the Preparation thereof and
`Methods for the Use thereof” (published Jan. 7, 1999) (“Desai”)
`
`Li et al., “Fluorescein Binding to Normal Human Serum Proteins
`Demonstrated by Equilibrium Dialysis,” Arch Ophalmol. vol.
`100, 484–87 (March 1982)
`
`FDA Guideline on Sterile Drug Products Produced by Aseptic
`Processing (June 1987, reprinted June 1991 and Feb. 1997)
`
`EMEA Guidance on Manufacture of the Finished Dosage Form
`(April 1996)
`
`Elan Pharma Int’l Ltd. v. Abraxis BioScience, Inc., Judgment and
`Verdict Form, No. 06-438-GMS, Dkt. 614 (D. Del. June 16,
`2008)
`
`Damascelli, B et al. “Intraarterial chemotherapy with
`polyoxyethylated castor oil free paclitaxel, incorporated in
`albumin nanoparticles (ABI-007),” Cancer 2001 Nov;
`92(10):2592–2602 (“Damascelli”)
`
`Ibrahim et al., “Phase I and pharmacokinetic study of ABI-007, a
`Cremophor-free, protein-stabilized, nanoparticle formulation of
`paclitaxel,” Clin Cancer Res. 2002 May; 8:1038–44 (“Ibrahim”)
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`1023
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`U.S. Application No. 11/553,339, Declaration of Neil P. Desai
`Pursuant to 37 C.F.R. § 1.132 (dated Apr. 14, 2010)
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`I, Cory J. Berkland, Ph.D., hereby declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am currently appointed as the Solon E. Summerfield Distinguished
`
`Professor in the Department of Pharmaceutical Chemistry and the Department of
`
`Chemical and Petroleum Engineering at the University of Kansas. I have been
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`retained by Petitioner Cipla Ltd. in connection with its request for inter partes
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`review of U.S. Patent No. 7,820,788 (“the ’788 patent”). A copy of the ’788 patent
`
`has been marked EX1001. I have reviewed and am familiar with the ’788 patent.
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`Generally, it describes and claims pharmaceutical compositions comprising the
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`anticancer drug paclitaxel bound to the protein albumin and formulated as
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`nanoparticles, and methods of using such compositions to treat diseases including
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`cancer.
`
`2.
`
`I have been asked to provide my opinions regarding the patentability
`
`of claims 1–12 of the ’788 patent (the “challenged claims”). This declaration
`
`includes a discussion of my background and qualifications, the legal standards
`
`used in my analysis, an overview of the ʼ788 patent from the perspective of a
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`person of ordinary skill in the art at the time that the patent was filed (a “skilled
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`artisan”), and my opinions regarding the patentability of the challenged claims.
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`3.
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`I am being compensated for my work in this proceeding at my
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`standard 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.
`
`4.
`
`As set forth more fully below, it is my opinion that claims 1–9 and
`
`11–12 of the ʼ788 patent are anticipated by a previously published international
`
`patent application, WO 99/00113 to Desai et al. (“Desai”) (EX1006). Additionally,
`
`it is my opinion that claims 1–12 would have been obvious to a skilled artisan in
`
`view of Desai, either alone or in combination with another previously published
`
`international patent application, WO 00/06152 to Kadima et al. (“Kadima”)
`
`(EX1004), and a previously issued patent, U.S. Patent No. 5,399,363 to Liversidge
`
`et al. (EX1005). The bases for my opinions are set forth in this declaration.
`
`II. BACKGROUND AND QUALIFICATIONS
`
`5.
`
`I received a B.S. in Chemical Engineering from Iowa State University
`
`in December 1998, and an M.S. in Chemical Engineering from the University of
`
`Illinois in May 2001. I received a Ph.D. in Chemical and Biomolecular
`
`Engineering from the University of Illinois in May 2003. From 2004 to 2009, I was
`
`an Assistant Professor in the Department of Chemical and Petroleum Engineering
`
`and the Department of Pharmaceutical Chemistry at The University of Kansas.
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`Since 2009, I have been a Professor in these two departments with tenure.
