Please add new Claims 51 to 62 as follows:
`
`-4 -
`
`51.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`the active ingredient deferiprone or a physiologically acceptable salt thereof for
`
`preventing the risk of heart disease in patients having iron overload.
`
`52.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`the active ingredient deferiprone or a physiologically acceptable salt thereof for
`
`stabilizing the risk of heart disease in patients having iron overload.
`
`53.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`the active ingredient deferiprone or a physiologically acceptable salt thereof for
`
`reducing the risk of heart disease in patients having iron overload.
`
`54.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`an .oral dosage form of deferiprone or a physiologically acceptabJe salt thereof with
`
`other excipients.
`
`55.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`daily administration of an amount of deferiprone or a physiologically acceptable salt
`
`thereof substantially in the range of up to 150mg/kg to the patient.
`
`56.
`
`The effective thera12eutic amount of claims 8, 9, 10 and 18 further comprising
`
`administration of a daily dosage amount of deferiprone or a physiologically
`
`acceptable salt thereof substantially in the range of up to 125 mg/kg to the patient.
`
`57.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`administration of a daily dosage amount of deferiprone or a physiologically
`
`acceptable salt thereof substantially in the range of 25mg/kg to 75mg/kg to the
`
`patient.
`
`
`111 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`-5-
`
`58.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 wherein
`
`deferiprone is administered in a manner selected from the group of intravenously,
`
`transdermally, rectally, orally, bucally, or aurally.
`
`59.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 wherein
`
`deferiprone is administered orally.
`
`60.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 wherein the dosage
`
`form is a sustained release formulation.
`
`61.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 wherein
`
`deferiprone has a cardio preferred/selective
`
`function when compared
`
`to
`
`desferrioxamine or other alternative chelating agents utilized in patients suffering
`
`iron overload .
`
`. 62. · .. The effective therapeutic amount of claims 8,. 9, 10 and 18 wherein ....
`
`deferiprone is administered in addition to desferrioxamine.
`
`REMARKS
`
`Enclosed is a cheque in the amount of $4,888.00 U.S. in payment of the filing
`
`fee for the National Phase Entry in the United States. If there should occur an
`
`overpayment or an underpayment of fees in respect of this application, the
`
`Commissioner is authorized to access Deposit Account Number 08-3255 to make the
`
`appropriate adjustments and advised Applicants' Agent.
`
`Attached hereto as Exhibit A is a marked-up version of the changes made to
`
`the claims by the present voluntary amendment. The attached pages are entitled
`
`"EXHIBIT A - CLAIMS WITH MARKINGS TO SHOW CHANGES".
`
`
`112 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`- 6 -
`
`Also attached hereto as Exhibit B are sheets that contains a clean set of all
`
`pending claims following entry of this amendment. These sheets are entitled
`
`"EXHIBIT B - CLEAN SET OF ALL PENDING CLAIMS FOLLOWING ENTRY
`
`OF THE PRESENT VOLUNTARY AMENDMENT". All of the currently pending
`
`claims are consolidated in this list for the convenience of the Examiner.
`
`If the Examiner has any questions, he/she is respectfully requested to contact
`
`Applicants' Agent, Neil H. Hughes at (905) 771-6414 at their convenience.
`
`Respectfully subJ~
`
`£_ ll y,
`Neil H . Hkt.e{, ; .Eng
`
`Registration No. 33;636
`Agent for Applicant
`
`NHH:mse
`Enclosures
`
`
`113 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`U.S. National Phase Application of
`PCT Applic. No. PCT /CAOl/00956
`
`- 7 -
`
`EXHIBIT A
`
`Amendment A
`
`CLAIMS WITH MARKINGS TO SHOW CHANGES
`
`Please cancel claims 3, 4, 5, 6, 7, 14, 15, 16, 17, 19, 20, 21, 27, 28, 29, 34, 36, 38, 40, 42,
`
`44, 46, 48 and 50.
