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 IPR2018-00151
`Patent 8,138,229 B2
`Issued: March 20, 2012
`
`Title: COMPOSITIONS AND METHODS OF
`DELIVERY OF PHARMACOLOGICAL AGENTS
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`_________________
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`PETITION FOR INTER PARTES REVIEW
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`IPR2018-00151 (8,138,229 B2)
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`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1
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`I.
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`II. MANDATORY NOTICES ............................................................................. 4
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`III. REQUIREMENTS FOR REVIEW ................................................................. 5
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`IV. LEVEL OF ORDINARY SKILL IN THE ART ............................................. 6
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`V.
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`THE PRIOR ART AND THE ʼ229 PATENT ................................................ 7
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`A.
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`B.
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`C.
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`Taxol® (paclitaxel) was an FDA-approved “wonder drug,” but initially
`could only be administered with a toxic solvent. .................................. 7
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`The inventors repeatedly patented albumin-paclitaxel nanoparticles as
`a solution to the known problems of Taxol®. ........................................ 8
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`Desai (EX1006) specifically discloses a nanoparticle formulation with
`an albumin-paclitaxel ratio of 9:1. ......................................................10
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`D. Desai, Kadima (EX1004), and Liversidge (EX1005) taught varying
`ranges of albumin-paclitaxel ratios, and taught lowering the ratio to
`increase drug concentration and reduce cost. ......................................11
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`E.
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`The inventors obtained their third round of patents on
`albuminpaclitaxel by arguing that a 9:1 ratio has “unexpected”
`benefits. ...............................................................................................13
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`VI. PLAIN AND ORDINARY MEANINGS .....................................................17
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`A.
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`B.
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`C.
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`“the weight ratio of albumin to paclitaxel in the composition” and “the
`ratio (w/w) of albumin to the paclitaxel in the pharmaceutical
`composition” .......................................................................................17
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`“a particle size of less than about 200 nm” .........................................19
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`“about 0.5% to about 5% by weight of albumin” and “about 5% by
`weight of albumin” ..............................................................................20
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`VII. ANALYSIS OF GROUNDS FOR TRIAL ...................................................21
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`A. GROUND I: ANTICIPATION UNDER 35 U.S.C. §102(b) ..............21
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`1.
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`Claim 1 is anticipated. ...............................................................21
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`a.
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`Albumin-paclitaxel combination ....................................21
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`IPR2018-00151 (8,138,229 B2)
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`b.
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`c.
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`Particle size of less than about 200 nm ..........................22
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`Albumin-paclitaxel ratio of about 1:1 to 9:1 ..................23
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`d. Weight concentration of albumin ...................................24
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`Claims 3 and 6 are anticipated. .................................................25
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`Claims 15, 19, and 21–23 are anticipated. ................................26
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`Claims 29, 34, and 38 are anticipated. ......................................28
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`Claims 7 and 33 are anticipated. ...............................................29
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`Claims 2, 8, 11–14, 16, 24, 27–28, 30, 35, and 39 are
`anticipated. ................................................................................29
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`Claims 4–5, 9–10, 17–18, 25–26, 31–32, 36–37, and 40–41 are
`anticipated. ................................................................................30
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`Claims 42–48 are anticipated. ...................................................30
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`The “starting” albumin-paclitaxel ratio does not change. ........30
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`2.
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`3.
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`4.
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`5.
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`6.
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`7.
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`8.
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`9.
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`B.
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`GROUNDS II–III: OBVIOUSNESS UNDER 35 U.S.C. §103(a) .....34
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`1.
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`Claim 1 would have been obvious. ...........................................34
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`a.
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`GROUND II.A: Desai alone ...........................................34
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`i.
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`ii.
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`The albumin-paclitaxel ratio of about 9:1 falls
`within a range disclosed by Desai. .......................36
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`Desai would have motivated a skilled artisan to
`lower Capxol™’s albumin-paclitaxel ratio. ..........38
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`iii. A skilled artisan would have reasonably expected
`the claimed albumin-paclitaxel ratio of 9:1 to
`retain stability. ......................................................39
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`iv.
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`The claimed albumin weight percentage when the
`formulation is reconstituted in saline falls within a
`range disclosed by Desai. .....................................42
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`b.