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`6. My areas of expertise include drug formulation using particulates and
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`powders, microencapsulation of pharmaceuticals, and controlled-release drug
`
`delivery. Through collaborations with industrial and academic partners, and close
`
`relationships with other experts in controlled release, I have developed
`
`considerable expertise in the formulation and characterization of particles and
`
`powders.
`
`7.
`
`The primary focus of my research has been the design and analysis of
`
`drug delivery approaches for improving the performance of therapeutic agents. I
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`have worked on particles and aspects of pharmaceutical formulation and delivery,
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`including nanoparticle formulations, since 1997. Among other areas, I have
`
`conducted research aimed to elucidate important parameters (e.g., particle size,
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`morphology, surface chemistry) for controlling the release or dissolution of drugs.
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`8. My research group at the University of Kansas currently works on
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`formulation approaches designed to modify drug dissolution kinetics and to control
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`drug release rates. My work has encompassed microencapsulation, nanoparticle
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`formulations, and polymers for delivering small molecules, proteins, and DNA. I
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`have expertise in analyzing the performance of such formulations and in applying
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`mathematical models to elucidate the underlying phenomena controlling the
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`dissolution or release of such drugs. I have also designed and taught classes on
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`drug delivery that focus primarily on drug transport in pharmaceutical formulations
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`and through different biological barriers in the human body.
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`9.
`
`I have been a member of various professional organizations, including
`
`the American Institute of Chemical Engineers, the American Chemical Society, the
`
`American Association of Pharmaceutical Scientists, and the Controlled Release
`
`Society. I am a Fellow of the American Institute of Medical and Biological
`
`Engineering, and have received honors and awards from various national and
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`international organizations, including the Leading Light Award from the
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`University of Kansas, the Nagai Foundation Distinguished Lectureship, and the
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`Controlled Release Society Young Investigator Award. Other awards and honors I
`
`have received are listed in my CV, which is attached as the Appendix to this
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`declaration.
`
`10.
`
`I have sat on editorial and scientific advisory boards of scientific
`
`journals including Therapeutic Delivery, the Journal of Pharmaceutical Sciences,
`
`and the Journal of Pharmaceutical Innovation.
`
`11.
`
`I have published on such topics as drug delivery, nanoparticle
`
`formulation, surface modification, controlled release, and biomaterials. I have
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`published approximately 150 articles in peer-reviewed journals, three book
`
`chapters, and have been named as a co-inventor on more than 50 U.S. patents or
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`applications.
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`12.
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`I have served as a consultant in the area of drug formulation and
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`delivery for U.S. and international companies, and have testified as an expert
`
`witness in the area of drug formulation and delivery in several trials. My
`
`publications, including publications authored within the past ten years, are listed in
`
`my CV.
`
`13.
`
`I have been involved in the development of numerous pharmaceutical
`
`products, both in my capacity at the University of Kansas and as a company
`
`founder. For instance, I am a co-founder of four companies: Orbis Biosciences,
`
`Inc., Savara Pharmaceuticals, Inc., Orion BioScience, Inc., and Bond Biosciences,
`
`Inc. I am the acting Chief Scientific Officer at Orbis Biosciences. Orbis develops
`
`controlled-release delivery systems, including parenteral, injectable formulations. I
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`was also a Member of the Scientific Advisory Board and the former Chief
`
`Technology Officer for Savara Pharmaceuticals, Inc. in Austin, Texas. Savara
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`specializes in the development of pulmonary drug products. I am also the
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`Chairperson of the Board of Directors of Orion BioScience, Inc., which develops
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`injectable immune-specific therapies for autoimmune diseases.
`
`III. LEGAL STANDARDS USED IN MY ANALYSIS
`
`14.
`
`I am not a patent attorney, nor have I independently researched patent
`
`law. Counsel for Petitioner have explained certain legal standards to me that I have
`
`relied upon in forming my opinions set forth in this Declaration.
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`A.
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`15.
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`Prior art
`
`I have been informed that the law provides certain categories of
`
`information, known as prior art, that may be used to render patent claims
`
`anticipated or obvious. The reference materials I discuss in this declaration are
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`prior art at least because they would have been available to members of the public
`
`as of December 9, 2002, and are relevant to the subject matter of the ʼ788 patent.
