Claim Chart for the Petition for Inter Partes Review of
`U.S. Patent No. 7,772,209
`
`Ground 1: Claims 1-22 of U.S. Patent No. 7,772,209 are obvious over
`Rusthoven in view of EP 005 and the knowledge of a POSA.
`
`Prior Art
`Element
`1 pre 1
`• A method for Rusthoven discloses a phase II study with pemetrexed
`administering
`disodium:
`pemetrexed
`Ex. 1011 at 1194 ("Multitargeted Antifolate L Y231514
`disodium to a
`[pemetrexed disodium] as First-Line Chemotherapy for
`patient in need
`Patients with Advanced Non-Small-Cell Lung Cancer: A
`thereof comprising
`Phase II Study.")~
`!d. ("Eligible patients ... initially received MTA 600 mg/m2
`intravenously (IV) for 10 minutes every 3 weeks.").
`Ex. 1024, Bleyer Decl. ~ 106.
`a) administering an EP 005 teaches administering an effective amount of folic
`effective amount of acid:
`folic acid and
`Ex. 1010 (Passim). For example, id. at Cover
`("Pharmaceutical preparations for lowering blood and tissue
`levels of homocysteine are disclosed, comprising: ... b)
`folate or a suitable active metabolite of folate or a substance
`which releases folate in vivo .... ")~
`!d. at 4 ("[A] pharmaceutical preparation for lowering levels
`of homocysteine or for the prophylaxis or treatment of
`elevated levels of homocysteine in a patient of a
`combination which comprises ... b) folate or a suitable
`active metabolite of folate or a substance which releases
`folate in vivo .... ")~
`!d. at 19 ("A pharmaceutical preparation which comprises in
`combination, each in a concentration and form effective to
`suppress homocysteine levels in plasma ... b) folate or a
`suitable active metabolite of folate or a substance which
`releases folate in vivo .... ").
`
`Ex. 1024, BleyerDecl. ~~ 107-09.
`
`1 Claim 1 is divided into elements for ease of explanation.
`1
`
`NEPTUNE GENERICS 1004- 00001
`
`APOTEX 1004-0001
`
`

`
`b) an effective
`EP 005 teaches administering an effective amount of
`vitamin B12 (methylmalonic acid lowering agent):
`amount of a
`methylmalonic acid Ex. 1010 (Passim). For example, id. at Cover
`lowering agent
`("Pharmaceutical preparations for lowering blood and tissue
`followed by
`levels of homocysteine are disclosed, comprising: ... c)
`vitamin B12 .... ");
`!d. at 5, 19 ("[T]he preparation is formulated to make
`available to the patient ... an effective dosage of the vitamin
`B 12 in less than 1 hour after administration.");
`
`!d. at 6 ("the vitamin B 12 ... to be galenically formulated
`for the preparation to release an effective dosage .... ");
`!d. at 19 ("A pharmaceutical preparation which comprises in
`combination, each in a concentration and form effective to
`suppress homocysteine levels in plasma ... c) vitamin
`B12 .... ").
`Ex. 1024, Bleyer Decl. ~~ 111-18.
`c) administering an Rusthoven discloses administering an effective amount of
`effective amount of pemetrexed disodium:
`pemetrexed
`Ex. 1011 at 1194 ("Eligible patients ... initially received
`disodi urn, wherein MTA [pemetrexed disodium] 600 mg/m2 intravenously (IV)
`for 10 minutes every 3 weeks.").
`Ex. 1024, Bleyer Decl. ~ 106.
`
`d) the
`EP 005 teaches that methylmalonic acid lowering agent
`(vitamin B 12) is selected from cyanocobalamin or
`methylmalonic acid
`hydroxyco balamin:
`lowering agent is
`selected from the
`Ex. 1010 (Passim). For example, id. at 6 ("Vitamin B12
`group consisting of may be used in the form of cyanocobalamin or
`vitamin B12,
`hydroxycabalamin or both .... ");
`hydroxy cobalamin,
`cyano-10-
`chloroco balamin,
`aquoco balamin
`perchlorate, aquo-
`1 0-co balamin
`perchlorate,
`azidoco balamin,
`
`!d. at 12 ("The tablets containing vitamin B 12 (20 Jlg
`cyanocobalamine) only were formulated as immediate
`release tablets .... ");
`!d. at 13 ("Invention "B": prepared as described in Example
`3, however, with the following changes in composition:
`cyanocobalamin 400 Jlg, folic acid 1 mg.");
`
`2
`
`NEPTUNE GENERICS 1004-00002
`
`APOTEX 1 004 - 0002
`
`

