`Case IPR2017-00904
`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. 6,774,122
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
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`
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`INNOPHARMA LICENSING, LLC,
`Petitioner
`
`v.
`
`
`ASTRAZENECA AB,
`Patent Owner
`
`
`
`
`
`
`
`
`Case IPR2017-00904
`Patent No. 6,774,122
`
`
`
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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. 6,774,122
`
`
`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 IPR2017-00904
`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. 6,774,122
`
`
`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 ’122 Patent ............................................................. 13
`
`B.
`
`The ’122 Patent Prosecution History ............................................... 17
`
`C. Relevant Related Prosecution Histories .......................................... 19
`
`i.
`
`ii.
`
`The Sawchuk Declaration ...................................................... 19
`
`The Gellert Declaration .......................................................... 21
`
`V.
`
`LEVEL OF ORDINARY SKILL IN THE PERTINENT ART .............. 24
`
`VI. BROADEST REASONABLE CONSTRUCTION ................................... 25
`
`VII. UNDERSTANDING OF THE LAW ......................................................... 25
`
`VIII. TECHNICAL OVERVIEW OF THE ASPECTS OF FORMULATION
`SCIENCE RELEVANT TO MY OPINIONS ........................................... 30
`
`IX. DETAILED INVALIDITY ANALYSIS.................................................... 34
`
`A.
`
`Summary of Opinions ....................................................................... 35
`
`B.
`
`Primary Prior Art Relied on in this Declaration ........................... 37
`
`i.
`
`Howell 1996 .............................................................................. 37
`
`ii. McLeskey 1998 ........................................................................ 40
`
`iii. O’Regan ................................................................................... 44
`
`
`
`ii
`
`InnoPharma Exhibit 1012.0002
`
`

`

`Case IPR2017-00904
`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. 6,774,122
`
`
`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 IPR2017-00904
`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. 6,774,122
`
`
`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 ....107
`
`i.
`
`ii.
`
`A Person of Ordinary Skill in the Art Would Have Been
`Motivated to Combine Howell 1996, McLeskey 1998, and
`O’Regan .................................................................................107
`
`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 ..........108
`
`iii. The Combination of Howell 1996, McLeskey 1998, and
`O’Regan Teaches Each Element of the Challenged Claim
` .................................................................................................110
`
`F.
`
`Secondary Considerations Do Not Overcome the Prima Facie
`Case of Obviousness ........................................................................117
`
`X.
`
`SUPPLEMENTATION .............................................................................123
`
`XI. CONCLUSION ..........................................................................................123
`
`
`
`iv
`
`InnoPharma Exhibit 1012.0004
`
`

`

`Case IPR2017-00904
`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. 6,774,122
`
`
`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. 6,774,122 (“the ’122 patent” or “the patent”).
`
`
`2.
`
`I have been asked to provide my opinions on the validity of claims 1,
`
`2, 5, and 9 of the ’122 patent (“the challenged claims”).
`
`
`3.
`
`In preparing this Declaration, I have reviewed the ’122 patent, the file
`
`history of the ’122 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
`
`8,329,680 (“the ’680 patent”). I have also reviewed the petition for inter partes
`
`review of the ’122 patent filed by Mylan Pharmaceuticals, Inc. (IPR2016-01316)
`
`(“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 related ’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”)
`
`DeLuca, “Formulation of Small Volume
`Parenterals,” Pharmaceutical Dosage
`Forms: Parenteral Medications Volume 1
`173-248 (Avis ed., 2d ed. 1992)
`
`Chwalisz was published in 1998
`and is attached as Exhibit 1089 to
`the IPR.
`
`DeLuca was published in 1992 and
`is attached as Exhibit 1018 to the
`IPR.
`
`2
`
`InnoPharma Exhibit 1012.0006
`
`

`

`
`
`
`
`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)
`
`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)
`
`FDA’s Inactive Ingredient Database
`(1996) (“IIG”)
`
`Howell was published in 1996 and
`is attached as Exhibit 1007 to the
`IPR.
`
`IIG was published in 1996 and is
`attached as Exhibit 1080 to the
`IPR.
`
`3
`
`InnoPharma Exhibit 1012.0007
`
`

`

`
`
`
`
`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)
`
`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.
`
`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.
`
`4
`
`InnoPharma Exhibit 1012.0008
`
`

`

`
`
`
`
`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
`
`a referee for more than 19 journals, including the Journal of Controlled
`
`
`
`8
`
`InnoPharma Exhibit 1012.0012
`
`

`

`
`
`Release, Critical Reviews
`
`In Therapeutic Drug Carrier Systems,
`
`Pharmaceutical Research, Nature, International Journal of Pharmaceuti cs, 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
`12.
`
`
`
`9
`
`InnoPharma Exhibit 1012.0013
`
`

