UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`ACTAVIS LLC,
`Petitioner
`
`v.
`
`ABRAXIS BIOSCIENCE, LLC,
`Patent Owner
`
`
`Case IPR2017-01101
`Patent 7,820,788 B2
`
`
`
`DECLARATION OF CORY J. BERKLAND, Ph.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
`
`
`
`
`
`
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`TABLE OF CONTENTS
`
`Page
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`BACKGROUND AND QUALIFICATIONS ................................................. 2
`
`III. LEGAL STANDARDS USED IN MY ANALYSIS ...................................... 5
`
`A.
`
`B.
`
`C.
`
`Prior art .................................................................................................. 5
`
`Person of ordinary skill in the art .......................................................... 6
`
`Anticipation ........................................................................................... 7
`
`D. Obviousness ........................................................................................... 8
`
`IV. THE ʼ788 PATENT ....................................................................................... 11
`
`A.
`
`B.
`
`C.
`
`The alleged invention .......................................................................... 11
`
`Challenged claims ............................................................................... 16
`
`Claim construction .............................................................................. 17
`
`V.
`
`THE PRIOR ART .......................................................................................... 19
`
`A. Desai (EX1006) ................................................................................... 19
`
`B.
`
`C.
`
`Kadima (EX1004) ............................................................................... 27
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`Liversidge (EX1005) ........................................................................... 29
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`VI. ANTICIPATION ........................................................................................... 31
`
`A.
`
`Claims 1–9 and 11–12 of the ʼ788 patent are anticipated. .................. 31
`
`1.
`
`Claim 1 is anticipated by Desai. ............................................... 31
`
`a.
`b.
`c.
`
`Albumin-paclitaxel combination .................................... 31
`Particle size of less than about 200 nm .......................... 32
`Albumin-paclitaxel ratio of about 1:1 to 9:1 .................. 33
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`2.
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`Claims 2–9 and 11–12 are anticipated by Desai. ...................... 34
`
`B.
`
`The “starting” ratio of albumin to paclitaxel does not change. ........... 37
`
`VII. OBVIOUSNESS ............................................................................................ 40
`
`A.
`
`Claim 1 of the ʼ788 patent would have been obvious. ........................ 41
`
`1.
`
`Obviousness over Desai alone .................................................. 41
`
`a.
`
`b.
`
`c.
`
`The albumin-paclitaxel ratio of about 9:1 falls
`within a range disclosed by Desai. ................................. 44
`A skilled artisan would have been motivated to
`lower Capxol’s 13.3:1 albumin-paclitaxel ratio. ............ 46
`A skilled artisan would have reasonably expected an
`albumin-paclitaxel ratio of 9:1 to retain stability. .......... 48
`Obviousness over Desai, Kadima, and Liversidge ................... 51
`
`2.
`
`B.
`
`C.
`
`a.
`
`Kadima and Liversidge also disclose ranges of
`albumin-paclitaxel ratios, including about 9:1. .............. 51
`Kadima teaches additional reasons to lower a 13.3:1
`ratio of albumin to paclitaxel to about 9:1. ..................... 53
`The other challenged claims would have been obvious. ..................... 56
`
`b.
`
`There are no relevant secondary considerations indicating that
`the challenged claims would not have been obvious. ......................... 59
`
`1.
`
`2.
`
`The allegedly “unexpected” cell-binding results lack a
`nexus to the ʼ788 patent and would have been expected. ......... 61
`
`The allegedly “unexpected” clinical data did not compare
`the closest prior art and would have been expected. ................ 64
`
`VIII. CONCLUSION .............................................................................................. 68
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`
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`EXHIBITS CITED
`
`Description
`
`EX
`
`1001
`
`1004
`
`1005
`
`1006
`
`1007
`
`1009
`
`1010
`
`1011
`
`1017
`
`1018
`
`1023
`
`
`
`Desai et al., U.S. Patent No. 7,820,788 B2, “Compositions and Meth-
`ods of Delivery of Pharmacological Agents” (issued Oct. 26, 2010)
`(the “ʼ788 patent”)
`Kadima et al., WO 00/06152, “Pharmaceutically Acceptable Compo-
`sition 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 An-
`ticancer Nanoparticles” (issued Mar. 21, 1995) (“Liversidge”)
`Desai et al., WO 1999/000113, “Novel Formulations of Pharmaco-
`logical 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 Pro-
`cessing (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 polyoxyethyl-
`ated 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”)
`U.S. Application No. 11/553,339, Declaration of Neil P. Desai Pur-
`suant 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 re-
`
`tained by Petitioner Actavis LLC in connection with its request for inter partes re-
`
`view 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.