`
`Please amend the claims as follows:
`
`30. (Amended)
`
`The method of [any of the previous] claims 1, 2, 11, 12, 13, 22, 23,
`
`24, 25 and 26 further comprising the active ingredient deferiprone or a
`
`physiologically acceptable salt thereof for preventing the risk of heart disease in
`
`patients having iron overload.
`
`31. (Amended)
`
`The method of [any of the prev~ous] claims 1, 2, 11, 12, 13, 22, 23,·
`
`24, 25 and 26 further comprising
`
`the active
`
`ingredient deferiprone or a
`
`physiologically acceptable salt thereof for stabilizing the risk of heart disease in
`
`patients having iron overload.
`
`32. (Amended)
`
`The method of [any of the previous] claims 1, 2, 11, 12, 13, 22, 23,
`
`24, 25 and 26 further comprising
`
`the active ingredient deferiprone or a
`
`physiologically acceptable salt thereof for reducing the risk of heart disease in
`
`patients having iron overload.
`
`33. (Amended)
`
`The method of [any of the previous] claims 1, 2, 11, 12, 13, 22, 23,
`
`24, 25 and 26 further comprising an oral dosage form of deferiprone or a
`
`physiologically acceptable salt thereof with other excipients.
`
`35. (Amended)
`
`The method of [any of the previous] claims 1, 2, 11, 12, 13, 22, 23,
`
`24, 25 and 26 further comprising daily administration of an amount of deferiprone or
`
`
`114 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`- 8 -
`
`a physiologically acceptable salt thereof substantially in the range of up to 150mg/kg
`
`to the patient.
`
`37. (Amended)
`
`The method of [any of the previous] claims 1, 2, 11, 12, 13, 22, 23,
`
`24, 25 and 26 further comprising administration of a daily dosage amount of
`
`deferiprone or a physiologically acceptable salt thereof substantially in the range of
`
`up to 125 mg/kg to the patient.
`
`39. (Amended)
`
`The method of [any of the previous] claims 1, 2, 11, 12, 13, 22, 23,
`
`24, 25 and 26 further comprising administration of a daily dosage amount of
`
`deferiprone or a physiologically acceptable salt thereof substantially in the range of
`
`25mg/kg to 75mg/kg to the patient.
`
`41. (Amended)
`
`The method of [any of the previous] claims 1, 2, 11, 12, 13, 22, 23,
`
`24, 25 and 26 wherein deferiprone is administered in a manner selected from the
`
`group o.f. intravenously, transdermally, rectally, orally, bucally~ or·aurally.
`
`43. (Amended)
`
`The method of [any of the previous] claims 1, 2, 11, 12, 13, 22, 23,
`
`24, 25 and 26 wherein deferiprone is administered orally.
`
`45. (Amended)
`
`The method of [any of the previous] claims 1, 2, 11, 12, 13, 22, 23,
`
`24, 25 and 26 wherein the dosage form is a sustained release formulation.
`
`47. (Amended)
`
`The method of [any of the previous] claims 1, 2, 11, 12, 13, 22, 23,
`
`24, 25 and 26 wherein deferiprone has a cardio preferred/selective function when
`
`compared to desferrioxamine or other alternative chelating agents utilized in
`
`patients suffering iron overload.
`
`49. (Amended)
`
`The method of [any of the previous] claims 1, 2, 11, 12, 13, 22, 23,
`
`24, 25 and 26 wherein deferiprone is administered in addition to desferrioxamine.
`
`
`115 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`Please add the following claims:
`
`- 9 -
`
`51.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`the active ingredient deferiprone or a physiologically acceptable salt thereof for
`
`preventing the risk of heart disease in patients having iron overload.
`
`52.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`the active ingredient deferiprone or a physiologically acceptable salt thereof for
`
`stabilizing the risk of heart disease in patients having iron overload.
`
`53.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`the active ingredient deferiprone or a physiologically acceptable salt thereof for
`
`reducing the risk of heart disease in patients having iron overload.
