IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Application No.: 14/100,717
`
`Examiner: LAU, JONATHAN S
`
`Group Art Unit: 1673
`
`Confirmation No.: 2813
`
`Customer No.: 26263
`
`Applicant: HELENEK, MARY JANE
`
`Filed: 09 December 2013
`
`Title: METHODS AND COMPOSITIONS
`FOR ADMINISTRATION OF IRON
`
`Docket No.: 30015730-0065
`
`09 June 2014
`
`FILED ELECTRONICALLY VIA EFS-WEB
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`AMENDMENT AND RESPONSE TO OFFICE ACTION
`
`UNDER 37 C.F.R. § 1.111
`
`Sir:
`
`In response to the Office Action of 07 February 2014, Applicants request the
`
`Office to enter the following amendments and consider the remarks set forth below.
`
`Because 07 June 2014, falls on a weekend, this Response is being filed on the
`
`next following business day, 09 June 2014, and is, therefore, timely filed as of the four
`
`month date.
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`Page 1 of 19
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`Pharmacosmos, Exh. 1020, p. 1
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`

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`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`IN THE CLAIMS
`
`1. (currently amended) 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, ar-t--iro,r.t--9,lt,H:K}Fh::.<tH--GOH-"lf.Jl·HK;--·an iron sorbitol
`
`hydrogenated dextran complex_;
`
`2. (canceled)
`
`3. (original) The method of claim 1, wherein the iron carbohydrate complex has
`
`substantially no cross reactivity with anti-dextran antibodies.
`
`4. (original) The method of claim 1, wherein the disease, disorder, or condition
`
`comprises anemia.
`
`5. (original) The method of claim 4, wherein the anemia comprises iron
`
`deficiency anemia.
`
`6. (original) The method of claim 4, wherein:
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`Page 2 of 19
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`Pharmacosmos, Exh. 1020, p. 2
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`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`(i) the anemia comprises an iron deficiency anemia associated with chronic blood
`
`loss; acute blood loss; pregnancy; childbirth; childhood development; psychomotor and
`
`cognitive development in children; breath holding spells; heavy uterine bleeding;
`
`menstruation; chronic recurrent hemoptysis; idiopathic pulmonary siderosis; chronic
`
`internal bleeding; gastrointestinal bleeding; parasitic infections; chronic kidney disease;
`
`dialysis; surgery or acute trauma; and chronic ingestion of alcohol, chronic ingestion of
`
`salicylates, chronic ingestion of steroids; chronic ingestion of non-steroidal anti(cid:173)
`
`inflammatory agents, or chronic ingestion of erythropoiesis stimulating agents;
`
`(ii) the anemia is of a chronic disease selected from the group consisting of
`
`rheumatoid arthritis; cancer; Hodgkins leukemia; non-Hodgkins leukemia; cancer
`
`chemotherapy; inflammatory bowel disease; ulcerative colitis thyroiditis; hepatitis;
`
`systemic lupus erythematosus; polymyalgia rheumatica; scleroderma; mixed connective
`tissue disease; Sojgren's syndrome; congestive heart failure I cardiomyopathy; and
`
`idiopathic geriatric anemia;
`
`(iii) the anemia is due to impaired iron absorption or poor nutrition;
`
`(iv) the anemia is associated with Crohn's Disease; gastric surgery; ingestion of
`
`drug products that inhibit iron absorption; or chronic use of calcium.
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`7. (original) The method of claim 1 wherein the disease, disorder, or condition is
`
`selected from the group consisting of restless leg syndrome; blood donation; hair loss;
`
`and attention deficit disorder.
`
`8. (original) The method of claim 1 wherein the single dosage unit of elemental
`
`iron is at least about 1 .0 grams.
`
`9. (original) The method of claim 1 wherein the single dosage unit of elemental
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`iron is at least about 1 .5 grams.
`
`10. (original) The method of claim 1 wherein the single dosage unit of elemental
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`iron is at least about 2.0 grams.
