`Case IPR2017-00900
`Declaration of Diane J. Burgess, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,329,680
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`INNOPHARMA LICENSING, LLC,
`Petitioner
`
`v.
`
`
`ASTRAZENECA AB,
`Patent Owner
`
`
`
`
`
`
`
`
`Case IPR2017-00900
`Patent No. 8,329,680
`
`
`
`
`
`
`
`
`
`
`
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`
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`
`
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`
`
`
`DECLARATION OF DIANE J. BURGESS, Ph.D., UNDER 37 C.F.R. § 1.68
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 8,329,680
`
`
`Mail Stop: Patent Board
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`InnoPharma Exhibit 1012.0001
`
`

`

`Case IPR2017-00900
`Declaration of Diane J. Burgess, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,329,680
`
`
`TABLE OF CONTENTS
`
`
`Page
`
`INTRODUCTION ......................................................................................... 1
`
`I.
`
`II.
`
`BACKGROUND AND QUALIFICATIONS .............................................. 7
`
`III. MATERIALS CONSIDERED FOR THIS DECLARATION ................ 13
`
`IV. BACKGROUND .......................................................................................... 13
`
`A. Overview of the ’680 Patent ............................................................. 13
`
`B.
`
`Prosecution History of the ’680 Patent ............................................ 16
`
`i.
`
`ii.
`
`The Sawchuk Declaration ...................................................... 18
`
`The Gellert Declaration .......................................................... 20
`
`V.
`
`LEVEL OF ORDINARY SKILL IN THE PERTINENT ART .............. 23
`
`VI. BROADEST REASONABLE CONSTRUCTION ................................... 24
`
`VII. UNDERSTANDING OF THE LAW ......................................................... 25
`
`VIII. TECHNICAL OVERVIEW OF THE ASPECTS OF FORMULATION
`SCIENCE RELEVANT TO MY OPINIONS ........................................... 29
`
`IX. DETAILED INVALIDITY ANALYSIS.................................................... 33
`
`A.
`
`Summary of Opinions ....................................................................... 34
`
`B.
`
`Primary Prior Art Relied on in this Declaration ........................... 37
`
`i.
`
`Howell 1996 .............................................................................. 37
`
`ii. McLeskey 1998 ........................................................................ 40
`
`iii. O’Regan ................................................................................... 43
`
`iv. DeFriend .................................................................................. 45
`
`
`
`ii
`
`InnoPharma Exhibit 1012.0002
`
`

`

`Case IPR2017-00900
`Declaration of Diane J. Burgess, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,329,680
`
`
`C. Ground 1: The Challenged Claims are Obvious Over Howell 1996
` ............................................................................................................. 45
`
`i.
`
`ii.
`
`A Person of Ordinary Skill in the Art Would Have Been
`Motivated by the Results in Howell 1996 to Develop a
`Formulation to Achieve Those Results ................................. 45
`
`A Person of Ordinary Skill in the Art Would Have Had a
`Reasonable Expectation of Success in Developing a
`Formulation to Achieve the Pharmacokinetic Results
`Reported in Howell 1996 by Routine Experimentation ...... 49
`
`iii. The Precise Amounts of the Formulation Recited in the
`Claims are the Result of Routine Experimentation ............. 58
`
`iv. A Person Of Skill in the Art Would Not Have Been
`Motivated to Formulate Fulvestrant Using Alternative
`Routes of Administration ....................................................... 60
`
`v.
`
`Each Element of the Challenged Claims is rendered
`Obvious by Howell 1996 ......................................................... 68
`
`D. Ground 2: The Challenged Claims are Obvious Over the
`Combination of Howell 1996 and McLeskey 1998 ......................... 76
`
`i.
`
`ii.
`
`A Person of Ordinary Skill in the Art Would Have Been
`Motivated to Combine Howell 1996 and McLeskey 1998 ... 76
`
`A Person of Ordinary Skill in the Art Would Have Had a
`Reasonable Expectation of Success in Following the
`McLeskey 1998 Castor Oil-Based Formulation to Achieve
`the Pharmacokinetic Results Reported in Howell 1996 ...... 82
`
`iii. Dr. Illum’s Argument that it Was Unknown Whether the
`Castor Oil-Based Formulations Used in Howell 1996 and
`McLeskey 1998 Were Solutions or Suspensions is Irrelevant
`and Mistaken ........................................................................... 87
`
`iv. Dr. Sawchuk’s Criticisms of the McLeskey 1998 Reference
`are Mistaken and Contradict Dr. Gellert’s Declaration ..... 90
`
`
`
`iii
`
`InnoPharma Exhibit 1012.0003
`
`

