`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`
`
`PHARMACOSMOS A/S,
`Petitioner,
`
`v.
`
`LUITPOLD PHARMACEUTICALS, INC.,
`Patent Owner.
`
`
`
`_______________
`
` Cases1 IPR2015-01490; Patent 7,754,702 B2
`
` IPR2015-01493; Patent 8,431,549 B2
`____________________________________________________________
`
`
`PATENT OWNER
`ORAL HEARING DEMONSTRATIVES
`
`
`
`
`1 The word-for-word identical paper is being filed in each proceeding identified in
`
`the heading.
`
`
`
`IPR2015-01490; IPR2015-01493
`
`
`
`
`
`Oral Hearing Demonstratives
`
`
`
`
`
`
`Date: September 15, 2016
`
`
`
`Respectfully submitted,
`
`/George E. Quillin/
`
`
`
`George E. Quillin
`Registration No. 32,792
`Counsel for Patent Owner
`
`
`
`Michael D. Kaminski
`Registration No. 32,904
`Counsel for Patent Owner
`
`
`
`
`
`
`Foley & Lardner LLP
`3000 K Street, N.W.
`Suite 600
`Washington, D.C. 20007
`
`
`
`
`
`
`
`
`
`Grounds Instituted
`U.S. Patent No. 8, 431,549 (IPR2015‐01493)
`Claim
`Basis
`Prior Art
`1‐5, 9, 16, 19
`§ 102
`van Zyl‐Smit (Ex. 1004)
`1, 12‐14
`§ 102
`Groman (Ex. 1003)
`
`U.S. Patent No. 7,754,702 (IPR2015‐01490)
`Claim
`Basis
`Prior Art
`1‐3, 10‐13, 23,
`§ 102
`Geisser (Ex. 1003,
`25, 27, 41‐43
`English translation)
`28
`Groman (Ex. 1004)
`17,47
`Geisser (Ex. 1003),
`Groman (Ex. 1004)
`van Zyl‐Smit (Ex. 1006)
`van Zyl‐Smit (Ex. 1006),
`Funk (Ex. 1026)
`
`1,14,15
`30
`
`§ 102
`§ 103
`
`§ 102
`§ 103
`
`#
`
`2
`3,4
`
`#
`
`1
`
`2
`3
`
`4
`5
`
`2
`
`
`
`Claim Construction
`
`Claim Construction
`
`3
`
`
`
`“substantially non‐immunogenic
`carbohydrate component”
`PATENT OWNER
`PETITIONER
`“low risk” requires:
`A carbohydrate component resulting
`in a “low risk of
`‐ An incidence of adverse events
`lower than iron dextran
`anaphylactoid/hypersensitivity
`(‘549 POR, pp. 6‐7/’702 POR, pp. 7‐
`reactions.” (‘549 Pet, p. 20/’702 Pet,
`8)
`p. 13)
`‐ A large enough cohort
`(‘549 POR pp. 7‐9/’702 POR, pp. 9‐
`10)
`Immunogenicity of the component
`should be considered in relation to the
`whole complex.
`(‘549 POPR, pp. 20‐22/’702 POPR, pp.
`19‐23)
`“the specification guides a POSITA to
`identify a carbohydrate component
`that is substantially non‐immunogenic,
`and use it in a complex with iron.”
`(‘549 Reply to POR, p. 10/’702 Reply to
`POR, pp. 9‐10)
`
`Disagrees with Patent Owner, but
`provides no alternative definition of
`“low risk”. (‘549 Reply to POR, pp. 8‐
`12/’702 Reply to POR, pp. 8‐11)
`
`BOARD
`A carbohydrate
`component
`resulting in a
`“low risk of
`anaphylactoid/
`hypersensitivity
`reactions.”
`(Paper 11,
`IPR2015‐10493,
`p. 7)
`
`4
`
`
`
`“substantially non‐immunogenic carbohydrate
`component”
`“[S]ubstantially non‐immunogenic” requires an incidence of
`adverse events lower than iron dextran.
`• Specification clearly disparages iron dextran:
`
`•
`
`• Specification also cites Fishbane: “[t]he risk for immediate severe
`anaphylactoid reactions appears to be, at a minimum,
`approximately 0.6% with IV iron dextran, and this agent has been
`associated with a number of deaths during the past several
`decades.” Ex. 2012, p. 2 (emphasis added).
`• Complex exemplified in the specification demonstrates “drug‐
`related treatment‐emergent adverse events of hypersensitivity was
`0.2%, the same as that observed with oral iron (0.2%).” Ex. 1001,
`col. 26: 12‐14.
`
`5
`
`
`
`•
`
`•
`
`•
`
`•
`
`Determination of “substantially non‐
`immunogenic” Requires a Large Enough Cohort
`
`For an adverse event with an incidence rate of 0.5%, a sample size of 200
`subjects will theoretically contain only one subject who exhibits that
`adverse event.