`
`cobalamin,
`cyanocobalamin, or
`chloroco balamin.
`
`!d. at 16 ("One dosage unit of injectable solution contains
`1000 Jlg hydroxycobalamin, 1100 Jlg folic acid and 5,0 mg
`pyridoxine, dissolved in saline for intramuscular
`injection.");
`!d. at 20 ("[V]itamin B 12 is used in the form of
`cyanocobalamin or hydroxycobalamin or both .... ");
`Ex. 1024, Bleyer Dec I. ~~ 111-18.
`EP 005 teaches vitamin B12 (methylmalonic acid lowering
`2. The method of
`claim 1, wherein the agent):
`methylmalonic acid Ex. 1010 (Passim). For example, id. at 2 ("[P]harmaceutical
`lowering agent is
`preparations for lowering levels of homocysteine or for the
`vitamin B12.
`prophylaxis or for treatment of elevated levels of
`homocysteine in patients and for counteracting the harmful
`effects associated with homocysteine contain ... vitamin
`B12.");
`
`!d. ("Three pathways exist by means of which blood and
`tissue levels of homocysteine are controlled to ensure
`homocysteine homeostasis: ... 2. Remethylation to
`methionine which requires folate (as substrate) and vitamin
`B12 as co-factor .... ");
`
`!d. at 3 ("[I]t is known that ... vitamin B 12 and folate play a
`role in regulating the methionine - homocysteine pathway
`and controlling levels of homocysteine .... ").
`
`Ex. 1024, BleyerDecl. ~~ 111-18, 139.
`EP 005 teaches administering various dosages of vitamin
`3. The method of
`claim 2, wherein the B 12 by intramuscular injection:
`vitaminB12 is
`Ex. 1010 at 2 ("[P]harmaceutical preparations for lowering
`administered as an
`levels of homocysteine or for the prophylaxis or for
`intramuscular
`treatment of elevated levels of homocysteine in patients and
`injection of about
`for counteracting the harmful effects associated with
`500 Jlg to about
`homocysteine.");
`1500 Jlg.
`!d. at 5, 19 ("The preparation may be galenically formulated
`for parenteral administration, preferably by infusion or by
`intramuscular injection.");
`
`3
`
`NEPTUNE GENERICS 1004-00003
`
`APOTEX 1 004 - 0003
`
`

`
`!d. ("The preparations in accordance with the invention are
`formulated to provide approximate daily dosages as follows
`(Jlg/d/kg body weight).
`
`a} Vitamin 86
`
`b) Folic Acid
`
`Broadest range
`
`preferred range
`
`more preferred range
`
`typical example
`
`15-750
`
`30·400
`
`75·250
`
`150
`
`1 ,5-150
`
`7,5·50
`
`10·30
`
`15
`
`7·10
`
`7,5
`
`These dosages may be exceeded somewhat for short
`durations, e.g. at the beginning of the treatment.");
`!d. at 8 ("The following quantities refer to one daily dose for
`an adult patient of approximately 70kg body weight.
`(PL=pyridoxal; Fol=folate; B12=Vitamin B 12) Quantities
`are given in milligrams per day.")
`
`PL
`
`Bl2
`
`!d. at 9 ("a pharmaceutical formulation comprising ... folic
`acid and vitamin B 12 ... is provided for as illustrated in the
`following table:-
`
`4
`
`NEPTUNE GENERICS 1004-00004
`
`APOTEX 1 004 - 0004
`
`

