UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`
`
`PHARMACOSMOS A/S
`Petitioner
`
`v.
`
`LUITPOLD PHARMACEUTICALS, INC.
`Patent Owner
`
`
`
`Patent No. 7,754,702
`Issue Date: July 13, 2010
`Title: METHODS AND COMPOSITIONS FOR ADMINISTRATION OF IRON
`_______________
`
`Inter Partes Review No. 2015-01490
`____________________________________________________________
`
`PATENT OWNER PRELIMINARY RESPONSE
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`4815-5933-0601.3
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`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`
`
`PHARMACOSMOS A/S
`Petitioner
`
`v.
`
`LUITPOLD PHARMACEUTICALS, INC.
`Patent Owner
`
`
`
`Patent No. 7,754,702
`Issue Date: July 13, 2010
`Title: METHODS AND COMPOSITIONS FOR ADMINISTRATION OF IRON
`_______________
`
`Inter Partes Review No. 2015-01490
`____________________________________________________________
`
`PATENT OWNER PRELIMINARY RESPONSE
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`4815-5933-0601.3
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`IPR2015-01490
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`Patent Owner Preliminary Response
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`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`SUMMARY OF ARGUMENT ....................................................................... 1
`
`III. BACKGROUND ............................................................................................. 1
`
`A. Overview of the ’702 Patent .................................................................. 2
`
`B.
`
`Prosecution History ............................................................................... 8
`
`1.
`
`
`2.
`
`
`3.
`
`
`The ’702 Patent ........................................................................... 8
`
`The ’549 Patent ......................................................................... 11
`
`The ’612 Patent ......................................................................... 14
`
`C.
`
`Person of Ordinary Skill in the Art ..................................................... 16
`
`IV. CLAIM CONSTRUCTION .......................................................................... 17
`
`A.
`
`“iron carbohydrate complex …[having] a substantially non-
`immunogenic carbohydrate component” ............................................ 19
`
`1.
`
`
`2.
`
`
`3.
`
`
`4.
`
`
`The plain meaning of “iron carbohydrate complex” ................ 19
`
`The specification defines “iron carbohydrate complex” in
`terms of its characteristics ......................................................... 19
`
`A person of ordinary skill in the art would not look to the
`carbohydrate component out of context of the complex. ......... 21
`
`The exemplary embodiments of the specification teach
`administration of the complex as a whole. ............................... 23
`
`
` Whether a component is “non-immunogenic” can only be 5.
`revealed with a large sample size.............................................. 23
`
`B.
`
`“substantially no cross-reactivity with anti-dextran antibodies” ........ 26
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`1.
`
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`2.
`
`
`The dextran in “anti-dextran antibodies” is branched. ............. 26
`
`The term “substantially no cross-reactivity with anti-
`dextran antibodies” is a characteristic of the whole “iron
`carbohydrate complex.” ............................................................ 27
`
`“single dosage unit”............................................................................. 28
`
`“iron carboxymaltose complex” .......................................................... 30
`
`“iron polymaltose complex” ................................................................ 31
`
`C.
`
`D.
`
`E.
`
`V.
`
`CONCLUSION .............................................................................................. 32
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`TABLE OF AUTHORITIES
`
`
`CASES
`In re Cuozzo Speed Techs., LLC, 793 F.3d 1268 (Fed. Cir. 2015) .......................... 17
`
`In re Translogic Tech., Inc., 504 F.3d 1249 (Fed. Cir. 2007) ................................. 17
`
`Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) ......................................... 17
`
`STATUTES
`
`35 U.S.C. § 21(b) ....................................................................................................... 1
`
`37 C.F.R. § 1.7(a) ....................................................................................................... 1
`
`37 C.F.R. § 42.1 ......................................................................................................... 1
`
`37 C.F.R. § 42.100(b) .............................................................................................. 17
`
`
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`Exhibit No.
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`EXHIBITS
`Description
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`Imferon US Drug Monograph, Revised May 1989
`
`INFeD US Drug Monograph, Revised September 1996
`
`Ferrosig Drug Product Data Sheet, Revised July 2003
`
`European Search Report, October 21, 2009 in EP 07716309
`
`Prosecution History of the ’549 Patent
`
`Prosecution History of the ’612 Patent
`
`Prosecution History of U.S. Application No. 13/847,254
`
`Parham, The Immune System. Garland Science 2000 p. 1-30.
