Filed on behalf of: Abraxis Biosciences, LLC
`
`Filed: July 12, 2017
`
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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`ACTAVIS LLC
`Petitioner,
`
`v.
`
`ABRAXIS BIOSCIENCE, LLC
`Patent Owner
`_______________________
`
`Case IPR2017-01104
`U.S. Patent 8,138,229
`_______________________
`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`
`
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`
`
`

`

`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`
`
`
`I. 
`II. 
`
`TABLE OF CONTENTS
`Introduction ..................................................................................................... 1 
`Background ..................................................................................................... 4 
`A. 
`The need for and development of Abraxane® ..................................... 4 
`B. 
`The ’229 patent ..................................................................................... 9 
`III.  Level of Ordinary Skill in the Art and Claim Construction ......................... 10 
`A. 
`Level of ordinary skill in the art ......................................................... 10 
`B. 
`Claim construction ............................................................................. 10 
`1. 
`The ratio term concerns the finished composition ................... 10 
`2. 
`The other claim terms do not require construction .................. 17 
`IV.  The Board Should Deny Institution Under 35 U.S.C. § 325(d) ................... 17 
`V. 
`The Petition Fails to Demonstrate a Reasonable Likelihood that Any
`Challenged Claim is Unpatentable ............................................................... 20 
`A.  Desai does not anticipate the challenged claims (Ground I) .............. 21 
`1. 
`Petitioner’s anticipation argument relies on its erroneous
`construction of the ratio term ................................................... 22 
`Desai’s starting albumin-to-paclitaxel ratio increases
`during manufacturing ............................................................... 22 
`Desai alone does not render obvious any of the challenged
`claims (Ground II.A) .......................................................................... 32 
`1. 
`Desai does not disclose a range of albumin-to-paclitaxel
`ratios that includes 9:1 ............................................................. 32 
`A POSA would have not have been motivated to reduce
`Capxol™’s albumin-to-paclitaxel ratio ................................... 34 
`A POSA would not have had a reasonable expectation
`that the claimed albumin-to-paclitaxel ratio of 9:1 would
`be stable .................................................................................... 42 
`Desai, Kadima, and Liversidge in combination do not render
`obvious any of the challenged claims (Ground II.B) ......................... 46 
`
`2. 
`
`2. 
`
`3. 
`
`B. 
`
`C. 
`
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`

`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`
`1. 
`
`2. 
`
`Kadima does not teach a ratio in the range of the claimed
`invention and teaches away from lowering CapxolTM’s
`13:1 ratio to about 9:1 .............................................................. 46 
`A POSA would have no reason to combine, with a
`reasonable expectation of success, Desai, Kadima, and
`Liversidge ................................................................................. 52 
`Claim 20 is also nonobvious (Grounds III.A and III.B) .................... 55 
`Secondary considerations support nonobviousness ........................... 56 
`1. 
`The cell-binding results were unexpected and have a
`nexus to the ’229 patent ........................................................... 57 
`Clinical studies compared a claimed composition with
`the closest prior art and the results were unexpected .............. 60 
`VI.  Conclusion .................................................................................................... 64 
`
`
`
`D. 
`E. 
`
`2. 
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`

`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`
`TABLE OF AUTHORITIES
`
`
`
`
`
`
`
`
`
`CASES
`ACTV, Inc. v. Walt Disney Co.,
`346 F.3d 1082 (Fed. Cir. 2003) .......................................................................... 11
`
`
`
`
`
`
`
`
`
`
`
`PAGE
`
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) .......................................................................... 63
`
`AstraZeneca Pharm. LP v. Anchen Pharm., Inc.,
`C.A. No. 10-1835, 2012 WL 1065458 (D.N.J. Mar. 29, 2012) ......................... 45
`
`Atofina v. Great Lakes Chem. Corp.,
`441 F.3d 991 (Fed. Cir. 2006) ............................................................................ 21
`
`Biotec Biologische Naturverpackungen GmbH & Co. KG v. Biocorp,
`Inc., 249 F.3d 1341 (Fed. Cir. 2001) .................................................................. 25
`
`Canon, Inc. v. Papst Licensing GMBH & Co. Kg,
`No. IPR2016-01202 ............................................................................................ 20
`
`C.R. Bard, Inc. v. Medtronic, Inc.,
`250 F.3d 760 (Fed. Cir. 2000) ............................................................................ 54
`
`Cadence Pharm. Inc. v. Exela PharmSci Inc.,
`780 F.3d 1364 (Fed. Cir. 2015) .......................................................................... 20
`
`Cont’l Can Co. USA, Inc. v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) .......................................................................... 21
`
`Creative Integrated Sys., Inc. v. Nintendo of Am., Inc.,
`526 F. App’x 927 (Fed. Cir. 2013) ..................................................................... 15
`
`Cumberland Pharm. Inc. v. Mylan Institutional LLC,
`846 F.3d 1213 (Fed. Cir. 2017) .......................................................................... 46
`
`
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`- iii -
