IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`Attorney Docket No. 083441.0104
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`7,754,702
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`January 8, 2007
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`July 13, 2010
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`Methods and Compositions for Administration of Iron
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`Patent:
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`Inventor: Mary Jane Helenek et al. :
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`Filed:
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`Issued:
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`Title:
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`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`US Patent and Trademark Office
`PO Box 1450
`Alexandria, Virginia 22313-1450
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`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 7,754,702
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`Attorney Docket No. 083441.0104
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`:
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`:
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`:
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`7,754,702
`
`
`
`January 8, 2007
`
`July 13, 2010
`
`Methods and Compositions for Administration of Iron
`
`
`Patent:
`
`Inventor: Mary Jane Helenek et al. :
`
`Filed:
`
`Issued:
`
`Title:
`
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`US Patent and Trademark Office
`PO Box 1450
`Alexandria, Virginia 22313-1450
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 7,754,702
`
`
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`Petition for Inter Partes Review of U.S. Patent No. 7,754,702
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`TABLE OF CONTENTS
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`I. MANDATORY NOTICES AND FEES............................................................ 1
`
`A. Real Parties-in-Interest ....................................................................................... 1
`
`B. Related Matters .................................................................................................. 1
`
`C. Lead And Back-up Counsel And Service Information ...................................... 1
`
`D. Payment .............................................................................................................. 2
`
`II. CERTIFICATION OF GROUNDS FOR STANDING .................................... 2
`
`III. OVERVIEW OF CHALLENGE AND RELIEF REQUESTED ...................... 2
`
`A. Prior Art Patents And Printed Publications ....................................................... 2
`
`B. Additional Documents Relied On ...................................................................... 3
`
`C. Grounds For Challenge ...................................................................................... 3
`
`IV. OVERVIEW OF THE ‘702 PATENT ............................................................... 4
`
`A. Overview Of The Disclosure ............................................................................. 4
`
`B. Overview Of The Prosecution History .............................................................. 6
`
`V. CLAIM CONSTRUCTION ............................................................................. 10
`
`A.
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`Iron Carboxymaltose Complex ........................................................................ 11
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`B.
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`Iron Polymaltose .............................................................................................. 11
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`C.
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`Iron Sorbitol Complex/Iron Polyglucose Sorbitol Carboxymethyl Ether
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`Complex ................................................................................................................... 12
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`Petition for Inter Partes Review of U.S. Patent No. 7,754,702
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`D. Substantially Non-Immunogenic Carbohydrate Component .......................... 13
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`E. Anti-Dextran Antibodies .................................................................................. 13
`
`F. Substantially No Cross-Reactivity With Anti-Dextran Antibodies ................. 14
`
`VI. LEVEL OF ORDINARY SKILL IN THE ART ............................................. 14
`
`VII. SUMMARY OF PRIOR ART ......................................................................... 14
`
`A. State of the Art ................................................................................................. 14
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`B. Summary of Primary Prior Art References...................................................... 16
`
`VIII.
`
`IDENTIFICATION OF HOW THE CHALLENGED CLAIMS ARE
`
`UNPATENTABLE .................................................................................................. 22
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`A. Ground 1: Claims 1, 2, 3, 10, 11, 12, 13, 23, 25, 26, 27, 41, 42, And 43 Are
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`Anticipated By Geisser ............................................................................................ 22
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`B. Ground 2: Claim 28 Is Anticipated By Groman ............................................. 39
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`C. Ground 3: Claims 17, 34 And 47 Are Obvious Under 35 U.S.C. §103 Over
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`Geisser In View Of Groman .................................................................................... 44
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`D. Ground 4: Claims 14 and 15 Are Anticipated By Van Zyl-Smit ................... 50
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`E. Ground 5: Claim 30 Is Obvious Under 35 U.S.C. §103 Over Van Zyl-Smit In
`
`View Of Funk ........................................................................................................... 55
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`IX. CONCLUSION ................................................................................................ 57
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`Active: 19767694.1
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`- ii -
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`Petition for Inter Partes Review of U.S. Patent No. 7,754,702
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`EXHIBITS
`
`
`Description
`United States (U.S.) Patent No. 7,754,702 (“the ‘702 patent”)
`International Patent Publ. No. WO2004037865 (“Geisser”)
`Certified translation of International Patent Publ. No.