`
`2-50
`
`S·lS
`
`5,0
`
`Folate
`Vitamin Bl2
`
`1-1:2
`l 0.1 000
`
`5-l5
`50.100
`
`3(H000
`10.100
`
`ID0-700
`15-:50
`
`:500
`
`Id. at 16 ("One dosage unit of injectable solution contains
`1000 Jlg hydroxycobalamin ... dissolved in saline for
`intramuscular injection.").
`
`Ex. 1024, Bleyer Decl. ~~ 125-28, 141.
`See supra Claim 3.
`
`EP 005 discloses time programmed dosage regimen for
`vitamin B 12 administration:
`
`Ex. 1 0 10 at 19 ("[T]he preparation is formulated to make
`available to the patient . . . an effective dosage of the vitamin
`B12 .... ");
`I d. at 5 ("The preparation may be galenically formulated for
`parenteral administration, preferably by infusion or by
`intramuscular injection. The latter form inherently provides
`for a retarded availability of the ingredients .... ");
`
`5
`
`NEPTUNE GENERICS 1004-00005
`
`APOTEX 1 004 - 0005
`
`4. The method of
`claim 2, wherein the
`vitaminB12 is
`administered as an
`intramuscular
`injection of about
`1000 Jlg.
`5. The method of
`claim 2, 3 or 4,
`wherein the vitamin
`B 12 administration
`is repeated about
`every 6 to about
`every 12 weeks
`following the
`administration of
`vitamin B 12 until
`the administration
`
`

`
`of the pemetrexed
`disodium is
`discontinued.
`
`!d. at 20 ("[T]he dosage regimen is time programmed,
`providing for different dosage rates during different periods
`of a course of treatment.").
`Ex. 1024, Bleyer Decl. ~~ 90-92, 142-44.
`
`EP 005 teaches prophylytic treatment with folic acid:
`6. The method of
`claim 5 wherein the Ex. 1010 at Cover ("Pharmaceutical preparations for
`folic acid is
`lowering blood and tissue levels of homocysteine are
`administered 1 to 3
`disclosed, comprising: ... b) folate or a suitable active
`weeks prior to the
`metabolite of folate or a substance which releases folate in
`first administration
`VIVO....
`~
`of the pemetrexed
`disodium.
`
`0
`
`" )
`
`!d. at 2 ("[P]harmaceutical preparations for lowering levels
`of homocysteine or for the prophylaxis or treatment of
`elevated levels of homocysteine in patients and for
`counteracting the harmful effects associated with
`homocysteine.")~
`
`0
`
`" )
`
`!d. at 3 ("Regarding the treatment and prophylaxis of
`hyperhomocysteineaemia, it is known that ... vitamin B 12
`and folate play a role in regulating the methionine -
`homocysteine pathway and controlling levels of
`h
`omocysteme... .
`;
`!d. at 20 ("[T]he dosage regimen is time programmed,
`providing for different dosage rates during different periods
`of a course of treatment.").
`Ex. 1024, Bleyer Decl. ~~ 145-46.
`EP 005 teaches prophylytic treatment with folic acid:
`7. The method of
`claim 5 wherein the Ex. 1 0 10 at Cover ("Pharmaceutical preparations for
`folic acid is
`lowering blood and tissue levels of homocysteine are
`administered from
`disclosed, comprising: ... b) folate or a suitable active
`about 1 to about 24 metabolite of folate or a substance which releases folate in
`hours prior to
`VIVO....
`administration of
`the pemetrexed
`disodium.
`
`0
`
`" )
`
`~
`
`!d. at 2 ("[P]harmaceutical preparations for lowering levels
`of homocysteine or for the prophylaxis or treatment of
`elevated levels of homocysteine in patients and for
`counteracting the harmful effects associated with
`homocysteine.")~
`
`6
`
`NEPTUNE GENERICS 1004-00006
`
`APOTEX 1 004 - 0006
`
`

