a) administering an
`effective amount of
`folic acid and
`
`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.
`Element
`Prior Art
`1pre1. A method for
`Rusthoven discloses a phase II study with pemetrexed
`administering
`disodium:
`pemetrexed
`Ex. 1011 at 1194 (“Multitargeted Antifolate LY231514
`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.”);
`Id. (“Eligible patients … initially received MTA 600 mg/m2
`intravenously (IV) for 10 minutes every 3 weeks.”).
`Ex. 1024, Bleyer Decl. ¶ 106.
`EP 005 teaches administering an effective amount of folic
`acid:
`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....”);
`Id. 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....”);
`Id. 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, Bleyer Decl. ¶¶ 107–09.
`
`
`1 Claim 1 is divided into elements for ease of explanation.
`1
`
`
`
`Teva – Fresenius
`Exhibit 1004-00001
`
`

`
`
`
`EP 005 teaches administering an effective amount of
`vitamin B12 (methylmalonic acid lowering agent):
`Ex. 1010 (Passim). For example, id. at Cover
`(“Pharmaceutical preparations for lowering blood and tissue
`levels of homocysteine are disclosed, comprising: … c)
`vitamin B12....”);
`Id. at 5, 19 (“[T]he preparation is formulated to make
`available to the patient … an effective dosage of the vitamin
`B12 in less than 1 hour after administration.”);
`Id. at 6 (“the vitamin B12 … to be galenically formulated
`for the preparation to release an effective dosage….”);
`Id. 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.
`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. ¶ 106.
`EP 005 teaches that methylmalonic acid lowering agent
`(vitamin B12) is selected from cyanocobalamin or
`hydroxycobalamin:
`Ex. 1010 (Passim). For example, id. at 6 (“Vitamin B12
`may be used in the form of cyanocobalamin or
`hydroxycabalamin or both….”);
`Id. at 12 (“The tablets containing vitamin B12 (20 µg
`cyanocobalamine) only were formulated as immediate
`release tablets….”);
`Id. at 13 (“Invention “B”: prepared as described in Example
`3, however, with the following changes in composition:
`cyanocobalamin 400 µg, folic acid 1 mg.”);
`
`2
`
`b) an effective
`amount of a
`methylmalonic acid
`lowering agent
`followed by
`
`c) administering an
`effective amount of
`pemetrexed
`disodium, wherein
`
`d) the
`methylmalonic acid
`lowering agent is
`selected from the
`group consisting of
`vitamin B12,
`hydroxycobalamin,
`cyano–10–
`chlorocobalamin,
`aquocobalamin
`perchlorate, aquo–
`10–cobalamin
`perchlorate,
`azidocobalamin,
`
`
`
`Teva – Fresenius
`Exhibit 1004-00002
`
`

`
`cobalamin,
`cyanocobalamin, or
`chlorocobalamin.
`
`2. The method of
`claim 1, wherein the
`methylmalonic acid
`lowering agent is
`vitamin B12.
`
`3. The method of
`claim 2, wherein the
`vitamin B12 is
`administered as an
`intramuscular
`injection of about
`500 μg to about
`1500 μg.
`
`
`
`Id. at 16 (“One dosage unit of injectable solution contains
`1000 µg hydroxycobalamin, 1100 µg folic acid and 5,0 mg
`pyridoxine, dissolved in saline for intramuscular
`injection.”);
`Id. at 20 (“[V]itamin B12 is used in the form of
`cyanocobalamin or hydroxycobalamin or both….”);
`Ex. 1024, Bleyer Decl. ¶¶ 111–18.
`EP 005 teaches vitamin B12 (methylmalonic acid lowering
`agent):
`Ex. 1010 (Passim). For example, id. 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 contain … vitamin
`B12.”);
`Id. (“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 ….”);
`Id. at 3 (“[I]t is known that … vitamin B12 and folate play a
`role in regulating the methionine - homocysteine pathway
`and controlling levels of homocysteine….”).
`Ex. 1024, Bleyer Decl. ¶¶ 111–18, 139.
`EP 005 teaches administering various dosages of vitamin
`B12 by intramuscular injection:
`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.”);
`Id. at 5, 19 (“The preparation may be galenically formulated
`for parenteral administration, preferably by infusion or by
`intramuscular injection.”);
`
`
`
`3
`
`Teva – Fresenius
`Exhibit 1004-00003
`
`

