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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`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 REPLY TO PATENT OWNER RESPONSE
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`________________________
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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 REPLY TO PATENT OWNER RESPONSE
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`TABLE OF CONTENTS
`INTRODUCTION ............................................................................................ 1
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`I.
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`II. BACKGROUND .............................................................................................. 1
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`III. SUMMARY OF ARGUMENT ........................................................................ 4
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`IV. PERSON OF ORDINARY SKILL IN THE ART ........................................... 8
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`V. CLAIM CONSTRUCTION .............................................................................. 8
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`A.
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`“substantially non-immunogenic carbohydrate component” ........................ 8
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`B.
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`C.
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`“iron sorbitol” .............................................................................................. 11
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`“iron carboxymaltose unit” ......................................................................... 11
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`D. Claim 28 ...................................................................................................... 12
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`VI. PATENT OWNER HAS NOT SUCCESSFULLY REBUTTED GROUNDS
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`FOR INVALIDITY ................................................................................................. 12
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`A. GROUND 1 ................................................................................................. 12
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`B. GROUND 2 ................................................................................................. 15
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`C. GROUND 3 ................................................................................................. 16
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`D. GROUND 4 ................................................................................................. 20
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`E. GROUND 5 ................................................................................................. 23
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`VII. CONCLUSION ............................................................................................... 26
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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”)
`U.S. Patent Application Publication No. 2003/0232084
`(“Groman”)
`Declaration of Robert Linhardt
`van Zyl-Smit and Halkett (2002) Nephron 92:316-323 (“van Zyl-
`Smit”)
`F.D.A. Orange Book Listing for Injectafer® injection
`F.D.A. Advisory Committee Briefing Document on NDS-22-054
`for Injectafer®, February 1, 2008
`U.S. Patent No. 7,612,109 (“the ‘109 patent”)
`Patent Term Extension Application for the ‘109 patent
`U.S. Patent No. 7,871,597 (“the ‘597 patent”)
`Excerpt of prosecution history of U.S. Patent No. 8,895,612 (“the
`‘612 patent”)
`Neiser et al. (2011) Port. J. Nephrol. Hypert. 25(3), 219-224
`(“Neiser”)
`Funk et al. (2001) Hyperfine Interactions 136:73-95 (“Funk”)
`Jahn et al. (2011) Eur. J. Pharma and Biopharma 78:480-91
`(“Jahn”)
`Neiser, 2015, Biometals 1-21 (“Neiser 2015”)
`Prescribing Information for Injectafer®
`Danielson (2004) Structure, Chemistry, and Pharmacokinetics of
`Intravenous Iron Agents, Journal of the American Society of
`Nephrology 15:593-598 (“Danielson”)
`Geisser et al., 1992, Structure / Histotoxicity Relationship of
`Parenteral Iron Preparations, Drug Res. 42(11):1439-1452
`(“Geisser 1992”)
`Dr. Adriana Manzi’s Second Corrected Declaration
`Transcript of May 2016 Deposition of Dr. Adriana Manzi
`June 2005 Press Release for Venofer®
`Fishbane, Am. J. Kidney Dis. 41(5 Suppl):18-26 (2003)
`(“Fishbane”)
`Transcript of March 2016 Deposition of Dr. Robert Linhardt
`Declaration of Dr. Adriana Manzi
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`Exhibit No.
`1001
`1003
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`1004
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`1005
`1006
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`1012
`1013
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`1014
`1015
`1019
`1020
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`1022
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`1026
`1029
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`1035
`1046
`1048
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`1049
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`1053
`1054
`1058
`2012
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`2056
`2080
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`2081
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`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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`Petitioner replies to Patent Owner’s Response to Petitioner’s challenges to
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`the ‘702 patent under Grounds 1-5.
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`Patent Owner has failed to rebut Petitioner’s proof that claims 1-3, 10-15,
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`17, 23, 25, 27, 28, 30, 41-43, and 47 are unpatentable and should be canceled.
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`II. BACKGROUND
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`
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`The problem addressed by the ‘702 patent is that parenteral iron
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`supplementation, a treatment for iron deficiency (e.g., iron deficiency anemia), was
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`known to have health risks and dosage limitations. Ex. 1001, 1:20-34. According
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`to the ‘702 patent, iron dextran had “been associated with an incidence of
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`anaphylactoid-type reactions (i.e., dyspnea, wheezing, chest pain, hypotension,
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`urticaria, angioedema) … believed to be caused by the formation of antibodies to
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`the dextran moiety.” Id., 1:47-54. Other parenteral iron products, the ‘702 patent
`
`notes, were also associated with serious side effects, albeit at lower frequency than
`
`iron dextran. Id., 1:55-57; Response, 2. For example, toxic effects could result
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`from the rate of iron release. Ex. 1006, 7; Ex. 1029, 2.