`
`Folb, The Safety of Iron Dextran and a Comparison with Iron
`Sucrose for Intravenous Use, Submitted to the WHO October 2004
`
`Zager et al., Kidney Int. 2004 66(1):144-56
`
`Agarwal et al., Kidney Int. 2004 65(6):2279-89
`
`Fishbane, Am. J. Kidney Dis. 2003 41(5 Suppl):18-26
`
`Cisar et al., J. Exp. Med. 1975 142(1):435-59
`
`Wallerstein, Blood. 1968 32(4):690-5
`
`Volhardt, Organic Chemistry, W.H. Freeman Co 2007 p. 1096-138
`
`USPTO PaFT Help Page
`
`Luitpold Pharmaceuticals, Inc. Executive Biographies
`
`
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`iv
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`I.
`
`INTRODUCTION
`
`Pursuant to 35 U.S.C. § 313 and 37 C.F.R. § 42.107, Patent Owner Luitpold
`
`Pharmaceuticals, Inc. (“Patent Owner” or “Luitpold”) files this Preliminary
`
`Response to the Petition of Pharmacosmos A/S (“Petitioner” or “Pharmacosmos”)
`
`challenging claims 1, 2, 3, 10, 11, 12, 13, 14, 15, 17, 23, 25, 26, 27, 28, 30, 34, 41,
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`42, 43, and 47 of U.S. Patent No. 7,754,702 (“the ’702 Patent”).
`
`This preliminary response is timely filed within three months of the Board’s
`
`notice, mailed July 10, 2015, according the Petition a filing date. The three-month
`
`nominal due date falls on October 10, 2015 which is a Saturday, and Monday the
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`12th is Columbus Day, a federal holiday. Under 37 C.F.R. § 42.1, 37 C.F.R. §
`
`1.7(a), and 35 U.S.C. § 21(b), therefore, the actual due date is Tuesday the 13th.
`
`II.
`
`SUMMARY OF ARGUMENT
`
`Patent Owner offers proposed claim constructions for two terms for which
`
`Petitioner has not proffered a construction and five terms addressed by the
`
`Petitioner. If the Board adopts Petitioner’s construction for claim 28, then the
`
`Board should not institute trial on Ground 2’s claim 28.
`
`III. BACKGROUND
`
`The ’702 patent issued from U.S. Patent Application No. 11/620,986, which
`
`claims priority to U.S. Provisional Application No. 60/757,119 filed January 6,
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`2006. Petitioner does not challenge the ’702 patent’s entitlement to the earliest
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`priority date of January 6, 2006. Continuation applications claim priority through
`
`the ‘702 patent: 12/787,283 which issued as U.S. Patent No. 8,431,549 (the ‘549
`
`patent) and 14/100,717 which issued as U.S. Patent No. 8,895,612 (the ‘612
`
`patent). The ‘549 patent is the subject of IPR2015-01493 and the ‘612 patent is the
`
`subject of IPR2015-01495.
`
`A. Overview of the ’702 Patent
`
`The specification of the ’702 patent details the need in the art for iron
`
`formulations with low health risk that may be administered in high doses.
`
`In addition to noting the risks associated with iron dextran, the background
`
`section of the specification details that “[a]lthough serious and life-threatening
`
`reactions occur most frequently with iron dextran, they are also known to occur
`
`with other parenteral iron products.” Ex. 1001, p. 4 col. 1:39-41. Moreover, the
`
`specification points out that “non-life threatening reactions such as arthralgia, back
`
`pain, hypotension, fever, myalgia, pruritus, vertigo, and vomiting” can preclude
`
`high dosing of known iron formulations. Ex. 1001, p. 4 col. 1:42-46.
`
`In discussing further issues with dosing, the specification posits that
`
`“[v]arious pharmacokinetic studies suggest that doses of iron complexes higher
`
`than 200 mg of iron are generally unsuitable and that the conventional therapy
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`prescribes repeated applications of lower doses over several days. See Geisser et
`
`al., (1992) Arzneimittelforschung 42: 1439-1452.” Ex. 1001, p. 4 col. 2:9-13.