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`Page 3 of 19
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`Pharmacosmos, Exh. 1020, p. 3
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`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`11. (canceled)
`
`FILED VIA EFS-Web
`
`12. (original) The method of claim 1 wherein the single dosage unit of elemental
`
`iron is administered in about 5 minutes or less.
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`13. (original) The method of claim 1 wherein the iron carbohydrate complex is
`
`an iron carboxymaltose complex.
`
`14. (original) The method of claim 13, wherein
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`(i) the iron carboxymaltose complex has a chemical formula of [FeOx (OH)y
`
`(H20)z ]n [{(C5H100s)m (C5H1207 )}1 ]k, where n is about 103, m is about 8, I is about 11,
`and k is about 4; contains about 28% elemental iron; and has a molecular weight of
`
`about 150,000 Da; or
`
`(ii) the iron carboxymaltose complex is a polynuclear iron (111)-hydroxide 4(R)(cid:173)
`
`(poly-(1-A )-O-a-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate.
`
`15. (original) The method of claim 1, wherein the iron carbohydrate complex is
`
`an iron polyglucose sorbitol carboxymethyl ether complex.
`
`16. (original) The method of claim 15, wherein the iron polyglucose sorbitol
`
`carboxymethyl ether complex is a polyglucose sorbitol carboxymethyl ether-coated non(cid:173)
`
`stoichiometric magnetite complex.
`
`17. (original) The method of claim 1, wherein
`
`mean iron core size is at least about 1 nm but no greater than about 9 nm; or
`mean size of a particle of the iron carbohydrate complex is no greater than about
`
`35 nm.
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`Page 4 of 19
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`Pharmacosmos, Exh. 1020, p. 4
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`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`18. (original) The method of claim 1, wherein the iron carbohydrate complex is
`
`administered parenterally.
`
`19. (original) The method of claim 18, wherein
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`(i) parenteral administration comprises intravenous infusion and the single unit
`
`dose of iron carbohydrate complex is administered at a concentration of about 1000 mg
`
`elemental iron in about 200 ml to about 300 ml of diluent;
`
`(ii) parenteral administration comprises bolus injection and the single unit dose of
`
`iron carbohydrate complex is administered at a concentration of about 1000 mg
`
`elemental iron in about 200 ml to about 300 ml of diluent; or
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`(iii) parenteral administration comprises intramuscular injection and the single
`
`unit dose of iron carbohydrate complex is administered at a concentration of about 500
`
`mg elemental iron in less than about 10 ml diluent.
`
`20. (original) The method of claim 1 further comprising a second administration
`
`of said iron carbohydrate complex upon recurrence of at least one symptom of the
`
`disease, disorder, or condition.
`
`21. (new) The method of claim 1, wherein iron carbohydrate complex does not
`
`have an iron release rate of 115 µg/dl at a concentration of 2,000 µg/dl.
`
`22. (new) The method of claim 1, wherein the iron carbohydrate complex is an
`
`iron polyisomaltose complex.
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`Page 5 of 19
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`Pharmacosmos, Exh. 1020, p. 5
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`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`REMARKS
`
`Upon entry of this amendment, claims 1-22 are pending. Claim 1 has been
`
`amended. Claim 21 and 22 have been added. No claims have been withdrawn.
`
`Claims 2 and 11 have been canceled.
`
`Support for the amendment to claim 1 appears at least at claim 2, claim 11, and
`
`claim 15. Support for new claim 21 appears at least at page 13, ,-r0045, which
`
`incorporates by reference U.S. Patent Pub. No. 2004/0180849 (see page 3, ,-r0026 of
`
`U.S. Patent Pub. No. 2004/0180849). Support for new claim 22 appears at least at
`
`claim 1.
`
`No new matter has been added by way of this response.
`
`Restriction Status
`
`There has been no Invention Restriction or Species Restriction in the present
`
`application. Applicants understand the Office to be examining the full scope of all
`
`claims.
`
`Examination Status
`
`Applicants note the absence of any analysis or rejection over 35 U.S.C. § 112.
