thepatentsearchfirm.com€¦ · Web viewThus, when cells are presented with both MTX and N5mH4F, only those cells which possess sufficient vitamin B12-dependent N5-methyltetrahydrofolate:homocysteine

Invalidity Chart – ComprehensiveSearch against US 7772209 B2

Client Ref. No.: XXXXXXXXXX TPSF Ref. No: XXXXXXXXXX

For: Client

May 11, 20XX

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Client Logo

Table of Content

1 Search Overview & Background..........................................................................................32 Search Scope.......................................................................................................................4

2.1 Objective of the Search................................................................................................4

2.2 Assumptions.................................................................................................................4

2.3 Data Sources.................................................................................................................4

3 Methodology...................................................................................................................... 54 Search Strategy...................................................................................................................6

4.1 Term Set.......................................................................................................................6

4.2 Relevant Classes Identified...........................................................................................8

4.3 Search Strings...............................................................................................................9

4.4 Glossary of Specific Search Operators Used...............................................................10

5 Relevance Criteria.............................................................................................................115.1 Relevant Criteria.........................................................................................................11

5.2 Non-Relevant Criteria.................................................................................................11

6 Search Results...................................................................................................................126.1 Claim Elements to be mapped....................................................................................12

6.2 Summary of Search Results........................................................................................12

6.3 Detailed Analysis of Search Results............................................................................13

6.3.1 Patent Results.....................................................................................................13

6.3.2 Claim Element mapping for Dependent Claims...................................................36

7 Non-Disclosure:.................................................................................................................388 Disclaimer......................................................................................................................... 38

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1 Search Overview & Background

Client asked The Patent Search Firm to conduct a Prior Art Search to identify patent and non-patent references that could affect the validity of the patent “US 7772209 B2”that is related to “Antifolate combination therapies”

TPSF has gone through the US 7772209 B2 and has developed the following understanding:

1. A method for administering pemetrexed disodium to a patient comprising administering an effective amount of folic acid and an effective amount of a methylmalonic acid lowering agent followed by administering an effective amount of pemetrexed disodium, whereinmethylmalonic acid lowering agent is selected from the group consisting of vitamin B12, hydroxycobalamin, cyano-10-chlorocobalamin, aquocobalamin perchlorate, aquo-10-cobalamin perchlorate, azidocobalamin, cobalamin, cyanocobalamin, or chlorocobalamin.

2. An improved method for administering pemetrexed disodium to a patient in need of chemotherapeutic treatment, wherein 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;b) Administration of about 500 μg to about 1500 μg of vitamin B12, prior to the first administration of pemetrexed disodium; andc) Administration of pemetrexed disodium.

Further, as per the client’s instructions, TPSF has to carry out the search as per the following variant:

VARIANT COVERAGE SEARCH LANGUAGE

Comprehensive

Patent Search in 92+ Countries [25+ Countries Full Texts] English + German +

FrenchNon-Patent Search

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http://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/7772209

http://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/7772209

2 Search Scope

2.1 Objective of the Search

The objective of our search will be to capture documents that disclose:

1. A method for administering pemetrexed disodium wherein the method comprises administering folic acid and methylmalonic acid lowering agent followed by administration of effective amount of pemetrexed disodium.

2. A method for administration of pemetrexed disodium wherein the method comprises administering folic acid and methylmalonic acid lowering agent followed by administering an effective amount of pemetrexed disodium wherein, methylmalonic acid lowering agent is selected from the group consisting of vitamin B12, hydroxycobalamin, cyano-10-chlorocobalamin, aquocobalamin perchlorate, aquo-10-cobalamin perchlorate, azidocobalamin, cobalamin, cyanocobalamin, or chlorocobalamin.

3. A method for administering pemetrexed disodium to a patient in need of chemotherapeutic treatment wherein, the method comprises administration of folic acid (about 350 μg and about 1000 μg) and methylmalonic acid lowering agent along with pemetrexed disodium.

4. A method for administering pemetrexed disodium to a patient in need of chemotherapeutic treatment wherein, the method comprises administration of folic acid (about 350 μg and about 1000 μg) and methylmalonic acid lowering agent along with pemetrexed disodium wherein the methylmalonic acid lowering agent is Vitamin B12(about 500 μg to about 1500 μg).

5. A method for administering pemetrexed disodium to a patient in need of chemotherapeutic treatment wherein, the method comprises administration of folic acid and Vitamin B12 along with pemetrexed disodium wherein, folic acid and methylmalonic acid lowering agent (preferably Vitamin B12) are administered prior to first administration of pemetrexed disodium.