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`GROUND II.B: Desai, Kadima, and Liversidge ............43
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`IPR2018-00151 (8,138,229 B2)
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`i.
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`ii.
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`Kadima and Liversidge also disclose ranges of
`albumin-paclitaxel ratios including 9:1. ...............43
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`Kadima teaches additional reasons to lower
`Capxol™’s 13.3:1 ratio to about 9:1. ....................45
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`2.
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`3.
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`4.
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`5.
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`6.
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`7.
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`8.
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`Claims 3 and 6 would have been obvious.................................47
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`Claims 15, 19, and 21–23 would have been obvious. ..............48
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`Claim 20 would have been obvious. .........................................49
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`Claims 29, 34, and 38 would have been obvious. ....................50
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`Claims 7 and 33 would have been obvious...............................51
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`Claims 2, 8, 11–14, 16, 24, 27–28, 30, 35, and 39 would have
`been obvious. ............................................................................52
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`Claims 4, 5, 9, 10, 17–18, 25–26, 31–32, 36–37, and 40–41
`would have been obvious. .........................................................52
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`9.
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`Claims 42–48 would have been obvious. .................................52
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`10. There is no probative evidence of secondary considerations. ..53
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`a.
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`b.
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`c.
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`The allegedly “unexpected” cell-binding results lack a
`nexus to the ʼ229 patent and were expected. ..................53
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`The allegedly “unexpected” clinical data did not compare
`the closest prior art and were expected. ..........................56
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`Blocking patents prevented others from developing the
`claimed invention............................................................59
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`VIII. CONCLUSION ..............................................................................................60
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`IPR2018-00151 (8,138,229 B2)
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`TABLE OF AUTHORITIES
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` Page(s)
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`Cases
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`Abraxis BioScience, LLC v. Actavis LLC,
`C.A. No. 16-1925-JMV-MF ................................................................................. 4
`
`Abraxis BioScience, LLC v. Cipla Ltd.,
`C.A. No. 16-9074-JMV-MF ................................................................................. 4
`
`Apotex, Inc. v. Cephalon, Inc.,
`2012 WL 1080148 (E.D. Pa. Mar. 28, 2012) ..................................................... 19
`
`Brown & Williamson Tobacco Corp. v. Philip Morris Inc.,
`229 F.3d 1120 (Fed. Cir. 2000) .......................................................................... 46
`
`Cent. Admixture Pharmacy Servs., Inc. v. Advanced Cardiac Sols., P.C.,
`482 F.3d 1347 (Fed. Cir. 2007) .......................................................................... 20
`
`Cohesive Techs., Inc. v. Waters Corp.,
`543 F.3d 1351 (Fed. Cir. 2008) .......................................................................... 20
`
`Exxon Chem. Patents, Inc. v. Lubrizol Corp.,
`64 F.3d 1553 (Fed. Cir. 1995) ...................................................................... 18, 19
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) .....................................................................passim
`
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) .............................................................. 37, 38, 39
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`In re GPAC Inc.,
`57 F.3d 1573 (Fed. Cir. 1995) ............................................................................ 53
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`In re Harris,
`409 F.3d 1339 (Fed. Cir. 2005) .................................................................... 44, 45
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`In re Merck & Co.,
`800 F.2d 1091 (Fed. Cir. 1986) .............................................................. 40, 47, 59
`
`In re Omeprazole Patent Litig.,
`483 F.3d 1364 (Fed. Cir. 2007) .......................................................................... 23
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`IPR2018-00151 (8,138,229 B2)
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`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ............................................................................ 2
`
`Ineos USA LLC v. Berry Plastics Corp.,
`783 F.3d 865 (Fed. Cir. 2015) ................................................................ 24, 25, 26
`
`Kao Corp. v. Unilever U.S., Inc.,
`441 F.3d 963 (Fed. Cir. 2006) ............................................................................ 56
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`Mars, Inc. v. H.J. Heinz Co., L.P.,
`377 F.3d 1369 (Fed. Cir. 2004) .......................................................................... 19
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`Mitsubishi Chem. Corp. v. Barr Labs., Inc.,
`718 F. Supp. 2d 382 (S.D.N.Y. 2010), aff’d, 435 F. App’x 927
`(Fed. Cir. 2011) ................................................................................................... 51
`
`Mylan Pharms. Inc. v. Allergan, Inc.,
`IPR2016-01127, Paper 8 at 18-19 (PTAB Dec. 8, 2016) ................................... 25
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`nXn P’ners, LLC v. Nissan Chem. Indus., Ltd.,
`IPR2016-00694, Paper 7 (PTAB Aug. 31, 2016) ............................................... 31
`
`PAR Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .................................................................... 35, 45
`
`Petroleum Geo-Services Inc. v. Western-Geco LLC,
`IPR2014-01478, Paper 18 (PTAB Mar. 17, 2015) ............................................. 53
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 41
`
`Sanofi-Synthelabo v. Apotex Inc.,
`492 F. Supp. 2d 353 (S.D.N.Y. 2007), aff’d, 550 F.3d 1075 (Fed.