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`The ‘702 patent allegedly overcomes these problems and allows the use of
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`high doses of
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`iron carbohydrate complexes with only a “low risk of
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`anaphylactoid/hypersensitivity
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`reactions,” offering an
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`iron carboxymaltose
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`complex termed “VIT-45”1 as its only working example. Ex. 1001, 3:15-17, 11:1-
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`2, 15:13-42, 18:1-26:46. In addition to covering iron carboxymaltose, the claims
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`of the ‘702 patent include other species of iron carbohydrate that were already
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`known and used in the prior art: iron polyglucose sorbitol carboxymethyl ether
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`(e.g., ferumoxytol, a preferred embodiment), iron mannitol, iron polymaltose, iron
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`gluconate, and iron sorbitol. Id., 10:45-57, 11:30-44, 26:58-61, 28:30-32. The
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`‘702 patent provides no reason that would explain why these other known iron
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`supplements would be rendered any safer than they had otherwise been, and the
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`overbreadth of the claims challenged herein runs to their demise.
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`
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`Patent Owner has presented a biased view of the use of iron supplements in
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`the prior art, alleging that “doses of iron complexes higher than 200 mg of iron are
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`generally unsuitable.” Response, 22. As support, Patent Owner offers nuanced
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`1 Injectafer®, the Patent Owner’s product, is also referred to as VIT-45. Ex. 1012;
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`Ex. 1013, 6; Ex. 1015, 70-71 (Exhibit H).
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`2 The specification (and Patent Owner’s Response) cites Geisser 1992 (Ex. 1049)
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`as supporting authority, but Geisser 1992 makes no such teaching. Rather,
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`although Geisser 1992 acknowledges that iron dextran can lead to anaphylaxis in
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`susceptible individuals, Geisser 1992 notes that iron dextran can be administered
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`as a “total dose infusion” (“TDI”) and is otherwise a safe and effective agent at
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`“high therapeutic doses.” Ex. 1049, 3, 13. 200 mg appears in Geisser 1992 in the
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`evidence that is ambiguous regarding the amounts administered. Response, 2-3.
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`For example, Danielson, Ex. 1048, presented in Patent Owner’s Response as
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`supportive of clinical usage in 2004, is cited for showing packaging3 at “doses”
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`below 100 mg rather than the amount administered. Response, citing Ex. 1048, 2.
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`As an example of the discrepancies between the amount of iron carbohydrate
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`packaged and the amount administered, Venofer®, which is a product of Patent
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`Owner, is listed by Danielson as packaged at 100 mg/5 ml but according to its
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`2005 press release (Ex. 1058), Venofer® could be used at single dose infusions of
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`200 mg or 500 mg. Ex. 1058, 2. Further, in addition to the referenced table,
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`Danielson also teaches iron dextran doses up to 500 mg, and doses of 500 mg and
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`250 mg of iron sucrose and ferric gluconate, respectively. Ex. 1048, e.g., 1, 4-5.
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`Even assuming arguendo that doses of 100-200 mg iron were more
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`commonly used, physicians administered higher doses in their discretion and
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`reported favorable results. Petition, 14-16. Frequent use of a lower dose, with
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`dose (200 mg/kg) administered to a single mouse, not a cautionary threshold. Id.,
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`2, 13.
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`3 This backpedals from Patent Owner’s Preliminary Response, which essentially
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`copied portions of a table from Danielson (Ex. 1048, 2) but changed the heading of
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`a column denoted “Packaging” to read “Dose, As Listed.” Preliminary Response,
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`3-7.
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`occasional (successful) administration of higher doses, is not a “teaching away”
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`from higher doses and does not render administration of higher doses patentable
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`and ripe for claiming.
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`In accordance with this background and as further discussed below, the prior
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`art discloses administration of at least 600 mg doses of several iron carbohydrate
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`complexes encompassed by the claims under review with low risk of anaphylaxis
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`or hypersensitivity adverse reactions. Thus, the evidence of record establishes, by
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`at least a preponderance of the evidence, that the overbroad claims under review
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`lack novelty or are obvious and should be found invalid.
