UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Pharmacosmos A/S
`
`Petitioner
`
`V.
`
`Luitpold Pharmaceuticals, Inc.
`
`Patent Owner
`
`Case Unassigned
`Patent 8,431,549
`
`DECLARATION OF ROBERT LINHARDT
`
`Filed on behalf of
`Pharmacosmos A/S
`
`By:
`
`Lisa Kole (PTO Reg. No. 35,225)
`Steven Lendaris (PTO Reg. No. 53,202)
`Paul Ragusa (PTO Reg. No. 38,587)
`Baker Botts L.L.P.
`30 Rockefeller Plaza
`New York, NY 10112
`Telephone: (212) 408-2500
`Facsimile: (212) 408-2501
`Email:
`lisa.kole@bakerbotts.com
`steven.lendaris@bakerbotts.com
`paul.ragusa@bakerbotts.com
`
`PGR2020-00009
`PharmacosmosA/S v. American Regent,Inc.
`Petitioner Ex. 1110 - Page 1
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`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1110 - Page 1
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Pharmacosmos A/S
`
`Petitioner
`
`V.
`
`Luitpold Pharmaceuticals, Inc.
`
`Patent Owner
`
`Case Unassigned
`Patent 8,431,549
`
`DECLARATION OF ROBERT LINHARDT
`
`Filed on behalf of
`Pharmacosmos A/S
`
`By:
`
`Lisa Kole (PTO Reg. No. 35,225)
`Steven Lendaris (PTO Reg. No. 53,202)
`Paul Ragusa (PTO Reg. No. 38,587)
`Baker Botts L.L.P.
`30 Rockefeller Plaza
`New York, NY 10112
`Telephone: (212) 408-2500
`Facsimile: (212) 408-2501
`Email:
`lisa.kole@bakerbotts.com
`steven.lendaris@bakerbotts.com
`paul.ragusa@bakerbotts.com
`
`PGR2020-00009
`PharmacosmosA/S v. American Regent,Inc.
`Petitioner Ex. 1110 - Page 1
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`PGR2020-00009
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`TABLE OF CONTENTS
`OVERVIEW oocescecenecereeeseeeseeessesseessescssaeesnessnassesasessassensesarerstereneeegs I
`LEVEL AND PERSON OF ORDINARYSKILL IN THEART............ 4
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`1.
`Il.
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`THE. THE 549 PATENT 0.0. ec eeeseccceseseeseeeeesenseesaseneesasesessnessesenesenesenssnees 4
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`TV.
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`POLYISOMALTOSE 000... cecescceeenteeesseeseseseeeseessesssensaecessnesensnenaeens 4
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`Vv.
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`POLYGLUCOSE CARBOXYMETHYL ETHER ue 11
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`VI. CARBOXYMALTOSE AND POLYMALTOSE....00.0 ee ceeeeeeenee 16
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`VIL. CONCLUSION 0.00. ccccssscrsscrsesneenrserssensosseesnecssssssersasrasesesensenasonessegs 19
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`VITL. FIGURES oon. ceeeeeeererneeenteasesasscasesceseccaeeseesaeeeaeeeaenseeteesseteneoute 21
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`I, Robert Linhardt, do hereby declare as follows:
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`OVERVIEW
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`I, Robert Linhardt, am over the age of eighteen (18) and otherwise
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`L
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`1.
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`competent to makethis declaration.
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`2.
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`I have been retained by Baker Botts L.L.P. to act as an expert witness in a
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`matter on behalf of their client, Pharmacosmos A/S. The matter is a Request for
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`Inter Partes Review of United States Patent No. 8,431,549 by Helenek (“the ‘549
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`Patent”), which is a continuation of United States Application No. 11/620,986,
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`filed January 8, 2007, now United States Patent No. 7,754,702 (“the ‘702 patent”).
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`I am being compensated for my time in connection with this matter at my standard
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`consulting rate, which is $600.00 per hour. My compensation is not dependent on
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`the outcomeofthis matter.
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`3.
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`In this Declaration, I provide opinions relating to the following claims of the
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`“549 patent: 1, 2, 3, 4, 5, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 19, and 21.