`Cir. 2008) ............................................................................................................ 60
`
`Titanium Metals Corp. of Am. v. Banner,
`778 F.2d 775 (Fed. Cir. 1985) ............................................................................ 22
`
`Trivascular, Inc. v. Samuels,
`812 F.3d 1056 (Fed. Cir. 2016) .......................................................................... 17
`
`Waddington N. Am., Inc. v. Sabert Corp.,
`2010 WL 4363137 (D.N.J. Oct. 27, 2010) ......................................................... 19
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`IPR2018-00151 (8,138,229 B2)
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`Wyeth v. Lupin Ltd.,
`579 F. Supp. 2d 711 (D. Md. 2008) .................................................................... 19
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`Statutes
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`35 U.S.C. §102(b) ........................................................................................ 1, 4, 6, 21
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`35 U.S.C. §103(a) ................................................................................................ 6, 34
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`35 U.S.C. § 315(c) ..................................................................................................... 1
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`Other Authorities
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`37 C.F.R. § 42.8 ......................................................................................................... 4
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`37 C.F.R. § 42.22 .................................................................................................... 1,5
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`37 C.F.R. §42.100 .................................................................................................... 17
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`37 C.F.R. § 42.104 ..................................................................................................... 5
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`37 C.F.R. §42.108 .................................................................................................... 31
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`37 C.F.R. § 42.122 ..................................................................................................... 1
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`IPR2018-00151 (8,138,229 B2)
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`LIST OF EXHIBITS
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`EX
`
`Description
`
`1001 Desai et al., U.S. Patent No. 8,138,229 B2, “Compositions and Methods of
`Delivery of Pharmacological Agents” (issued Mar. 20, 2012) (the “ʼ229
`patent”)
`1002 Declaration of Cory J. Berkland, Ph.D.
`in Support of Petition for Inter Partes Review
`
`1003 Desai et al., U.S. Patent No. 5,439,686, “Methods for In Vivo Delivery of
`Substantially Water Insoluble Pharmacologically Active Agents and
`Compositions Useful therefor” (issued Aug. 8, 1995) (the “ʼ686 patent”)
`
`1004 Kadima et al., WO 2000/006152, “Pharmaceutically Acceptable
`Composition Comprising an Aqueous Solution of Paclitaxel and Albumin”
`(published Feb. 10, 2000) (“Kadima”)
`
`1005 Liversidge et al., U.S. Patent No. 5,399,363, “Surface Modified Anticancer
`Nanoparticles” (issued Mar. 21, 1995) (“Liversidge”)
`
`1006 Desai et al., WO 1999/000113, “Novel Formulations of Pharmacological
`Agents, Methods for the Preparation thereof and Methods for the Use
`thereof” (published Jan. 7, 1999) (“Desai”)
`
`1007 Li et al., “Fluorescein Binding to Normal Human Serum Proteins
`Demonstrated by Equilibrium Dialysis,” Arch Ophalmol. vol. 100, 484–87
`(March 1982)
`1008 Physicians’ Desk Reference® 309, 881–887 (54th ed. 2000) “Taxol®
`(paclitaxel) Injection” (“Taxol® label”)
`
`1009 FDA Guideline on Sterile Drug Products Produced by Aseptic Processing
`(June 1987, reprinted June 1991 and Feb. 1997)
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`1010 EMEA Guidance on Manufacture of the Finished Dosage Form (April
`1996)
`
`1011 Elan Pharma Int’l Ltd. v. Abraxis BioScience, Inc., Judgment and Verdict
`Form, No. 06-438-GMS, Dkt. 614 (D. Del. June 16, 2008)
`
`1012 Elan Pharma Int’l Ltd. v. Abraxis BioScience, Inc., Sixth Day of Trial, No.
