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 8,895,612
`
`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
`
`Active 19556628.2
`
`Pharmacosmos, Exh. 1013, p. 1
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Pharmacosmos A/S
`
`Petitioner
`
`v.
`
`Luitpold Pharmaceuticals, Inc.
`
`Patent Owner
`
`Case Unassigned
`Patent 8,895,612
`
`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
`
`Active 19556628.2
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`Pharmacosmos, Exh. 1013, p. 1
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`OVERVIEW .................................................................................................. 1
`
`II. LEVEL AND PERSON OF ORDINARY SKILL IN THE ART ............. 3
`
`III. THE '612 PATENT ....................................................................................... 4
`
`IV. POLYISOMALTOSE ................................................................................... 4
`
`V.
`
`POLYGLUCOSE CARBOXYMETHYL ETHER .................................. 10
`
`VI. CARBOXYMALTOSE ............................................................................... 16
`
`VII. POLYMALTOSE ........................................................................................ 21
`
`VIII. CONCLUSION ............................................................................................ 23
`
`IX. FIGURES ..................................................................................................... 25
`
`Active 19556628.2
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`Pharmacosmos, Exh. 1013, p. 2
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`
`
`I, Robert Linhardt, do hereby declare as follows:
`
`OVERVIEW
`
`I, Robert Linhardt, am over the age of eighteen ( 18) and otherwise
`
`I.
`
`1.
`
`competent to make this declaration.
`
`2.
`
`I have been retained by Baker Botts L.L.P. to act as an expert witness in a
`
`matter on behalf of their client, Pharmacosmos A/S. The matter is a Request for
`
`Inter Partes Review of United States Patent No. 8,895,612 by Helenek ("the '612
`
`Patent"), which is a continuation of United States Patent Application No.
`
`13/847,254, filed March 19, 2013, which is a continuation of United States Patent
`
`Application No. 12/787,283, filed May 25, 2010, now United States Patent No.
`
`8,431,549 ("the '549 patent"), which is a continuation of United States Patent
`
`Application No. 11/620,986, filed January 8, 2007, now United States Patent No.
`
`7,754,702 ("the '702 patent"). I am being compensated for my time in connection
`
`with this matter at my standard consulting rate, which is $600.00 per hour. My
`
`compensation is not dependent on the outcome of this matter.
`
`3.
`
`In this Declaration, I provide opinions relating to the following claims of the
`
`'612 patent: 1, 2, 3, 4, 5, 7, 8, 11, 12, 15, 16, 17, and 20.
`
`4.
`
`In preparing this Declaration, I reviewed and considered the '612 patent and
`
`considered each of the documents listed in paragraph 5 below, in light of my
`
`general knowledge as a professor and researcher in the fields of carbohydrate
`
`Active 19556628.2
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`1
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`Pharmacosmos, Exh. 1013, p. 3
`
`
`
`chemistry (for about 35 years) and medicinal chemistry/pharmacy (for about 21
`
`years). A copy of my curriculum vitae ("CV") is attached as Appendix A.
`
`In
`
`formulating my opinions, I have relied upon my experience and have considered
`
`the viewpoint of a person of ordinary skill in the art ("POSIT A") around 2006.
`
`5.