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`I have
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`included in this declaration a Figures section. The Figures present structures and
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`reactions of various carbohydrates and iron carbohydrate complexes. The Figures
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`are intended as an aid to explain the relevant chemistry of the ‘549 patent and the
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`references that I have reviewed. All Figures were prepared by me or under my
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`direction.
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`4,
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`In preparing this Declaration, I reviewed and considered the ‘549 patent and
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`considered each of the documents listed in paragraph 5 below,
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`in light of my
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`general knowledge as a professor and researcher in the fields of carbohydrate
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`chemistry (for about 35 years) and medicinal chemistry/pharmacy (for about 21
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`years). A copy of my curriculum vitae (“CV”) is attached as Appendix A.
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`In
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`formulating my opinions, I have relied upon my experience and have considered
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`the viewpoint of a person of ordinary skill in the art (“POSITA”) around 2006.
`5.
`In formulating my opinion, I have considered the following documents:
`
`Ex. 1004
`
`
`
`
`
`
` Ex. 1001
`United States Patent No. 8,431,549 (“the ‘549 patent”)
`
`Ex. 1002
`U.S. Patent No. 5,541,158 (“the ‘158 patent”)
`Ex. 1003
`United States Patent Application 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”)
`United States Patent No. 3,100,202 (“Muller”)
`Declaration Under 37 C.F.R. 1.132 of Richard Lawrence
`Auerbachet al., 2004, J. Clinical Oncol. 22(7):1301-1307
`
`Ex. 1011
`Ex. 1012
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`fxn (“Auerbach”)
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`Ex. 1016
`United States Patent No. 6,599,498 (“the ‘498 patent”)
`
`Product documentation for Promit®
`
`European Pharmacopeia for Dextran 1 (2005)
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`
`
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`Ex. 1030
`Merck Index (14th Edition) for Dextran (2006)
`Ex. 1032
`Canadian Patent No. 623411 (“the ‘411 patent”)
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`Ex. 1035
`Neiser, 2015, Biometals 1-21 (“Neiser 2015”)
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`Ex. 1038
`Ex. 1039
`Ex. 1040
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`
`) —
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`Ex. 1041
`Ex. 1042
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`Ex. 1043
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`Ex. 1044
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`Ex. 1045
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`
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`Ex. 1046
`Ex. 1047
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`Ex. 1049
`
`States Pharmacopeia for Dextran 1 (USP 28:
`nited
`Product documentation for Dextran T1
`United States Patent No. 7,754,702 (“the ‘702 patent”)
`Excerpts of the File History of the ‘702 Patent (“the ‘702 patent File
`History”)
`United States Patent No. 8,895,612 (“the ‘612 patent”)
`Excerpts of the File History of the ‘612 Patent (“the ‘612 patent File
`History”)
`Excerpts of the File History of the ‘549 Patent (“the ‘549 patent File
`History”)
`English translation of International Patent Application Publication
`No. WO 2004/037865 (“Geisser”)
`Neiser et al., 2011, Port. J. Nephrol. Hypert. 25(3):2 19-224
`(“Neiser’)
`Prescribing Information for Injectafer®
`Funket al., 2001, Hyperfine Interactions 136: 73-95 (“Funk’’)
`Danielson, 2004, Structure, Chemistry, and Pharmacokinetics of
`IntravenousIron Agents, Journal of the American Society of
`Nephrology 15:593-598 (“Danielson”)
`Geisseret al., 1992, Structure / Histotoxicity Relationship of
`Parenteral Iron Preparations, Drug Res. 42(11):1439-1452 (“Geisser
`1992”)
`United States Patent No. 3,076,798 (“the ‘798 Patent”)
`United States Patent No. 4,599,405 (“the ‘405 Patent”)
`Letter to Editor regarding Neiseret al. (2011, Port. J. Nephrol.
`
`
`
`
`Ex. 1052
`
`aan Hypert. 25(3):219-224),Port. J. Nephrol. Hypert. 26(4)
`
`Ex. 1053
`
`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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`I,
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`LEVEL AND PERSON OF ORDINARY SKILL IN THE ART
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`6,
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`I understand that a POSITA is one who is presumed to be aware of all
`
`pertinent art, thinks along conventional wisdom in the art, and is a person of
`
`ordinary creativity. The field of the ‘549 patent is treatment of iron deficiency-
`
`related conditions with iron carbohydrate complexes.