`06-438-GMS, Dkt. 624 (D. Del. June 9, 2008)
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`IPR2018-00151 (8,138,229 B2)
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`Description
`EX
`1013 Elan Pharma Int’l Ltd. v. Abraxis BioScience, Inc., Seventh Day of Trial,
`No. 06-438-GMS, Dkt. 625 (D. Del. June 10, 2008)
`
`1014 Grinstaff et al., U.S. Patent No. 5,498,421, “Composition Useful for In Vivo
`Delivery of Biologics and Methods Employing Same (issued Mar. 12,
`1996) (the “ʼ421 patent”)
`1015 Patient Information Leaflet, “ABRAXANE® for Injectable Suspension
`(paclitaxel protein-bound particles for injectable suspension) (albumin-
`bound)” (revised May 2007)
`1016 Administrative Documents, New Drug Application No. 21-660
`
`1017 Damascelli, B et al. “Intraarterial chemotherapy with polyoxyethylated
`castor oil free paclitaxel, incorporated in albumin nanoparticles (ABI-
`007),” Cancer 2001 Nov; 92(10):2592–2602 (“Damascelli”)
`1018 Ibrahim et al., “Phase I and pharmacokinetic study of ABI-007, a
`Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel,”
`Clin Cancer Res. 2002 May; 8:1038–44 (“Ibrahim”)
`1019 U.S. Application No. 11/553,339, Non-Final Office Action (mailed Apr.
`28, 2009)
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`1020 U.S. Application No. 11/553,339, Amendment in Response to Non-Final
`Office Action (dated Oct. 27, 2009)
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`1021 U.S. Application No. 11/553,339, Final Office Action (mailed Dec. 31,
`2009)
`
`1022 U.S. Application No. 11/553,339, Amendment After Final Action Under 37
`C.F.R. §1.116 (dated Apr. 14, 2010)
`
`1023 U.S. Application No. 11/553,339, Declaration of Neil P. Desai Pursuant to
`37 C.F.R. §1.132 (dated Apr. 14, 2010) (the “Inventor Declaration”)
`
`1024 U.S. Application No. 11/553,339, Notice of Allowance and Fee(s) Due
`(mailed June 1, 2010)
`
`1025 FDA, Approved Drug Products with Therapeutic Equivalence Evaluations
`(33d ed. 2013) (“Orange Book”)
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`IPR2018-00151 (8,138,229 B2)
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`EX
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`Description
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`1026 Desai et al., “Protein Stabilized Pharmacologically Active Agents, Methods
`for the Preparation Thereof and Methods for the Use
`Thereof,” U.S. Patent No. 5,916,596 (issued Jun. 29, 1999)
`
`1027 Remington’s Pharmaceutical Sciences (18th ed. 1990), Chapt. 85,
`“Intravenous Admixtures” (“Remington’s”)
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`1028 Camden, U.S. Patent No. 6,177,460 B1, “Method of Treatment for Cancer
`or Viral Infections” (issued Jan. 23, 2001)
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`IPR2018-00151 (8,138,229 B2)
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`I.
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`INTRODUCTION
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`Petitioners Apotex Inc. and Apotex Corp. (“Apotex”) request inter partes
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`review and cancellation of claims 1–48 of U.S. Patent No. 8,138,229 B2 (the “ʼ229
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`patent”). Petitioners are filing, concurrently herewith, a Motion for Joinder under
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`35 U.S.C. § 315(c) and 37 C.F.R. §§ 42.22 & 42.122(b) to the inter partes review
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`involving the same patent and the same grounds of invalidity in Actavis LLC v.
