IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Patent:
`
`8,431,549
`
`
`
`
`
`:
`
`Attorney Docket No. 083441.0103
`
`Inventor: Mary Jane Helenek et al. :
`
`Filed:
`
`May 25, 2010
`
`Issued:
`
`April 30, 2013
`
`:
`
`:
`
`Title:
`
`Methods and Compositions for Administration of Iron
`
`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. 8,431,549
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1109 - Page 1
`
`

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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
`
`TABLE OF CONTENTS
`
`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 Upon .................................................................. 2
`
`C. Grounds For Challenge ...................................................................................... 4
`
`IV. OVERVIEW OF THE ‘549 PATENT ............................................................... 4
`
`A. Overview Of The Disclosure ............................................................................. 4
`
`B. Overview Of The Prosecution History .............................................................. 7
`
`V. CLAIM CONSTRUCTION ............................................................................. 14
`
`A. Disease, Disorder Or Condition ....................................................................... 14
`
`B.
`
`Iron Polyisomaltose Complex .......................................................................... 15
`
`C.
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`Iron Sorbitol Complex/ Iron Polyglucose Sorbitol Carboxymethyl Ether
`
`Complex ................................................................................................................... 18
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
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`D.
`
`Iron Polymaltose Complex .............................................................................. 19
`
`E. Substantially Non-Immunogenic Carbohydrate Component .......................... 20
`
`F. Anti-Dextran Antibodies .................................................................................. 20
`
`G. Substantially No Cross-Reactivity With Anti-Dextran Antibodies ................. 20
`
`VI. LEVEL OF ORDINARY SKILL IN THE ART ............................................. 21
`
`VII. SUMMARY OF PRIOR ART ......................................................................... 21
`
`A. State Of The Art ............................................................................................... 21
`
`B. Summary Of Primary Prior Art References ..................................................... 24
`
`VIII. IDENTIFICATION OF HOW THE CHALLENGED CLAIMS ARE
`
`UNPATENTABLE .................................................................................................. 29
`
`A. Ground 1: Claims 1, 7, 8, 15, 17, And 21 Are Anticipated By The ‘158
`
`Patent ........................................................................................................................ 29
`
`B. Ground 2: Claims 2, 3, 4, 5, 9, 16, And 19 Are Anticipated By Van Zyl-
`
`Smit.. ........................................................................................................................ 37
`
`C. Ground 3: Claims 12 And 13 Are Anticipated By Groman ............................ 46
`
`D. Ground 4: Claims 10 And 14 Are Anticipated By Groman ............................ 51
`
`E. Ground 5: Claim 10 Is Obvious Over Van Zyl-Smit In View Of Groman ..... 56
`
`IX. CONCLUSION ................................................................................................ 59
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
`
`EXHIBITS
`
`Description
`United States (U.S.) Patent No. 8,431,549 (“the ‘549 patent”)
`U.S. Patent No. 5,541,158 (“the ‘158 patent”)
`U.S. Patent Appln. Publication No. 2003/0232084 (“Groman”)
`van Zyl-Smit and Halkett, 2002, Nephron 92:316-323 (“van Zyl-
`Smit”)
`Marchasin, 1964, Blood 23:354-358 (“Marchasin”)
`Prosecution history of the ‘549 patent
`U.S. Patent Application Publication No. 2004/0180849 by Helenek
`(“Helenek”)