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`In my opinion, a POSITA
`
`would hold at least a bachelor’s level degree in chemistry or biochemistry with
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`some related post-graduate experience (academic or industrial) in the area of
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`carbohydrates and their metal complexes.
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`TH,
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`THE ‘549 PATENT
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`7.
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`The ‘549 patent relates to methods of treating various disorders and
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`conditions associated with iron deficiency or dysfunctional iron metabolism in
`
`which a single dosage unit of iron carbohydrate complex providing about 0.6
`
`grams of elemental iron is administered. The claimsof the ‘549 patent specify that
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`the carbohydrate component of the iron carbohydrate complex is substantially non-
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`immunogenic.
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`IV.
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`POLYISOMALTOSE
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`8.
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`The subject matter of the ‘549 patent includes iron carbohydrate complexes
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`in which the carbohydrate component is polyisomaltose. Claims 1 and 21 cover
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`methods of treating a disease, disorder, or condition characterized by iron
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`deficiency or dysfunctional
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`iron metabolism that administer at least about 0.6
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`grams of elemental iron as a single dosage unit of iron polyisomaltose complex,
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`and recite the term “iron polyisomaltose.”
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`To me,
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`iron polyisomaltose is a
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`complex formed between iron and a carbohydrate that is a polymer of glucose
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`linked primarily by a-1-6 glycosidic linkages, where two glucose residues joined
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`by an a-1-6 glycosidic linkage is known as isomaltose (see Figure B, below).
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`9,
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`The ‘549 patent (Ex. 1001) discusses polyisomaltose at column 3, lines 33-
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`37, and at column 10, lines 44-54. The second instance, at column 10, line 48,
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`recites “iron polyisomaltose (iron dextran),” indicating that polyisomaltose and
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`dextran are the same or equivalent.
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`10.
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`It
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`is consistent with usage in the art
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`to use the terms “dextran” and
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`“polyisomaltose” interchangeably. There are instances where “polyisomaltose”is
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`used to refer to dextran that has been processed to remove most or all of its
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`branches (e.g., in the ‘411 patent, Ex. 1032 at pages 4-5). A branched polymer,
`
`like dextran, has a core a-1-6 structure that is more stable to acidic conditions such
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`as those used to decrease molecular weight, so that when you treat native dextran
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`with acid or similar agents, debranching occurs preferentially, leaving behind an
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`increasingly linear molecule. However, there are a number of commonly cited
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`examples where highly processed, essentially purely linear molecules are referred
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`to, in standard terminology, as “dextran.” One such example is the pharmaceutical
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`compound Dextran 1. According to the 2005 United States Pharmacopeia for
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`Dextran 1
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`(Ex. 1037), Dextran 1
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`is a glucose polymer with linkages that are
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`“almost exclusively o-1,6” with an average molecular weight of 1000 Da.
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`Similarly, Dextran Tl
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`is a technical grade dextran with a molecular weight and
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`configuration equivalent
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`to Dextran |
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`(based on web pages “Pharmaceutical
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`Quality Dextran” and “Technical Quality Dextran” from the Pharmacosmos
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`website; Ex. 1038). Dextrin Tl
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`is also comprised of essentially purely linear
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`molecules
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`and
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`is nonetheless
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`referred to
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`as
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`“dextran”
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`rather
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`than as
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`“polyisomaltose.” Therefore, standard usage in the art does not dictate that the
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`term “dextran” only be used for large or branched molecules.
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`ll.
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`‘To clarify, when I say that Dextran 1 or Dextran T1 are “almost exclusively
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`a-1-6” linkages or “essentially purely linear” I mean that the vast majority -
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`virtually all - of the carbohydrate molecules are purely linear (that is, contain only
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`a-1-6 glycosidic linkages). Because Dextran 1 and Dextran T1 are highly
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`processed forms of native dextran, there could be branched molecules present, but
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`they would be extremely rare.
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`I would assume that any product prepared from
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`native dextran could potentially contain branched molecules, even at undetectable
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`levels.
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`12. An anti-dextran antibody is one that specifically recognizes dextran, which
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`is a primarily a-1-6 linked oligomer or polymerof glucose.