`For 0.6‐0.7 % incidence rate, a sample/cohort size of 145‐165 would
`theoretically contain one subject who exhibits the adverse event.
`Spinowitz refers to a population of of 2400 in another reference
`(Wallerstein) and calls it a “relatively small cohort.” Ex. 1011, p. 5.
`
`Spinowitz also refers to its own study with 21 subjects and notes that “the
`number of exposures is too small to draw any definitive conclusions” with
`regard to anaphylaxis. Ex. 1011, p. 5.
`
`6
`
`
`
`“iron polyisomaltose complex”
`
`Only in IPR2015‐01493
`PATENT OWNER
`“A POSITA would understand ‘polyisomaltose’ to mean an
`essentially purely linear chemical structure of repeating α 1‐6
`linked units which may be optionally reduced” (‘549 POPR, pp.
`27‐29)
`
`PETITIONER
`“Proper Construction”
`
`“because the specification provides no basis
`for differentiating between them, iron
`polyisomaltose and iron dextran should be
`regarded as synonyms for the purpose of
`claim construction.” (‘549 Pet, pp. 15‐17)
`
`“The term ‘polyisomaltose’ does not include ‘dextran.’” (‘549
`POPR, pp. 29‐31)
`
`“Construing ‘iron polyisomaltose complex’ as including iron
`dextran complexes would be inconsistent with the claimed
`genus of “iron carbohydrate complex.” (‘549 POPR, p. 34)
`
`“The term ‘polyisomaltose’ is not limited to a structure of
`reduced repeating α‐1‐6 linked glucose units with a molecular
`weight of 1000 Da.” This limitation is arbitrary. (‘549 POPR, pp.
`31‐32)
`
`“The term ‘hydrogenated dextran’ does not cover
`‘polyisomaltose.’” “Hydrogenated dextran” was deleted from
`the claims during prosecution. (‘549 POPR, pp. 32‐33)
`
`“Alternative Construction”
`
`“polyisomaltose can be essentially linear,
`reduced, and have a molecular weight of
`approximately 1000 Da (whereby it is
`substantially non‐immunogenic.)” (‘549 Pet,
`pp. 17‐18)
`
`7
`
`
`
`Parenthetical in Specification Does Not Mean
`Equivalence
`• This issue comes from the Petitioner wanting to exploit
`the mistake in the specification.
`• The specification says “iron polyisomaltose (iron
`dextran)”, in one place. Ex. 1001, 10:51.
`• A POSITA would not understand these terms to be
`synonymous or equivalent. ‘549 POPR, p. 29.
`• Deletion of “(iron dextran)” from a pending continuing
`application was a correction, not a nefarious act. Patent
`Owner cannot make that correction here.
`• Petitioner wants to continue to equate the terms, to try
`to encompass prior art that relates to iron dextran as
`relating to iron polymaltose.
`
`8
`
`
`
`Iron Dextran Complex Is Not a Claimed Species
`
`•
`
`The specification disparages iron dextran.
`– “Iron dextran, the first parenteral iron product available in the United States
`(US), has been associated with an incidence of anaphylactoid‐type reactions
`(i.e., dyspnea, wheezing, chest pain, hypotension, urticaria, angioedema). ...
`This high incidence of anaphylactoid reactions is believed to be caused by the
`formation of antibodies to the dextran moiety.” Ex. 1001, 1:47‐54.
`• Dextran is a branched glucan polysaccharide as seen in figure from
`Petitioner’s expert Declaration.
`
`Linhardt Declaration (Exs. 1005, 1014), Figure C
`
`9
`
`
`
`Art cited during prosecution shows
`“polyisomaltose” and “dextran” are different.
`• Muller, Ex. 1009/1031 p. 1 col. 2:48‐53:
`
`See citation by Examiner in Ex. 1006, p. 112.
`
`10
`
`
`
`Post‐filing art explicitly states
`“polyisomaltose” is different from “dextran”
`• Kalra, Ex. 2013, p. 2:
`
`11
`
`
`
`The Lawrence Declaration differentiated
`branched dextran from linear polyisomaltose
`• Ex. 1011 (submitted in prosecution), p. 2 ¶4:
`
`12
`
`
`
`Board Agreed with PO’s Construction of
`“iron polyisomaltose” in Related IPR
`
`“Patent Owner contends that ‘the parenthetical ‘dextran’ should not be considered to indicate equivalence’
`(Prelim Resp. 30), and that Petitioner’s construction is inconsistent with the understanding in the art of the
`term polyisomaltose and with the specification of the ‘612 patent (id at 29). Patent Owner contends that there
`is ample evidence of record that the two terms are not freely interchangable (id.) and that ‘Petitioner’s
`construction also ignores the disparaging remarks about dextran in the specification (id. at 30). For example,
`patent Owner points to the statement in U.S. Patent No. 3,100, 202 to Muller, issued August 6, 1963, and cited
`by the Examiner during prosecution: ‘While ‘polyisomaltose’ is a term used loosely for ‘dextran’…the latter is a
`compound of very high molecular weight, whereas polyisomaltose is a degradation product of dextran
`consisting of polymerized glucose residues joinder predominantly by 1,6 linkages. Prelim Resp. 28 (citing Ex.
