UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`CIPLA LTD.,
`Petitioner
`
`v.
`
`ABRAXIS BIOSCIENCE, LLC,
`Patent Owner
`
`
`
`Case IPR2018-00164
`Patent 8,138,229 B2
`Issued: March 20, 2012
`
`Title: COMPOSITIONS AND METHODS OF
`DELIVERY OF PHARMACOLOGICAL AGENTS
`
`
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`

`

`IPR2018-00164 (8,138,229 B2)
`
`TABLE OF CONTENTS
`
`Page
`INTRODUCTION ........................................................................................... 1
`
`OVERVIEW .................................................................................................... 4
`
`I.
`
`II.
`
`III. MANDATORY NOTICES ............................................................................. 4
`
`IV. REQUIREMENTS FOR REVIEW ................................................................. 7
`
`V.
`
`LEVEL OF ORDINARY SKILL IN THE ART ............................................. 8
`
`VI. THE PRIOR ART AND THE ʼ229 PATENT ................................................ 8
`Taxol® (paclitaxel) was an FDA-approved “wonder drug,” but
`initially could only be administered with a toxic solvent. .................... 8
`
`A.
`
`B.
`
`C.
`
`The inventors repeatedly patented albumin-paclitaxel
`nanoparticles as a solution to the known problems of Taxol®. ........... 10
`Desai (EX1006) specifically discloses a nanoparticle
`formulation with an albumin-paclitaxel ratio of 9:1. .......................... 12
`
`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. ...................................................................................................... 12
`
`E.
`
`The inventors obtained their third round of patents on
`albumin-paclitaxel by arguing that a 9:1 ratio has
`“unexpected” benefits. ........................................................................ 15
`
`VII. PLAIN AND ORDINARY MEANINGS ..................................................... 19
`
`A.
`
`B.
`
`C.
`
`“the weight ratio of albumin to paclitaxel in the composition”
`and “the ratio (w/w) of albumin to the paclitaxel in the
`pharmaceutical composition” .............................................................. 19
`
`“a particle size of less than about 200 nm” ......................................... 22
`
`“about 0.5% to about 5% by weight of albumin” and “about
`5% by weight of albumin” .................................................................. 22
`
`
`
`

`

`
`VIII. ANALYSIS OF GROUNDS FOR TRIAL ................................................... 23
`
`IPR2018-00164 (8,138,229 B2)
`
`A. GROUND I: ANTICIPATION UNDER 35 U.S.C. §102(b) .............. 23
`
`1.
`
`Claim 1 is anticipated. ............................................................... 23
`
`a.
`
`b.
`
`c.
`
`Albumin-paclitaxel combination .................................... 24
`
`Particle size of less than about 200 nm .......................... 25
`
`Albumin-paclitaxel ratio of about 1:1 to 9:1 .................. 26
`
`d. Weight concentration of albumin ................................... 26
`
`Claims 3 and 6 are anticipated. ................................................. 28
`
`Claims 15, 19, and 21–23 are anticipated. ................................ 29
`
`Claims 29, 34, and 38 are anticipated. ...................................... 31
`
`Claims 7 and 33 are anticipated. ............................................... 32
`
`Claims 2, 8, 11–14, 16, 24, 27–28, 30, 35, and 39 are
`anticipated. ................................................................................ 32
`
`Claims 4–5, 9–10, 17–18, 25–26, 31–32, 36–37, and
`40–41 are anticipated. ............................................................... 33
`
`Claims 42–48 are anticipated. ................................................... 33
`
`The “starting” albumin-paclitaxel ratio does not change. ........ 33
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`B.
`
`GROUNDS II–III: OBVIOUSNESS UNDER 35 U.S.C.
`§103(a) ................................................................................................. 37
`
`1.
`
`Claim 1 would have been obvious. ........................................... 37
`
`a.
`
`GROUND II.A: Desai alone ........................................... 37
`
`i.
`
`ii.
`
`The albumin-paclitaxel ratio of about 9:1
`falls within a range disclosed by Desai. ............... 40
`
`Desai would have motivated a skilled
`artisan to lower CapxolTM’s albumin-
`paclitaxel ratio. ..................................................... 41
`
`
`
`ii
`
`