`
`. : ... :
`
`54.·
`
`·The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`,., ··,..-.:.,,_ an.oral dosage form of deferiprone or a physiologically acceptable salt thereof with
`
`other excipients.
`
`, ..
`. _,
`· · .;:. ·.
`
`55.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`daily administration of an amount of deferiprone or a physiologically acceptable salt
`
`thereof substantially in the range of up to 150mg/kg to the patient.
`
`56.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`administration of a daily dosage amount of deferiprone or a physiologically
`
`acceptable salt thereof substantially in the range of up to 125 mg/kg to the patient.
`
`57.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`administration of a daily dosage amount of deferiprone or a physiologically
`
`acceptable salt thereof substantiallv in the range of 25mg/kg to 75mg/kg to the
`
`patient.
`
`
`116 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`- 10 -
`
`58.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 wherein deferiprone
`
`is administered
`
`in a manner selected from
`
`the group of
`
`intravenously,
`
`transdermally, rectally, orally, bucally, or aurally.
`
`59.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 wherein deferiprone
`
`is administered orally.
`
`60.
`
`· The effective therapeutic amount of claims 8. 9, 10 and 18 wherein the dosage
`
`form is a sustained release formulation.
`
`61.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 wherein deferiprone
`
`has a cardio preferred/selective function when compared to desferrioxarnine or
`
`other alternative chelating agents utilized in patients suffering iron overload.
`
`62. · ·,. :The effective therapeutic amount of claims 8, 9, 10 and 18 wherein deferiprone
`
`. is adininistered;.in addition" to desfetrioxarnine.
`
`I•
`
`,i · :·
`
`
`117 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`U.S. National Phase Application of
`PCT Applic. No. PCT /CAOl/00956
`
`- 11 -
`
`EXHIBITB
`
`Amendment A
`
`CLEAN SET OF ALL PENDING CLAIMS
`
`FOLLOWING ENTRY OF THE PRESENT AMENDMENT
`
`1.
`
`A method of treating iron induced cardiac disease in a patient with iron
`
`overload, such as in thalassemia or the like comprising administering to the patient a
`
`therapeutically effective amount of deferiprone or a physiologically acceptable salt
`
`thereof sufficient to treat iron induced cardiac disease normally associated with iron
`
`overload.
`
`2.
`
`A method of preventing iron induced cardiac disease in a patient with iron
`
`overload, such as in thalassemia or the like comprising administering to the patient a
`therapeutically effective a~c;m~!·' of ,d~feriprone or a _physiologically acceptable salt
`. . .. ·
`.. .. '
`. ~.
`.
`.
`. ·.
`thereof sufficient to treat iron induced cardiac disease normally associated with iron
`
`overload.
`
`8.
`
`An effective
`
`therapeutic amount of deferiprone or a physiologically
`
`acceptable salt thereof for the prevention of the risk of heart disease in patients
`
`having iron overload, such as in thalassemia or the like, comprising an effective
`
`amount of deferiprone or a physiologically acceptable salt thereof sufficient to treat
`
`iron induced cardiac disease normally associated with iron overload.
`
`9.
`
`An effective
`
`therapeutic amount of deferiprone or a physiologically
`
`acceptable salt thereof for the stabilization of the risk of heart disease in patients
`
`having iron overload, such as in thalassemia or the like comprising an effective
`
`amount of deferiprone or a physiologically acceptable salt thereof sufficient to treat
`
`iron induced cardiac disease normally associated with iron overload.
`
`
`118 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`-12-
`
`10. An effective
`
`therapeutic amount of deferiprone or a physiologically
`
`acceptable salt thereof for the reduction of the risk of heart disease in patients having
`
`iron overload, such as in thalassemia or the like comprising an effective amount of
`
`deferiprone or a physiologically acceptable salt thereof sufficient to treat iron
`
`induced cardiac disease normally associated with iron overload.
`
`11.
