`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`ACTAVIS LLC,
`Petitioner
`
`v.
`
`ABRAXIS BIOSCIENCE, LLC,
`Patent Owner
`
`
`Case IPR2017-01104
`Patent 8,138,229 B2
`
`
`
`DECLARATION OF CORY J. BERKLAND, Ph.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
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`
`
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`
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`Actavis - IPR2017-01104, Ex. 1002, p. 1 of 108
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`TABLE OF CONTENTS
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`Page
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`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
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`BACKGROUND AND QUALIFICATIONS ................................................. 2
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`III. LEGAL STANDARDS USED IN MY ANALYSIS ...................................... 5
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`A.
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`B.
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`C.
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`Prior art .................................................................................................. 5
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`Person of ordinary skill in the art .......................................................... 6
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`Anticipation ........................................................................................... 8
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`D. Obviousness ........................................................................................... 9
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`IV. THE ʼ229 PATENT ....................................................................................... 11
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`A.
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`B.
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`C.
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`The alleged invention .......................................................................... 11
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`Challenged claims ............................................................................... 16
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`Claim construction .............................................................................. 18
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`V.
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`THE PRIOR ART .......................................................................................... 20
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`A. Desai (EX1006) ................................................................................... 20
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`B.
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`C.
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`D.
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`Kadima (EX1004) ............................................................................... 29
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`Liversidge (EX1005) ........................................................................... 31
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`Taxol label (EX1008) .......................................................................... 33
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`VI. ANTICIPATION ........................................................................................... 33
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`A.
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`Claims 1–19 and 21–48 of the ʼ229 patent are anticipated. ................ 33
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`1.
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`Claim 1 is anticipated by Desai. ............................................... 33
`
`a.
`b.
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`Albumin-paclitaxel combination .................................... 34
`Particle size of less than about 200 nm .......................... 35
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`Actavis - IPR2017-01104, Ex. 1002, p. 2 of 108
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`Albumin-paclitaxel ratio of about 1:1 to 9:1 .................. 36
`c.
`d. Weight percentage of albumin ........................................ 36
`Claims 3 and 6 are anticipated by Desai. .................................. 38
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`Claims 15, 19, and 21–23 are anticipated by Desai. ................. 39
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`Claims 29, 34, and 38 are anticipated by Desai. ....................... 41
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`Claims 7 and 33 are anticipated by Desai. ................................ 43
`
`Claims 2, 8, 11, 12, 13, 14, 16, 24, 27, 28, 30, 35, and 39
`are anticipated by Desai. ........................................................... 43
`
`Claims 4, 5, 9, 10, 17, 18, 25, 26, 31, 32, 36, 37, 40, and
`41 are anticipated by Desai. ...................................................... 44
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`Claims 42–48 are anticipated by Desai. .................................... 44
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`2.
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`3.
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`4.
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`5.
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`6.
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`7.
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`8.
`
`B.
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`The “starting” ratio of albumin to paclitaxel does not change. ........... 45
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`VII. OBVIOUSNESS ............................................................................................ 48
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`A.
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`Claim 1 of the ʼ229 patent would have been obvious. ........................ 49
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`1.
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`Obviousness over Desai alone .................................................. 49
`
`a.
`
`b.
`
`The albumin-paclitaxel ratio of about 9:1 falls
`within a range disclosed by Desai. ................................. 52
`A skilled artisan would have been motivated to
`lower Capxol’s 13.3:1 albumin-paclitaxel ratio. ............ 54
`A skilled artisan would have reasonably expected an
`albumin-paclitaxel ratio of 9:1 to retain stability. .......... 56
`The claimed weight percentage of albumin, when
`the albumin-paclitaxel formulation is reconstituted
`in saline, falls within a range disclosed by Desai. .......... 59
`Obviousness over Desai, Kadima, and Liversidge ................... 61
`
`c.
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`d.
`
`a.
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`Kadima and Liversidge also disclose ranges of
`albumin-paclitaxel ratios, including about 9:1. .............. 61
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`
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`2.
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`Actavis - IPR2017-01104, Ex. 1002, p. 3 of 108
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`B.
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`C.
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`D.
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`E.
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`F.
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`G.
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`H.
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`I.
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`J.
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`b.