`

`Case IPR2017-00900
`Declaration of Diane J. Burgess, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,329,680
`
`
`v.
`
`The Combination of Howell 1996 and McLeskey 1998
`Teaches Each Element of the Challenged Claim ...............102
`
`E. Ground 3: The Challenged Claims are Obvious Over the
`Combination of Howell 1996, McLeskey 1998, and O’Regan ....106
`
`i.
`
`ii.
`
`A Person of Ordinary Skill in the Art Would Have Been
`Motivated to Combine Howell 1996, McLeskey 1998, and
`O’Regan .................................................................................106
`
`O’Regan Confirms that a Person of Ordinary Skill in the
`Art Would Have Had a Reasonable Expectation of Success
`in Administering the McLeskey 1998 Castor Oil-Based
`Formulation Intramuscularly to Humans to Achieve the
`Pharmacokinetic Results Reported in Howell 1996 ..........107
`
`iii. The Combination of Howell 1996, McLeskey 1998, and
`O’Regan Teaches Each Element of the Challenged Claim
` .................................................................................................109
`
`iv.
`
`The Combination of Howell 1996, McLeskey 1998,
`O’Regan, and DeFriend Teaches Each Element of Claims 2
`and 6 .......................................................................................116
`
`F.
`
`Secondary Considerations Do Not Overcome the Prima Facie
`Case of Obviousness ........................................................................118
`
`X.
`
`SUPPLEMENTATION .............................................................................124
`
`XI. CONCLUSION ..........................................................................................124
`
`
`
`iv
`
`InnoPharma Exhibit 1012.0004
`
`

`

`Case IPR2017-00900
`Declaration of Diane J. Burgess, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,329,680
`
`
`I, Diane J. Burgess, Ph.D. hereby declare as follows:
`
`I.
`
`INTRODUCTION
`
`
`1.
`
`I have been retained as an expert witness on behalf of InnoPharma,
`
`LLC (“InnoPharma”) for the above-captioned Petition for Inter Partes Review
`
`(“IPR”) of U.S. Patent No. 8,329,680 (“the ’680 patent” or “the patent”).
`
`
`2.
`
`I have been asked to provide my opinions on the validity of claims 1,
`
`2, 3, and 6 of the ’680 patent (“the challenged claims”).
`
`
`3.
`
`In preparing this Declaration, I have reviewed the ’680 patent, the file
`
`history of the ’680 patent, and the file histories of the following related patents:
`
`U.S. Patent Nos. 8,466,139 (“the ’139 patent”), 7,456,160 (“the ’160 patent”), and
`
`6,774,122 (“the ’122 patent”). I have also reviewed the petition for inter partes
`
`review of the ’680 patent filed by Mylan Pharmaceuticals, Inc. (IPR2016-01325)
`
`(“Mylan IPR”), the supporting declarations and exhibits, the Patent Owner’s
`
`Response to that Petition, the supporting declarations and exhibits, and the Board’s
`
`decision denying institution of inter partes review on the ’680 patent (IPR2016-
`
`01325, paper 11). In addition, I have reviewed numerous prior art references that
`
`would have been available to one skilled in the art before the time of the alleged
`
`invention.
`
`
`4.
`
`I have been advised and it is my understanding that patent claims in
`
`an IPR are given their broadest reasonable construction in view of the patent
`
`
`InnoPharma Exhibit 1012.0005
`
`