`

`
`
`group composed of a research technician, assistant research professors, post -
`
`doctoral 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 to prevent the
`
`foreign body reaction that would otherwise result in loss of sensor sensitivity
`
`and eventual sensor
`
`failure. Major contributions
`
`include:
`
`improved
`
`understanding of the mechanism of complex coacervation of polymers;
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`correlation of interfacial properties with emulsion and nanoparticle stability,
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`development of novel microcapsule dosage forms; modeling of
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`the
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`pharmacokinetics of proteins implanted in microsphere dosage forms; the
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`development of a novel composite coating for implantable devices that
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`minimizes the inflammatory response and prevents fibrous encapsulation; the
`
`
`
`10
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`InnoPharma Exhibit 1012.0014
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`
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`development of a method that allows long-term intracellular and intranuclear
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`tracking of gene therapeutics and gene delivery vectors as well as the design
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`of safe, efficient and stable non-viral gene delivery systems; development of
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`“real-time” and accelerated performance tests for modified release parenteral
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`formulations;
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`the development of
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`a
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`“smart” microsphere/hydrogel
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`biocompatible coating that has been shown to prevent the foreign body
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`response in animal models in excess of 3 months; application of quality -by-
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`design principles to nanoparticles and liposomes; and novel manufacturing
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`methods for complex dosage forms. As part of our research, my group
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`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
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`devices, long releasing contraceptive implants (~ five years) and extended
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`release
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`in situ forming gels. My
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`research group also
`
`focuses on
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`nanoparticulate dosage forms for poorly soluble drugs as well as on the
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`development of stable nano- and micro-emulsions and multiple emulsions.
`
` My research is funded by extramural grants from companies and
`13.
`
`funding agencies. 25 graduate students working under my direction have
`
`obtained their doctorate degrees. Also, as part of my academic career, I have
`
`taught courses in Controlled Drug Delivery, Foundations of Pharmaceutics,
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`Drug Discovery and Development, Advanced Biopharmaceutics, and
`
`
`
`11
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`InnoPharma Exhibit 1012.0015
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`Interfacial and Colloid Chemistry.
`
`
`14.
`
`I have received various honors and awards throughout my career.
`
`In 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, and the CRS’s Distinguished Service Award. In 2013, I was awarded
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`the AAPS IPEC Ralph Shangraw Memorial Award for outstanding research
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`in the area of pharmaceutical excipients. In 2011, I received the APSTJ
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`Nagai
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`International Woman Scientist Award
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`from
`
`the
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`Japanese
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`Pharmaceutical Science Association. I was the first recipient of the CRSI
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`Fellowship for outstanding contributions in the area of drug delivery in 2010.
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`In 2007, I received the Outstanding Manuscript Award from the AAPS
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`Journal. I was elected Pharmacy School Teacher of the Year in 2005. And in
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`1991, I was awarded the Outstanding Teacher of the Year Award.
`
`
`15.
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`I am a named inventor of two issued U.S. patents and three
`
`pending U.S. patent applications, none of which are at issue in this
`
`proceeding.
`
` Based on my academic credentials and research over the past
`16.
`
`thirty plus years, I am an expert in pharmaceutical drug development,
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`particularly the development of controlled release formulations.
`
`
`17.
`
`I am being compensated at my standard rate of $600 for providing my
`
`
`
`12
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`InnoPharma Exhibit 1012.0016
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`opinions and analysis in this proceeding. My compensation is not contingent in
`
`any way on the substance of my opinions. Within the past four years, I have
`
`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.).
`
`III. MATERIALS CONSIDERED FOR THIS DECLARATION
`
`
`18.
`
`In addition to my general knowledge, education, and experience, I
`
`considered the materials listed in Exhibit B in forming my opinions.
`
`IV. BACKGROUND
`
`A. Overview of the ’122 Patent
`
` The ’122 patent was filed on January 9, 2001, and asserts priority to
`19.
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`British applications filed on January 10, 2000 and April 12, 2000. The ’122 patent
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`is generally directed to a “sustained release pharmaceutical formulation” of
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`fulvestrant “adapted for administration by injection.” Ex. 1001 at Abstract.
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` Fulvestrant is a steroidal antiestrogen that was first patented and
`20.
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`described more than a decade before the earliest priority date of the ’122 patent.