`
`The Office has an administrative burden "to clearly articulate any rejection early in the
`
`prosecution process so that the applicant has the opportunity to provide evidence of
`
`patentability and otherwise reply completely at the earliest opportunity." MPEP § 706
`
`(emphasis added). If the Office subsequently presents a rejection under 35 U.S.C. §
`
`112 in a subsequent Office Action, Applicants respectfully request the Office to provide
`
`a basis as to why such rejection was not addressed in the first Action.
`
`Claim Rejections under 35 U.S.C. § 102 over Geisser
`
`Applicants respectfully traverse and, for the following reasons, request
`
`reconsideration and withdrawal of the rejection of claims 1, 3-5, 8, 13, 14, and 18 under
`
`pre-AIA 35 U.S.C. §102(b) as being anticipated by Geisser et al., WO 2004/037865,
`
`evidenced by English language equivalent US 7,612, 109 ("Geisser").
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`Page 6 of 19
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`Pharmacosmos, Exh. 1020, p. 6
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`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`Anticipation under 35 U.S.C. §102 can be found only when the reference
`
`discloses exactly what is claimed. MPEP §2131.03(111). For anticipation, the cited
`
`reference must teach every aspect of the claimed invention either explicitly or impliedly,
`
`and any feature not directly taught must be inherently present. MPEP §706.02(V).
`
`Claim 11 is not rejected as anticipated by Geisser. In the interest of furthering
`
`prosecution, claim 1 has been amended to recite "the single dosage unit of elemental
`
`iron is administered in about 15 minutes or less". As such, all features of canceled
`
`claim 11 have been incorporated into claim 1.
`
`For at least the above reasons, claim 1 is not prima facie anticipated by Geisser.
`
`The above argument applies equally to claim 1 and claims dependent thereon or
`
`featuring pertinent elements thereof, such as claims 3-5, 8, 13, 14, and 18.
`
`Claim Rejections under 35 U.5.C. § 102 over Helenek
`
`Applicants respectfully traverse and, for the following reasons, request
`
`reconsideration and withdrawal of the rejection of claims 1-3, 7-12, and 18-20 under pre(cid:173)
`
`AIA 35 U.S.C. §102(b) as being anticipated by Helenek et al., US 2004/0180849
`
`("Helenek"). Claims 2 and 11 have been canceled, making the above rejection moot as
`
`to these claims.
`
`Standards of novelty are as discussed above.
`
`Helenek discloses treatment of Restless Leg Syndrome (RLS) with an iron
`
`complex having an iron release rate greater than iron dextran (IOI). Specifically,
`
`Helenek discloses treatment of RLS with iron sucrose compositions having an iron
`
`release rate greater than IOI, as quantified by at least 115 µg/dl at a concentration of at
`
`least 2,000 µg/dl (see Helenek, page 3, ,-r0026).
`
`The Office asserts that Helenek discloses 1,000 mg elemental iron single dose of
`
`iron polyisomaltose (wrongfully equated with iron dextran), iron polymaltose, iron
`
`gluconate, iron sorbitol, and iron hydrogenated dextran as direct injections administered
`
`from 2 to 5 minutes (citing page 3, ,-roo21; page 5, ,-r,-r0051-0052; page 7, ,-r0097). As
`
`shown below, these assertions are incorrect at least because methods of Helenek apply
`
`only to iron carbohydrate complexes having an iron release rate greater than IOI.
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`Page 7 of 19
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`Pharmacosmos, Exh. 1020, p. 7
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`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`(1) Helenek methods are limited to iron carbohydrates with iron release rates
`
`greater than IOI.
`
`Helenek discloses treatment of Restless Leg Syndrome (RLS) with an iron
`
`complex having an iron release rate greater than iron dextran (IOI) (see Abstract; page
`
`2, ,-r,-r0012-0015; page 3, ,-r0018). Helenek defines IOI as iron dextran solutions, such as
`
`INFeD® and Dexferrum® (page 2, ,-roo11 ). Helenek discloses IOI has a release rate of
`
`69.5-113.5 µg/dl and, accordingly, sets a cutoff of a release rate greater than 115 µg/dl
`
`for any iron carbohydrate to be used in the disclosed methods (see page 3, ,-r0026).
