UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`
`
`PHARMACOSMOS A/S,
`Petitioner,
`
`v.
`
`LUITPOLD PHARMACEUTICALS, INC.,
`Patent Owner.
`
`
`
`_______________
`
` Cases1 IPR2015-01490; Patent 7,754,702 B2
` IPR2015-01493; Patent 8,431,549 B2
`____________________________________________________________
`
`CORRECTED DECLARATION OF DR. ADRIANA MANZI
`
`
`
`
`1 The word-for-word identical paper is filed in each proceeding identified in the
`
`heading.
`
`
`
`4830-3717-4576.1
`
`Luitpold Pharmaceuticals, Inc., Ex. 2080
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`IPR2015-01490; IPR2015-01493
`
`
`
`Declaration of Dr. Manzi
`
`TABLE OF CONTENTS
`
`
`
`I. 
`
`II. 
`
`QUALIFICATIONS ........................................................................................ 1 
`
`OVERVIEW .................................................................................................... 3 
`
`III.  THE ’702 and ’549 PATENTS ....................................................................... 8 
`
`IV.  PERSON OF ORDINARY SKILL IN THE ART ........................................ 11 
`
`V. 
`
`PATENT OWNER RESPONSE ................................................................... 12 
`
`A. 
`
`B. 
`
`C. 
`
`D. 
`
`E. 
`
`F. 
`
`“substantially non-immunogenic carbohydrate component” .............. 13 
`
`“iron sorbitol complex” does not include “iron polyglucose
`sorbitol carboxymethyl ether complex” .............................................. 16 
`
`“iron carboxymaltose complex” .......................................................... 19 
`
`van Zyl-Smit ........................................................................................ 20 
`
`1. 
`
`2. 
`
`3. 
`
`van Zyl-Smit does not teach a “substantially non-
`immunogenic carbohydrate component” .................................. 20 
`
`van Zyl-Smit’s sample size is not large enough to
`demonstrate “substantial non-immunogenicity” ....................... 21 
`
`The results of van Zyl-Smit are not generalizable to iron
`polymaltose ............................................................................... 22 
`
`Funk ..................................................................................................... 23 
`
`Groman ................................................................................................ 26 
`
`1. 
`
`2. 
`
`3. 
`
`Groman’s complex is not an “iron sorbitol complex” .............. 26 
`
`Groman does not teach a rate of administration of “about
`15 minutes or less” .................................................................... 27 
`
`The complexes of Groman and Geisser are not
`“structurally analogous” ............................................................ 28 
`i
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`4830-3717-4576.1
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

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`IPR2015-01490; IPR2015-01493
`
`
`
`Declaration of Dr. Manzi
`
`VI.  PATENT OWNER’S MOTION TO AMEND ............................................. 30 
`
`A. 
`
`B. 
`
`State of the Art .................................................................................... 32 
`
`Prior Art of Record .............................................................................. 35 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`6. 
`
`Art Relating Specifically to Iron Dextran Complexes .............. 35 
`
`Art Relating Specifically to Restless Leg Syndrome ............... 36 
`
`Art Relating Specifically to “Ferumoxytol” ............................. 37 
`
`Art Relating Specifically to Iron Polymaltose Complexes ....... 39 
`
`Art Relating to Other Iron Carbohydrate Complexes ............... 40 
`
`Other .......................................................................................... 43 
`
`VII.  CONCLUSION .............................................................................................. 44 
`
`
`
`4830-3717-4576.1
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`ii
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`IPR2015-01490; IPR2015-01493
`
`
`
`Declaration of Dr. Manzi
`
`I, Dr. Adriana E. Manzi, declare as follows:
`
`I.
`1.
`
`QUALIFICATIONS
`
`
`
`I have been retained by Foley and Lardner LLP to act as an expert witness in
`
`a matter on behalf of its client, Luitpold Pharmaceuticals, Inc. (“Patent Owner”).
`
`The matter is Inter Partes Review No. 2015-01490 of United States Patent No.
`
`7,754,702 by Helenek (“the ’702 Patent”) and Inter Partes Review No. 2015-
`
`01493 of United States Patent No. 8,431,549 by Helenek (“the ’549 Patent”)
`
`brought by Pharmacosmos A/S (“Petitioner”).
`
`2.