`
`What was needed by January 2006 was a pharmaceutical product that could be
`
`administered at high doses and with a relatively short time for administration.
`
`As of 2004, for example, commercially available iron carbohydrate
`
`compounds were packaged at doses below 100 mg. Ex. 1048, p. 2.
`
`A list of about a dozen commercial iron carbohydrate products, their status
`
`as of 2006, and their respective doses is included in the table below.
`
`Table 1: Listing of iron carbohydrate products prior to the earliest effective
`filing date of the ’702 patent.
`
`TRADE
`NAME
`
`PRODUCER/
`DISTRIBUTOR
`
`DOSE, AS
`LISTED
`
`NOTES
`AND CITATIONS
`
`Iron dextran
`
`Imferon
`
`Fisons Ltd.
`
`Pharmaceutical
`
`Division, United
`
`Kingdom
`
`This product was
`
`withdrawn from the US
`
`market in 1990 and
`
`100 mg/2 ml
`
`other markets by 1996.
`
`Ex. 1048, p. 2.
`
`The label states that
`
`“[i]ndividual doses of 2
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`mL or less may be
`
`given on a daily basis”
`
`and that it “is given
`
`undiluted and slowly (1
`
`ml or less per minute).”
`
`Ex. 2001, p. 2.
`
`The label states that it
`
`should be administered
`
`“undiluted at a slow
`
`gradual rate not to
`
`exceed 50 mg (1 ml) per
`
`minute.” Ex. 2002, p.
`
`2; see also Ex. 1048, p.
`
`2.
`
`Cosmofer appears to be
`
`Watson
`
`INFeD
`
`Pharmaceuticals,
`
`100 mg/2 ml
`
`United States
`
`100 mg/2 ml
`
`the name for INFeD in
`
`Europe. Ex. 1048, p. 2.
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`Cosmofer
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`Pharmacosmos,
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`Denmark
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`Dexferrum
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`American Regent,
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`100 mg/2 ml; 50
`
`United States
`
`mg/ 1 ml
`
`Ex. 1048, p. 2.
`
`DexIron
`
`American Regent,
`
`100 mg/2 ml; 50
`
`the name for Dexferrum
`
`United States
`
`mg/ 1 ml
`
`in Canada. Ex. 1048, p.
`
`DexIron appears to be
`
`2.
`
`Infufer
`
`Sabex, Canada
`
`100 mg/2 ml
`
`Ex. 1048, p. 2.
`
`Ferric gluconate
`
`Watson
`
`Ferrlecit
`
`Pharmaceuticals,
`
`62.5 mg/ 5 ml
`
`Ex. 1048, p. 2.
`
`United States
`
`Iron polymaltose
`
`Maltofer
`
`Vifor International,
`
`Switzerland
`
`100 mg/2 ml
`
`Ex. 1048, p. 2.
`
`Ferrosig
`
`Zuellig Pharama
`
`Limited, New Zealand
`
`The data sheet states
`
`100 mg/ 2ml
`
`that the packaged dose
`
`should be diluted in
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`saline, resulting in a
`
`concentration of at most
`
`5 mg/ml. It further
`
`notes that, if a dose of
`
`50 ml administered at a
`
`rate of 5-10 drops per
`
`minute is well tolerated,
`
`“the rate may be
`
`increased to 30
`
`drops/minute (based on
`
`a drop volume of
`
`0.067ml).” Ex. 2003, p.
`
`2.
`
`This product was
`
`withdrawn from the
`
`market prior to 2004.
`
`Ex. 1048, p. 2.
`
`Iron saccharate
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`Ferivenin
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`Laevosan, Austria
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`20 mg/ml
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`Ferrum Vitis Neopharma, Germany 20 mg/ml
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`This product was
`
`withdrawn from the
`
`market prior to 2004.
`
`Ex. 1048, p. 2.
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`Fesin
`
`Yoshitomi, Japan
`
`40 mg/2 ml
`
`Ex. 1048, p. 2.
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`Iron sorbitol
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`Jectofer
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`Astra Zeneca, United
`
`Kingdom
`
`100 mg/2 ml
`
`This product was
`
`withdrawn from the
`
`market prior to 2004.
`
`Ex. 1048, p. 2.