2.2 Assumptions

Assumptions1. Questel Orbit database was used for conducting Patent searches.2. Google, Scholar, Science-Direct, and PubMed was used for conducting non-patent searches.3. The term 'Patent' has been used as a collective term for Patents and Published Applications.4. The comprehensiveness of this search has been governed by the upper cap on the effort to be invested.5. This search has been carried out as per our Comprehensive Variant and covers in 92 jurisdictions using keywords in English, German & French languages.

2.3 Data Sources

Data SourcesFor Bibliographic Data (including title, abstract):Questel OrbitEspacenetGoogle Patents

For Non-Patent Searches:Google ScholarScience-DirectPubMed

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http://www.questel.com/Prodsandservices/coverage.htm

3 Methodology

The following methodology was adopted for performing the Invalidity search:

MethodologyTask Details OutputStep 1 Understanding

TPSF developed a thorough understanding of the technology area and client’s requirements to prepare a strategy for the report

A preliminary strategy for the search was prepared including keyword-based search, citations search

Step II aKeyword-based Patent Searching

TPSF generated a list of keywords to be used for conducting the patent and non-patent search for the project, as per the preliminary search strategy. Further, the list of search strategy was used to perform patent searches on Questel Orbit patent database.The patents obtained from the search were analyzed to identify relevant/ related patents.

A set of relevant/related patents

Step II bPatent Citations Searching

TPSF conducted Forward-Backward and Backward-Forward citation analysis for relevant/related patents obtained from the searches II a.

A set of relevant/related patents

Step IIINon-Patent Searching

The search strings prepared for the patent search were modified to adapt to searching syntax for non-patent searches. Searches were carried out on Google to obtain a list of non-patent documents matching the keyword criteria. These non-patent documents were screened on the basis of free-information (mostly abstract).

A set of relevant/related results

Step IVDeliverable Preparation

An MS Word Document containing the project overview, search strategy, relevance criteria, and the results was prepared.

MS Word Deliverable

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4 Search Strategy

The following search strings, some combinations and/or some syntactical variations of them were used to conduct searches Questel Orbit to extract patents for analysis or extract other relevant information to assist in searching.

Similarly, syntactical variations of these strings were run on non-patent databases as well.

4.1 Term Set

Keyword Based Search

Term Set Keywords

FBP binding agent Broad Term Set

(("FBP") OR ((folic OR folique OR Folsäure) W (binding OR verbindlich OR obligatoire) W (proteins OR Eiweiß OR protein))) 3D ((binding OR verbindlich OR obligatoire) W (agent OR agents OR Agens OR Vertreterin))

FBP binding agent Narrow Term Set

((Folic OR folique OR Folsäure) W (acid OR sauer OR acide)) OR folate OR folacin OR folacine OR ((vitamin OR vitamine) 2W ("Ф" OR "M" OR "B9" OR ("B" W "9") OR "Bc" OR "Be")) OR (pteroyl 4W ((glutamic OR Glutaminsäure OR glutamique) W (acid OR sauer OR acide))) OR (pteroyl 4W (glutamate OR Glutamat)) OR "C19H19N7O6" OR ("C" W "19" W "H" W "19" W "N" W "7" W "O" W "6") OR Folvite OR Foliamin OR tetrahydrolfolate OR Folicet OR ((+amino 3W oxo 4W +pteridin+) W ((+pentanedioic OR glutamic OR (pentane W dioic)) W acid)) OR Folsav OR Folipac OR Folsan OR Facid OR Folcysteine OR ((+methyl OR +formyl) 9W (tetrahydrofolic OR (tetra W hydro W folic) OR (tetra W hydrofolic) OR (tetrahydro W folic)) W acid) OR ((+methyl OR +formyl) 9W (tetrahydrofolate OR (tetra W hydro W folate) OR (tetra W hydrofolate) OR (tetrahydro W folate) OR (tetra W hydro W folat) OR (tetra W hydrofolat) OR (tetrahydro W folat)))

Antifolate Broad Term Set

(((antineoplastic OR antineoplastischen OR antinéoplasique) OR (anti W neoplastic)) 2D (agent OR agents OR Agens OR Vertreterin)) OR antifolate OR Antifolat OR antifolates OR (folate 2D (antagonist OR antagonists OR antagoniste)) OR antifols OR antifol OR antifoliques