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`Abraxis BioScience, LLC, IPR2017-01104 (“Actavis IPR”), which was filed on
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`April 4, 2017. The instant Petition is substantially identical to the Petition filed in
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`the Actavis IPR. Claims 1–48 of the ’229 patent are directed to nanoparticles
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`combining (1) albumin, a known protein in human blood, with (2) paclitaxel, a
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`known anticancer drug, in which the albumin-paclitaxel ratio is about 9:1. As
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`shown below, the claimed invention was disclosed in a single prior art reference,
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`which anticipates claims 1–19 and 21–48. Independently, all claims would have
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`been obvious to a person of ordinary skill in the art. The allegedly “unexpected”
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`results that were asserted during prosecution lack a nexus to the claims and, in any
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`event, were entirely expected.
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`Anticipation. First, claims 1–19 and 21–48 are anticipated under 35 U.S.C.
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`§102(b) by an international patent application publication authored by two of the
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`ʼ229 patent’s inventors. EX1006 (“Desai”). The very first example in Desai
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`teaches a process of preparing albumin-paclitaxel “nanoparticles,” in which 270
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`mg of albumin and 30 mg of paclitaxel were combined. Id. at 62. As confirmed by
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`Petitioners’ declarant and nanoparticle formulation expert, Dr. Cory Berkland, the
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`disclosed process necessarily results in the claimed formulation with an albumin-
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`paclitaxel ratio of 9:1. EX1002 ¶107. And just like the ʼ229 patent, Desai teaches
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`methods of administering this formulation by intravenous injection to treat diseases
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`including cancer.
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`Obviousness. Second, and independently, all claims—even if they were not
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`anticipated—would have been obvious. The prior art “discloses a range encom-
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`passing” the claimed range of about 9:1, and thus “is sufficient to establish a prima
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`facie case of obviousness.” In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003).
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`That fact alone shifts the burden of production to Patent Owner to show the “criti-
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`cality” of the claimed ratio (id.)—a burden Patent Owner cannot meet.
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`Moreover, as its preferred embodiment, Desai undisputedly discloses an al-
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`bumin-paclitaxel nanoparticle formulation trademarked as “Capxol™” that “con-
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`tains 30 mg of paclitaxel and approximately 400 mg of human serum albumin”—
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`i.e., an albumin-paclitaxel ratio of 13.3:1. EX1006, 38. Reducing Capxol™’s al-
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`bumin-paclitaxel ratio of 13.3:1 to the claimed ratio of about 9:1 would have been
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`obvious. Indeed, Desai itself expressly encourages “developing formulations of
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`paclitaxel … at higher concentrations” to “reduce the time of administration” for
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`intravenous injection. EX1006, 21. As Desai explains, providing a higher concen-
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`tration of paclitaxel—e.g., by reducing the albumin-paclitaxel ratio—not only
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`“minimizes patient discomfort at receiving large volumes of fluid,” but can “result
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`IPR2018-00151 (8,138,229 B2)
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`in a higher response rate” to the drug. Id. at 54, 19–20.
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`In addition, as taught in a prior patent application publication to Kadima et
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`al., “[a]lbumin is an expensive ingredient” and “a cost-limiting component” in drug
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`formulations. EX1004 (“Kadima”), 10, 33. To obtain a “commercially feasible
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`method for using a serum albumin to administer paclitaxel,” Kadima expressly in-
`
`structs skilled artisans to use “a high … ratio” of paclitaxel to albumin—i.e., a low
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`ratio of albumin to paclitaxel. Id. at 33. Indeed, the ʼ229 patent inventors selected
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`a ratio of about 9:1 for that very reason, noting that “compositions with lower
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`amounts of albumin are preferred as this can greatly reduce cost….” EX1001,
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`34:53–55. A skilled artisan would have had the same motivation.
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`
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`Secondary considerations. During prosecution, the patentee argued that the
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`claimed albumin-paclitaxel ratio of about 9:1 produces “unexpected results.”
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`Although Petitioners have no burden at this stage to rebut such objective indicia,
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`Petitioners will show that the unexpected results asserted during prosecution
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`cannot overcome the strong prima facie case of obviousness.