`WO2004037865 (“Geisser”)
`U.S. Patent Application Publication No. 2003/0232084
`(“Groman”)
`Declaration of Robert Linhardt
`van Zyl-Smit and Halkett (2002) Nephron 92:316-323 (“van Zyl-
`Smit”)
`Prosecution history of the ‘702 patent
`U.S. Patent No. 5,624,668 (“the ‘668 patent”)
`U.S. Patent Application Publication No. 2004/0180849 (“the ‘849
`application”)
`Auerbach et al. (2004) J. Clinical Oncol. 22(7):1301-1307
`(“Auerbach”)
`Spinowitz et al. (2005) Kidney Int’l. 68:1801-1807 (“Spinowitz”)
`F.D.A. Orange Book Listing for Injectafer® injection
`F.D.A. Advisory Committee Briefing Document on NDS-22-054
`for Injectafer®, February 1, 2008
`U.S. Patent No. 7,612,109 (“the ‘109 patent”)
`Patent Term Extension Application for the ‘109 patent
`F.D.A. Orange Book Listing for Feraheme® ferumoxytol injection
`U.S. Patent No. 6,599,498 (“the ‘498 patent”)
`Patent Term Extension Application for the ‘498 patent
`U.S. Patent No. 7,871,597 (“the ‘597 patent”)
`Excerpt of prosecution history of U.S. Patent No. 8,895,612 (“the
`‘612 patent”)
`Excerpt of prosecution history of European Patent Application
`EP1973549
`Neiser et al. (2011) Port. J. Nephrol. Hypert. 25(3), 219-224
`(“Neiser”)
`British Pharmacopoeia Monograph for Iron Sorbitol (2003)
`Prescribing information for Feraheme®
`“Feraheme (ferumoxytol) Drug Safety Communication,” 3/ 30/
`2015
`Funk et al. (2001) Hyperfine Interactions 136:73-95 (“Funk”)
`
`Exhibit No.
`1001
`1002
`1003
`
`1004
`
`1005
`1006
`
`1007
`1008
`1009
`
`1010
`
`1011
`1012
`1013
`
`1014
`1015
`1016
`1017
`1018
`1019
`1020
`
`1021
`
`1022
`
`1023
`1024
`1025
`
`1026
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`Active: 19767694.1
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`Petition for Inter Partes Review of U.S. Patent No. 7,754,702
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`1027
`1028
`1029
`1030
`1031
`1032
`1033
`1034
`1035
`1036
`1037
`1038
`1039
`1040
`1041
`1042
`1043
`1044
`1045
`
`1046
`1047
`1048
`
`1049
`
`1050
`1051
`1052
`
`Merriam Webster Dictionary definition for Hematinic agent
`European Pharmacopeia for Dextran 1 (2005)
`Jahn et al. (2011) Eur. J. Pharma and Biopharma 78:480-91
`Merck Index (14th Edition) for Dextran (2006)
`U.S. Patent No. 3,100,202
`Canadian Patent No. 623411
`Product documentation for Promit®
`U.S. Patent No. 5,541,158
`Neiser, 2015, Biometals 1-21
`Richter (1986) New Trends in Allergy II, 272-283
`United States Pharmacopeia for Dextran 1 (USP 28; 2005)
`Product documentation for Dextran T1
`Declaration Under 37 C.F.R. 1.132 of Richard Lawrence
`Excerpts of the File History of the ‘702 Patent
`U.S. Patent No. 8,895,612
`Excerpts of the File History of the ‘612 Patent
`Excerpts of the File History of U.S. Patent No. 8,431,549
`U.S. Patent No. 8,431,549
`Reply to the Letter to the Editor regarding Neiser et al. (2011,
`Port. J. Nephrol. Hypert. 25(3):219-224), Port. J. Nephrol. Hypert.
`26(4):308-312
`Prescribing Information for Injectafer®
`Marchasin (1964) Blood 23:354-358
`Danielson (2004) Structure, Chemistry, and Pharmacokinetics of
`Intravenous Iron Agents, Journal of the American Society of
`Nephrology 15:593-598
`Geisser et al., 1992, Structure / Histotoxicity Relationship of
`Parenteral Iron Preparations, Drug Res. 42(11):1439-1452
`U.S. Patent No. 3,076,798
`U.S. Patent No. 4,599,405
`Letter to Editor regarding Neiser et al. (2011, Port. J. Nephrol.
`Hypert. 25(3):219-224), Port. J. Nephrol. Hypert. 26(4)
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`I. MANDATORY NOTICES AND FEES
`A. Real Parties-in-Interest
`Pharmacosmos A/S is the real party-in-interest (referred to herein as
`
`“Pharmacosmos” or “Petitioner”).