`1010, 2:48‐53). We further note statements in the ‘612 patent to the effect that serious and life‐threatening
`reactions occur more frequently with iron dextran. ‘ (Ex. 1001, 1:43‐44), “i[i]ron dextran…has been associated
`with an incidence of anaphylactoid‐type reaction” (id. at 1:51‐53) and “[t]his high incidence of anaphylactoid
`reactions is believed to be caused by the formation of antibodies to the dextran moiety” (id. at 1:56‐58).
`Finally, we note that the ‘612 patent emphasizes that the iron carbohydrate complexes of the invention
`preferably have various characteristics – including a ‘non‐immunogenic carbohydrate component’ and
`‘substantially on cross‐reactivity with anti‐dextran antibodies’ (id. at 3:28‐31).
`
`Having considered the evidence of record, we agree with Patent Owner that Petitioner has not
`established adequately that the claim term ‘iron polyisomaltose’ would be understood by one
`of ordinary skill in the art in the context of the entire disclosure of the ’612 patent to
`encompass Marchasin’s ‘iron dextran.’”
`
`Pharmacosmos A/S v. Luitpold Pharmaceuticals Inc., IPR 2015-01495, Paper 11, pp. 12-14 (PTAB January 8,
`2016) (emphasis added)
`NOTE: The ‘612 patent is a child of both the ‘702 and ‘549 patents.
`
`13
`
`
`
`“iron carboxymaltose complex”
`
`Only in IPR2015‐01490
`
`PATENT OWNER
`“Patent Owner agrees with Petitioner’s
`expert with regard to his description of
`carboxymaltose ‘a maltose or
`maltodextrin, comprised of maltose
`type units, in which the aldehyde group
`of the reducing sugar end has been
`oxidized to form a carboxylic acid group.
`Maltose is a D‐glucopyranose dimer
`linked through an α 1‐4 glycosidic bond’
`Ex. 1005, ¶8.” ‘702 POR, pp. 14‐15
`
`PETITIONER
`“at least includes an iron carbohydrate
`complex ‘obtained from an aqueous
`solution of iron(III) salt and an aqueous
`solution of the oxidation product of one
`or more maltodextrins using an aqueous
`hypochlorite solution at a pH value
`within the alkaline range.” ‘702 Pet, p.
`11.
`
`14
`
`
`
`“iron sorbitol complex”
`PATENT OWNER
`PETITIONER
`“a person of ordinary skill in the art
`“a complex of iron and sorbitol” with the
`(‘POSITA’) would not consider ‘iron
`structure of sorbitol , which has the
`sorbitol’ to refer to iron polyglucose
`structure:
`sorbitol carboxymethyl ether, but
`instead refer to iron complexed with
`sorbitol monosaccharide…Petitioner
`elects to construe ‘iron sorbitol’ as
`would a POSITA, but without prejudice if
`patentee can provide evidence that iron
`polyglucose sorbitol carboxymethyl
`ether would indeed be considered an
`iron sorbitol by a POSITA” (‘549 Pet, pp.
`18‐19/’702 Pet, p. 12)
`
`“this interpretation does not include iron
`polyglucose sorbitol carboxymethyl
`ether.”
`(‘549 POR, pp. 9‐13/’702 POR, pp. 10‐14)
`
`(Ex. 2015, p. 18)
`
`The term “iron sorbitol” in claim 1 does not include “iron polyglucose sorbitol
`carboxymethyl ether” in the dependent claims. Same in both patents.
`
`15
`
`
`
`Patent Owner, Petitioner, and Both Experts
`All Agree on “iron sorbitol complex.”
`• “Petitioner agrees with Patent Owner that the
`broadest reasonable interpretation of ‘iron
`sorbitol complex’ is ‘a complex of iron and
`sorbitol’ where sorbitol is a sugar alcohol that is
`not part of a polymer.’ [sic.] Response, 12. Iron
`polyglucose sorbitol carboxymethyl ether (e.g.,
`ferumoxytol; Feraheme®) is not an iron sorbitol.”
`(‘549 POR Reply, p. 12; ‘702 POR Reply, p. 11)
`
`The term “iron sorbitol” does not include “iron
`polyglucose sorbitol carboxymethyl ether”.