`
`In formulating my opinion, I have considered the following documents:
`
`Ex. 1001
`Ex. 1002
`
`Ex. 1004
`
`Ex. 1005
`Ex. 1006
`
`Ex. 1010
`Ex. 1011
`
`Ex. 1016
`Ex. 1023
`Ex. 1024
`Ex. 1025
`Ex. 1027
`Ex. 1028
`
`Ex. 1029
`Ex. 1030
`Ex. 1031
`Ex. 1033
`Ex. 1035
`Ex. 1037
`
`United States Patent No. 8,895,612 ("the '612 patent")
`United States Patent Application Publication No. 2003/0232084
`("Groman")
`English translation of International Patent Application Publication
`No. WO 2004/037865 ("Geisser")
`Marchasin, 1964, Blood 23:354-358 ("Marchasin")
`van Zyl-Smit and Halkett (2002) Nephron 92:316-323 ("van Zyl(cid:173)
`Smit")
`United States Patent No. 3,100,202 ("Muller")
`Auerbach et al., 2004, J. Clinical Oncol. 22(7): 1301-1307
`("Auerbach")
`United States Patent No. 6,599,498 ("the '498 Patent")
`Product documentation for Dextran Tl
`United States Patent No. 8,431,549 ("the '549 Patent")
`Declaration Under 37 C.F.R. 1.132 ofRichard Lawrence
`Product documentation for Promit®
`Neiser et al., 2011, Port. J. Nephrol. Hypert. 25(3):219-224
`("N eiser")
`Jahn et al., 2011, Eur. J. Pharma and Biopharma 78:480-91 ("Jahn")
`Richter, 1986, New Trends in Allergy II, p. 272-283
`European Pharmacopeia for Dextran 1 (2005)
`Canadian Patent No. 623411 ("the '411 patent")
`Neiser, 2015, Biometals 1-21 ("Neiser 2015")
`United States Pharmacopeia for Dextran 1 (USP 28; 2005)
`
`Active 19556628.2
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`Pharmacosmos, Exh. 1013, p. 4
`
`
`
`~1~6fjj~!li;~1
`Ex. 1038
`Ex. 1039
`Ex. 1040
`
`Ex. 1041
`Ex. 1042
`
`Ex. 1043
`
`Ex. 1044
`Ex. 1045
`
`Ex. 1046
`Ex. 1047
`Ex. 1048
`
`Ex. 1049
`
`Ex. 1050
`Ex. 1051
`
`''"-'
`
`,,
`,, "<
`
`·~ •,;"'
`.·,··<·,.·>: ... ;;,:'.'\ ,,"_;,·.,·· ... ;
`.>:··: '•
`.;
`United States Patent No. 4,599,405 ("the '405 Patent")
`United States Patent No. 7,754,702 ("the '702 Patent")
`Excerpts of the File History of the '702 Patent ("the '702 patent File
`History")
`U.S. Patent No. 5,541,158("the'158 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")
`Merck Index (14th Edition) for Dextran (2006)
`Letter to Editor regarding Neiser et al. (2011, Port. J. Nephrol.
`Hypert. 25(3):219-224), Port. J. Nephrol. Hypert. 26(4)
`Prescribing Information for Injectafer®
`Funk et al., 2001, Hyperfine Interactions 136: 73-95 ("Funlc")
`Danielson, 2004, Structure, Chemistry, and Pharmacokinetics of
`Intravenous Iron Agents, Journal of the American Society of
`Nephrology 15:593-598 ("Danielson")
`Geisser et al., 1992, Structure I Histotoxicity Relationship of
`Parenteral Iron Preparations, Drug Res. 42(11):1439-1452 ("Geisser
`1992")
`United States Patent No. 3,076,798 ("the '798 Patent")
`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
`
`IL
`
`6.
`
`LEVEL AND PERSON OF ORDINARY SKILL IN THE ART
`
`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 '612 patent is treatment of iron deficiency-
`
`related conditions with iron carbohydrate complexes. In my opinion, a POSIT A
`
`Active 19556628.2
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`Pharmacosmos, Exh. 1013, p. 5
`
`
`
`would hold at least a bachelor's level degree in chemistry or biochemistry with
`
`some related post-graduate experience (academic or industrial) in the area of
`
`carbohydrates and their metal complexes.
`
`III.
`
`THE '612 PATENT
`
`7.
`
`The '612 patent claims methods of treating various disorders and 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 in about 15 minutes or less. The claims of the '612 patent
`
`further specify that the carbohydrate component of the iron carbohydrate complex
`
`is substantially non-immunogenic.
`
`IV. POLYISOk!ALTOSE
`
`8.