`
`Generally, it describes and claims pharmaceutical compositions comprising the an-
`
`ticancer drug paclitaxel bound to the protein albumin and formulated as nanoparti-
`
`cles, and methods of using such compositions to treat diseases including 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 in-
`
`cludes 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 person of
`
`ordinary skill in the art at the time that the patent was filed (a “skilled artisan”),
`
`and my opinions regarding the patentability of the challenged claims.
`
`3.
`
`I am being compensated for my work in this proceeding at my stand-
`
`ard hourly consulting rate of $500.00 per hour. My compensation is in no way
`
`contingent on the substance of my opinions or the outcome of this proceeding.
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`4.
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`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 pa-
`
`tent 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 in-
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`ternational 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 Engineer-
`
`ing from the University of Illinois in May 2003. From 2004 to 2009, I was an As-
`
`sistant Professor in the Department of Chemical and Petroleum Engineering and
`
`the Department of Pharmaceutical Chemistry at The University of Kansas. Since
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`2009, I have been a Professor in these two departments with tenure.
`
`6. My areas of expertise include drug formulation using particulates and
`
`powders, microencapsulation of pharmaceuticals, and controlled-release drug de-
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`
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`livery. Through collaborations with industrial and academic partners, and close re-
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`lationships 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
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`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 con-
`
`ducted research aimed to elucidate important parameters (e.g., particle size, mor-
`
`phology, surface chemistry) for controlling the release or dissolution of drugs.
`
`8. My research group at the University of Kansas currently works on for-
`
`mulation approaches designed to modify drug dissolution kinetics and to control
`
`drug release rates. My work has encompassed microencapsulation, nanoparticle
`
`formulations, and polymers for delivering small molecules, proteins, and DNA. I
`
`have expertise in analyzing the performance of such formulations and in applying
`
`mathematical models to elucidate the underlying phenomena controlling the disso-
`
`lution or release of such drugs. I have also designed and taught classes on drug de-
`
`livery that focus primarily on drug transport in pharmaceutical formulations and
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`through different biological barriers in the human body.
`
`9.
`
`I have been a member of various professional organizations, including
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`the American Institute of Chemical Engineers, the American Chemical Society, the
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`
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`American Association of Pharmaceutical Scientists, and the Controlled Release
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`Society. I am a Fellow of the American Institute of Medical and Biological Engi-
`
`neering, and have received honors and awards from various national and interna-
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`tional organizations, including the Leading Light Award from the University of
`
`Kansas, the Nagai Foundation Distinguished Lectureship, and the Controlled Re-
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`lease Society Young Investigator Award. Other awards and honors I have received
`
`are listed in my CV, which is attached as the Appendix to this declaration.
`
`10.
`
`I have sat on editorial and scientific advisory boards of scientific jour-
`
`nals 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 formu-
`
`lation, surface modification, controlled release, and biomaterials. I have published
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`approximately 150 articles in peer-reviewed journals, three book chapters, and
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`have been named as a co-inventor on more than 50 U.S. patents or applications.
`
`12.
`
`I have served as a consultant in the area of drug formulation and de-
`
`livery 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, in-
`
`cluding 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
`
`
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`founder. For instance, I am a co-founder of four companies: Orbis Biosciences,
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`Inc., Savara Pharmaceuticals, Inc., Orion BioScience, Inc., and Bond Biosciences,
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`Inc. I am the acting Chief Scientific Officer at Orbis Biosciences. Orbis develops
`
`controlled-release delivery systems, including parenteral, injectable formulations.
`
`I was also a Member of the Scientific Advisory Board and the former Chief Tech-
`
`nology Officer for Savara Pharmaceuticals, Inc. in Austin, Texas. Savara special-
`
`izes in the development of pulmonary drug products. I am also the Chairperson of
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`the Board of Directors of Orion BioScience, Inc., which develops injectable im-
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`mune-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.
`
`A.
`15.
`
`Prior art
`
`I have been informed that the law provides certain categories of infor-
`
`mation, known as prior art, that may be used to render patent claims anticipated or
`
`obvious. The reference materials I discuss in this declaration are 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
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`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.
`16.
`
`Person of ordinary skill in the art
`
`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 pur-
`
`poses of my analysis, and without offering any opinion as to whether the ʼ788 pa-
`
`tent’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
`
`skilled artisan. The person of ordinary skill in the art is a hypothetical person who
`
`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-
`
`clude, (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
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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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`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 capa-
`
`bility 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 ordi-
`
`nary skill will be able to fit the teachings of multiple patents or prior art references
`
`together like pieces of a puzzle.
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`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,
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`chemical engineering, pharmaceutics, pharmacy, or a related discipline, and/or
`
`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
`
`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
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`skilled artisan. I understand that this principle is called “anticipation.” I have also
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`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 require-
`
`ments 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 es-
`
`tablish that an element of a claim is “inherent” in the disclosure of a prior art refer-
`
`ence, it must be clear to one skilled in the art that the missing element is an inevita-
`
`ble 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
`
`unpatentable if the differences between the claim and the prior art are such that the
`
`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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`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 ar-
`
`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
`
`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
`
`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 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-
`
`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.
`
`24.
`
`I understand that when every limitation of a claim is disclosed in the
`
`cited prior art references, the question of obviousness turns on whether a hypothet-
`
`ical person of ordinary skill in the art would have been motivated to combine those
`
`teachings to derive the claimed subject matter with a reasonable expectation of
`
`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
`
`necessary to show obviousness.
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`25.
`
`I have been informed that a claimed invention can be rendered obvi-
`
`ous 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
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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.
`
`26.
`
`I have been informed that examples of sufficient rationales for estab-
`
`lishing 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, or
`products in the same way;
`
` choosing from a finite number of identified, predictable solutions that
`would be obvious to try; and
`
` 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.
`
`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
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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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`IV. THE ʼ788 PATENT
`A. The alleged invention
`28. The ʼ788 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 se-
`
`rum albumin, and methods of treating diseases, including cancer, by administering
`
`such compositions. EX1001, cover, abst.
`
`29. As background, the ʼ788 patent explains that “many drugs for paren-
`
`teral use, especially those administered intravenously, cause undesirable side ef-
`
`fects” that are “administration related.” Id. at 1:27–31. “Many of these drugs,” the
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`patent explains, “are insoluble in water, and are thus formulated with solubilizing
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`agents, surfactants, solvents, and/or emulsifiers that are irritating, allergenic, or
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`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 ʼ788 patent acknowledges is sold under the
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`brand name Taxol, was known to be “active against carcinomas of the ovary,
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`breast, lung, esophagus and head and neck.” Id. at 4:31–33. “Taxol, however, has
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`been shown to induce toxicities associated with administration.” Id. at 4:33–34.
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`“Because paclitaxel is poorly soluble in water, cremophor [i.e., polyethoxylated
`
`castor oil] typically is used as a solvent, requiring large infusion volumes and spe-
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`cial 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 ʼ788 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 dis-
`
`closes compositions comprising paclitaxel together with a pharmaceutical carrier,
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`which is preferably human serum albumin. Id. at 2:54–58. “Preferably, the formu-
`
`lation is essentially free of cremophor,” thus avoiding its “side effects that can be
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`severe.” Id. at 11:67–12:6.