`
`B. Related Matters
`There are no existing judicial or administrative matters that would affect, or
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`be affected by, a decision
`
`in
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`this proceeding.
`
` Concurrently herewith,
`
`Pharmacosmos is filing petitions for inter partes review of two patents related to
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`the patent for which review is sought herein, U.S. Patent No. 7,754,702.
`
`C. Lead And Back-up Counsel And Service Information
`
`Lead Counsel
`Name: Lisa Kole
`Address: Baker Botts L.L.P. , 30
`Rockefeller Plaza, NY, NY 10112
`Phone: 212-408-2628
`Fax: 212-259-2428
`E-mail: lisa.kole@bakerbotts.com
`USPTO Reg. No. 35,225
`
`Back-up Counsel
`Name: Steven Lendaris
`Address: Baker Botts L.L.P., 30
`Rockefeller Plaza, NY, NY 10112
`Phone: 212-408-2535
`Fax: 212-259-2535
`E-mail: steven.lendaris@bakerbotts.com
`USPTO Reg. No. 53,202
`
`Name: Paul Ragusa
`Address: Baker Botts L.L.P., 30
`Rockefeller Plaza, NY, NY 10112
`Phone: 212-408-2588
`Fax: 212-259-2588
`E-mail: paul.ragusa@bakerbotts.com
`USPTO Reg. No. 38,587
`
`Please address all correspondence
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`to
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`lead and back-up counsel.
`
`Pharmacosmos also consents to service by e-mail.
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`Active: 19767694.1
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`1
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`Payment
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`D.
`Under 37 C.F.R § 42.103(a), the Office is authorized to charge the fee set
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`forth in 37 C.F.R. § 42.15(a) to Deposit Account No. 02-4377 as well as any
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`additional fees that might be due in connection with this Petition.
`
`II. CERTIFICATION OF GROUNDS FOR STANDING
`Pharmacosmos certifies under 37 C.F.R § 42.104(a) that the patent for which
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`review is sought is available for inter partes review (“IPR”) and that
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`Pharmacosmos is not barred or estopped from requesting an IPR challenging the
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`patent claims on the grounds identified in this Petition.
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`III. OVERVIEW OF CHALLENGE AND RELIEF REQUESTED
`Under 37 C.F.R §§ 42.22(a)(1) and 42.104 (b)(1)-(2), Pharmacosmos asks
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`that the Board review the accompanying prior art and analysis, institute a trial for
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`IPR of claims 1, 2, 3, 10, 11, 12, 13, 14, 15, 17, 23, 25, 26, 27, 28, 30, 34, 41, 42,
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`43 and 47 of U.S. Patent No. 7,754,702 (“the ‘702 patent”), and cancel those
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`claims as unpatentable.
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`Prior Art Patents And Printed Publications
`
`A.
`Pharmacosmos relies upon the following prior art to the ‘702 patent.
`
`Ex.
`
`Description
`
`1002 Geisser
`1003 Certified translation of
`Geisser
`1004 Groman
`1006 van Zyl-Smit
`
`Filing Date
`
`Publication
`Date
`Oct. 20, 2003 May 6, 2004
`Oct. 20, 2003 May 6, 2004
`
`Prior Art
`Under
`102(b)
`102(b)
`
`April 9, 2003 Dec. 18, 2003 102(b)
`n/a
`2002
`102(b)
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`Active: 19767694.1
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`2
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`
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`
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`1026 Funk
`n/a
`B. Additional Documents Relied On
`Additional documents relied upon include the following materials.
`
`2001
`
`102(b)
`
`Ex.