`Hamstra et al., 1980, JAMA 243(17):1726-1731 (“Hamstra”)
`U.S. Patent No. 3,100,202 by Muller et al. (“Muller”)
`U.S. Patent No. 5,624,668 to Lawrence (“the ‘668 patent”)
`Declaration Under 37 C.F.R. 1.132 of Richard Lawrence
`Auerbach et al., 2004, J. Clinical Oncol. 22(7):1301-1307
`(“Auerbach”)
`Spinowitz et al., 2005, Kidney Int’l. 68:1801-1807 (“Spinowitz”)
`Declaration of Robert Linhardt
`F.D.A. Orange Book Listing for Feraheme® 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”)
`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
`Arond and Frank, 1954, J. Phys. Chem. 58(11):953–957 (“Arond”)
`Summary of Product Characteristics (SPC) for Monofer®
`Product documentation for Promit®
`Jahn et al. 2011, Eur. J. Pharma and Biopharma 78:480-91 (“Jahn”)
`Richter, 1986, New Trends in Allergy II, p. 272-283. (“Richter”)
`European Pharmacopeia for Dextran 1 (2005)
`Excerpt of Prosecution History of European Patent Application
`EP1973549
`Merck Index for Dextran (2006)
`Feraheme® ferumoxytol injection Prescribing Information
`
`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
`1027
`1028
`1029
`
`1030
`1031
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
`
`1032
`1033
`1034
`
`1035
`1036
`1037
`1038
`1039
`1040
`1041
`1042
`1043
`1044
`
`1045
`1046
`1047
`1048
`
`1049
`
`1050
`1051
`1052
`
`1053
`
`Canadian Patent No. 623411 (“the ‘411 patent”)
`Merriam Webster Dictionary definition for Hematinic agent
`Guidelines for Administration of IV Iron Polymaltose in Chronic
`Kidney Disease via Continuous Intravenous Infusion (“Polymaltose
`Administration Guidelines”)
`Neiser, 24 March 2015, Biometals 1-21 (“Neiser 2015”)
`“Feraheme (ferumoxytol) Drug Safety Communication,” 3/30/2015
`United States Pharmacopeia for Dextran 1 (USP 28:2005)
`Product documentation for Dextran T1
`U.S. Patent No. 7,754,702
`Excerpts of the File History of U.S. Patent No. 7,754,702
`U.S. Patent No. 8,895,612
`Excerpts of the File History of U.S. Patent No. 8,895,612
`Excerpts of the File History of the ‘549 Patent
`English translation of International Patent Application Publication
`No. WO 2004/037865
`Neiser et al., 2011, Port. J. Nephrol. Hypert. 25(3):219-224
`Prescribing Information for Injectafer®
`Funk et al., 2001, Hyperfine Interactions 136: 73-95
`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)
`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
`
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`

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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
`
`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
`
`be affected by, a decision
`
`in
`
`this proceeding.
`
` Concurrently herewith,
`
`Pharmacosmos is filing petitions for inter partes review (“IPR”) of two patents
`
`related to the patent for which review is sought herein, U.S. Patent No. 8,431,549.
`
`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
`
`to
`
`lead and back-up counsel.
`
`Pharmacosmos also consents to service by e-mail.
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
`
`D.
`
`Payment
`
`Under 37 C.F.R § 42.103(a), the Office is authorized to charge the fee set
`
`forth in 37 C.F.R. § 42.15(a) to Deposit Account No. 02-4377 as well as any
`
`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
`
`review is sought is available for IPR and that Pharmacosmos is not barred or
`
`estopped from requesting an IPR challenging the patent claims on the grounds
`
`identified in this Petition.
`
`III. OVERVIEW OF CHALLENGE AND RELIEF REQUESTED
`
`Under 37 C.F.R §§ 42.22(a)(1) and 42.104 (b)(1)-(2), Pharmacosmos asks
`
`that the Board review the accompanying prior art and analysis, institute a trial for
`
`IPR of claims 1, 2, 3, 4, 5, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 19, and 21 of U.S.
`
`Patent No. 8,431,549 (“the ‘549 patent”), and cancel those claims as unpatentable.
`
`A.
`
`Prior Art Patents And Printed Publications
`
`Pharmacosmos relies upon the following prior art to the ‘549 patent.
`
`Ex.
`
`Description
`
`Filing Date
`
`1002 the ‘158 patent
`1003 Groman
`1004 van Zyl-Smit
`
`09/19/1989
`04/09/2003
`n/a
`
`B.
