`Filed on behalf of: Abraxis Biosciences, LLC
`
`
`Filed: February 16, 2018
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`
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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`APOTEX INC. AND APOTEX CORP.
`Petitioners
`
`v.
`
`ABRAXIS BIOSCIENCE, LLC
`Patent Owner
`_______________________
`
`Case IPR2018-00152
`U.S. Patent 7,820,788
`_______________________
`
`
`PATENT OWNER PRELIMINARY RESPONSE
`
`
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`
`
`

`

`IPR2018-00152
`U.S. Patent 7,820,788
`
`TABLE OF CONTENTS
`TABLE OF CONTENTS ........................................................................................ i
`TABLE OF AUTHORITIES ................................................................................iv
`TABLE OF ABBREVIATIONS ......................................................................... vii
`LIST OF EXHIBITS ........................................................................................... viii
`I.
`INTRODUCTION ........................................................................................ 1
`II.
`BACKGROUND ........................................................................................... 4
`A.
`The Development of Abraxane® ......................................................... 4
`B.
`The ’788 Patent .................................................................................... 8
`C.
`Procedural History ................................................................................ 9
`III. LEVEL OF ORDINARY SKILL IN THE ART AND CLAIM
`CONSTRUCTION ...................................................................................... 10
`A.
`The POSA ........................................................................................... 10
`B.
`Claim Construction............................................................................. 10
`1.
`The plain language of the claim is directed to the finished
`pharmaceutical product ............................................................ 11
`The specification and prosecution history support this
`construction .............................................................................. 12
`Petitioners’ proposed construction is flawed ........................... 14
`3.
`IV. THE PETITION FAILS TO DEMONSTRATE A
`REASONABLE LIKELIHOOD THAT ANY CHALLENGED
`CLAIM IS ANTICIPATED (GROUND I)............................................... 14
`A. Desai Does Not Expressly Disclose The Weight Ratio ..................... 15
`1.
`Example 1 does not teach a final albumin-paclitaxel
`weight ratio of 9:1 .................................................................... 15
`The remainder of Desai is silent about the weight ratio in
`the final composition ................................................................ 16
`Desai Does Not Inherently Disclose The Weight Ratio .................... 16
`1.
`Petitioners ignore that Example 1 produces Capxol,
`which has a final albumin-to-paclitaxel ratio of 13.3:1,
`not 9:1....................................................................................... 18
`
`2.
`
`2.
`
`B.
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`C.
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`V.
`
`C.
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`D.
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`2.
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`3.
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`2.
`
`IPR2018-00152
`U.S. Patent 7,820,788
`Petitioners’ argument that Example 16, rather than
`Example 1, produces Capxol is incorrect ................................ 19
`Because of paclitaxel loss during processing, a 9:1
`starting ratio will not necessarily remain in the finished
`product...................................................................................... 26
`Dependent Claim 11 Requires Exactly “1:1 To 9:1” And Is Not
`Anticipated Either Expressly Or Inherently ....................................... 29
`THE PETITION FAILS TO DEMONSTRATE A
`REASONABLE LIKELIHOOD THAT DESAI ALONE
`RENDERS OBVIOUS ANY OF THE CHALLENGED CLAIMS
`(GROUND II.A) .......................................................................................... 30
`A. Desai Does Not Teach All Of The Claimed Elements....................... 30
`B.
`Desai Does Not Disclose A Range Of Final Albumin-To-
`Paclitaxel Weight Ratios That Includes 9:1 ....................................... 31
`1.
`A POSA would not modify Example 1 ................................... 32
`2.
`A POSA would have no motivation to modify the 1%
`albumin concentration and not other parameters ..................... 33
`A POSA Would Have Sought To Maximize The Benefits
`Conferred By Albumin ....................................................................... 35
`1.
`Albumin increases efficacy ...................................................... 35
`2.
`Albumin plays a critical stabilization role ............................... 36
`3.
`Albumin inhibits crystallization ............................................... 37
`There Was No Motivation To Reduce Capxol’s Albumin-To-
`Paclitaxel Ratio ................................................................................... 37
`1.