`
`I am being compensated for my time in connection with this matter. My
`
`compensation is not dependent on the outcome of this matter.
`
`3.
`
`I earned a “Licenciature” degree (five-year program equivalent to a
`
`combination of Bachelor and Master of Science degree focusing on Food Sciences
`
`and Industrial Chemistry) and a Ph.D. degree in organic chemistry from the
`
`University of Buenos Aires, in Argentina. My Doctoral Thesis focused on the
`
`study of plant polysaccharides and the relationship between their structure and
`
`properties. I conducted four years of postdoctoral research in biochemistry and
`
`glycobiology at the Cancer Center, Department of Medicine, University of
`
`California San Diego followed by seven years as an Adjunct Assistant Professor.
`
`In parallel, I was the Director of the Glycobiology Core Facility, that conducted
`
`4830-3717-4576.1
`
`1
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`IPR2015-01490; IPR2015-01493
`
`
`
`Declaration of Dr. Manzi
`
`carbohydrate analysis for University of California investigators as well as external
`
`institutions and the private sector.
`
`4.
`
`A copy of my curriculum vitae (“CV”) is Exhibit 2057. As reflected in my
`
`CV, I have significant expertise in carbohydrate chemistry and biochemistry
`
`(glycobiology) as well as in the development of pharmaceutical products. I have
`
`worked on research on plant and animal polysaccharides as well as carbohydrate-
`
`containing natural molecules from 1978 to 1998. From 1998 to 2006, I worked on
`
`the development of carbohydrate therapeutics (for inflammation and
`
`xenotransplantation) at positions of increasing responsibilities at the Baxter
`
`International group. During this period I worked on glycoconjugates (molecules
`
`containing carbohydrates and peptides or lipids), polysaccharide solutions for
`
`dialysis (i.e., icodextrin based), and polysaccharide vaccines as well as natural and
`
`recombinant glycoproteins for different indications. I have been involved in many
`
`projects encompassing carbohydrate-containing molecules, including the
`
`evaluation of antigenicity of these molecules, and have encountered many issues
`
`related to the isolation of natural polysaccharides. Ex. 2057, pp. 3-5.
`
`5.
`
`Since 2006, as part of my consulting work, I supported many projects
`
`related to carbohydrate-containing molecules from polysaccharides to
`
`glycoproteins and glycolipids. My work includes all CMC (chemistry
`
`manufacturing and controls) aspects of carbohydrate-containing molecules,
`2
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`4830-3717-4576.1
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`IPR2015-01490; IPR2015-01493
`
`
`
`Declaration of Dr. Manzi
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`including molecular characterization, synthesis and/or isolation from natural
`
`sources as well as expression on cells (i.e., bacterial, mammalian, insect, yeast,
`
`etc.), development of analytical methods for testing these molecules, evaluation of
`
`their stability, formulation, and establishing specifications. Ex. 2057, pp.1-3.
`
`6.
`
`As part of my responsibilities, I also support clients’ writing technical
`
`opinion papers. I have also assisted in filings for regulatory agencies and
`
`participated in meetings with regulators. Ex. 2057, p. 2.
`
`II. OVERVIEW
`7.
`In this Declaration, I provide opinions relating to (1) the prior art cited by
`
`Petitioner in the instituted grounds of the inter partes review (for the Patent Owner
`
`Responses) and (2) the prior art cited by Petitioner and of record in the prosecution
`
`of the ’702 and ’549 patents (for Patent Owner’s Motions to Amend). In preparing
`
`this Declaration, I reviewed and considered the ’702 and ’549 patents, the Petitions
`
`for Inter Partes Review,2 and the material listed in paragraph 8 below in light of
`
`my general knowledge.
`
`
`2 Cites to the two petitions are provided as Petition, p. [cite, IPR2012-
`
`01490]/Petition, p. [cite, IPR2012-01493]. Where only one Petition or Declaration
`
`
`
`4830-3717-4576.1
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`3
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

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`IPR2015-01490; IPR2015-01493
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`
`
`Declaration of Dr. Manzi
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`8.
`
`In formulating my opinions I have relied upon my experience and have
`
`considered the viewpoint of a person of ordinary skill in the art (“POSITA”) as of
`
`January 2006. I have also considered the following documents, listed in numerical
`
`order of presentation in IPR2015-01490 3:
`
`Exhibit No.
`IPR2015-01490
`
`Exhibit No.
`IPR2015-01493
`
`Description
`
`1001
`
`1003
`
`1004
`
`1039
`
`1044
`
`1003
`
`U.S. Patent No. 8,431,549 (“the ’702 patent”)
`
`WO 2004/037865 (English translation) (“Geisser”)
`
`U.S. Publication No. 2003/0232084 (“Groman”)
`
`
`is referred to, the relevant text includes a clause specifying which IPR is referred
`
`to.
`
`3 The exhibit numbering in prior filings is not identical between the two instituted
`
`IPRs; thus, cites where exhibit numbers differ between the two proceedings are
`
`given as Ex. [IPR2015-01490 No.]/[IPR2015-01493 No.], [citation].
`
`4830-3717-4576.1
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`4
`
`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`

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`IPR2015-01490; IPR2015-01493
`
`
`
`Declaration of Dr. Manzi
`
`Exhibit No.
`IPR2015-01490
`
`Exhibit No.
`IPR2015-01493
`
`Description
`
`1005
`
`1006
`
`1007
`
`1009
`
`1011
`
`1014
`
`1017
`
`1021
`
`1023
`
`1026
`
`1014
`
`1004
`
`2004
`
`1007
`
`1013
`
`1021
`
`1016
`
`1029
`
`2053
`
`1047
`
`Declaration of Robert Linhardt4
`
`van Zyl-Smit et al. Nephron 92:316-323 (2002)
`(“van Zyl-Smit”)
`
`Prosecution History of ’702 patent
`(only pp. 94-117 and 282-333)
`
`U.S. Publication No. 2004/0180849 (“Helenek”)
`
`Spinowitz et al. Kidney Int’l 68:1801-1807(2005)
`(“Spinowitz”)
`
`U.S. Patent No. 7,612,109
`
`U.S. Patent No. 6,599,498 (“the ’498 patent”)
`
`Excerpt of Prosecution History of European Patent
`Application EP1973549
`
`British Pharmacopoeia Monograph for iron
`sorbitol (2003)
`
`Funk et al. Hyperfine Interactions 136:73-
`95(2001) (“Funk”)
`
`
`4 These two exhibits are not identical; rather, they both reflect opinions on the
`
`same issues from Dr. Robert J. Linhardt. Where the same statements occur at
`
`different places, the cites are given as Ex. 1005, [cite, IPR2012-01490]/ Ex. 1014,
`
`[cite, IPR2012-01493].
`
`4830-3717-4576.1
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`5
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`IPR2015-01490; IPR2015-01493
`
`
`
`Declaration of Dr. Manzi
`
`Exhibit No.
`IPR2015-01490
`
`Exhibit No.
`IPR2015-01493
`
`Description
`
`1009
`
`1002
`
`1001
`
`1005
`
`1031
`
`1034
`
`1044
`
`1047
`
`1035
`
`1041
`
`1049
`
`2003
`
`U.S. Patent No. 3,100,202 (“Mueller”)
`
`U.S. Patent No. 5,541,158 (“Vance”)
`
`Neiser et al., Biometals 1-21 (2015)
`
`U.S. Patent No. 8,895,612(“the ’612 patent”)
`
`U.S. Patent No. 8,431,549 (“the ’549 patent”)
`
`Marchasin et al. Blood 23(3):354-358(1964)
`(“Marchasin”)
`
`Geisser et al. Areneim. Forsch./Drug Res.
`41(II)(12):1439-1452 (1992) (“Geisser paper”)
`
`Ferrosig Drug Product Data Sheet, Revised July
`2003
`
`2005
`
`1006
`
`Prosecution History of ’549 patent
`(only pp. 191-238)
`
`2014
`
`2018
`
`2013
`
`2015
`
`2012
`
`2036
`
`2037
`
`2038
`
`Fishbane, Am. J. Kidney Dis. 41(5 Suppl):18-26
`(2003) (“Fishbane”)
`
`Cisar et al. J. Exp. Med. 142(1):435-459 (1975)
`(“Cisar”)
`
`Volhardt, Organic Chemistry, W.H. Freeman Co
`2007 p. 1096-138 (“Vollhardt”)
`
`Fielding et al. British Medical Journal 279-283
`(1961) (“Fielding”)
`
`Kabat et al. J. Immunol. 70:514-531(1953)
`(“Kabat”)
`
`WO 1997/011711 (“Lawrence PCT”)
`
`4830-3717-4576.1
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`6
`
`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`IPR2015-01490; IPR2015-01493
`
`
`
`Declaration of Dr. Manzi
`
`Exhibit No.
`IPR2015-01490
`
`Exhibit No.
`IPR2015-01493
`
`Description
`
`2039
`
`2040
`
`2041
`
`2042
`
`2043
`
`2044
`
`2045
`
`2046
`
`2047
`
`2048
`
`2049
`
`2050
`
`2051
`
`U.S. Patent No. 6,960,571 to Helenek (“the ’571
`patent”)
`
`Landry et al. Am. J. Nephrol. 25(4):400-410
`(2005) (“Landry”)
`
`Beshara et al. Br J Haematol. 120(5):853-9 (2003).
`(“Beshara”)
`
`Haines et al. Internal Med. Journal 39: 252-255
`(2009) (“Haines”)
`
`Newnham et al. Internal Med. Journal 36(10): 672-
`674 (2006) (“Newnham”)
`
`Andersson Br Med J. 2(5247):275-279 (1961).
`(“Andersson”)
`
`Bailie et al. Neprol. Dial. Transplant 20:1443-1449
`(2005) (“Bailie”)
`
`NKF-KDOQI (2000) (“Eschbach”)
`
`MacDougall Neprol. Dial. Transpland 15(Ed.
`Comments):1743-1745 (2000) (“MacDougall”)
`
`Kudasheva et al. J. Inorganic Biochem. 98:1757-
`1769 (2004) (“Kudasheva”)
`
`Van Wyck et al. J. Am Soc Nephrol 15: S91-92,
`S107-S111 (2004)(“Van Wyck”)
`
`U.S. Publication No. 2008/0234226
`
`Sipe et al. Brain Iron Metabolism and
`Neurodegenerative Disorders 24(2-3):188-196
`(2002) (“Sipe”)
`
`4830-3717-4576.1
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`7
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`

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`IPR2015-01490; IPR2015-01493
`
`
`
`Declaration of Dr. Manzi
`
`Exhibit No.
`IPR2015-01490
`
`Exhibit No.
`IPR2015-01493
`
`Description
`
`2052
`
`Sofic et al. J. Neural Transm. 74: 199-205 (1988)
`(“Sofic”)
`
`2054
`
`2055
`
`1010
`
`1008
`
`2081
`
`2082
`
`2083
`
`2084
`
`2085
`
`2086
`
`2087
`
`U.S. Patent No. 5,624, 668 (“Lawrence”)
`
`Hamstra et al. JAMA 243:1726-1731(1980)
`(“Hamstra”)
`
`Walters et al. Nephrol. Dial. Transplant 20:1438–
`1442 (2005) (“Walters”)
`
`Lindvall et al. Brit. J. Pharmacol. 17:358-371
`(1961). (“Lindvall”)
`
`U.S. Provisional Application 60/757,119 (“the
`’119 Application”)
`
`Lam-Po-Tang, et al. Peritoneal Dialysis
`International Jul-Aug 23:405-406 (2003)
`
`Sax, N. I. and Lewis, R. J., Hawley’s Condensed
`Chemical Dictionary, Van Nostrand Reinhold
`Company, Eleventh Ed. (1987), p. 797, 1081-1082
`
`Morris, et al. Journal of Supramolecular Structure
`6:259-274 (1977)
`
`KDOQI Clinical Practice Guidelines and Clinical
`Practice Recommendations for Anemia in Chronic
`Kidney Disease (2006)
`
`
`
`III. THE ’702 and ’549 PATENTS
`9.
`The specifications of the ’702 and ’549 patents and the as-filed
`
`
`
`specifications (Ex. 1007/2005 pp. 282-333 and Ex. 2004/1006 pp. 191-238) are
`
`4830-3717-4576.1
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`8
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`

`
`IPR2015-01490; IPR2015-01493
`
`
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`Declaration of Dr. Manzi
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`substantively identical and detail the need in the art for iron formulations with low
`
`health risk that may be administered in high doses.
`
`10.
`
`In addition to noting the risks associated with iron dextran, the background
`
`section of the specification details that “[a]lthough serious and life-threatening
`
`reactions occur most frequently with iron dextran, they are also known to occur
`
`with other parenteral iron products.” Ex. 1001/1039, p. 4 col. 1:39-41; Ex.
`
`1044/1001, p. 5 col. 1:39-41. Moreover, the specification points out that “non-life
`
`threatening reactions such as arthralgia, back pain, hypotension, fever, myalgia,
`
`pruritus, vertigo, and vomiting” can preclude high dosing of known iron
`
`formulations. Ex. 1001/1038, col. 1:41-46; Ex. 1044/1001, col. 1:42-46.
`
`11.
`
`In discussing further issues with dosing, the specification posits that
`
`“[v]arious pharmacokinetic studies suggest that doses of iron complexes higher
`
`than 200 mg of iron are generally unsuitable and that the conventional therapy
`
`prescribes repeated applications of lower doses over several days. See Geisser et
`
`al., (1992) Arzneimittelforschung 42: 1439-1452.” Ex. 1001/1039, col. 2:9-13; Ex.
`
`1044/1001, col. 2:9-13.
`
`12. The ’702 and ’549 patents relate to a method of treating a disease, disorder,
`
`or condition by administering iron carbohydrate complexes at high doses.
`
`13.
`
`Independent claim 1 of the ’702 patent reads:
`
`4830-3717-4576.1
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`9
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`

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`IPR2015-01490; IPR2015-01493
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`
`
`Declaration of Dr. Manzi
`
`A method of treating a disease, disorder, or condition characterized by
`
`iron deficiency or dysfunctional iron metabolism resulting in
`
`reduced bioavailability of dietary iron,
`
`comprising administering to a subject in need thereof an iron
`
`carbohydrate complex in a single dosage unit of at least about
`
`0.6 grams of elemental iron;
`
`wherein
`
`the iron carbohydrate complex is selected from the group
`
`consisting of an iron carboxymaltose complex, an iron mannitol
`
`complex, an iron polymaltose complex, an iron gluconate
`
`complex, and an iron sorbitol complex; and
`
`the iron carbohydrate complex has a substantially non-
`
`immunogenic carbohydrate component and substantially no
`
`cross reactivity with anti-dextran antibodies
`
`wherein said disease, disorder or condition is not Restless Leg
`
`Syndrome.
`
`Ex. 1001/1039, col. 26:49-67
`
`14.
`
`Independent claim 1 of the ’549 patent reads:
`
`A method of treating a disease, disorder, or condition characterized by
`
`iron deficiency or dysfunctional iron metabolism resulting in
`10
`
`4830-3717-4576.1
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`

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`IPR2015-01490; IPR2015-01493
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`
`
`Declaration of Dr. Manzi
`
`reduced bioavailability of dietary iron, comprising administering to
`
`a subject in need thereof an iron carbohydrate complex in a single
`
`dosage unit of at least about 0.6 grams of elemental iron,
`
`wherein
`
`the iron carbohydrate complex is selected from the group
`
`consisting of an iron mannitol complex, and an iron
`
`polyisomaltose complex, an iron polymaltose complex, an iron
`
`gluconate complex, and an iron sorbitol complex;
`
`the iron carbohydrate complex has a substantially non-
`
`immunogenic carbohydrate component; and
`
`the disease, disorder or condition is not Restless Leg Syndrome.
`
`Ex. 1044/1001, col. 26:49-64.
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`15.
`I understand that the term “a person of ordinary skill in the art” (“POSITA”)
`
`is a patent term designating a hypothetical person who is presumed to have known
`
`the relevant art at the time of the invention. A POSITA is also presumed to be one
`
`of ordinary creativity, not an expert.
`
`16. For the purposes of this proceeding, I understand that the Petitioner has
`
`proposed that the POSITA would hold at least a bachelor’s level degree in
`
`chemistry or biochemistry with some related academic or industrial experience in
`11
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`4830-3717-4576.1
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`

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`IPR2015-01490; IPR2015-01493
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`Declaration of Dr. Manzi
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`the area of carbohydrates and their metal complexes. The ’702 patent Petition, p.
`
`14; the ’549 patent Petition, p. 21. I disagree, however, to the extent that
`
`Petitioner’s “at least” treats one with, say, a Ph.D. as ordinarily skilled just like one
`
`with a B.S.
`
`17. Furthermore, since the patents are directed to methods of treatment, “some
`
`relevant academic or industrial experience” requires some experience in either the
`
`production of biologics for pharmaceutical use or the administration of such
`
`compounds in the context of their pharmaceutical use.
`
`V.
`18.
`
`PATENT OWNER RESPONSE
`I understand that Inter Partes Review of the ’702 patent has been instituted
`
`on the following grounds:
`
`(1) Ground 1 – alleged anticipation of claims 1-3, 10-13, 23, 25, 27, and 41-43
`
`over WO 2004/037865 (“Geisser,” Ex. 1002 , citations to English translation,
`
`provided as Ex. 1003),
`
`(2) Ground 2 – alleged anticipation of claim 28 over US 2003/0232084
`
`(“Groman,” Ex. 1004),
`
`(3) Ground 3 – alleged obviousness of claims 17 and 47 over the combination of
`
`Geisser and Groman,
`
`(4) Ground 4 – alleged anticipation of claims 1, 14, and 15 over van Zyl-Smit (Ex.
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`1006), and
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`4830-3717-4576.1
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`12
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`IPR2015-01490; IPR2015-01493
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`Declaration of Dr. Manzi
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`(5) Ground 5 – alleged obviousness of claim 30 over the combination of van Zyl-
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`Smit and Funk (Ex. 1026) .
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`19.
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`I also understand that Inter Partes Review of the ’549 patent has been
`
`instituted on the following grounds:
`
`(1) Ground 2 – alleged anticipation of claims 1-5, 9, 15, 16, and 19 over van Zyl-
`
`Smit (Ex. 1004), and
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`(2) Ground 3 – alleged anticipation of claims 1 and 12-14 over Groman (Ex. 1003).
`
` “substantially non-immunogenic carbohydrate component”
`
`A.
`I have been informed that the Board has construed the term “substantially
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`20.
`
`non-immunogenic carbohydrate component,” recited in claim 1 of the ’702 and
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`’549 patents, as a carbohydrate component resulting in a “low risk of
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`anaphylactoid/hypersensitivity reactions.” However, it is my opinion that this
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`construction is incomplete.
`
`21.
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`In particular, the Board’s construction does not indicate what “low” risk
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`means. Because the specification disparages iron dextran, it is my opinion that
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`“substantially non-immunogenic,” i.e., “low risk,” should be understood in relation
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`to the adverse events exhibited by iron dextran. For example, the specification
`
`states that iron dextran “the first parenteral iron product available in the United
`
`States (US), has been associated with an incidence of anaphylactoid-type
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`reactions” (Ex. 1001/1039, col. 1:47-49; Ex. 1044/1001, col.1:47-49) and cites
`13
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`IPR2015-01490; IPR2015-01493
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`Declaration of Dr. Manzi
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`Fishbane (Exhibit 2012). Fishbane discloses that “[t]he risk for immediate severe
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`anaphylactoid reactions appears to be, at a minimum, approximately 0.6% with IV
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`iron dextran, and this agent has been associated with a number of deaths during the
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`past several decades.” Ex. 2012, p. 2. Fishbane also references other studies in
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`which anaphylactoid reactions upon intravenous iron dextran administration were
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`at levels of 1.8% and 1.7%. Ex. 2012, p. 2.
`
`22.
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`In this regard, I also reviewed the reference Walters (Ex. 2081), which for
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`iron dextran found that “without regard to severity of reaction, [the] overall per
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`patient adverse drug event (ADE) rate [was] 0.69% (337 out of 48,509) and per
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`exposure rate [was] 0.03% (337 out of 1 066 099).” Ex. 2081, p. 1. Based on
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`Fishbane and Walters, it is my opinion that a POSITA would understand the
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`overall adverse event incidence rate for iron dextran is about 0.6-0.7%, and a
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`POSITA would understand “substantially non-immunogenic” to require an
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`incidence rate lower than that of iron dextran.
`
`23.
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` It is also my opinion that the determination of “substantial non-
`
`immunogenicity,” i.e., having an adverse event incidence rate lower than iron
`
`dextran, requires the administration of the carbohydrate to a cohort large enough to
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`reveal adverse events were they to arise.
`
`24. While the statistical calculations for sample size can be complicated when
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`several variables are included, a simple calculation can illustrate the need for a
`14
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`4830-3717-4576.1
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`IPR2015-01490; IPR2015-01493
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`
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`Declaration of Dr. Manzi
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`sufficiently large sample size. For example, for an adverse event having an
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`incidence rate of 1% and assuming a uniform distribution in the sample population,
`
`a sample size of 100 subjects would theoretically have one subject that exhibits the
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`adverse event. For an adverse event with an incidence rate of 0.5%, a sample size
`
`of 200 subjects will theoretically contain only one subject who exhibits that
`
`adverse event. Based on this simplistic calculation, one can understand that for an
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`adverse event having a low incidence rate of, say, about 0.6%, a large enough
`
`sample size is required to reveal the adverse event, or alternatively, determine that
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`the adverse event is not exhibited.
`
`25.
`
`It is generally understood in the field of iron carbohydrate complexes that
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`the risk for severe anaphylactoid reactions to intravenous iron dextran is about
`
`0.6 %. Ex. 2012, p. 2; Ex. 2081, p. 1. It can be intuitively understood that the
`
`lower the incidence level of an adverse event, the greater the sample size required
`
`to observe that event or to confidently determine the lack of such adverse event.
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`Thus, to learn whether an iron carbohydrate complex has a “substantially non-
`
`immunogenic carbohydrate component” requires a sample size sufficient to reveal
`
`adverse immune effects were they to arise.
`
`26. Spinowitz cautions about the dangers of iron dextran, “which was recalled
`
`by the FDA in 1990,” and warns that “serious adverse reactions to iron dextran
`
`may be induced by relatively low doses.” Ex. 1011/1013, p. 5. Regarding cohort
`15
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`4830-3717-4576.1
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`IPR2015-01490; IPR2015-01493
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`Declaration of Dr. Manzi
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`size, Spinowitz cites his reference “[15]” which turns out to be a 1964 article
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`disclosing intravenous infusions of iron dextran in 37 patients (Marchasin, Ex.
`
`1047/1005, p. 1). Spinowitz also refers to a cohort size of “almost 2400” from a
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`1968 review article compiling different iron dextran studies (Wallerstein, Ex.
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`2014/2015) and characterizes that size as a “relatively small cohort.” Ex.
`
`1011/1013, p. 5. One consequence of a small cohort, says Spinowitz, is that “it is
`
`not possible to accurately describe serious adverse reaction rates.” Ex. 1011/1013,
`
`p. 5. In the same vein and commenting on his own ferumoxytol study (n=21),
`
`Spinowitz reports: “Anaphylaxis and immediate hypotension were not observed in
`
`this small study, but the number of exposures is too small to draw any definitive
`
`conclusions.” Ex. 1011/1013, p. 5. That is, even though those adverse events were
`
`“not observed,” the “too small” size of his ferumoxytol cohort precluded “any
`
`definitive conclusions.” Ex. 1011/1013, p. 5. Thus, Spinowitz recognizes a need
`
`for a sample size that is sufficiently large to reveal the existence of infrequent but
`
`serious adverse reactions.
`
`B.
`
`“iron sorbitol complex” does not include “iron polyglucose
`sorbitol carboxymethyl ether complex”
`27. Claim 1 recites an “iron sorbitol complex.” Ex. 1001/1039, col. 26:61; Ex.