`
`A method of preventing the risk of heart disease in patients having iron
`
`overload, such as in thalassemia or the like comprising the administration of a
`
`therapeutically effective amount of deferiprone or a physiologically acceptable salt
`
`thereof sufficient to treat iron induced cardiac disease normally associated with iron
`
`overload.
`
`12.
`
`A method of stabilizing the risk of heart disease in patients having iron
`
`overload , such as in thalassemia or the like comprising the administration of a
`
`::.'.
`
`therapeutically effective amount of defer!.prone or ~ physiologicaUy acceptable salt
`thereof sufficient to treat iron induced ca~diac dise~se normally associated with iron
`overload.
`
`13.
`
`A method of reducing the risk of heart disease in patients having iron
`
`overload, such as in thalassemia or the like comprising the administration of a
`
`therapeutically effective amount of deferiprone or a physiologically acceptable salt
`
`thereof sufficient to treat iron induced cardiac disease normally associated with iron
`
`overload.
`
`18.
`
`A
`
`therapeutically effective amount of deferiprone or physiologically
`
`acceptable salt thereof for the prevention, treatment, or reversal of heart disease in
`
`patients having an iron overload condition of the heart comprising an effective
`
`amount of deferiprone or a physiologically acceptable salt thereof to preferentially
`
`
`119 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`- 13-
`
`reduce the iron stores in the heart in comparison to the iron stores in less critical
`
`organs/tissue in the body.
`
`22.
`
`A method of treating/preventing/or reversing heart disease in a patient
`
`having an iron overload condition of the heart comprising administering to the
`
`patient a therapeutically effective amount of deferiprone, or a physiologically
`
`acceptable salt thereof in order to preferentially reduce the iron stores in the heart in
`
`comparison to less critical organs/tissue in the body.
`
`23.
`
`A method of treating/preventing/or reversing heart disease in patients
`
`having an iron overload condition of the heart comprising administering to the
`
`p~9ent a therapeutically effecp.ve amount '?,£. . ~7/edpr._on,e or a physiologically
`
`:~:): :
`
`;. ...~
`
`acceptable salt thereof to preferentially reduce ·the iron stores in the heart in
`
`comparison to the iron stores in less critical organs/tissue in the body.
`
`24.
`
`A method of treating/preventing/or reversing heart disease in patients
`
`having an iron overload condition of the heart comprising a therapeutically effective
`
`amount of deferiprone or a physiologically acceptable salt thereof to preferentially
`
`reduce the iron stores in the heart in comparison to the iron stores in less critical
`
`organs/tissue in the body.
`
`25.
`
`A method of treatment, prevention, or reversal of heart disease in a patient
`
`having an iron overload condition of the heart comprising administering to the
`
`
`120 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`- 14 -
`
`patient a therapeutically effective amount of deferiprone or a physiologically
`
`acceptable salt thereof for the direct preferential reduction/removal of iron (for
`
`example - intracellular iron) stores in the heart.
`
`26.
`
`A method to prevent/treat/reverse the occurrence of iron-induced cardiac
`
`disease in patients with an iron overload condition such as thalassemia or the like,
`
`comprising ·administering to said patient a therapeutically effective amount of
`
`deferiprone or a physiologically acceptable salt thereof, wherein deferiprone's
`
`efficacy is cardio preferential when compared with its ability to lower total iron
`
`stores in the body.
`
`30.
`
`..The method of claims 1, 2, 11, 12, 13,.22, 23, 24, 25 and 2q.f.urther comprisLTlg
`.
`. .
`.·
`.
`the active ingredient deferiprone or a physiologically acceptable salt thereof for
`
`preventing the risk of heart disease in patients having iro.n overload.
`
`31.
`
`The method of claims l, 2, 11, 12, 13, 22, 23, 24, 25 and 26 further comprising
`
`the active ingredient deferiprone or a physiologically acceptable salt thereof for
`
`stabilizing the risk of heart disease in patients having iron overload.
`
`32.
`
`The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 further comprising
`
`the active ingredient deferiprone or a physiologically acceptable salt thereof for
`
`reducing the risk of heart disease in patients having iron overload.