`1005
`1007
`1010
`1011
`1012
`1013
`
`Description
`Declaration of Robert Linhardt
`Prosecution History of the ‘702 patent
`Auerbach
`Spinowitz
`F.D.A. Orange Book Listing for Injectafer® injection
`FDA Advisory Committee Briefing Document on NDS 22-054 for
`Injectafer®, February 1, 2008
`the ‘109 patent
`1014
`Patent Term Extension Application for the ‘109 patent
`1015
`F.D.A. Orange Book Listing for Feraheme® ferumoxytol injection
`1016
`the ‘498 patent
`1017
`Patent Term Extension Application for the ‘498 patent
`1018
`the ‘597 patent
`1019
`Excerpt of prosecution history of U.S. Patent No. 8,895,612
`1020
`Excerpt of prosecution history of EP Patent Appln. EP1973549
`1021
`Neiser
`1022
`British Pharmacopoeia Monograph for Iron Sorbitol (2003)
`1023
`Prescribing information for Feraheme®
`1024
`Feraheme (ferumoxytol) Drug Safety Communication
`1025
`1027 Merriam Webster Dictionary definition for Hematinic agent
`C. Grounds For Challenge
`Pharmacosmos requests cancelation of the challenged claims under the
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`following statutory grounds:
`
`Grounds
`
`Claims
`
`Description
`
`1
`
`2
`
`1, 2, 3, 10, 11, 12, 13, 23,
`25, 26, 27, 41, 42, and 43
`28
`
`Anticipated under 35 U.S.C. § 102(b)
`by Geisser
`Anticipated under 35 U.S.C. § 102(b)
`by Groman
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`Active: 19767694.1
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`3
`
`
`
`
`
`3
`
`4
`
`5
`
`17, 34 and 47
`
`14 and 15
`
`30
`
`Obvious under 35 U.S.C. §103(a) over
`Geisser in view of Groman
`Anticipated under 35 U.S.C. § 102(b)
`by van Zyl-Smit
`Obvious under 35 U.S.C. §103(a) over
`van Zyl-Smit in view of Funk
`
`As demonstrated below, for each of the numbered grounds, there is a
`
`reasonable likelihood that Petitioner will prevail with respect to at least one of the
`
`challenged claims. See 35 U.S.C. § 314(a).
`
`IV. OVERVIEW OF THE ‘702 PATENT
`The ‘702 patent is assigned to Luitpold Pharmaceuticals, Inc. (herein,
`
`“Luitpold” or “Patentee”). The ‘702 patent is listed in the Food and Drug
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`Administration Orange Book as covering Injectafer®, a “ferric carboxymaltose
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`injection” marketed by American Regent, Inc., a Luitpold company. Ex. 1012.
`
`A. Overview Of The Disclosure
`The ‘702 patent extolls the merits of parenteral iron therapy but cautions that
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`“many currently available parenteral iron drugs . . . have health risks and dosage
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`limitations associated with their use.” Ex. 1001 at 1:31-34. In particular, “[i]ron
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`dextran . . . has been associated with an incidence of anaphylactoid-type reactions
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`(i.e., dyspnea, wheezing, chest pain, hypotension, urticaria, angioedema) . . .
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`believed to be caused by the formation of antibodies to the dextran moiety.” Id. at
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`1:47-54.
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`Active: 19767694.1
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` Purportedly, the invention of the ‘702 patent overcomes these problems and
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`allows the use of high doses of iron carbohydrate complexes with only a “low risk
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`of anaphylactoid/hypersensitivity reactions.” Id. at 11:5. See also id at 3:14-16,
`
`and 15:16-44. Single doses range from at least 0.6 grams (g) of an iron
`
`carbohydrate to no specified upper limit. Id. at 7:16-30. The doses can be
`
`administered rapidly, in time frames ranging from 15 minutes or less to 2 minutes
`
`or less, with no specified lower limit. Id. at 7:42-58. The examples relate to a
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`single species of iron carboxymaltose referred to as VIT-45 (an alternative name
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`for ferric carboxymaltose and Injectafer®1), said to be represented by the chemical
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`formula: [FeOx(OH)y(H2O)z]n [{(C6H10O5)m (C6H12O7)}l]k, where n is about 1032,
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`m is about 8, l is about 11, and k is about 4. Id. at 11:65-12:1.
`
`Despite exemplifying only the iron carboxymaltose VIT-45, the disclosure
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`contemplates using a wide variety of iron carbohydrate complexes including those
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`known in the prior art. See, e.g., id. at 10:46-47 (“[i]ron carbohydrate complexes
`
`1 Other alternative names are Ferinject® or FCM. Ex. 1013 at 7. See also the
`
`F.D.A. Orange Book Listing for Injectafer® (Ex. 1012), the Orange Book-Listed
`
`‘109 Patent (Ex. 1014), and the corresponding application for Patent Term
`
`Extension, Ex. 1015, especially at Exhibit H (Investigational New Drug
`
`Application for VIT-45 used as basis for Injectafer® FDA approval).
`
`2 It is assumed that 103 is intended to mean 103.
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`Active: 19767694.1
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`5
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`
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`are commercially available, or have well known syntheses”). Special attention is
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`given to ferumoxytol (developed by Advanced Magnetics, Inc.), which, although
`
`chemically a derivatized form of dextran, is never referred to as such in the
`
`specification. See, e.g., id. at 13:33-59. Instead, the ‘702 patent describes
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`ferumoxytol as “a supraparamagnetic iron oxide that is coated with a low
`
`molecular weight semi-synthetic carbohydrate, polyglucose sorbitol carboxymethyl
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`ether,” citing the ‘498 patent.3 Id. at 13:39-41. The ‘702 patent asserts that
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`ferumoxytol “is known in the art to be effective for treating anemia (at single unit
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`doses lower than described herein)” for example “up to 420 mg4 per injection.” Id.