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`III. SUMMARY OF ARGUMENT
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`Patent Owner argues that Geisser (Ex. 1003) does not anticipate claims 1-3,
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`10-13, 23, 25, 27, and 41-43 (Ground 1) because it “does not teach an iron
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`carbohydrate complex having a ‘substantially non-immunogenic carbohydrate
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`component’” or a complex having “substantially no cross-reactivity with anti-
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`dextran antibodies.” Response, 3. Patent Owner’s argument lacks merit. Geisser
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`teaches that its iron carboxymaltose complexes “demonstrate reduced toxicity and
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`… prevent the dangerous anaphylactic shocks that can be induced by dextran” (Ex.
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`1003, 3:26-28), so that they are deemed to contain a “substantially non-
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`immunogenic carbohydrate component.” Because carboxymaltose is not dextran,
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`the resulting complexes would not, by definition, substantially cross-react with
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`anti-dextran antibodies. Accordingly, the claims are anticipated by Geisser.
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`Patent Owner offers two arguments to avoid Petitioner’s contention that
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`Groman (Ex. 1004) anticipates claim 28 (Ground 2). The first is a rebuttal based
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`solely on (its own) erroneous claim dependency. Patent Owner argues that because
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`the iron carbohydrate species of claim 28 is not encompassed by claim 1 (upon
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`which it improperly depends), claim 28 is immune to novelty challenge because
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`anticipation of a dependent claim requires anticipation of its parent claim (which
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`they allege would be impossible here). Response, 18-20. Petitioner counters that
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`claim 28, properly construed, can be anticipated by Groman’s teaching of each and
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`all of its elements. Second, Patent Owner argues that Groman’s disclosure of a
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`dose “to about 600 mg” cannot anticipate the claimed range of “at least about 600
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`mg,” citing Atofina v. Great Lakes Chemical Corp., 441 F.3d 991 (Fed. Cir. 2006).
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`Response, 20-22. Petitioner points out that Atofina recognized a criticality in the
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`claimed range which is absent from the claims at issue, so that Atofina does not
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`apply and Groman anticipates claim 28.
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`Patent Owner argues against combining Groman and Geisser to render
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`claims 17 and 47 obvious (Ground 3), contending that they fail to teach every
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`element of those claims and that there would have been no motivation for a
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`POSITA to combine them. Response, 4. As reasoned above, Geisser teaches all
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`the elements of claim 1, upon which these claims depend. Groman adds the
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`elements of rapid (claim 17) and bolus (claim 47) administration. The
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`carboxymethylated dextran of Groman
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`is structurally analogous
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`to
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`the
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`carboxymaltose of Geisser, so that both would be expected to form tight, stable
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`complexes with iron and avoid undesirable toxic effects, and a person of ordinary
`
`skill in the art (“POSITA”) would have been motivated to combine their teachings
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`with a reasonable expectation of success. Petition, 46. While Patent Owner has
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`pointed to structural dissimilarities between these molecules, it has failed to show
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`these compounds to be meaningfully different and offered no argument or evidence
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`that would link the purported differences to iron binding properties. In fact, post-
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`filing evidence of record shows that the iron-binding properties of ferumoxytol
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`(representative of Groman) and Injectafer (a.k.a VIT-45) are equivalent. Ex. 1035.
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`Accordingly, Geisser and Groman teach all elements of the claims, and a POSITA
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`would have been motivated to combine them to render claims 17 and 47 obvious.
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`Patent Owner contends that claims 1, 14, and 15 are not anticipated by van
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`Zyl-Smit (Ex. 1006) (Ground 4) because van Zyl-Smit doesn’t test polymaltose
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`separately, study a sufficient number of patients, or consider enough types of
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`polymaltose. Response, 4. However, there is nothing in the specification or claims
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`to support such requirements. To the contrary, the specification provides no
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`requirement for statistical boundaries of “substantially non-immunogenic” and
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`only the genus of polymaltose (but no species) is disclosed and claimed. van Zyl-
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`Smit’s disclosure is commensurate with the claims and insofar as it teaches a
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`species of polymaltose, a species anticipates a genus. See, e.g., In re Slayter, 276
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`F.2d 408, 411, 125 USPQ 345, 347 (CCPA 1960); In re Gosteli, 872 F.2d 1008, 10
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`USPQ2d 1614 (Fed. Cir. 1989)).