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`13. As part of my preparation, I reviewed the Declaration Under 37 C.F.R.
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`§1.132 by co-inventor Richard Lawrence(the “Lawrence Declaration”; Ex. 1011).
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`In his Declaration, Mr. Lawrence says
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`that “[o]ne example of an iron
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`polyisomaltose complex is an iron isomaltoside (e.g., Monofer®) where the
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`carbohydrate component is a pure linear chemical structure of repeating a linked
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`glucose units” (Ex. 1011 at page 2, 94).
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`In my view, contrary to Mr. Lawrence’s
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`statement, a precise usage of “polyisomaltose” would not include a hydrogenated
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`polyisomaltose, and, based on my understanding from Jahn et al. (cited by the
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`Lawrence Declaration, Ex. 1026),
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`the 1000 Da carbohydrate component of
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`Monofer®, because it is so small, would properly be referred to as a “reduced(i.e.,
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`hydrogenated) oligoisomaltose” or “oligoisomaltoside.” Making the distinction
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`between a reduced (hydrogenated) and not reduced (non-hydrogenated) molecule
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`is consistent with usage in the ‘549 patent (Ex. 1001), because the specification at
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`column 3, lines 33-37, and at column 10, lines 44-54, in particular at column 3,
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`line 37, and at column 10, line 50,
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`lists “hydrogenated dextran” as a separate
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`species, which would indicate that the term “polyisomaltose (dextran)” does not
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`include hydrogenated polyisomaltose (a.k.a. “polyisomaltoside”Vhydrogenated
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`dextran.
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`14. After its discussion of polyisomaltose, the Lawrence Declaration goes on to
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`state that “[i]n contrast, a dextran is a branched glucan with straight chains having
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`al-6 glycosidic linkages and branches beginning from o1-3 linkages” (Ex. 1011 at
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`pages 2-3, §4). This sentence creates the misleading impression that there is a
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`bright-line distinction between polyisomaltose and dextran when there is not. The
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`Lawrence Declaration goes on, citing Jahn et al., to discuss how research in the
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`1970s and 1980s showedthat “isomaltose oligomers” (implied to be examples of
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`polyisomaltose and distinct from dextran) can act as haptens against circulating
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`anti-dextran antibodies and prevent or block anaphylaxis (Ex. 1011 at page 3, 95).
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`But if one looks to, for example, a Richter reference cited by Jahn (Ex. [1027]),
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`you find that the hapten being referred to is Dextran 1, which I discussed above in
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`paragraphs 10 and 11 (Ex. 1027 at page 5). The Richter article uses the term
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`“dextran” in two ways--first, to refer to “clinical dextran”' which was used atthe
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`time as a blood plasma substitute/expander, and, second, to “hapten-dextran”(e.g.,
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`Dextran 1), which was used prophylactically to avoid anaphylactic reactions to
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`clinical dextran (Ex. 1027 at pages 2, 3, and 4). Richter used the term “dextran” to
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`apply to both large (at least partially) branched polymeric molecules as well as to
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`small, essentially purely linear oligomers. Richter was published in 1986, but this
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`overlap in terminology continues to the present day, where Neiser, 2015 refers to
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`‘Tn discussing “Historical Background” Richter teaches that dextran having a
`molecular weight of 70,000 was introduced as a blood plasma substitute in 1947,
`and sometimes caused “mild allergic reactions,” but “[c]hange to a more linear
`dextran reduced the incidence ofallergic reactions.” Ex. 1027 at page 2.
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`the carbohydrate component of iron isomaltoside 1000 (i.e., Monofer®) as “a
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`reduced Dextran 1000” (Ex. 1035 at page 3).
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`15.
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`The Lawrence Declaration states that “[a]ccording to Jahn et al., the ability
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`to administer high doses (e.g., up to 1,600 mg elemental
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`iron) of the iron
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`isomaltoside Monofer® (i.e., one example of an iron polyisomaltose) arises from
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`reduced immunogenic potential and absence of dextran-induced anaphylactic
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`reactions” (Ex. 1011 at page 3, 95).
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`I would disagree with this characterization,
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`and would interpret Jahn et al.