Antifolate Narrow Term Set

((pemetrexed or premetrexed) 2W disodium) OR ((pemetrexed or premetrexed) 2W di W sodium) OR Alimta OR "ALIMTA" OR Pemetrexed OR Pleumet OR Pemecad OR Rolazar OR Tifolar OR "C20H19N5Na2O6" OR ("C" W "20" W "H" W "19" W "N" W "5" W "Na" W "2" W "O" W "6") OR "MTA" OR (Pemetrexed 2W Hydrate) OR (+amino 5W dihydro 10W +pyrrolo 7W pyrimdin+ 6W +glutamic 1W acid) OR Tomudex OR Methotrexate OR Lometrexol OR lométrexol OR Proguanil OR Pyrimethamine OR Pyrimethamin OR Trimethoprim OR triméthoprime OR (fluorouracil) OR (fluoro W uracil) OR (folate 2W antimetabolite+) OR (Folate 2W (anti W metabolite+)) OR "MTX" OR Aminopterin OR "AMT" OR Trimetrexate OR trimétrexate OR Trimetrexat OR "TMQ" OR "LMTX" OR Premetrexed

Methylmalonic acid ((("MMA") OR ((Methylmalonic OR Methylmalonsäure OR

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lowering agent Broad Term Set

méthylmalonique) 2W (acid OR sauer OR acide))) 2D ((lowering OR abaissement OR senken) 2W (agent OR agents OR Agens OR Vertreterin)))

Methylmalonic acid lowering agent Narrow Term Set

((Vitamin OR vitamine) 2W "B12") OR ((Vitamin OR vitamine) 2W "B" W "12") OR cobalamin OR cobalamine OR (Co W balamin) OR ((aquocobalamin OR aquocobalamine) 2W (Perchlorat OR perchlorate)) OR (aquo 3W cobalamin 2W perchlorate) OR hydroxycobalamin OR hydroxycobalamine OR (hydroxy W cobalamin) OR (cyano 3W (chlorocobalamin OR (chloro W cobalamin))) OR azidocobalamin OR azidocobalamine OR (azido 2W cobalamin) OR (azido 2W cobalamine) OR (cyanocobalamin) OR cyanocobalamine OR (cyano 2W cobalamin) OR (cyano 2W cobalamine) OR (chlorocobalamin) OR (chloro 2W cobalamin) OR hydroxocobalamin OR hydroxocobalamine OR (hydroxo W (cobalamin OR cobalamine))

Toxicity Term Set

Toxicity OR Toxizität OR toxicité OR ((toxic OR toxique OR giftig OR toxisch) 2D (event OR Ereignis OR événement)) OR neutropenia OR neutropenie OR (Neutronen W Penia) OR ((neutron OR neutrons) W penia) OR thrombopenia OR thrombopénie OR (thrombo 2W Penia) OR ((toxic OR toxique OR giftig OR toxisch) 2W (death OR mort OR décès OR trépas OR Tod OR Sterben)) OR fatigue OR Müdigkeit OR Ermüdung OR Übermüdung OR fatiguer OR anorexia OR anorexie OR Magersucht OR nausea OR Übelkeit OR Brechreiz OR nausée OR rash OR (eruption 2D cutanées) OR rashes OR Hautausschläge OR infection OR Infektion OR Ansteckung OR diarrhea OR diarrhea OR Durchfall OR mucositis OR Mukositis OR mucite OR anemia OR anémie OR Anämie OR Blutarmut OR mortality OR mortalité OR Sterblichkeit OR (((nonhematologic) OR (non W hematologic)) 2W event) OR myelosuppression OR (myelo W suppression) OR (myelo W Unterdrückung) OR (suppression D de D myélo)

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4.2 Relevant Classes IdentifiedThe following Classes were used in combination with the term sets provided above:

Class Definitions

A61P 35/00 Antineoplastic agents [7]

A61K 45/06 ·Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca [2]

A61K 31/714 Cobalamins, e.g. cyanocobalamin, vitamin B12 [7]

A61K 31/519 ortho- or peri-condensed with heterocyclic rings [7]

C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 (esters with inorganic acids C07H 11/00; metal salts, see parent compounds) [2]

C12P 19/42 Cobalamins, i.e. vitamin B12, LLD factor [3]

A23L 1/302 Vitamins [4]

A61P 3/02 ·Nutrients, e.g. vitamins, minerals [7]

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4.3 Search Strings

S. No. Search String

1 <IN> Full Patent Specification(FBP binding agent Narrow Term Set) AND (Antifolate Narrow Term Set) AND (Methylmalonic acid lowering agent Narrow Term Set)