`Petitioners have not identified a motivating problem to be
`solved ....................................................................................... 37
`A POSA would not have had a reasonable expectation
`that the claimed ratio of 9:1 would be stable ........................... 43
`VI. THE PETITION FAILS TO DEMONSTRATE A
`REASONABLE LIKELIHOOD THAT ANY CHALLENGED
`CLAIM WOULD HAVE BEEN OBVIOUS OVER THE
`COMBINATION OF DESAI, KADIMA, AND LIVERSIDGE
`(GROUND II.B) .......................................................................................... 46
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`3.
`
`4.
`
`IPR2018-00152
`U.S. Patent 7,820,788
`A. Desai In Combination With Kadima Does Not Render The
`Claims Obvious .................................................................................. 47
`1.
`Kadima does not teach the claimed weight ratio ..................... 47
`2.
`A POSA would not have been motivated to reduce the
`ratio based on cost .................................................................... 50
`Kadima teaches away from reducing the ratio from
`13.3:1 to 9:1 ............................................................................. 52
`A POSA would have had no reason to combine Desai
`and Kadima with a reasonable expectation of success ............ 55
`Desai In Further View Of Liversidge Does Not Render The
`Claims Obvious .................................................................................. 56
`1.
`An albumin-paclitaxel weight ratio of “about 1:1 to about
`9:1” is not prima facie obvious ................................................ 56
`A POSA would have no reason to combine Desai and
`Liversidge with a reasonable expectation of success .............. 58
`VII. DEPENDENT CLAIM 11 IS NONOBVIOUS ........................................ 59
`VIII. SECONDARY CONSIDERATIONS SUPPORT
`NONOBVIOUSNESS ................................................................................. 59
`A.
`The Cell-Binding Results Were Unexpected And Have A
`Nexus To The Claims ......................................................................... 60
`The Results Of Clinical Studies Were Unexpected ........................... 62
`B.
`IX. CONCLUSION ........................................................................................... 65
`
`
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`B.
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`2.
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`TABLE OF AUTHORITIES
`
`IPR2018-00152
`U.S. Patent 7,820,788
`
`Page
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`
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`CASES
`
`ACTV, Inc. v. Walt Disney Co.,
`346 F.3d 1082 (Fed. Cir. 2003) .......................................................................... 11
`
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) .......................................................................... 65
`
`AstraZeneca Pharm. LP v. Anchen Pharm., Inc.,
`No. 10-cv-1835 JAP TJB, 2012 WL 1065458 (D.N.J. Mar. 29,
`2012) ................................................................................................................... 45
`
`Atofina v. Great Lakes Chem. Corp.,
`441 F.3d 991 (Fed. Cir. 2006) ............................................................................ 15
`
`Avaya Inc. v. Network-1 Security Solutions, Inc.,
`IPR2013-00071, Paper 103 (P.T.A.B. May 22, 2014) ....................................... 25
`
`Continental Can Co. U.S.A. v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) .............................................................. 17, 20, 25
`
`Cumberland Pharm. Inc. v. Mylan Institutional LLC,
`846 F.3d 1213 (Fed. Cir. 2017) .......................................................................... 46
`
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) .............................................................. 53, 54, 55
`
`Electro Med. Sys., S.A. v. Cooper Life Scis., Inc.,
`34 F.3d 1048 (Fed. Cir. 1994) ............................................................................ 17
`
`Eli Lilly & Co. v. Actavis Elizabeth LLC,
`435 F. App’x 917 (Fed. Cir. 2011) ..................................................................... 18
`
`Exxon Chem. Patents, Inc. v. Lubrizol Corp.,
`64 F.3d 1553 (Fed. Cir. 1995) ............................................................................ 14
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`IPR2018-00152
`U.S. Patent 7,820,788
`
`Finnigan Corp. v. Int’l Trade Commission,
`180 F.3d 1354 (Fed. Cir. 1999) .......................................................................... 25
`
`Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc.,
`655 F.3d 1291 (Fed. Cir. 2011) .......................................................................... 57
`
`In re Gordon,