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`instead as teaching that, while Monofer’s low
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`immunogenic potential makes a test dose unnecessary, the high single dosage and
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`rapid infusion rate is possible due to a low level of free iron (Ex. 1026 at page 10).
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`16. Another document that I reviewed in my preparation is Groman et al. (Ex.
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`1003). Groman discloses the preparation and use of iron complexed with a
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`reduced (hydrogenated) dextran, which can be a reduced (hydrogenated) Dextran
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`Tl.
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`In Example 10 (Ex. 1003 at paragraphs [0177]-[0178] on pages 29-30),
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`Groman describes the reduction of Dextran T1, which, as discussed above, I
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`understand to be a primarily a-1-6 linked polymer of glucose of a molecular
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`weight of approximately 1000 Da and a technical grade version of Dextran 1. That
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`a “technical grade” dextran was used would be relevant to either the manufacturing
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`method used and/or the purity of the dextran, and would restrict its commercial
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`uses, but would be irrelevant to the structure of the carbohydrate molecules, so that
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`(pharmaceutical grade) Dextran 1 and (technical grade) Dextran T1 carbohydrate
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`molecules are essentially the same.
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`17.
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`Groman then discloses that the reduced Dextran T1 is reacted with ferric
`
`chioride in Example 28 (Ex. 1003 at paragraphs [0230]-[0231] on page 33) to
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`prepare an iron carbohydrate complex having a mean volume diameter of 18 nm.
`
`I would consider the reduced Dextran Tl described in Example 10 of Gromanto
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`be an essentially linear oligoisomaltoside which, when complexed with iron
`
`according to Example 28, would fall within the Lawrence Declaration’s definition
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`of “iron polyisomaltose.”
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`18.
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`In addition to disclosing reduced Dextran T1, Groman also discloses treating
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`patients suffering from anemia (Ex. 1003 at paragraph [0082] on page 23) by
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`administering a dose of elemental
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`iron, comprised in an iron/reduced dextran
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`complex (Ex. 1003 at paragraphs [0008] (pages 15-16), [0020] (page 17), [0029]
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`(page 18), [0034] (page 18) and [0091] (page 24)), of up to 600 mg (0.6 grams; Ex.
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`1003 at paragraphs [0015] and [0016] on pages 16-17). Groman further teaches
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`that its iron carbohydrate complexeshave “minimal detectable free iron,” “minimal
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`incidence of anaphylaxis” and are “immunosilent” (Ex. 1003 at paragraphs [0004]
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`(page 15), [0005] (page 15), [0009] (page 16), [0016] (pages 16-17), and [0104]
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`(page 25)). Therefore, although I don’t think that a reduced (hydrogenated)
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`oligoisomaltose should properly be considered a “polyisomaltose,” if one applies
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`statements made in the Lawrence Declaration, then Groman’s disclosure regarding
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`reduced Dextran T1 would meetall the limitations of claim 1 of the ‘549 patent.
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`Vv.
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`POLYGLUCOSE CARBOXYMETHYL ETHER
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`19.
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`The subject matter of the ‘549 patent also includes iron carbohydrate
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`complexes
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`in which the
`
`carbohydrate component
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`is polyglucose sorbitol
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`carboxymethyl ether. Methods of treating a disease, disorder, or condition
`
`characterized by iron deficiency or dysfunctional iron metabolism that administer,
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`at
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`least about 0.6 grams of elemental
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`iron as a single dosage unit of iron
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`polyglucose sorbitol carboxymethyl ether are covered in at least claims 12 and 13.
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`I say “at least” because claim 12 depends upon claim 1, which would suggest that
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`iron polyglucose sorbitol carboxymethyl ether falls within the categories of iron
`
`carbohydrate complexes listed in claim 1. However, in my view iron polyglucose
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`sorbitol carboxymethyl ether would not fall within any of the categories of iron
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`carbohydrate complexeslisted in claim 1. To me, the term “iron sorbitol complex”
`
`would refer iron complexed with sorbitol monosaccharide. However, the ‘549
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`patent (Ex. 1001) describes iron polyglucose sorbitol carboxymethyl ether at
`
`column 3, lines 38 through 39, column 11, lines 36 through 40, and column 13,
`
`lines 27 through 57.
