throbber
PTO/SB/16 (04-04)
`Approved for use through 07/31/2006. OMB 0651-0032
`
`PROVISIONAL APPL/CATION FOR PA TENT COVER SHEET
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c).
`
`"""""""
`r-
`~E8):ness Mail Label No.: EV 674725935 US
`0
`
`INVENTOR(S)
`
`Date of Deposit: January 6, 2006
`
`-CJ)
`
`::::>
`--
`~,
`~<::
`
`Given Name (first and middle if any)
`Family Name and Surname
`Helenek
`Marv Jane
`Tokars
`Marc L.
`Lawrence
`Richard P.
`Additional inventors are named on the __ accompanying sheet(s).
`
`Residence
`(Citv and either State or Foreion Countrv)
`Brookville, New York
`Douglassville, Pennsylvania
`Calverton, New York
`
`TITLE OF INVENTION (500 characters max)
`
`Methods and Compositions for Administration of Iron
`
`ENCLOSED APPLICATION PARTS
`
`~ Specification [Total Pages ~
`
`D CD(s), Number of CDs [Total __J
`
`~ Drawing(s)
`
`[Total Sheets 1]
`
`~ Other: Return Postcard
`
`~ Application Data Sheet. See 37 CFR 1.76
`
`METHOD OF PAYMENT OF FILING FEES
`
`D Applicant claims small entity status. See CFR 1.27.
`
`APPLICATION SIZE FEE (37 CFR 1.16(s))
`If the specification and drawings exceed 100 sheets of paper, the application size fee due is $250 ($125 for small
`entitvl for each additional 50 sheets or fraction thereof. See 35 U.S.C. 41 lall1 llGl and 37 CFR 1.16(s).
`
`$
`
`BASIC FEE
`
`$200.00
`
`TOTAL
`
`$200.00
`
`~ The enclosed credit card payment form to charge the amount of $200.00 covers the filing fee
`application size fee.
`~ In connection with this application, the Director is hereby authorized to credit overpayments or to charge
`any additional fee required to Deposit Account No. 19-3140. A duplicate copy of this sheet is enclosed
`for fee processing.
`
`and/or
`
`The invention was made by an agency of the United States Government or under a contract with an agency of
`the United States Government.
`
`~No.
`D Yes, the name of the U.S. Government agency and the Government contract number are: __ .
`
`~ CUSTOMER NO. 26263
`
`Dated: January 6. 2006
`
`Luitpold Pharmaceuticals, Inc., Ex. 2083, P. 1
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`Express Mail No. 674725935 US
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`Patent
`
`METHODS AND COMPOSITIONS FOR ADMINISTRATION OF IRON
`
`FIELD OF THE INVENTION
`
`cooo11 The present invention generally relates to treatment of iron(cid:173)
`related conditions with iron carbohydrate complexes.
`
`BACKGROUND
`
`cooo21 Parenteral iron therapy is known to be effective in a variety of
`diseases and conditions including, but not limited to, severe iron deficiency, iron
`
`deficiency anemia, problems of intestinal iron absorption, intestinal iron
`
`intolerance, cases where regular intake of an oral iron preparation is not
`
`guaranteed, iron deficiency where there is no response to oral therapy (e.g.,
`
`dialysis patients), and situations where iron stores are scarcely or not at all
`
`formed but would be important for further therapy (e.g., in combination with
`
`erythropoietin ). Geisser et al., Arzneimittelforschung (1992) 42( 12), 1439-1452.
`
`There exist various commercially available parenteral iron formulations. But
`
`many currently available parenteral iron drugs, while purportedly effective at
`
`repleting iron stores, have health risks and dosage limitations associated with
`
`their use.
`
`[00031 Currently available parenteral iron formulations approved for
`
`use in the U.S. include iron dextran (e.g., lnFed, Dexferrum), sodium ferric
`
`gluconate complex in sucrose (Ferrlecit), and iron sucrose (Venofer). Although
`
`serious and life-threatening reactions occur most frequently with iron dextran,
`
`they are also known to occur with other parenteral iron products. In addition,
`
`non-life threatening reactions such as arthralgia, back pain, hypotension, fever,
`
`myalgia, pruritus, vertigo, and vomiting also occur. These reactions, while not
`
`life-threatening, often preclude further dosing and therefore iron repletion.