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`Id. at 1:45-55. The ’122 patent acknowledges that antiestrogens have been long
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`known to be efficacious against “many benign and malignant diseases of the breast
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`and reproductive tract,” and that “the rationale for [their] design and testing” was
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`described in the literature well before the ’122 patent. Id. at 1:16-22; 1:43-46.
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` The ’122 patent similarly acknowledges that the formulation of
`21.
`13
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`InnoPharma Exhibit 1012.0017
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`sustained release steroidal dosage forms was well-known in the art. Indeed, the
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`’122 patent recognizes that “there are a number of sustained release injectable
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`steroidal formulations which have been commercialised,” including formulations
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`that could achieve an extended release for as long as 8 weeks. Id. at 2:55-67. The
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`’122 patent concedes that a number of these steroidal formulations included
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`“additional excipients such as benzyl benzoate, benzyl alcohol and ethanol”—the
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`same excipients AstraZeneca now seeks to claim. Id. at 2:61-65. A number of the
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`formulations also contained castor oil, which was known to have a “greater
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`solvating ability” for steroidal compounds since at least 1964—nearly forty years
`
`before the earliest priority date of the ’122 patent. Id. at 5:20-25.
`
` Each of the components of the formulation recited in the claims of the
`22.
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`’122 patent has a well-known purpose in the formulation. The castor oil is the
`
`primary vehicle, which acts as a solvent for the fulvestrant. The ethanol, benzyl
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`alcohol, and benzyl benzoate are all cosolvents, which improve the solubility of
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`fulvestrant in the castor oil. Ex. 1079 at 0003, 0006, 0009. Additionally, the
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`benzyl alcohol functions as an antimicrobial preservative and an anesthetic at the
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`concentration used. Id. at 0006.
`
` Because the fulvestrant compound itself and the utility of these
`23.
`
`excipients were well-known, oil-based formulations of fulvestrant were developed
`
`long before the ’122 patent. For example, the ’122 patent acknowledges that
`
`
`
`14
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`InnoPharma Exhibit 1012.0018
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`another AstraZeneca inventor, Dukes, first disclosed a fulvestrant pharmaceutical
`
`formulation in 1989—approximately 11 years before the ’122 patent. Ex. 1001 at
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`3:60-67. Like the claimed formulation, the Dukes formulation included 50 mg/ml
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`fulvestrant, castor oil, and benzyl alcohol. Id.
`
` The ’122 patent asserted that its improvement over this established
`24.
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`prior art was the “surprising” discovery that benzyl benzoate—a non-aqueous ester
`
`solvent—increased the solubility of fulvestrant. Id. at 5:48-55. The ’122 inventors
`
`made this assertion despite the fact that benzyl benzoate was known in the art to
`
`“enhance steroid solubility in oils” (Ex. 1018 at 0027) and that the 6 castor oil-
`
`based commercially available steroid formulations in Table 1 contained benzyl
`
`benzoate. Ex. 1001 at Table 1; Table 2.
`
` As issued, the ’122 patent includes 9 claims. I have been asked to
`25.
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`opine on claims 1, 2, 5, and 9 in my analysis, which I have included below:
`
`1. A method of treating a hormonal dependent benign or
`
`malignant disease of the breast or reproductive tract by
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`administration to a human in need of such treatment an
`
`intra-muscular injection of a pharmaceutical formulation
`
`comprising fulvestrant, a mixture of 10% weight of
`
`ethanol per volume of formulation, 10% weight of benzyl
`
`alcohol per volume of formulation and 15% weight of
`
`
`
`15
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`InnoPharma Exhibit 1012.0019
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`benzyl benzoate per volume of formulation and a
`
`sufficient amount of a castor oil vehicle, whereby a
`
`therapeutically significant blood plasma fulvestrant
`
`concentration of at least 2.5 ngml−1 is attained for at least
`
`2 weeks after injection.
`
`2. The method as claimed in claim 1 wherein the benign
`
`or malignant disease is breast cancer.
`
`5. A method of treating a hormonal dependent benign or
`
`malignant disease of the breast or reproductive tract by
`
`administration to a human in need of such treatment an
`
`intra-muscular injection of a pharmaceutical formulation
`
`comprising fulvestrant, a mixture of 10% weight of
`
`ethanol per volume of formulation, 10% weight of benzyl
`
`alcohol per volume of formulation and 15% weight of
`
`benzyl benzoate per volume of formulation and a
`
`sufficient amount of a castor oil vehicle whereby the
`
`formulation comprises at least 45 mg/ml of fulvestrant.
`
`9. The method as claimed in claim 5 wherein the benign
`
`or malignant disease is breast cancer.
`
`16
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`InnoPharma Exhibit 1012.0020
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`B.
`
`
`26.
`
`The ’122 Patent Prosecution History
`
`I have reviewed the prosecution history of the ’122 patent in forming
`
`my opinions expressed in this declaration. Below, I discuss two aspects of the
`
`prosecution history that are especially relevant to my opinion: (1) the claimed
`
`elements that the Patent Office recognized were well known in the art and obvious;
`
`and (2) the lack of meaningful discussion of two critical pieces of prior art. I
`
`understand that other aspects of the prosecution history relevant to the ’122
`
`patent’s validity are being discussed by other experts.
`
` First, the Patent Office recognized that numerous aspects of the ’122
`27.
`
`patent claims were well known in the art and obvious to a person of skill in the art.
`
`Specifically, in an August 27, 2003 Office Action, the Patent Office recognized
`
`that “[o]ne of ordinary 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 . . . .” Ex. 1006 at 05