`
`The subject matter of the '612 patent includes iron carbohydrate complexes
`
`in which the carbohydrate component is polyisomaltose. Claims 1 and 20 cover
`
`methods of treating a disease, disorder, or condition characterized by iron
`
`deficiency or dysfunctional iron metabolism that administer at least about 0.6
`
`grams of elemental iron as a single dosage unit of iron polyisomaltose complex in
`
`about 15 minutes or less, and recite the term "iron polyisomaltose." To me, iron
`
`polyisomaltose is a complex formed between iron and a carbohydrate that is a
`
`polymer of glucose linked primarily by a-1-6 glycosidic linkages, where two
`
`Active 19556628.2
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`4
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`Pharmacosmos, Exh. 1013, p. 6
`
`
`
`glucose residues joined by an a-1-6 glycosidic linkage is known as isomaltose (see
`
`Figure B, below).
`
`9.
`
`The '612 patent (Ex. 1001) discusses polyisomaltose at column 3, lines 39-
`
`43, and at column 10, lines 49-60. The second instance, at column 10, line 54,
`
`recites "iron polyisomaltose (iron dextran)," indicating that polyisomaltose and
`
`dextran are the same or equivalent.
`
`10.
`
`It is consistent with usage m the art to use the terms "dextran" and
`
`"polyisomaltose" interchangeably. There are instances where "polyisomaltose" is
`
`used to refer to dextran that has been processed to remove most or all of its
`
`branches (e.g., in the '411 patent, Ex. 1033 at pages 4-5). A branched polymer,
`
`like dextran, has a core a-1-6 structure that is more stable to acidic conditions such
`
`as those used to decrease molecular weight, so that when you treat native dextran
`
`with acid or similar agents, debranching occurs preferentially, leaving behind an
`
`increasingly linear molecule. However, there are a number of commonly cited
`
`examples where highly processed, essentially purely linear molecules are referred
`
`to, in standard terminology, as "dextran." One such example is the pharmaceutical
`
`compound Dextran 1. According to the 2005 United States Pharmacopeia for
`
`Dextran 1 (Ex. 1037), Dextran 1 is a glucose polymer with linkages that are
`
`"almost exclusively a-1,6" with an average molecular weight of 1000 Da.
`
`Similarly, Dextran Tl is a technical grade dextran with a molecular weight and
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`Active 19556628.2
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`Pharmacosmos, Exh. 1013, p. 7
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`
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`configuration equivalent to Dextran 1 (based on web pages "Pharmaceutical
`
`Quality Dextran" and "Technical Quality Dextran" from the Pharmacosmos
`
`website; Ex. 1023). Dextrin Tl is also comprised of essentially purely linear
`
`molecules and
`
`is nonetheless
`
`referred
`
`to as "dextran"
`
`rather
`
`than as
`
`"polyisomaltose." Therefore, standard usage in the art does not dictate that the
`
`term "dextran" only be used for large or branched molecules.
`
`11. To clarify, when I say that Dextran 1 or Dextran Tl are "almost exclusively
`
`a-1-6" linkages or "essentially purely linear" I mean that the vast majority -
`
`virtually all - of the carbohydrate molecules are purely linear (that is, contain only
`
`a-1-6 glycosidic linkages). Because Dextran 1 and Dextran Tl are highly
`
`processed forms of native dextran, there could be branched molecules present, but
`
`they would be extremely rare. I would assume that any product prepared from
`
`native dextran could potentially contain branched molecules, even at undetectable
`
`levels.
`
`12. An anti-dextran antibody is one that specifically recognizes dextran, which
`
`is a primarily a-1-6 linked oligomer or polymer of glucose.
`
`13. As part of my preparation, I reviewed the Declaration Under 37 C.F.R. §
`
`1.132 by co-inventor Richard Lawrence (the "Lawrence Declaration"; Ex. 1025).