`
`[ o o 04 l
`
`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). See generally Fish bane, Am J Kidney Dis (2003) 41 (5Suppl), 18-
`26; Landry et al. (2005) Am J Nephrol 25, 400-410, 407. This high incidence of
`
`anaphyla~toid reactions is believed to be caused by the formati~n of antibodies
`
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`to the dextran moiety. Other parenteral iron products (e.g., iron sucrose and iron
`
`gluconate) do not contain the dextran moiety, and the incidence of anaphylaxis
`with these products is markedly lower. Fishbane, Am J Kidney Dis (2003)
`
`41(5Suppl), 18-26; Geisser et al., Arzneimittelforschung (1992) 42(12), 1439-52.
`
`However, the physical characteristics of, for example, iron gluconate and iron
`
`sucrose lead to dosage and administration rate limitations. Negative
`
`characteristics include high pH, high osmolarity, low dosage limits (e.g.,
`
`maximum 500 mg iron once per week, not exceeding 7 mg iron/kg body weight),
`
`and the long duration of administration (e.g., 100 mg iron over at least 5 minutes
`
`as an injection; 500 mg iron over at least 3.5 hours as a drip infusion).
`
`Furthermore, injectable high molecular mass substances produce more allergic
`
`reactions than the corresponding low molecular mass substances. Geisser et al.
`
`(1992) Arzneimittelforschung 42: 1439-1452.
`
`cooosJ Ferumoxytol is a newer parenteral iron formulation but limited
`information is available as to its efficacy and administration. See e.g., Landry et
`al. (2005) Am J Nephrol 25, 400-410, 408; and Spinowitz et al. (2005) Kidney Intl
`68, 1801-1807; U.S. Patent No. 6,599,498.
`
`[0006] Various pharmacokinetic studies suggest that doses of iron
`
`complexes higher than 200 mg of iron are generally unsuitable and that the
`
`conventional therapy model prescribes repeated applications of lower doses
`
`over several days. See Geisser et al., (1992) Arzneimittelforschung 42: 1439-
`
`1452. For example, to achieve iron repletion under current therapy models, a
`
`total dose of 1 g typically requires 5 to 1 O sessions over an extended period of
`
`time. These delivery modes incur significant expense for supplies such as
`
`tubing and infusate, costly nursing time, multiple administrations, and patient
`
`inconvenience.
`
`SUMMARY OF THE INVENTION
`
`[0007] Among the various aspects of the present invention is the
`
`provision of a method of treatment of iron-associated diseases, disorders, or
`
`conditions with iron formulations. Briefly, therefore, the present invention is
`
`directed to use of iron carbohydrate complexes that can be administered
`
`parenterally at relatively high single unit dosages, thereby providing a safe and
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`Express Mail No. 674725935 US
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`Patent
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`efficient means for delivery of a total dose of iron in fewer sessions over the
`
`course of therapeutic treatment.
`
`coooaJ The present teachings include methods of treating a disease,
`disorder, or condition characterized by iron deficiency or dysfunctional iron
`
`metabolism through the administration of at least 0.6 grams of elemental iron via
`
`a single unit dosage of an iron carbohydrate complex to a subject that is in need
`
`of such therapy.
`
`Coo o 9 J Other objects and features will be in part apparent and in part
`pointed out hereinafter.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0010] Those of skill in the art will understand that the drawings,
`
`described below, are for illustrative purposes only. The drawings are not
`
`intended to limit the scope of the present teachings in any way.
`
`coo111 FIG 1 is a series of electron micrographs that depict the particle
`size of three iron carbohydrate complexes. FIG 1 A is an electron micrograph
`
`depicting the particle size of Dexferrum (Iron Dextran). FIG 1 Bis an electron
`
`micrograph depicting the particle size of Venofer (Iron Sucrose). FIG 1 C is an
`
`electron micrograph depicting the particle size of Vit -45 (Iron Carboxymaltose ).
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0012) The present invention makes use of iron carbohydrate
`
`complexes that can be administered parenterally at relatively high single unit
`
`dosages for the therapeutic treatment of a variety of iron-associated diseases,
`
`disorders, or conditions. Generally, states indicative of a need for therapy with
`
`high single unit dosages of iron carbohydrate complexes include, but are not
`
`limited to iron deficiency anemia, anemia of chronic disease, and states
`
`characterized by dysfunctional iron metabolism. Efficacious treatment of these,
`
`and other, diseases and conditions with parenteral iron formulations (supplied at
`
`lower single unit dosages than those described herein) is generally known in the
`
`art. See e.g., Van Wyck et al. (2004) J Am Soc Nephrol 15, S91-S92. The
`
`present invention is directed to use of iron carbohydrate complexes that can be
`
`administered parenterally at'relatively high single unit dosages, thereby providing
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`a safe and efficient means for delivery of a total dose of iron in fewer sessions
`
`over the course of therapeutic treatment.