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`Iron sucrose
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`Vifor International,
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`Switzerland
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`100 mg/ 5 ml
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`Ex. 1048, p. 2.
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`Venofer
`
`
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`What was needed by January 2006 was a pharmaceutical product that could
`
`be administered at high doses and a relatively short time for administration, and
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`that did not have the immunogenicity and toxicity of the other agents. In order to
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`fulfill the long felt need in the art, the specification discloses iron carbohydrate
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`complexes along with methods for high dose administration and rapid rates of
`
`administration that significantly ameliorate adverse reactions, unlike iron dextran.
`
`Among the complexes contemplated in the ‘702 patent are iron carboxymaltose
`
`complex VIT-45 and ferumoxytol. VIT-45 is exemplified in the Examples of the
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`’702 patent. Ferumoxytol is referred to by both its proprietary and chemical name
`
`in the specification of the ‘598 patent, and disclosures thereof are included by
`
`citation to U.S. Patent No. 6,599,498 (“the ’498 patent,” Ex. 1017) – the parent of
`
`the Groman reference (Ex. 1004) cited by Petitioner (Petition, p. 2).
`
`B.
`
`Prosecution History
`
`1.
`Prior to the examination of the ’702 patent, Patent Owner alerted the
`
`The ’702 Patent
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`Examiner to the ’498 patent and disclosed additional references, including the
`
`other references cited in the specification. Ex. 1007, p. 251-252. An additional set
`
`of references cited in the corresponding European prosecution was disclosed to the
`
`Examiner during prosecution (Ex. 1007, p. 27-28); this included a citation of
`
`WO2004/037865 (“Geisser,” Ex. 1002) and the European Search Report on which
`
`it was listed as a relevant reference. Geisser was listed in the European Search
`
`Report as an “X” reference, indicating the highest possible relevance. Ex. 2004, p.
`
`1. All of the disclosed references were marked “considered” by the Examiner, and
`
`thus, listed on the face of the ’702 patent. Ex. 1001, p. 1.
`8
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`As originally filed, the application resulting in the ’702 patent contained 60
`
`original claims. Claim 1 recited:
`
`A method of treating a disease, disorder, or condition characterized by iron
`
`deficiency or dysfunctional iron metabolism, comprising administering to a
`
`subject in need thereof an iron carbohydrate complex in a single dosage unit
`
`of at least about 0.6 grams of elemental iron, wherein the iron carbohydrate
`
`complex has a substantially non-immunogenic carbohydrate component and
`
`substantially no cross reactivity with anti-dextran antibodies.
`
`A requirement for an election of species was issued in response to these claims.
`
`Ex. 1007, p. 239-244.
`
`Although Patent Owner elected iron carboxymaltose as a species for
`
`examination purposes (Ex. 1007, p. 235), the Examiner’s subsequent search was
`
`not limited to iron carboxymaltose. Indeed, the Examiner’s search terms included
`
`at least “ferumoxytol” and “poly$3maltose,” wherein “$3” functions as a search
`
`operator for variations of three letters between “poly” and “maltose.” Ex. 1007, p.
`
`212-213; see also 2016, p. 4.
`
`Accordingly, contrary to Petitioner’s innuendo (Petition at p. 9-10), the
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`Examiner’s search encompassed ferumoxytol and the Groman ‘498 patent was
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`submitted to the Examiner, so the Examiner must have been aware of the ‘498
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`patent’s teaching.
`
`In the resulting Office Action, the Examiner required the applicant to more
`
`particularly identify the structural requirements of the claimed iron carbohydrate
`
`complexes and cited a combination of references – U.S. Patent No. 5,624,668
`
`(“Lawrence,” Ex. 1008) and U.S. Patent No. 6,960,571 (also cited as US
`
`2004/0180849, Ex. 1009) – as allegedly rendering the claims obvious. Ex. 1007, p.
`
`195-203.
`
`To advance prosecution, claim 1 was amended to recite specific iron
`
`carbohydrate complexes disclosed in the specification – with the addition of the
`
`Markush clause “wherein the iron carbohydrate complex is selected from the group
`
`consisting of an iron carboxymaltose complex, an iron mannitol complex, an iron
`
`polyisomaltose complex, an iron polymaltose complex, an iron gluconate complex,
`
`an iron sorbitol complex, and an iron hydrogenated dextran complex.” Ex. 1007,
`
`p. 167.