2

<IN> Claims, Title, Abstract(Methylmalonic acid lowering agent Broad Term Set) OR (Methylmalonic acid lowering agent Narrow Term Set)AND<IN> Full Patent Specification((Antifolate Broad Term Set) OR (Antifolate Narrow Term Set)) S (Toxicity Term Set)

3

<IN> Claims, Title, Abstract(Methylmalonic acid lowering agent Broad Term Set) OR (Methylmalonic acid lowering agent Narrow Term Set)AND<IN> Full Patent Specification(Antifolate Broad Term Set) S (Antifolate Narrow Term Set)

4

<IN> Claims, Title, Abstract(Methylmalonic acid lowering agent Broad Term Set) OR (Methylmalonic acid lowering agent Narrow Term Set)AND<IN> Full Patent Specification(Antifolate Broad Term Set) OR (Antifolate Narrow Term Set))

5

<IN> Claims, Title, Abstract(Antifolate Broad Term Set) OR (Antifolate Narrow Term Set)AND<IN> Full Patent Specification(Methylmalonic acid lowering agent Broad Term Set) OR (Methylmalonic acid lowering agent Narrow Term Set)

6

<IN> Claims, Title, Abstract(FBP binding agent Broad Term Set) OR (FBP binding agent Narrow Term Set)AND<IN> Full Patent Specification(Methylmalonic acid lowering agent Broad Term Set) OR (Methylmalonic acid lowering agent Narrow Term Set)AND(Toxicity Term Set)

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<IN> Claims, Title, Abstract((Antifolate Broad Term Set) OR (Antifolate Narrow Term Set)) S (Toxicity Term Set)ANDAny Classification: A61P-035/00 OR A61K-045/06 OR A61K-031/714 OR A61K-031/519 OR C07H-023/00 OR C12P-019/42 OR A23L-001/302 OR A61P-003/02

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4.4 Glossary of Specific Search Operators Used

Operators Definitions

+ Any number of characters (in Questel Orbit)

nW Search for words in the same sentence and appearing within n words of one another, in the written order. If n is omitted, the number defaults to one (in Questel Orbit)

nD Search for words in the same sentence and appearing within n words of one another, but in either order. If n is omitted, the number defaults to one (in Questel Orbit)

S Search terms occur in the same sentence (in Questel Orbit)

P Search for words in the same paragraph (in Questel Orbit)

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5 Relevance Criteria

Documents identified from the search were manually analyzed and tagged as relevant and not-relevant. Provided below is the description of each category.

5.1 Relevant CriteriaThose patent and non-patent references were considered as Relevant, which disclosed:

1. Composition comprising pemetrexed disodium (or broadly antifolate), folic acid (or broadly FBP binding protein) and methylmalonic acid lowering agents.

2. Compositions comprising folic acid (or broadly FBP binding protein), methylmalonic acid lowering agent (Vitamin B12) and pemetrexed disodium (or broadly antifolate) wherein the composition is used as a chemotherapeutic treatment/ for reducing toxicity associated with antifolates.

3. Method of administering a composition of pemetrexed disodium (or broadly antifolate) for chemotherapy, wherein composition essentially comprises folic acid (or broadly FBP binding proteins) and Vitamin B12 (or broadly methylmalonic acid lowering agent).

5.2 Non-Relevant CriteriaThose patent and non-patent references were considered as Non-Relevant, which disclosed:

1. Patents claiming a composition comprising antifolate with vitamins other than Folic acid and Vitamin B12 wherein, the composition is not being used for reduction of tumor growth or toxicity associated with an antifolate.

2. Patents claiming FBP binding protein/MMA lowering agents OR their method of preparation, wherein the document does not disclose the use of the claimed compound for reduction of tumor growth or toxicity associated with an antifolate.

3. Patents claiming Antifolates or method of production/preparation of antifolates.4. Patents claiming Amino acid solutions comprising folic acid and vitamin B12 as additives

wherein the solution is used with an anticancer agent and enhances the effect of the agent. (For Reference See- GB2029220A)

5. Patents claiming a vitamin composition comprising folic acid and vitamin B12 wherein the composition is used for lowering serum homocysteine levels without disclosing the use of the composition in reduction of tumor growth or toxicity (For reference see- WO1997014422A1)

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https://www.google.com/patents/WO1997014422A1?cl=en&dq=WO9714422&ei=BGlYVK_nJs3CPJKtgegE

http://worldwide.espacenet.com/publicationDetails/biblio?CC=GB&NR=2029220A&KC=A&FT=D&ND=&date=19800319&DB=&locale=en_EP

6 Search Results

6.1 Claim Elements to be mapped

All Independent and dependent claims of the patent US7772209 were mapped.