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`

`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`
`Dell, Inc. v. Selene Comm. Tech., LLC,
`No. IPR2014-01411 ............................................................................................ 52
`
`Eli Lilly & Co. v. Actavis Elizabeth LLC,
`435 F. App’x 917 (Fed. Cir. 2011) ..................................................................... 24
`
`Exxon Chem. Patents, Inc. v. Lubrizol Corp.,
`64 F.3d 1553 (Fed. Cir. 1995) ............................................................................ 14
`
`Finnigan Corp. v. Int’l Trade Commission,
`180 F.3d 1354 (Fed. Cir. 1999) .......................................................................... 31
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) .......................................................................... 63
`
`In re Kahn,
`441 F.3d 977, 990 (Fed. Cir. 2006) .................................................................... 54
`
`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988) ............................................................................ 45
`
`In re Oelrich,
`666 F.2d 578, 581 (C.C.P.A. 1981) .................................................................... 21
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 35
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .................................................................... 35, 37
`
`Mars, Inc. v. H.J. Heinz Co.,
`377 F.3d 1369 (Fed. Cir. 2004) .......................................................................... 15
`
`Netword, LLC v. Centraal Corp.,
`242 F.3d 1347 (Fed. Cir. 2001) .......................................................................... 13
`
`Nike, Inc. v. Adidas AG,
`812 F.3d 1326 (Fed. Cir. 2016) .......................................................................... 14
`
`
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`

`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`
`Nora Lighting, Inc. v. Juno Manufacturing, LLC,
`No. IPR2015-00601 ............................................................................................ 18
`
`Novartis Pharms. Corp. v. Watson Labs., Inc.,
`611 F. App’x 988 (Fed. Cir. 2015) ..................................................................... 35
`
`N.P.Z., Inc. v. Stephens,
`No. IPR2015-01860 ............................................................................................ 20
`
`Oil States Energy Services, LLC v. Greene’s Energy Group, LLC,
`No. 16-712 (U.S.) ........................................................................................passim
`
`Ortho McNeil Pharmaceutical, Inc. v. Barr Labs.,
`C.A. No. 03-4678, 2009 U.S. Dist. LEXIS 62721 (D.N.J. July 21,
`2009) ................................................................................................................... 56
`
`PPC Broadband, Inc. v. Corning Optical Communications RF,
`LLC, 815 F.3d 747 (Fed. Cir. 2016) ................................................................... 14
`
`Par Pharm., Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 30
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .................................................................... 11, 13
`
`Power Integrations, Inc. v. Lee,
`797 F.3d 1318 (Fed. Cir. 2015) .......................................................................... 14
`
`PowerOasis, Inc. v. T-Mobile U.S.A., Inc.,
`522 F.3d 1299 (Fed. Cir. 2008) .......................................................................... 20
`
`Rapoport v. Dement,
`254 F.3d 1053 (Fed. Cir. 2001) .......................................................................... 30
`
`Ricoh Co., Ltd. v. Quanta Computer Inc.,
`550 F.3d 1325 (Fed. Cir. 2008) .......................................................................... 54
`
`
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`

`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`
`Shire LLC v. Amneal Pharm., LLC,
`802 F.3d 1301 (Fed. Cir. 2015) .......................................................................... 20
`
`Transclean Corp. v. Bridgewood Servs., Inc.,
`290 F.3d 1364 (Fed. Cir. 2002) .......................................................................... 21
`
`TRW Automotive US LLC, v. Magna Elecs, Inc.,
`No. IPR2014-00258 ...................................................................................... 26, 62
`
`UCB, Inc. v. Accord Healthcare, Inc.,
`201 F. Supp. 3d 491, 538–539 (D. Del. Aug. 12, 2016) .................................... 56
`
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
`200 F.3d 795 (Fed. Cir. 1999) ............................................................................ 17
`
`Zelinksi v. Brunswick Corp.,
`185 F.3d 1311 (Fed. Cir. 1999) .......................................................................... 25
`
`STATUTES
`
`35 U.S.C. § 314(a) ................................................................................................... 20
`
`35 U.S.C. § 325(d) ................................................................................... 1, 17, 19, 20
`
`OTHER AUTHORITIES
`37 C.F.R. § 42.24(a) ................................................................................................... 1
`
`37 C.F.R. § 42.24(a)(i) ............................................................................................... 1
`
`37 C.F.R. § 42.24(b)(1) .............................................................................................. 1
`
`37 C.F.R. § 42.65(a) ........................................................................................... 26, 62
`
`37 C.F.R. § 42.108(c) ............................................................................................... 25
`
`
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`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`
`LIST OF EXHIBITS
`
`
`Description
`EX
`2001 Declaration of Nicholas A. Peppas, Sc.D.