`
`at 34-58. The ‘702 patent fails to identify what is new about its methods which
`
`allow them to avoid risks associated with ferumoxtol or other previously available
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`iron carbohydrate complexes.
`
`B. Overview Of The Prosecution History
`The earliest priority date claimed for the ‘702 patent is January 6, 2006,
`
`based on U.S. Provisional Application No. 60/757,119.
`
`3 “Ferumoxytol” is the generic name for commercially available “Feraheme®,”
`
`(Ex. 1024) and a Patent Term Extension (Ex. 1018) of the ‘498 patent (Ex. 1017)
`
`was filed based on the approval of Feraheme®.
`
`4 In fact, Spinowitz (Ex. 1011), cited in the ‘702 specification, teaches
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`administration of 510 mg. Ex. 1001 at 2:7-8, 13:38-39 and 13:46-47.
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`Active: 19767694.1
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`The originally filed claims were directed to methods of “treating a disease,
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`disorder or condition characterized by iron deficiency or dysfunctional iron
`
`metabolism” comprising administering a single dosage unit of iron carbohydrate
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`complex of at least 0.6 grams of elemental iron. Ex. 1007 at 323-330. The type of
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`carbohydrate was not specified, but the claims required that the complex “has a
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`substantially non-immunogenic carbohydrate component and substantially no
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`cross-reactivity with anti-dextran antibodies.” Id. During prosecution, Luitpold
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`was required to surrender claim scope that would encompass any type of iron
`
`carbohydrate complex, and instead list particular compound classes. Id. at 241-
`
`244. In response to a species election requirement (later withdrawn), Luitpold had
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`elected iron carboxymaltose, but attempted to also include iron mannitol, iron
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`polyisomaltose,
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`iron polymaltose,
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`iron gluconate,
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`iron sorbitol, and
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`iron
`
`hydrogenated dextran in the claim scope. Id. at 235-236. The Examiner rejected
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`the claims as
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`lacking enablement (in part) for failing
`
`to explain how
`
`polyisomaltose and iron hydrogenated dextran, both being forms of dextran, could
`
`exhibit substantially no cross-reactivity with anti-dextran antibodies. Id. at 142-
`
`151. To remove this rejection, Luitpold deleted polyisomaltose and iron
`
`hydrogenated dextran from the claims. Id. at 123 and 133.
`
`The Examiner rejected the claims as obvious under 35 U.S.C. §103 over the
`
`‘668 patent (Ex. 1008) in view of the ‘849 application (Ex. 1009) to Helenek et al.
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`Active: 19767694.1
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`7
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`
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`(each sharing two named inventors with the ‘702 patent). Ex. 1007 at 199-203.
`
`The ‘668 patent was cited as teaching ferric oxyhydroxide dextran as a parenteral
`
`iron supplement, and was combined with the ‘849 application’s teaching of doses
`
`of iron carbohydrate complexes up to 2 grams for treatment of chronic disease (the
`
`neurologic condition, Restless Legs Syndrome). Id. Luitpold’s response, which
`
`included a Declaration Under 37 C.F.R. 1.132 by co-inventor Lawrence, contended
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`that the cited references would create no reasonable expectation for iron
`
`carboxymaltose, and that the art, taken as a whole, taught against the use of high
`
`doses of iron carbohydrate complexes. See id. at 178, 183, 184 and 187-191. The
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`Examiner was persuaded by Luitpold’s arguments and the rejection was removed.
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`Id. at 141-142.