`

`
`
`specification, file history, and the understanding of one having ordinary skill in the
`
`relevant art at the time of the purported invention.
`
`
`5.
`
`In forming the opinions expressed in this Declaration, I relied upon
`
`my education, training, and experience in the relevant field of the art, and have
`
`considered the viewpoint of a person having ordinary skill in the relevant art, as of
`
`January 9, 2000. My opinions directed to the invalidity of the challenged claims
`
`are based, at least in part, on the following prior art publications:
`
`
`
`
`
`Reference
`
`
`Ansel, “Dosage Form Design:
`Biopharmaceutic and Pharmacokinetic
`Considerations,” Pharmaceutical Dosage
`Forms and Drug Delivery Systems 101-
`41 (1999)
`
`Balant-Gorgia, Pharmacokinetic
`Optimisation of the Treatment of
`Psychosis, 25 CLIN. PHARMACOKINET.
`217-236 (1993)
`
`Date of Public Availability
`
`Ansel was published in 1999 and is
`attached as Exhibit 1091 to the
`IPR.
`
`Balant-Gorgia was published in
`1993 and is attached as Exhibit
`1097 to the IPR.
`
`Chien, Solubilization of Steroids by
`Multiple Co-Solvent Systems, 23 CHEM.
`PHARM. BULL. 1085-90 (1975)
`
`Chien was published in 1975 and is
`attached as Exhibit 1098 to the
`IPR.
`
`Chwalisz, Modulation of Oestrogenic
`Effects by Progesterone Antagonists in
`the Rat Uterus, 4 HUMAN REPRODUCTION
`UPDATE 570-83 (1998) (“Chwalisz”)
`
`DeFriend, Investigation of a New Pure
`Antiestrogen (ICI 182780) in Women
`with Primary Breast Cancer, 54 CANCER
`RESEARCH 408-14 (1994) (“DeFriend”)
`
`Chwalisz was published in 1998
`and is attached as Exhibit 1089 to
`the IPR.
`
`DeFriend was published in 1994
`and is attached as Exhibit 1038 to
`the IPR.
`
`2
`
`InnoPharma Exhibit 1012.0006
`
`

`

`
`
`
`
`DeLuca, “Formulation of Small Volume
`Parenterals,” Pharmaceutical Dosage
`Forms: Parenteral Medications Volume 1
`173-248 (Avis ed., 2d ed. 1992)
`
`Dukes, Antiuterotrophic effects of a pure
`antioestrogen, ICI 182,780: magnetic
`resonance imaging of the uterus in
`ovariectomized monkeys, 135 J.
`ENDOCRINOLOGY 239–247 (1992)
`(“Dukes 1992”)
`
`Ford, “Parenteral Products,”
`Pharmaceutics: The Science of Dosage
`Form Design 359-80 (Aulton ed., 1st ed.
`1988)
`
`Foster, The Mouse in Biomedical
`Research, Volume III 401-37 (1983)
`
`DeLuca was published in 1992 and
`is attached as Exhibit 1018 to the
`IPR.
`
`Dukes 1992 was published in 1992
`and is attached as Exhibit 1036 to
`the IPR.
`
`Ford was published in 1988 and is
`attached as Exhibit 1099 to the
`IPR.
`
`Foster was published in 1983 and
`is attached as Exhibit 1100 to the
`IPR.
`
`Gupta, Injectable Drug Development:
`Techniques to Reduce Pain and Irritation
`215-66 (1999)
`
`Gupta was published in 1999 and is
`attached as Exhibit 1101 to the
`IPR.
`
`Handbook of Pharmaceutical
`Excipients 7-9, 35-39, 82-83 (Wade ed.,
`2d. ed. 1994)
`
`Handbook of Pharmaceutical
`Excipients was published in 1994
`and is attached as Exhibit 1079 to
`the IPR.
`
`Howell, Clinical Studies with the Specific
`“Pure” Antioestrogen ICI 182780, 5 THE
`BREAST 192-95 (1996)
`
`Howell Breast was published in
`1996 and is attached as Exhibit
`1041 to the IPR.
`
`Howell, Pharmacokinetics,
`Pharmacological and Anti-tumor Effects
`of the Specific Anti-Oestrogen ICI
`182780 in Women with Advanced Breast
`Cancer, BRITISH J. OF CANCER, 74, p.
`300-308 (1996)
`
`Howell was published in 1996 and
`is attached as Exhibit 1007 to the
`IPR.
`
`3
`
`InnoPharma Exhibit 1012.0007
`
`