`
`8. The method
`according to any
`one of claims 1-4,
`wherein between
`0.3 mg to about 5
`mg of folic acid is
`administered orally.
`
`!d. at 3 ("Regarding the treatment and prophylaxis of
`hyperhomocysteineaemia, it is known that ... vitamin B 12
`and folate play a role in regulating the methionine -
`homocysteine pathway and controlling levels of
`homocysteine .... ");
`!d. at 20 ("[T]he dosage regimen is time programmed,
`providing for different dosage rates during different periods
`of a course of treatment.").
`Ex. 1024, Bleyer Decl. ~~ 145-46.
`
`EP 005 teaches oral administration of various dosages of
`folic acid:
`Ex. 1 0 10 at 5, 19 ("[T]he preparation . . . preferably designed
`for oral administration.");
`!d. at 11 ("[A] sub-linqual tablet ... is produced in such a
`manner that the PL, vitamin B12 and folate components are
`liberated and absorbed mainly under the tongue. Such a
`tablet can also be formulated to contain all or any one of the
`three vitamins for use where patient problems are related to
`only one of these vitamins.");
`!d. at 5, 19 ("The preparations in accordance with the
`invention are formulated to provide approximate daily
`dosages as follows (Jlg/d/kg body weight).
`
`a} Vitamin 86
`
`b) Folic Acid
`
`Broadest range
`
`preferred range
`
`more preferred range
`
`typical example
`
`15-750
`
`30-400
`
`75-250
`
`150
`
`1,5-150
`
`7,5-50
`
`10-30
`
`15
`
`These dosages may be exceeded somewhat for short
`durations, e.g. at the beginning of the treatment.");
`!d. at 8 ("The following quantities refer to one daily dose for
`an adult patient of approximately 70kg body weight.
`(PL=pyridoxal; Fol=folate; Bl2=Vitamin B 12) Quantities
`are given in milligrams per day.
`
`7
`
`NEPTUNE GENERICS 1004-00007
`
`APOTEX 1 004 - 0007
`
`

`
`PL
`
`Bl:Z
`
`0 folic
`!d. at 9 ("a pharmaceutical formulation comprising 0
`0 is provided for as illustrated in the
`acid and vitamin B 12 0
`following table:-
`
`0
`
`0
`
`Folate
`
`Vitamin Bl2
`
`1-12
`10-1000
`
`5·15
`S0-100
`
`acetate
`
`Ascorbie acid
`
`10
`
`30·1000
`10-100
`
`100-700
`
`1:5-50
`
`500
`20
`
`!d. at 14 ("Gelatine capsules, filled with a granulate,
`formulated for timed release (over about 8 hours) in a
`manner known per se, contained per capsule:-
`
`8
`
`NEPTUNE GENERICS 1004-00008
`
`APOTEX 1 004 - 0008
`
`

`
`10 mg
`3mg
`4mg
`20 mg
`50 llg
`200 mg
`mg
`0 mg.
`
`ascorbic acid
`folic acid
`calcium
`
`Id. at 17
`
`The preparation according to the invention was formulated as follows (per oral dosage unit):-
`
`b)
`c)
`
`cyanocobalamin
`
`(ii) = 10 mg
`
`2mg
`8 mg; (i)
`
`0.65mg
`0,4 mg.
`
`Ex. 1024, Bleyer Decl. ~~ 147-49.
`
`See supra Claim 8.
`
`See supra Claim 8.
`
`Rust hoven discloses administration of cisplatin to the
`patient
`
`Ex. 1011 at 1198 ("Our group is presently conducting a
`phase II combination study ofMT A and cisplatin in
`advanced NSCLC.").
`
`Rusthoven teaches admnistering pemetrexed disodium as
`first-line chemotherapy for patients:
`Ex. 1011 at 1194 ("Multitargeted Antifolate L Y231514
`[pemetrexed disodium] as First-Line Chemotherapy for
`Patients with Advanced Non-Small-Cell Lung Cancer: A
`Phase II Study.");
`
`9. The method of
`claim 8 wherein
`about 350 Jlg to
`about 1000 Jlg of
`folic acid is
`administered.
`10. The method of
`claim 9 wherein 350
`Jlg to 600 Jlg of folic
`acid is administered.
`11. The method of
`claim 1 further
`comprising the
`administration of
`cisplatin to the
`patient.
`12pre. An improved
`method for
`administering
`pemetrexed
`disodium to a
`patient in need of
`chemotherapeutic
`treatment, wherein
`
`9
`
`NEPTUNE GENERICS 1004-00009
`
`APOTEX 1 004 - 0009
`
`