`
`16
`
`
`
`Geisser
`Grounds 1 and 3 in IPR2015‐1490
`
`17
`
`
`
`Petitioner’s Arguments
`• Anticipation
`– Petitioner contends that Geisser discloses iron
`carboxymaltose recited in the claims and
`therefore inherently anticipates the “substantially
`non‐immunogenic carbohydrate component.”
`– Petitioner argues that Geisser’s dose (500‐1000
`mg iron) anticipates the claimed range.
`– Petitioner argues that Geisser discloses the
`claimed methods.
`
`18
`
`
`
`Petitioner Does Not Meet Its Burden to
`Demonstrate Anticipation Over Geisser
`• Petitioner has not shown that Geisser necessarily
`discloses “iron carboxymaltose”, because Geisser
`only describes “methods of making” but does not
`characterize the complex.
`– They only cite the much later “Orange Book” listing.
`• Petitioner has not demonstrated that Geisser
`discloses “an iron carbohydrate complex with a
`substantially non‐immunogenic carbohydrate
`complex”.
`
`19
`
`
`
`Groman
`Grounds 3 and 4 in IPR2015‐01493
`Grounds 2 and 3 in IPR2015‐01490
`
`20
`
`
`
`Petitioner’s Arguments
`• Anticipation
`– Petitioner contends that Groman discloses “iron
`polyglucose sorbitol carboxymethyl ether” and thus
`allegedly anticipates certain claims of the ‘702 and ‘549
`patents.
`– Petitioner contends that Groman also discloses “iron
`polyisomaltose” (that it is “dextran T1”) and thus allegedly
`also anticipates claim 14 of the ‘549 patent.
`• Obviousness (only in IPR2015‐0190, ‘702 patent)
`– Petitioner contends that a POSITA would have been
`motivated to administer the iron complex of Geisser
`according to the rate (claim 17) or as a bolus (claim 47),
`allegedly disclosed in Groman.
`
`21
`
`
`
`Groman Does Not Disclose “iron sorbitol”
`The independent claim 1 in each patent recites “iron sorbitol complex.”
`‘702 patent, col. 26:58‐62
`‘549 patent, col. 26:56‐60
`
`•
`
`• As Petitioner states: “Iron polyglucose sorbitol carboxymethyl ether (e.g.,
`ferumoxytol; Feraheme®) is not an iron sorbitol.” (‘549 POR Reply, p. 12;
`‘702 POR Reply, p. 11)
`• Groman discloses only “iron polyglucose sorbitol carboxymethyl ether “
`(not an “iron sorbitol complex”) and therefore does not anticipate claim 1.
`“Iron polyglucose sorbitol carboxymethyl ether” is recited in dependent
`claims. This is a separate issue, because of the mistake in dependency.
`– Dependent claims 12‐13 of ‘549 patent and claims 28‐29 of ‘702 patent.
`
`•
`
`22
`
`
`
`Groman Does Not Disclose “iron polyisomaltose”
`(Claim 14 in IPR2015‐01493, )
`• Petitioner incorrectly points to Dextran T1 in Groman as being
`an “essentially linear” hydrogenated dextran. ‘549 Pet. 55.
`• However, Dextran T1 is not “essentially linear” because it is
`not processed to remove branching. Dr. Manzi Declaration,
`Ex. 2089/1053, ¶ 77.
`– Dr. Lindhardt says the opposite, but without any support. Lindhardt
`Decl., ‘549 Ex. 1014, ¶ 10.
`• Only linearity is in the end terminal sugar residue to a linear
`polyol. Groman, Ex. 1003/1004, Scheme 1, ¶[0070]. Not
`enough to make it “essentially linear.”
`
`23
`
`
`
`•
`
`Carbohydrates of Geisser and Groman are Not
`“Structurally Similar” (Obviousness)
`• Petitioner contends that the carbohydrates in Geisser and Groman are
`“structurally analogous”, based on binding to iron. ‘702 Pet. 46.
`The carbohydrates of Geisser and Groman are “structurally different”.
`– Geisser’s carbohydrates are ‐1→4 linked; Groman’s carbohydrates are 1 →6 linked.
`Ex. 2089/1053, ¶50.
`“[D]ifferent glyosidic linkages provide different degrees of flexibility or
`rigidity resulting in different properties of the polysaccharides.” Dr. Manzi
`Declaration, Ex. 2089/1053, ¶50; Morris (Ex. 2086).
`• Morris (Ex. 2086) shows different conformations for 1‐4 and 1‐6
`linkages.
`
`•
`
`24
`
`
`
`Carbohydrates of Geisser and Groman are
`“Structurally Different”
`• Geisser’s carboxyl group is at the terminal carbon; Groman’s carboxymethyl groups
`are at 2, 3, 4 positions of the sugar.