`
`1044/1001, col. 26:59-60. A POSITA would understand the term “sorbitol” to be a
`
`sugar alcohol having the following structure, as seen in an Organic Chemistry
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`4830-3717-4576.1
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`16
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`IPR2015-01490; IPR2015-01493
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`
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`Declaration of Dr. Manzi
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`textbook, an excerpt of which is provided as Exhibit 2015/2018:
`
` (Ex. 2015/2018 (“Vollhardt”), p. 18)
`
`28. Therefore, it is my opinion that the meaning of the term “iron sorbitol
`
`complex” would be understood by a POSITA as referring to “a complex of iron
`
`and sorbitol,” with the structure of sorbitol as shown above. The interpretation of
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`“iron sorbitol complex” as “a complex of iron and sorbitol” is also supported by
`
`(“Lindvall”), titled “Studies on a new Intramuscular Haematinic, Iron-Sorbitol,”
`
`which describes “a complex of iron, sorbitol and citric acid.” Ex. 2082, p. 1. A
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`British Pharmacopoeia listing for iron sorbitol also states that iron sorbitol is a
`
`colloid solution of a complex of “iron (III), Sorbitol and Citric acid, stabilised with
`
`Dextrin and Sorbitol.” Ex. 1023/2053 p. 1. I understand that the Petitioner
`
`construes “iron sorbitol complex” as “a complex of iron and sorbitol
`
`monosaccharide.” Petition, p. 12; Petition, p. 18. I disagree with this construction
`
`to the extent that sorbitol is generally not called a “monosaccharide,” but rather an
`
`alditol or sugar alcohol. Ex. 2015/2018, p. 17. A “monosaccharide” is commonly
`
`understood by a POSITA as the monomeric form of a carbohydrate, which has the
`17
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`4830-3717-4576.1
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`IPR2015-01490; IPR2015-01493
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`Declaration of Dr. Manzi
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`general formula CnH2nOn. Ex. 2015/2018, pp. 3-4. Furthermore, Hawley’s
`
`Condensed Chemical Dictionary provides a definition of “monosaccharide” as
`
`“[a]ny of several simple sugars having the formula C6H12O6” and a chemical
`
`formula for sorbitol as “C6H8(OH)6.” Ex. 2085, pp. 3, 4.
`
`29.
`
`In my opinion, the term “iron sorbitol complex” does not include an “iron
`
`polyglucose sorbitol carboxymethyl ether complex.” Based on the specifications
`
`of the ’702 and ’549 patents, a POSITA would understand the term “iron
`
`polyglucose sorbitol carboxymethyl ether complex” to refer to ferumoxytol. Ex.
`
`1001/1044, col. 13:31-47; Ex. 1001/1039, col.13:27-44. Further, consistent with
`
`the reference to ferumoxytol and the references cited in the ’702 and ’549 patents,
`
`an iron polyglucose sorbitol carboxymethyl ether complex is generally understood
`
`by a POSITA to mean iron complexed to glucose polymer (“polyglucose”) where
`
`the terminal glucose monomer is reduced (“sorbitol”) and carboxymethylated
`
`(“carboxymethylether”). An “iron polyglucose sorbitol carboxymethyl ether
`
`complex” cannot be understood by a POSITA to be an “iron sorbitol complex.”
`
`30.
`
`I understand that the Patent Owner made arguments during prosecution of
`
`the corresponding European application, indicating that ferumoxytol is an “iron
`
`sorbitol complex.” Ex. 1021/1029, p. 3. However, I believe that a POSITA would
`
`understand these arguments to be scientifically inaccurate in view of the
`18
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`IPR2015-01490; IPR2015-01493
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`Declaration of Dr. Manzi
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`understanding of the terms “iron sorbitol complex” and “iron polyglucose sorbitol
`
`carboxymethyl ether complex.”
`
`31.
`
`I understand that in U.S. Patent No. 8,895,612 (Ex. 1041), a patent in the
`
`same family as the ’702 and ’549 patents, “iron polyglucose sorbitol
`
`carboxymethyl ether complex” is recited in claim 1 as a distinct and separate
`
`species from “iron sorbitol complex,” which is consistent with an understanding of
`
`the two complexes being distinct from each other.
`
`C.
`“iron carboxymaltose complex”
`32. This paragraph relates to IPR2015-01490. The claims of the ’702 patent
`
`recite the iron carbohydrate complex “iron carboxymaltose complex.” It is my
`
`opinion that the Petitioner’s expert is correct in his description of carboxymaltose
`
`as “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 -1-4
`
`glycosidic bond.” Ex. 1005 in IPR2015-01490, p. 7. Thus, the C-1 position of the
`
`reducing end monosaccharide is carboxylated. Ex. 1005 of IPR2015-01490, p. 28,
`
`Figure H. It is also my opinion that a POSITA would understand that because the
`
`iron carboxymaltose complex is a part of claim 1, it must have a “substantially
`
`non-immunogenic carbohydrate component.”
`
`19
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`4830-3717-4576.1
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`Luitpold Pharmaceuticals, Inc., Ex. 2080
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`

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`IPR2015-01490; IPR2015-01493
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`
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`Declaration of Dr. Manzi
`
`D.
`van Zyl-Smit
`I understand that the Board instituted inter partes review as to claims 1