`
`33. · The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 further comprising
`
`an oral dosage form of deferiprone or a physiologically acceptable salt thereof with
`
`other excipients.
`
`
`121 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`- 15 -
`
`35.
`
`The method of claims l, 2, 11, 12, 13, 22, 23, 24, 25 and 26 further comprising
`
`daily administration of an amount of deferiprone or a physiologically acceptable salt
`
`thereof substantially in the range of up to 150mg/kg to the patient.
`
`37.
`
`The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 further comprising
`
`administration of a daily dosage amount of deferiprone or a physiologically
`
`acceptable salt thereof substantially in the range of up to 125 mg/kg to the patient.
`
`39.
`
`The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 further comprising
`
`administration of a daily dosage amount of deferiprone or a physiologically
`
`acceptable salt thereof substantially in the range of 25mg/kg to 75mg/kg to the
`
`patient.
`
`41.
`
`The method of claims l, 2, 11, 12, 13, 22, 23, 24, 25 and 26 wherein deferiprone
`
`is admi nistP.red
`
`in a manner selected from
`
`the group . of ··· .. intravenously,
`
`:.'(.' -. :;·
`
`··transdermally, redally, orally, bucally, or aurally.
`
`i.
`
`43.
`
`The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 wherein deferiprone
`
`is administered orally.
`
`45.
`
`The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 wherein the dosage
`
`form is a sustained release formulation.
`
`47.
`
`The method of claims l, 2, 11, 12, 13, 22, 23, 24, 25 and 26 wherein deferiprone
`
`has a cardio preferred/ selective function when compared to desferrioxamine or
`
`other alternative chelating agents utilized in patients suffering iron overload.
`
`49.
`
`The method of claims 1, 2, 11, 12, 13, 22, 23, 24, 25 and 26 wherein deferiprone
`
`is administered in addition to desferrioxamine.
`
`
`122 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`-16-
`
`51.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`the active ingredient d eferiprone or a physiologically acceptable salt thereof for
`
`preventing the risk of heart disease in patients having iron overload.
`
`52.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`the active ingredient deferiprone or a physiologically acceptable salt thereof for
`
`stabilizing the risk of heart disease in patients having iron overload.
`
`53.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`the active ingredient deferiprone or a physiologically acceptable salt thereof for
`
`reducing the risk of heart disease in patients having iron overload.
`
`54.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`an oral dosage form of deferiprone or a physiologically acceptable salt thereof with
`
`other excipients.
`
`55.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`daily administration of an amount of deferiprone or a physiologically acceptable salt
`
`thereof substantially in the range of up to 150mg/kg to the patient.
`
`56.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`administration of a daily dosage amount of deferiprone or a physiologically
`
`acceptable salt thereof substantially in the range of up to 125 mg/kg to the patient.
`
`57.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 further comprising
`
`administration of a daily dosage amount of deferiprone or a physiologically
`
`acceptable salt thereof substantially in the range of 25mg/kg to 75mg/kg to the
`
`patient.
`
`
`123 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`. '
`
`- 17 -
`
`58.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 wherein
`
`deferiprone is administered in a manner selected from the group of intravenously,
`
`transdermally, rectally, orally, bucally, or aurally.
`
`59.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 wherein
`
`deferiprone is administered orally.
`
`60.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 wherein the dosage
`
`form is a sustained release formulation.
`
`61.
`
`The effective therapeutic amount of claims 8, 9, 10 and 18 wherein
`
`deferiprone has a cardio preferred/selective function when compared
`
`to
`
`desferrioxamine or other alternative chelating agents utilized in patients suffering
`
`iron overload.
`
`62.
`
`'
`The effective therapeutic amount of claims 8, 9, 10 and 18 wherein:
`
`deferiprone is administered in addition to desferrioxamine.
`
`
`124 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`·1·1 !'""! ';~~· "ii
`-
`
`..ji
`
`•1::~· "ti ji·i•..