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`Patent Owner argues against combining van Zyl-Smit and Funk to render
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`claim 30 obvious (Ground 5), contending that they fail to teach every element of
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`that claim (including iron core size) and that there would have been no motivation
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`for a POSITA to combine them. Response, 35. Patent Owner bases its argument
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`on testimony of its expert, Dr. Manzi, that Funk does not teach iron core size,
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`contradicting the testimony of Petitioner’s expert, Dr. Linhardt. Id., 35-36.
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`Shortly before and during her cross-examination Dr. Manzi changed her testimony,
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`now maintaining that it is not clear what Funk teaches, that the method of Funk
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`could, in fact, measure iron core size, and recognizing that a later publication cites
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`Funk as teaching iron core size. Ex. 1053, ¶43; Ex. 1054, 83:5- 85:20. The weight
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`of the evidence confirms Petitioner’s interpretation of Funk. As both van Zyl-Smit
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`and Funk relate to iron polymaltose and their pharmacologic properties (Ex. 1006,
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`1, 7; Ex. 1026, 1, 2-3), there would have been motivation for a POSITA to
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`combine them and use a polymaltose according to van Zyl-Smit with an iron core
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`size disclosed in Funk, rendering Claim 30 unpatentably obvious.
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`IV. PERSON OF ORDINARY SKILL IN THE ART
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`Petitioner and Patent Owner agree that a POSITA would hold an
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`undergraduate degree in chemistry or biochemistry with some related academic or
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`industrial experience in the area of carbohydrates and their metal complexes.
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`Response, 4; Petition, 14. While Patent Owner disagrees that a POSITA would
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`hold “at least” these qualifications, contending that the definition could include a
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`hyper-qualified person. Response, 4. As explained by Dr. Linhardt, “a POSITA is
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`one who is presumed to be aware of all pertinent art, thinks along conventional
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`wisdom in the art, and is a person of ordinary creativity,” thereby excluding a
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`person of extraordinary skill. Ex. 1005, ¶6.
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`V. CLAIM CONSTRUCTION
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`A.
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`“substantially non-immunogenic carbohydrate component”
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`Petitioner’s construction of “substantially non-immunogenic carbohydrate
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`component” requires assessment of the immunogenicity of the carbohydrate
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`component, rather than the complex as a whole. Petition, 13. In related IPR2015-
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`01493, the Board has preliminarily agreed with Petitioner, remarking that the
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`specification highlights the relationship between anaphylactoid reactions and
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`antibodies toward the dextran moiety and therefore 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 by the Board to be a carbohydrate component
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`resulting in a “low risk of anaphylactoid/hypersensitivity reactions,” implicitly less
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`than prior art dextran. Id. Petitioner urges the Board to apply this construction to
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`the claims of the ‘702 patent.
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`Patent Owner contends that (i) the immunogenicity of the complex as a
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`whole should be considered; (ii) the threshold of “low risk” should be less than
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`0.6-0.7% adverse event rate; and (iii) determining a “substantially non-
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`immunogenic component” requires a large enough cohort. Response, 7-10.4 The
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`evidence of record fails to support Patent Owner’s proposed claim construction.
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`Considering point (i), neither the specification nor claims support construing
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`this term to apply to the complex as a whole. Petition, 13. Instead, the
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`specification guides a POSITA to identify a carbohydrate component that is
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`4 Patent Owner has relied on statements regarding claim construction made by its
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`expert, Dr. Manzi, in her Declaration. Ex. 2080, ¶21. However, in Dr. Manzi’s
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`cross-examination, she admitted that she was provided no guidelines as to how
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`terms are supposed to be construed (Ex. 1054, 37:7-39:5) but stated that she did
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`not believe that the specification of the ‘702 patent (provided a definition for
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`“substantially non-immunogenic,” require an adverse incident rate lower than
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`dextran, or indicate a minimum sample size for testing. Ex. 1054, 51:8-21, 58:8-
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`substantially non-immunogenic, and use it in a complex with iron. Ex. 1001, 3:17-
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`25, 10:58-11:5.