`
`A declaration from Mr. Richard P. Lawrence identifying issues with the
`
`Examiner’s interpretation of the art was also submitted. Ex. 1007, p. 187-191.
`
`The Examiner subsequently withdrew the pending rejections and issued a
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`new Office Action indicating doubts regarding enablement but indicating that the
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`claims contained allowable subject matter. As to reasons for allowance, the
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`Examiner clarified that the references cited by Patent Owner – Macdougall
`
`(Nephrol. Dial. Transplant, 2000, 15, p. 1743-1745), Andersson (British Medical
`
`Journal, 1961, p. 275-279), Fielding (British Medical Journal, 1961, p. 279-283),
`
`and Nissenson et al. (Kidney International, 2003, 64(Supplement 87), p. 864-871)
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`– teach limiting the dose of iron carbohydrate complexes in order to avoid adverse
`
`events. Thus, “it would not have been obvious to one of ordinary skill in the art to
`
`increase the dosage because the reasonable expectation of increased adverse events
`
`caused by increased dosage constitutes a teaching away from increasing the
`
`dosage.” Ex. 1007, p. 151-153.
`
`Without acquiescing to the merits of the pending rejections (Ex. 1007, p.
`
`132-133), Patent Owner amended the claims in accordance with the subject matter
`
`deemed allowable by the Examiner. Ex. 1007, p. 123. Shortly thereafter, the
`
`Examiner issued a Notice of Allowance. Ex. 1007, p. 9.
`
`The ’549 Patent
`
`
`2.
`Prior to examination of the ’549 patent, Patent Owner alerted the Examiner
`
`to all references cited in the prosecution history of the ’702 patent. Ex. 2005, p.
`
`171-174; p. 142-143. In addition, foreign office communications in related
`
`applications were disclosed to the Examiner. Additional references were disclosed
`
`to the Examiner during prosecution, including the English language equivalent of
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`Geisser, U.S. Patent No. 7,612,109 (“the’109 patent” Ex. 1014). Ex. 2005, p. 47.
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`All of the disclosed references were marked “considered” by the Examiner, and,
`
`thus, listed on the face of the ’549 patent.
`
`As originally filed, the application resulting in the ’549 patent contained 20
`
`original claims. Claim 1 recited:
`
`A method of treating a disease, disorder, or condition characterized by iron
`
`deficiency or dysfunctional iron metabolism resulting in reduced
`
`bioavailability of dietary iron, comprising administering to a subject in need
`
`thereof an iron carbohydrate complex in a single dosage unit of at least about
`
`0.6 grams of elemental iron; wherein the iron carbohydrate complex is
`
`selected from the group consisting of an iron carboxymaltose complex, an
`
`iron mannitol complex, an iron polyisomaltose complex, an iron polymaltose
`
`complex, an iron gluconate complex, an iron sorbitol complex, and an iron
`
`hydrogenated dextran complex.
`
`The Examiner issued an election of species requirement. Ex. 2005, p. 134-140.
`
`Patent Owner elected iron polyisomaltose as the iron carbohydrate species for
`
`examination. Ex. 2005, p. 129.
`
`The Examiner raised the same scope of enablement issue articulated in the
`
`prosecution history of the ’702 patent; in describing the issue, the Examiner noted:
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`“one of skill in the art would expect anti-dextran antibodies to cross react with
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`polyisomaltose, which is a linear α(1-6) chain of dextran.” Ex. 2005, p. 104. The
`
`Examiner also alleged the claims were obvious over Hamstra et al. JAMA, 1930,
`
`243(17) (“Hamstra”) and U.S. Patent No. 3,100,202 (“Muller,” Ex. 1050) –
`
`sometimes in view of Lawrence. Ex. 2005, p. 100-112.
`
`In response, the claims were amended to remove iron carboxymaltose and to
`
`incorporate the limitation wherein “the iron carbohydrate complex has a
`
`substantially non-immunogenic carbohydrate component.” Ex. 2005, p. 56. Along
`
`with this amendment, a terminal disclaimer was filed over the ’702 patent. Ex.
`
`2005, p. 44.