`

`
`
`
`
`FDA’s Inactive Ingredient Database
`(1996) (“IIG”)
`
`Jorgensen, Pharmacokinetic Studies in
`Volunteers of Intravenous and Oral Cis
`(Z)-Flupentixol and Intramuscular Cis
`(Z)-Flupentixol Decanoate in Viscoleo®,
`18 EUR. J. CLIN. PHARMACOL. 355-60
`(1980)
`
`Kohler, Plasma and Tissue
`Concentrations Following Intramuscular
`Administration of Etofenamat.
`Pharmacokinetics of Etofenamat and
`Flufenamic Acid in Plasma, Synovium,
`and Tissues of Patients with Chronic
`Polyarthritis after Administration of an
`Oily Solution of Etofenamat, 42
`ARZNEIMITTEL-FORSCHUNG (English
`Abstract) (1992)
`
`McLeskey, Tamoxifen-resistant
`fibroblast growth factor-transfected
`MCF-7 cells are cross-resistant in vivo to
`the antiestrogen ICI 182,780 and two
`aromatase inhibitors, 4 CLIN. CANCER
`RESEARCH 697–711 (1998)
`
`IIG was published in 1996 and is
`attached as Exhibit 1080 to the
`IPR.
`
`Jorgensen was published in 1980
`and is attached as Exhibit 1077 to
`the IPR.
`
`Kohler was published in 1992 and
`is attached as Exhibit 1076 to the
`IPR.
`
`McLeskey was published in March
`1998 and is attached as Exhibit
`1008 to the IPR.
`
`Nema, Excipients and Their Use in
`Injectable Products, 51 PDA J. PHARM.
`SCI. & TECH. 166-71 (1997)
`
`Nema was published in 1997 and is
`attached as Exhibit 1102 to the
`IPR.
`
`Ogasawara, Effects of Experimental
`Chemoendocrine Therapy with a
`Combination of a Pure Antiestrogen and
`5-Fluorouracil on Human Breast Cancer
`Cells Implanted in Nude Mice, 29
`SURGERY TODAY 149-56 (1999)
`
`Ogasawara was published in 1999
`and is attached as Exhibit 1103 to
`the IPR.
`
`4
`
`InnoPharma Exhibit 1012.0008
`
`

`

`
`
`
`
`Oldham, “Mass Transport to
`Electrodes,” Chemical Kinetics 79-143
`(Bamford ed., 1986)
`
`Oldham was published in 1986 and
`is attached as Exhibit 1104 to the
`IPR.
`
`O’Regan, Effects of the Antiestrogens
`Tamoxifen Toremifene and ICI 182,780
`on Endometrial Cancer Growth, 90 J.
`NAT’L CANCER INST. 1552 (1998)
`
`Osborne, Comparison of the Effects of a
`Pure Steroidal Antiestrogen with Those
`of Tamoxifen in a Model of Human
`Breast Cancer, 87 J. NATIONAL CANCER
`INSTITUTE 746-50 (1995)
`
`Parczyk, Progesterone Receptor
`Repression by Estrogens in Rat Urine
`Epithelial Cells, 63 J. STEROID BIOCHEM.
`MOLEC. BIOL. 309-16 (1997)
`
`O’Regan was published in October
`1998 1998 and is attached as
`Exhibit 1009 to the IPR.
`
`Osborne was published in 1995
`and is attached as Exhibit 1039 to
`the IPR.
`
`Parczyk was published in 1997 and
`is attached as Exhibit 1048 to the
`IPR.
`
`Powell, Compendium of Excipients for
`Parenteral Formulations, 52 PDA J.
`PHARM. SCI. & TECH. 238-311 (1998)
`
`Powell was published in 1998 and
`is attached as Exhibit 1105 to the
`IPR.
`
`Remington’s Pharmaceutical Sciences
`1538-39, 1545-50, 1686-88 (18th ed.
`1990)
`
`Remington was published in 1990
`and is attached as Exhibit 1106 to
`the IPR.
`
`Riffkin, Castor Oil as a Vehicle for
`Parenteral Administration of Steroid
`Hormones, 53 J. PHARM. SCIS. 891-95
`(1964)
`
`Roberts, Investigation of Cosolvent
`Effects on the Solvation of AOT Reverse
`Micelles in Supercritical Ethane, 102 J.
`PHYS. CHEM. B 9074-80 (1998)
`
`Robertson, J.F.R. et al., Duration Of
`Remission To ICI 182,780 Compared To
`Megestrol Acetate In Tamoxifen Resistant
`Breast Cancer, THE BREAST, Vol. 6:186-
`189 (1997) (“Robertson 1997”)
`
`Riffkin was published in August
`1964 and is attached as Exhibit
`1033 to the IPR.
`
`Roberts was published in 1998 and
`is attached as Exhibit 1107 to the
`IPR.
`
`Robertson 1997 was published in
`1997 and is attached as Exhibit
`1043 to the IPR.
`
`5
`
`InnoPharma Exhibit 1012.0009
`
`