`
`!r"" iJ..?·li;f1iif.i .. ~~~1·'"· 4
`.. 1 .. .I ....... ..... ..11 .. I ,.JI -··· I 0 '1 :.J . .L .L 0
`OT12Rec'dPCT/PTO 2 0 DEC 2002
`PCT/CAOl/00956
`
`W002/02114
`
`A NEW USE FOR DEFERIPRONE
`
`s
`
`FIELD OF INVENTION
`
`I
`
`the
`for
`deferiprone
`of
`use
`the
`to
`relates
`invention
`The
`prevention/stabilization/reduction of the risk of heart disease, such as heart
`failure, in patients having an iron overload condition such as is found in those
`suffering from for example, thalassemia, hemochromatosis, and myelodysplasia,
`and corresponding methods of treatment involving deferiprone therefor.
`
`10
`
`BACKGROUND OFTIIE INVENTION
`
`15 Although ·reference is made in the following discussion to thalassemia
`specifically, the invention is not intended to be interpreted as limited only tO the
`treatment thereof. Any chronic iron overload condition would benefit from
`treatment by utilizing the method described herein as well as the _other aspects of
`the invention.
`For ~ample, those suffering from hemocluomatosis and
`transfused sickle cell anemia would also benefit.
`
`2 0
`
`2 5
`
`3 O
`
`Thalassemia, among other afflictions, must be treated by regular transfusions of
`red blood·cells in order to extend the life of the patient. However, transfusions
`create a widespread iron overlo.ad in the patient. Iron overload is dangerous
`since the excessive iron can cause toxic degenerative changes in the heart, liver
`and endocrine organs.
`
`While blood transfusions constitute the major source of increased iron load,
`having about 1 mg of iron per ml of transfused red blood cells, increased iron
`absorption from the gastrointestinal tract can be observed in some diseases and
`also cause iron overload. Typically, only 1 mg of the di~tary iron is absorbed per
`day. However, some conditions such as thalassemia, dyserythropoietic anemias,
`sideroblastic ~emias, . and hereditary hemochromatosis are associated with
`
`I
`
`
`125 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`WO 02/02114
`
`PCT/CAOl/00956
`
`-2-
`
`increased absorption of dietary iron. However, only 1 mg of iron is lost each day
`through sloughing of cells from skin and mucosa! surfaces and the body does not
`have any organ that can perform the role of regulating the iron excretion in
`conditions of iron overload. Consequently, increased dietary iron absorption can
`also lead to iron overload and iron-induced organ toxicity, the most serious of
`which is heart damage. Thus, even without · blood transfusions, conditions such
`as thalassemia, or hemochromatosis lead to increased body levels of iron,
`resulting in iron toxicity and eventually heart damage.
`
`Iron chelators are drugs that enhance the iron excretion. Iron overload is most
`often treated by the use of the iron chelator desferrioxamine. However, because
`desferrioxamine is not effective when given orally, it has to be gfven by a
`parenteral route. To be clinically effective, relatively
`large amounts of
`desferrioxamine are required to be infused daily for 8' to 12 hours and this regime
`has ·to be maintained for the life span of these patients. Due to the obvious
`difficulties associated with such a regune, an extensive amount of research has
`been directed towards the development of alternative iron chelators.
`
`Recently another iron chelator, deferiprone by oral administration, has been used
`succe~fully for removal of iron in thalassemia patients who could not comply
`with desferrioxamine. While patient compliance is greater with deferiprone, it is
`not more effective than desferrioxamine in generally removing iron from the
`body. In some patients deferiprone is known to produce agranulocytoisis, which
`is a sudden decline in white blood cells in the body. Therefore, deferiprone has
`been approved in Europe for use in patients with thalassemia major for whom
`desferrioxamine is contraindicated or who demonstrate serious toxicity concerns
`with desferrioxamine therapy. According to regulatory bodies, desferrioxamine
`is currently the agent of choice.