`

`
`
`IPR2018-00164 (8,138,229 B2)
`
`iii. A skilled artisan would have reasonably
`expected the claimed albumin-paclitaxel
`ratio of 9:1 to retain stability. ............................... 43
`
`iv.
`
`The claimed albumin weight percentage
`when the formulation is reconstituted in
`saline falls within a range disclosed by
`Desai. .................................................................... 46
`
`b.
`
`GROUND II.B: Desai, Kadima, and Liversidge ............ 47
`
`i.
`
`Kadima and Liversidge also disclose
`ranges of albumin-paclitaxel ratios
`including 9:1. ........................................................ 47
`
`ii.
`
`Kadima teaches additional reasons to lower
`CapxolTM’s 13.3:1 ratio to about 9:1. ................... 49
`Claims 3 and 6 would have been obvious................................. 52
`
`Claims 15, 19, and 21–23 would have been obvious. .............. 53
`
`Claim 20 would have been obvious. ......................................... 54
`
`Claims 29, 34, and 38 would have been obvious. .................... 55
`
`Claims 7 and 33 would have been obvious............................... 56
`
`Claims 2, 8, 11–14, 16, 24, 27–28, 30, 35, and 39 would
`have been obvious. .................................................................... 57
`
`Claims 4, 5, 9, 10, 17–18, 25–26, 31–32, 36–37, and
`40–41 would have been obvious. .............................................. 57
`
`Claims 42–48 would have been obvious. ................................. 57
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10. There is no probative evidence of secondary
`considerations. ........................................................................... 58
`
`a.
`
`The allegedly “unexpected” cell-binding results
`lack a nexus to the ʼ229 patent and were
`expected. ......................................................................... 59
`
`iii
`
`

`

`
`
`IPR2018-00164 (8,138,229 B2)
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`b.
`
`c.
`
`The allegedly “unexpected” clinical data did not
`compare the closest prior art and were expected. ........... 62
`
`Blocking patents prevented others from
`developing the claimed invention. .................................. 65
`
`IX. CONCLUSION .............................................................................................. 66
`
`
`
`
`
`
`iv
`
`

`

`
`
`IPR2018-00164 (8,138,229 B2)
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Abraxis BioScience, LLC v. Actavis LLC,
`C.A. No. 16-1925-JMV-MF ................................................................................. 5
`
`Abraxis BioScience, LLC v. Cipla Ltd.,
`C.A. No. 16-9074-JMV-MF ................................................................................. 5
`
`Apotex, Inc. v. Cephalon, Inc.,
`2012 WL 1080148 (E.D. Pa. Mar. 28, 2012) ..................................................... 22
`
`Brown & Williamson Tobacco Corp. v. Philip Morris Inc.,
`229 F.3d 1120 (Fed. Cir. 2000) .................................................................... 50, 51
`
`Cent. Admixture Pharmacy Servs., Inc. v. Advanced Cardiac Sols.,
`P.C.,
`482 F.3d 1347 (Fed. Cir. 2007) .......................................................................... 23
`
`Cohesive Techs., Inc. v. Waters Corp.,
`543 F.3d 1351 (Fed. Cir. 2008) .......................................................................... 23
`
`Exxon Chem. Patents, Inc. v. Lubrizol Corp.,
`64 F.3d 1553 (Fed. Cir. 1995) ............................................................................ 21
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) .......................................................... 41, 46, 52, 64
`
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) .......................................................................... 41
`
`In re GPAC Inc.,
`57 F.3d 1573 (Fed. Cir. 1995) ............................................................................ 59
`
`In re Harris,
`409 F.3d 1339 (Fed. Cir. 2005) .................................................................... 48, 49
`
`In re Merck & Co.,
`800 F.2d 1091 (Fed. Cir. 1986) .......................................................................... 44
`
`v
`
`