`

`
`
`
`
`Sawka, Physiological Consequences of
`Hypohydration: Exercise Performance
`and Thermoregulation, 24 MEDICINE &
`SCIENCE IN SPORTS & EXERCISE 657-70
`(1992)
`
`Sawka was published in 1992 and
`is attached as Exhibit 1108 to the
`IPR.
`
`Simmons, The Laboratory Mouse:
`Selection and Management 127-128
`(1970)
`
`Simmons was published in 1970
`and is attached as Exhibit 1109 to
`the IPR.
`
`Spiegel, Use of Nonaqueous Solvents in
`Parenteral Products, 52 J. PHARM. SCIS.
`917-27 (1963)
`
`Spiegel was published in 1963 and
`is attached as Exhibit 1072 to the
`IPR.
`
`Ting, Solubility of Naproxen in
`Supercritical Carbon Dioxide with and
`without Cosolvents, 32 IND. ENG. CHEM.
`RES. 1471-81 (1993)
`
`Tse, Bioavailability of Parenteral Drugs
`I. Intravenous and Intramuscular Doses,
`34 J. PARENTERAL DRUG ASSOCIATION
`409-21 (1980) (“Tse I”)
`
`Tse, Bioavailability of Parenteral Drugs
`II. Parenteral Doses Other Than
`Intravenous and Intramuscular Routes,
`34 J. PARENTERAL DRUG ASSOCIATION
`484-95 (1980) (“Tse II”)
`
`U.S. Patent No. 5,183,814 (“Dukes ’814
`Patent”)
`
`U.S. Patent No. 4,212,863 (“Cornelius
`’863 Patent”)
`
`United States Pharmacopeia 23, National
`Formulary 18 (1995) (“USP 23”)
`
`Ting was published in 1993 and is
`attached as Exhibit 1110 to the
`IPR.
`
`Tse I was published in 1980 and is
`attached as Exhibit 1094 to the
`IPR.
`
`Tse II was published in 1980 and is
`attached as Exhibit 1111 to the
`IPR.
`
`Dukes ’814 Patent was published
`on February 2, 1993 and is
`attached as Exhibit 1047 to the
`IPR.
`
`Cornelius ’863 Patent was
`published on July 15, 1980 and is
`attached as Exhibit 1112 to the
`IPR.
`
`USP 23 was published on January
`1, 1995 and is attached as Exhibit
`1113 to the IPR.
`
`6
`
`InnoPharma Exhibit 1012.0010
`
`

`

`
`
`
`
`Wakeling, A Potent Specific Pure
`Antiestrogen with Clinical Potential, 51
`CANCER RESEARCH 3867-73 (1991)
`(“Wakeling 1991”)
`
`Wakeling, ICI 182,780, A New
`Antioestrogen with Clinical Potential, 43
`J. STEROID BIOCHEM. MOLEC. BIOL. 173-
`77 (1992) (“Wakeling 1992”)
`
`Wakeling, The Future of New Pure
`Antiestrogens in Clinical Breast Cancer,
`25 BREAST CANCER RESEARCH &
`TREATMENTS 1-9 (1993) (“Wakeling
`1993”)
`
`Wunsche, Estrogenic Regulation of
`Clusterin mRNA in Normal and
`Malignant Endometrial Tissue, 76 INT. J.
`CANCER 684-88 (1998) (“Wunsche”)
`
`Wakeling 1991 was published in
`1991 and is attached as Exhibit
`1031 to the IPR.
`
`Wakeling 1992 was published in
`1992 and is attached as Exhibit
`1040 to the IPR.
`
`Wakeling 1993 was published in
`1993 and is attached as Exhibit
`1058 to the IPR.
`
`Wunsche was published in 1998
`and is attached as Exhibit 1088 to
`the IPR.
`
`II. BACKGROUND AND QUALIFICATIONS
`
`
`6.
`
`A copy of my current curriculum vitae is attached as Exhibit A. A
`
`summary of my relevant experience and qualifications are provided below.
`
`
`7.
`
`In 1979, I received a Bachelor of Science degree in Pharmacy from
`
`the University of Strathclyde, Glasgow, UK. In 1984, I received a doctorate in
`
`Pharmaceutics from the University of London, UK. I joined the faculty at the
`
`University of Connecticut in 1993 and was promoted to Full Professor of
`
`Pharmaceutics in 1999. I am currently a Distinguished Professor at the University
`
`of Connecticut (appointed in 2009) and hold positions as the Pharmaceutics
`
`Discipline Coordinator, and the Chair of the School of Pharmacy Study Abroad
`
`Committee.
`
`
`
`7
`
`InnoPharma Exhibit 1012.0011
`
`