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`Kadima teaches additional reasons to lower a 13.3:1
`ratio of albumin to paclitaxel to about 9:1. ..................... 62
`Claims 3 and 6 would have been obvious. .......................................... 66
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`Claims 15, 19, and 21–23 would have been obvious. ......................... 67
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`Claim 20 would have been obvious. ................................................... 68
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`Claims 29, 34, and 38 would have been obvious. ............................... 69
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`Claims 7 and 33 would have been obvious. ........................................ 71
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`Claims 2, 8, 11, 12, 13, 14, 16, 24, 27, 28, 30, 35, and 39 would
`have been obvious. .............................................................................. 72
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`Claims 4, 5, 9, 10, 17, 18, 25, 26, 31, 32, 36, 37, 40, and 41
`would have been obvious. ................................................................... 72
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`Claims 42–48 would have been obvious. ............................................ 73
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`There are no relevant secondary considerations indicating that
`the challenged claims would not have been obvious. ......................... 74
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`1.
`
`2.
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`The allegedly “unexpected” cell-binding results lack a
`nexus to the ʼ229 patent and would have been expected. ......... 75
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`The allegedly “unexpected” clinical data did not compare
`the closest prior art and would have been expected. ................ 78
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`VIII. CONCLUSION .............................................................................................. 83
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`Actavis - IPR2017-01104, Ex. 1002, p. 4 of 108
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`EXHIBITS CITED
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`Description
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`EX
`
`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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`1008
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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
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`
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`Desai et al., U.S. Patent No. 8,138,229 B2, “Compositions and Meth-
`ods of Delivery of Pharmacological Agents” (issued Mar. 20, 2012)
`(the “ʼ229 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)
`Physicians’ Desk Reference® 309, 881–887 (54th ed. 2000) “Taxol®
`(paclitaxel) Injection” (“Taxol label”)
`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”)
`
`
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`Actavis - IPR2017-01104, Ex. 1002, p. 5 of 108
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`1023
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`1027
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`1028
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`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)
`Remington’s Pharmaceutical Sciences (18th ed. 1990), Chapt. 85,
`“Intravenous Admixtures” (“Remington’s”)
`Camden, U.S. Patent No. 6,177,460 B1, “Method of Treatment for
`Cancer or Viral Infections” (issued Jan. 23, 2001)
`
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`Actavis - IPR2017-01104, Ex. 1002, p. 6 of 108
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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
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`Professor in the Department of Pharmaceutical Chemistry and the Department of
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`Chemical and Petroleum Engineering at the University of Kansas. I have been re-
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`tained by Petitioner Actavis LLC in connection with its request for inter partes re-
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`view of U.S. Patent No. 8,138,229 (“the ’229 patent”). A copy of the ’229 patent
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`has been marked EX1001. I have reviewed and am familiar with the ’229 patent.
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`Generally, it describes and claims pharmaceutical compositions comprising the an-
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`ticancer drug paclitaxel bound to the protein albumin and formulated as nanoparti-
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`cles, and methods of using such compositions to treat diseases including cancer.
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`2.
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`I have been asked to provide my opinions regarding the patentability
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`of claims 1–48 of the ’229 patent (the “challenged claims”). This declaration in-
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`cludes a discussion of my background and qualifications, the legal standards used
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`in my analysis, an overview of the ʼ229 patent from the perspective of a person of
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`ordinary skill in the art at the time that the patent was filed (a “skilled artisan”),
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`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 stand-
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`ard hourly consulting rate of $500.00 per hour. My compensation is in no way
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`contingent on the substance of my opinions or the outcome of this proceeding.
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`Actavis - IPR2017-01104, Ex. 1002, p. 7 of 108
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`4.
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`As set forth more fully below, it is my opinion that claims 1–19 and
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`21–48 of the ʼ229 patent are anticipated by a previously published international pa-
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`tent application, WO 99/00113 to Desai et al. (“Desai”) (EX1006). Additionally, it
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`is my opinion that claims 1–19 and 21–48 would have been obvious to a skilled ar-
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`tisan in view of Desai, either alone or in combination with another previously pub-
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`lished international patent application, WO 00/06152 to Kadima et al. (“Kadima”)
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`(EX1004), and a previously issued patent, U.S. Patent No. 5,399,363 to Liversidge
`
`et al. (EX1005). It is also my opinion that claim 20 would have been obvious to a
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`skilled artisan in view of Desai and the 2000 FDA-approved labeling for Taxol (the
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`“Taxol label”) (EX1008), and optionally in further view of Kadima and Liversidge.
