UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`PHARMACOSMOS A/S,
`Petitioner,
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`LUITPOLD PHARMACEUTICALS, INC.,
`Patent Owner.
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`IPR2015-01490; Patent 7,754,702 B2
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`PETITIONER’S OPPOSITION TO PATENT OWNER’S
`MOTION TO AMEND
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`PHARMACOSMOS A/S,
`Petitioner,
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`v.
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`LUITPOLD PHARMACEUTICALS, INC.,
`Patent Owner.
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`IPR2015-01490; Patent 7,754,702 B2
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`PETITIONER’S OPPOSITION TO PATENT OWNER’S
`MOTION TO AMEND
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`IPR2015-01490
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`TABLE OF CONTENTS
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`I.
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`INTRODUCTION ............................................................................................... 1
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`II. ARGUMENT ...................................................................................................... 3
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`A. The Substitute Claims Are Not Supported By The Specification ................. 3
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`1. The Claims Are Not Enabled Or Adequately Described ........................... 3
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` a). VIT-45 ........................................................................................................... 3
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` b). Iron Mannitol, Iron Gluconate And Iron Sorbitol ......................................... 4
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` c). Any Subject/Any Route................................................................................. 6
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` d). Iron Core Size No Greater Than About 9 nm ............................................... 7
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`2. The Substitute Claims Are Indefinite ......................................................... 9
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`3. The Claims Are Unpatentable Under 35 U.S.C. § 112 ............................ 10
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`B. The Amended Claims Are Obvious ............................................................ 11
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`1. The Proposed Substitute Claims Are Obvious Over Geisser in View of
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`van Wyck........................................................................................................... 12
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`2.
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`It Would Have Been Obvious To Copy Prior Art Stable Iron
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`Carbohydrate Complexes With Iron Core Diameters Less Than 9 nm ............ 15
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`3.
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`Patent Owner Has Not Distinguished Restless Leg Syndrome Art ......... 18
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`4.
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`Patent Owner Has Not Distinguished Dextran-Related Art .................... 20
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`5. Additional Art Not Properly Considered ................................................. 24
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`III. CONCLUSION .............................................................................................. 25
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`EXHIBITS RELIED UPON
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`Description
`United States (U.S.) Patent No. 7,754,702 (“the ‘702 patent”)
`Certified
`translation of
`International Patent Publ. No.
`WO2004037865 (“Geisser”)
`Declaration of Robert Linhardt
`van Zyl-Smit and Halkett (2002) Nephron 92:316-323 (“van Zyl-
`Smit”)
`Spinowitz et al. (2005) Kidney Int’l. 68:1801-1807 (“Spinowitz”)
`F.D.A. Orange Book Listing for Injectafer® injection
`F.D.A. Advisory Committee Briefing Document on NDS-22-054
`for Injectafer®, February 1, 2008
`Patent Term Extension Application for the ‘109 patent
`U.S. Patent No. 6,599,498 (“the ‘498 patent”)
`Funk et al. (2001) Hyperfine Interactions 136:73-95 (“Funk”)
`Jahn et al. (2011) Eur. J. Pharma and Biopharma 78:480-91
`Neiser, 2015, Biometals 1-21 (“Neiser 2015”)
`Marchasin, 1964, Blood 23:354-358 (“Marchasin”)
`Danielson (2004) Structure, Chemistry, and Pharmacokinetics of
`Intravenous Iron Agents, Journal of the American Society of
`Nephrology 15:593-598
`Adriana Manzi Second Corrected Declaration
`Transcript of May 2016 Deposition of Dr. Adriana Manzi
`Wang et al., JAMA. 314(19):2062-2068 (2015) (“Wang”)
`Wang et al., JAMA. 314(19):2062-2068 (2015), Supplementary
`Content (“Wang Supplementary Content”)
`Keating, Drugs 75(1):101-127 (2015) (“Keating”)
`Presentation from the Galencia Group
`Charles River monograph for C57BL/6 mice
`Webpage for the San Diego zoo
`Egeli et al., 1999, Res. Vet. Sci. 66(3):179-184
`Document regarding Imferon®’s recall
`U.S. Patent Publication No. 2006/0116349
`Geisser et al. Drug. Res. 41(1):32-37 (1991) (“Geisser 1991”)
`Fishbane, Am. J. Kidney Dis. 41(5 Suppl):18-26 (2003)
`(“Fishbane”)
`U.S. Patent No. 6,960,571 (“the ‘571 patent”)
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`Exhibit No.