`

`
`
`
`8.
`
`I have served as an executive of several professional organizations
`
`focused on the field of pharmaceutics and drug development. For example, I was
`
`the 2002 President of the American Association of Pharmaceutical Scientists
`
`(“AAPS”), which is the largest professional organization globally representing
`
`scientists in pharmaceutics, biopharmaceutics, and related disciplines. From 2009
`
`until 2010, I was president of the Controlled Release Society (“CRS”), which is a
`
`professional organization focused on developments
`
`in controlled release
`
`technologies.
`
`
`9.
`
`I currently serve on the boards of eleven international journals: The
`
`AAPS Journal, AAPS Pharm Sci Tech, The
`
`International Journal of
`
`Pharmaceutics, The Journal of Microencapsulation, The Journal of Pharmacy and
`
`Pharmacology, The Journal of Drug Delivery Science and Technology, Current
`
`Drug Discovery, Critical Reviews in Therapeutic Drug Carrier Systems, The
`
`Journal of Drug Delivery & Transformational Research, Acta Pharmaceutica
`
`Sinica B, and the Journal of Diabetes Science & Technology.
`
`
`10.
`
`I am currently an editor of The
`
`International Journal of
`
`Pharmaceutics. From 2003 until 2012, I was an editor for the Journal of Drug
`
`Delivery Science and Technology. From 1999 until 2004, I was an editor for the
`
`American Association of Pharmaceutical Science Journal. I also serve as referee
`
`for more than 19 journals, including the Journal of Controlled Release, Critical
`
`
`
`8
`
`InnoPharma Exhibit 1012.0012
`
`

`

`
`
`Reviews In Therapeutic Drug Carrier Systems, Pharmaceutical Research, Nature,
`
`International Journal of Pharmaceutics, and the Journal of Pharmacy And
`
`Pharmacology, to name a few. In my roles as editor and referee, I routinely
`
`analyze the scientific methodologies, data, descriptions, and analyses provided in
`
`submissions to confirm that such methodologies, data, descriptions, and analyses
`
`are scientifically rigorous and correctly support any conclusions and hypotheses
`
`drawn there from. In cases where the data does not conclusively support a
`
`proposition set forth in the article, I may suggest additional experiments for the
`
`author(s) to conduct to confirm such proposition or may suggest rejection of the
`
`manuscript from publication.
`
` My research group has studied controlled release formulations for
`11.
`
`more than thirty years. I have authored or co-authored 168 refereed scientific
`
`articles, most of which have been published in high-impact scientific journals. I
`
`have also authored two pharmaceutical books relating to drug delivery and
`
`authored 35 chapters related to drug delivery in various scientific books. In
`
`addition, my research has been presented 556 times at major international scientific
`
`meetings, and I have been invited to present on more than 272 occasions, including
`
`giving 21 keynote and plenary addresses.
`
` At the University of Connecticut, I direct an active research group
`12.
`
`composed of a research technician, assistant research professors, post-doctoral
`
`
`
`9
`
`InnoPharma Exhibit 1012.0013
`
`

`

`
`
`fellows, graduate students, professional students, and undergraduate students. My
`
`research is focused on colloid and interfacial chemistry as they relate to drug
`
`delivery and implantable biosensors for metabolic monitoring. Research efforts
`
`cover the basic science of interfacial chemistry, the application of this in
`
`preformulation and formulation, the development of novel drug delivery systems,
`
`and the in vitro and in vivo testing of these drug delivery systems including
`
`investigation of biopharmaceutics and pharmacodynamics. This research is applied
`
`to solving problems with respect to drug and gene delivery and focuses on
`
`microsphere, nanoparticle, liposome, emulsion and hydrogel delivery systems. In
`
`the area of implantable biosensors, efforts are focused on biocompatible coatings
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`to prevent the foreign body reaction that would otherwise result in loss of sensor
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`sensitivity and eventual sensor failure. Major contributions include: improved
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`understanding of the mechanism of complex coacervation of polymers; correlation
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`of interfacial properties with emulsion and nanoparticle stability, development of
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`novel microcapsule dosage forms; modeling of the pharmacokinetics of proteins
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`implanted in microsphere dosage forms; the development of a novel composite
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`coating for implantable devices that minimizes the inflammatory response and
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`prevents fibrous encapsulation; the development of a method that allows long-term
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`intracellular and intranuclear tracking of gene therapeutics and gene delivery
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`vectors as well as the design of safe, efficient and stable non-viral gene delivery
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`10
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`InnoPharma Exhibit 1012.0014
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`systems; development of “real-time” and accelerated performance tests for
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`modified release parenteral formulations;
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`the development of a “smart”
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`microsphere/hydrogel biocompatible coating that has been shown to prevent the
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`foreign body response in animal models in excess of 3 months; application of
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`quality-by-design principles
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`to nanoparticles and
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`liposomes; and novel
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`manufacturing methods for complex dosage forms. As part of our research, my
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`group develops extended release formulations, for example long-term (1-6 months)
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`releasing microspheres to counter the foreign body response to implanted devices,
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`long releasing contraceptive implants (~ five years) and extended release in situ
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`forming gels. My research group also focuses on nanoparticulate dosage forms for
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`poorly soluble drugs as well as on the development of stable nano- and micro-
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`emulsions and multiple emulsions.
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` My research is funded by extramural grants from companies and
`13.
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`funding agencies. 25 graduate students working under my direction have obtained
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`their doctorate degrees. Also, as part of my academic career, I have taught courses
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`in Controlled Drug Delivery, Foundations of Pharmaceutics, Drug Discovery and
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`Development, Advanced Biopharmaceutics, and Interfacial and Colloid Chemistry.
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`14.
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`I have received various honors and awards throughout my career. In
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`2014, I was the recipient of the AAPS Research Achievement Award in
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`Formulation Design and Development, the AAPS Outstanding Educator Award,
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`11
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`InnoPharma Exhibit 1012.0015
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`and the CRS’s Distinguished Service Award. In 2013, I was awarded the AAPS
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`IPEC Ralph Shangraw Memorial Award for outstanding research in the area of
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`pharmaceutical excipients. In 2011, I received the APSTJ Nagai International
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`Woman Scientist Award from the Japanese Pharmaceutical Science Association. I
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`was the first recipient of the CRSI Fellowship for outstanding contributions in the
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`area of drug delivery in 2010. In 2007, I received the Outstanding Manuscript
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`Award from the AAPS Journal. I was elected Pharmacy School Teacher of the
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`Year in 2005. And in 1991, I was awarded the Outstanding Teacher of the Year
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`Award.
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`15.
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`I am a named inventor of two issued U.S. patents and three pending
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`U.S. patent applications, none of which are at issue in this proceeding.
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` Based on my academic credentials and research over the past thirty
`16.
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`plus years, I am an expert in pharmaceutical drug development, particularly the
`
`development of controlled release formulations.
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`
`17.
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`I am being compensated at my standard rate of $600 for providing my
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`opinions and analysis in this proceeding. My compensation is not contingent in
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`any way on the substance of my opinions. Within the past four years, I have
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`testified in the following matters: Amneal Pharmaceuticals, LLC vs. Endo
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`Pharmaceuticals Inc., C.A. Nos. IPR2014-00360, IPR2014-01365, and Shire LLC,
`
`et al. v. Abhai, LLC, No. 1:15-cv-13909 (D. Mass.).
`
`
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`12
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`InnoPharma Exhibit 1012.0016
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`III. MATERIALS CONSIDERED FOR THIS DECLARATION
`
`
`18.
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`In addition to my general knowledge, education, and experience, I
`
`considered the materials listed in Exhibit B in forming my opinions.
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`IV. BACKGROUND
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`A. Overview of the ’680 Patent
`
` U.S. Patent No. 8,329,680, entitled “Formulation,”
`19.
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`issued on
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`December 11, 2012. The patent lists two inventors, John Evans and Rosalind
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`Grundy, and is assigned to AstraZeneca AB.