`
`Helenek only recites iron polyisomaltose, iron polymaltose, iron sorbitol, and iron
`
`hydrogenated dextran in a generic listing of examples of iron carbohydrate complexes
`
`but does not assert that all such examples can be used in that invention (page 3,
`
`,-roo21 ).
`
`In fact, immediately thereafter, Helenek makes clear that "[i]n the present
`
`invention, the iron complex must have a release rate of at least 115 µg/dl at a
`
`concentration of at least 2,000 µg/dl" (Helenek, page 3, ,-r0026, emphasis added; see
`
`Abstract; page 2, ,-r,-r0012-0015; page 5, ,-r,-r0049, 0050). Similarly, Helenek recites that
`
`"any iron complex that has a release rate greater than that of IOI is an effective RLS
`
`therapeutic" (page 3, ,-r0018).
`
`Helenek does not disclose that each of the iron carbohydrate complexes recited
`
`in ,-roo21 are suitable for use in that invention by way of having an iron release rate
`
`greater than IOI-rather, only that those complexes having a release rate greater than
`
`IOI (set at 115 µg/dl) read on the dosage recitation in ,-r0051 of Helenek. Helenek
`
`provides iron release rates for only iron gluconate (Ferrlecit), iron sucrose (Venofer),
`
`and iron dextran (Dexferrum and INFeD, i.e., both examples of IOI) (see FIG. 1, Table
`
`2).
`
`The Declaration of Lawrence (filed 26 August 2009 in US App Ser No.
`
`11/620,986) evidences that methods disclosed in Helenek include only those iron
`
`carbohydrate complexes having an iron release rate greater than IOI (see ,-r5).
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`Page 8 of 19
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`Pharmacosmos, Exh. 1020, p. 8
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`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`(2) Iron Carbohydrates of Claim 1 have Release Rates Lower Than IOI.
`
`(A) Iron Carboxymaltose.
`
`As further evidenced in the Declaration of Lawrence (filed 26 August 2009 in US
`
`App Ser No. 11/620,986), VIT-45, an iron carboxymaltose complex, has an iron release
`
`rate less than IOI (see TABLE A; ,-r,-r6-7). Because an iron carboxymaltose complex has
`
`an iron release rate less than IOI, methods of Helenek cannot be applied thereto (see
`
`,-r7).
`
`(B) Iron polyglucose sorbitol carboxymethyl ether.
`
`Jahn et al. 2011 Eur J Pharma and Biopharma 78, 480-491, evidences that
`
`ferumoxytol has an iron release rate much lower than iron dextran (see page 489,
`
`Section 4.3; FIG. 7; FIG. 9). Feraheme® (ferumoxytol) is described by Jahn et al. 2011
`
`as an iron carboxymethyl dextran. As discussed on page 22, ,-r,-r0075-0076 of the
`
`present application, ferumoxytol (i.e. an iron polyglucose sorbitol carboxymethyl ether;
`
`more specifically, a polyglucose sorbitol carboxymethyl ether-coated non-stoichiometric
`
`magnetite) is a preferred complex for use methods of the present disclosure and falls
`
`within the scope of claim 1 (see also claims 15-16). Because the iron polyglucose
`
`sorbitol carboxymethyl ether has an iron release rate less than IOI, methods of Helenek
`
`cannot be applied thereto.
`
`(C) Iron Polyisomaltose.
`
`Helenek does not disclose administration of "an iron polyisomaltose [having] a
`
`substantially non-immunogenic carbohydrate component", as recited in claim 1.
`
`The Office equates administration of an iron polyisomaltose with administration of
`
`an iron dextran (Action of 07 February 2014, page 4, lines 8-9).