`1001
`1003
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`1005
`1006
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`1011
`1012
`1013
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`1015
`1017
`1026
`1029
`1035
`1047
`1048
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`1053
`1054
`1055
`1056
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`1057
`1059
`1060
`1061
`1062
`1063
`1064
`1065
`2012
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`2039
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`2041
`2048
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`2049
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`2080
`2081
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`Beshara et al. Br J Haematol. 120(5):853-9 (2003) (“Beshara”)
`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”)
`Declaration of Dr. Adriana Manzi
`Walters et al. Nephrol. Dial. Transplant 20:1438–1442 (2005)
`(“Walters”)
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`I.
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`INTRODUCTION
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`Patent Owner has failed to meet its burden of proving that its proposed
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`substitute claims are patentable. Importantly, Patent Owner has not followed the
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`Board’s directive to establish, under controlling precedent, how the substitute
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`claims find support and why such claims are patentable over the prior art. Instead,
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`Patent Owner has chosen to propose overbroad and fatally indefinite claims which
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`are neither enabled nor adequately described.
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`Regarding patentability over the prior art, the proposed substitute claims are
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`rendered obvious by Geisser (Ex. 1003) in view of van Wyck (Ex. 2049),
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`optionally further in view of United States Patent No. 6,599,498 (Ex. 1017) and/or
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`Funk (Ex. 1026). In addition, the proposed claims are unpatentable over prior art
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`relating to Restless Legs Syndrome and/or iron dextran which Patent Owner
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`identified in its Motion but failed to distinguish.
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`But even if they could be considered free of prior art (and they cannot), the
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`substitute claims trample upon the exacting requirements of 35 U.S.C. § 112. The
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`proposed claims use indefinite language and would encompass any species (so
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`there is no frame of reference for “high dose”), any route, and employ prior art
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`agents disparaged by the specification without offering any guidance how to
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`improve upon them.
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`Accordingly, no amendment or substitution of the claims should be allowed.
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`II. BACKGROUND
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`Patent Owner has filed a Motion to Amend (“Motion”) requesting that,
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`should claims fall under Grounds 1-5 of the Petition, they be replaced by one or
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`more of proposed substitute claims 58-74, having received permission from the
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`Board to file such Motion to Amend in an Order dated March 11, 2016 (Paper 22,
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`“Order”). In the Order, the Board reminded Patent Owner that it “has the burden
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`of proof to establish that it is entitled to the requested relief.” Order, 2, citing 37
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`C.F.R. § 42.20(c). The Board further stated that Patent Owner “is required to
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`explain why the claims are patentable over the prior art of record” (citing Microsoft
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`Corp. v. Proxycom, Inc., 789 F.3d 1292, 1307-1308 (Fed. Cir. 2015)) and directed
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`Patent Owner “that it should point to where written description support occurs in
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`the originally filed disclosure for any proposed substitute claim as a whole”
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`(emphasis in original) and “must point out and discuss how the proposed substitute
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`claims are supported by the originally filed disclosure in the body of the motion.”
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`Order, 2, 4.
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`Except for a revision in dependency, the only claim bearing amendments is
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`substitute claim 58, which amends claim 1 by deleting iron polymaltose as a
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`species of iron carbohydrate and adding the limitation, “wherein the iron
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`carbohydrate complex comprises an iron core with a mean iron core size of no
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`greater than about 9 nm.”