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`20.
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`To understand the meaning of “iron polyglucose sorbitol carboxymethyl]
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`ether” in the specification of the ‘549 patent, I would look to the ‘498 patent
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`(Ex.
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`1016) cited at column 13, lines 39 through 40 of the ‘549 patent.
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`I do not believe
`
`that the word “polyglucose”is used in the ‘498 patent, but two polymers of glucose
`
`are mentioned, dextran and pullulan (see, for example, the Ex. 1016 at column 2,
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`lines 3 through 5, column 7 “Scheme 1”at lines 3 through 30 showing production
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`of polyglucose sorbitol from dextran, and column 12, lines 29 through 31), dextran
`
`being glucose units primarily joined in o-1-6 linkages, and pullulan being glucose
`
`units joined in both a-1-4 and a-1-6 linkages. The primarily o-1-6 linked structure
`
`of dextran is presented below in Figure C. The structure of pullulan, which
`
`includes both a-1-4 and a-1-6 linkages, is presented below in Figure F.
`
`I would
`
`consider both dextran and pullulan to be examples of polyglucose.
`
`Further,
`
`according to the ‘498 patent,
`
`the end reducing sugar of the polyglucose is
`
`hydrogenated (in other words, “reduced”; see, for example, Ex. 1016 at column 2,
`
`lines 4 through 9) to form a sorbitol residue. Reduced dextran is a type of
`polyglucose sorbitol. Reduction of dextran according to the methods described in
`
`the ‘498 patent is presented in Figure D. If a carboxymethyl group is added to the
`
`reduced
`
`polyglucose (ie.,
`
`polyglucose
`
`sorbitol),
`
`polyglucose
`
`sorbitol
`
`carboxymethyl
`
`ether
`
`is produced (for example, by reacting the reduced
`
`dextran/polyglucose sorbitol with bromoacetic acid under alkaline conditions; see
`
`Ex, 1016 at column 2, lines 16 through 19, Example 5 at column 14, line 55,
`
`through column 15, line 23). Preparation of carboxymethylated reduced dextran
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`(one type of polyglucose sorbitol carboxymethyl ether) according to the methods
`
`described in the ‘498 patent is presented in Figure E. The polyglucose sorbitol
`
`carboxymethyl ether is then complexed with iron (Ex. 1016 at column4, lines 17
`
`through 18, and column 10,
`
`lines 42 through 57).
`
`Therefore to me,
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`iron
`
`polyglucose sorbitol carboxymethyl ether means iron complexed with a glucose
`
`polymer where the glucose units are joined through glycosidic linkages that could
`
`be a-1-4 or a-1-6 or a combination, which could be dextran, or pullulan, or dextrin
`
`or maltodextrin, where the end reducing sugar is hydrogenated (reduced), where
`
`hydroxyl groupsof at least some glucose units are joined to a carboxymethyl group
`
`through an ether linkage.
`
`I would consider carboxymethylated reduced dextran to
`
`be an example of a polyglucose sorbitol carboxymethylether.
`
`21. Groman
`
`discloses
`
`essentially
`
`the
`
`same
`
`iron
`
`polyglucose
`
`sorbitol
`
`carboxymethyl! ether complexesas the ‘498 patent, and carboxymethylated reduced
`
`dextran is a particular example of a polyglucose sorbitol carboxymethyl ether
`
`taught by Groman. Both Groman and the ‘498 patent disclose treating patients
`
`suffering from anemia (Ex. 1003 at paragraph [0082] on page 23), but Groman
`
`goes further,
`
`teaching administration of a dose of iron polyglucose sorbitol
`
`carboxymethyl ether complex of up to 600 mg (0.6 grams) (Ex. 1003 at paragraphs
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`[0015] and [0016] on pages 16-17). Groman also teaches that its iron carbohydrate
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`complexes would exhibit minimal cross-reactivity with a rat anti-dextran antibody
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`and hence be immunesilent
`in a subject, providing minimal
`incidence of
`anaphylactic response (Ex. 1003 at paragraph [0104] on page 25). Therefore, |
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`|
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`believe that Gromanteachesall the elements of claim 12 of the ‘549 patent.
`
`22.