`733 F.2d 900 (Fed. Cir. 1984) ...................................................................... 54, 55
`
`In re Haruna,
`249 F.3d 1327 (Fed. Cir. 2001) .......................................................................... 54
`
`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988) ............................................................................ 45
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .............................................................. 38, 39, 40
`
`Merck Sharp & Dohme B.V. v. Warner Chilcott Company,
`LLC, No. 16-cv-2583, 2017 WL 4711478 (Fed. Cir. 2017) .............................. 32
`
`Minnesota Mining & Mfg. Co. v. Johnson & Johnson Orthopaedics,
`Inc.,
`976 F.2d 1559 (Fed. Cir. 1992) .......................................................................... 17
`
`Novartis Pharms. Corp. v. Watson Labs., Inc.,
`611 F. App’x 988 (Fed. Cir. 2015) ..................................................................... 38
`
`PAR Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 31
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .......................................................................... 11
`
`Ricoh Co., Ltd. v. Quanta Computer Inc.,
`550 F.3d 1325 (Fed. Cir. 2008) .............................................................. 54, 55, 59
`
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`IPR2018-00152
`U.S. Patent 7,820,788
`
`Southwire Co. v. Cerro Wire LLC,
`870 F.3d 1306 (Fed. Cir. 2017) .......................................................................... 31
`
`Takeda Pharm. Co. v. Zydus Pharm. USA, Inc.,
`743 F.3d 1359 (Fed. Cir. 2014) .................................................................... 11, 30
`
`TRW Automotive US LLC,
`No. IPR2014-00258, Paper 18 ............................................................................ 64
`
`Wesley Jessen Corp. v. Bausch & Lomb, Inc.,
`209 F. Supp. 2d 348 (D. Del. 2002).................................................................... 25
`
`OTHER AUTHORITIES
`
`37 C.F.R. § 42.24 ....................................................................................................... 1
`
`37 C.F.R. § 42.65(a) ................................................................................................. 64
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`IPR2018-00152
`U.S. Patent 7,820,788
`
`TABLE OF ABBREVIATIONS
`
`BRC
`EX2070
`ID
`Pet.
`PO
`POSA
`PTO
`
`Broadest Reasonable Construction
`Deposition of Cory Berkland, Ph.D., November 30, 2017
`Institution Decision in IPR2017-01101 (Paper 7)
`IPR2018-00152 Petition for Inter Partes Review
`Patent Owner
`Person of Ordinary Skill in the Art
`United States Patent and Trademark Office
`
`- vii -
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`IPR2018-00152
`U.S. Patent 7,820,788
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`LIST OF EXHIBITS
`
`Description
`EX
`2001 Declaration of Nicholas A. Peppas, Sc.D., In Support of PO’s Preliminary
`Response, submitted in IPR2017-01101; 01103; 01104
`2002 Frye, D. K., Taxane Chemotherapy-Advances in Treatment for Breast
`Cancer. US Oncological Disease. 2006; 1(1):40-41
`2003 Paclitaxel (Taxol®) Formulation and Prodrugs: The Chemistry and
`Pharmacology of Taxol® and its Derivatives, Elsevier B.V. 1995; 103-130
`2004 Gelderblom et al., Cremophor EL: the drawbacks and advantages of
`vehicle selection for drug formulation. Eur J Cancer 2001; 37:1590-1598
`2005 Desai et al., US 5,916,596, “Protein Stabilized Pharmacologically Active
`Agents, Methods for the Preparation Thereof and Methods for the Use
`Thereof” (issued Jun. 29,1999)
`2006 FDA News. “Phase III Trial of Tocosol Paclitaxel Does Not Meet Primary
`Endpoint” (published 2017)
`2007 Paz-Ares et al., Phase III trial comparing paclitaxel poliglumex vs
`docetaxel in the second-line treatment of non-small-cell lung cancer. Brit J
`Cancer. 2008; 98:1608-1613
`2008 Langer et al., Phase III Trial Comparing Paclitaxel Poliglumex (CT-2103,
`PPX) in Combination with Carboplatin Versus Standard Paclitaxel and
`Carboplatin in the Treatment of PS 2 Patients with Chemotherapy-Naïve
`Advanced Non-small Cell Lung Cancer. J Thorac Oncol. 2008; 3:623-630
`2009 Hamaguchi et al., NK105, a paclitaxel-incorporating micellar nanoparticle
`formulation, can extend in vivo antitumour activity and reduce the
`neurotoxicity of paclitaxel, Brit J Cancer. 2005; 92:1240-1246
`2010 FirstWord Pharma, “Results of Phase III study of NK105, a novel
`macromolecular micelle encapsulating an anticancer drug” (created July
`12, 2016)
`2011 Full Prescribing Information, Abraxane® , revised July 2015
`2012 Schnitzer et al., Albondin-mediated Capillary Permeability to Albumin. J
`Biol Chem. 1994; 269(8):6072-6082
`2013 Schnitzer J.E., gp60 is an albumin-binding glycoprotein expressed by
`continuous endothelium involved in albumin transcytosis. Am J Physiol.