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`Patent Owner’s Motion should be denied.
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`II. ARGUMENT
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`For the reasons explained below, the substitute claims, amended as proposed
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`by Patent Owner, are not patentable.
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`A.
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`The Substitute Claims Are Not Supported By The Specification
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`1.
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`The Claims Are Not Enabled Or Adequately Described
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`According to 35 U.S.C. §112, first paragraph (pre-America Invents Act),
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`“[t]he specification shall contain a written description of the invention, and of the
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`manner and process of making and using it, in such full, clear, concise, and exact
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`terms as to enable any person skilled in the art to which it pertains, or with which it
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`is most nearly connected, to make and use the same, and shall set forth the best
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`mode contemplated by the inventor of carrying out his invention.” The substitute
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`claims do not comply with this requirement.
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`a). VIT-45
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`A skilled artisan would understand how generally
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`iron
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`carboxymaltose but would not know how to make an iron carboxymaltose that
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`could be successfully used according to the claims. The specification of the ‘702
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`patent presents a scheme for making iron carboxymaltose that contains a number
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`of variables (Ex. 1001, 3:42-53), taken almost verbatim from Geisser (Ex. 1003),
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`without attribution. Ex. 1005, ¶10. However, there is no guidance given as to how
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`to apply this general method to produce an iron carboxymaltose with the desired
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`properties. The only iron carboxymaltose species used in the working examples is
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`VIT-45. As acknowledged by Patent Owner’s expert, Dr. Manzi, the specification
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`does not disclose how VIT-45 is made. Ex. 1054, 61:8-19. In addition, the
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`formula provided for VIT-45, [FeOx (OH)y(H20)z]n [{(C6H10O5)m(C6H12O7)}l]k,
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`“where n is about 103, m is about 8, l is about 11, and k is about 4,” is incomplete
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`(values for x, y and z are not provided) and incorrect, because the value “103”
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`stated in the specification, claims, and all members of this patent family, appears to
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`correspond to 103 in the formula stated in the Prescribing Information for VIT-45’s
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`commercial embodiment, Injectafer®1, but there is no basis for 103 in the ‘702
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`specification or prosecution history. Ex. 1001, 3:54-56, Ex. 1046, 6. Therefore, a
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`POSITA is not provided with an enabling disclosure to make the only compound
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`demonstrated in the working examples of the ‘702 patent.
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`b).
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`Iron Mannitol, Iron Gluconate And Iron Sorbitol
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`The proposed substitute claims seek to cover use of iron mannitol, iron
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`gluconate, and iron sorbitol, all compounds known in the art. If these compounds
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`were not previously administered at higher single unit dosages according to the
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`1 Injectafer® is the commercial name for VIT-45 (Ex. 1012; Ex. 1013, 6; Ex. 1015,
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`70-71 (Exhibit H)).
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`claims - at least about 0.6 grams (claim 1/substitute claim 58) or the higher doses
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`set forth in claims 10-15 (substitute claims 61-66) - - what has changed that now
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`they can be administered this way? The specification offers no explanation of
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`what needs to be done to make these compounds safe at higher single unit dosages.
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`Petition, 5-6. To use any of these claimed iron carbohydrate species, a POSITA
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`would need to perform undue experimentation in an unpredictable art. In re
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`Wands, 858 F.2d 731 (Fed. Cir. 1988).
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`According to the ‘702 patent specification, parenteral iron products that lack
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`dextran were known to be associated with serious side effects, albeit at lower
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`frequency than iron dextran. Ex. 1001, 1:55-57; Patent Owner Response
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`(“Response”), 2. For example, toxic effects could result from the rate of iron
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`release. Ex. 1006, 7; Ex. 1029, 2. The specification of the ‘702 patent touts VIT-
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`45 as being “more stable that iron gluconate and sucrose” and producing “a slow
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`and competitive delivery of the complexed iron … resulting in an acute toxicity
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`one-fifth that of iron sucrose” and allowing “administration of higher single unit
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`doses over shorter periods of time, than, for example, iron gluconate or iron
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`sucrose.” Ex. 1001, 12:23-32. Iron gluconate is included within the scope of the
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`issued and substitute claims. Even allowing that one embodiment encompassed by
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`a claim may be superior to another, what disclosure enables iron gluconate to be
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`safely used at higher doses? According to Danielson’s 2004 review of intravenous
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`iron agents, ferric gluconate was administered at doses only up to 250 mg. Ex.