`Carboxymaltose oxidation
`Oxidation at
`terminal position
`
`Ferumoxytol oxidation
`
`Oxidation at internal
`(2, 3, 4) positions
`
`Linhardt Declaration, Fig. H
`
`Ex. 1035, Fig. 4, p. 12
`• No concept in patent law considering “structurally different” compounds for
`obviousness purposes.
`
`25
`
`
`
`No Motivation to Combine Geisser and
`Groman
`• Groman’s and Geisser’s carbohydrates are
`“structurally different”.
`• Therefore, a POSITA would not have been
`motivated to combine their disclosures.
`
`26
`
`
`
`van Zyl‐Smit
`Ground 2 in IPR2015‐01493
`Grounds 4 and 5 in IPR2015‐01490
`
`27
`
`
`
`Petitioner’s Arguments
`• Petitioner contends that van Zyl‐Smit’s
`disclosure of “iron polymaltose complex”
`anticipates claim 1 of each patent.
`
`28
`
`
`
`There Is No Clear Teaching That The
`Carbohydrate Component In van Zyl‐Smit Is
`“Substantially Non‐Immunogenic”
`• van Zyl‐Smit does not administer or test the
`carbohydrate polymaltose alone, i.e., separate from
`its complexation to iron.
`• On the contrary, van Zyl‐Smit only discloses
`adminstration of iron polymaltose complex (Ex.
`1006/1004, p. 2):
`
`29
`
`
`
`The Sample Size in van Zyl‐Smit is
`Too Small.
`• van Zyl‐Smit administered iron polymaltose to only 62
`patients (Ex. 1006/1004, p. 2):
`
`• For 0.6‐0.7 % incidence rate, cohort size of 145‐165 would
`theoretically contain one subject who exhibits the adverse
`event.
`• Thus, lack of immunogenic effect in a 62 subject cohort is not
`sufficient to demonstrate “substantial non‐immunogenicity.”
`– For a 62 subject cohort with one subject who exhibits the adverse
`event, the incidence rate would have to be 1.6%.
`
`30
`
`
`
`Other Iron Polymaltoses Were Known To Be
`Immunogenic
`• Ferrosig® is another brand of “iron
`polymaltose”.
`• The package insert for Ferrosig® warns:
`“[p]arenterally administered iron preparations can
`cause allergic or anaphylactoid reactions.” Ex. 2003,
`p. 4.
`
`31
`
`
`
`Dextrins Were Known to Exhibit
`Immunogenic Effects
`• van Zyl–Smit says “iron polymaltose (dextrin)”
`• A study by Lam Po‐Tang (Ex. 2084)
`administered icodextrin (another dextrin) and
`observed an immunogenic response:
`“[It is] plausible that either the same or a similar
`epitope [as dextran] may also be responsible for the
`hypersensitivity reaction seen with icodextrin.” Ex.
`2084, p. 3.
`
`32
`
`
`
`Funk
`Ground 5 in IPR2015‐01490
`
`33
`
`
`
`Dr. Manzi’s Declaration
`• Funk measured and provided “particle sizes”
`for four different iron carbohydrates. But it is
`not clear what is being measured: whole
`complex or iron core.
`• Before her deposition, Dr. Manzi corrected her
`Declaration to note this lack of clarity:
`
`34
`
`
`
`There Is No Motivation to Combine
`van Zyl‐Smit and Funk
`• Petitioner contends that it would have been obvious to use the
`particle size of the iron dextrin from Funk for the treatment of iron
`deficiency as disclosed in van Zyl‐Smit. ‘702 Pet. 55.
`• However, Petitioner and its expert omit a key portion of Funk. The
`full sentence of Funk reads:
`
`•
`
`•
`
`Iron dextrin and iron polymaltose are two different species in Funk,
`while van Zyl‐Smit discloses “iron polymaltose (dextrin).”
`Iron dextrin and iron polymaltose in Funk are on opposite ends of
`the dissolution spectrum.
`• Funk provides no teaching about which dissolution rate is better.
`• A POSITA would have no basis to pick iron dextrin or iron
`polymaltose from Funk because van Zyl‐Smit mixes up the two.
`
`35
`
`
`
`‘549 Patent Motion to Amend
`
`36
`
`
`
`Substitute Claim 24
`Substitute Claim
`Issued Claim
`
`24. 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 mannitol complex,
`and an iron polyisomaltose complex, an iron
`polymaltose complex, an iron gluconate complex,
`and an iron sorbitol complex,
`the iron carbohydrate complex has a substantially
`non‐immunogenic carbohydrate component, and
`the disease, disorder or condition is not
`Restless Leg Syndrome.