`In Support of Patent Owner’s Preliminary Response
`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.
`
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`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`
`2019
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`2014
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`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
`2021 Wani, et al., Plant antitumor agents. VI. The isolation and structure of
`taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J
`Am Chem Soc. 1971; 93(9):2325–7
`Intentionally Left Blank
`2022
`2023 Chromatographic Techniques for the Characterization of Proteins: Physical
`Methods to Characterize Pharmaceutical Proteins, Springer Science and
`Business Media, New York, NY, 1995, Vol. 7:243–299
`2024 Girard et al., Separation of Human Serum Albumin Components by RP-
`HPLC and CZE and their Characterization by ESI-MS. Chromatographia.
`1999; 49: S21–S27
`2025 The Application of HPLC for Proteins, High Performance Liquid
`Chromatography: Principles and Methods in Biotechnology. John Wiley &
`Sons, Chichester, UK, 1996, 411–467
`2026 Sparreboom et al., Determination of paclitaxel in human plasma using
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`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`
`2032
`
`single solvent extraction prior to isocratic reversed-phase high-
`performance liquid chromatography with ultraviolet detection. J.
`Chromatogr B. 1998; 705:159–164
`2027 Martin et al., Assay of paclitaxel (Taxol) in plasma and urine by high-
`performance liquid chromatography. J. Chromatogr B. 1998; 709:281–288
`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
`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
`2037 Hunz et al., Plasma And Tissue Pharmacokinetics Of Epirubicin And
`Paclitaxel In Patients Receiving Neoadjuvant Chemotherapy For Locally
`Advanced Primary Breast Cancer. Clin Pharmacol Ther. 2007; 81(5):659–
`668
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`U.S. Patent 8,138,229
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`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
`(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–
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`2046 Curnis et al., Improving Chemotherapeutic Drug Penetration in Tumors by
`Vascular Targeting and Barrier Alteration. J Clin Invest. 2002;
`110(4):475–482
`2047 Yuan, F., Transvascular Drug Delivery in Solid Tumors. Semin in Radiat
`Oncol. 1998; 8(3):164–175
`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
`2051 USP Monograph, Paclitaxel. 30(40):1279
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`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`
`http://www.pharmacopeia.cn/v29240/usp29nf24s0_m60190.html
`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
`2056 Pyo et al., Preparation and Dissolution Profiles of the Amorphous,
`Dihydrated Crystalline, and Anhydrous Crystalline Forms of Paclitaxel.
`Drying Technol. 2007; 25(10):1759–1767
`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)
`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
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`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`
`I.
`
`Introduction
`
`In three nearly identical petitions (IPR2017-01101, IPR2017-01103, and
`
`IPR2017-01104), Actavis LLC (the “Petitioner”) seeks inter partes review (“IPR”)
`
`of three related patents owned by Abraxis Bioscience, LLC (“Abraxis” or “Patent
`
`Owner”)—U.S. Pat. Nos. 7,820,788 (“the ’788 patent”), 7,923,536 (“the ’536
`
`patent”), and 8,138,229 (“the ’229 patent”)1—alleging that all claims of each
`
`patent are anticipated or rendered obvious by the same prior art: Desai (EX1006),
`
`or Desai in view of Kadima (EX1004) and Liversidge (EX1005). The United
`
`States Patent and Trademark Office (the “Office”) considered all of this art during
`
`prosecution of the ’788, ’536 and ’229 patents and determined that the claimed
`
`inventions were patentable over it. Under 35 U.S.C. § 325(d), the Board should
`
`exercise its discretion to deny the petitions because Petitioner submitted nothing
`
`that was not already before the Office during prosecution. Even if considered on
`
`the merits, Petitioner’s asserted grounds do not warrant review.
`
`Petitioner’s arguments rest on a fundamental claim construction error:
`
`Petitioner argues that the “weight ratio of albumin to paclitaxel in the composition”
`
`
`1 The ’229 patent issued from U.S. Appl. No. 12/910,693 as a continuation of U.S.