`
`First, claim 1 recites "an iron polyisomaltose [having] a substantially non(cid:173)
`
`immunogenic carbohydrate component". It was understood in the art that the dextran
`
`carbohydrate component is immunogenic. Thus, iron dextran does not read on "an iron
`
`polyisomaltose [having] a substantially non-immunogenic carbohydrate component", as
`
`recited in claim 1.
`
`Page 9 of 19
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`Pharmacosmos, Exh. 1020, p. 9
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`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`Second, at the time of filing, and as acknowledged by the Office (in US App Ser
`
`No., 12/787,283, Action of June 6, 2012, page 4, lines 8-11 ), an iron polyisomaltose is
`
`understood as a type of iron carbohydrate complex that includes isomaltose units in the
`
`carbohydrate component. An isomaltose is a disaccharide similar to maltose, but with a
`
`a-(1-6)-linkage between two glucose units instead of an a-(1-4 )-linkage (see Lawrence
`
`Declaration, ,-r4, filed 06 December 2012, in US App Ser No., 12/787,283). One
`
`example of an iron polyisomaltose complex is an iron isomaltoside (e.g., Monofer®),
`
`where the carbohydrate component is a pure linear chemical structure of repeating a1-6
`
`linked glucose units (Id. at ,-r4 ).
`
`In contrast, a dextran is a branched glucan with straight
`
`chains having a1-6 glycosidic linkages and branches beginning from a1-3 linkages.
`
`It was understood at the time of filing that isomaltose oligomers prevent or block
`
`anaphylaxis to dextrans (Coulson and Stevens 1961 J lmmun 86, 241; evidenced by
`
`Jahn et al. 2011 Eur J Pharma and Biopharma 78, 480-491, at 489, column 1, lines 53-
`
`58; see Lawrence Declaration, ,-r5). It was also understood at the time of filing that
`
`isomaltose oligomers acted as haptens against circulating anti-dextran antibodies
`
`(retrospective summary in Jahn et al. 2011 Eur J Pharma and Biopharma 78, 480-491,
`
`at 489, column 1, lines 58-60; see Lawrence Declaration, ,-r5). A hapten can bind an
`
`antibody without inducing anaphylaxis or an immune response (see term definition in
`
`retrospective summary of Jahn et al. 2011 Eur J Pharma and Biopharma 78, 480-491,
`
`at 489, column 2, lines 3-5; see Lawrence Declaration, ,-r5).
`
`For at least the above reasons, the Office is incorrect in equating an iron dextran
`
`to "an iron polyisomaltose [having] a substantially non-immunogenic carbohydrate
`
`component", as recited in claim 1.
`
`Third, Jahn et al. 2011 Eur J Pharma and Biopharma 78, 480-491, evidences
`
`that iron "isomaltoside" (i.e., an iron polyisomaltose) does not have an iron release rate
`
`higher than iron dextran (page 489, Section 4.3; FIG. 7; FIG. 9).
`
`Thus, Helenek does not disclose administration of "an iron polyisomaltose
`
`[having] a substantially non-immunogenic carbohydrate component", as recited in claim
`
`1. Because an iron polyisomaltose has an iron release rate less than IOI, methods of
`
`Helenek cannot be applied thereto.
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`Page 10of19
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`Pharmacosmos, Exh. 1020, p. 10
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`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`(3) Single High Dose in Helenek Applies Only to Iron Sucrose.
`
`The Office selectively represents the disclosure of Helenek with respect to
`
`optimized dosage of iron carbohydrate complexes having an iron release rate greater
`
`than IOI. The pertinent passage of Helenek is as follows (emphasis added):
`
`An appropriate dosage level will generally be about 10 mg to
`1000 mg of elemental iron per dose, which can be
`administered in single or multiple doses, particularly at
`least 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0,
`150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0,
`800.0, 900.0, 1000.0, and 2000.0 milligrams of elemental
`iron, and furthermore up to the maximal tolerated dose
`(MTD) per administration. Preferably, the dosage level will
`be about 0.1 to about 1000 mg per dose; most preferably
`about 100 mg to about 500 mg per dose.