`
`
`
`Id. (“The preparations in accordance with the invention are
`formulated to provide approximate daily dosages as follows
`(μg/d/kg body weight).
`
`
`
`These dosages may be exceeded somewhat for short
`durations, e.g. at the beginning of the treatment.”);
`Id. 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 B12) Quantities
`are given in milligrams per day.”)
`
`;
`Id. at 9 (“a pharmaceutical formulation comprising … folic
`acid and vitamin B12 … is provided for as illustrated in the
`following table:-
`
`
`
`4
`
`Teva – Fresenius
`Exhibit 1004-00004
`
`

`
`
`
`;
`Id. at 16 (“One dosage unit of injectable solution contains
`1000 µg 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 B12 administration:
`Ex. 1010 at 19 (“[T]he preparation is formulated to make
`available to the patient … an effective dosage of the vitamin
`B12….”);
`Id. 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
`
`4. The method of
`claim 2, wherein the
`vitamin B12 is
`administered as an
`intramuscular
`injection of about
`1000 μg.
`5. The method of
`claim 2, 3 or 4,
`wherein the vitamin
`B12 administration
`is repeated about
`every 6 to about
`every 12 weeks
`following the
`administration of
`vitamin B12 until
`the administration
`
`
`
`Teva – Fresenius
`Exhibit 1004-00005
`
`

`
`of the pemetrexed
`disodium is
`discontinued.
`
`6. The method of
`claim 5 wherein the
`folic acid is
`administered 1 to 3
`weeks prior to the
`first administration
`of the pemetrexed
`disodium.
`
`7. The method of
`claim 5 wherein the
`folic acid is
`administered from
`about 1 to about 24
`hours prior to
`administration of
`the pemetrexed
`disodium.
`
`
`
`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, Bleyer Decl. ¶¶ 90–92, 142–44.
`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....”);
`Id. 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.”);
`Id. at 3 (“Regarding the treatment and prophylaxis of
`hyperhomocysteineaemia, it is known that … vitamin B12
`and folate play a role in regulating the methionine -
`homocysteine pathway and controlling levels of
`homocysteine….”);
`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, Bleyer Decl. ¶¶ 145–46.
`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....”);
`Id. 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
`
`Teva – Fresenius
`Exhibit 1004-00006
`
`

`
`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.
`
`
`
`Id. at 3 (“Regarding the treatment and prophylaxis of
`hyperhomocysteineaemia, it is known that … vitamin B12
`and folate play a role in regulating the methionine -
`homocysteine pathway and controlling levels of
`homocysteine….”);
`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, Bleyer Decl. ¶¶ 145–46.
`EP 005 teaches oral administration of various dosages of
`folic acid:
`Ex. 1010 at 5, 19 (“[T]he preparation … preferably designed
`for oral administration.”);
`Id. 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.”);
`Id. at 5, 19 (“The preparations in accordance with the
`invention are formulated to provide approximate daily
`dosages as follows (μg/d/kg body weight).
`
`
`
`These dosages may be exceeded somewhat for short
`durations, e.g. at the beginning of the treatment.”);
`Id. 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 B12) Quantities
`are given in milligrams per day.
`
`
`
`7
`
`Teva – Fresenius
`Exhibit 1004-00007
`
`

`
`
`
`;
`Id. at 9 (“a pharmaceutical formulation comprising … folic
`acid and vitamin B12 … is provided for as illustrated in the
`following table:-
`
`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:–
`
`;
`
`
`
`8
`
`Teva – Fresenius
`Exhibit 1004-00008
`
`