`
`Unfortunately, the Examiner did not consider the closest art against the
`
`claims. The ‘668 patent was cited as the primary reference despite teaching a
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`dextran
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`(polyisomaltose) derivative,
`
`rather
`
`than
`
`the
`
`elected
`
`species,
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`carboxymaltose. Presumably the Examiner would have cited Geisser (Ex. 1002)
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`had he been aware that it discloses (as will be discussed in detail below) iron
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`carboxymaltose species encompassing VIT-45 at doses up to 1 g to treat iron
`
`deficiency anemia. Geisser had been submitted in an Information Disclosure
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`Statement, but, except for its abstract, was in German. A U.S. national stage
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`equivalent of Geisser, the ‘109 patent (Ex. 1014), in English, issued while
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`Active: 19767694.1
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`8
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`
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`prosecution of the ‘702 patent was still ongoing, but was not submitted for the
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`Examiner’s consideration. The relevance of Geisser is underscored by the listing
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`of the ‘109 patent in the Food and Drug Administration Orange Book - together
`
`with the ‘702 patent - as covering Injectafer® ferric carboxymaltose (a.k.a. VIT-
`
`45). Ex. 1012. Further, a Patent Term Extension of the ‘109 patent has been filed
`
`for coverage of Injectafer®. See Ex. 1015. Even more telling, in the prosecution
`
`of the ‘612 patent, a grandchild of the ‘702 patent, where the Examiner had access
`
`to the ‘109 patent (and therefore a full English translation of Geisser), claims
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`containing substantially the same limitations as claim 1 of the ‘702 patent were
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`rejected under 35 U.S.C. 102(b) as anticipated by Geisser, and Luitpold, rather
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`than disputing the basis for the rejection, added a limitation requiring rapid
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`administration. Ex. 1020 at 2, 7 and 22-24.
`
`The ‘702 patent specification points to the ‘498 patent as teaching
`
`ferumxytol, but the ‘498 patent’s continuation-in-part (Groman, Ex. 1004;
`
`published in 2003), is a better ferumoxytol reference. Groman adds to the
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`disclosure of its parent single doses of [ferumoxytol] providing up to .6 grams of
`
`elemental iron, administered rapidly over an interval that can be 15 minutes or less
`
`with “minimal incidence of anaphylaxis.” See Ex. 1004 at [0016].5 Proper
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`5 The ‘498 patent, which was considered by the Examiner, does not contain any
`
`reference to a 600 mg dose or any dose administered rapidly.
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`Active: 19767694.1
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`9
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`analysis by the Examiner was made even more elusive by the ‘702 patent’s use of
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`the terms “ferumoxytol,” “polyglucose” and “sorbitol,” for the carbohydrate
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`complex disclosed in the ‘498 patent, where neither the ‘498 patent (nor Groman)6
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`use those terms, although the ‘498 patent and Groman both call their compounds
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`“carboxymethyl reduced dextran.” See, e.g., Ex. 1017 at 5:19-26 and Ex. 1004 at
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`[0044]. Accordingly, searching the terms provided by the ‘702 patent, it is not
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`surprising that the Examiner did not find Groman. Given the Examiner’s
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`requirement that polyisomaltose (dextran) and hydrogenated dextran be removed
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`from the claims to reach allowance, it is unlikely that he realized that ferumoxytol,
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`iron complexed with polyglucose sorbitol carboxymethyl ether, is a processed,
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`derivatized form of dextran.
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`V. CLAIM CONSTRUCTION
`This Petition shows that the challenged claims of the ‘702 patent (Ex. 1001)
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`are unpatentable when given their broadest reasonable interpretation. The
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`constructions set forth below are provided for purposes of this IPR only.7
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`6 “Ferumoxytol” is the term used in Spinowitz (Ex. 1011) and polyglucose sorbitol
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`carboxymethyl ether is the term used in the prescribing information for Feraheme®
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`(Ex. 1024).
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`7 Federal district courts employ different standards of proof and approaches to
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`claim interpretation that are not applied by the USPTO for an IPR.
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`Active: 19767694.1
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`10
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`Iron Carboxymaltose Complex
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`A.
`The broadest reasonable construction of “iron carboxymaltose complex” in
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`claims 1, 23, 25, 26, and 27 at least includes an iron carbohydrate complex
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`“obtained from an aqueous solution of iron(III) salt and an aqueous solution of the
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`oxidation product of one or more maltodextrins using an aqueous hypochlorite
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`solution at a pH value within the alkaline range” as explicitly described in the ‘702
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`patent. Ex. 1001 at 4:57-61. See also Ex. 1005 at ¶8.
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`Iron Polymaltose
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`B.
`The broadest reasonable construction of “iron polymaltose complex” in
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`claim 1 at least includes a complex formed between iron and a carbohydrate that is
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`a repeating polymer of D-glucopyranose units linked primarily through α-1-4
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`glycosidic bonds, where a dimer comprised of two glucose residues joined by an α-
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`1-4 glycosidic bond is known as maltose. Ex. 1005 at ¶8. Dextrin or maltodextrin
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`are other terms used in the art to refer to an oligomer or polymer of glucose linked
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`by α-1-4 glycosidic bonds. Id. at ¶8. Because the specification states that
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`“[e]xamples of iron carbohydrate complexes include … iron polymaltose (iron
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`dextrin),” and because the specification provides no basis for differentiating
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`between them, iron polymaltose and iron dextrin should be regarded as synonyms
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`for the purpose of claim construction. Ex. 1001 at 10:46-57.