`
`As noted above, these teachings apply only to those iron carbohydrate
`
`complexes having an iron release rate greater than IOI. Furthermore, the above
`
`passage recites that the 10 to 1000 mg of elemental iron can be administered in
`
`multiple doses with each administration not exceeding the maximal tolerated dose
`
`(MTD). The only example of a single 1000 mg dose in Helenek is for iron sucrose (see
`
`e.g., Helenek, page 5, ,-r0052; page 7, ,-r0095), which is an iron carbohydrate not recited
`
`in claim 1.
`
`Conclusion
`
`For at least the above reasons, claim 1 is not prima facie anticipated by Helenek.
`
`The above argument applies equally to claim 1 and claims dependent thereon or
`
`featuring pertinent elements thereof, such as claims 3, 7-10, 12, and 18-20.
`
`Claim Rejections under 35 U.5.C. §103(a)
`
`Applicants respectfully traverse and, for the following reasons, request
`
`reconsideration and withdrawal of the rejection of claims 1, 4-6, 8-12, and 18-20 under
`
`35 U.S.C. §103(a) as being unpatentable over Hamstra et al. 1980 JAMA 243(17),
`
`Page 11 of 19
`
`Pharmacosmos, Exh. 1020, p. 11
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`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`1726-1731 ("Hamstra") in view of Muller et al., US 3, 100,202 ("Muller"). Claim 11 has
`
`been canceled, making the above rejection moot as to this claim.
`
`To establish obviousness of a claim, the prior art must disclose or suggest each
`
`element of the claim; there must be some apparent reason that would have prompted
`
`one of ordinary skill in the art to combine the elements and/or modify a reference(s) so
`
`as to reach all requirements of the claim; and there must have been a reasonable
`expectation of success of the combination and/or modification. MPEP § 2143; KSR Int'/
`Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007).
`
`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 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 sorbitol complex, and an iron
`hydrogenated dextran complex; the single dosage unit of
`elemental iron is administered in about 15 minutes or less;
`and the iron carbohydrate complex has a substantially non(cid:173)
`immunogenic carbohydrate component.
`
`Cited References Fail to Disclose All Claim Elements
`
`Neither Hamstra nor Muller disclose all features of the claims.
`
`The Office asserts that Hamstra discloses intravenous injection of iron dextran
`
`1,000 mg or >1,000 mg of elemental iron per injection. But iron dextran is not recited as
`
`an iron carbohydrate complex in claim 1; and Hamstra does not disclose such dosage
`
`for any other iron carbohydrate.
`
`To overcome the inadequacies of Hamstra, the Office cites Muller. But Muller
`
`fails to overcome the inadequacies of Hamstra. While Muller discloses a method for
`
`making an iron polyisomaltose, Muller fails to provide any information concerning
`
`dosage or administration protocol.
`
`Page 12 of 19
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`Pharmacosmos, Exh. 1020, p. 12
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`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`Insufficient Reason to Modify Cited References to Reach All Claim Features
`
`The present inventors have found that, in spite of the teachings of the prior art, it
`
`is possible to administer the combination of high single dose (e.g., at least 0.6 g iron)
`
`and short administration time (e.g., 15 minutes or less) for those iron carbohydrate
`
`complexes recited in claim 1 without causing significant adverse side effects in a
`
`patient.
`
`Applicants have discovered that certain characteristics of iron carbohydrate
`
`complexes make them amenable to administration at dosages higher than
`
`contemplated by conventional administration protocols at the time of filing (see page 17,
`
`,-r0060). As described in the application, an iron carbohydrate complex of the claims can
`
`have 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 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 I hypersensitivity reactions (page 17,
`
`,-r0060). For example, the effect of iron core size and/or molecular weight is discussed at
`
`page 23, ,-r0079 - page 24, ,-r0082. The application also provides guidance as to
`
`measuring or determining the presence of such features in an iron carbohydrate
`
`complex (see page 18, ,-r0061 ). As disclosed in the application, the iron carbohydrate
`
`complexes recited in claim 1 have one or more of the above described features.