`

`
`In re Omeprazole Patent Litig.,
`483 F.3d 1364 (Fed. Cir. 2007) .......................................................................... 26
`
`IPR2018-00164 (8,138,229 B2)
`
`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) ...................................................................... 27, 29
`
`Kao Corp. v. Unilever U.S., Inc.,
`441 F.3d 963 (Fed. Cir. 2006) ............................................................................ 62
`
`Mars, Inc. v. H.J. Heinz Co., L.P.,
`377 F.3d 1369 (Fed. Cir. 2004) .......................................................................... 21
`
`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) ................................................................................................... 56
`
`Mylan Pharms. Inc. v. Allergan, Inc.,
`IPR2016-01127, Paper 8 (PTAB Dec. 8, 2016) ................................................. 28
`
`nXn P’ners, LLC v. Nissan Chem. Indus., Ltd.,
`IPR2016-00694, Paper 7 (PTAB Aug. 31, 2016) ............................................... 35
`
`PAR Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .................................................................... 39, 49
`
`Petroleum Geo-Services Inc. v. Western-Geco LLC,
`IPR2014-01478, Paper 18 (PTAB Mar. 17, 2015) ............................................. 58
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 45, 46
`
`Sanofi-Synthelabo v. Apotex Inc.,
`492 F. Supp. 2d 353 (S.D.N.Y. 2007), aff’d, 550 F.3d 1075 (Fed.
`Cir. 2008) ...................................................................................................... 65, 66
`
`Titanium Metals Corp. of Am. v. Banner,
`778 F.2d 775 (Fed. Cir. 1985) ............................................................................ 25
`
`Trivascular, Inc. v. Samuels,
`812 F.3d 1056 (Fed. Cir. 2016) .......................................................................... 19
`
`vi
`
`

`

`
`Waddington N. Am., Inc. v. Sabert Corp.,
`2010 WL 4363137 (D.N.J. Oct. 27, 2010) ......................................................... 22
`
`IPR2018-00164 (8,138,229 B2)
`
`Wyeth v. Lupin Ltd.,
`579 F. Supp. 2d 711 (D. Md. 2008) .................................................................... 22
`
`Statutes
`
`35 U.S.C. §102(b) ........................................................................................ 1, 4, 7, 23
`
`35 U.S.C. §103(a) ............................................................................................ 4, 7, 37
`
`Other Authorities
`
`37 C.F.R. §42.8(b) ..................................................................................................... 4
`
`37 C.F.R. §42.22(a)(1) ............................................................................................... 6
`
`37 C.F.R. §42.100(b) ............................................................................................... 19
`
`37 C.F.R. §42.104 ...................................................................................................... 7
`
`37 C.F.R. §42.104(b) ................................................................................................. 7
`
`37 C.F.R. §42.108(c) .......................................................................................... 34, 35
`
`
`
`
`
`
`vii
`
`

`

`
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`IPR2018-00164 (8,138,229 B2)
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`EXHIBITS CITED
`
`EX
`
`Description
`
`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”)
`
`Declaration of Cory J. Berkland, Ph.D. in Support of Petition for
`Inter Partes Review
`
`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”)
`
`Kadima et al., WO 2000/006152, “Pharmaceutically Acceptable
`Composition Comprising an Aqueous Solution of Paclitaxel and
`Albumin” (published Feb. 10, 2000) (“Kadima”)
`
`Liversidge et al., U.S. Patent No. 5,399,363, “Surface Modified
`Anticancer Nanoparticles” (issued Mar. 21, 1995) (“Liversidge”)
`
`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”)
`
`Li et al., “Fluorescein Binding to Normal Human Serum Proteins
`Demonstrated by Equilibrium Dialysis,” Arch Ophalmol. vol.
`100, 484–87 (March 1982)
`Physicians’ Desk Reference® 309, 881–887 (54th ed. 2000)
`“Taxol® (paclitaxel) Injection” (“Taxol® label”)
`
`FDA Guideline on Sterile Drug Products Produced by Aseptic
`Processing (June 1987, reprinted June 1991 and Feb. 1997)
`
`EMEA Guidance on Manufacture of the Finished Dosage Form
`(April 1996)
`
`Elan Pharma Int’l Ltd. v. Abraxis BioScience, Inc., Judgment and
`Verdict Form, No. 06-438-GMS, Dkt. 614 (D. Del. June 16,
`
`viii
`
`