`
`The references I discuss herein are from the same field of endeavor as the claimed
`
`invention (even if they address a different problem), and/or are reasonably
`
`pertinent to the problem faced by the inventor (even if they are not in the same
`
`field of endeavor as the claimed invention).
`
`B.
`
`Person of ordinary skill in the art
`
`16.
`
`I understand that U.S. provisional application no. 60/432,317, to
`
`which the ’788 patent claims priority, was filed on December 9, 2002, as stated on
`
`the front of the patent under the title “Related U.S. Application Data.” For
`
`purposes of my analysis, and without offering any opinion as to whether the ʼ788
`
`patent’s claim to priority is valid or appropriate, I have used the December 9, 2002
`
`date as the relevant date for my analysis of the prior art.
`
`17.
`
`I understand that the assessment of the patentability of the claims of
`
`the ’788 patent must be undertaken from the perspective of a hypothetical person
`
`of ordinary skill in the art of the earliest priority date of the ’788 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
`
`include, (i) type of problems encountered in the art, (ii) prior art solutions to those
`
`problems, (iii) rapidity with which innovations are made, (iv) sophistication of the
`
`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.
`
`18.
`
`I understand that the hypothetical person having ordinary skill in the
`
`art to which the claimed subject matter pertains would, of necessity have the
`
`capability of understanding the scientific and engineering principles applicable to
`
`the pertinent art. I further understand that a person of ordinary skill in the art is also
`
`a person of ordinary creativity, not an automaton. In many cases a person of
`
`ordinary skill will be able to fit the teachings of multiple patents or prior art
`
`references together like pieces of a puzzle.
`
`19. Based on these factors, my knowledge and expertise, and the prior art
`
`to the ’788 patent (i.e., publications before December 9, 2002), it is my opinion
`
`that a skilled artisan would include a person with an advanced degree in chemistry,
`
`chemical engineering, pharmaceutics, pharmacy, or a related discipline, and/or
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`having experience formulating compounds for use in pharmaceutical compositions,
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`including nanoparticle suspensions, for several years. Further, it is my opinion that
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`the skilled artisan would know how to evaluate potential drug therapies for in vitro
`
`and in vivo activity, including with biological assays.
`
`C. Anticipation
`
`20.
`
`I have been informed that a claim is not patentable if a single prior art
`
`reference describes every element of the claim, either expressly or inherently, to a
`
`skilled artisan. I understand that this principle is called “anticipation.” I have also
`
`been informed that, to anticipate a patent claim, the prior art reference does not
`
`need to use the same words as the claim. However, it must describe the
`
`requirements of the claim with sufficient clarity that a skilled artisan would have
`
`been able to make and use the claimed invention based on that single prior art
`
`reference.
`
`21.
`
`In addition, I have been informed and understand that, in order to
`
`establish that an element of a claim is “inherent” in the disclosure of a prior art
`
`reference, it must be clear to one skilled in the art that the missing element is an
`
`inevitable part of what is explicitly described in the prior art reference, and that it
`
`would have been recognized as necessarily present by a skilled artisan.
`
`D. Obviousness
`
`22.
`
`I have been informed that, even if every element of a claim is not
`
`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
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`invention was made. For purposes of obviousness, I understand that a skilled
`
`artisan may rely on a single prior art reference, or multiple references in
`
`combination.
`
`23.
`
`I have been informed that the following four factors are considered
`
`when determining whether a patent claim would have been obvious to a skilled
`
`artisan: (a) the level of ordinary skill in the art; (b) the scope and content of the
`
`prior art; (c) the differences between the prior art and the claim; and (d) any
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`“secondary considerations” tending to prove nonobviousness. These secondary
`
`considerations, which I understand are also called “objective indicia” or “objective
`
`evidence,” may include factors such as: (i) the invention’s satisfaction of a long-
`
`felt unmet need in the art; (ii) unexpected results of the invention; (iii) skepticism
`
`of the invention by experts; (iv) teaching away from the invention in the prior art;
`
`(v) commercial success of an embodiment of the invention; and (vi) praise by
`
`others for the invention. I have also been informed that there must be an adequate
`
`nexus or connection between the evidence that is the basis for an asserted
`
`secondary consideration and the scope of the invention claimed in the patent.