`
`37
`
`
`
`Claim Correspondence Chart
`
`Issued
`Claim
`1
`2
`3
`4
`5
`9
`12
`13
`14
`15
`16
`19
`
`Substitute
`Claim
`24
`25
`26
`27
`28
`29
`CANCELED
`CANCELED
`33
`30
`31
`32
`
`•
`
`Issued claims 12 and 13 would be
`cancelled (“iron polyglucose sorbitol
`carboxymethyl ether”).
`• Claims 25‐33 “transfer” over from
`original issued claims, without
`change.
`
`38
`
`
`
`The amendments narrow Claim by
`deleting a member of the Markush
`group.
`
`Thus, the full scope of these claims
`has already been examined.
`
`39
`
`
`
`The Amendments are Responsive to
`the Grounds.
`
`• van Zyl‐Smit
`– “an iron polymaltose complex” is deleted from the
`substitute claims.
`– van Zyl‐Smit is cited for anticipation based on its alleged
`teaching of high dose administration of an “iron
`polymaltose complex”, only.
`• Groman
`– Improper dependent claims 12 & 13 relating to “iron
`polyglucose sorbitol carboxymethyl ether” would be
`cancelled.
`– Groman is cited for anticipation based on its alleged
`teaching of “iron polyglucose sorbitol carboxymethyl
`ether”, only.
`
`40
`
`
`
`‘702 Patent Motion to Amend
`
`41
`
`
`
`Substitute Claim 58 in ‘702 Patent
`Substitute Claim
`Issued Claims
`
`A method of treating a disease, disorder, or
`58.
`condition characterized by iron deficiency or
`dysfunctional iron metabolism resulting in reduced
`bioavailability of dietary iron, comprising
`administering to a subject in need thereof an iron
`carbohydrate complex in a single dosage unit of at
`least about 0.6 grams of elemental iron;
`wherein
`the iron carbohydrate complex is selected from
`the group consisting of an iron carboxymaltose
`complex, an iron mannitol complex, an iron
`polymaltose complex, an iron gluconate complex,
`and an iron sorbitol complex; and
`the iron carbohydrate complex has a substantially
`non‐immunogenic carbohydrate component and
`substantially no cross reactivity with anti‐dextran
`antibodies
`wherein said disease, disorder or condition
`is not Restless Leg Syndrome, and
`wherein the iron carbohydrate complex
`comprises an iron core with a mean iron core size
`of no greater than about 9 nm.
`
`42
`
`
`
`Correspondence chart
`
`Issued
`Claim
`1, 30
`2
`3
`10‐15
`17
`23
`25
`27
`28
`29
`41‐43
`47
`
`Substitute
`Claim
`58
`59
`60
`61‐66
`74
`67
`68
`69
`CANCELED
`DISCLAIMED
`70‐72
`73
`
`•
`
`Issued claims 28 and 29 would
`be cancelled/disclaimed (“iron
`polyglucose sorbitol
`carboxymethyl ether”).
`• Claims 59‐74 “transfer” over
`from original issued claims,
`without change.
`
`43
`
`
`
`The amendments narrow the claim
`by deleting a member of the
`Markush group and adding a
`limitation from a pre‐existing
`dependent claim.
`
`Thus, the full scope of these claims
`has already been examined.
`
`44
`
`
`
`The Amendments are Responsive to
`Grounds.
`
`• Geisser
`– Claims amended to specify mean iron core size
`– Geisser is silent on mean iron core size:
`“Geisser (Ex. 1003/1044 and Ex. 1014/1021) is silent on the properties of the iron,
`such as mean iron core size, in the iron carbohydrate complexes it generates; indeed,
`Geisser offers no physicochemical characterization of the iron used in its methods
`aside from molecular weight and percent composition of the final complex.” (Dr.
`Manzi Declaration, Ex. 2089/1053, ¶87)
`• Groman
`– Improper dependent claims relating to “iron polyglucose sorbitol
`carboxymethyl ether” are canceled or disclaimed
`– Groman is cited for anticipation based on its alleged teaching of “iron
`polyglucose sorbitol carboxymethyl ether”
`• van Zyl‐Smit and Funk
`– “an iron polymaltose complex” is deleted from the substitute claims
`– van Zyl‐Smit is cited for anticipation and obviousness based on its alleged
`teaching of high dose administration of an iron polymaltose complex
`– Funk is cited for obviousness based on its alleged teaching of mean iron core
`size of iron polymaltose
`
`45
`
`
`
`Summary of Petitioner’s Opposition
`• Petitioner alleges that the substitute claims are not
`enabled and are not supported by the specification and
`are “indefinite”.
`– The Petitioner alleges that the specification does not
`enable all of the remaining, previously claimed species.