`
`5
`
`LO
`
`LS
`
`W
`
`~5
`
`W Children who have untreated thalassemia generally die in the first decade of life
`from anemia and septicemia. When palliative transfusions are introduced,
`children live into ~eir late teens, but eventually succumb to :heart failure if iron
`
`
`126 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`WO 02/02114
`
`PCT/CAOl/00956
`
`- 3-
`
`overload is not treated. With the introduction of frequent chronic transfusion
`therapy and the use of subcutaneous desferrioxamine, most children are now
`surviving into adulthood. However, many still die before 30 years of age, most
`from heart failure.
`
`Since there is no question that desferrioxamine can eliminate iron from the
`body, thus reducing the total body iron load, there are 2 possible reasons why
`there remains a high level of premature cardiac deaths in desferrioxamine
`treated patients: one is that patients do not take adequate amounts of the
`injectable chelator, and the other is that, while it removes iron from the liver
`and possibly the blood, its effect on the heart are secondary, not specific for this
`organ.
`
`The number of patients who are compliant"with this therapy is limited since the
`use of desferrioxamine normally requires the use of an infusion pump for 8 to 12
`hours, 5-7 days a week as long as patients continue to receive regular .blood
`transfusions. This is a rigorous and uncomfortable treatment regime and many
`patients cannot or will not comply, which results in an increased iron load and
`. iron toxicity in various organs, including the heart.
`
`5
`
`10
`
`15
`
`· However, it is apparent that this is not• the only reason that thalassemia patients
`receiving desferrioxamine therapy develop iron-induced heart disease. Three
`separate techniques are generally employed in the assessment of iron overload:
`measurement of serum ferritin concentrations; measurement of hepatic iron
`concentrations by chemical means following a liver biopsy; and assessment of
`fron co~centrations in the liver or heart or other organs by physical devices, such
`as SQUID (super quantum interference device) and MRI (magiietic imaging
`resonance). The lack of adequate compliance with injectable desferrioxatnine
`leads to a generalized increased iron overload as revealed by increases in iron
`concentrations assessed by the above methods, and thus also to increased levels
`of iron in the heart. However, data now reveal that iron-induced heart disease
`occurs even in patients who are compliant with desferrioxamine, and even some
`
`2 5
`
`~ O
`
`I
`
`
`127 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`W002/02114
`
`PCT/CAOt/00956
`
`-4-
`
`of those who do not have high levels of total body iron as assessed by serum
`ferritin or liver iron concentrations. It has thus become evident that lowering of
`the total body iron alone is insufficient to protect against iron-induced heart
`damage ..
`
`5
`
`10
`
`15
`
`There exists therefore a long felt need to improve the life expectancy of those
`patients who normally develop an iron overload condition, for example
`thalassemia patients, who are at risk of . developing or who have developed
`cardiac disease, and to delay the onset of .heart failure in the patient as long as
`possible. ·This need also applies to others suffering from conditions of chronic
`iron overload to for example those secondary to blood transfusions or those
`associated with increased dietary iron absorp~on. Applicant is aware of the
`following technical literature which discusses the clinical use of chelating agents
`in· conditions of chronic iron overload. These references are referred to in the
`detailed description of the invention.
`
`..
`
`List of References
`
`20
`
`1. Gabutti V, Piga A Results of Long-Term hon-Chelating Therapy. Acta Haematol 1996;
`95:26-36.
`
`25
`
`30
`
`35
`
`2. Wolfe LC, Olivieri NF, Sallan D, Colan S, Rose V, Propper RD et al. Prevention of
`cardiac disease by subcutaneous desferrioxamine in patients with thalassemia major. N
`Engl J Med 1985; 312(25): 1600-1603.
`3. Aldouri MA, Wonke B. Hoffbrand AV, Flynn OM, Ward SE, Agnew JE et al High
`in Beta-Th.alassemia Patients Receiving Regular
`Incidence of Cardiomyopathy
`Transfusion and Iron Chelation: Reversal by Intensified Chelation. Acta Haematol 1990;
`84:113-117.