`

`
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`IPR2018-00164 (8,138,229 B2)
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`2008)
`
`Elan Pharma Int’l Ltd. v. Abraxis BioScience, Inc., Sixth Day of
`Trial, No. 06-438-GMS, Dkt. 624 (D. Del. June 9, 2008)
`
`Elan Pharma Int’l Ltd. v. Abraxis BioScience, Inc., Seventh Day
`of Trial, No. 06-438-GMS, Dkt. 625 (D. Del. June 10, 2008)
`
`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”)
`Patient Information Leaflet, “ABRAXANE® for Injectable
`Suspension (paclitaxel protein-bound particles for injectable
`suspension) (albumin-bound)” (revised May 2007)
`
`Administrative Documents, New Drug Application No. 21-660
`
`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”)
`
`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”)
`
`U.S. Application No. 11/553,339, Non-Final Office Action
`(mailed Apr. 28, 2009)
`
`U.S. Application No. 11/553,339, Amendment in Response to
`Non-Final Office Action (dated Oct. 27, 2009)
`
`U.S. Application No. 11/553,339, Final Office Action (mailed
`Dec. 31, 2009)
`
`U.S. Application No. 11/553,339, Amendment After Final Action
`Under 37 C.F.R. § 1.116 (dated Apr. 14, 2010)
`
`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”)
`
`ix
`
`

`

`IPR2018-00164 (8,138,229 B2)
`
`U.S. Application No. 11/553,339, Notice of Allowance and Fee(s)
`Due (mailed June 1, 2010)
`
`FDA, Approved Drug Products with Therapeutic Equivalence
`Evaluations (33d ed. 2013) (“Orange Book”)
`
`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)
`
`Remington’s Pharmaceutical Sciences (18th ed. 1990), Chapt. 85,
`“Intravenous Admixtures” (“Remington’s”)
`
`Camden, U.S. Patent No. 6,177,460 B1, “Method of Treatment
`for Cancer or Viral Infections” (issued Jan. 23, 2001)
`
`
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`
`
`
`
`x
`
`

`

`
`I.
`
`INTRODUCTION
`
`IPR2018-00164 (8,138,229 B2)
`
`Petitioner Cipla Ltd. requests inter partes review and cancellation of claims
`
`1–48 of U.S. Patent No. 8,138,229 B2 (the “’229 patent”). These claims are
`
`directed to nanoparticles combining (1) albumin, a known protein in human blood,
`
`with (2) paclitaxel, a known anticancer drug, in which the albumin-paclitaxel ratio
`
`is about 9:1. As shown below, the claimed invention was disclosed in a single prior
`
`art reference, which anticipates claims 1–19 and 21–48. Independently, all claims
`
`would have been obvious to a person of ordinary skill in the art. The allegedly
`
`“unexpected” results that were asserted during prosecution lack a nexus to the
`
`claims and, in any event, were entirely expected.
`
`Anticipation. First, claims 1–19 and 21–48 are anticipated under 35 U.S.C.
`
`§102(b) by an international patent application publication authored by two of the
`
`’229 patent’s inventors. EX1006 (“Desai”). The very first example in Desai
`
`teaches a process of preparing albumin-paclitaxel “nanoparticles,” in which 270
`
`mg of albumin and 30 mg of paclitaxel were combined. Id. at 62. As confirmed by
`
`Petitioner’s declarant and nanoparticle formulation expert, Dr. Cory Berkland, the
`
`disclosed process necessarily results in the claimed formulation with an albumin-
`
`paclitaxel ratio of 9:1. EX1002 ¶107. And just like the ’229 patent, Desai teaches
`
`methods of administering this formulation by intravenous injection to treat diseases
`
`including cancer.
`
`
`
`

`

`
`
`IPR2018-00164 (8,138,229 B2)
`
`Obviousness. Second, and independently, all claims—even if they were not
`
`anticipated—would have been obvious. The prior art “discloses a range
`
`encompassing” the claimed range of about 9:1, and thus “is sufficient to establish a
`
`prima facie case of obviousness.” In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir.
`
`2003). That fact alone shifts the burden of production to Patent Owner to show the
`
`“criticality” of the claimed ratio (id.)—a burden Patent Owner cannot meet.
`
`Moreover, as its preferred embodiment, Desai undisputedly discloses an
`
`albumin-paclitaxel nanoparticle formulation trademarked as “CapxolTM” that
`
`“contains 30 mg of paclitaxel and approximately 400 mg of human serum
`
`albumin”— i.e., an albumin-paclitaxel ratio of 13.3:1. EX1006, 38. Reducing
`
`CapxolTM’s albumin-paclitaxel ratio of 13.3:1 to the claimed ratio of about 9:1
`
`would have been obvious. Indeed, Desai itself expressly encourages “developing
`
`formulations of paclitaxel...at higher concentrations” to “reduce the time of
`
`administration” for intravenous injection. EX1006, 21. As Desai explains,
`
`providing a higher concentration of paclitaxel—e.g., by reducing the albumin-
`
`paclitaxel ratio—not only “minimizes patient discomfort at receiving large
`
`volumes of fluid,” but can “result in a higher response rate” to the drug. Id. at 54,
`
`19–20.
`
`In addition, as taught in a prior patent application publication to Kadima et
`
`al., “[a]lbumin is an expensive ingredient” and “a cost-limiting component” in drug
`
`2
`
`