`
`A second declaration from Mr. Lawrence (Ex. 1039) was offered in support
`
`of enablement, demonstrating that a linear polyisomaltose – Monofer ® – did not
`
`cross react with anti-dextran antibodies; the declaration distinguished between
`
`branched dextran and linear polyisomaltose, which the Examiner had noted may be
`
`considered as a linear -1-6 linked chain of dextran (Ex. 2005, p. 104). Ex. 2005,
`
`p. 73-76. Patent Owner argued that the claims were indeed enabled, citing the
`
`specification as providing means of assessing immunogenicity and/or cross-
`
`reactivity to anti-dextran antibodies and citing the example of Monofer® to show
`
`that such iron polyisomaltoses exist. Ex. 2005, p. 62-66.
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`In response to the Examiner’s obviousness rejection, arguments – entirely
`
`independent of the declaration – distinguished the cited art from the claims,
`
`particularly with respect to the prior art dealing with high dose iron dextran. Ex.
`
`2005, p. 69-70. To support non-obviousness, Patent Owner pointed to the reasons
`
`for allowance of the ’702 patent and the Examiner’s observation that the prior art
`
`specifically taught away from an increased dose to minimize adverse events. Ex.
`
`2005, p. 70.
`
`An interview was then conducted. Shortly thereafter, an Examiner’s
`
`amendment deleting “iron hydrogenated dextran complex” and carving out
`
`Restless Leg Syndrome from the scope of the claims was issued along with a
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`Notice of Allowance. Ex. 2005, p. 15-27.
`
`The ’612 Patent
`
`
`3.
`The application resulting in the ’612 patent was filed with a Track 1 request,
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`and, thus, prosecution was expedited. Ex. 2006, p. 165-166.1
`
`
`1 A prior filed “regular” track application in this family – U.S. Application
`
`No. 13/847,254 – was abandoned to pursue this expedited prosecution. See Ex.
`
`2007.
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`4815-5933-0601.3
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`14
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`Patent Owner Preliminary Response
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`Prior to examination of the ’612 patent, Patent Owner alerted the Examiner
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`to all references cited in the prosecution history of its parent applications. Ex.
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`2006, p. 165-166. In addition, foreign office communications in related
`
`applications were disclosed to the Examiner. Ex. 1007, p. 72-75. Additional
`
`references were disclosed to the Examiner during prosecution, including U.S.
`
`Patent No. 7,871,597 and U.S. Publication No. 2003/0232084 (“Groman,” Ex.
`
`1004) and Marchasin et al. (“Marchasin,” Ex. 1047). Ex. 2006, p. 29; p. 24. All of
`
`the references were marked “considered” by the Examiner, and, thus, listed on the
`
`face of the ’612 patent.
`
`The application resulting in the ’612 patent was filed with the same 20
`
`original claims as the application resulting in the ’549 patent.
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`In the first Office Action on the merits, the Examiner cited Geisser and
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`Helenek as anticipating these claims. The Examiner further alleged the claims
`
`were obvious over the combination of Hamstra and Muller – sometimes in view of
`
`Lawrence. Lastly, the Examiner issued an obviousness type double patenting
`
`rejection over the ’702 and ’549 patents. Ex. 2006, p. 113-125.
`
`Claim 1 was amended to delete “an iron gluconate complex,” incorporate
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`“an iron polyglucose sorbitol carboxymethyl ether complex,” and recite that “the
`
`single dosage unit of elemental iron is administered in about 15 minutes or less;
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`4815-5933-0601.3
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`15
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`IPR2015-01490
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`Patent Owner Preliminary Response
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`and the iron carbohydrate has a substantially non-immunogenic carbohydrate
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`component.” Ex. 2006, p. 41. Along with this amendment, terminal disclaimers
`
`were filed over the ’702 and ’549 patents.
`
`The combination of the amendments, terminal disclaimers, and arguments –
`
`including those reiterating the conclusions drawn in the first Lawrence declaration
`
`cited in prosecution of the ’702 patent – overcame the rejections. Ex. 2006, p. 15-
`
`18; p. 7. However, in the subsequent Examiner’s amendment and Notice of
`
`Allowance, the Examiner deleted “hydrogenated dextran complex” in response to
`
`newly identified art – Kabat et al. J. Immunol. 1953, 70:514-532 – allegedly
`
`pertaining to such complexes.2 Ex 2006, p. 18-20.