`
`Appl. No. 11/553,339, now the ’788 patent. The ’536 patent issued from U.S.
`
`Appl. No. 12/758,413, which is also a continuation of U.S. Appl. No. 11/553,339.
`
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`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`
`(“about 1:1 to about 9:1” in representative claim 1) should be construed to include
`
`the ratio of the starting ingredients as opposed to the weight ratio of albumin to
`
`paclitaxel in the finished formulation. (Pet. 18.) On the intrinsic evidence—
`
`including the claim language as a whole and the Patent Office’s own understanding
`
`during prosecution—Petitioner’s construction is not correct. The weight ratio is
`
`limited to the finished pharmaceutical composition. Moreover, under that proper
`
`construction, there is no likelihood the claims are invalid. Indeed, Petitioner’s
`
`incorrect construction permeates its principal asserted grounds—Petitioner relies
`
`on Desai and other prior art for purported disclosures of an albumin-to-paclitaxel
`
`ratio between 1:1 and 9:1 that, as Petitioner concedes, concern the starting
`
`materials, not the claimed finished pharmaceutical nanoparticle composition.
`
`Although Petitioner alternately argues that the prior art anticipates or renders
`
`the claims obvious even if the claimed ratio is limited to the finished composition,
`
`this alternate argument is made only in cursory fashion, failing to meet the
`
`requirements for institution. Moreover, this argument is contrary to the prior art.
`
`For instance, in contending that Desai anticipates the claims under a (proper)
`
`construction in which the weight ratio refers to the finished pharmaceutical product,
`
`Petitioner fails to provide any evidence that Desai discloses, either expressly or
`
`inherently, a pharmaceutical composition having the albumin-to-paclitaxel ratios as
`
`claimed. Indeed, Petitioner completely ignores that the albumin-to-paclitaxel ratio
`
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`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`
`of the finished composition disclosed in Desai is 13.3:1, not 9:1. Petitioner seeks
`
`instead to use the 9:1 ratio of starting materials in Desai’s Example 1, arguing that
`
`this ratio would carry through to the finished composition, but this argument fails
`
`to account for the substantial, and expected, loss of paclitaxel that would occur
`
`during the many manufacturing steps in Example 1 that, in turn, would increase the
`
`weight ratio of albumin to paclitaxel.
`
`Petitioner’s obviousness grounds fail for similar reasons. In addition to
`
`relying on impermissible hindsight, Petitioner ignores that the prior art, and other
`
`references that would have been available to a POSA, teach away from the claimed
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`invention. Petitioner fails to provide any motivation to combine the prior art with a
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`reasonable expectation of success. Moreover, Petitioner relies on an expert
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`declaration that is entitled to little or no weight because it is riddled with
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`conclusory assertions or incorrect information. For instance, Petitioner and its
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`declarant contend that Kadima discloses a range of albumin-to-paclitaxel weight
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`ratios that falls within the claimed 1:1 to 9:1 range, but Kadima does not. Its ratios
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`are molar ratios, not weight ratios; when converted to weight ratios, Kadima’s
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`formulations have albumin-to-paclitaxel weight ratios far higher than the claims—
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`39:1 to 780:1. Because Petitioner has failed to demonstrate that there is a
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`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
`reasonable likelihood that it would prevail, the Board should decline institution.2
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`II. Background
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`A. The need for and development of Abraxane®
`Prior to the advent of Abraxane®, a commercial embodiment of the ’229
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`patent, there was a long-felt need for a stable, safer, and more efficacious
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`formulation and delivery system for paclitaxel chemotherapy. (EX2003, 104–109,
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`125–27.) Paclitaxel, a type of taxane, was isolated and identified in the late 1960’s
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`as having activity against cancer. (EX2001 ¶ 23, EX2021.)
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`Paclitaxel, however, has notoriously poor water solubility, presenting
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`challenges for effective delivery. (EX2001 ¶ 24.) Various paclitaxel delivery
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`systems were investigated to improve the solubility and pharmacological properties
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`of paclitaxel. The most widely known delivery platform is a cosolvent system
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`brought to market by Bristol-Myers Squibb as Taxol®, which consists of paclitaxel
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`in a 50:50 mixture of Cremophor EL® (a polyoxyethylated castor oil) and ethanol.
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`Taxol®, though, has several undesirable aspects. Taxol® requires large infusion
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`volumes and special tubing and filters and has been shown to induce significant
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`acute and cumulative toxicity. (EX1001, 4:32–45; EX2002.) Moreover, the
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`2 For issue preservation, Abraxis notes the pending matter, Oil States Energy
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`Services, LLC v. Greene’s Energy Group, LLC, No. 16-712 (U.S.).