`- viii -
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`IPR2018-00152
`U.S. Patent 7,820,788
`
`2019
`
`2014
`
`1992; 262:H246-H254
`John et al., Quantitative analysis of albumin uptake and transport in the rat
`microvessel endothelial monolayer. Am J Physiol-Lung C. 2003;
`284:L187-L196
`2015 Laino, C., June 3, 2009, “Abraxane Beats Standard Breast Cancer
`Treatment” www.webmd.com/breast-cancer/news/20090609/breast-
`cancer-drug-abraxane-is-effective
`2016 Blum et al., Phase II Study of Weekly Albumin-Bound Paclitaxel for
`Patients with Metastatic Breast Cancer Heavily Pretreated with Taxanes.
`Clin Breast Cancer. 2007; 7(11):850-856
`2017 Gradishar et al., Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel
`Compared with Polyethylated Castor Oil-Based Paclitaxel in Women with
`Breast Cancer. J Clin Oncol. 2005; 23(31):7794-7803
`2018 Zhang et al., Nab-Paclitaxel is an Active Drug in Preclinical Model of
`Pediatric Solid Tumors. Clin Cancer Res. 2013; 19(21):5972-5983
`Irizarry et al., Cremophor EL-containing paclitaxel-induced anaphylaxis: a
`call to action. Community Oncology. 2009; 6(3):132-134
`2020 Rajeshkumar et al., Superior Therapeutic Efficacy of nab-Paclitaxel over
`Cremophor-based paclitaxel in locally advanced and metastatic models of
`human pancreatic cancer. Brit J Cancer. 2016; 115:442-453
`Intentionally Left Blank
`2021
`2022
`Intentionally Left Blank
`Intentionally Left Blank
`2023
`Intentionally Left Blank
`2024
`Intentionally Left Blank
`2025
`Intentionally Left Blank
`2026
`Intentionally Left Blank
`2027
`2028 Tian et al., Degradation of Paclitaxel and Related Compounds in Aqueous
`Solutions I: Epimerization. J Pharm Sci. 2008; 97(3):1224-1235
`2029 Tian et al., Degradation of Paclitaxel and Related Compounds in Aqueous
`Solutions II: Nonepimerization Degradation Under Neutral to Basic pH
`Conditions. J Pharm Sci. 2008; 97(8):3100-3108
`2030 Tian et al., Degradation of Paclitaxel and Related Compounds in Aqueous
`Solutions III: Degradation Under Acidic pH Conditions and Overall
`
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`U.S. Patent 7,820,788
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`2032
`
`Kinetics. J Pharm Sci. 2010; 99(3):1288-1298
`2031 Pillai et al., Pharmaceutical Glass Interactions: A Review of Possibilities. J
`Pharm Sci & Res. 2016; Vol. 8(2):103-111
`“Sticky Containers, Vanishing Drugs”
`http://blogs.sciencemag.org/pipeline/archives/2008/08/29/sticky_container
`s_vanishing_drugs (August 29, 2008)
`2033 Mani et al., Delivery of paclitaxel from cobalt-chromium alloy surfaces
`without polymeric carriers. Biomaterials. 2010; 31(20):5372-5384
`2034 Green et al., Measurement of paclitaxel and its metabolites in human
`plasma using liquid chromatography/ion trap mass spectrometry with a
`sonic spray ionization interface. Rapid Commun Mass Sp. 2006;
`20(14):2183-2189
`2035 Heldman et al., Paclitaxel Stent Coating Inhibits Neointimal Hyperplasia
`at 4 Weeks in a Porcine Model of Coronary Restenosis. Circulation. 2001;