`
`Person of Ordinary Skill in the Art
`
`C.
`Patent Owner agrees with Petitioner to the extent that a person of ordinary
`
`skill in the art (“POSITA”) for this patent would hold an undergraduate degree in
`
`
`2 A search conducted prior to allowance encompassed examining the
`
`immunogenicity of dextran and non-dextran compounds, as evidenced by the
`
`Examiner’s identification of a reference titled “Is there a difference between the
`
`allergic potencies of the iron sucrose and low molecular weight iron dextran?” Sav
`
`et al. 2007 in the Search History. Ex. 2006, p. 31.
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`4815-5933-0601.3
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`16
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`Patent Owner Preliminary Response
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`chemistry or biochemistry with some related academic or industrial experience in
`
`the area of carbohydrates and their metal complexes. Petition, p. 14. Patent
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`Owner disagrees, however, to the extent that Petitioner’s “at least” treats one with,
`
`say, a PhD as ordinarily skilled just like one with a B.S. None of the three named
`
`inventors of the ’549 patent has a Ph.D. Ex. 2017, p. 1-2; Ex. 1039, p. 2.
`
`Petitioner’s expert repeatedly draws conclusions based on his own view or his
`
`personal opinion as distinct from those of a POSITA.
`
`IV. CLAIM CONSTRUCTION
`
`The claims of a patent must be given their broadest reasonable interpretation
`
`consistent with the specification as it would be understood by one of ordinary skill
`
`in the art. 37 C.F.R. § 42.100(b); see In re Cuozzo Speed Techs., LLC, 793 F.3d
`
`1268, 1278-80 (Fed. Cir. 2015); In re Translogic Tech., Inc., 504 F.3d 1249, 1257
`
`(Fed. Cir. 2007); see also Phillips v. AWH Corp., 415 F.3d 1303, 1316 (Fed. Cir.
`
`2005). Consistent with the law, Patent Owner presents arguments for claim
`
`construction in the context of the specification, prosecution history, and
`
`understanding in the art.
`
`Independent claim 1 recites:
`
`A method of treating a disease, disorder, or condition characterized by
`iron deficiency or dysfunctional iron metabolism resulting in reduced
`bioavailability of dietary iron, comprising administering to a subject
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`4815-5933-0601.3
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`17
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`IPR2015-01490
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`Patent Owner Preliminary Response
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`in need thereof an iron carbohydrate complex in a single dosage unit
`of at least about 0.6 grams of elemental iron; wherein the iron
`carbohydrate complex is selected from the group consisting of an iron
`carboxymaltose complex, an iron mannitol complex, an iron
`polymaltose complex, an iron gluconate complex, and an iron sorbitol
`complex; and the iron carbohydrate complex has a substantially non-
`immunogenic carbohydrate component and substantially no cross
`reactivity with anti-dextran antibodies
`wherein said disease, disorder or condition is not Restless Leg
`Syndrome.
`
`Ex. 1001, p. 16 col. 26:49-67.
`
`Patent Owner offers claim constructions for the terms “iron carbohydrate
`
`complex...[having] a substantially non-immunogenic carbohydrate component,”
`
`“substantially no cross reactivity to anti-dextran antibodies,” “single dosage unit,”
`
`“iron carboxymaltose complex,” and “iron polymaltose complex,” recited in this
`
`claim.
`
`To the extent the Board agrees with Petitioner that the “iron polyglucose
`
`sorbitol carboxymethel ether complex” of claim 28 does not “fall within a category
`
`of iron carbohydrate complex recited in claim 1” (Petition, p. 39), thus alleging
`
`that claim 28 is an improper dependent claim, the Board should not institute trial
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`on Ground 2.
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`4815-5933-0601.3
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`18
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`IPR2015-01490
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`Patent Owner Preliminary Response
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`A.
`
`“iron carbohydrate complex …[having] a substantially non-
`immunogenic carbohydrate component”
`
`Petitioner offers a construction of “substantially non-immunogenic
`
`carbohydrate component” out of the context of the “iron carbohydrate complex”
`
`that is the subject of independent claim 1. Petition, p. 13. Specifically, Petitioner
`
`argues that the immunogenicity of the iron carbohydrate complex should be
`
`considered only with respect to the carbohydrate component. Id.