`
`Additional Documents Relied Upon
`
`Publication
`Date
`07/30/1996
`12/18/2003
`2002
`
`Prior Art
`Under
`102(b)
`102(b)
`102(b)
`
`Additional documents relied upon include the following materials.
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
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`Exhibit No.
`1005
`1006
`1007
`1008
`1009
`1010
`1011
`1012
`1013
`1014
`1015
`1016
`1017
`1018
`1019
`1020
`
`1021
`1022
`1023
`1024
`1025
`1026
`1027
`1028
`1029
`1030
`1031
`1032
`1033
`1034
`1035
`1036
`
`1037
`1038
`
`Description
`
`Marchasin
`Prosecution history of the ‘549 patent
`Helenek
`Hamstra
`Muller
`the ‘668 patent
`Declaration Under 37 C.F.R. 1.132 of Richard Lawrence
`Auerbach
`Spinowitz
`Declaration of Robert Linhardt
`F.D.A. Orange Book Listing for Feraheme® injection
`the ‘498 patent
`Patent Term Extension Application for the ‘498 patent
`the ‘597 patent
`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
`the ‘109 patent
`Patent Term Extension Application for the ‘109 patent
`Arond
`Summary of Product Characteristics (SPC) for Monofer®
`Product documentation for Promit®
`Jahn
`Richter
`European Pharmacopeia for Dextran 1 (2005)
`Excerpt of Prosecution History for EP Patent Appln. EP1973549
`Merck Index for Dextran (2006)
`Feraheme® ferumoxytol injection Prescribing Information
`the ‘411 patent
`Merriam Webster Dictionary definition for Hematinic agent
`Polymaltose Administration Guidelines
`Neiser, 24 March 2015, Biometals 1-21 (“Neiser 2015”)
`“Feraheme (ferumoxytol) Drug Safety Communication,”
`3/30/2105
`United States Pharmacopeia for Dextran 1 (USP 28:2005)
`Material Specification Sheet for Dextran T1
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
`
`C.
`
`Grounds For Challenge
`
`Pharmacosmos requests cancelation of the challenged claims under the
`
`following statutory grounds:
`
`Grounds
`
`Claims
`
`Description
`
`1
`
`2
`
`3
`4
`5
`
`1, 7, 8, 15, 17,
`and 21
`2, 3, 4, 5, 9, 16
`and 19
`12 and 13
`10 and 14
`10
`
`Anticipated under 35 U.S.C. §102 (b) by the ‘158
`patent
`Anticipated under 35 U.S.C. §102 (b) by van Zyl-
`Smit
`Anticipated under 35 U.S.C. §102 (b) by Groman
`Anticipated under 35 U.S.C. §102 (b) by Groman
`Obvious under 35 U.S.C. §103 over van Zyl-Smit in
`view of Groman
`
`As demonstrated below, for each of the numbered grounds, there is at least 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 ‘549 PATENT
`
`The ‘549 patent is assigned to Luitpold Pharmaceuticals, Inc. (herein,
`
`“Luitpold” or “Patentee”).
`
`A.
`
`Overview Of The Disclosure
`
`The ‘549 patent extolls the merits of parenteral (non-oral) iron therapy for
`
`anemia, but cautions that “many currently available parenteral iron drugs … have
`
`health risks and dosage limitations associated with their use.” Ex. 1001 at 1:32-35.
`
`In particular, “[i]ron dextran … has been associated with an incidence of
`
`anaphylactoid-type reactions (i.e., dyspnea, wheezing, chest pain, hypotension,
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
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`urticaria, angioedema) … believed to be caused by the formation of antibodies to
`
`the dextran moiety.” Id. at 1:47-54.
`
` Purportedly the ‘549 patent overcomes these problems and allows the use of
`
`high doses of
`
`iron carbohydrate complexes with only a “low risk of
`
`anaphylactoid/hypersensitivity reactions.” Id. at 3:15-17, 11:1-2 and 15:13-42.