`103:2289-2295
`2036 Fukazawa et al., Reduction of non-specific adsorption of drugs to plastic
`containers used in bioassays or analyses. J Pharmacol Tox Met. 2010;
`61:329-333
`Intentionally Left Blank
`2037
`2038 Pfeifer et al., Precipitation of paclitaxel during infusion by pump. Am J
`Hosp Pharm. 1993; 50:2518-2521
`2039 Xu et al., Stability of paclitaxel in 5% dextrose injection or 0.9% sodium
`chloride injection at 4, 22, or 32 °C. Am J Hosp Pharm. 1994;51:3058-
`3060
`2040 Trissel et al., Pharmaceutical properties of paclitaxel and their effects on
`preparation and administration. Pharmacotherapy. 1997; 17(5 Part
`2):133S-139S
`2041 Kattige, Long-term physical and chemical stability of a generic paclitaxel
`infusion under simulated storage and clinical-use conditions. Eur J Hosp
`Pharm-S P. 2006; 12(6):129-134
`2042 Lee et al., Hydrotropic solubilization of paclitaxel: analysis of chemical
`structures for hydrotropic property. Pharmacol Res. 2003; 20(7):1022-
`1030
`2043 Feng, et al., Effects of emulsifiers on the controlled release of paclitaxel
`
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`(Taxol®) from nanospheres of biodegradable polymers. J Control Release.
`2001; 71(1):53-69
`2044 Vilker et al., The Osmotic Pressure of Concentrated Protein Solutions:
`Effect of Concentration and pH in Saline Solutions of Bovine Serum
`Albumin. J Colloid Interf Sci. 1981; 79(2):548-566
`2045 Fogh-Andersen et al., Ionic Binding, Net Charge, and Donnan Effect of
`Human Serum Albumin as a Function of pH. Clin Chem. 1993; 39(1):48-
`52
`Intentionally Left Blank
`2046
`Intentionally Left Blank
`2047
`Intentionally Left Blank
`2048
`Intentionally Left Blank
`2049
`2050 Ziller et al., Control of Crystal Growth in Drug Suspension: 1) Design of a
`Control Unit and Application to Acteaminophen Suspensions). Drug Dev
`Ind Pharm. 1988; 14(15-17):2341-2370
`Intentionally Left Blank
`2051
`2052 Garnett et al., The effects of serum and human albumin on calcium
`hydroxyapatite crystal growth. Biochem J. 1990; 266:863-868
`2053 Kommanaboyina et al., Trends in Stability Testing, with Emphasis on
`Stability During Distribution and Storage. Drug Dev Ind Pharm. 1999;
`25(7):857-868
`2054 Surapaneni et al., Designing Paclitaxel Drug Delivery Systems Aimed at
`Improved Patient Outcomes: Current Status and Challenges. ISRN
`Pharmacol. 2012; 1-15
`2055 Flynn, G.L., Solubility Concepts and Their Applications to the
`Formulation of Pharmaceutical Systems: Part I. Theoretical Foundations.
`PDA J Pharm Sci Tech. 1984; 38:202-209
`Intentionally Left Blank
`2056
`2057 Steinhardt et al., Differences between Bovine and Human Serum
`Albumins: Binding Isotherms, Optical Rotatory Dispersion, Viscosity,
`Hydrogen Ion Titration, and Fluorescence Effects. Biochemistry-US.
`1971; 10(22):4005-4015
`2058 U.S. Application No. 12/910,693, Notice of Allowance (mailed Dec. 27,
`2011)
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`2059 Diaz et al., Molecular Recognition of Taxol by Microtubules. J Biol Chem.