`
`the improvement
`compnses:
`
`a) administration of
`between about 350
`)lg and about 1 000
`)lg of folic acid
`prior to the first
`administration of
`pemetrexed
`disodium;
`
`!d. ("Eligible patients ... initially received MTA 600 mg/m2
`intravenously (IV) for 10 minutes every 3 weeks.").
`Ex. 1024, Bleyer Decl. ~ 119.
`EP 005 teaches prophylactic treatment with folic acid:
`Ex. 1 0 10 at 2 ("The . . . pharmaceutical preparations for
`lowering levels of homocysteine or for the prophylaxis or
`treatment of elevated levels of homocysteine in patients and
`for counteracting the harmful effects associated with
`homocysteine.");
`!d. at 3 ("Regarding the treatment and prophylaxis of
`hyperhomocysteineaemia, it is known that ... vitamin B 12
`and folate play a role in regulating the methionine -
`homocysteine pathway and controlling levels of
`homocysteine .... ");
`!d. at 20 ("[T]he dosage regimen is time programmed,
`providing for different dosage rates during different periods
`of a course of treatment.");
`!d. at 5, 19 ("The preparations in accordance with the
`invention are formulated to provide approximate daily
`dosages as follows ()lg/d/kg body weight).
`
`a) Vilamin 86
`
`b) Folic Acid
`
`Broadest range
`
`preferred range
`
`more preferred range
`
`typical example
`
`15-750
`
`30-400
`
`75-250
`
`150
`
`1,5-150
`
`7,5-50
`
`10·30
`
`15
`
`7-10
`
`7.5
`
`These dosages may be exceeded somewhat for short
`durations, e.g. at the beginning of the treatment.");
`!d. at 8 ("The following quantities refer to one daily dose for
`an adult patient of approximately 70kg body weight.
`(PL=pyridoxal; Fol=folate; B12=Vitamin B 12) Quantities
`are given in milligrams per day.
`
`10
`
`NEPTUNE GENERICS 1004-00010
`
`APOTEX 1004-0010
`
`

`
`PL
`
`Bl:Z
`
`0 folic
`!d. at 9 ("a pharmaceutical formulation comprising 0
`0 is provided for as illustrated in the
`acid and vitamin B 12 0
`following table:-
`
`0
`
`0
`
`Folate
`
`Vitamin Bl2
`
`1-12
`10-1000
`
`5·15
`S0-100
`
`acetate
`
`Ascorbie acid
`
`10
`
`30·1000
`10-100
`
`100-700
`
`1:5-50
`
`500
`20
`
`!d. at 14, 17 ("Gelatine capsules, filled with a granulate,
`formulated for timed release (over about 8 hours) in a
`manner known per se, contained per capsule:-
`
`11
`
`NEPTUNE GENERICS 1004-00011
`
`APOTEX 1004 - 0011
`
`

`
`b) administration of
`about 500 Jlg to
`about 1500 Jlg of
`vitamin B 12, prior
`to the first
`administration of
`pemetrexed
`disodium; and
`
`10 mg
`3 mg
`4 mg
`20 mg
`50 llg
`200 mg
`mg
`0 mg.
`
`ascorbic acid
`folic acid
`calcium
`
`The preparation according to the invention was formulated as follows (per oral dosage unit):·
`
`2mg
`8 mg; (i) + (ii) = 10 mg
`
`cyanocobalamin
`
`0,65mg
`0,4 mg.
`
`Ex. 1024, Bleyer Decl. ~~ 120-30.
`EP 005 teaches prophylactic treatment with vitamin B12:
`Ex. 1010 at 2 ("[P]harmaceutical preparations for lowering
`levels of homocysteine or for the prophylaxis or for
`treatment of elevated levels of homocysteine in patients and
`for counteracting the harmful effects associated with
`homocysteine.");
`!d. at 3 ("Regarding the treatment and prophylaxis of
`hyperhomocysteineaemia, it is known that ... vitamin B 12
`and folate play a role in regulating the methionine -
`homocysteine pathway and controlling levels of
`homocysteine .... ");
`I d. at 9 ("Examples of ... situations in which blood
`homocysteine levels may be elevated[, including] ...
`cancers," and "folate antagonistic drug [e.g., pemetrexed],
`which has tendency to raise homocysteine levels.");
`Id. at 5, 19 ("The preparations in accordance with the
`invention are formulated to provide approximate daily
`dosages as follows (Jlg/d/kg body weight).
`
`a) Vitamin 86
`
`b) Folic Acid
`
`Broadest range
`
`preferred range
`
`more preferred range
`
`typical example
`
`15·750
`
`30·400
`
`75·250
`
`150
`
`1.5·150
`
`7,5·50
`
`10·30
`
`15
`
`12
`
`NEPTUNE GENERICS 1004- 00012
`
`APOTEX 1004-0012
`
`