`
`In his Declaration, Mr. Lawrence says
`
`that "[o]ne example of an
`
`iron
`
`polyisomaltose complex is an iron isomaltoside (e.g., Monofer®), where the
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`Active 19556628.2
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`Pharmacosmos, Exh. 1013, p. 8
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`
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`carbohydrate component is a pure linear chemical structure of repeating a linked
`
`glucose units" (Ex. 1025 at page 2-3, i!4). In my view, contrary to Mr. Lawrence's
`
`statement, a precise usage of "polyisomaltose" would not include a hydrogenated
`
`"polyisomaltose," and, based on my understanding from Jahn et al. (Ex. 1029;
`
`cited by the Lawrence Declaration), the 1000 Da carbohydrate component of
`
`Monofer®, because it is so small, would properly be referred to as a "reduced (i.e.,
`
`hydrogenated) oligoisomaltose" or "oligoisomaltoside." Making the distinction
`
`between a reduced (hydrogenated) and not reduced (non-hydrogenated) molecule
`
`is consistent with usage in the '612 patent (Ex. 1001), because the specification at
`
`column 3, lines 39-43, and at column 10, lines 49-60, in particular at column 3,
`
`line 43, and at column 10, lines 55-56, lists "hydrogenated dextran" as a separate
`
`species, which would indicate that the term "polyisomaltose ( dextran)" does not
`
`include hydrogenated polyisomaltose (a.k.a. "polyisomaltoside")/hydrogenated
`
`dextran.
`
`14. After its discussion of polyisomaltose, the Lawrence Declaration goes on to
`
`state that "[i]n contrast, a dextran is a branched glucan with straight chains having
`
`al-6 glycosidic linkages and branches beginning from al-3 linkages" (Ex. 1025 at
`
`pages 2-3, i!4). This sentence creates the misleading impression that there is a
`
`bright-line distinction between polyisomaltose and dextran when there is not. The
`
`Lawrence Declaration goes on, citing Jahn et al., to discuss how research in the
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`1970s and 1980s showed that "isomaltose oligomers" (implied to be examples of
`
`polyisomaltose and distinct from dextran) can act as haptens against circulating
`
`anti-dextran antibodies and prevent or block anaphylaxis (Ex. 1025 at page 3, if5).
`
`But if one looks to, for example, a Richter reference (Ex. 1030) cited by Jahn, you
`
`find that the hapten being referred to is Dextran 1, which I discussed above in
`
`paragraphs 10 and 11. The Richter article uses the term "dextran" in two ways - -
`
`first, to refer to "clinical dextran" 1 which was used at the time as a blood plasma
`
`substitute/expander, and, second, to "hapten-dextran" (e.g. Dextran 1), which was
`
`used prophylactically to avoid anaphylactic reactions to clinical dextran (Ex. 1030
`
`at pages 2, 3, and 4). Richter used the term "dextran" to apply to both large (at
`
`least partially) branched polymeric molecules as well as to small, essentially purely
`
`linear oligomers. Richter was published in 1986, but the overlap in terminology
`
`continues to the present day, where Neiser, 2015 refers to the carbohydrate
`
`component of iron isomaltoside 1000 (i.e., Monofer®) as "a reduced Dextran
`
`1000" (Ex. 1035 at page 3).
`
`15. The Lawrence Declaration states that "[a]ccording to Jahn et al., the ability
`
`to administer high doses (e.g., up to 1,600 mg elemental iron) of the iron
`
`isomaltoside Mono fer® (i.e., one example of an iron polyisomaltose) arises from
`
`1 In discussing "Historical Background" Richter teaches that dextran having a
`molecular weight of70,000 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 of allergic reactions." Ex. 1030 at page 2.
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`Active 19556628.2
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`Pharmacosmos, Exh. 1013, p. 10
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`
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`reduced immunogenic potential and absence of dextran-induced anaphylactic
`
`reactions" (Ex. 1025 at page 3, if5). I would disagree with this characterization,
`
`and would interpret Jahn et al. instead as teaching that, while Monofer's low
`
`immunogenic potential makes a test dose unnecessary, the high single dosage and
`
`rapid infusion rate is possible due to a low level of free iron (Ex. 1029 at page 10).