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`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
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`cremophor solvent system that was used to facilitate paclitaxel dissolution can
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`have severe side effects, including allergic hypersensitivity and anaphylactic
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`reactions. (See, e.g., EX2004, Abstract; EX1001, 4:32–51.) As a result, there was
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`a long-felt need for a formulation that could overcome paclitaxel’s water
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`insolubility while eliminating adverse reactions associated with solvent-containing
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`formulations, such as Taxol®.
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`Others attempted to develop safer and more efficacious taxane delivery
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`methods but failed. (See, e.g., EX2005, 3:17–29; EX2006 (discussing failure of α-
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`tocopherol (vitamin-E) bound paclitaxel to improve on toxicity or efficacy of
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`Cremophor delivery method); EX2007, 1612 (discussing failure of polyglutamate
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`polymer bound paclitaxel to achieve higher tumor reduction); EX2008, 623
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`(paclitaxel polyglumex failed to provide superior survival and, even more
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`surprising, demonstrated much lower response rate compared to paclitaxel);
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`EX2009; EX2010 (phase III study failed to meet criteria for progression free
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`survival).)
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`Abraxis solved the long-felt industry need when it developed the ’229 patent
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`and related technology embodied in Abraxane®, a novel cremophor-free
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`formulation of paclitaxel. Abraxane® is a breakthrough injectable
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`chemotherapeutic drug indicated for the treatment of metastatic breast cancer,
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`metastatic non-small cell lung cancer, and metastatic adenocarcinoma of the
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`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
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`pancreas. (EX2011, 1.) Unlike solvent-containing formulations, Abraxane® is
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`comprised of nanoparticles consisting of a solid core of non-crystalline, amorphous
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`paclitaxel surrounded by a shell of human serum albumin. (Id.) The mean size of
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`the nanoparticles is approximately 130 nanometers. (Id.) Abraxane® is presented
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`lyophilized, and each vial contains 900 mg albumin per 100 mg paclitaxel (i.e., a
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`9:1 weight ratio of albumin to paclitaxel) prior to reconstitution with 0.9% saline.
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`(Id.) To date, no one has successfully developed an FDA-approved paclitaxel
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`formulation with greater efficacy than Abraxane®.
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`The development of Abraxane® was a lengthy and iterative process,
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`requiring several successive achievements over many years, and the Patent Office
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`issued various patents to Abraxis protecting those inventive achievements.
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`Inventions covered by other patents not the subject of the present Petitions include
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`Abraxis’s initial development of a novel technique for formulating microparticles
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`in which paclitaxel is encased in an albumin shell—the Desai reference cited by
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`Petitioner discloses that development (EX1006)—as well as Abraxis’s subsequent
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`development of the ability to reduce the size of the albumin-paclitaxel particles to a
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`nano-scale, and to create such nanoparticles in which the paclitaxel existed in a
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`stable amorphous solid core—as set forth in Abraxis’s U.S. Patent No. 8,853,260.
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`The ’229 patent is directed to the subsequent discovery that reducing the
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`albumin-to-paclitaxel weight ratio in the finished formulation had surprisingly
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`Preliminary Response in IPR2017-01104
`U.S. Patent 8,138,229
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`beneficial effects. At the time of the invention, it was known that albumin-based
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`paclitaxel nanoparticle compositions could utilize the natural receptor mediated
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`albumin transportation process to facilitate the delivery of paclitaxel to tumor sites.
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`(See, e.g., EX2012, 6072–73; EX2013, H246, H253; EX2014, L187, L195;
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`EX1006, 28:10–15, 147:2–4.) In particular, albumin can cross the endothelium
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`(outer wall) of blood vessels via gp60 receptors (also called “albondin”), using a
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`process known as transcytosis. (See, e.g., EX2012, 6072–73; EX2013, H246,
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`H253; EX2014, L187, L195.) With regard to albumin-containing pharmaceutical
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`compositions for treating cancer, POSAs viewed albumin as important for
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`delivering the active ingredient to the tumor site, and would have expected that
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`increasing the amount of albumin in the composition would achieve greater
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`therapeutic effectiveness, since more active ingredient would be delivered to the
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`tumor. (See, e.g., EX1006, 28:10–15, 147:2–4.)
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`However, the ’229 inventors unexpectedly found that reducing the albumin-
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`to-paclitaxel weight ratio in the finished formulation to 9:1 or below showed both
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`higher therapeutic efficac