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`1048, 1. Nor does the specification provide any helpful information regarding use
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`of iron mannitol or iron sorbitol. The specification fails to enable any of these
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`embodiments.
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`Further, there is no probative evidence that, on the effective filing date of the
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`‘702 patent, Patent Owner was in possession of these purported embodiments of
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`the invention, so that they are not adequately described.
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`c). Any Subject/Any Route
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`Although the working examples of the ‘702 patent and all the prior art
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`previously cited in this IPR relate to parenteral use of iron carbohydrate, it is
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`notable that only claims 41-52 and 55-57 are limited to parenteral administration.
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`It follows that the remaining claims attempt to encompass administration by other
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`routes.2 Patent Owner has failed to explain how any of the claimed compounds
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`could be used via any means of administration whatsoever.
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`Further, none of the claims specify the species of subject being treated,
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`literally encompassing mouse to elephant. Logically, the consequences to a mouse
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`2 “Any route of delivery of the single unit dose of iron carbohydrate complex is
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`acceptable so long as iron from the iron complex is released such that symptoms
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`are treated.” Ex. 1001, 6:48-50.
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`and to an elephant of receiving at least 0.6 grams of iron as a single unit dose
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`would be very different. The laboratory strain of mouse, C57BL/6 weights
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`between 20 and 30 grams. Ex. 1060, 4. According to the website of the San Diego
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`zoo, elephants weight between 6,000 and 15,000 pounds, where one pound equals
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`about 453 grams. Ex. 1061, 2. Administering 0.6 grams of iron to each of these
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`animals would be expected to have very different consequences. That the claims
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`can reach non-human species is relevant, as parenteral iron carbohydrate complex
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`supplementation is used in veterinary medicine.3
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`Based on the working examples and prior art, the dosages recited in the
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`claims would have relevance to human subjects but relevance to non-human
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`subjects is not explored in the specification and there is no direction provided
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`regarding how to use the disclosed methods in non-human subjects. As none of the
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`claims are limited to human subjects, all of the claims are unpatentable for lack of
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`enablement and lack of written description.
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`d).
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`Iron Core Size No Greater Than About 9 nm
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`The ‘702 patent specification teaches that “[o]ne of the primary determinants
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`of iron bioactivity is the size of the core and the surface area to volume ratio” and
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`3 Egeli et al., 1999, Res. Vet. Sci. 66(3):179-184 discloses administering 180 mg
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`elemental iron as iron dextran subcutaneously to day-old piglets. Ex. 1062, 2.
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`“[g]enerally, the rate of labile iron release in each agent is inversely related to the
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`size of its iron core” (citing van Wyck, Ex. 2049). Ex. 1001, 14:24-44. Further, it
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`teaches that a smaller iron core allows wider distribution and (desirably) donation
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`of iron to transferrin, but also that the smaller the core the greater the amount of
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`labile iron and at some point, the particles may be too small to be accessible. Id.,
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`14:45-52. Iron sucrose is advanced as an example of an iron carbohydrate
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`complex having an iron core smaller than VIT-45 (e.g., core size of 2.8 nm for
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`Venofer®, compared to 4.4 nm for VIT-45), where iron sucrose has a less stable
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`complex with iron and five-fold greater acute toxicity than VIT-45. Id., 12:23-34.