`
`Single doses range from at least 0.6 grams (g) of elemental iron (as iron
`
`carbohydrate) to no specified upper limit. Id. at 7:17-30. 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 7:41-47. Subjects in need of treatment
`
`include those having “a clinical need to deliver iron rapidly or in higher doses
`
`and/or in subjects with functional iron deficiency such as those on erythropoietin
`
`therapy.” Id. at 9:14-19 and 9:54-57.
`
`The examples relate to a single species of iron carboxymaltose1 referred to
`
`as VIT-45 (an alternative name for ferric carboxymaltose and Injectafer®2). Id. at
`
`1 Carboxymaltose is a maltodextrin (a repeating oligomer or polymer of D-
`
`glucopyranose units linked primarily through α-1-4 glycosidic bonds) in which the
`
`aldehyde of the reducing sugar has been oxidized to form a carboxylic acid group.
`
`Ex. 1014 at ¶25.
`
`2 Injectafer® is marketed by Luitpold. Other alternative names are Ferinject or
`
`FCM. See, e.g., Ex. 1020 at 7. See also the F.D.A. Orange Book Listing for
`
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`11:60-63. Despite exemplifying only VIT-45, the disclosure contemplates using a
`
`wide variety of iron carbohydrate complexes known in the prior art (“[i]ron
`
`carbohydrate complexes are commercially available, or have well known
`
`syntheses”; id. at 10:43-44), extending beyond iron carboxymaltose, even
`
`including iron polyisomaltose (iron dextran) and hydrogenated dextran complexes.
`
`Id. at 10:44-50. Special attention is given to ferumoxytol (developed by Advanced
`
`Magnetics, Inc.), which, although chemically a derivatized form of dextran, is
`
`never referred to as such in this specification. Instead, the ‘549 patent describes
`
`ferumoxytol as “a supraparamagnetic iron oxide that is coated with a low
`
`molecular weight semi-synthetic carbohydrate, polyglucose sorbitol carboxymethyl
`
`ether,” citing the ‘498 patent.3 Id. at 13:27-57; Ex. 1016. The ‘549 patent asserts
`
`that ferumoxytol “is known in the art to be effective for treating anemia (at single
`
`Injectafer® (Ex. 1019), the Orange Book listed ‘109 patent (Ex. 1021), and the
`
`corresponding application for Patent Term Extension, Ex. 1022, especially Exhibit
`
`H (Investigational New Drug Application for VIT-45 used as basis for Injectafer®
`
`FDA approval).
`
`3 “Ferumoxytol” is the generic name for commercially available “Feraheme®.” Ex.
`
`1031. A Patent Term Extension of the ‘498 patent was filed based on the approval
`
`for Feraheme®. Ex. 1017.
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
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`unit doses lower than described herein)” for example “up to 420 mg4 per
`
`injection.” Ex. 1001 at 13:27-57. The ‘549 patent fails to identify anything new
`
`about its methods that would avoid risks associated with ferumoxytol or other
`
`previously available iron carbohydrate complexes, e.g., iron polyisomaltose
`
`(dextran).
`
`B.
`
`Overview Of The Prosecution History
`
`The earliest priority date claimed for the ‘549 patent is January 6, 2006,
`
`based on U.S. Provisional Application No. 60/757,119. It is a continuation of an
`
`application now issued as U.S. Patent No. 7,754,702.
`
`The originally filed method of treatment claims encompassed use of iron
`
`carboxymaltose, iron mannitol, iron polyisomaltose, iron polymaltose, iron
`
`gluconate, iron sorbitol and iron hydrogenated dextran complex. In response to a
`
`species election requirement, Luitpold elected to pursue iron polyisomaltose. Ex.
`
`1006 at 129. In the first office action on the merits, the Examiner contended that
`
`the specification failed to provide enablement for an iron polyisomaltose complex
`
`that has a substantially non-immunogenic carbohydrate complex and substantially
`
`no cross reactivity with anti-dextran antibodies. Id. at 103-106. The Examiner also
`
`rejected claims as obvious over Hamstra (Ex. 1008) in view of Muller (Ex. 1009).