`2002; 275(34):26265-26276
`2060 Chen et al., Albumin-bound nanoparticle (nab) paclitaxel exhibits
`enhanced paclitaxel tissue distribution and tumor penetration. Cancer
`Chemoth Pharm. 2015; 76:699-712
`2061 Evangelio et al., Fluorescent Taxoids as Probes of the Microtubule
`Cytoskeleton. Cell Motil Cytoskel. 1998; 39:73-90
`Intentionally Left Blank
`2062
`Intentionally Left Blank
`2063
`Intentionally Left Blank
`2064
`Intentionally Left Blank
`2065
`2066 Declaration of Dr. David Oupicky, Ph.D.
`In Support of PO’s Preliminary Response
`2067 Declaration of Dr. Christopher Vellturo, Ph.D.
`In Support of PO’s Preliminary Response
`2068 Declaration of Dr. Katherine Tkaczuk, M.D.
`In Support of PO’s Preliminary Response
`2069 Affidavit of Dr. Neil P. Desai (April 11, 2014)
`2070 Cory Berkland, Ph.D., Deposition Transcript (November 30, 2017)
`2071 O’Hagan et al., March 3, 2009, “Bringing pharma R&D back to health”
`http://www.bain.com/publications/articles/bringing-pharma-r-and-d-back-
`to-health.aspx
`2072 DiMasi et al., Innovation in the pharmaceutical industry: New estimates of
`R&D costs. J Health Econ. 2016; 47:20-33
`2073 Thomas et al., 2016, “Clinical Development Success Rates 2006-2015”,
`Bio Industry Analysis Published Reports
`https://www.bio.org/sites/default/files/Clinical%20Development%20Succe
`ss%20Rates%202006-2015%20-
`%20BIO,%20Biomedtracker,%20Amplion%202016.pdf
`2074 Wong et al., 2018 Estimation of clinical trial success rates and related
`parameters, Biostatics https://doi.org/10.1093/biostatistics/kxx069
`“Abraxane Prices, Coupons and Patient Assistance Programs”
`https://www.drugs.com/price-guide/abraxane
`“Drug Approvals – From Invention to Market – a 12- Year Trip”
`
`2075
`
`2076
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`U.S. Patent 7,820,788
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`https://www.medicinenet.com/script/main/art.asp?articlekey=9877
`2077 Lipsky et al., From Idea to Market: The Drug Approval Process. J Am
`Board Fam Pract. 2001; 14(5):362-67
`2078 DiMasi et al., Risks in new drug development: Approval success rates for
`investigational drugs. Clin Pharmacol Ther 2001; 69(5):297-307
`2079 Hay et al., Clinical development success rates for investigational drugs.
`Nature Biotech. 2014; 32(1):40-51
`2080 Kamb et al., Why is cancer drug discovery so difficult? Nature Reviews
`Drug Discovery 2007; 6:115-120
`2081 DiMasi et al., Clinical Approval Success Rates for Investigational Cancer
`Drugs. Clin Pharmacol & Therap 2013; 94(3):329-335
`2082 Gilbert et al., Rebuilding Big Pharma’s Business Model, In Vivo, the
`Business and Medicine Report, Windhover Information 2003; 21(10):73-
`80
`2083 Food and Drug Administration, Innovation/Stagnation: Challenge and
`Opportunity on the Critical Path to New Medical Products. 2004
`2084 Congressional Budget Office, Research and Development in the
`Pharmaceutical Industry. 2006
`2085 DiMasi et al., Trends in Risks Associated With New Drug Development:
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`Therapeutics (2010); 87(3):272-77
`2086 Mak et al., Lost in translation: animal models and clinical trials in cancer
`treatment. Am J Transl Res (2014);6(2):114-118
`2087 National Comprehensive Cancer Network, February 2017, “Breast Cancer
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`https://www.nccn.org/patients/guidelines/content/PDF/stage_IV_breast.pdf
`2088 National Comprehensive Cancer Network, January 2017, “Pancreatic
`Cancer”
`https://www.nccn.org/patients/guidelines/content/PDF/pancreatic.pdf
`2089 National Comprehensive Cancer Network, 2018, “Lung Cancer”
`https://www.nccn.org/patients/guidelines/lung-nsclc/50/
`2090 H. Gelderblom et al., Cremophor EL: the drawbacks and advantages of
`vehicle selection for drug formulation. European Journal of Cancer (2001);
`37:1590–1598
`
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`IPR2018-00152
`U.S. Patent 7,820,788
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`2091 Prakash Vishnu and Vivek Roy. Safety and Efficacy of nab-Paclitaxel in
`the Treatment of Patients with Breast Cancer, Breast Cancer: Basic and
`Clinical Research (2011):5 53–65
`2092 NCCN Practice Guidelines in Oncology: Breast Cancer. February 7, 2018
`
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`IPR2018-00152
`U.S. Patent 7,820,788
`
`I.