`
`These dosages may be exceeded somewhat for short
`durations, e.g. at the beginning of the treatment.");
`!d. at 8 ("The following quantities refer to one daily dose for
`an adult patient of approximately 70kg body weight.
`(PL=pyridoxal; Fol=folate; B12=Vitamin B 12) Quantities
`are given in milligrams per day.
`
`PL
`
`Folale
`
`Bl2
`
`!d. at 9 ("a pharmaceutical formulation comprising ... folic
`acid and vitamin B 12 ... is provided for as illustrated in the
`following table:-
`
`13
`
`NEPTUNE GENERICS 1004- 00013
`
`APOTEX 1004-0013
`
`

`
`,._
`
`~~ i!lll
`
`•
`::-., .. ~.......!.~
`Folate
`Vitamin Bl2
`
`2-50
`
`S·lS
`
`5,0
`
`1-1:2
`
`5-l5
`
`l 0.1 000
`
`50.100
`
`3(H000
`
`ID0-700
`
`10.100
`
`15-:50
`
`:500
`20
`
`Id. at 20 ("[T]he dosage regimen is time programmed,
`providing for different dosage rates during different periods
`of a course of treatment.").
`Ex. 1024, BleyerDecl. ~~ 131-38.
`Rusthoven discloses administering an effective amount of
`pemetrexed disodium:
`Ex. 1011 at 1194 ("Eligible patients ... initially received
`MTA [pemetrexed disodium] 600 mg/m2 intravenously (IV)
`for 10 minutes every 3 weeks.").
`Ex. 1024, Bleyer Decl. ~ 119.
`Rusthoven discloses administration of cisplatin to the
`patient
`Ex. 1011 at 1198 ("Our group is presently conducting a
`phase II combination study ofMT A and cisplatin in
`advanced NSCLC. ").
`
`EP 005 teaches administering various dosages of vitamin
`B 12 by intramuscular injection:
`Ex. 1010 at 2 ("[P]harmaceutical preparations for lowering
`levels of homocysteine or for the prophylaxis or for
`
`14
`
`c) administration of
`pemetrexed
`disodium.
`
`13. The method of
`claim 12 further
`comprising the
`administration of
`cisplatin to the
`patient.
`14. The method of
`claim 12, wherein
`vitaminB12 is
`administered as an
`intramuscular
`
`NEPTUNE GENERICS 1004-00014
`
`APOTEX 1004-0014
`
`

`
`injection of about
`500 )lg to about
`1500 )lg.
`
`treatment of elevated levels of homocysteine in patients and
`for counteracting the harmful effects associated with
`homocysteine.");
`!d. at 5, 19 ("The preparation may be galenically formulated
`for parenteral administration, preferably by infusion or by
`intramuscular injection.");
`!d. ("The preparations in accordance with the invention are
`formulated to provide approximate daily dosages as follows
`()lg/d/kg body weight).
`
`a} Vitamin BB
`
`b) Folic Acid
`
`Broadest range
`
`preferred range
`
`more preferred range
`
`typical example
`
`15-750
`
`30-400
`
`75-250
`
`150
`
`1 ,5-150
`
`7,5-50
`
`10-30
`
`15
`
`7·10
`
`7,5
`
`These dosages may be exceeded somewhat for short
`durations, e.g. at the beginning of the treatment.");
`!d. at 8 ("The following quantities refer to one daily dose for
`an adult patient of approximately 70kg body weight.
`(PL=pyridoxal; Fol=folate; Bl2=Vitamin B 12) Quantities
`are given in milligrams per day.")
`
`PL
`
`Bl2
`
`15
`
`NEPTUNE GENERICS 1004- 00015
`
`APOTEX 1004-0015
`
`