`
`16. Another document that I reviewed in my preparation is Groman et al. (Ex.
`
`1002). Groman discloses the preparation and use of iron complexed with a
`
`reduced (hydrogenated) dextran, which can be a reduced (hydrogenated) Dextran
`
`Tl.
`
`In Example 10 (Ex. 1002 at paragraphs [O 177]-[0178] on pages 29-30),
`
`Groman describes the reduction of Dextran Tl, which, as discussed above, I
`
`understand to be a primarily a-1-6 linked polymer of glucose of a molecular
`
`weight of approximately 1000 Da and a technical grade version of Dextran 1. That
`
`a "technical grade" dextran was used would be relevant to either the manufacturing
`
`method used and/or the purity of the dextran, and would restrict its commercial
`
`uses, but would be irrelevant to the structure of the carbohydrate molecules, so that
`
`(pharmaceutical grade) Dextran 1 and (technical grade) Dextran Tl carbohydrate
`
`molecules are essentially the same.
`
`17. Groman then discloses that the reduced Dextran Tl is reacted with ferric
`
`chloride in Example 28 (Ex. 1002 at paragraphs [0230]-[023 l] on page 33) to
`
`prepare an iron carbohydrate complex having a mean volume diameter of 18 nm.
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`Pharmacosmos, Exh. 1013, p. 11
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`
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`I would consider the reduced Dextran Tl described in Example 10 of Groman to
`
`be an essentially purely linear oligoisomaltoside which, when complexed with iron
`
`according to Example 28, would fall within the Lawrence Declaration's definition
`
`of"iron polyisomaltose."
`
`18.
`
`In addition to disclosing reduced Dextran Tl, Groman also discloses treating
`
`patients suffering from anemia (Ex. 1002 at paragraph [0082] on page 23) by
`
`administering a dose of elemental iron, comprised in an iron/reduced dextran
`
`complex (Ex. 1002 at paragraphs [0008] (pages 15-16), [0020] (page 17), [0029]
`
`(page 18), [0034] (page 18) and [0091] (page 24)), of up to 600 mg (0.6 grams; Ex.
`
`1002 at paragraphs [0015] and [0016] (pages 16-17) ). Groman further teaches that
`
`its iron carbohydrate complexes have "minimal detectable free iron," "minimal
`
`incidence of anaphylaxis" and are "immunosilent." (Ex. 1002 at paragraphs [0004]
`
`(page 15), [0005] (page 15), [0009] (page 16), [0016] (pages 16-17), and [0104]
`
`(page 25)). Therefore, although I don't think that a reduced (hydrogenated)
`
`oligoisomaltose should properly be considered a "polyisomaltose," if one applies
`
`statements made in the Lawrence Declaration, then Groman's disclosure regarding
`
`reduced Dextran Tl would meet all the limitations of claim 1 of the '612 patent.
`
`V.
`
`POLYGLUCOSE CARBOXYMETHYL ETHER
`
`19. The subject matter of the '612 patent also includes Iron carbohydrate
`
`complexes
`
`in which
`
`the carbohydrate component
`
`is polyglucose sorbitol
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`Active 19556628.2
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`Pharmacosmos, Exh. 1013, p. 12
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`
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`carboxymethyl ether. Methods of treating a disease, disorder, or condition
`
`characterized by iron deficiency or dysfunctional iron metabolism that administer,
`
`in about 15 minutes or less, at least about 0.6 grams of elemental iron as a single
`
`dosage unit of iron polyglucose sorbitol carboxymethyl ether are covered by, for
`
`example, claim 1. The
`
`'612 patent describes
`
`iron polyglucose sorbitol
`
`carboxymethyl ether at, for example, column 13, lines 34 through 62.