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`As to point (ii), what constitutes a “low risk,” Patent Owner contends that 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, and that rate would be, referring to
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`Fishbane (Ex. 2012), which is cited in the specification, and Walters (Ex. 2081),
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`which is not, about 0.6-0.7%. Response, 32. Petitioner notes first that Patent
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`Owner’s proposal is based on considering the complex as a whole, as both
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`Fishbane and Walters relate to iron dextran complexes. Further, there is no basis
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`in the specification for an arbitrary risk threshold of 0.6-0.7%,5 as confirmed by
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`Dr. Manzi during her cross-examination. Ex. 1054, 51:14-17. Rather, the
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`specification sets the risk bar for the iron carbohydrate complex at “less than about
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`5% of treated patients.” Ex. 1001, 15:25-26.
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`Finally, Patent Owner’s position, that what constitutes a “substantially non-
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`immunogenic carbohydrate component” requires a “large enough cohort,” is ironic,
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`5 In its Response, Patent Owner states (at 8) that, according to the specification, the
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`adverse event rate of VIT-45 is 0.2%. However, the Prescribing Information for
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`Injectafer®, and Patent Owner’s own product, reports a “serious or severe” adverse
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`event rate of 1.5%. Ex. 1046, 3.
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`as there are no working examples supporting most of the carbohydrates listed in
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`the ‘702 patent claims, let alone a “large cohort.” The specification gives no
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`indication that a statistically rigorous study is required to identify which
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`carbohydrates would be “substantially non-immunogenic.” Instead, the use of the
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`term “substantially” suggests that a more relaxed standard should be applied. For
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`all these reasons, Petitioner disagrees with Patent Owner’s claim construction.
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`B.
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`“iron sorbitol”
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`Petitioner agrees with Patent Owner
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`that
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`the broadest reasonable
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`interpretation of “iron sorbitol complex” is “a complex of iron and sorbitol” where
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`sorbitol is a sugar alcohol that is not part of a polymer.” Response, 12. Iron
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`polyglucose sorbitol carboxymethyl ether (e.g., ferumoxytol; Feraheme®) is not an
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`iron sorbitol.
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`C.
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`“iron carboxymaltose unit”
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`Petitioner agrees with Patent Owner that carboxymaltose is a “maltose or
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`maltodextrin, comprised of maltose type units, in which the aldehyde group of the
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`reducing sugar end has been oxidized to form a carboxylic acid group” where
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`“[m]altose is a D-glucanopyranose dimer linked through an α-1-4 glycosidic
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`bond.” Response, 14. Petitioner notes its proffered construction “at least includes”
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`carboxymaltose prepared by the recited method and does not contradict this
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`definition. Patent Owner contends (Response, 14-15) that “substantially non-
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`immunogenic carbohydrate component” should be conflated with “iron
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`carboxymaltose,” for which Petitioner finds no basis; rather the claims are directed
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`to iron carboxymaltose which separately meets the limitation of being substantially
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`non-immunogenic.6
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`D. Claim 28
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`Although claim 28 is an improperly dependent claim, it should be construed
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`to contain the limitations of claim 1 except for the categories of iron carbohydrate,
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`where the species of iron carbohydrate is supplied by claim 28 itself. Petition, 39.
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`VI. PATENT OWNER HAS NOT SUCCESSFULLY REBUTTED
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`GROUNDS FOR INVALIDITY
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`A. GROUND 1
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`Patent Owner argues that Geisser does not anticipate the claims because it
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`“does not teach an iron carbohydrate complex having a “substantially non-
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`immunogenic carbohydrate component” or a complex having “substantially no
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`cross-reactivity with anti-dextran antibodies.” Response, 3.
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`To the contrary, Geisser advances its iron carboxymaltose complexes as
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`having “reduced toxicity” and preventing “the dangerous anaphylactic shocks that
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`can be induced by dextran.” Ex. 1003, 3:26-28,10:7-10; Petition, 16-18, 22-39.
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`6 Patent Owner cites Dr. Manzi’s Declaration as support for its construction. Ex.
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`1054, 37:7-39:5.
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`According to Geisser, the high complex stability results in low toxicity so that “[i]t
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`becomes possible to apply the medications parenterally, as a one time dose” which
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`“can amount to 500 to 1000 mg iron.” Ex. 1003, 10:14-17. Therefore, the iron
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`carboxymaltose disclosed in Geisser meets the definition of a “substantially non-
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`immunogenic carbohydrate component” because it results in a “low risk of
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`anaphylactoid/hypersensitivity reactions,” which would be less than the risk of
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`administering dextran. Further, because carboxymaltose is not dextran, the
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`resulting complexes would (by definition) substantially not cross-react with anti-
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`dextran antibodies. As noted in the Board’s Decision, “a disclosure of a specific
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`iron carbohydrate complex is likewise a disclosure of its inherent properties.”