`
`INTRODUCTION
`Patent Owner Abraxis Bioscience, LLC (“PO”) submits this Patent Owner
`
`Preliminary Response to the petition for inter partes review (“IPR”) filed by
`
`Apotex Inc. and Apotex Corp. (collectively, “Petitioners”) seeking to invalidate
`
`PO’s U.S. Patent No. 7,820,788 (“the ’788 patent”). In nearly identical petitions,
`
`Petitioners also seek IPR of two additional patents owned by PO that are related to
`
`the ’788 patent: U.S. Pat. Nos. 8,138,229 (“the ’229 patent”) and 7,923,536
`
`(“the ’536 patent”). In each of the three petitions, Petitioner asserts that all claims
`
`of each challenged patent are anticipated or rendered obvious by the same prior art:
`
`Desai (EX1006), or Desai in view of Kadima (EX1004) and Liversidge (EX1005).
`
`In Institution Decisions on substantively identical petitions filed several
`
`months earlier, the Board rejected certain arguments that Petitioners here continue
`
`to urge. In particular, the Board adopted PO’s proposal that “the weight ratio of
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`albumin to paclitaxel in the composition” term (and similar “weight ratio” terms in
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`all of the challenged claims) refers to the final product injected into the patient, not
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`the starting materials as proposed in those prior petitions and by Petitioners here.
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`If the Board maintains that construction here, that alone would dispense with the
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`principal invalidity argument that Petitioners continue to assert—i.e., that the
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`disclosed 9:1 ratio in Example 1 of the Desai publication (EX1006) is the same as
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`the “about 9:1” albumin-to-paclitaxel weight ratio for the final pharmaceutical
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`composition as required by the sole independent challenged claim. Petitioner
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`concedes that this ratio in Desai’s Example 1 concerns the starting materials, not
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`the final pharmaceutical composition.
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`Although the Board found that the earlier petitioner presented a reasonable
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`likelihood of showing the unpatentability of at least one of the challenged claims
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`and, therefore, the Board instituted IPR, there is no basis to reach the same
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`conclusion with respect to Petitioners here.1 Fundamental to those earlier
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`Institution Decisions were the Board’s preliminary views that (1) stitching together
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`different Examples in Desai mathematically supports that Example 1’s 9:1 starting
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`ratio remains the same in the finished product; and (2) PO had not cited “specific
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`evidence regarding quantitative amounts of paclitaxel that would have been lost
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`during the processing” of Example 1, to result in a pharmaceutical composition
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`with an albumin-to-paclitaxel ratio that is significantly different than a starting
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`ratio of 9:1. (ID, 17-19.)2 In those earlier proceedings, however, the record before
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`1 The Board did not issue a Final Written Decision in those earlier IPRs,
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`because the PO and that petitioner settled prior to submission of a Patent Owner
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`Response.
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`2 ID refers to the Institution Decision in IPR2017-01101 (Paper 7).
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`the Board was less developed than it is here. In particular, the Board did not have
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`the following evidence directly relevant to the reasons it instituted those earlier
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`IPRs3:
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`• the Declaration of Dr. David Oupicky (EX2066), in which Dr.
`Oupicky opines that paclitaxel is lost during manufacture and thus the
`Desai starting material ratio would not end up at 9:1 in the finished
`pharmaceutical composition, directly addressing the Board’s
`statement that PO did not provide such evidence in the earlier IPRs;
`• the Declaration of Dr. Christopher Vellturo (EX2067), in which Dr.