`
`[0013]
`
`Iron deficiency anemia is associated with, for example, 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-steroidial anti-inflammatory
`
`agents, or chronic ingestion of erythropoiesis stimulating agents.
`
`[00141 Anemia of chronic disease is associated with, for example,
`
`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.
`
`coo1s1 Anemia is also associated with, for example, Crohn's Disease;
`
`gastric surgery; ingestion of drug products that inhibit iron absorption; and
`
`chronic use of calcium.
`
`[00161 States characterized by dysfunctional iron metabolism and
`
`treatable with the single unit dosages of iron carbohydrate complexes described
`
`herein include, but are not limited to, restless leg syndrome; blood donation;
`
`Parkinson's disease; hair loss; and attention deficit disorder.
`
`[00171 Again, each of the above listed states, diseases, disorders, and
`
`conditions, as well as others, can benefit from the treatment methodologies
`
`described herein. Generally, treating a state, disease, disorder, or condition
`
`includes preventing or delaying the appearance of clinical symptoms in a
`
`mammal that may be afflicted with or predisposed to the state, disease, disorder,
`
`or condition but does not yet experience or display clinical or subclinical
`
`symptoms thereof. Treating can also include inhibiting the state, disease,
`
`disorder, or condition, e.g., arresting br reducing the development of the disease
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`or at least one clinical or subclinical symptom thereof. Furthermore, treating can
`include relieving the disease, e.g., causing regression of the state, disease,
`disorder, or condition or at least one of its clinical or subclinical symptoms.
`
`[0018] The benefit to a subject to be treated is either statistically
`
`significant or at least perceptible to the patient or to the physician. Measures of
`
`efficacy of iron replacement therapy are generally based on measurement of
`
`iron-related parameters in blood. The aim of treatment is usually to return both
`
`Hb and iron stores to normal levels. Thus, efficacy of iron replacement therapy
`
`can be interpreted in terms of the ability to normalise Hb levels and iron stores.
`
`The effectiveness of treatment with one or more single unit doses of iron
`
`carbohydrate compiex, as described herein, can be demonstrated, for example,
`
`by improvements in ferritin and transferrin saturation, and in raising hemoglobin
`
`levels in anemic patients. Iron stores can be assessed by interpreting serum
`
`ferritin levels. TfS is frequently used, in addition, to diagnose absolute or
`
`functional iron deficiencies. In patients with iron deficiency, serum transferrin is
`
`elevated and will decrease following successful iron treatment.
`
`ADMINISTRATION
`Single Dosage Unit
`[0019] Methods of treatment of various diseases, disorders, or
`
`conditions with iron complex compositions comprise the administration of the
`
`complex in single unit dosages of at least 0.6 grams of elemental iron to about at
`
`least 2.5 grams of elemental iron. Administration of single unit dosages can be,
`
`for example, over pre-determined time intervals or in response to the
`
`appearance and/or reappearance of symptoms. For example, the iron
`
`carbohydrate complex can be re-administered upon recurrence of at least one
`
`symptom of the disease or disorder. As another example, the iron carbohydrate
`
`complex can be re-administered at some time period after the initial
`
`administration (e.g., after 4 days to 12 months).
`
`coo201 Any route of delivery of the single unit dose of iron carbohydrate
`complex is acceptable so long as iron from the iron complex is released such
`
`that symptoms are treated. The single unit dose of iron carbohydrate complex
`
`can be administered parenterally, for example intravenously or intramuscularly.
`
`Intravenous administration can be delivered as a bolus or preferably as an
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`infusion. For example, VIT-45 can be intravenously injected as a bolus without
`
`dilution. If applied as an infusion, the iron carbohydrate complex can be diluted
`with sterile saline (e.g., VIT-45 0.9% mN NaCl or 500 mg iron in up to 250 ml
`
`NaCl).
`
`[0021] Generally, total iron dosage will depend on the iron deficit of the
`
`patient. One skilled in the art can tailor the total iron dose required for a subject
`
`while avoiding iron overload, as overdosing with respect to the total required
`
`amount of iron has to be avoided, as is the case for all iron preparations.