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`24.
`
`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
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`hypothetical person of ordinary skill in the art would have been motivated to
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`combine those teachings to derive the claimed subject matter with a reasonable
`
`expectation of success. Further, I understand that obviousness does not require
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`absolute predictability. Only a reasonable expectation that the beneficial result will
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`be achieved is necessary to show obviousness.
`
`25.
`
`I have been informed that a claimed invention can be rendered
`
`obvious by the combination of teachings in the prior art even if there is no explicit
`
`teaching to combine them. Instead, any problem known in the field at the time of
`
`the alleged invention can provide a sufficient rationale to combine the elements of
`
`the prior art in the manner claimed in the patent.
`
`26.
`
`I have been informed that examples of sufficient rationales for
`
`establishing obviousness include the following:
`
`•
`
`•
`
`•
`
`•
`
`combining prior art elements according to known methods to
`
`yield predictable results;
`
`substituting known elements for other known elements to
`
`obtain predictable results;
`
`using a known technique to improve similar devices, methods,
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`or products in the same way;
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`choosing from a finite number of identified, predictable
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`solutions that would be obvious to try; and
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`•
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`providing some teaching, suggestion, or motivation to modify
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`the prior art reference or to combine teachings in prior art
`
`references to arrive at the claimed invention.
`
`27.
`
`I understand that where there is a range disclosed in the prior art, and
`
`the claimed invention falls within that range, the burden of production falls
`
`upon the patentee to come forward with evidence that (1) the prior art taught away
`
`from the claimed invention; (2) there were new and unexpected results relative to
`
`the prior art; or (3) there are other pertinent secondary considerations. For purposes
`
`of this analysis, I understand that a prior art reference does not “teach away” from
`
`a claimed invention unless it criticizes, discredits, or otherwise discourages
`
`investigation into the invention claimed.
`
`IV. THE ʼ788 PATENT
`
`A. The alleged invention
`
`28. The ’788 patent is entitled “Compositions and Methods of Delivery of
`
`Pharmacological Agents,” and generally relates to pharmaceutical compositions
`
`comprising paclitaxel and a pharmaceutically acceptable carrier, such as human
`
`serum albumin, and methods of treating diseases, including cancer, by
`
`administering such compositions. EX1001, cover, abst.
`
`29. As background, the ’788 patent explains that “many drugs for
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`parenteral use, especially those administered intravenously, cause undesirable side
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`effects” that are “administration related.” Id. at 1:27–31. “Many of these drugs,”
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`the patent explains, “are insoluble in water, and are thus formulated with
`
`solubilizing agents, surfactants, solvents, and/or emulsifiers that are irritating,
`
`allergenic, or toxic when administered to patients.” Id. at 1:31–34. The patent goes
`
`on to state that known “drugs that exhibit administration-associated side effects
`
`include, for example, Taxol (paclitaxel).” Id. at 1:52–54.
`
`30. Paclitaxel, which as the ’788 patent acknowledges is sold under the
`
`brand name Taxol, was known to be “active against carcinomas of the ovary,
`
`breast, lung, esophagus and head and neck.” Id. at 4:31–33. “Taxol, however, has
`
`been shown to induce toxicities associated with administration.” Id. at 4:33–34.
`
`“Because paclitaxel is poorly soluble in water, cremophor [i.e., polyethoxylated
`
`castor oil] typically is used as a solvent, requiring large infusion volumes and
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`special tubing and filters.” Id. at 4:37–39. “Cremophor is associated with side
`
`effects that can be severe, including anaphylaxis and other hypersensitivity
`
`reactions that can require pretreatment” with various drugs. Id. at 4:39–43.
`
`31. The ’788 patent discloses compositions and methods that supposedly
`
`reduce or eliminate the cremophor-related side effects that had been associated
`
`with the administration of paclitaxel. Id. at 2:34–45. Specifically, the patent
`
`discloses compositions comprising paclitaxel together with a pharmaceutical
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`carrier, which is preferably human serum albumin. Id. at 2:54–58. “Preferably, the
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`formulation is essentially free of cremophor,” thus avoiding its “side effects that
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`can be severe.” Id. at 11:67–12:6.