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`According to the patentee, the ratio of about 9:1 unexpectedly provides “en-
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`hanced cellular binding of paclitaxel,” “is more efficacious,” and “has substantially
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`reduced toxicity.” EX1023 ¶¶ 7, 23. Yet, the “cellular binding” experiment that
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`the patentee relied on to support these assertions could not have shown any unex-
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`pected results of the claimed invention—because the experiment did not test any
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`albumin-paclitaxel formulation, let alone one with an albumin-paclitaxel ratio of
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`IPR2018-00151 (8,138,229 B2)
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`about 9:1. EX1002 ¶204. Moreover, the patentee’s “efficacy” and “toxicity” tests
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`showed only an insignificant difference in degree compared to an albumin-
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`paclitaxel ratio of 19:1, which is not even the closest prior art. Regardless, all of
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`these results would have been fully expected. Infra 53–59.
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`The Board should institute inter partes review and cancel claims 1–48 of the
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`ʼ229 patent as unpatentable under 35 U.S.C. §§ 102(b) and/or 103(a).
`
`II. MANDATORY NOTICES
`
`Pursuant to 37 C.F.R. § 42.8(b), Petitioners state as follows:
`
`1.
`
`Real parties-in-interest. Petitioners Apotex Inc. and Apotex Corp. are
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`the real parties-in-interest. Additional real parties-in-interest are Apotex
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`Pharmaceuticals Holdings Inc., Apotex Holdings Inc., and Panacea Biotec Limited.
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`2.
`
`Related matters. The ʼ229 patent is asserted in two district court liti-
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`gations filed in the U.S. District Court for the District of New Jersey, captioned
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`Abraxis BioScience, LLC v. Actavis LLC, C.A. No. 16-1925-JMV-MF; and Abraxis
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`BioScience, LLC v. Cipla Ltd., C.A. No. 16-9074-JMV-MF. The ’229 patent is
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`also challenged in one petition for inter partes review, captioned Actavis LLC v.
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`Abraxis BioScience, LLC, IPR2017-01104. Petitioners and Actavis LLC have also
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`filed petitions for inter partes review of U.S. Patent Nos. 7,820,788 (IPR2018-
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`00152 and IPR2017-01101, respectively), and 7,923,536 (IPR2018-00153 and
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`IPR2017-01103, respectively). Both the ʼ536 patent and the ʼ229 patent are
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`continuations of the ʼ788 patent.
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`IPR2018-00151 (8,138,229 B2)
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`3.
`
`Lead and back-up counsel. Petitioners identify the following:
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`
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`
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`
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`
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`Lead counsel:
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`John Josef Molenda (Reg. No. 47,804)
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`Back-up counsel: Vishal Gupta (Reg. No. 67,284)
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`Back-up counsel: Siew Yen Chong (Reg. No. 62,108)
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`Back-up counsel: Fang Bu*
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`* Back-up counsel to seek pro hac vice admission.
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`4.
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`Service information. Petitioners identify the following:
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` Email address:
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`Abraxane@Steptoe.com
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` Mailing address:
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`STEPTOE & JOHNSON LLP
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`1114 Avenue of the Americas, 35th Floor
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`New York, NY 10036
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` Telephone number: 212-506-3900
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` Fax number:
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`212-506-3950
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`Please address all correspondence to lead counsel at the address shown
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`above. Petitioners consent to electronic service at the above listed email address.
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`III. REQUIREMENTS FOR REVIEW
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`Pursuant to 37 C.F.R. § 42.104, Petitioners state as follows:
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`a.
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`Grounds for standing. Petitioners certify that (1) the ’229 patent is
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`available for IPR; and (2) Petitioners are not barred or estopped from requesting re-
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`view of any claim on the grounds identified in this Petition. The Office is author-
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`ized to charge all fees due in connection with this matter to Deposit Account No.
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`IPR2018-00151 (8,138,229 B2)
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`19-4293.
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`b.
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`Identification of challenge. Pursuant to 37 C.F.R. §§ 42.104(b) and
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`42.22(a)(1), Petitioners request review and cancelation of claims 1–48 of the ʼ229
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`patent pursuant to the following statement of precise relief requested:
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`Ground
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`Claims
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`Basis
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`Reference(s)
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`I
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`1–19, 21–48 § 102(b)
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`Desai (EX1006)
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`II.A
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`1–19, 21–48 § 103(a)
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`Desai (EX1006)
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`II.B
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`1–19, 21–48 § 103(a)
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`III.A
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`20
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`§103(a)
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`Desai (EX1006), Kadima (EX1004),
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`and Liversidge (EX1005)
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`Desai (EX1006) and Taxol® label
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`(EX1008)
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`Desai (EX1006), Taxol® label (EX1008),
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`III.B
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`20
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`§103(a)
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`Kadima (EX1004), and Liversidge
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`(EX1005)
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`IV. LEVEL OF ORDINARY SKILL IN THE ART
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`The ʼ229 patent claims priority to U.S. provisional application no.