`
`!d. at 9 ("a pharmaceutical formulation comprising ... folic
`acid and vitamin B 12 ... is provided for as illustrated in the
`following table:-
`
`Folate
`
`Vitamitl B12
`
`1-12
`1 0-l 000
`
`5·1S
`S0-700
`
`0
`
`30-1000
`l0-100
`
`1!10-700
`
`l:MO
`
`soo
`
`!d. at 16 ("One dosage unit of injectable solution contains
`1000 Jlg hydroxycobalamin ... dissolved in saline for
`intramuscular injection.").
`Ex. 1024, Bleyer Decl. ~~ 125-28, 141.
`See supra Claim 14.
`
`EP 005 teaches oral administration of various dosages of
`folic acid:
`Ex. 1 0 10 at 5, 19 ("[T]he preparation . . . preferably designed
`for oral administration.");
`!d. at 11 ("[A] sub-linqual tablet ... is produced in such a
`manner that the PL, vitamin B12 and folate components are
`liberated and absorbed mainly under the tongue. Such a
`
`16
`
`NEPTUNE GENERICS 1004-00016
`
`APOTEX 1004-0016
`
`15. The method of
`claim 14, wherein
`vitaminB12 is
`administered as an
`intramuscular
`injection of about
`1000 Jlg.
`16. The method of
`claim 15, wherein
`between 0. 3 mg to
`about 5 mg of folic
`acid is administered
`orally.
`
`

`
`tablet can also be formulated to contain all or any one of the
`three vitamins for use where patient problems are related to
`only one of these vitamins.");
`!d. at 5, 19 ("The preparations in accordance with the
`invention are formulated to provide approximate daily
`dosages as follows (J.lg/d/kg body weight).
`
`Broadost rango
`
`preferred range
`
`more preferred range
`
`a) Vitamin 86
`
`b) Folic Acid
`
`15-750
`
`30-400
`
`75-250
`
`150
`
`1.5-150
`
`7,5-50
`
`10-30
`
`15
`
`These dosages may be exceeded somewhat for short
`durations, e.g. at the beginning of the treatment.");
`!d. at 8 ("The following quantities refer to one daily dose for
`an adult patient of approximately 70kg body weight.
`(PL=pyridoxal; Fol=folate; B12=Vitamin B 12) Quantities
`are given in milligrams per day.
`
`PL
`
`BIZ
`
`!d. at 9 ("a pharmaceutical formulation comprising ... folic
`acid and vitamin B 12 ... is provided for as illustrated in the
`following table:-
`
`17
`
`NEPTUNE GENERICS 1004-00017
`
`APOTEX 1004-0017
`
`

`
`2-50
`
`S·lS
`
`5,0
`
`Folate
`Vitamin Bl2
`
`1-1:2
`
`5-l5
`
`l 0.1 000
`
`50.100
`
`3(H000
`
`10.100
`
`ID0-700
`15-:50
`
`:500
`
`Id. at 14 ("Gelatine capsules, filled with a granulate,
`formulated for timed release (over about 8 hours) in a
`manner known per se, contained per capsule:-
`
`10 mg
`3mg
`4mg
`20 mg
`50 JJ.g
`200 mg
`mg
`Omg.
`
`ascorbic acid
`folic acid
`calcium "'"'1rhntl'"n"'t"
`
`Id. at 17
`
`The preparation according to the invention was formulated as follows (per oral dosage unit):·
`
`a)
`
`b)
`c)
`
`(i)
`(ii)
`
`pyridoxal
`pyridoxine
`
`2mg
`8 mg; (i) + (ii) = 10 mg
`
`folate
`cyanocobalamin
`
`0,65mg
`0,4mg.
`
`Ex. 1024, Bleyer Decl. ~~ 147-49.
`See supra Claim 16.
`
`17. The method of
`claim 16 wherein
`about 350 Jlg to
`about 1000 Jlg of
`
`18
`
`NEPTUNE GENERICS 1004- 00018
`
`APOTEX 1004-0018
`
`