`
`
`
`Id. at 17
`
`;
`
`Ex. 1024, Bleyer Decl. ¶¶ 147–49.
`See supra Claim 8.
`
`
`
`See supra Claim 8.
`
`Rusthoven discloses administration of cisplatin to the
`patient:
`Ex. 1011 at 1198 (“Our group is presently conducting a
`phase II combination study of MTA and cisplatin in
`advanced NSCLC.”).
`Rusthoven teaches admnistering pemetrexed disodium as
`first-line chemotherapy for patients:
`Ex. 1011 at 1194 (“Multitargeted Antifolate LY231514
`[pemetrexed disodium] as First-Line Chemotherapy for
`Patients with Advanced Non-Small-Cell Lung Cancer: A
`Phase II Study.”);
`
`9
`
`9. The method of
`claim 8 wherein
`about 350 μg to
`about 1000 μg of
`folic acid is
`administered.
`10. The method of
`claim 9 wherein 350
`μg to 600 μg 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
`
`
`
`Teva – Fresenius
`Exhibit 1004-00009
`
`

`
`the improvement
`comprises:
`
`a) administration of
`between about 350
`μg and about 1000
`μg of folic acid
`prior to the first
`administration of
`pemetrexed
`disodium;
`
`
`
`Id. (“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. 1010 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.”);
`Id. at 3 (“Regarding the treatment and prophylaxis of
`hyperhomocysteineaemia, it is known that … vitamin B12
`and folate play a role in regulating the methionine -
`homocysteine pathway and controlling levels of
`homocysteine….”);
`Id. at 20 (“[T]he dosage regimen is time programmed,
`providing for different dosage rates during different periods
`of a course of treatment.”);
`Id. at 5, 19 (“The preparations in accordance with the
`invention are formulated to provide approximate daily
`dosages as follows (μg/d/kg body weight).
`
`
`
`These dosages may be exceeded somewhat for short
`durations, e.g. at the beginning of the treatment.”);
`Id. 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 B12) Quantities
`are given in milligrams per day.
`
`
`
`10
`
`Teva – Fresenius
`Exhibit 1004-00010
`
`

`
`
`
`;
`Id. at 9 (“a pharmaceutical formulation comprising … folic
`acid and vitamin B12 … is provided for as illustrated in the
`following table:-
`
`Id. 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
`
`Teva – Fresenius
`Exhibit 1004-00011
`
`

`
`
`
`
`
`b) administration of
`about 500 μg to
`about 1500 μg of
`vitamin B12, prior
`to the first
`administration of
`pemetrexed
`disodium; and
`
`
`
`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.”);
`Id. at 3 (“Regarding the treatment and prophylaxis of
`hyperhomocysteineaemia, it is known that … vitamin B12
`and folate play a role in regulating the methionine -
`homocysteine pathway and controlling levels of
`homocysteine….”);
`Id. 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 (μg/d/kg body weight).
`
`
`
`12
`
`
`
`Teva – Fresenius
`Exhibit 1004-00012
`
`

`
`
`
`These dosages may be exceeded somewhat for short
`durations, e.g. at the beginning of the treatment.”);
`Id. 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 B12) Quantities
`are given in milligrams per day.
`
`;
`Id. at 9 (“a pharmaceutical formulation comprising … folic
`acid and vitamin B12 … is provided for as illustrated in the
`following table:-
`
`
`
`13
`
`Teva – Fresenius
`Exhibit 1004-00013
`
`

`
`
`
`;
`
`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, Bleyer Decl. ¶¶ 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 of MTA and cisplatin in
`advanced NSCLC.”).
`EP 005 teaches administering various dosages of vitamin
`B12 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
`vitamin B12 is
`administered as an
`intramuscular
`
`
`
`Teva – Fresenius
`Exhibit 1004-00014
`
`

`
`injection of about
`500 μg to about
`1500 μg.
`
`
`
`treatment of elevated levels of homocysteine in patients and
`for counteracting the harmful effects associated with
`homocysteine.”);
`Id. at 5, 19 (“The preparation may be galenically formulated
`for parenteral administration, preferably by infusion or by
`intramuscular injection.”);
`Id. (“The preparations in accordance with the invention are
`formulated to provide approximate daily dosages as follows
`(μg/d/kg body weight).
`
`
`
`These dosages may be exceeded somewhat for short
`durations, e.g. at the beginning of the treatment.”);
`Id. 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 B12) Quantities
`are given in milligrams per day.”)
`
`
`
`15
`
`;
`
`Teva – Fresenius
`Exhibit 1004-00015
`
`