`

`
`formulations. EX1004 (“Kadima”), 10, 33. To obtain a “commercially feasible
`
`IPR2018-00164 (8,138,229 B2)
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`method for using a serum albumin to administer paclitaxel,” Kadima expressly
`
`instructs skilled artisans to use “a high...ratio” of paclitaxel to albumin—i.e., a low
`
`ratio of albumin to paclitaxel. Id. at 33. Indeed, the ʼ229 patent inventors selected a
`
`ratio of about 9:1 for that very reason, noting that “compositions with lower
`
`amounts of albumin are preferred as this can greatly reduce cost....” EX1001,
`
`34:53–55. A skilled artisan would have had the same motivation.
`
`Secondary considerations. During prosecution, the patentee argued that the
`
`claimed albumin-paclitaxel ratio of about 9:1 produces “unexpected results.”
`
`Although Petitioner has no burden at this stage to rebut such objective indicia,
`
`Petitioner will show that the unexpected results asserted during prosecution cannot
`
`overcome the strong prima facie case of obviousness.
`
`According to the patentee, the ratio of about 9:1 unexpectedly provides
`
`“enhanced cellular binding of paclitaxel,” “is more efficacious,” and “has
`
`substantially reduced toxicity.” EX1023 ¶¶ 7, 23. Yet, the “cellular binding”
`
`experiment that the patentee relied on to support these assertions could not have
`
`shown any unexpected results of the claimed invention—because the experiment
`
`did not test any albumin-paclitaxel formulation, let alone one with an albumin-
`
`paclitaxel ratio of about 9:1. EX1002 ¶204. Moreover, the patentee’s “efficacy”
`
`and “toxicity” tests showed only an insignificant difference in degree compared to
`
`3
`
`

`

`
`an albumin-paclitaxel ratio of 19:1, which is not even the closest prior art.
`
`IPR2018-00164 (8,138,229 B2)
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`Regardless, all of these results would have been fully expected. Infra 58–64.
`
`The Board should institute inter partes review and cancel claims 1–48 of the
`
`’229 patent as unpatentable under 35 U.S.C. §§ 102(b) and/or 103(a).
`
`II. OVERVIEW
`
`The Board already instituted Inter Partes review of claims 1–48 on the same
`
`grounds raised in this Petition on October 10, 2017.1 See IPR2017-1104 (Paper 7).
`
`The Board found that Petitioner Actavis has demonstrated a reasonable likelihood
`
`that claims 1–48 are unpatentable based on those grounds. The present petition is
`
`substantially identical to the petition in IPR2017-01104. A motion for joinder with
`
`IPR2017-01104 is being concurrently filed.
`
`III. MANDATORY NOTICES
`
`Pursuant to 37 C.F.R. §42.8(b), Petitioner states as follows:
`
`1.
`
`Real parties-in-interest. Petitioner Cipla Ltd. is the real party-in-
`
`interest, with a registered office at Cipla House, Peninsula Business Park,
`
`Ganpatrao Kadam Marg, Lower Parel, Mumbai – 400013, Maharashtra, India. Out
`
`of an abundance of caution, and for purposes of this Petition only, Petitioner
`
`additionally discloses Cipla USA, Inc., located at 1560 Sawgrass Corporate
`
`1 The Board has instituted review in IPR2017-01101, IPR2017-01103, and
`
`IPR2017-01104.
`
`4
`
`