`
`The present application thus provides a method of treating iron associated
`
`diseases, disorders, or conditions with iron carbohydrate complexes that can be
`
`administered parenterally at relatively high single unit dosages of at least 0.6 g iron and
`
`in 15 minutes or less. thereby providing a safe and efficient means for delivery of a total
`
`dose of iron in fewer sessions and less time per session over the course of therapeutic
`
`treatment (see Application, page 3, ,-ro008; page 8, ,-r0026). The present claims recite
`
`use of an iron carbohydrate complex (selected from an iron carboxymaltose complex,
`
`Page 13 of 19
`
`Pharmacosmos, Exh. 1020, p. 13
`
`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`an iron mannitol complex, an iron polyisomaltose complex, an iron polymaltose
`
`complex, an iron sorbitol complex, an iron polyglucose sorbitol carboxymethyl ether
`
`complex, and an iron hydrogenated dextran complex) in a single dosage unit of at least
`
`about 0.6 grams of elemental iron administered in 15 minutes or less.
`
`The reduced administration time has considerable advantages as it is less
`
`unpleasant for the patient and less time consuming for the medical staff supervising the
`
`treatment. In view of this it is submitted that the amended claims are nonobvious over
`
`the cited prior art.
`
`In a determination of obviousness, the proper question is whether one of ordinary
`
`skill in the art would have seen an obvious benefit to upgrading conventional protocols
`
`using iron carbohydrate complex so as to reach the single unit dosage and timing
`
`requirements for particular iron carbohydrate compounds recited in claim 1 (see KSR
`
`Int'/ Co., at 424). The mere fact that references can be combined or modified does not
`
`render the resultant combination obvious unless there is some apparent reason that
`
`suggests the desirability of the combination. MPEP §2143.01 (Ill).
`
`The Office has failed to provide sufficient reason to modify Muller and/or Hamstra
`
`so as to reach all features of claim 1.
`
`First, the prior art evidences that disclosure related to iron dextran cannot
`
`necessarily be extrapolated to other iron carbohydrate complexes. For example,
`
`Macdougall (1999) discloses that "[t]he only i.v. iron preparation that can be given as a
`
`single dose of 500 to 1000 mg is iron dextran" (see Macdougall, page 64, column 2,
`emphasis added). As reflected in Zager 2006 Clin J Am Soc Nephrol 1, S24-S31,
`differential degrees of iron toxicity exist for iron carbohydrate complexes depending on
`
`the nature of the CHO carrier (see Zager, page S26, column 2) and various iron
`
`carbohydrate complexes differentially exert acute toxicity and a proinflammatory effect
`
`(see Zager, page S29, column 1 ). Thus, disclosure related to the dosage of iron
`
`dextran cannot be extrapolated to other iron carbohydrate complexes.
`
`Second, the prior art teaches away (i.e., criticizes, discredits, or otherwise
`
`discourages, see MPEP §2141.02(VI)) from high doses of iron carbohydrate complexes.
`
`The present Application discloses that while iron dextran compositions can be given at
`
`Page 14 of 19
`
`Pharmacosmos, Exh. 1020, p. 14
`
`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`high dose, the prior art recognizes that the immune response and risk of anaphylaxis
`
`limits use of iron dextran. To achieve iron repletion under conventional therapy models,
`
`a total dose of 1 g of elemental iron typically required 5 to 10 sessions over an extended
`
`period of time, incurring significant expense for supplies, nursing time, and patient
`
`inconvenience (see Application, ,-ro007).
`
`Macdougall (1999) Kidney International 55(69), 61-66 discloses that "[t]he only
`
`i.v. iron preparation that can be given as a single dose of 500 to 1000 mg is iron
`
`dextran" (see Macdougall, page 64, column 2). The present Application discloses that
`
`while iron dextran compositions can be given at high dose, the immune response and
`
`risk of anaphylaxis limits its use. Further, Macdougall discloses that iron sodium
`
`gluconate is useful for only low-dose administration "because its toxicity limits the dose
`
`to a maximum single administration of 62.5 to 125 mg" (see Macdougall, page 64,
`
`column 1 ).