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`Decision, 8.
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`Petitioner has pointed out that Geisser matured into the ‘109 Patent (Ex.
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`1014), which has a Patent Term Extension covering VIT-45 (a.k.a Injectafer®), and
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`is listed, together with the ‘702 Patent, in the Orange Book as covering Injectafer®
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`(a.k.a. VIT-45). Ex. 1012; Ex. 1015. Patent Owner has tried to deflect these facts,
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`contending that VIT-45 is a species of iron carboxymaltose not described by
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`Geisser, so that its properties cannot be extrapolated to the genus of Geisser iron
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`carboxymaltoses. Response, 16.
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`What Patent Owner overlooks is that VIT-45 is exemplary of the very
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`features that Geisser attributes to its genus of iron carboxymaltose. The purpose of
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`Geisser is to administer higher doses of safer iron carbohydrate with reduced risk
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`of immune reaction relative to iron dextran. Ex. 1003, 3-4. Petitioner’s expert, Dr.
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`Linhardt, stated “I consider the iron carboxymaltose complexes described in
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`Geisser to be identical or nearly identical to iron carboxymaltose complex
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`embodiments of the ‘702 patent, both in terms of synthetic methods and chemical
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`properties.” Ex. 1005, ¶10. He notes that “Geisser describes a general synthetic
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`method that is nearly identical to the method described in the ‘702 patent.” Id.
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`Patent Owner argues that lack of reactivity with anti-dextran antibodies is
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`not an inherent property of iron carboxymaltose. Response, 17. However, Patent
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`Owner has not disputed the definition that such antibodies “specifically recognize
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`dextran.” Petition, 13. Dr. Linhardt states “I would not expect an anti-dextran
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`antibody to cross-react with iron carboxymaltose, in which the carbohydrate is a
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`primarily α-1-4 linked oligomer or polymer of glucose.” Ex. 1005, ¶8. Patent
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`Owner has not disputed this assertion.
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`Finally, with regard to genus/species, the claims under consideration are not
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`directed specifically to VIT-45, but rather to the genus iron carboxymaltose, and
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`Geisser’s disclosure is commensurate with these claims.
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`By disclosing, expressly or inherently, each and every element of claims 1-3,
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`10-13, 23, 25, 27, and 41-43, Geisser anticipates those claims and renders them
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`invalid under 35 U.S.C. § 102(b).
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`B. GROUND 2
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`Patent Owner first argues that claim 28 should be exempt from challenge
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`because it is improperly dependent. Response, 18-20. According to Patent Owner,
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`because the iron carbohydrate species recited in claim 28 is not encompassed by
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`claim 1, claim 28 should be considered immune to challenge because anticipation
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`of a dependent claim also requires anticipation of its parent claim (which they
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`allege would be impossible here). Id. To agree to this proposition would permit
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`Patent Owner to later attempt to correct the dependency of claim 28 toward
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`recapturing subject matter already vetted in these proceedings.
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`Second, Patent Owner argues that Groman’s disclosure of a dose “to about
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`600 mg” cannot anticipate the claimed range of “at least about 600 mg,” citing
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`Atofina. Id., 20-21. As characterized by Patent Owner, “[i]n Atofina, the Federal
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`Circuit held that the prior art temperature range of 100-500°C did not describe the
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`claimed range of 330-450°C with sufficient specificity to be anticipatory.”
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`Response, 21. Here, Atofina is distinguishable. As noted by the Board in related
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`IPR2015-01493, “[t]he key to the court’s conclusion in Atofina ‘was the fact that
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`the evidence showed that a person of ordinary skill in the art would have expected
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`the [method] to operate differently, or not at all, outside of the temperature range
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`claimed in the patent-in-suit.”’ Decision (Paper 11) in IPR2015-01493, 16. In the
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`present case, no criticality is attributed to 600 mg of iron. As the claims fail to
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`specify the species or weight of the intended recipient, the absolute amount of iron
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`administered lacks relevance other than as an arbitrary threshold. Accordingly, the
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`exception in Atofina does not apply, and Groman teaches each element of claim 28
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`and renders it invalid under 35 U.S.C. § 102(b).