`
`4. Brittenham GM, Griffith PM, Nienhuis AW, McLaren CE, Young NS, Tucker EE et al.
`Efficacy of Desferrioxamine. in Preventing Complications of Iron Overload in Patients
`with Thalassemia Major. N Engl J Med 1994; 331(9):567-573.
`
`5. Giardina PJV, Ehlers KH, Engle MA, Grady RW, Hilgartner MW. 1he Effect of
`Subcutaneous Desferrioxamine on the Cardiac Profile of Thal.assemia Major: A Five-Year
`Study. Ann N Y Acad Sci 1985; 445:282-292.
`
`10
`
`6. Borgna-Pignatti C, Rugo1oggo S,. DeStefano P, Piga A, et al. Survival and Disease
`Complications in Thalassemia Major. Ann N YAcad Sci 1998; 850:227-231.
`
`
`128 of 435
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1004
`
`

`

`W002/02114
`
`PCT/CAOI/00956
`
`-5-
`
`7. Olivieri NF, Nathan DG, MacMillan JH, Wayne AS, Liu P, McGee A et al. Survival in
`Medically Treated Patients with Homozygous Beta-Thalassemia. N Engl J Med 1994;
`331(9):574-578.
`.
`
`5
`
`8. Addis A, Loebstein R, Koren G, Bin.arson TR. Meta-analytic review of the clinical
`effectiveness of oral deferiprone (Deferiprone). Eur J Clin Pharmacol 1999; 55:1-6.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`~ 0
`
`15
`
`5 0
`
`· 9. Grady RW, Hilgartner MW, Giardina PJV. Deferiprone: Its Effectiveness Relative to
`6th International Conference on Tha1assemia and
`the
`that of Desfenioxamine.
`Haem.oglobinopa.thie5, Abstract #2. 1997.
`
`10. Olivieri NF, Brittenham GM, Armstrong SAM, Basran RK, Daneman R,. Daneman N et
`aL Fixst Prospective Randomized Trial of the Iron Chelators De.fe.riprone (Deferip.rone)
`and Deferoxamine. Blood 86(10 Suppl. 1), 249a. 1995.
`
`11. Olivieri NF, Belluzzo N, Muraca M1 MacKenzie CC1 Mil.one S, Polsinelli K et al.
`Evidence of Reduction in Hepatic, Cardiac and Pituitary Iron Stores in Patients with
`Tha1assemia Major During Long-Term Therapy with the Orally Active Iron Ol.el.ating
`Agent Deferiprone. Blood 84[10 Suppl 11109a. 1994.
`·
`
`12. Link G, Konijin AM, Heishko C. Cardioprotective effect of alpha-tocopherol, a5corbate,
`desfer.ri.oxantlne, and deferiprone: mitochondrial function in cultured, iron-loaded heart
`cells. J Lab·Clin Med 1999; 133: 179-188.
`
`13. De Franceschi L, Sha1ev 0, Piga A, Collell M, Olivieri 0, Corrocher R et al. De:fe:riprone
`therapy in homozygous human beta-thalassemia removes erythrocyte membrane free iron
`and reduces KO contransport activity. J Lab Oin Med 1999; 133:64-69.
`14. Carthew P, Smith AG, Hider RC, Dorman .B, Edwards RE, Francis JE. Potentiation of
`iron accwnulation in cardiac m.yocytes during the treatment of iron overload in gerbils
`with the hydroxypridinone iron chelator CP94. Biometals 1994; 7:267-271.
`
`15. Hider RC, Kayyli R, Evans P, Macl<innon S. The production of Hydroxyl Radicals by
`Deferiprone-iron compounds under physiological conditions. Blood 94[101406a. 1999.
`
`16. Engle MA, Erlandson M, Smith CH. Late Cardiac Complications of Cltronic, Severe,
`Refractory Anemia with Hemochromatosis. Circulation 1964; 30: