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`UNITED STATES PATENT AND TRADEMARK OFFICE
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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 CORY J. BERKLAND, Ph.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
`
`
`
`
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`TABLE OF CONTENTS
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`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
`
`Obviousness ........................................................................................... 7
`
`IV. THE ʼ260 PATENT ....................................................................................... 10
`
`A.
`
`B.
`
`C.
`
`The alleged invention .......................................................................... 10
`
`Challenged claims ............................................................................... 14
`
`Claim construction .............................................................................. 17
`
`1.
`
`2.
`
`3.
`
`“wherein the pharmaceutical formulation is … stable for at
`least 3 days under at least one of room temperature or
`refrigerated conditions” ............................................................ 17
`
`“wherein the solid core is substantially free of polymeric
`material”; “wherein a portion of the paclitaxel is contained
`within the albumin coating and a portion of the paclitaxel
`is associated with the free albumin” ......................................... 18
`
`“wherein a portion of the paclitaxel is contained within the
`albumin coating and a portion of the paclitaxel is
`associated with the free albumin” ............................................. 19
`
`V.
`
`THE PRIOR ART .......................................................................................... 20
`
`A. Desai (EX1003) ................................................................................... 20
`
`B.
`
`C.
`
`Shively (EX1004) ................................................................................ 25
`
`Liversidge (EX1005) ........................................................................... 26
`
`
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`D.
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`Remington’s (EX1006) ........................................................................ 29
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`VI. OBVIOUSNESS ............................................................................................ 33
`
`A.
`
`Claim 1 of the ʼ260 patent would have been obvious. ........................ 33
`
`1.
`
`2.
`
`3.
`
`A skilled artisan would have prepared Desai’s albumin-
`paclitaxel shells as 200-nm nanoparticles. ................................ 34
`
`A skilled artisan would have suspended the albumin-
`paclitaxel nanoparticles at a concentration of 5 mg/ml. ........... 39
`
`A skilled artisan would have reasonably expected the
`albumin-paclitaxel nanoparticles to remain stable. .................. 42
`
`a.
`
`b.
`
`A skilled artisan would expect no substantial
`precipitation—an inherent result of small
`nanoparticles. .................................................................. 43
`
`A skilled artisan would expect no substantial change
`in particle size—an inherent result of albumin. ............. 51
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`H.
`
`I.
`
`J.
`
`Claims 2–3 would have been obvious. ................................................ 63
`
`Claims 4 and 18–22 would have been obvious. .................................. 64
`
`Claims 5–6 would have been obvious. ................................................ 65
`
`Claims 7–9 would have been obvious. ................................................ 67
`
`Claims 10–11 would have been obvious. ............................................ 71
`
`Claims 12–14 and 16–17 would have been obvious. .......................... 73
`
`Claim 15 would have been obvious. ................................................... 75
`
`Claims 23–27 would have been obvious. ............................................ 76
`
`There are no relevant secondary considerations indicating that
`the challenged claims would not have been obvious. ......................... 77
`
`1.
`
`The allegedly “unexpected” stability of albumin-paclitaxel
`nanoparticles was not compared to the closest prior art. .......... 79
`
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`2.
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`The allegedly “unexpected” stability of smaller particles
`and narrower size distributions would have been expected...... 81
`
`VII. CONCLUSION .............................................................................................. 84
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`EXHIBITS CITED
`
`Exhibit
`
`Description
`
`1001
`
`1003
`
`1004
`
`1005
`
`1006
`
`1009
`
`1010
`
`1011
`
`1021
`
`1024
`
`1026
`1027
`
`
`
`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 “ʼ260 patent”)
`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”)
`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)
`U.S. Application No. 11/520,479, Declaration of Neil P. Desai
`Pursuant to 37 C.F.R. § 1.132 (dated Jan. 27, 2012)
`(“First Inventor Declaration”)
`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”)
`U.S. Pharmacopoeia 23 (1995 ed.) (excerpted)
`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”)
`
`
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`Liversidge et al., U.S. Patent No. 5,145,684, “Surface Modified Drug
`Nanoparticles” (issued Sept. 8, 1992)
`Noureddini et al., “Densities of Vegetable Oils and Fatty Acids,” 69
`JAOCS 1184 (Dec. 1992)
`
`1028
`
`1029
`
`
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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. 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-
`
`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 1–27 of the ’260 patent (the “challenged claims”). This declaration in-
`
`cludes a discussion of my background and qualifications, the legal standards used
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`in my analysis, an overview of the ʼ260 patent from the perspective of a person of
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`ordinary skill in the art at the time 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-
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`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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`
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`4.
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`As set forth more fully below, it is my opinion that the challenged
`
`claims are unpatentable because they would have been obvious to a skilled artisan
`
`as of June 1997 in view of U.S. Patent No. 5,439,686 to Desai et al. (“Desai”)
`
`(EX1003), U.S. Patent No. 5,407,683 to Shively (“Shively”) (EX1004), U.S. Pa-
`
`tent No. 5,399,363 to Liversidge et al. (“Liversidge”) (EX1005), and Remington’s
`
`Pharmaceutical Sciences (18th ed. 1990) (“Remington’s”) (EX1006). 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-
`
`livery. Through collaborations with industrial and academic partners, and close re-
`
`lationships with other experts in controlled release, I have developed considerable
`
`expertise in the formulation and characterization of particles and powders.
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`
`
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`7.
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`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-
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`ducted research aimed to elucidate important parameters (e.g., particle size, mor-
`
`phology, 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 for-
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`mulation 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 disso-
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`lution or release of such drugs. I have also designed and taught classes on drug de-
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`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
`
`the American Institute of Chemical Engineers, the American Chemical Society, the
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`American Association of Pharmaceutical Scientists, and the Controlled Release
`
`Society. I am a Fellow of the American Institute of Medical and Biological Engi-
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`
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`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
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`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
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`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-
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`nals including Therapeutic Delivery, the Journal of Pharmaceutical Sciences, and
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`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
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`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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`
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`Inc. I am the acting Chief Scientific Officer at Orbis Biosciences. Orbis develops
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`controlled-release delivery systems, including parenteral, injectable formulations.
`
`I was also a Member of the Scientific Advisory Board and the former Chief Tech-
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`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
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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 ʼ260 patent. The references I
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`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
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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).
`
`B.
`16.
`
`Person of ordinary skill in the art
`
`I understand that U.S. provisional application no. 60/051,021, to
`
`which the ’260 patent claims priority, was filed on June 27, 1997, as stated on the
`
`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 ʼ260 patent’s
`
`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.
`
`17.
`
`I understand that the assessment of the patentability of the claims of
`
`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
`
`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-
`
`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
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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-
`
`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.
`
`19. 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), 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
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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
`
`the skilled artisan would know how to evaluate potential drug therapies for in vitro
`
`and in vivo activity, including with biological assays.
`
`C. Obviousness
`20.
`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
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`
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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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`21.
`
`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
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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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`22.
`
`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
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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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`23.
`
`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
`
`the alleged invention can provide a sufficient rationale to combine the elements of
`
`the prior art in the manner claimed in the patent.
`
`24.
`
`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.
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`
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`25.
`
`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
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`claimed invention unless it criticizes, discredits, or otherwise discourages investi-
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`gation into the invention claimed.
`
`26.
`
`I also understand that even if a claim limitation is missing from the
`
`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
`
`not appreciated by persons of skill in the art at the time of the invention.
`
`IV. THE ʼ260 PATENT
`A. The alleged invention
`27. The ʼ260 patent is entitled “Formulations of Pharmacological Agents,
`
`Methods for the Preparation thereof and Methods for the Use thereof,” and gener-
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`ally relates to “methods for the production of particulate vehicles for the intrave-
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`nous administration of pharmacologically active agents”—specifically, for “deliv-
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`ery of substantially water insoluble pharmacologically active agents (e.g., the anti-
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`cancer drug Taxol®),” i.e., paclitaxel. EX1001, 1:8–14.
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`28. As the ʼ260 patent acknowledges, paclitaxel, which at the time the pa-
`
`tent was filed had been sold in a formulation called Taxol, was known “to have
`
`significant antineoplastic and anticancer effects,” and “excellent antitumor activity
`
`in a wide variety of tumor models.” Id. at 2:62–65.
`
`29. Pacltaxel’s “poor aqueous solubility … , however, presents a problem
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`for human administration.” Id. at 3:3–5. “Accordingly,” the “Taxol formulations
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`require a cremaphor to solubilize the drug.” Id. at 3:8–9. “The human clinical
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`dose range is 200–500 mg,” and in Taxol “[t]his dose is dissolved in a 1:1 solution
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`of ethanol:cremaphor and diluted with saline of about 300–1000 ml of fluid given
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`intravenously.” Id. at 3:9–12. “The large dilution results in large volumes of infu-
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`sion (typical dose 175 mg/m2) up to 1 liter and infusion times ranging from 3 hours
`
`to 24 hours.” Id. at 3:20–22. More specifically, “Taxol is currently approved for
`
`administration at concentrations between 0.6–1.2 mg/ml.” Id. at 9:7–10. The ʼ260
`
`patent states that “[i]t is desirable to reduce these infusion volumes, by developing
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`formulations of paclitaxel that are stable at higher concentrations so as to reduce
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`the time of administration.” Id. at 9:10–14.
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`30. Another problem with Taxol was that “[t]he presence of cremaphor in
`
`this formulation has been linked to severe hypersensitivity reactions … and conse-
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`quently requires premedication of patients with” various drugs. Id. at 3:14–20. “It
`
`is also desirable to eliminate premedication since this increases patient discomfort
`
`and increases the expense and duration of treatment.” Id. at 9:1–3.
`
`31. The ʼ260 patent discloses compositions and methods that supposedly
`
`reduce or eliminate the administration-related problems of Taxol. Id. at 9:25–30.
`
`Specifically, the patent discloses a formulation of paclitaxel consisting of a freeze-
`
`dried, i.e., “lyophilized powder for reconstitution and intravenous administration,”
`
`which “[w]hen reconstituted with a suitable aqueous medium … forms a stable
`
`colloidal solution of paclitaxel.” Id. at 11:56–60. The formulation’s “two major
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`components … are unmodified paclitaxel and human serum albumin (HSA).” Id.
`
`at 11:62–64. Unlike Taxol, this formulation is “cremophor-free.” Id. at 11:49.
`
`32. The size of the particles in this “colloidal suspension may range from
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`20 nm to 8 microns with a preferred range of about 20–400 nm.” Id. at 11:60–62.
`
`As the patent acknowledges, particles as small as “a few nanometers (nm) to 100
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`nm” were known in the prior art. Id. at 2:19–24. Further citing the prior art, the
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`ʼ260 patent explains that “[i]njectable controlled-release nanoparticles can provide
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`a pre-programmed duration of action,” and were known to “offer several profound
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`advantages over conventionally administered medicaments, including automatic
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`assured patient compliance with the dose regimen, as well as drug targeting to spe-
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`cific tissues or organs.” Id. at 1:56–63.
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`33. The ʼ260 patent states that albumin, a known protein in the blood, is
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`“employed as a stabilizing agent” in its claimed formulations. E.g., id. at 23:29–
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`40. As the patent explains: “Since albumin is present on the colloidal drug parti-
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`cles (formed upon removal of the organic solvent), formation of a colloidal disper-
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`sion which is stable for prolonged periods is facilitated, due to a combination of
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`electrical repulsion and steric stabilization.” Id. at 10:55–59. According to the
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`ʼ260 patent, the formulation thus has “inherent stability.” Id. at 14:22–29.
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`34. Example 23, which is entitled “Preparation of Protein-Walled Poly-
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`meric Shells Containing a Solid Core of Pharmaceutically Active Agent,” explains
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`the process of making the claimed albumin-coated paclitaxel nanoparticles. Id. at
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`36:35–37:3. In general, the particles are formed by dissolving the drug (e.g.,
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`paclitaxel) in a solvent, dispersing it into an aqueous protein (e.g., albumin) solu-
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`tion using sonication or homogenization, and removing the solvents. Id. As the
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`ʼ260 patent notes, and as is evident from Example 23, the process is performed “in
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`the absence of any polymeric core material for the particles.” Id. at abst.; see id. at
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`9:63–64. Moreover, the ʼ260 patent explains that, in the resulting particles, “a por-
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`tion of [the] pharmacologically active agent is contained within [the] protein coat-
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`ing and a portion of [the] pharmacologically active agent is associated with [the]
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`free protein.” Id. at 15:50–53.