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`Active: 19767694.1
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`11
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`C.
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`Iron Sorbitol Complex/Iron Polyglucose Sorbitol Carboxymethyl
`Ether Complex
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`Because claim 28 recites iron polyglucose sorbitol carboxymethyl ether and
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`depends upon claim 1, and in view of statements made by Luitpold in related
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`cases, it could be argued that the broadest reasonable construction of “iron
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`sorbitol”
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`in claim 1 would at
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`least
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`include “iron polyglucose sorbitol
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`carboxymethyl ether, one example of which is ferumoxytol.” In a corresponding
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`European patent application, Luitpold has referred to iron polyglucose sorbitol
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`carboxymethyl ether as an iron sorbitol. Ex. 1021 at 3 (emphasis of relevant
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`paragraph added). However, a person of ordinary skill in the art (“POSITA”)
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`would not consider “iron sorbitol” to refer to iron polyglucose sorbitol
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`carboxymethyl ether, but instead to refer to iron complexed with sorbitol
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`monosaccharide.8 Ex. 1005 at ¶14. See also Ex. 1001 at 10:46-57. Petitioner
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`elects to construe “iron sorbitol” as would a POSITA, but without prejudice to
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`asserting a broader construction if patentee can provide evidence that iron
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`polyglucose sorbitol carboxymethyl ether would indeed be considered an iron
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`sorbitol by a POSITA.
`
`
`8 See the 2003 British Pharmacopoeia monograph for iron sorbitol, which states
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`that iron sorbitol is a “colloid solution of a complex of iron(III), Sorbitol and Citric
`
`acid, stabilised with Dextrin and Sorbitol.” Ex. 1023 at 1.
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`Active: 19767694.1
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`12
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`
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`The broadest reasonable construction of “iron polyglucose sorbitol
`
`carboxymethyl ether complex” in claim 28 at least includes a complex formed
`
`between iron and a polymer of glucose that contains a sorbitol residue, where the
`
`glucose units are joined through glycosidic linkages that could be α-1-6, α-1-4 or a
`
`combination thereof, a carboxymethyl moiety and an ether linkage, one example of
`
`which is “ferumoxytol.” Ex. 1005 at ¶15. See also Ex. 1001 at 13:31-59.
`
`Substantially Non-Immunogenic Carbohydrate Component
`
`D.
`The broadest reasonable construction of “substantially non-immunogenic
`
`carbohydrate component” in claim 1 is a carbohydrate component resulting in a
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`“low risk of anaphylactoid/hypersensitivity reactions.” Ex. 1001 at 11:5 and
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`15:16-44. That the carbohydrate component is substantially non-immunogenic
`
`does not necessarily mean that the iron carbohydrate complex is also substantially
`
`non-immunogenic in view of the specification, which consistently considers
`
`separately the immunogenicity of the carbohydrate and the iron complex of which
`
`it is a part. Ex. 1001 at 3:17-24, 10:58 to 11:5, and claims 1 and 2.
`
`Anti-Dextran Antibodies
`
`E.
`The broadest reasonable construction of “anti-dextran antibodies” is
`
`“antibodies that specifically recognize dextran,” where a dextran is a primarily α-1-
`
`6 linked oligomer or polymer of glucose. Ex. 1005 at ¶8.
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`
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`Active: 19767694.1
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`13
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`
`
`
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`Substantially No Cross-Reactivity With Anti-Dextran Antibodies
`
`F.
`The broadest reasonable construction of “substantially no crossreactivity
`
`with anti-dextran antibodies” would at least include essentially no cross-reactivity
`
`with anti-dextran antibodies, for example, as would be exhibited by a carbohydrate
`
`which is not a primarily α-1-6 linked oligomer or polymer of glucose (e.g.,
`
`carboxymaltose or polymaltose; not dextran). Ex. 1005 at ¶8 and ¶23.
`
`VI. LEVEL OF ORDINARY SKILL IN THE ART
`The level of ordinary skill in the art is evidenced by the references. See In re
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`GPAC Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995). A person of ordinary skill in the
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`art (“POSITA”) for this patent would hold at least a bachelor’s level degree in
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`chemistry or biochemistry with some related post-graduate experience (academic
`
`or industrial) in the area of carbohydrates and their metal complexes. Ex. 1005 at
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`¶6.
`
`VII. SUMMARY OF PRIOR ART
`A.