`
`The plain meaning of “iron carbohydrate complex”
`
`
`1.
`Petitioner has not presented a construction of the term “iron carbohydrate
`
`complex.” The plain meaning of the term is a complex between iron and a
`
`carbohydrate, such as the subgeneric species listed in claim 1, e.g., an iron
`
`carboxymaltose complex, an iron mannitol complex, an iron polymaltose complex,
`
`an iron gluconate complex, and an iron sorbitol complex. Ex. 1001, p. 16 col.
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`26:58-62; Ex. 2015, p. 4. By itself, that plain meaning is overbroad here.
`
`
`2.
`
`The specification defines “iron carbohydrate complex” in
`terms of its characteristics
`
`The specification describes an “iron carbohydrate complex” as preferably
`
`having one or more of the following characteristics:
`
`a nearly neutral pH (e.g., about 5 to about 7); physiological
`osmolarity; stable carbohydrate component; an iron core size no
`greater than about 9 nm; mean diameter particle size no greater than
`about 35 nm, preferably about 25 nm to about 30 nm; slow and
`19
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`4815-5933-0601.3
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`IPR2015-01490
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`Patent Owner Preliminary Response
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`competitive delivery of the complexed iron to endogenous iron
`binding sites; serum half-life of over about 7 hours; low toxicity; non-
`immunogenic carbohydrate component; no cross reactivity with anti-
`dextran antibodies; and/or low risk of anaphylactoid/hypersensitivity
`reactions.
`
`Ex. 1001, p. 8-9 col.10:61-11:5.
`
`Similarly, claim 1 of the ’702 patent requires that “the iron carbohydrate
`
`complex has a substantially non-immunogenic carbohydrate component.” Ex.
`
`1001, p. 16 col. 26:63-64. Here, as in the specification, the “carbohydrate
`
`component” is defined only in context of the “complex.” Thus, a logical
`
`construction of “iron carbohydrate complex” requires that the carbohydrate must
`
`be substantially non-immunogenic in the context of its role as a component in the
`
`complex and not as an independent carbohydrate. Hence, the immunogenicity is
`
`determined by the complex as a whole.
`
`Thus, based on the specification and the plain meaning of the term, for the
`
`purpose of assessing any limitations pertinent to immune effect, “iron carbohydrate
`
`complex” should be construed as a complex including both the iron and the
`
`carbohydrate as recited in claim 1.
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`4815-5933-0601.3
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`20
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`Patent Owner Preliminary Response
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`3.
`
`A person of ordinary skill in the art would not look to the
`carbohydrate component out of context of the complex.
`
`An ordinarily skilled artisan would not consider the immunogenicity of the
`
`carbohydrate separately from the complex as a whole.
`
`Classical immunology teaches that the body generates an immune response
`
`to “antigens” which are displayed and interact with immune receptors. Ex. 2008,
`
`p. 21. The immune system relies on the presentation of these antigens to generate
`
`specific immune responses. Ex. 2008, p. 24. Thus, immunogenicity depends on
`
`which antigens are exposed to the immune system. With different complexing
`
`strategies, it is possible that antigens may be exposed differently based on
`
`conformational differences among the various complexes with iron; thus immune
`
`reactions can vary based on the carbohydrate motifs involved and the mode of
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`binding to the iron moiety, both of which may contribute to differing presentations
`
`to the immune system.
`
`Petitioner would have the Board construe the claims to exclude compounds
`
`whose antigen exposure may be decreased as a result of complexation to iron and
`
`include compounds whose antigen exposure may be increased as a result of
`
`complexation to iron. Viewing the carbohydrate absent the iron, thus, would not
`
`be consistent with the fundamentals of immunology.
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`4815-5933-0601.3
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`21
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`IPR2015-01490
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`Patent Owner Preliminary Response
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`Further, it is understood that modifying the structure and molecular weight
`
`of a compound may have an impact on the immune response. In the context of
`
`iron carbohydrate complexes, the molecular weight of the complex is increased
`
`compared to the molecular weight of the carbohydrate itself. Ex. 1048, p. 3
`
`(showing the molecular weights of three different
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