`
`[00221 The total iron dosage can be delivered as a single unit dosage
`
`or a series of single unit dosages. An appropriate single unit dosage level will
`
`generally be at least 0.6 grams of elemental iron, particularly at least 0.7 grams;
`
`at least 0.8 grams; at least 0.9 grams; at least 1.0 grams; at least 1.1 grams; at
`
`least 1.2 grams; at least 1.3 grams; at least 1.4 grams; at least 1.5 grams; at
`
`least 1.6 grams; at least 1.7 grams; at least 1.8 grams; at least 1.9 grams; at
`
`least 2.0 grams; at least 2.1 grams; at least 2.2 grams; at least 2.3 grams; at
`
`least 2.4 grams; or at least 2.5 grams. For example, a single unit dosage is at
`
`least 1.0 grams of elemental iron. As another example, a single unit dosage is at
`
`least 1.5 grams of elemental iron. As a further example, a single unit dosage is
`
`at least 2.0 grams of elemental iron. In yet another example, a single unit
`
`dosage is at least 2.5 grams of elemental iron.
`
`[00231 An appropriate single unit dosage level can also be determined
`
`on the basis of patient weight. For example, an appropriate single unit dosage
`
`level will generally be at least 9 mg of elemental iron per kg body weight,
`
`particularly at least 10.5 mg/kg, at least 12 mg/kg, at least 13.5 mg/kg, at least
`
`15 mg/kg, at least 16.5 mg/kg, at least 18 mg/kg, at least 19.5 mg/kg, at least 21
`
`mg/kg, at least 22.5 mg/kg, at least 24 mg/kg, at least 25.5 mg/kg, at least 27
`
`mg/kg, at least 28.5 mg/kg, at least 30 mg/kg, at least 31.5 mg/kg, at least 33
`
`mg/kg, at least 34.5 mg/kg, at least 36 mg/kg, or at least 37.5 mg/kg.
`
`[0024] Preferably, a single unit dosage can be administered in less
`
`than 15 minutes. For example, the single unit dosage can be administered in
`
`less than 14 minutes, less than 13 minutes, less than 12 minutes, less than 11
`
`minutes, less than 10 minutes, less than 9 minutes, less than 8 minutes, less
`
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`than 7 minutes, less than 6 minutes, less than 5 minutes, less than 4 minutes,
`
`less than 3 minutes, or less than 2 minutes.
`
`Regimen
`[00251 Administration of iron can occur as a one-time delivery of a
`
`single unit dose or over a course of treatment involving delivery of multiple single
`
`unit doses. Multiple single unit doses can be administered, for example, over
`
`pre-determined time intervals or in response to the appearance and
`
`reappearance of symptoms. The frequency of dosing depends on the disease or
`
`disorder being treated, the response of each individual patient, and the
`
`administered amount of elemental iron. An appropriate regime of dosing
`
`adequate to allow the body to absorb the imn from the bloodstream can be, for
`
`example, a course of therapy once every day to once every eighteen months.
`
`[00261 Such consecutive single unit dosing can be designed to deliver
`
`a relatively high total dosage of iron over a relatively low period of time. For
`
`example, a single unit dose (e.g., 1000 mg) can be administered every 24 hours ..
`
`As illustration, a total dose of 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg
`
`of elemental iron can be delivered via consecutive daily single unit doses of
`
`about 600 mg to about 1000 mg of elemental iron. Given that a single unit dose
`
`of 1000 mg can be intravenously introduced into a patient in a concentrated form
`
`over, for example, two minutes, such administrative protocol provides a
`
`practitioner and patient with an effective, efficient, and safe means to deliver
`
`elemental iron.
`
`[00271 As another example, a single unit dose can be administered
`
`every 3-4 days. As a further example, a single unit dose can be administered
`
`once per week. Alternatively, the single unit doses of iron complex may be
`
`administered ad hoc, that is, as symptoms reappear, as long as safety
`
`precautions are regarded as practiced by medical professionals.
`
`[00281
`
`It will be understood, however, that the specific dose and
`
`frequency of administration for any particular patient may be varied and depends
`
`upon a variety of factors, including the activity of the employed iron complex, the
`
`metabolic stability and length of action of that complex, the age, body weight,
`
`general h~alth, sex, diet, mode and time of administration, rate o,f excretion, drug
`
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`combination, the severity and nature of the particular condition, and the host
`
`undergoing therapy.