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`5.
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`The bases for my opinions are set forth in this declaration.
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`II. BACKGROUND AND QUALIFICATIONS
`6.
`I received a B.S. in Chemical Engineering from Iowa State University
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`in December 1998, and an M.S. in Chemical Engineering from the University of
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`Illinois in May 2001. I received a Ph.D. in Chemical and Biomolecular Engineer-
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`ing from the University of Illinois in May 2003. From 2004 to 2009, I was an As-
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`sistant Professor in the Department of Chemical and Petroleum Engineering and
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`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.
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`Actavis - IPR2017-01104, Ex. 1002, p. 8 of 108
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`7. My areas of expertise include drug formulation using particulates and
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`powders, microencapsulation of pharmaceuticals, and controlled-release drug de-
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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
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`expertise in the formulation and characterization of particles and powders.
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`8.
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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-
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`phology, surface chemistry) for controlling the release or dissolution of drugs.
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`9. 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.
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`Actavis - IPR2017-01104, Ex. 1002, p. 9 of 108
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`10.
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`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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`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-
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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.
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`11.
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`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.
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`12.
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`I have published on such topics as drug delivery, nanoparticle formu-
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`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.
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`13.
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`I have served as a consultant in the area of drug formulation and de-
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`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-
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`cluding publications authored within the past ten years, are listed in my CV.
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`Actavis - IPR2017-01104, Ex. 1002, p. 10 of 108
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`14.
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`I have been involved in the development of numerous pharmaceutical
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`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
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`controlled-release delivery systems, including parenteral, injectable formulations.
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`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-
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`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.
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`III. LEGAL STANDARDS USED IN MY ANALYSIS
`15.
`I am not a patent attorney, nor have I independently researched patent
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`law. Counsel for Petitioner have explained certain legal standards to me that I
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`have relied upon in forming my opinions set forth in this Declaration.
`
`A.
`16.
`
`Prior art
`
`I have been informed that the law provides certain categories of infor-
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`mation, known as prior art, that may be used to render patent claims anticipated or
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`obvious. The reference materials I discuss in this declaration are prior art at least
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`because they would have been available to members of the public as of December
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`Actavis - IPR2017-01104, Ex. 1002, p. 11 of 108
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`9, 2002, and are relevant to the subject matter of the ʼ229 patent. The references I
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`discuss herein are from the same field of endeavor as the claimed invention (even
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`if they address a different problem), and/or are reasonably pertinent to the problem
`
`faced by the inventor (even if they are not in the same field of endeavor as the
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`claimed invention).
`
`B.
`17.
`
`Person of ordinary skill in the art
`
`I understand that U.S. provisional application no. 60/432,317, to
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`which the ’229 patent claims priority, was filed on December 9, 2002, as stated on
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`the front of the patent under the title “Related U.S. Application Data.” For pur-
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`poses of my analysis, and without offering any opinion as to whether the ʼ229 pa-
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`tent’s claim to priority is valid or appropriate, I have used the December 9, 2002
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`date as the relevant date for my analysis of the prior art.
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`18.
`
`I understand that the assessment of the patentability of the claims of
`
`the ’229 patent must be undertaken from the perspective of a hypothetical person
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`of ordinary skill in the art as of the earliest priority date of the ’229 patent, i.e., a
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`skilled artisan. The person of ordinary skill in the art is a hypothetical person who
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`is presumed to have known the relevant art as of the effective filing date. Factors
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`that may be considered in determining the level of ordinary skill in the art may in-
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`clude, (i) type of problems encountered in the art, (ii) prior art solutions to those
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`problems, (iii) rapidity with which innovations are made, (iv) sophistication of the
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`Actavis - IPR2017-01104, Ex. 1002, p. 12 of 108
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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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`19.