`
`20. To understand the meaning of "iron polyglucose sorbitol carboxymethyl
`
`ether" in the specification of the '612 patent, I would look to the '498 patent (Ex.
`
`1016) cited at column 13, lines 45-46 of the '612 patent (Ex. 1001).
`
`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, Ex. 1016 at column
`
`2, lines 3 through 5, column 7 "Scheme 1" at lines 3 through 30 showing
`
`production of polyglucose sorbitol from dextran, and column 12, lines 29 through
`
`31 ), dextran being glucose units primarily joined in a-1-6 linkages, and pullulan
`
`being glucose units joined in both a-1-4 and a-1-6 linkages. The primarily a-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.
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`Pharmacosmos, Exh. 1013, p. 13
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`
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`1016 at column 2, lines 4 through 9) to form a sorbitol residue. Reduction of
`
`dextran according to the methods described in the '498 patent to provide reduced
`
`dextran (a polyglucose sorbitol) is presented in Figure D. If a carboxymethyl
`
`group is added to the reduced polyglucose (i.e., polyglucose sorbitol), polyglucose
`
`sorbitol carboxymethyl ether is produced (for example, by reacting the 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 (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 column 4, lines 17 through 18, and column
`
`10,
`
`lines 42
`
`through 57).
`
`Therefore
`
`to me,
`
`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 groups of
`
`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 carboxymethyl ether.
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`Pharmacosmos, Exh. 1013, p. 14
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`
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`21. Groman (Ex. 1002) discloses essentially the same iron polyglucose sorbitol
`
`carboxymethyl ether complexes as 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. 1002 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. 1002 at paragraphs
`
`[0015] and [0016] on pages 16-17). Groman also teaches that its iron carbohydrate
`
`complexes would exhibit minimal cross-reactivity with a rat anti-dextran antibody
`
`and hence be immunosilent in a subject, providing minimal incidence of
`
`anaphylactic response (Ex. 1002 at paragraph [0104] on page 25).
`
`22. Groman broadly refers to its iron carbohydrate complexes as iron oxide
`
`complexed with polyol. Both reduced dextran (e.g., reduced Dextran Tl) 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 1 mL/sec, and provide minimal detectable free iron and
`
`minimal incidence of anaphylaxis (Ex. 1002 at paragraphs [0009], [0011], and
`
`[0015] on page 16). As regards rate of administration, Groman discloses iron
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`oxide polyol at iron concentrations of about 1-4 mg/kg of body weight in a total
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`volume of about 1-15 ml (Ex. 1002 at paragraph [0016] on pages 16-17). For a
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`Active 19556628.2
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`13
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`Pharmacosmos, Exh. 1013, p. 15
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`
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`human weighing 80 kg (approximately 176 pounds), this would correspond to
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`dilution of 80-320 mg in 1-15 ml. If the greatest amount were incorporated in the
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`largest volume, 320 mg would be contained in 15 ml. Groman further discloses a
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`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. 1002 at paragraph [0016] on pages 16-17). A dose of 600 mg, at a
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`dilution of 320 mg per 15 ml, would be contained in 28.2 ml. Administration of
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`the 600 mg dose at a rate of 1 ml/sec would occur over 28.2 seconds, and at a rate
`
`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
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`administration of a single dose of iron carbohydrate complex (iron carboxymethyl
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`reduced dextran (iron polyglucose sorbitol carboxymethyl ether complex) or of
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`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. By teaching the elements of claim 1 as discussed above in paragraph
`
`21, and also disclosing an administration interval that can be about 15 minutes or
`
`less, Groman discloses all the elements of claim 1 of the '612 patent.
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`Active 19556628.2
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`14
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`Pharmacosmos, Exh. 1013, p. 16
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`
`
`23. Claim 15 of the '612 patent adds to claim 1 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 '612 patent indicates
`
`that light scattering can be used to determine mean particle size of iron
`
`carbohydrate complexes (Ex. 1001 at column 13, lines 53-54). The '612 patent
`
`describes mean particle size in terms of mean diameters (Ex. 1001 at column 15,
`
`lines 7-16).