`

`
`Parkway, Suite 130, Sunrise, FL 33323, InvaGen Pharmaceuticals, Inc., located at
`
`IPR2018-00164 (8,138,229 B2)
`
`7 Oser Avenue, Hauppauge, NY 11788, and Cipla (EU) Limited, with an office at
`
`Hillbrow House, Hillbrow Road, Esher, Surrey, KT109NW.
`
`2.
`
`Related matters. The ’229 patent is asserted in two district court
`
`litigations filed in the U.S. District Court for the District of New Jersey, captioned
`
`Abraxis BioScience, LLC v. Actavis LLC, C.A. No. 16-1925-JMV-MF; and Abraxis
`
`BioScience, LLC v. Cipla Ltd., C.A. No. 16-9074-JMV-MF.
`
`The ’229 patent is subject of IPR2017-01104, filed by Actavis LLC. Actavis
`
`also filed IPR2017-01103 against Abraxis Bioscience, LLC’s U.S. Patent No.
`
`7,923,536, IPR2017-01101 against Abraxis Bioscience, LLC’s U.S. Patent No.
`
`7,820,788, and IPR2017-01100 against Abraxis Bioscience, LLC’s U.S. Patent No.
`
`8,853,260. The Board instituted inter partes review of the ’536 patent, the ’229
`
`patent, and the ’788 patent on October 10, 2017. The Board declined to institute
`
`inter partes review of the ’260 patent.
`
`Petitioner is contemporaneously filing petitions for inter partes review of
`
`U.S. Patent Nos. 7,820,788 and 7,923,536. Both the ’229 patent and the ’536
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`patent are continuations of the ’788 patent.
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`3.
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`Lead and back-up counsel. Petitioner identifies the following:
`
`Lead Counsel
`
`Back-Up Counsel
`
`Michael J. Freno (Reg. No. 57,163)
`
`Anil Patel*
`
`5
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`

`

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`K&L GATES LLP
`925 Fourth Avenue, Suite 2900
`Seattle, WA 98104
`Telephone: 206.370.7947
`Facsimile: 206.623.7022
`Email: michael.freno@klgates.com
`
`
`* Counsel to seek pro hac vice admission.
`
`IPR2018-00164 (8,138,229 B2)
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`K&L GATES LLP
`1000 Main Street, Suite 2550
`Houston, TX 77002
`Telephone: 713.815.7304
`Facsimile: 713.583.9417
`Email: anil.patel@klgates.com
`
`Jason A. Engel (Reg. No. 51,654)
`K&L GATES LLP
`70 W. Madison Street, Suite 3100
`Chicago, IL 60602
`Telephone: 312.807.4236
`Facsimile: 312.827.8145
`Email: jason.engel.ptab@klgates.com
`
`Peter L. Giunta (Reg. No. 55,207)
`K&L GATES LLP
`599 Lexington Avenue
`New York, NY 10022
`Telephone: 212.536.3910
`Facsimile: 212.536.3901
`Email: peter.giunta@klgates.com
`
`Elizabeth Weiskopf *
`K&L GATES LLP
`925 Fourth Avenue, Suite 2900
`Seattle, WA 98104
`Telephone: 206.370.7964
`Facsimile: 206.623.7022
`Email: elizabeth.weiskopf@klgates.com
`
`
`4.
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`Service information. Please address all correspondence to lead
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`counsel at the address shown above. Petitioner consents to electronic service at the
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`above listed email address.
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`6
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`

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`IV. REQUIREMENTS FOR REVIEW
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`IPR2018-00164 (8,138,229 B2)
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`Pursuant to 37 C.F.R. §42.104, Petitioner states as follows:
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`a.
`
`Grounds for standing. Petitioner certifies that (1) the ’229 patent is
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`available for IPR; and (2) Petitioner is not barred or estopped from requesting
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`review of any claim on the grounds identified in this Petition. The Office is
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`authorized to charge all fees due in connection with this matter to Deposit Account
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`No. 02-1818.
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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), Petitioner requests 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
`
`Basis
`
`1–19, 21–48
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`§102(b)
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`1–19, 21–48
`
`§103(a)
`
`1–19, 21–48
`
`§103(a)
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`Reference(s)
`
`Desai (EX1006)
`
`Desai (EX1006)
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`Desai (EX1006), Kadima (EX1004),
`and Liversidge (EX1005)
`Desai (EX1006) and Taxol® label
`(EX1008)
`
`I
`
`II.A
`
`II.B
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`III.A
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`III.B
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`
`
`§103(a)
`
`20
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`20
`
`§103(a) Desai (EX1006), Taxol® label (EX1008),
`Kadima (EX1004), and Liversidge
`(EX1005)
`
`7
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`