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`I understand that the hypothetical person having ordinary skill in the
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`art to which the claimed subject matter pertains would, of necessity have the capa-
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`bility of understanding the scientific and engineering principles applicable to the
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`pertinent art. I further understand that a person of ordinary skill in the art is also a
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`person of ordinary creativity, not an automaton. In many cases a person of ordi-
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`nary skill will be able to fit the teachings of multiple patents or prior art references
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`together like pieces of a puzzle.
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`20. Based on these factors, my knowledge and expertise, and the prior art
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`to the ’229 patent (i.e., publications before December 9, 2002), it is my opinion
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`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
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`the skilled artisan would know how to evaluate potential drug therapies for in vitro
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`and in vivo activity, including with biological assays.
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`Actavis - IPR2017-01104, Ex. 1002, p. 13 of 108
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`C. Anticipation
`21.
`I have been informed that a claim is not patentable if a single prior art
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`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
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`need to use the same words as the claim. However, it must describe the require-
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`ments of the claim with sufficient clarity that a skilled artisan would have been
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`able to make and use the claimed invention based on that single prior art reference.
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`22.
`
`In addition, I have been informed and understand that, in order to es-
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`tablish that an element of a claim is “inherent” in the disclosure of a prior art refer-
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`ence, it must be clear to one skilled in the art that the missing element is an inevita-
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`ble part of what is explicitly described in the prior art reference, and that it would
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`have been recognized as necessarily present by a skilled artisan.
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`23.
`
`I understand that when a patent claims a range, that range is antici-
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`pated by a prior art reference if the reference discloses a point within the range. If
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`the prior art discloses its own range, rather than a specific point, then the prior art
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`is anticipatory if it describes the claimed range with sufficient specificity such that
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`a skilled artisan would conclude that there is no difference in how the invention
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`operates over the ranges. Further, I understand that a patentee must establish the
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`Actavis - IPR2017-01104, Ex. 1002, p. 14 of 108
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`“criticality” of a claimed range to the claimed invention in order to avoid anticipa-
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`tion by a prior art reference disclosing a broader, overlapping range.
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`D. Obviousness
`24.
`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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`claim as a whole would have been obvious to a skilled artisan at the time the in-
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`vention was made. For purposes of obviousness, I understand that a skilled artisan
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`may rely on a single prior art reference, or multiple references in combination.
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`25.
`
`I have been informed that the following four factors are considered
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`when determining whether a patent claim would have been obvious to a skilled ar-
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`tisan: (a) the level of ordinary skill in the art; (b) the scope and content of the prior
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`art; (c) the differences between the prior art and the claim; and (d) any “secondary
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`considerations” tending to prove nonobviousness. These secondary considerations,
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`which I understand are also called “objective indicia” or “objective evidence,” may
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`include factors such as: (i) the invention’s satisfaction of a long-felt unmet need in
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`the art; (ii) unexpected results of the invention; (iii) skepticism of the invention by
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`experts; (iv) teaching away from the invention in the prior art; (v) commercial suc-
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`cess of an embodiment of the invention; and (vi) praise by others for the invention.
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`Actavis - IPR2017-01104, Ex. 1002, p. 15 of 108
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`I have also been informed that there must be an adequate nexus or connection be-
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`tween the evidence that is the basis for an asserted secondary consideration and the
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`scope of the invention claimed in the patent.
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`26.
`
`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-
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`ical person of ordinary skill in the art would have been motivated to combine those
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`teachings to derive the claimed subject matter with a reasonable expectation of
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`success. Further, I understand that obviousness does not require absolute predicta-
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`bility. Only a reasonable expectation that the beneficial result will be achieved is
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`necessary to show obviousness.
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`27.
`
`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
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`teaching to combine them. Instead, any problem known in the field at the time of
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`the alleged invention can provide a sufficient rationale to combine the elements of
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`the prior art in the manner claimed in the patent.
`
`28.
`
`I have been informed that examples of sufficient rationales for estab-
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`lishing obviousness include the following:
`
` combining prior art elements according to known methods to yield
`predictable results;
`
`
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`Actavis - IPR2017-01104, Ex. 1002, p. 16 of 108
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` substituting known elements for other known elements to obtain
`predictable results;
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` using a known technique to improve similar devices, methods, or
`products in the same way;
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` 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.
`
`29.