`
`In my opinion, the "mean size of a particle" of the '612 patent,
`
`measured in nm, describes the diameter of an iron carbohydrate complex particle
`
`and, therefore, the mean particle size of the '612 patent is equivalent to the mean
`
`volume diameter of Groman.
`
`In Table 10, Groman describes particles of iron
`
`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. 1002 at paragraphs [0280]-[0282] and Table 10
`
`on page 37). Further, Groman discloses iron complexed with reduced Dextran Tl
`
`having a mean volume diameter of 18 nm (Ex. 1002 at paragraphs [0230]-[023 l]
`
`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 Tl fall within the scope of claim 1, all
`
`limitations of claim 15 are met, because Groman teaches particle sizes of those
`
`Active 19556628.2
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`15
`
`Pharmacosmos, Exh. 1013, p. 17
`
`
`
`complexes that are between 12 and 21 nm or 18 nm, respectively, both being "no
`
`greater than about 35 nm."
`
`VL CARBOXYM'ALTOSE
`
`24.
`
`I consider the carboxymaltose as defined in the '612 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
`
`is a D-glucopyranose dimer linked through an a-1-4 glycosidic bond. The
`
`structure of maltose, with its characteristic a-1-4 glycosidic bond, is presented
`
`below in Figure A. By contrast, isomaltose is the D-glucopyranose dimer linked
`
`through an a-1-6 glycosidic bond.
`
`The structure of isomaltose, with its
`
`characteristic a-1-6 glycosidic bond, is presented below in Figure B. Maltodextrin
`
`is a repeating oligomer or polymer of D-glucopyranose units linked 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 consider an iron carboxymaltose
`
`complex to be a complex between carboxymaltose and iron. For example, an iron
`
`carboxymaltose complex may be obtained, according to the '612 patent, from an
`
`aqueous solution of iron(III) salt and an aqueous solution of the oxidation product
`
`of one or more maltodextrins using an aqueous hypochlorite solution at a pH value
`
`Active 19556628.2
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`16
`
`Pharmacosmos, Exh. 1013, p. 18
`
`
`
`within the alkaline range. Ex. 1001 at column 4, lines 60-64. I would not expect
`
`an anti-dextran antibody to cross-react with iron carboxymaltose.
`
`25. Another reference that I reviewed as part of my preparation is a translation
`
`of Geisser (Ex. 1004).
`
`I consider Geisser to disclose carboxymaltose, iron
`
`carboxymaltose complexes, and methods for making
`
`iron carboxymaltose
`
`complexes. Geisser oxidizes maltodextrin with sodium hypochlorite. This results
`
`in the oxidation of the aldehyde group of the end reducing sugar to produce a
`
`carboxymaltose (see, for example, Ex. 1004 at page 5, lines 4-6 and lines 16-18).
`
`Oxidation of maltodextrin according to Geisser, with conversion of the aldehyde
`
`group of the end reducing sugar to a carboxy group, thereby generating
`
`carboxymaltose, is presented below in Figure H. Bromide may be added to
`
`catalyze the oxidation process (Ex. 1004 at page 5, lines 20-26). The iron
`
`carboxymaltose complex may then be prepared by reacting the carboxymaltose
`
`with an iron salt (Ex. 1004 at page 6, line 4, to page 8, line 26). The working
`
`examples of Geisser produce similar iron carboxymaltose products at molecular
`
`weights ranging from about 118 to 271 kilodaltons.
`
`26.