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`V. LEVEL OF ORDINARY SKILL IN THE ART
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`IPR2018-00164 (8,138,229 B2)
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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, Petitioner 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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`Such a person would have an advanced degree in chemistry, chemical
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`engineering, pharmaceutics, pharmacy, or a related discipline, and/or having
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`experience formulating compounds for use in pharmaceutical compositions,
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`including nanoparticle suspensions, for several years. Id. ¶20. A skilled artisan
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`would know how to evaluate potential drug therapies for in vitro and in vivo
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`activity, including with biological assays. Id.
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`VI. THE PRIOR ART AND THE ʼ229 PATENT
`
`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
`initially could only be administered with a toxic solvent.
`
`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
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`IPR2018-00164 (8,138,229 B2)
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`anticancer wonder-drug” and was “approved by the [Food and] Drug
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`Administration” in 1992 under the brand name Taxol®. Id. at 7; EX1008.
`
`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 thus
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`formulated with a solvent called “polyethoxylated castor oil”—or Cremophor®—
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`”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
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`steroids.” EX1006, 8. “Although it appear[ed] possible to minimize the side effects
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`of administering Taxol in an emulsion by use of a long infusion duration, the long
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`infusion 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
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`hypersensitivity reactions,” and “shorten[s] the duration of infusion of Taxol.” Id.
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`IPR2018-00164 (8,138,229 B2)
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`at 20.
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`B.
`
`The inventors repeatedly patented albumin-paclitaxel
`nanoparticles as a solution to the known problems of Taxol®.
`In 1995, two of the ’229 patent’s inventors obtained U.S. Patent No.
`
`5,439,686 (the “’686 patent”), which disclosed their solution to “the problem of
`
`taxol administration”—a formulation that allows “its delivery as an aqueous
`
`suspension of micron size particles.” EX1003, 10:14–16. “This approach,” they
`
`explained, “facilitate[s] the delivery of taxol at relatively high concentrations and
`
`obviate[s] the use of emulsifiers [e.g., Cremophor®] and their associated toxic side
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`effects.” 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-
`
`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.
`
`Despite this earlier patent on albumin-paclitaxel nanoparticles, the inventors
`
`later obtained a second round of patents on the very same invention, including U.S.
`
`Patent No. 8,853,260 (the “’260 patent”). In 1999, the inventors published
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`substantially the same disclosure that would later issue as the ’260 patent in an
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`IPR2018-00164 (8,138,229 B2)
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`international patent publication, Desai. EX1006.2
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`Like the ’686 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.,
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`Cremophor],” the “disadvantage of such known compositions [being] their
`
`propensity to produce allergic side effects.” Id. at 23. Likewise, in Desai’s
`
`compositions, “proteins (e.g., human serum albumin) are employed as a stabilizing
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`agent.” Id.
`
`As Desai explains, “[a] large number of conventional pharmacologically
`
`active agents [e.g., paclitaxel] circulate in the blood stream bound to carrier
`
`proteins...of which the most common example is serum albumin.” Id. at 25. Simply
`
`put, “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
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`of...nanoparticles []less than 200 nm diameter.” Id. at 23. This size corresponds to
`
`Desai’s “preferred embodiment,” in which “the average diameter of the...particles
`
`is no greater than about 200 nm.” Id. at 38.
`
`
`2 This disclosure was also issued as U.S. Patent No. 5,916,596 in 1999. EX1026.
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`11
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`IPR2018-00164 (8,138,229 B2)
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`C. Desai (EX1006) specifically discloses a nanoparticle formulation
`with an albumin-paclitaxel ratio of 9:1.
`
`Example 1 of Desai describes a process in which 30 mg of paclitaxel is
`
`combined with 27 ml of human serum albumin solution at a concentration of 1%
`
`(w/v), which corresponds to 270 mg of albumin—i.e., an albumin-paclitaxel ratio
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`of 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
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`particles was 160–220[ nm],” measured as the “Z-average” using a standard device
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`ca