`State of the Art
`Van Zyl-Smit (Ex. 1006), Auerbach (Ex. 1010) and Spinowitz (Ex. 1011)
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`are evidence of the state of the art. Spinowitz was cited as background by the ‘702
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`patent. Ex. 1001 at 2:4-8.
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`Van Zyl-Smit, published in 2002, reports intravenous administration of up to
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`3.2 grams of iron elemental iron complexed with polymaltose (dextrin) as a single
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`dose with “no anaphylactoid [or] delayed reactions.” Ex. 1006 at 2 and 6.
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`Active: 19767694.1
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`14
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`
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`Auerbach teaches that, shortly before the priority date of the ‘702 patent, some
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`practitioners believed
`
`that
`
`intravenous
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`iron dextran (INFeD®) could be
`
`administered safely, even at elemental iron doses of 1,000-3,000 mg, where
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`adverse effects “were few and did not require discontinuation of therapy.” Ex.
`
`1010 at 6. According to the Auerbach paper, out of 41 patients receiving relatively
`
`high doses of intravenous iron dextran, three (7%) experienced an adverse event,
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`only one of which was an acute hypersensitivity reaction. Id. at 5.
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`However, adverse events, including a low incidence of anaphylaxis (Ex.
`
`1010 at 2 and 6), had been reported for iron dextran, and even a relatively low risk
`
`is better avoided if possible. According to Spinowitz, newer parenteral iron
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`preparations such as ferric gluconate and iron sucrose were “considered safer” but
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`were administered at relatively low doses and slow infusion rates, requiring
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`multiple doses to achieve sufficient iron supplementation. Ex. 1011 at 1-2. There
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`was, at least implicitly, a need for a more efficient parenteral iron formulation.
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`According to Spinowitz, “[f]erumoxytol was designed to minimize potential
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`immunologic reactions, such as those seen with commercially available iron
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`dextran products.” Id. at 2. Spinowitz reports the results of a Phase II clinical trial
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`in which 21 patients were treated with “ferumoxytol in a regimen of 4 doses of 255
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`mg iron in 2 weeks or 2 doses of 510 mg iron in 1 to 2 weeks” where ferumoxytol
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`was administered at a rate of up to 30 mg iron/sec (i.e., for 510 mg iron, about 17
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`Active: 19767694.1
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`15
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`
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`seconds). Id. at 1 (Methods). Ferumoxytol was found “effective in stimulating
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`erythropoiesis.” Id. at 5. See also id. at 4 (Table 2). Mild to moderate adverse
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`effects were observed in 5 patients, none of which were deemed sufficient to
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`warrant discontinuation of dosing. Id at 4-5.
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`Spinowitz reports the observed safety of ferumoxytol, administered as a dose
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`of 510 mg over 17 seconds, as of 2005, approximately contemporaneous with the
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`priority date of the ‘702 patent and illustrative of the knowledge of the POSITA
`
`when the ‘702 patent was filed. However, it may be noted that on March 30, 2015,
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`the F.D.A. strengthened the warnings of possible severe adverse reactions
`
`associated with ferumoxytol, and required that it be administered as an IV infusion
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`over a minimum of 15 minutes, rather than the previously approved 17 second
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`interval. Ex. 1025. Accordingly, even with the heightened recent warning,
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`ferumoxytol may be administered in a 15 minute period.
`
`B.
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`Summary of Primary Prior Art References
`
`1.
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`Geisser
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`Geisser discloses
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`iron carboxymaltose complexes for
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`the parenteral
`
`(including intravenous) treatment of iron deficiency anemia, which, because of
`
`high complex stability (and consequently low toxicity) can be used at high single
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`doses, for example, “500 to 1000 mg iron.” Ex. 1003 at 2 (Abstract) and 3:4-8,
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`3:26-28, 9:30-31 and 10:16-17. The iron carboxymaltose complexes of Geisser are
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`Active: 19767694.1
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`16
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`
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`characterized as having “reduced toxicity and [] prevent[s] the dangerous
`
`anaphylactic shocks that can be induced by dextran.” Ex. 1003 at 3:26-28 and
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`10:7-10.
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`Specifically, Geisser discloses iron carboxymaltose complexes and methods
`
`for making them by combining an iron salt with “the product of oxidation of one or
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`more maltodextrins.” Ex. 1003 at 4. Because the term “carboxymaltose” is not
`
`used by Geisser, the relevance of Geisser to the ‘702 patent is not immediately
`
`apparent. However, Geisser is, in fact, highly relevant; its
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