`
`32. Human serum albumin is a highly soluble protein, and is the most
`
`abundant protein in human blood plasma. Id. at 5:15–18. The ’788 patent
`
`acknowledges that the intravenous use of human serum albumin solution was
`
`known in the art. Id. at 5:21–22. Human serum albumin has “multiple hydrophobic
`
`binding sites,” allowing it to bind to hydrophobic, water-insoluble drugs like
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`paclitaxel. Id. at 5:29–46. The ’788 patent theorizes that “the inclusion of proteins
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`such as albumin in the inventive pharmaceutical compositions results in a
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`reduction in side effects associated with administration of the pharmaceutical
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`composition that is due, at least in part, to the binding of human serum albumin to
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`any free drug that is present in the composition.” Id. at 5:52–58.
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`33. The ’788 patent states generally that “[t]he amount of albumin
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`included in the pharmaceutical composition of the present invention will vary
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`depending on the pharmaceutical active agent, other excipients, and the route and
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`site of intended administration,” so long as “the amount of albumin included in the
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`composition is an amount effective to reduce one or more side effects the active
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`pharmaceutical agent due to the [ ] administration of the inventive pharmaceutical
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`composition to a human.” Id. at 5:59–66. In general, “compositions with lower
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`amounts of albumin are preferred as this can greatly reduce cost,” among other
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`alleged reasons. Id. at 35:34–36.
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`34. The ’788 patent discloses a wide range of albumin-paclitaxel ratios for
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`its compositions: “Exemplary ranges for protein-drug preparations are protein to
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`drug ratios (w/w) of 0.01:1 to about 100:1. More preferably, the ratios are in the
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`range of 0.02:1 to about 40:1.” Id. at 11:58–61. As the patent explains, “the ratio of
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`protein to pharmaceutical agent will have to be optimized for different protein and
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`pharmaceutical agent combinations.” Id. at 11:61–63. The patent then discloses
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`certain “preferred” ranges, and concludes by stating: “Most preferably, the ratio is
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`about 1:1 to about 9:1.” Id. at 11:66–67.
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`35. The patent includes examples of various pharmaceutical
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`compositions. None of these examples discloses a formulation with an albumin-
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`paclitaxel ratio of about 9:1. The only examples that mention the ratio of albumin
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`to paclitaxel disclose ratios of 27:1, 4.5:1, and 10:1, and each of these examples
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`makes clear that the ratio is calculated based on the ingredients used to make the
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`composition, and/or that the ratio of the final composition remains the same as the
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`ratio of the starting ingredients. See id. at 35:44–47 (Example 47); 36:10–13
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`(Example 48); 36:42–61 (Example 49).
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`36. For instance, Example 47 states: “30 mg of paclitaxel was dissolved in
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`3.0 ml methylene chloride. The solution was added to 27.0 ml of human serum
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`albumin solution (3% w/v) (corresponding to a ratio of albumin to paclitaxel of
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`27).” Id. at 35:44–47. Likewise, Example 48 states: “300 mg of paclitaxel was
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`dissolved in 3.0 ml methylene chloride. The solution was added to 27 ml of human
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`serum albumin solution (5% w/v) (corresponding to a ratio of albumin to paclitaxel
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`of 4.5).” Id. at 36:10–13. In both of these examples, the recited ratio is based on the
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`starting materials used to make the composition.
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`37. Similarly, Example 49 states: “135 mg of paclitaxel was dissolved in
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`3.0 ml methylene chloride. The solution was added to 27 ml of human serum
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`albumin solution (5% w/v).” Id. at 36:42–44. In other words, 135 mg of paclitaxel
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`was combined with 1,350 mg of albumin (27 ml of 5% w/v solution),
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`corresponding to a 10:1 ratio. After reciting several process steps, Example 49
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`states: “The calculated ratio (w/w) of albumin to paclitaxel in this invention
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`composition is approximately 10.” Id. at 36:42–61. Apparently, therefore, the
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`albumin-paclitaxel ratio of Example 49 was either “calculated” based on the
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`starting materials, or measured after the process steps were completed, at which
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`point the ratio remained the same as the ratio of starting materials.