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`According to the specification, this lower acute toxicity of VIT-45 allows for
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`higher doses. Id. It follows that an iron core could be too small to avoid toxicity
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`from labile iron, and, therefore, too small to allow higher doses. The proposed
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`amendment to the claims, adding the limitation that the “complex comprises an
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`iron core with a mean iron core size of no greater than about 9 nm” has no
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`minimum value and, therefore, would cover iron core sizes resulting in acute
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`toxicity from labile free iron, which would not be safe to use at high doses. The
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`‘702 patent specification recites a number of ranges that offer a lower limit to core
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`size, which Patent owner chose not to claim. Id., 14:55-59. The Patent Owner has
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`not shown that the specification enables or supports the full scope of the proposed
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`substitute claims. Accordingly none of substitute claims 58-74 should be allowed.
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`2. The Substitute Claims Are Indefinite
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`According to 35 U.S.C. §112, second paragraph (pre-America Invents Act),
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`“[t]he specification shall conclude with one or more claims particularly pointing
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`out and distinctly claiming the subject matter which the applicant regards as his
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`invention.” The proposed substitute claims do not meet this standard.
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`The specification provides no clear boundaries for the meaning of
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`“substantially non-immunogenic carbohydrate component.” In order to compare
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`the claims with the prior art, it has been necessary, in this IPR, for Petitioner to
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`construe this term. Petitioner’s construction of “substantially non-immunogenic
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`carbohydrate component” requires assessment of the immunogenicity of the
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`carbohydrate component, rather than the complex as a whole. Petition, 13. In
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`related IPR2015-01493, the Board has preliminarily agreed with Petitioner,
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`remarking that the specification highlights the relationship between anaphylactoid
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`reactions and antibodies toward the dextran moiety and focuses on “obtaining a
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`carbohydrate component that can overcome these deficiencies associated with a
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`dextran moiety.” Decision (Paper 11) (IPR2015-01493), 6-7. In the IPR2015-
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`01493 proceeding, “substantially non-immunogenic carbohydrate component” has
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`further been preliminarily construed to be a carbohydrate component resulting in a
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`“low risk of anaphylactoid/hypersensitvity reactions,” implicitly less than prior art
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`dextran. Id.
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`In its Response to the Petition, Patent Owner has pointed out that it is not
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`clear what “low risk” means and has argued that a POSITA would understand that
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`a “low risk” of adverse events would be less than 0.6-0.7%. Response, 7. On the
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`first point, Petitioner agrees that the definition of “low risk” is unclear, but that
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`lack of clarity stems from the deficient specification of the ‘702 patent. As to the
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`second point that an arbitrary threshold should be set, Petitioner disagrees and
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`finds Patent Owner’s conclusion to be improperly based on adverse events caused
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`by the complex as a whole and, in any case, unsupported by the specification.
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`Patent Owner improperly looks outside the specification to arrive at this arbitrary
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`numerical value, consulting one reference cited in the specification (Fishbane, Ex.
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`2012) and another which is not (Walters, Ex. 2081). That Patent Owner should
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`need to look so far to find support illustrates the deficiency in the specification.
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`Patent Owner’s expert, Dr. Manzi, confirmed that the specification does not define
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`“substantially non-immunogenic” and “does not provide the value of the
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`percentage of drug adverse events that occur upon administration of the
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`carbohydrate component of any of the iron carbohydrate complexes” disclosed.
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`Ex. 1054, 51:8-21, 63:13-18.
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`3.
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`The Claims Are Unpatentable Under 35 U.S.C. § 112
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`For the reasons set forth above, all proposed substitute claims 58-74 are
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`indefinite, lack written description, and are unenabled, so that they are
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`unpatentable under 35 U.S.C. § 112 and should be refused. For the same reasons,
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`claims currently involved in this IPR proceedings containing one or more of the
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`above terms, including claims 1-3, 10-15, 17, 23, 25, 27, 28, 30, 41-43, and 47
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`should also be deemed unpatentable. Petitioner further requests that the claims not
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`challenged in this IPR proceeding but which contain one or more of the above
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`terms, including claims 4-9, 16, 18-22, 24, 26, 29, 31-40, 44-46, and 48-57 be
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`deemed invalid under 35 U.S.C. §112 and cancelled.