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`60/432,317, which was filed on December 9, 2002. EX1001. Without conceding
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`that this priority claim is valid, Petitioners and declarant Dr. Cory Berkland use
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`December 9, 2002, as the relevant date for analyzing the level of skill and
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`knowledge of a hypothetical person of ordinary skill in the art. EX1002 ¶17.
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`IPR2018-00151 (8,138,229 B2)
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`Such a person would have an advanced degree in chemistry, chemical engi-
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`neering, pharmaceutics, pharmacy, or a related discipline, and/or having experi-
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`ence formulating compounds for use in pharmaceutical compositions, including
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`nanoparticle suspensions, for several years. Id. ¶20. A skilled artisan would know
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`how to evaluate potential drug therapies for in vitro and in vivo activity, including
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`with biological assays. Id.
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`V. THE PRIOR ART AND THE ʼ229 PATENT
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`As of December 2002, albumin and paclitaxel were well known in the art,
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`and their combination as albumin-paclitaxel nanoparticles had been claimed in two
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`generations of prior art patents—including with a 9:1 albumin-paclitaxel ratio.
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`A. Taxol® (paclitaxel) was an FDA-approved “wonder drug,” but ini-
`tially could only be administered with a toxic solvent.
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`As Desai explains, paclitaxel is a “naturally occurring” drug that was first
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`isolated in the early 1970s, and was known “to have significant antineoplastic [i.e.,
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`antitumor] and anticancer effects.” EX1006, 6–7. Due to its “excellent antitumor
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`activity in a wide variety of tumor models,” it became known as “the new anti-
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`cancer wonder-drug” and was “approved by the [Food and] Drug Administration”
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`in 1992 under the brand name Taxol®. Id. at 7; EX1008.
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`While paclitaxel’s therapeutic effects were impressive, its “poor aqueous
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`solubility” presented “a problem for human administration,” because the “delivery
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`of drugs that are inherently insoluble or poorly soluble in an aqueous medium can
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`be seriously impaired if oral delivery is not effective.” EX1006, 7. Taxol® was
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`thus formulated with a solvent called “polyethoxylated castor oil”—or Cremo-
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`phor®—“to solubilize the drug.” Id.; EX1008, 3.
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`Cremophor®, however, introduced its own problems. In “clinical trials,
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`[paclitaxel] itself did not show excessive toxic effects,” but Cremophor® caused
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`“severe allergic reactions,” requiring pre-treatment “with antihistamines and ster-
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`oids.” EX1006, 8. “Although it appear[ed] possible to minimize the side effects of
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`administering Taxol in an emulsion by use of a long infusion duration, the long in-
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`fusion duration [wa]s inconvenient for patients, and [wa]s expensive due to the
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`need to monitor the patients for the entire 6 to 24-hour infusion,” which required a
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`“night in the hospital.” Id. at 17–18. Thus, Desai recognized that following
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`Taxol®’s approval in 1992, it was “highly desirable to develop a formulation of
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`paclitaxel that obviates the need for premedication,” “does not cause hypersensitiv-
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`ity reactions,” and “shorten[s] the duration of infusion of Taxol.” Id. at 20.
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`B.
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`The inventors repeatedly patented albumin-paclitaxel nanoparti-
`cles as a solution to the known problems of Taxol®.
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`In 1995, two of the ʼ229 patent’s inventors obtained U.S. Patent No.