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`35. The ʼ260 patent provides only one example of stability data for its
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`claimed albumin-paclitaxel nanoparticle formulations. Example 37 states
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`“Capxol”—one embodiment of the claimed formulations—was “reconstituted with
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`sterile normal saline to concentrations of 1, 5, 10, and 15 mg/ml and stored at room
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`temperature and under refrigerated conditions.” Id. at 48:54–57. The patent states
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`that “[t]he suspensions was [sic] found to be homogeneous for at least three days
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`under these conditions.” Id. at 48:57–58. “Particle size measurements performed
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`at several time points indicated no change in size distribution,” and “[n]o precipita-
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`tion was seen under these conditions.” Id. at 48:58–61. The patent states that, by
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`contrast, “Taxol … precipitates in within about 24 hours after reconstitution at the
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`recommended concentrations of 0.6–1.2 mg/ml.” Id. at 48:61–64.
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`B. Challenged claims
`36. Claim 1 of the ʼ260 patent is directed to a pharmaceutical formulation
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`comprising nanoparticles having a solid core of paclitaxel and an albumin coating,
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`in which the size of the nanoparticles is less than 400 nm, the paclitaxel is at a con-
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`centration between 5 mg/ml and 15 mg/ml, and the formulation is an aqueous sus-
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`pension that is stable for at least three days at room temperature or under refriger-
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`ated conditions.
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`37. 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 formulation “is a stable aqueous suspen-
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`sion reconstituted from a sterile lyophilized powder.”
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`38. Claim 3 depends from claim 2 and limits the paclitaxel concentration
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`in the reconstituted suspension to 5 mg/ml.
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`39. Claim 4 depends from claim 2 and limits the average diameter of the
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`nanoparticles to a size no greater than 220 nm.
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`40. Claims 5 and 6 further define the stability of the formulations of
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`claims 1 and 2, respectively. Claim 5 requires that “there is substantially no pre-
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`cipitation of paclitaxel for at least 3 days under at least one of room temperature or
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`refrigerated conditions.” Claim 6 requires that “the average nanoparticle size does
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`not substantially change for at least 3 days under at least one of room temperature
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`or refrigerated conditions.”
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`41. Claims 7–9 depend from claim 1 and recite various structural charac-
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`teristics of claim 1’s formulation. Claim 7 specifies that “the solid core is substan-
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`tially free of polymeric material.” Claim 8 specifies that “the albumin coating has
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`free albumin associated therewith, and … a portion of the paclitaxel is contained
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`within the albumin coating and a portion of the paclitaxel is associated with the
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`free albumin.” Claim 9 specifies that “at least a portion of the albumin is cross-
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`linked by disulfide bonds.”
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`42. Claims 10 and 11 depend from claim 1 and recite whether the
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`paclitaxel is crystalline or amorphous. Claim 10 requires that it be “substantially
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`amorphous,” whereas claim 11 requires that it be “substantially crystalline.”
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`43. Claims 12–16 cover methods of treatment using the claimed composi-
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`tions. Claim 12 is directed to using the composition of claim 1 in an effective
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`amount to treat a tumor, whereas claim 16 is specifically directed to treating breast
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`cancer. Claims 13 and 17 depend from claims 12 and 16, respectively, and recite
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`various methods of administration that include intravenous administration. Claim
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`14 depends from claim 13 and limits the method to intravenous administration.
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`Claim 15 depends from claim 14 and requires that the infusion volume for intrave-
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`nous administration be no greater than 200 ml.
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`44. Similar to claim 4, claims 18–22 depend from claims 1, 2, 3, 7, and 8,
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`respectively, and limit the average diameter of the nanoparticles to a size no
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`greater than about 200 nm.
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`45. Claims 23–27 depend from claims 1, 2, 3, 7, and 10, respectively, and
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`specify that the albumin in the formulation is human albumin.
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`C. Claim construction
`46. 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 the broadest reasonable interpretation of a
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`patent claim generally corresponds to its plain and ordinary meaning to a person of
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`ordinary skill in the art.
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`1.
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`“wherein the pharmaceutical formulation is … stable for at
`least 3 days under at least one of room temperature or re-
`frigerated conditions”
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`47.
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`In my opinion, a skilled artisan would have understood that the broad-
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`est reasonable interpretation of this term, which appears in claim 1 of the ʼ260 pa-
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`tent and is incorporated by reference in all of the other claims, would at least in-
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`clude compositions in which, for at least three days at room temperature (about
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`20–25°C) or under refrigerat