`
`Groman broadly refers to its iron carbohydrate complexes as iron oxide
`
`complexed with polyol. Both reduced dextran (e.g., reduced Dextran T1) and
`
`polyglucose sorbitol carboxymethyl ether are polyols. Groman states that its iron
`
`oxide polyol complexes can be administered at rates substantially greater than 1
`
`mL/min, even a rate of | mL/sec, and provide minimal detectable free iron and
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`minimal incidence of anaphylaxis (Ex. 1003 at paragraphs [0009], [0011], and
`
`[0015] on page 16). As regards rate of administration, Groman discloses iron
`
`oxide polyol at iron concentrations of about 1-4 mg/kg of body weight in a total
`
`volume of about 1-15 ml (Ex. 1003 at paragraph [0016] on pages 16-17). For a
`
`human weighing 80 kg (approximately 176 pounds), this would correspond to
`
`dilution of 80-320 mg in 1-15 ml. If the greatest amount were incorporated in the
`
`largest volume, 320 mg would be contained in 15 ml. Groman further discloses a
`
`total single dose of elemental iron from about 50 mg to 600 mg, and a parenteral
`
`rate of administration “substantially greater than 1 mL/min,” or a rate of 1
`
`ml/second (Ex. 1003 at paragraph [0016] on pages 16-17). A dose of 600 mg,at a
`
`dilution of 320 mg per 15 ml, would be contained in 28.2 ml. Administration of
`
`the 600 mg dose at a rate of 1 ml/sec would occur over 28.2 seconds, andat a rate
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`of “substantially greater than 1 mL/min” would occur in (substantially) less than
`
`28 minutes.
`
`If a more concentrated solution (as contemplated in the disclosed
`
`ranges) were administered, the infusion time would be shorter, and with a more
`
`dilute solution,
`
`the infusion time would be longer.
`
`Thus, Groman teaches
`
`administration of a single dose of iron carbohydrate complex (iron carboxymethyl
`
`reduced dextran (iron polyglucose sorbitol carboxymethyl ether complex) or of
`
`hydrogenated (reduced) dextran having, for example, having a molecular weight
`
`of about 1000 Da) - of up to 0.6 grams, in less than 28 minutes, in less than fifteen
`
`minutes, in less than five minutes, in less than two minutes, and even in less than
`
`one minute.
`
`23.
`
`Claim 13 adds to claim 12 the limitation that the iron polyglucose sorbitol
`
`carboxymethyl ether complex is a non-stoichiometric magnetite complex. To me,
`
`all the iron complexes disclosed by Groman are non-stoichiometric in that they are
`
`all mixtures.
`
`I would therefore conclude that claim 13 is not novel, as its elements
`
`were previously described by Groman.
`
`24.
`
`Claim 14 of the ‘549 patent adds to claim | that either the mean iron core
`
`size is between about
`
`1 and 9 nm or “mean size of a particle of the iron
`
`carbohydrate complex is no greater than about 35 nm.” The ‘549 patent indicates
`
`that
`
`light scattering can be used to determine mean particle size of iron
`
`carbohydrate complexes (Ex. 1001 at column 13, lines 47-48). The ‘549 patent
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`
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`describes mean particle size in terms of mean diameters (Ex. 1001 at column 15,
`
`lines 2-12).
`
`In my opinion, the “mean size of a particle” of the ‘549 patent,
`
`measured in nm, describes the diameter of an iron carbohydrate complex particle
`
`and, therefore, the mean particle size of the ‘549 patent is equivalent to the mean
`
`volume diameter of Groman.
`
`In Table 10, Groman describes particles of tron
`
`complexed with carboxymethyl
`
`reduced dextran,
`
`a polyglucose
`
`sorbitol
`
`carboxymethyl ether, with mean volume diameters between 12 and 21 nm, as
`
`measured by light scattering (Ex. 1003 at paragraphs [0280]-[0282] and Table 10
`
`on page 37). Further, Groman discloses iron complexed with reduced Dextran T1
`
`having a mean volume diameter of 18 nm (Ex. 1003 at paragraphs [0230]-[023 1]
`
`on page 33 and Table 8 on page 34), Because I understand mean volume diameter
`
`and particle size to be the same, if either iron complexed with polyglucose sorbitol
`
`carboxymethyl ether or reduced Dextran T1 fall within the scope of claim 1, all
`
`limitations of claim 14 are met, because Groman teaches particle sizes of those
`
`complexes that are between 12 and 21 nm or 18 nm,respectively, both being “no
`
`greater than about 35 nm.”