`– The Petitioner alleges that the specification does not
`enable all subjects or all routes of administration.
`– Petitioner alleges that claims are indefinite.
`• Petitioner also improperly requests that even
`unchallenged claims be cancelled.
`• Petitioner next alleges that all of the amended claims
`are “obvious” for prior art reasons.
`• Petitioner provides only attorney arguments.
`
`46
`
`
`
`The Enablement Attacks Are Unjust
`• None of the rules, Trial Practice Guide, or Board
`precedential decisions require a Motion to
`Amend to show enablement.
`• There is no notice in the Board’s Paper 21 that
`such a requirement exists.
`• It would be unjust to deny relief on Patent
`Owner’s Motion.
`– D’Amour v. Fisk, Interference No. 105,734 , Paper 430,
`p. 7 (BPAI, April 12, 2012)(McKelvey, J.)(“It would not
`be consistent with 37 CFR § 41.1(b) (rules to be
`construed to achieve inexpensive resolution of an
`interference) to impose upon a moving party the
`additional expense of establishing enablement when
`enablement may not be an issue.”)
`
`47
`
`
`
`The Substitute Claims Are Enabled
`• The specification enables methods of using VIT‐45 (iron
`carboxymaltose).
`• The general method of making VIT‐45 would enable a
`POSITA to make it without undue experimentation.
`• The disclosure and working examples allow a POSITA to
`determine immunological properties.
`• The methods of administration in the specification
`allow a POSITA to administer all the claimed species
`without undue experimentation.
`• A specification need not provide what is already known
`in the art.
`
`48
`
`
`
`“Subject” Can Only be Human
`• “Subject” in the claims refers to a human.
`• Throughout the specification and in the section entitled
`“Subject in Need Thereof,” the term “subject” and
`“patient” are used interchangeably. Ex. 1001, 9:18‐10:44.
`• The specification refers to clinical guidelines such as “NKF‐
`K/DOQI, Clinical Practice Guidelines for Anemia of Chronic
`Kidney Disease (2000)” and “target hemoglobin level of a
`patient” that are related to requirements for human
`therapy. Id. at 10:7‐29.
`• A POSITA would understand that the indications listed in
`the specification are for human treatment. Ex. 1001, 2:38‐
`64; 5:42‐6:2.
`– The specification also notes that “1700 subjects have been
`treated with an iron carboxymaltose complex (VIT‐45) in open
`label clinical trials (see e.g., Example 5)” again equating subject
`with human. Id. 13:16‐24.
`
`49
`
`
`
`The Substitute Claims Are Not Indefinite
`• “[S]ubstantially non‐immunogenic carbohydrate
`component” is not indefinite.
`• It has been construed by Petitioner, Patent
`Owner, even Board in IPR2015‐01493.
`• Nothing improper about looking outside the
`specification to construe claim terms.
`• Thus, choice of a particular adverse event rate for
`iron dextran is not arbitrary.
`– It is based on the incidence of anaphylactoid‐type
`reactions to iron dextran, which has been disparaged
`and disavowed in the specification.
`
`50
`
`
`
`Patent Owner Has Met Its Affirmative
`Burdens for the Motions to Amend
`• Patent Owner is required to show:
`– Patentability over the “material” prior art
`– Written support for the claims “as a whole”
`E.g., Masterimage 3D, Inc. v. RealD, Inc., IPR2015-
`00040 (PTAB July15, 2015); Idle Free Systems, Inc.
`v. Bergstrom, Inc., IPR 2012-00027 (PTAB June 11,
`2013).
`
`51
`
`
`
`Patent Owner Has Shown Written Description
`Support for The Substitute Claims
`• In its Motions, Patent Owner showed specific
`support for the substitute claims in the
`specification as filed and in the priority
`applications.
`• Patent Owner thus met its affirmative burden
`of demonstrating Written Description for its
`substitute claims.
`
`52
`
`
`
`The Burden for “Obviousness” is High.
`• As of January 2006, the prior art can be characterized
`by three themes:
`– High doses of any iron carbohydrate complexes should not
`be administered due to uncertainty of their possible
`immunogenic reactions.
`– More specifically, iron dextran complexes were to be
`administered with extra caution due to the risk of iron
`dextran related immunogenic reactions.
`– Based on these findings with iron dextran, understanding
`the rate of immunogenic reactions requires a cohort large
`enough to reveal adverse reaction incidence rates.
`(Ex. 2089/1053, ¶65)
`
`53
`
`
`
`None of this Prior Art is More “material”
`Than It Was Before the Motion to Amend
`• Polymaltose‐related art
`– this species is deleted from the claims.
`– no teaching that guidance pertinent to this species is extrapolatable.
`• Ferumoxytol‐related art
`– this species does not fall within the scope of the claims.