`
`Auerbach (2008) Kidney International 73, 528-530, in a retrospective summary of
`
`intravenous iron therapy, discloses the conventional understanding that doses of ferric
`
`gluconate larger than about 300 mg elemental iron are associated with high incidence of
`
`vasoactive and are "proscribed" (see Auerbach, page 73, column 3; citing Chandler et
`al. 2001 Am J Kidney Dis 38, 988-991 ). Such references demonstrate that from around
`2001 and continuing through at least 2008, elevated dosages of ferric gluconate were
`
`strongly discouraged for intravenous administration.
`
`The present Application, citing Geisser at al. 1992 Arnzneimittelforschung 42,
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`1439-1452 at page 2-3, ,-ro007, also discloses that doses of iron carbohydrate
`
`complexes higher than 200 mg of iron are generally unsuitable and that conventional
`
`therapy prescribes repeated applications of lower doses of iron carbohydrate complexes
`
`over several days. To achieve iron repletion under current therapy models, a total dose
`
`of 1 g of elemental iron typically requires 5 to 10 sessions over an extended period of
`
`time, incurring significant expense for supplies, nursing time, and patient inconvenience
`
`(see Application, page 2-3, ,-ro007).
`
`Page 15 of 19
`
`Pharmacosmos, Exh. 1020, p. 15
`
`

`

`Application No. 14/100,717
`Response dated 09 June 2014
`to Action of 07 February 2014
`
`FILED VIA EFS-Web
`
`Helenek, US 2004/0180849 discloses the use of a lower dosage of iron complex
`
`and/or slow infusion of iron complexes to avoid risk of anaphylaxis and toxicity (see e.g.,
`
`,-roo11, ,-r[0097], Table 4).
`Landry et al. 2005 Am J Nephrology 25, 400-410, at 408, reports the maximum
`total dose of a carboxylated reduced polysaccharide iron oxide complex (i.e.,
`
`ferumoxytol) to be up to 420 mg per injection (see Application, page 22, ,-r0076).
`
`Spinowitz (2005) Kidney International 68, 1801-1807 discloses parenteral iron
`
`preparations require multiple and/or time-consuming administration regimens (page
`
`1801, ,-r 8). Spinowitz et al. (2005) Kidney Int. discloses administration of ferumoxytol in
`
`4 doses of 255 mg iron in four weeks or 2 doses of 510 mg iron in 2 weeks.
`
`Furthermore, in the Notice of Allowance dated 05 April 2010, in parent US App
`
`Ser No. 11/620,986 (issued as US Pat No. 7,754,702), the Office acknowledges that
`
`"Nissenson et al. (Kidney International, 2003, 64(Supplement 87), pS64-S71 []teaches
`
`optimizing the maximum amount of iron carbohydrate complex to minimize adverse
`
`events" (page S67, emphasis added).
`
`Even Hamstra discourages high doses of iron dextran by reciting: "[t]he severe
`
`delayed reactions (Table 6) were usually associated with large doses of iron dextran
`
`given to relatively small patients" and "[d]ecreasing the dose to 250 mg or less per
`
`injection ... resulted in a decrease in incidence and severity of this type of reaction"
`
`(page 1730, column 3, ,-r2, emphasis added). Hamstra also recites "anaphylactoid
`
`reactions [from iron dextran] are serious and unpredictable" (Abstract, emphasis
`
`added). Thus, Hamstra recognizes the inherent risk of high dose iron dextran and
`
`recommends decreasing the dose to 250 mg or less per injection.
`
`As shown above, the prior art at the time of filing discouraged a skilled person
`
`from the combination of high single dose and low administration time for iron
`
`carbohydrate complexes and demonstrates repeated doses of lo