`
`4 In fact, Spinowitz teaches administration of 510 mg in 17 seconds. Ex. 1013 at 2
`
`and Table 1.
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
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`Ex. 1006 at 107-110. The Examiner argued that Hamstra teaches intravenous
`
`injections of iron dextran containing 501-999 mg of iron and that, although
`
`Hamstra “does not specifically teach the iron carbohydrate complex is an iron
`
`polyisomaltose complex,” Muller teaches an iron polyisomaltose that is suitable for
`
`parenteral injection. Id. at 107-108. In addition, a claim specifying mean iron core
`
`size was rejected as obvious over the ‘668 patent (Ex. 1010) for teaching iron
`
`dextran particles have a size range overlapping that claimed. Ex. 1006 at 109-110.
`
`In response to the first office action, Luitpold amended the claims to delete
`
`iron carboxymaltose complex from among the species listed and to incorporate the
`
`limitation that the iron carbohydrate complex has a substantially non-immunogenic
`
`carbohydrate complex. Id. at 56. To overcome the enablement rejection, Luitpold
`
`submitted a Declaration Under 37 C.F.R. § 1.132 from Richard Lawrence (“The
`
`Lawrence Declaration”; Ex. 1011) as evidence that the iron isomaltoside
`
`Monofer® is “[o]ne example of an iron polyisomaltose” that “avoids dextran-
`
`induced anaphylactic reactions . . . and reduces immunogenicity compared to
`
`dextran,” citing Jahn (Ex. 1026). Luitpold contended that Monofer® provides
`
`enablement for iron polyisomaltose. Ex. 1006 at 62-66.
`
`The Lawrence Declaration
`
`takes
`
`the position
`
`that dextran and
`
`polyisomaltose are distinct categories of compounds, the former always being
`
`immunogenic. Ex. 1011 at ¶4-5. This characterization has no basis in the
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
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`specification, which refers to polyisomaltose only twice, the second instance being
`
`“polyisomaltose (dextran).” Ex. 1001 at 3:37 and 10:50. To the contrary, this
`
`apposition of polyisomaltose and dextran signifies that, as used in the patent, the
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`terms are interchangeable, which is consistent with usage in the art. Ex. 1014 at
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`¶10.
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`The Lawrence Declaration contends that Monofer® (iron isomaltoside
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`1000) is an example of iron complexed with a substantially non-immunogenic
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`polyisomaltose, disregarding the facts that (i) Monofer® is hydrogenated (in other
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`words, “reduced”)5; (ii) so small as to be properly referred to as an oligomer rather
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`than a polymer; and (iii) developed by Petitioner Pharmacosmos (not Luitpold),
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`and commercially available only since 2009 (three years after the ‘549 patents’
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`effective filing date). Ex. 1014 at ¶13, Ex. 1024. The Lawrence Declaration avers
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`that Monofer® is “[o]ne example” of a “pure linear” polyisomaltose which is not
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`immunogenic, where “[i]n contrast, dextran is a branched glucan” that induces
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`anaphylactic reactions. Ex. 1011 at ¶¶4-5. As alleged support, the Declaration
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`relies on post-filing publication Jahn (Ex. 1026; published in 2011) for teaching
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`that Monofer® “avoids dextran-induced anaphylactic reactions” and “reduces
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`immunogenicity compared to dextran.” Ex. 1011 at ¶5. Jahn is also cited as
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`5 Luitpold does refer to Monofer® as an iron isomaltoside but does not explain that
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`it is hydrogenated (reduced).
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`evidence that “research in the 1970s and 1980s showed that isomaltose oligomers
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`acted as haptens against circulating antibodies” and that “a hapten can bind an
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`antibody without inducing anaphylaxis or an immune response.” Id. According to
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`the Lawrence Declaration, this historical experience with isomaltose oligomers as
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`haptens explains why high doses of Monofer® can be safely administered. Id.