`– no teaching that guidance pertinent to this species is extrapolatable.
`• Dextran‐related art
`– this species does not fall within the scope of the claims.
`– dextran is disparaged by the specification.
`• RLS related art
`– negative limitation on the claims excludes RLS.
`– RLS is a unique indication.
`• No other reference teaches high dose administration of any of the
`remaining claimed species!
`
`54
`
`
`
`Petitioner’s Arguments
`• Alleges that the ‘549 claims lack novelty over Groman.
`– Addressed above.
`• Alleges that Patent Owner has not distinguished:
`– RLS art (‘549 Opp, pp. 18‐21/’702 Opp, pp. 21‐24)
`– Dextran‐related art (‘549 Opp, pp. 18‐20/’702 Opp, pp. 20‐24),
`citing a 2015 publication from Wang (Ex. 1055 and Ex. 1056)
`alleging dextran is safe and effective!
`• Alleges that van Wyck (Ex. 2049), Beshara (Ex. 2041), and
`the German reference (Ex. 2004/1007, pp. 94‐117) were
`not properly considered in relation to the ‘702 claims.
`– All these prior art arguments were not in the Petitions!
`• Alleges that art relating to animals was not properly
`considered.
`
`55
`
`
`
`RLS is a unique indication
`• RLS is a specific indication that requires dosing
`conditions that differ from other indications.
`– Ex. 1007/1009, p. 4 ¶[0011]:
`
`• RLS dosing is tied to a parameter known as IDI
`(the release rate of an iron dextran)
`– Ex. 1007/1009, Abstract:
`
`56
`
`
`
`The prosecution history clarifies why RLS
`art is distinguishable from the claims.
`
`Ex. 2004/1007, p. 16
`
`57
`
`
`
`It has been established by Patent
`Owner that “iron dextran complex”
`does not fall within the scope of the
`claims.
`
`58
`
`
`
`van Wyck is silent on high dose
`administration of any of the claimed
`species.
`
`59
`
`
`
`Beshara relates to “iron polymaltose”.
`
`• Petitioner cites specification
`and 2015 reference by
`Keating (Ex. 1057) to
`suggest that Beshara relates
`to an iron carboxymaltose.
`– The Keating reference is
`unauthenticated and not
`prior art (2015).
`• Beshara explicitly states it
`relates to iron polymaltose.
`• Beshara does not teach high
`dose or immunogenicity of
`the compounds disclosed
`therein.
`
`Ex. 2041
`
`60
`
`
`
`There is no basis for Petitioner’s
`claim that Patent Owner has a
`burden to consider the German
`reference’s impact on inventorship.
`
`61
`
`
`
`Animal Art Does Not Apply
`• The claims are clearly directed to methods of treating a
`human.
`• The animal art is silent on immunogenicity and the claimed
`species.
`– The alleged certificate analysis of Anaemex® (Ex. 1068) is
`unauthenticated and
`• does not show what was intended by the term “Passed” used in the
`analysis;
`• does not show that the analysis relates to the same batch as the
`reference relating to this product;
`• does not show that this analysis was publically available as of January
`2006; or
`• does not support any other argument demonstrating that
`polyisomaltose was necessarily present in any reference or that a
`POSITA would have known polyisomaltose was present in its iron
`dextran product.
`
`62
`
`
`
`If The Issued Claims Are Found Unpatentable,
`The Motions to Amend Should Be Granted
`• The Board gave notice of two PO burdens;
`these are met:
`– There is no prior art challenge to the amended
`claims.
`– The amended claims have written support in both
`the provisional application and the original
`disclosure of the patent.
`• Patent Owner has also responded to
`Petitioner’s allegations of non‐enablement
`and indefiniteness.
`
`63
`
`
`
`END
`
`64
`
`
`
`IPR2015-01490; IPR2015-01493
`
`
`
`
`
`Oral Hearing Demonstratives
`
`
`CERTIFICATE OF SERVICE
`
`The undersigned certifies that a copy of the foregoing Patent Owner Oral
`
`Hearing Demonstratives is being served on September 15, 2016, by filing through
`
`the PTAB E2E System and delivering a copy via email to the counsel for Petitioner
`
`/George E. Quillin/
`George E. Quillin
`Registration No. 32,792
`Counsel for Patent Owner
`
`
`
`
`
`at the addresses of record:
`
`
`
`Lisa Kole
`Baker Botts L.L.P.,
`30 Rockefeller Plaza, 45th Floor,
`New York, NY 10112
`E-mail: lisa.kole@bakerbotts.com
`
`Steven Lendaris
`Baker Botts L.L.P.,
`E-mail: steven.lendaris@bakerbotts.com
`
`Paul Ragusa
`Baker Botts L.L.P.,
`E-mail: paul.ragusa@bakerbotts.com