`
`32. Human serum albumin is a highly soluble protein, and is the most
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`abundant protein in human blood plasma. Id. at 5:15–18. The ʼ788 patent
`
`acknowledges that the intravenous use of human serum albumin solution was
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`known in the art. Id. at 5:21–22. Human serum albumin has “multiple hydropho-
`
`bic binding sites,” allowing it to bind to hydrophobic, water-insoluble drugs like
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`paclitaxel. Id. at 5:29–46. The ʼ788 patent theorizes that “the inclusion of proteins
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`such as albumin in the inventive pharmaceutical compositions results in a reduc-
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`tion in side effects associated with administration of the pharmaceutical composi-
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`tion that is due, at least in part, to the binding of human serum albumin to any free
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`drug that is present in the composition.” Id. at 5:52–58.
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`33. The ʼ788 patent states generally that “[t]he amount of albumin in-
`
`cluded in the pharmaceutical composition of the present invention will vary de-
`
`pending on the pharmaceutical active agent, other excipients, and the route and 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
`
`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 al-
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`leged reasons. Id. at 35:34–36.
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`34. The ʼ788 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
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`of protein to pharmaceutical agent will have to be optimized for different protein
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`and pharmaceutical agent combinations.” Id. at 11:61–63. The patent then dis-
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`closes certain “preferred” ranges, and concludes by stating: “Most preferably, the
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`ratio is about 1:1 to about 9:1.” Id. at 11:66–67.
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`35. The patent includes examples of various pharmaceutical composi-
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`tions. None of these examples discloses a formulation with an albumin-paclitaxel
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`ratio of about 9:1. The only examples that mention the ratio of albumin to
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`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 (Ex-
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`ample 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 al-
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`bumin solution (3% w/v) (corresponding to a ratio of albumin to paclitaxel of 27).”
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`Id. at 35:44–47. Likewise, Example 48 states: “300 mg of paclitaxel was dis-
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`solved 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
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`the 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 albu-
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`min 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), correspond-
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`ing to a 10:1 ratio. After reciting several process steps, Example 49 states: “The
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`calculated ratio (w/w) of albumin to paclitaxel in this invention composition is ap-
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`proximately 10.” Id. at 36:42–61. Apparently, therefore, the albumin-paclitaxel
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`ratio of Example 49 was either “calculated” based on the starting materials, or
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`measured after the process steps were completed, at which point the ratio remained
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`the same as the ratio of starting materials.
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`38. There is no suggestion in the ʼ788 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 ʼ788 patent provides that the claimed compositions can be pre-
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`pared as nanoparticles. Id. at 9:33–35. Several examples in the patent describe na-
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`noparticle formulations. In each one, the example provides that “the typical aver-
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`age 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 (Ex-
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`ample 4); 16:28–31 (Example 5); 16:58–61 (Example 6); 17:22–24 (Example 7);
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`17:58–60 (Example 8); 18:26–28 (Example 9); 18:58–61 (Example 10); 19:19–21
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`(Example 11); 19:44–45; (Example 12); 19:63–65 (Example 13); 20:21–23 (Exam-
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`ple 14); 35:57–59 (Example 47); 36:23–25 (Example 48); 36:54–56 (Example 49).
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`The “Z-average” is one possible measurement of particle diameter, and a “Malvern
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`Zetasizer” is a particular device that is capable of determining that measurement.
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`B. Challenged claims
`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 composi-
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`tion is free of Cremophor.
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`43. Claim 4 is directed to a method of treating cancer, arthritis, or resteno-
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`sis 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 composi-
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`tion is administered “intravenously, intraarterially, intrapulmonarily, orally, by in-
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`halation, intravesicularly, intramuscularly, intratracheally, subcutaneously, intraoc-
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`ularly, intrathecally, or transdermally.”
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`48. Claim 9 depends from claim 8 and specifies that the method of admin-
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`istration 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
`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 rea-
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`sonable 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 inter-
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`pretation of the claims of a patent corresponds to their plain and ordinary meaning
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`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 broad-
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`est reasonable interpretation of the terms “weight ratio of albumin to paclitaxel in
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`the composition” and “ratio (w/w) of albumin to the paclitaxel in the pharmaceuti-
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`cal composition” in the challenged cla