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`B.
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`The Amended Claims Are Obvious
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`If Patent Owner’s Motion to Amend is being considered, presumably at least
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`claim 1 has been deemed unpatentable, and fallen to challenge based on Geisser or
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`van Zyl-Smit. Patent Owner hopes that by eliminating iron polymaltose and
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`adding a limitation regarding iron core size, its prior art problems will disappear.
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`However, as demonstrated below, Patent Owner’s adding the limitation regarding
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`core size is like giving snow in the winter, obvious over the art.
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`Patent Owner contends that the “threshold for obviousness here is high,”
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`alleging that fear of anaphylaxis to dextran discouraged high doses and that a large
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`cohort would be needed to assess adverse events. Petitioner disagrees. Whether or
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`not a high dose can be given relates to labile iron toxicity, not anaphylaxis. 1001,
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`1:28-2:1, 8:12-17; Ex. 2049, 3.
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`importantly, Patent Owner has
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`mischaracterized the use of iron supplements circa 2006, which did employ higher
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`doses, albeit less frequently than the 100-200 mg elemental iron cited by Patent
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`Owner. Frequent use of a lower dose, with occasional (successful) administration
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`of higher doses, is not “teaching away” from higher doses and does not render
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`administration of higher doses patentable and ripe for claiming. This point will be
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`discussed more fully in the section discussing dextran-related art, below. The
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`references cited by Petitioner - Geisser teaching 500-1,000 mg single unit doses,
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`van Zyl-Smit teaching 900-3,200 mg single unit doses, illustrate that higher doses
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`of elemental iron were known and used in the art. Prior art iron carbohydrate
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`complexes known to have desirable iron release profiles were smaller than 9 nm.
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`An iron core diameter is not a differentiating feature.
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`1.
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`The Proposed Substitute Claims Are Obvious Over Geisser
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`in View of van Wyck
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`Geisser discloses
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`iron carboxymaltose complexes for
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`the parenteral
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`(including intravenous) treatment of iron deficiency anemia, which, because of
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`high complex stability (and consequently low toxicity) can be used at high single
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`doses (for example, 500 to 1,000 mg) meeting, for reasons detailed in the Petition,
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`all the limitations of claims 1-3, 10-13, 23, 25, 26, 27, and 41-43 of the ‘702
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`patent. Petition, 16-18, 22-38. Patent Owner now seeks to add the limitation that
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`the iron core size, in the iron carbohydrate complex, is “no greater than about 9
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`nm.”
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`TThe ‘702 ppatent sets
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`this 9 nmm thresholdd as a bouundary deffining the
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`iron
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`core, annd provides, as its raationale, that “[g]enerrally, the rrate of labiile iron rellease
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`in each
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`agent is innversely reelated to thhe size of itts iron corre,” citing vvan Wyck,, Ex.
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`2049. TThe ‘702 ppatent sets
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`forth the rrange of iroon core sizzes most b
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`roadly as ““less
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`than aboout 9 nm bbut greater
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`than abouut 1 nm, aboout 2 nm …….” Ex. 1
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`001, 14:544-59.
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`There iis no data
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`suggestinng that theese boundaaries weree derived tthrough Paatent
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`Owner’s experimeentation, annd van Wyyck is, apprropriately,
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` credited.
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`FFigure 1 off van Wycck (Ex. 20049, 6) is
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`reproduceed below,
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`and showss the
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`relationshhip betweenn surface
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`area to voolume ratioo and coree radius. NNote
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`inverse
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`that the
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`curve platteaus for core radii ggreater thann 4 or 5 nmm (core diaameters greeater
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`than 8 oor 10 nm).
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`Accordiing to van
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`on sucrose ate and iroWyck, iroon glucona
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`are associiated with
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`high
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`levels oof labile iroon. Id. Inn view of ttheir undessirable leveels of labi
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`le iron andd the
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`relationship between increased core size and improved stability, a POSITA would
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`have been motivated to favor particles with a larger iron core size than ferric
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`gluconate or iron sucrose, i.e., core radii greater than about 2 nm (which would
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`have core diameters greater than about 4 nm). Based on Figure 14 of van Wyck,
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`the surface area to volume ratio doesn’t change very much once the radius exceeds
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`5-6 nm (diameter exceeding 10-12 nm).
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`Petitioner asserts that in view of Geisser and van Wyck, it would have been
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`obvious to make iron carboxymaltose with an iron core diameter greater than 4 nm
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`(based on Figure 1 of van Wyck) but less than 9 nm with a reasonable expectation
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`that it would have low labile iron-associated toxic effects and therefore could be
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`used at high doses.
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`A POSITA would have been motivated to combine Geisser with van Wyck
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`because Geisser indicates that use at high doses requires increased stability (Ex.
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`1001, 1:28 to 2:1) and van Wyck’s focus is the physical characteristics of iron
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`carbohydrate complexes that promote stability. Ex. 2049, 5. Further, Patent
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`4 The core size presented in Figure 1 of van Wyck was obtained from Kudasheva
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`(Ex. 2048) and is provided in nm, i.e., the average core size “was approximately 3
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`± 2 nm for the iron-sucrose, and approximately 2 ± 1 nm for the iron-gluconate.”
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`Ex. 2048, 1 (Abstract).
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`Owner’s citation of van Wyck in the ‘702 patent is an admission that it is relevant
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`art.
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`2.
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`It Would Have Been Obvious To Copy Prior Art Stable
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`Iron Carbohydrate Complexes With Iron Core Diameters Less Than 9 nm
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`In addition to the disclosure of van Wyck, a POSITA would also have been
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`aware that iron carbohydrate complexes that were regarded as having favorable
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`“labile iron” properties had iron cores that happened to be smaller than about 9 nm.
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`These would include ferumoxytol, acknowledged by Patent Owner to be in the
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`prior art (Ex. 1001, 13:33-47, citing U.S. Patent No. 6,599,498 (Ex. 1017)), and
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`having an iron core size of between 6.2 and 7.3 nm (Ex. 1001, 13:48-505), and iron
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`dextrin, which, according to Funk (Ex. 1026), has an iron core size6 of about 4.1
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`5 Iron core size is referred to as crystal size in the ‘702 patent which is the same as
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`iron core size according to Funk. Ex. 1026, 3, 4 (Table 1), 8.
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`6 Although Patent Owner’s expert, Dr. Manzi, in ¶43 of the original version of her
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`Declaration (Ex. 2080) stated that “[t]hese measurements correspond to the size of
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`the entire particle, not the iron core” prior to her cross-examination corrected her
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`declaration to state “[i]t is unclear from Funk if these measurements correspond to
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`the size of the entire particle, or the iron core” (Ex. 1053, ¶43, emphasis added).
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`In her cross-examination, Dr. Manzi explained that “this change better represented
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`nm. Ex. 1026, 4 (Table 1). Either or both of U.S. Patent No. 6,599,498 and/or
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`Funk could be added to the disclosures of Geisser and van Wyck to reinforce the
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`POSITA’s expectation that a particle size which is less than about 9 nm would
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`confer favorable labile iron properties and enable use at high doses of iron
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`carboxymaltose. In other words, a POSITA would have known, based on van
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`Wyck, that iron core size was relevant to labile iron release, and would have been
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`motivated to use an iron core size similar to that found in a prior art iron
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`carbohydrate complex with low free iron toxicity (that could be used at high doses)
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`- such as ferumoxytol (6-7 nm) or iron dextrin (4.1 nm), with a reasonable
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`expectation of success. Both of these values are lower than 9 nm.