`
`folic acid is
`administered.
`18. The method of
`claim 17 wherein
`350 )lg to 600 )lg of
`folic acid is
`administered.
`19. The method of
`claim 18 wherein
`folic acid is
`administered 1 to 3
`weeks prior to the
`first administration
`of the pemetrexed
`disodium.
`
`See supra Claim 16.
`
`EP 005 teaches prophylytic treatment with folic acid:
`Ex. 1010 at Cover ("Pharmaceutical preparations for
`lowering blood and tissue levels of homocysteine are
`disclosed, comprising: ... b) folate or a suitable active
`metabolite of folate or a substance which releases folate in
`VIVO....
`~
`
`" )
`
`0
`
`0
`
`" )
`
`!d. at 2 ("[P]harmaceutical preparations for lowering levels
`of homocysteine or for the prophylaxis or treatment of
`elevated levels of homocysteine in patients and for
`counteracting the harmful effects associated with
`homocysteine.")~
`!d. at 3 ("Regarding the treatment and prophylaxis of
`hyperhomocysteineaemia, it is known that ... vitamin B 12
`and folate play a role in regulating the methionine -
`homocysteine pathway and controlling levels of
`h
`omocysteme... . ;
`!d. at 20 ("[T]he dosage regimen is time programmed,
`providing for different dosage rates during different periods
`of a course of treatment.").
`Ex. 1024, Bleyer Decl. ~~ 145-46.
`20. The method of
`EP 005 teaches prophylytic treatment with folic acid:
`claim 18 wherein
`Ex. 1 0 10 at Cover ("Pharmaceutical preparations for
`the folic acid is
`lowering blood and tissue levels of homocysteine are
`administered from
`disclosed, comprising: ... b) folate or a suitable active
`about 1 to about 24 metabolite of folate or a substance which releases folate in
`hours prior to
`VIVO....
`administration of
`the pemetrexed di
`sodium.
`
`0
`
`" )
`
`~
`
`!d. at 2 ("[P]harmaceutical preparations for lowering levels
`of homocysteine or for the prophylaxis or treatment of
`elevated levels of homocysteine in patients and for
`
`19
`
`NEPTUNE GENERICS 1004- 00019
`
`APOTEX 1004-0019
`
`

`
`counteracting the harmful effects associated with
`homocysteine.");
`!d. at 3 ("Regarding the treatment and prophylaxis of
`hyperhomocysteineaemia, it is known that ... vitamin B 12
`and folate play a role in regulating the methionine -
`homocysteine pathway and controlling levels of
`h
`omocysteme... .
`;
`
`" )
`
`0
`
`!d. at 20 ("[T]he dosage regimen is time programmed,
`providing for different dosage rates during different periods
`of a course of treatment.").
`
`Ex. 1024, Bleyer Decl. ~~ 145-46.
`
`21. The method of
`EP 005 discloses time programmed dosage regimen for
`vitamin B 12 administration:
`claim 12, 18, or 19,
`wherein the vitamin Ex. 1 0 10 at 19 ("[T]he preparation is formulated to make
`B 12 administration
`available to the patient ... an effective dosage of the vitamin
`is repeated about
`B12 .... ");
`every 6 to about
`!d. at 5 ("The preparation may be galenically formulated for
`every 12 weeks
`parenteral administration, preferably by infusion or by
`following the
`intramuscular injection. The latter form inherently provides
`administration of
`for a retarded availability of the ingredients .... ");
`vitamin B 12 until
`administration of
`!d. at 20 ("[T]he dosage regimen is time programmed,
`pemetrexed
`providing for different dosage rates during different periods
`disodium is
`of a course of treatment.").
`discontinued.
`
`Ex. 1024, Bleyer Decl. ~~ 90-92, 142-44.
`
`22. The method of
`claim 21 further
`comprising the
`administration of
`cisplatin to the
`patient.
`
`Rusthoven discloses administration of cisplatin to the
`patient
`
`Ex. 1011 at 1198 ("Our group is presently conducting a
`phase II combination study ofMT A and cisplatin in
`advanced NSCLC.").
`
`20
`
`NEPTUNE GENERICS 1004- 00020
`
`APOTEX 1 004 - 0020