`Vellturo opines that a POSA would not have been motivated by cost
`to change Capxol’s formulation to a 9:1 ratio in the finished product;
`• the Declaration of Dr. Katherine Tkaczuk, M.D. (EX2068), in which
`Dr. Tkaczuk opines that a POSA would have found the efficacy of the
`9:1 formulation surprising;
`• Inventor Desai’s declaration submitted to the Indian patent office
`(“Desai Indian Declaration”) (EX2069) in which he attested that
`Example 1 of Desai produces Capxol with a final ratio of 13.3:1—
`and, consequently, Petitioners’ attempt to cobble together different
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`3 PO believes institution is unwarranted in view of the new evidence addressed
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`herein. In the event that the Board determines otherwise, PO will pursue targeted
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`discovery seeking from Apotex real-world evidence of paclitaxel loss as PO did with
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`Actavis.
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`Examples in Desai is inappropriate; and
`• the deposition testimony of Cory Berkland, Ph.D., (EX2070) the
`expert proffered by the prior petitioner and also by Petitioners here, in
`which Dr. Berkland made critical admissions exposing the legal and
`factual errors underlying his and Petitioners’ anticipation and
`obviousness arguments.
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`In the earlier IPRs, the Board did not have Dr. Berkland’s critical
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`admissions, which had not yet been tested by deposition. The Board likewise did
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`not have any testimony from Drs. Tkaczuk, Oupicky, or Vellturo, or the testimony
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`from Inventor Desai in the Indian patent office proceedings. All of this additional
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`evidence corroborates the novelty and nonobviousness of the challenged claims.
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`In light of the new evidence before the Board, Petitioners have failed to
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`demonstrate a reasonable likelihood that Desai anticipates the claims of the ’788
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`patent, or that Desai alone, or in combination with Kadima and Liversidge, renders
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`the claims obvious. The Board should deny institution.
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`II. BACKGROUND
`A. The Development of Abraxane®
`Paclitaxel, an anticancer chemotherapy drug, has notoriously poor water
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`solubility, presenting challenges for effective delivery. (EX2001 ¶ 24.) Prior to
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`PO’s development of Abraxane®, various delivery systems were investigated to
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`improve the solubility and pharmacological properties of paclitaxel. The most
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`widely known delivery platform is a cosolvent system brought to market by BMS
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`as Taxol®, which consists of paclitaxel in a 50:50 mixture of Cremophor EL® (a
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`polyoxyethylated castor oil) and ethanol. Taxol®, though, has several undesirable
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`characteristics. It requires large infusion volumes, special tubing and filters, and
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`has been shown to induce significant acute and cumulative toxicity. (EX1001,
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`4:31-44; EX2002.) Moreover, the cremophor solvent system used to facilitate
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`paclitaxel dissolution can have serious side effects, including allergic
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`hypersensitivity and anaphylactic reactions. (See, e.g., EX2004, Abstract;
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`EX1001, 4:31-50; EX2068 ¶ 18; EX2090; EX2091.) Consequently, there was a
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`need for a formulation that could overcome paclitaxel’s water insolubility while
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`eliminating adverse reactions associated with solvent-containing formulations,
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`such as Taxol®. Other researchers endeavored to develop safer and more
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`efficacious taxane delivery methods, but their efforts failed. (See, e.g., EX2005,
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`3:17-29; EX2006; EX2007, 1612; EX2008, 623; EX2009; EX2010.)
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`Abraxane® is a novel cremophor-free formulation of paclitaxel indicated for
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`the treatment of metastatic breast cancer, metastatic non-small cell lung cancer,
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`and metastatic adenocarcinoma of the pancreas. (EX2011, 1.) Unlike solvent-
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`containing formulations, Abraxane® is comprised of nanoparticles consisting of a
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`solid core of non-crystalline, amorphous paclitaxel surrounded by a shell of human
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`serum albumin. (Id.) The mean size of the nanoparticles is approximately 130
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`nanometers. (Id.) Abraxane® is presented lyophilized, and each vial contains 900
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`mg albumin per 100 mg paclitaxel (i.e., a 9:1 weight ratio of albumin to paclitaxel)
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`prior to reconstitution with 0.9% saline. (Id.) To date, no one has successfully
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`developed an FDA-approved paclitaxel formulation with greater efficacy than
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`Abraxane®.
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`The development of Abr