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`38. There is no suggestion in the ’788 patent that the ratio of albumin to
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`paclitaxel materially changes during the manufacturing process. Nor is there any
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`disclosed assay or discussion of how to measure or predict the ratio of albumin to
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`paclitaxel in the final pharmaceutical composition.
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`39. The ’788 patent provides that the claimed compositions can be
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`prepared as nanoparticles. Id. at 9:33–35. Several examples in the patent describe
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`nanoparticle formulations. In each one, the example provides that “the typical
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`average diameter” of the particles ranges from “50–220 nm (Z-average, Malvern
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`Zetasizer).” See id. at 14:62–63 (Example 1); 15:23–25 (Example 2); 16:1–3
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`(Example 4); 16:28–31 (Example 5); 16:58–61 (Example 6); 17:22–24 (Example
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`7); 17:58–60 (Example 8); 18:26–28 (Example 9); 18:58–61 (Example 10); 19:19–
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`21 (Example 11); 19:44–45; (Example 12); 19:63–65 (Example 13); 20:21–23
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`(Example 14); 35:57–59 (Example 47); 36:23–25 (Example 48); 36:54–56
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`(Example 49). The “Z-average” is one possible measurement of particle diameter,
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`and a “Malvern Zetasizer” is a particular device that is capable of determining that
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`measurement.
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`B. Challenged claims
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`40. Claim 1 of the ʼ788 patent is directed to a pharmaceutical composition
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`for injection comprising paclitaxel and albumin, formulated as particles having a
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`particle size of less than about 200 nm, “wherein the weight ratio of albumin to
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`paclitaxel in the composition is about 1:1 to about 9:1.”
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`41. Claim 2 depends from claim 1 (i.e., it incorporates all the limitations
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`of claim 1) and further requires that the albumin is human serum albumin.
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`42. Claim 3 depends from claim 1 and further requires that the
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`composition is free of Cremophor.
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`43. Claim 4 is directed to a method of treating cancer, arthritis, or
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`restenosis by administering the composition of claim 1.
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`44. Claim 5 depends from claim 4 and requires that the disease treated is
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`cancer.
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`45. Claim 6 depends from claim 4 and requires that the disease treated is
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`arthritis.
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`46. Claim 7 depends from claim 4 and requires that the disease treated is
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`restenosis.
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`47. Claim 8 depends from claim 4 and further requires that the
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`composition is administered “intravenously, intraarterially, intrapulmonarily,
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`orally, by inhalation, intravesicularly, intramuscularly, intratracheally,
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`subcutaneously, intraocularly, intrathecally, or transdermally.”
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`48. Claim 9 depends from claim 8 and specifies that the method of
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`administration is intravenous.
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`49. Claim 10 depends from claim 1 and specifies that “the ratio (w/w) of
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`albumin to the paclitaxel in the pharmaceutical composition is about 1:1 to about
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`5:1.”
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`50. Claim 11 depends from claim 1 and specifies that “the ratio (w/w) of
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`albumin to the paclitaxel in the pharmaceutical composition is 1:1 to 9:1.”
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`51. Claim 12 depends from claim 1 and specifies that “the ratio (w/w) of
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`albumin to the paclitaxel in the pharmaceutical composition is about 9:1.”
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`C. Claim construction
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`52. Counsel for Petitioner has informed me that in proceedings before the
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`Patent Office, the claims of a patent must be construed to have their broadest
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`reasonable interpretation in light of the specification and prosecution history of the
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`patent. Furthermore, I understand that, in general, the broadest reasonable
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`interpretation of the claims of a patent corresponds to their plain and ordinary
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`meaning from the perspective of a skilled artisan.
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`53.
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`In my opinion, a skilled artisan would have understood that the
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`broadest reasonable interpretation of the terms “weight ratio of albumin to
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`paclitaxel in the composition” and “ratio (w/w) of albumin to the paclitaxel in the
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`pharmaceutical composition” in the challenged clai