`
`(0029] The following provides but a few examples of treatment
`
`protocols for various diseases or disorders.
`
`(0030]
`
`Iron carbohydrate complex can be given as a single unit dose
`
`for the treatment of Restless Leg Syndrome. For example, 1000 mg of
`
`elemental iron from VIT-45 can be intravenously injected as a single dose (e.g.,
`
`1.5-5 mg iron/ml in normal saline) to a subject suffering from Restless Leg
`
`Syndrome. A single intravenous treatment can provide relief of symptoms for an
`
`extended period of time, approximately two to twelve months, although relief
`
`may be granted for shorter or longer periods. See U.S. Patent Pub. No.
`
`2004/0180849, incorporated herein by reference. If desired, post-infusion
`
`changes in central nervous system iron status can be monitored using
`
`measurements of cerebral spinal fluid (CSF) ferritin (and other iron-related
`
`proteins) and of brain iron stores using MRI. Post-infusion changes in Restless
`
`Leg Syndrome are assessed using standard subjective (e.g., patient diary, rating
`
`scale) and objective (e.g., P50, SIT, Leg Activity Meters) measures of clinical
`
`status. If desired, to better evaluate RLS symptom amelioration, CSF and serum
`
`iron values, MRI measures of brain iron and full clinical evaluations with sleep
`
`and immobilization tests are obtained prior to treatment, approximately two
`
`weeks after treatment, and again twelve months later or when symptoms return.
`
`Clinical ratings, Leg Activity Meter recordings and serum ferritin are obtained
`
`monthly after treatment. CSF ferritin changes can also be used to assess
`
`symptom dissipation.
`
`(00311
`
`Iron carbohydrate complex can be given as a single unit dose
`
`for the treatment of iron deficiency anemia secondary to heavy uterine bleeding.
`
`For example, a single unit dose of 1,000 mg of elemental iron from VIT-45 in 250
`
`cc normal saline can be intravenously injected into a subject suffering from iron
`
`deficiency anemia secondary to heavy uterine bleeding over 15 minutes every
`
`week until a calculated iron deficit dose has been administered. The iron deficit
`
`dose can be calculated as follows:
`
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`if baseline TSAT < 20% or Baseline Ferritin < 50
`ng/ml: Dose = Baseline weight (kg) x (15-Baseline
`Hgb [g/dL]) x 2.4 + 500 mg
`OR
`
`If baseline TSAT >20% and Baseline Ferritin > 50
`Dose =
`ng/mL:
`Baseline weight (kg) x (15-Baseline Hgb [g/dL]) x 2.4
`
`(NOTE: Baseline Hgb equals the average of the last
`two central lab Hgb's)
`
`[00321
`
`Iron carbohydrate complex can be giyen as a single unit dose
`
`for the treatment of iron deficiency anemia. A subject diagnosed as suffering
`
`from iron deficiency anemia can be, for example, intravenously injected with a
`
`dose of 1,000 mg of iron as VIT- 45 (or 15 mg/kg for weight < 66 kg) in 250 cc of
`
`normal saline over 15 minutes. Subjects with iron deficiency anemia secondary
`
`to dialysis or non-dialysis dependent-Chronic Kidney Disease (CKD) as per
`
`K/DOQI guidelines will generally have Hgb < 12 g/dL; TSAT < 25%; and Ferritin
`
`< 300 ng/mL. Subjects with iron deficiency anemia secondary to Inflammatory
`Bowel Disease will generally have Hgb < 12 g/dL; TSAT < 25%; and Ferritin <
`
`300 ng/mL. Subjects with iron deficiency anemia secondary to other conditions
`
`will generally have Hgb < 12 g/dL; TSAT < 25%; and Ferritin < 100 ng/mL.
`
`SUBJECT IN NEED THEREOF
`[00331 Single unit dosages of intravenous iron described herein can be
`
`administered to a subject where there is a clinical need to deliver iron rapidly or
`
`in higher doses and/or in subjects with functional iron deficiency such as those
`
`on erythropoietin therapy. A determination of the need for treatment with
`
`parenteral iron is within the abilities of one skilled in the art. For example, need
`
`can be assessed by monitoring a patient's iron status. The diagnosis of iron
`
`deficiency can be based on appropriate laboratory tests, for example,
`
`haemoglobin (Hb), serum ferritin, serum iron, transferrin saturation (TfS), and
`
`hypochromic red cells.