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`Thus Luitpold, via the Lawrence Declaration, led the Examiner to conclude
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`that the “isomaltose oligomers” used to protect against anaphylaxis were
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`“polyisomaltose” - and different from dextran. Luitpold failed to mention that
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`those same “isomaltose oligomers” were (and are) known in the art as Dextran 1.6
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`Further, the Lawrence Declaration (id., last sentence) inappropriately cites Jahn as
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`teaching that the reason that Monofer® can be used safety at high doses is that it is
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`comprised of (non-immunogenic) isomaltose oligomers, but no such teaching
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`appears in Jahn. Instead, Jahn teaches that the use of isomaltose oligomers in the
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`6 For example, Jahn cites Richter (Ex. 1027), which discusses the ability of the
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`isomaltose oligomer “Dextran 1” to protect against high molecular weight dextran-
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`associated anaphylaxis. Ex. 1026 at 2, Ex. 1027 at 5 and 5-10. The overlap of
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`terms continues to the present time; for example, a recent article, published in
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`March 2015 and co-authored by Vifor scientists, refers to Monofer® (iron
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`isomaltoside 1000) as “a reduced Dextran 1000.” Ex. 1035 at Abstract. See also
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`Ex. 1014 at ¶¶10, 11, 13 and 14.
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`iron complex provides “the rationale for eliminating
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`test dosing when
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`administering Monofer®,” but high doses of Monofer® are possible in view of its
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`low labile iron content and low “risk of free iron toxicity.” Ex. 1026 at 2, 10
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`(Sections 4.3 and 4.4) and 11 (Section 5). Ex. 1014 at ¶15.
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`Consistent with its newly adopted position during prosecution, that dextran
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`and polyisomaltose are readily distinguishable entities, Luitpold further argued that
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`Hamstra merely teaches doses for iron dextran, and Muller teaches the making of
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`an iron polyisomaltose and fails to provide any information regarding dosage. Ex.
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`1006 at 68-69. According to Luitpold, the dosage for iron dextran cannot be
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`extrapolated to other iron carbohydrate compounds (including polyisomaltose), and
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`the state of the art at the time of the invention taught away from administration of
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`high doses of iron dextran.7 Id. at 69.
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`A telephone interview with the Examiner was held during which Hamstra
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`and another reference, Helenek (Ex. 1007), were discussed. Ex. 1006 at 37-39.
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`According to the Interview Summary, the Examiner agreed to withdraw the species
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`7 If “high doses” of dextran would include doses greater than 0.6 grams of
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`elemental iron, it should be noted that Auerbach (Ex. 1012), published in 2004,
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`reports administering 1-3 grams of elemental iron without serious side effects
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`(discussed below). Id. at 1304. Petitioner acknowledges that F.D.A.- approved
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`doses of parental iron were lower than 0.6 grams.
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`election requirement, but cautioned that Hamstra may be applicable against species
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`of iron hydrogenated dextran complexes, which would require further examination
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`(the Examiner was of the opinion that both non-hydrogenated and hydrogenated
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`dextrans were immunogenic in man). Id. at 39. However, the Examiner suggested
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`that the cancelation of hydrogenated dextran complex from claim 1 would
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`overcome Hamstra and that the exclusion of Restless Leg Syndrome would
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`overcome Helenek to put the pending claims in condition for allowance. Id.
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`Apparently Luitpold agreed, because in the Notice of Allowance, the Examiner
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`amended claim 1 to delete iron hydrogenated dextran as a species of iron
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`carbohydrate complex and incorporated the limitation that the disorder, disease or
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`condition is not Restless Leg Syndrome. Id. at 20-21.
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` Accordingly, Luitpold presented the Examiner with a record that imagined
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`bright line differences between polyisomaltose and dextran, and the Examiner
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`allowed the claims apparently believing that they didn’t cover dextran. There is no
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`evidence that the Examiner was aware that polyglucose sorbitol carboxymethyl
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`ether, featured in dependent claims 12 and 13, is a derivatized dextran
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`(carboxymethyl reduced dextran) disclosed and referred to as such by Groman (Ex.