`
`
`
`Id. at 9 (“a pharmaceutical formulation comprising … folic
`acid and vitamin B12 … is provided for as illustrated in the
`following table:-
`
`;
`Id. at 16 (“One dosage unit of injectable solution contains
`1000 µg 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. 1010 at 5, 19 (“[T]he preparation … preferably designed
`for oral administration.”);
`Id. 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
`
`15. The method of
`claim 14, wherein
`vitamin B12 is
`administered as an
`intramuscular
`injection of about
`1000 μg.
`16. The method of
`claim 15, wherein
`between 0.3 mg to
`about 5 mg of folic
`acid is administered
`orally.
`
`
`
`Teva – Fresenius
`Exhibit 1004-00016
`
`

`
`
`
`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.”);
`Id. at 5, 19 (“The preparations in accordance with the
`invention are formulated to provide approximate daily
`dosages as follows (μg/d/kg body weight).
`
`
`
`These dosages may be exceeded somewhat for short
`durations, e.g. at the beginning of the treatment.”);
`Id. 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 B12) Quantities
`are given in milligrams per day.
`
`;
`Id. at 9 (“a pharmaceutical formulation comprising … folic
`acid and vitamin B12 … is provided for as illustrated in the
`following table:-
`
`
`
`17
`
`Teva – Fresenius
`Exhibit 1004-00017
`
`

`
`
`
`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:–
`
`Id. at 17
`
`;
`
`;
`
`
`
`17. The method of
`claim 16 wherein
`about 350 μg to
`about 1000 μg of
`
`
`
`Ex. 1024, Bleyer Decl. ¶¶ 147–49.
`See supra Claim 16.
`
`18
`
`Teva – Fresenius
`Exhibit 1004-00018
`
`

`
`folic acid is
`administered.
`18. The method of
`claim 17 wherein
`350 μg to 600 μg 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.
`
`20. The method of
`claim 18 wherein
`the folic acid is
`administered from
`about 1 to about 24
`hours prior to
`administration of
`the pemetrexed di
`sodium.
`
`
`
`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....”);
`Id. 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.”);
`Id. at 3 (“Regarding the treatment and prophylaxis of
`hyperhomocysteineaemia, it is known that … vitamin B12
`and folate play a role in regulating the methionine -
`homocysteine pathway and controlling levels of
`homocysteine….”);
`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, Bleyer Decl. ¶¶ 145–46.
`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....”);
`Id. 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
`
`Teva – Fresenius
`Exhibit 1004-00019
`
`

`
`
`
`counteracting the harmful effects associated with
`homocysteine.”);
`Id. at 3 (“Regarding the treatment and prophylaxis of
`hyperhomocysteineaemia, it is known that … vitamin B12
`and folate play a role in regulating the methionine -
`homocysteine pathway and controlling levels of
`homocysteine….”);
`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, Bleyer Decl. ¶¶ 145–46.
`EP 005 discloses time programmed dosage regimen for
`vitamin B12 administration:
`Ex. 1010 at 19 (“[T]he preparation is formulated to make
`available to the patient … an effective dosage of the vitamin
`B12….”);
`Id. 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….”);
`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, Bleyer Decl. ¶¶ 90–92, 142–44.
`Rusthoven discloses administration of cisplatin to the
`patient:
`Ex. 1011 at 1198 (“Our group is presently conducting a
`phase II combination study of MTA and cisplatin in
`advanced NSCLC.”).
`
`20
`
`21. The method of
`claim 12, 18, or 19,
`wherein the vitamin
`B12 administration
`is repeated about
`every 6 to about
`every 12 weeks
`following the
`administration of
`vitamin B12 until
`administration of
`pemetrexed
`disodium is
`discontinued.
`
`22. The method of
`claim 21 further
`comprising the
`administration of
`cisplatin to the
`patient.
`
`
`
`
`
`
`Teva – Fresenius
`Exhibit 1004-00020