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`Patent Owner has not established any criticality for 9 nm, which absent
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`evidence to the contrary appears to be an arbitrary figure chosen to include useful
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`compounds already known in the art, as well as VIT-45. If it would have been
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`[her] conclusions.” Ex. 1054, 30:1-16. Dr. Manzi further admitted that the X-ray
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`diffraction technique used by Funk could be used to measure the iron complex core
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`size, and further that post-filing publication Neiser 2015 (Ex. 1035) refers to Funk
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`as teaching iron core size. Ex. 1054, 82:16-83:4, 85:12-20; See also Ex. 1035, 9.
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`Petitioner asserts that the weight of the evidence favors Funk teaching iron core
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`size, so that Petitioner’s interpretation of Funk is correct.
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`obvious to a POSITA to make iron carboxymaltose with an iron core size ranging
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`between 4 and 7 nm, and administer it at doses greater than 600 mg, the claims
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`should not be rendered non-obvious for reciting an arbitrary upper size limit.
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`Patent Owner has said that there was no motivation in Geisser “to alter iron
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`core size to contravene dosing conventions.” This statement fails to acknowledge
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`that Geisser teaches use of high doses of iron carboxymaltose. Ex. 1003, 14-17.
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`Second, Geisser does state that to safely administer higher doses, stability is
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`important, providing the motivation to look to van Wyck’s disclosure regarding
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`iron core size. Id., 1:28 to 2:2. van Wyck is mentioned but not discussed in Patent
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`Owner’s Motion, dismissed among a list of references that purportedly do not
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`“teach high dose administration of the iron carbohydrate complexes claimed.”
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`Motion, 20. Patent Owner is adding a core size in hopes of conferring patentability
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`to its substitute claims; it would seem that van Wyck would have merited more
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`discussion.
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`Patent Owner fails to make a prima facie case for the relief requested and
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`fails to meet its burden to demonstrate the patentability of the claims over Geisser
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`and van Wyck, optionally further in view of U.S. Patent No. 6,599,498 and/or
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`Funk. As such, the proposed amended/substitute claims, including claims 58-73,
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`should be deemed obvious under 35 U.S.C. § 103 and not be allowed. Further, for
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`reasons set forth in its Petition, Groman (Ex. 1004) can be combined with Geisser
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`(which teaches that high stability enables rapid administration, Ex. 1003, 3:26-30
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`to 4:1, 8:16-17), van Wyck, and optionally the ‘498 Patent and/or Funk to render
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`claim 74 unpatentably obvious. Idle Free Systems, Inc. v. Bergstrom, Inc.,
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`IPR2012-0027 (PTAB June 11, 2013) (Paper 26), 37-38.
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`3.
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`Patent Owner Has Not Distinguished Restless Legs
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`Syndrome Art
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`In its Motion, Patent Owner identifies United States Patent No. 6,960,571
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`(Ex. 2039; “the ‘571 patent”) but purports to distinguish it from the substitute
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`claims, pointing out that Restless Legs Syndrome (“RLS”) has been carved out in
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`claim 1 and substitute claim 58, and contending that “Helenek further teaches that
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`the iron carbohydrate administration for RLS is different than administration for
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`other indications” (without explaining how). Motion, 18-19.
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`Claim 1 and substitute claim 58 indeed carve out RLS, but novelty is not the
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`sole determinant of patentability. Petitioner asserts that the claims are rendered
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`obvious by the ‘571 patent, which shares inventors with the ‘549 patent and
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`contains similar language.
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`According to the ‘571 patent, RLS is associated with lack of iron and
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`reduced dopamine synthesis in the brain. Ex. 2039, 2:4-6. RLS can be idiopathic,
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`but can also occur as a result of iron deficiency, in which case treating the
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`underlying iron deficiency “can reduce or eliminate symptoms [of RLS].” Id.,
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`3:24-29. As background, the ‘571 patent notes that intravenous iron dextran, at
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`“1000 mg/administration” is used to treat RLS, b
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