`
`[00341 A determination of the need for treatment with high dosages of
`
`parenteral iron can be also be determined through diagnosis of a patient as
`
`suffering from a disease, disorder, or condition that is associated with iron
`
`deficiency or dysfunctional iron metabolism. For example, many chronic renal
`
`failure patients receiving erythropoietin will require intravenous iron to maintain
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`target iron levels. As another example, most hemodialysis patients will require
`
`repeated intravenous iron administration, due to dialysis-associated blood loss
`
`and resulting negative iron balance.
`
`[00351 Monitoring frequency can depend upon the disease, disorder,
`
`or condition the patient is afflicted with or at risk for. For example, in a patient
`
`initiating erythropoietin therapy, iron indices are monitored monthly. As another
`
`example, in patients who have achieved target range Hb or are receiving
`
`intravenous iron therapy, TSAT and ferritin levels can be monitored every 3
`
`months.
`
`[00361 A patient's iron status can be indicative of an absolute or a
`
`functional iron deficiency, both of which can be treated with the compositions
`
`and methods described herein. An absolute iron deficiency occurs when an
`
`insufficient amount of iron is available to meet the body's requirements. The
`
`insufficiency may be due to inadequate iron intake, reduced bioavailability of
`
`dietary iron, increased utilization of iron, or chronic blood loss. Prolonged iron
`
`deficiency can lead to iron deficiency anemia-a microcytic, hypochromic
`
`anemia in which there are inadequate iron stores. Absolute iron deficiency is
`
`generally indicated where TSAT <20% and Ferritin <100 ng/ml.
`
`[0037] Functional iron deficiency can occur where there is a failure to
`
`release iron rapidly enough to keep pace with the demands of the bone marrow
`
`for erythropoiesis, despite adequate total body iron stores. In these cases,
`ferritin levels may be normal or high, but the supply of iron to the erythron is
`
`limited, as shown by a low transferrin saturation and an increased number of
`
`microcytic, hypochromic erythrocytes. Functional iron deficiency can be
`
`characterized by the following characteristics: Inadequate hemoglobin response
`
`to erythropoietin; Serum ferritin may be normal or high; Transferrin saturation
`
`(TSAT) usually <20%; and/or reduced mean corpuscular volume (MCV) or mean
`
`corpuscular hemoglobin concentration (MCHC) in severe cases. Functional iron
`
`deficiency (i.e., iron stores are thought to be adequate but unavailable for iron
`
`delivery) is generally indicated where TSAT <20% and Ferritin >100 ng/ml.
`
`[0038] Assessing the need for intravenous iron therapy as described
`
`herein can be according to the National Kidney Foundation's Kidney Disease
`
`10
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`Luitpold Pharmaceuticals, Inc., Ex. 2083, P. 11
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`Express Mail No. 674725935 US
`
`Patent
`
`Outcomes Quality Initiative. See NKF-K/DOQI, Clinical Practice Guidelines for
`Anemia of Chronic Kidney Disease (2000); Am J Kidney Dis (2001) 37(supp 1 ),
`
`S 182-8238. The DOQI provides optimal clinical practices for the treatment of
`
`anemia in chronic renal failure. The DOQI guidelines specify intravenous iron
`
`treatment of kidney disease based on hemoglobin, transferrin saturation (TSAT),
`
`and ferritin levels.
`
`[0039] Assessment of need for intravenous iron therapy can also be
`
`according to a patient's target iron level. For example, the target hemoglobin
`
`level of a patient can be selected as 11.0 g/dL to 12.0 g/dL (hematocrit
`
`approximately 33% to 36%). To achieve target hemoglobin with optimum
`
`erythropoietin doses, sufficient iron (e.g., VIT-45 or ferumoxytol) is provided to
`
`maintain TSAT ;:20% and ferritin ~ 00 ng/mL. In erythropoietin-treated patients,
`
`if TSAT levels are below 20%, the likelihood that hemoglobin will rise or
`
`erythropoietin doses fall after iron administration is high. Achievement of target
`
`hemoglobin levels with optimum erythropoietin doses is associated with
`
`providing sufficient iron to maintain TSAT above 20%.