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`1003) for rapid administration of up to 600 mg doses of iron. Ex. 1014 at ¶¶19-22.
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`Luitpold was apparently careful not to refer to ferumoxytol as a derivatized dextran
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`in the ‘549 specification or claims, using instead alias terms like “reduced
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`polysaccharide” or “polyglucose.” Ex. 1001 at 11:36-40 and 13:29-39. Nor does
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`the record show that the Examiner realized that the “isomaltose oligomers [that]
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`acted as haptens” discussed in the Lawrence Declaration are called “Dextran 1”
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`and Groman discloses, as working examples, reduced (hydrogenated) isomaltose
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`oligomers prepared using essentially the same carbohydrate as “Dextran 1.” Ex.
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`1003 at 230-231, Ex. 1006 at 62-63, Ex. 1014 at ¶¶16-18, Ex. 1011 at ¶5, Ex.
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`1025, Ex. 1026 at 2, Ex. 1027 at 5, Ex. 1028, Ex. 1037.
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`The broad scope of the claims, and the corresponding large universe of prior
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`art, was not fully explored during prosecution. Of note, claim 1, while providing a
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`dose
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`threshold,
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`is unrestricted as
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`to
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`the subject being
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`treated,
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`literally
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`encompassing mouse to elephant, and the administration route is unspecified. As
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`evidenced by dependent claims 3-6, a wide variety of conditions fall within the
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`scope of claim 1, extending even to hair loss. However, the Examiner did not
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`consider a patent disclosing administration of iron carbohydrate in conjunction
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`with blood donation (see Claim 6)/functional iron deficiency - the ‘158 patent (Ex.
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`1002) submitted with this Petition. And the prosecution focused so much on the
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`alleged distinction between polyisomaltose and dextran that little consideration
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`was given to other iron carbohydrate complexes included in claim 1, such as iron
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`polymaltose (dextrin), which, as reported by van Zyl-Smit in 2002 (Ex. 1004), was
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`administered at elemental iron doses between 900 and 3200 mg. As discussed
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
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`below, in view of the ‘158 Patent, van Zyl-Smit, and Groman, an IPR of claims 1,
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`2, 3, 4, 5, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 19, and 21 of the ‘549 patent should be
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`instituted and those claims should be cancelled as unpatentable.
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`V. CLAIM CONSTRUCTION
`This Petition establishes that the challenged claims of the ‘549 patent (Ex.
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`1001) 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.8
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`A. Disease, Disorder Or Condition
`The term “disease, disorder or condition” appears in the preamble of
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`independent claim 1. All other challenged claims depend therefrom. The broadest
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`reasonable construction of “a disease, disorder, or condition” to be treated would
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`include at least anemia, iron deficiency anemia, inadequate hemoglobin response
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`to erythropoietin (as a form of functional iron deficiency), and blood donation.”9
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`See Ex. 1001 at claims 3-6, and 9:54-57.
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`8 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 IPR.
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`9 As to “blood donation,” this term is sufficiently generic as to encompass patients
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`that were anemic because they had donated blood in the past, as well as patients
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`who are preparing to give a blood donation in the future (e.g., in contemplation of
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`surgery).
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,549
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`B.
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`Iron Polyisomaltose Complex
`1.
`The broadest reasonable construction of “iron polyisomaltose complex” in
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`Proper Construction
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`claims 1 and 21 at least includes: “a complex formed between iron and a
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`carbohydrate that is a polymer of glucose linked primarily by α-1-6 glycosidic
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`linkages, where two glucose residues joined by an α-1-6 glycosidic linkage is
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`known as isomaltose.” Ex. 1014 at ¶8. Because the specification states that
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`“[e]xamples of iron carbohydrate complexes include … iron polyisomaltose (iron
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`dextran),” and because the specification provides no basis for differentiating
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`between them, iron polyisomaltose and iron dextran should be regarded as
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`synonyms for the pur