`
`VI.
`
`CARBOXYMALTOSE AND POLYMALTOSE
`
`25.
`
`I consider the carboxymaltose as defined in the ‘549 patent to be a maltose
`
`or maltodextrin, comprised of maltose type units, in which the aldehyde group of
`
`the reducing sugar end has been oxidized to form a carboxylic acid group. Maltose
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`is a D-glucopyranose dimer linked through an a-l-4 glycosidic bond.
`
`The
`
`structure of maltose, with its characteristic a-1-4 glycosidic bond,
`
`is presented
`
`below in Figure A. Maltodextrin is a repeating oligomer or polymer of D-
`
`glucopyranose units linked primarily through a-1-4 glycosidic bonds. This type of
`
`carbohydrate can also be called a polymaltose or a dextrin. The structure of
`
`maltodextrin, with its characteristic a-1-4 glycosidic bonds, is presented below in
`
`Figure G.
`
`I would not expect an anti-dextran antibody to cross-react with iron
`
`carboxymaltose or iron polymaltose, in which, in both instances, the carbohydrate
`
`is a primarily a-1-4 linked oligomer or polymer of glucose.
`
`26.
`
`Based on my review, van Zyl-Smit (Ex. 1004) teaches iron polymaltose
`
`
`
`(dextrin) as an effective means for treating iron deficiencies (including anemia)
`
`and raising hemoglobin levels. Van Zyl-Smit teaches a dose range of 900-3200
`
`mg of iron over a four hour period (Ex. 1004 at page 2). Van Zyl-Smit indicates
`
`that the interaction of iron carbohydrate supplements with anti-dextran antibodies
`
`can cause dangerous anaphylactic reactions but reports that in its studies iron
`
`polymaltose (dextrin) did not cause anaphylaxis (Ex. 1004 at pages 6-7). Because
`
`van Zyl-Smit did not observe anaphylactoid reactions upon administration of iron
`
`polymaltose, and refers to iron polymaltose as a “safe and effective way of
`
`correcting iron deficiency” (Ex. 1004 at page 8),
`
`I would consider van Zyl-Smit to
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`teach that the polymaltose in the complexes is substantially non-immunogenic.
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`Because van Zyl-Smit discloses a method of treating iron deficiency, including
`
`anemia, by administering an iron polymaltose complex that contains more than 0.6
`
`grams of elemental iron and that is non-immunogenic and unreactive to anti-
`
`dextran antibodies, in my view at least claims 1,2, 3, 4, 5, 9, and 19 are not novel
`
`over van Zyl-Smit.
`
`27.
`
`In my opinion,
`
`the goal of van Zyl-Smit
`
`is
`
`to administer an iron
`
`carbohydrate complex that is stable and releases iron slowly, to minimize free iron
`
`concentration in the blood (Ex. 1004 at page 7). Groman also teachesthat its iron
`
`complexes “provide[ ] minimal detectable free iron” (Ex. 1003 at paragraph [0004]
`
`on page 15). Because Groman and van Zyl-Smit both relate to iron carbohydrate
`
`complexes with minimal free iron (and therefore
`
`less likely to have toxic side
`
`effects) that can be administered at high doses to treat iron deficiency, | think that a
`
`POSITA would have been motivated to put together the teachings and administer
`
`polymaltose according to van Zyl-Smit at a rapid administration rate according to
`
`Groman.
`
`In view of the slow iron release profile of polymaltose, I believe that it
`
`would have been obvious to administer the polymaltose of van Zyl-Smit at a dose
`
`of 0.6 g elemental iron and above at a rate disclosed in Groman,
`
`for example 15
`
`minutes or less, as covered by claim 10 of the ‘549 patent.
`
`28.
`
`Claim 16 depends from claims 1 and 15 and further requires that parenteral
`
`administration of the iron carbohydrate complex comprises intravenous infusion
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`Petitioner Ex. 1110 -
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