`
`[0040]
`
`Iron therapy can be given to maintain target hemoglobin while
`
`preventing iron deficiency and also preventing iron overload. Adjusting dosage
`
`of iron to maintain target levels of hemoglobin, hematocrit, and laboratory
`
`parameters of iron storage is within the normal skill in the art. For example,
`
`where a patient is anemic or iron deficient, intravenous iron can be administered
`
`when a patient has a ferritin <800, a TSAT<50, and/or a Hemoglobin <12. Iron
`
`overload can be avoided by withholding iron for TSAT >50% and/or ferritin >800
`
`ng/mL.
`
`[00411 Where a patient is not anemic or iron deficient but is in need of
`
`iron administration, for example a patient suffering from Restless Leg Syndrome,
`
`hemoglobin and TSAT levels are not necessarily relevant, while ferritin >800 can
`
`still provides a general cut off point for administration.
`
`IRON CARBOHYDRATE COMPLEX
`Iron carbohydrate complexes are commercially available, or
`[00421
`
`have well known syntheses. Examples of iron carbohydrate complexes include
`
`iron monosaccharide complexes, iron disacch~ride complexes, iron
`
`11
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`Luitpold Pharmaceuticals, Inc., Ex. 2083, P. 12
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`Express Mail No. 674725935 US
`
`Patent
`
`oligosaccharide complexes, and iron polysaccharide complexes, such as: iron
`
`carboxymaltose, iron sucrose, iron polyisomaltose (iron dextran), iron
`
`polymaltose (iron dextrin), iron gluconate, iron sorbital, iron hydrogenated
`
`dextran, which may be further complexed with other compounds, such as
`
`sorbital, citric acid and gluconic acid (for example iron dextrin-sorbitol-citric acid
`
`complex and iron sucrose-gluconic acid complex), and mixtures thereof.
`
`Co 04 3 l Applicants have discovered that certain characteristics of iron
`
`carbohydrate complexes make them amenable to administration at dosages far
`
`higher than contemplated by current administration protocols. Preferably, iron
`
`carbohydrate complexes for use in the methods described herein are those
`
`which have one or more of the following characteristics: a nearly neutral pH
`
`(e.g., 5.0-7.0); physiological osmolarity; stable carbohydrate component; an iron
`
`core size no greater than 9 nm; mean diameter particle size no greater than 25-
`
`30 nm; slow and competitive delivery of the complexed iron to endogenous iron
`
`binding sites; serum half-life of over 7 hours; low toxicity; non-immunogenic
`
`carbohydrate component; no cross reactivity with anti-dextran antibodies; and/or
`low risk of anaphylactoid I hypersensitivity reactions.
`
`[0044]
`
`It is within the skill of the art to test various characteristics of
`
`iron carbohydrate complexes as so determine amenability to use in the methods
`
`described herein. For example, pH and osmolarity are straightforward
`
`determinations performed on a sample formulation. Likewise, techniques such
`
`as electron micrograph imaging, transmission electron microscopy, and atomic
`
`force microscopy provide direct methods to analyze both iron core and particle
`
`size. See e.g., Figure 1; Table 1. The stability of the carbohydrate complex can
`
`be assessed through physicochemical properties such as kinetic characteristics,
`
`thermodynamic characteristics, and degradation kinetics. See Geisser et al.,
`
`Arzneimittelforschung (1992) 42(12), 1439-1452. Useful techniques to assess
`
`physical and electronic properties include absorption spectroscopy, X-ray
`
`diffraction analysis, transmission electron microscopy, atomic force microscopy,
`
`and elemental analysis. See Kudasheva et al. (2004) J lnorg Biochem 98, 1757-
`
`1769. Pharmacokinetics can be assessed, for example, by iron tracer
`
`experiments. Hypersensitivity reactions can be monitored and assessed as
`
`described in, for example, Bailie et al. (2005) Nephrol Dial Transplant, 20(7),
`12
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`Luitpold Pharmaceuticals, Inc., Ex. 2083, P. 13
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`Express Mail No. 674725935 US
`
`Patent
`
`1443-1449. Safety, efficacy, and toxicity in human subjects can be assessed, for
`
`example, as described in Spinowitz et al. (2005) Kidney Intl 68, 1801-1807.
`
`[00451 A particularly preferred iron carbohydrate complex will have a
`
`pH between 5.0-7.0; physiological osmolarity; an iron core size no greater than 9
`
`nm; mean diameter particle size no greater than 30 nm; serum half-life of over
`
`10 hours; a non-immunogenic carbohyd

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