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`5,439,686 (the “ʼ686 patent”), which disclosed their solution to “the problem of
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`taxol administration”—a formulation that allows “its delivery as an aqueous sus-
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`pension of micron size particles.” EX1003, 10:14–16. “This approach,” they ex-
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`plained, “facilitate[s] the delivery of taxol at relatively high concentrations and ob-
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`viate[s] the use of emulsifiers [e.g., Cremophor®] and their associated toxic side ef-
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`fects.” Id. at 10:20–22. The particles are “contained within a polymeric shell,”
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`preferably consisting of “albumin.” Id. at 4:9–17, 6:42–43. These albumin-
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`paclitaxel particles “allow[] for the delivery of high doses of the pharmacologically
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`active agent in relatively small volumes.” Id. at 5:22–25. The “preferred particle
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`radii fall in the range of about 0.1 up to about 5 micron”—i.e., nanoparticles with
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`diameters as small as about 200 nm. Id. at 9:15–16.
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`Despite this earlier patent on albumin-paclitaxel nanoparticles, the inventors
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`later obtained a second round of patents on the very same invention, including U.S.
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`Patent No. 8,853,260 (the “ʼ260 patent”). In 1999, the inventors published
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`substantially the same disclosure that would later issue as the ʼ260 patent in an
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`international patent publication, Desai. EX1006.1
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`Like the ʼ686 patent, Desai teaches the delivery of paclitaxel “in the form of
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`microparticles or nanoparticles,” which “obviates the necessity for administration
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`of substantially water insoluble pharmacologically active agents (e.g., Taxol) in an
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`emulsion containing, for example, ethanol and polyethoxylated castor oil [i.e., Cre-
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`mophor],” the “disadvantage of such known compositions [being] their propensity
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`to produce allergic side effects.” Id. at 23. Likewise, in Desai’s compositions,
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`“proteins (e.g., human serum albumin) are employed as a stabilizing agent.” Id.
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`As Desai explains, “[a] large number of conventional pharmacologically ac-
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`tive agents [e.g., paclitaxel] circulate in the blood stream bound to carrier proteins
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`… of which the most common example is serum albumin.” Id. at 25. Simply put,
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`1 This disclosure was also issued as U.S. Patent No. 5,916,596 in 1999. EX1026.
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`“albumin … [is] the natural carrier of the drug in the blood stream.” Id.
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`Desai “further provides a method for the reproducible formation of … nano-
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`particles []less than 200 nm diameter.” Id. at 23. This size corresponds to Desai’s
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`“preferred embodiment,” in which “the average diameter of the … particles is no
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`greater than about 200 nm.” Id. at 38.
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`C. Desai (EX1006) specifically discloses a nanoparticle formulation
`with an albumin-paclitaxel ratio of 9:1.
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`Example 1 of Desai describes a process in which 30 mg of paclitaxel is com-
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`bined with 27 ml of human serum albumin solution at a concentration of 1% (w/v),
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`which corresponds to 270 mg of albumin—i.e., an albumin-paclitaxel ratio of
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`270:30, or 9:1. Id. at 62; EX1002 ¶71.
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`Example 1 provides that “the typical diameter of the resulting paclitaxel par-
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`ticles was 160–220[ nm],” measured as the “Z-average” using a standard device
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`called a “Malvern Zetasizer.” EX1006, 63. Example 1 further provides that the
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`composition was lyophilized (i.e., freeze-dried) and “could be easily reconstituted
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`to the original dispersion by addition of sterile water or saline.” Id. at 63. “The
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`particle size after reconstitution was the same as before lyophilization.” Id. at 63.
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`In sum, as of 1999, Desai taught pharmaceutical compositions for injection
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`comprising albumin-paclitaxel nanoparticles smaller than about 200 nm, including
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`compositions with an albumin-paclitaxel ratio of 9:1.
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`D. Desai, Kadima (EX1004), and Liversidge (EX1005) taught vary-
`ing ranges of albumin-paclitaxel ratios, and taught lowering the
`ratio to increase drug concentration and reduce cost.
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`In addition to Example 1’s albumin-paclitaxel ratio of 9:1, Desai teaches a
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`range of similar albumin-paclitaxel ratios. EX1002 ¶75. For instance, Example 4
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`combines 30 mg of paclitaxel with 29.4 ml of 1% albumin (i.e., 294 mg), which
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`corresponds to a ratio of 9.8:1. EX1006, 65. Similarly, Example 5 combines 225
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`mg of paclitaxel and 97.0 ml of 3% albumin (i.