`
`I understand that where there is a range disclosed in the prior art, and
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`the claimed invention falls within that range, the burden of production falls upon
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`the patentee to come forward with evidence that (1) the prior art taught away from
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`the claimed invention; (2) there were new and unexpected results relative to the
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`prior art; or (3) there are other pertinent secondary considerations. For purposes of
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`this analysis, I understand that a prior art reference does not “teach away” from a
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`claimed invention unless it criticizes, discredits, or otherwise discourages investi-
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`gation into the invention claimed.
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`IV. THE ʼ229 PATENT
`A. The alleged invention
`30. The ʼ229 patent is entitled “Compositions and Methods of Delivery of
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`Pharmacological Agents,” and generally relates to pharmaceutical compositions
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`Actavis - IPR2017-01104, Ex. 1002, p. 17 of 108
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`comprising paclitaxel and a pharmaceutically acceptable carrier, such as human se-
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`rum albumin, and methods of treating diseases, including cancer, by administering
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`such compositions. EX1001, cover, abst.
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`31. As background, the ʼ229 patent explains that “many drugs for paren-
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`teral use, especially those administered intravenously, cause undesirable side ef-
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`fects” that are “administration related.” Id. at 1:28–32. “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 1:32–35. The patent goes on to state
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`that known “drugs that exhibit administration-associated side effects include, for
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`example, Taxol (paclitaxel).” Id. at 1:53–55.
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`32. Paclitaxel, which as the ʼ229 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 4:32–34. “Taxol, however, has
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`been shown to induce toxicities associated with administration.” Id. at 4:34–35.
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`“Because paclitaxel is poorly soluble in water, cremophor [i.e., polyethoxylated
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`castor oil] typically is used as a solvent, requiring large infusion volumes and spe-
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`cial tubing and filters.” Id. at 4:38–40. “Cremophor is associated with side effects
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`that can be severe, including anaphylaxis and other hypersensitivity reactions that
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`can require pretreatment” with various drugs. Id. at 4:40–43.
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`Actavis - IPR2017-01104, Ex. 1002, p. 18 of 108
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`33. The ʼ229 patent discloses compositions and methods that supposedly
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`reduce or eliminate the cremophor-related side effects that had been associated
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`with the administration of paclitaxel. Id. at 2:35–46. Specifically, the patent dis-
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`closes compositions comprising paclitaxel together with a pharmaceutical carrier,
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`which is preferably human serum albumin. Id. at 2:55–59. “Preferably, the formu-
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`lation is essentially free of cremophor,” thus avoiding its “side effects that can be
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`severe.” Id. at 12:3–9.
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`34. 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 ʼ229 patent
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`acknowledges that the intravenous use of human serum albumin solution was
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`known in the art. Id. at 5:22–23. Human serum albumin has “multiple hydropho-
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`bic binding sites,” allowing it to bind to hydrophobic, water-insoluble drugs like
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`paclitaxel. Id. at 5:30–47. The ʼ229 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 5:54–59.
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`35. The ʼ229 patent states generally that “[t]he amount of albumin in-
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`cluded in the pharmaceutical composition of the present invention will vary de-
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`pending on the pharmaceutical active agent, other excipients, and the route and site
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`Actavis - IPR2017-01104, Ex. 1002, p. 19 of 108
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`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 5:60–67. 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 34:53–55.
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`36. The ʼ229 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 11:61–64. 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 11:64–66. 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 12:2–3.
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`37. 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 34:62–65 (Example 47), 35:26–29 (Ex-
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`ample 48), 35:58–36:10 (Example 49).
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`38. 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 34:62–65. 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 35:26–29. 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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`39. 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 35:58–60. 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 36:9–10. Apparently, therefore, the albumin-paclitaxel ra-
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`tio of Example 49 was either “calculated” based on the starting materials, or meas-
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`ured after the process steps were completed, at which point the ratio remained the
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`same as the ratio of starting materials.
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`Actavis - IPR2017-01104, Ex. 1002, p. 21 of 108
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`40. There is no suggestion in the ʼ229 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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`41. The ʼ229 patent provides that the claimed compositions can be pre-
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`pared as nanoparticles. Id. at 9:36–38. 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 14:61–63 (Example 1); 15:23–25 (Example 2); 15:67–16:2
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`(Examp