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`C. GROUND 3
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`Patent Owner contends that Geisser and Groman are directed to structurally
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`different carbohydrate complexes and that a POSITA would not have been
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`motivated to combine them. Response, 22.
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`Petitioner, based on the testimony of Dr. Linhardt, concludes that “the
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`carboxyl groups of both carboxymethylated reduced dextran according to Groman
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`and carboxymaltose according to Geisser would form tight, stable complexes with
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`iron” such that “administration of either to a subject would yield low levels of free
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`iron and therefore would be unlikely to produce undesirable side effects.” Ex.
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`1005, ¶22. According to Dr. Linhardt, “because Groman and Geisser relate to
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`structurally analogous compounds that are both intended to be used for the
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`treatment of iron deficiency anemia, I think that a POSITA would have been
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`motivated to put together the teachings of the two references.” Id.
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`Patent Owner disputes these conclusions alleging, first, that the maltodextrin
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`of Geisser has α-1-4 linkages, whereas the carboxymethyl dextran of Groman has
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`α-1-6 linkages (Response, 23-24) and, second, that the carboxyl group of Geisser is
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`in the C-1 position; whereas, according to a post-filing publication (Neiser 2015,
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`Ex. 1035), the carboxyl group of Groman is not at that position. Response, 25,
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`referencing Ex. 1035, 2, and Ex. 2080, ¶52.
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`Nowhere does Patent Owner explain how these dissimilarities (the latter
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`appreciated only after the effective filing date of the ‘702 patent) are relevant or
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`link them to Petitioner’s contention that both carbohydrates would form tight
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`complexes with iron. Nor does Patent Owner provide any reason why a POSITA
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`would not have reasonably expected tight complexes with iron to form, or why
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`they would not have expected that both iron carbohydrate complexes would “yield
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`low levels of free iron and therefore would be unlikely to produce undesirable
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`toxic effects.” Petition, 46. There is no correlation drawn between the purported
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`differences identified by Patent Owner and expectations regarding, or actual, iron
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`binding. Ex. 2080, ¶¶50-52.
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`In Dr. Manzi’s cross-examination, she was asked whether the post-filing
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`reference referred to in her Declaration (Neiser 2015, Ex. 1035) disclosed any
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`information regarding the iron-binding capacity of ferric carboxymaltose and
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`ferumoxytol. She referenced page 1 of Neiser 2015 as giving an order of lability.
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`Ex. 1054, 84:12-23.
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` On
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`that page, Neiser 2015 discloses
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`that ferric
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`carboxymaltose and ferumoxytol have equivalent iron binding properties, a fact
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`that Patent Owner neglected to mention when pointing to Neiser 2015. The
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`differences in structure notwithstanding, exemplary compounds of Geisser and
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`Groman are reported to show equivalent iron binding properties as Dr. Linhardt
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`predicted, consistent with structural analogy. Ex. 1035, Abstract, 18.
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`Patent Owner’s evidence does not disprove Petitioner’s contentions that the
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`compounds of Geisser and Groman are structurally analogous and that a POSITA
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`would have believed them to be so on the effective filing date of the ‘702 patent.
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`Accordingly, a POSITA would have been motivated to combine the teachings of
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`Geisser and Groman, and would have reasonably expected that the use of iron
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`carboxymethyl dextran according to Groman could inform the use of iron
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`carboxymaltose according to Geisser.
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`Claim 17 relates to administration of iron carbohydrate complex “in about
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`15 minutes or less.” Geisser teaches that the “great complex stability” makes a
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`“high application speed” possible, suggesting, as an example, administration over
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`the course of 1 hour. Ex. 1003, 3:26-30 to 4:1, 8:16-17. Groman discloses rapid
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`administration of iron carbohydrate complex. Ex. 1004, ¶[0016]. Based on
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`calculations described in Dr. Linhardt’s Declaration (Ex. 1005, ¶18), Groman
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`teaches administration “of up to 0.6 grams, in less than 28 minutes, in less than
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`fifteen minutes, in less than five minutes, in less than two minutes, and even in less
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`than one minute.” Id., ¶18. In view of the combination of Geisser and Groman
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`and Geisser’s suggestion for “high application speed,” it would have been obvious
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`for a POSITA to administer the iron carboxymaltose complexes of Geisser faster
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`than Geisser suggests (one hour), in 15 minutes or less, with a reasonable
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`expectation of success.
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`Patent Owner refers to an undeclared IPR challenging related
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