`
`I consider the iron carboxymaltose complexes described Geisser to be
`
`identical or nearly identical to iron carboxymaltose complex embodiments of the
`
`'612 patent, both in terms of synthetic methods and chemical properties. The
`
`ranges of molecular weight are broader in the
`
`'612 patent (e.g., 90-800
`
`Active 19556628.2
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`17
`
`Pharmacosmos, Exh. 1013, p. 19
`
`
`
`kilodaltons), but the iron carboxymaltose complexes described by Geisser fall
`
`within that range. Geisser (Ex. 1004) at page 4, lines 15-23, describes a general
`
`synthetic method that is nearly identical to the method described in the '612 patent
`
`(Ex. 1001) at column 3, lines 49-59.
`
`27. Geisser teaches the use of iron carbohydrate complexes for therapy of iron(cid:173)
`
`deficiency anemia, especially for parenteral use (Ex. 1004 at page 3, lines 4-5),
`
`and that the iron carbohydrate complexes have the advantage of low toxicity and
`
`reduced risk of anaphylactic shock (Ex. 1004 at page 10, lines 7-9). Geisser
`
`teaches a single dose of 500 mg to 1000 mg iron (Ex. 1004 at page 10, lines 16-
`
`17).
`
`28.
`
`I believe that the name of the carboxymaltose component of the iron
`
`carbohydrate complex referred
`
`to
`
`in claim 12(ii), 4(R)-(poly-(l-+4)-0-a(cid:173)
`
`glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate, is correct based on
`
`the structures drawn in Figure 2 of the '612 patent, in view of the specification and
`
`my knowledge of stereochemistry and carbohydrate chemistry. The phrase within
`
`parentheses, "poly-(1-+4)-0-a-glucopyranosyl," describes a polyglucose (glucose
`
`polymer) with glucose residues linked via 1-+4 glycosidic linkages. Polyglucose
`
`connected primarily through 1-+4 linkages is known as polymaltose, dextrin, or
`
`maltodextrin, as described above. This polyglucose component is depicted in
`
`Figure I. Figure I (top structure and middle structure) shows two glucopyranose
`
`Active 19556628.2
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`18
`
`Pharmacosmos, Exh. 1013, p. 20
`
`
`
`nngs connected through a 1---?4 linkage. The central glucopyranose ring is
`
`bracketed with a subscript "n," indicating that there are multiple repeating glucose
`
`residues making up the polyglucose chain. The portion of the name outside of
`
`parentheses, "4(R)-... oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate," refers to an
`
`oxidized glucose residue, also known as a gluconic acid residue. The gluconic acid
`
`residue would have the chemical formula C6H 100 7• The word "hexanoate"
`
`indicates a 6 carbon chain with a carboxy group. The 2(R),3(S), 4(R), and S(R)
`
`designations refer to the chirality of the 2, 3, 4, and 5 positions along the 6 carbon
`
`gluconic acid residue. Like the polyglucose component, the gluconic acid residue
`
`component is depicted in Figure I. As shown in Figure I (top structure and middle
`
`structure), the gluconic acid residue binds directly to the iron core.
`
`29. Geisser describes, in his working examples, the way to make and use iron
`
`carboxymaltose having the chemical name "polynuclear iron (III)- hydroxide 4(R)(cid:173)
`
`(poly-(l ---74 )-0-a-glucopyranosyl)-oxy-2(R),3(S ),5(R),6-tetrahydroxy-hexanoate",
`
`as recited in claim 12(ii). The name used by Geisser ("oxidized maltodextrin") is
`
`another way of describing the carbohydrate part of the structure named in claim
`
`12(ii).
`
`30.
`
`In my view, the carboxymethylated reduced dextran disclosed in Groman is
`
`structurally analogous to the carboxymaltose disclosed in Geisser. Groman
`
`discloses the carboxymethylation of reduced dextran that would result in reduced
`
`Active 19556628.2
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`19
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`Pharmacosmos, Exh. 1013, p. 21
`
`
`
`dextran molecules having carboxymethyl groups throughout their structure (as
`
`discussed above, a type ofpolyglucose sorbitol carboxymethyl ether with primarily
`
`a-1-6 glycosidic linkages). Groman discloses that iron carboxymethylated reduc
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