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` The ’680 patent was filed on October 15, 2008, and claims two related
`20.
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`U.S. patents: U.S. Patent No. 6,774,122 and U.S. Patent No. 7,456,160. The ’680
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`patent also asserts priority to two foreign applications filed on January 10, 2000
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`and April 12, 2000. The applications of all four of these patents are incorporated
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`in their entireties. Ex. 1001 at 1:6-13.
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` The Abstract of the ’680 patent describes the invention as “a novel
`21.
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`sustained release pharmaceutical formulation for administration by injection”
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`containing the steroidal antiestrogen fulvestrant. Id. at Abstract. Antiestrogens
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`have been long known to be efficacious against breast and reproductive tract
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`diseases, and the rationale for their design was described in literature decades ago.
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`Id. at 1:23-25; 1:38-50. Fulvestrant specifically was first described in 1989, more
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`than a decade before the earliest priority date of the ’680 patent. Id. at 1:51-2:4.
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` Not only was fulvestrant well known in the art, the ’680 patent
`22.
`13
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`InnoPharma Exhibit 1012.0017
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`concedes that the sustained release formulation was well known. As the ’680
`
`patent states, “there are a number of sustained release injectable steroidal
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`formulations which have been commercialized,” with formulations achieving
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`extended release for periods from one to eight weeks. Id. at 2:54-66. The ’680
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`patent also notes that these formulations included “additional excipients such as
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`benzyl benzoate, benzyl alcohol, and ethanol,” in addition to castor oil, which has
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`been known to have a “greater solvating ability” for steroidal compounds since
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`1964. Id. at 2:61-65, 5:47-53.
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` The ’680 patent acknowledges
`23.
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`that oil-based formulations of
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`fulvestrant were developed decades ago—and well before the earliest priority date
`
`of the ’680 patent. Because these formulation techniques and the fulvestrant
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`compound itself were well known, oil-based formulations of fulvestrant were
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`developed long before the ’680 patent. U.S. Patent No. 5,183,814, invented by
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`AstraZeneca employee Michael Dukes, disclosed a fulvestrant pharmaceutical
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`formulation in 1989. Id. at 3:63-65. Much like the claims of the ’680 patent, that
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`formulation included castor oil, benzyl alcohol, and 50 mg/ml fulvestrant. Id.
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` The allegedly inventive element of ’680 patent is the discovery that
`24.
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`“the introduction of a non-aqueous ester solvent which is miscible in the castor oil
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`and an alcohol surprisingly eases the solubilisation of fulvestrant.” Id. at 6:8-18. In
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`making this claim, the ’680 patent fails to acknowledge that benzyl benzoate was
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`14
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`InnoPharma Exhibit 1012.0018
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`known in the art to enhance steroid solubility in oils, and that the castor-oil based
`
`commercially available steroid formulations in Table 1 contained benzyl benzoate.
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`See Exhibit 1018 at 0027; Ex. 1001 at Table 1, Table 2.
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` The ’680 patent includes two independent claims (claims 1 and 9) and
`25.
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`18 dependent claims. For the purposes of this report, I have been asked to opine
`
`on claims 1, 2, 3, and 6. Those claims read as follows:
`
`1. A method for treating a hormonal dependent benign or
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`malignant disease of the breast or reproductive tract
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`comprising administering intramuscularly to a human in
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`need of such treatment a formulation comprising:
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`
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`
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`about 50 mgml−1 of fulvestrant;
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`about 10% w/v of ethanol;
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`about 10% w/v of benzyl alcohol;
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`about 15% w/v of benzyl benzoate; and
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`a sufficient amount of castor oil vehicle;
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`wherein the method achieves a therapeutically
`
`significant blood plasma fulvestrant concentration of at
`
`least 2.5 ngml−1 for at least four weeks.
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`15
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`InnoPharma Exhibit 1012.0019
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`2. The method of claim 1, wherein the therapeutically
`
`significant blood plasma fulvestrant concentration is at
`
`least 8.5 ngml−1.
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`3. The method of claim 1, wherein the hormonal
`
`dependent benign or malignant disease of the breast or
`
`reproductive tract is breast cancer.
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`6. The method of claim 2, wherein the hormonal
`
`dependent benign or malignant disease of the breast or
`
`reproductive tract is breast cancer.
`
`B.
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`Prosecution History of the ’680 Patent
`
` The Patent Office found all pending claims obvious in light of four
`26.
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`references, “(Dukes (EP 0 346 014) in view of Lehmann et al. (US Patent Re.
`
`28,690), GB 1 569 286, Osborne et al., Journal of National Cancer Institute,
`
`1995;87(10):746-750, and Remington (Remington’s Pharmaceutical Sciences, 18th
`
`ed., 1990, page 219).” Ex. 1042 at 0252-53. The Patent Office found that “[i]t
`
`would have been obvious to one of ordinary skill in the art at the time the invention
`
`was made to employ benzyl benzoate, ethanol, castor oil, and benzyl alcohol, in the
`
`herein claimed weight percent, with fulvestrant in the dosage herein, in a method
`
`of treating postmenopausal symptoms such as urogenital atrophy in the vagina.”
`
`Ex. 1042 at 0254. And specifically, the Patent Office found that “[o]ne of ordinary
`
`
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`16
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`InnoPharma Exhibit 1012.0020
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`skill in the art would have been motivated to employ benzyl benzoate, ethanol,
`
`castor oil, and benzyl alcohol, in the herein claimed weight percent, with
`
`fulvestrant, in the dosage herein, in a method of treating postmenopausal
`
`symptoms such as urogenital atrophy or treating breast cancer,” “[c]astor oil and
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`benzyl alcohol are known to be effective as vehicle for fulvestrant,” “[e]thanol is a
`
`commonly used pharmaceutical solve