6.2 Summary of Search ResultsThe results of the search have been presented in the report below. The analysis below provides bibliographic details of the identified references and relevant excerpts from the identified references. The Patent number provided is also hyperlinked to the complete document, which includes all the figures and text.

You can access the web-link of the document by clicking over the Patent number. (If you are viewing in MS Word, then you’ll need to press your control key while you click.)

Summary of the Report:

Patent Results:

S. No.

Publication Number

Title Publication Date

Assignee Comment

IUS5563126A

(Cited by Applicant)

Method for treatment and prevention of deficiencies of vitamins B12, folic acid, and B6

8 Oct 1996

METABOLITE LAB INC

This patent document discloses identification of vitamins B12, folic acid, and B6 in a host by measuring homocysteine level and then administering at least one of cobalamin, folate or B6.

II EP0546870A(ISR : X)

Nutritive composition for prevention and therapy of infection diseases caused by immunosuppression

16 Jun 1993

SNOW BRAND MILK PROD CO LTD

Nutritive composition for patient being administered anticancer drugs (such as 5 FU). The nutritional composition of the invention comprises folic acid (0.1 mg) and vitamin B12 (50 micro grams).

III RU2114623METHOD OF SUPPRESSION OF TUMOR GROWTH

10 Jul 1998

G NAUCHNYJ TS ROSSIJSKOJ FEDER; SII NIOPIK; MO NI SKIJ ONKOLOGICHESK; IJ INST IM P A GERTSENA

This patent relates to treatment of malignant tumors with known cytostatics and mixture containing Hydroxy cobalamine, wherein the hydroxy cobalamine mixture is used mainly for reducing toxicity in tumor treatment.

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http://worldwide.espacenet.com/publicationDetails/biblio?DB=worldwide.espacenet.com&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=19980710&CC=RU&NR=2114623C1&KC=C1

http://worldwide.espacenet.com/publicationDetails/biblio?DB=EPODOC&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=19930616&CC=EP&NR=0546870A1&KC=A1

http://worldwide.espacenet.com/publicationDetails/biblio?CC=US&NR=5563126A&KC=A&FT=D

IV JPH06263639A

THERAPEUTIC AGENT FOR PRECANCEROUS CHANGE

20 Sep 1994

MEIJI SEIKA KAISHA

This patent document discloses elimination of precancerous change by administration of a large amount of folic acid and vitamin B12

V EP0505640A1

Improved therapeutic method

30 Sep 1992

Eli Lilly And Company

This patent document discloses use of a folate binding protein (such as folic acid) in the preparation of a medicament useful in lowering mammalian toxicity of antifolate drug (such as lomotrexol).

VI US5217974 A

Administering enzyme inhibitor as antitumor agent with folic acid or its derivatives to reduce toxicity

8 Jun 1993

Eli Lilly And Company

This patent document discloses method of treating tumors in mammal by pretreating them with toxicity reducing FBP (such as folic acid) and then administering Antifolate (such as lometrexol)

VII JPS55113721

IMMUNITY REGULATOR

2 Sep 1980

EISAI CO LTD This patent document discloses use of B12 as immunity enhancer and side effect preventer in cancer medication.

VIII CA2105177A1

Pharmaceutical preparations for lowering homocysteine levels

15 Mar, 1994

Vesta Medicines This patent document discloses treatment or prophylaxis of elevated plasma homocysteine levels by administering an intramuscular injection of Vitamin B12, folate and vitamin B6

IXCA2156826

A1

COMBINATION CISPLATIN/TAMOXIFEN THERAPY FOR HUMAN CANCERS

1 Sep 1994

RES DEV FOUNDATION

This document is related to administration of cisplatin with other anti-cancer drug (i.e. Tamoxifen) for treatment of human cancer.

Non-Patent Result:

S.No. Title Publication Details

1New approach to antifolate treatment of certain cancers asdemonstrated in tissue culture

Proc. Nat. Acad. Sci. USAVol. 72, No. 10, pp. 4018-4022, October 1975Cell Biology

COMMENT: This research publication reveals results of the experimental studies related to treatment of malignant tumor using

antifolate drug (i.e. MTX ), folic acid and B12. Further, this document discloses the relationship of vitamin B12 with toxicity

reduction.

ABSTRACT:

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http://www.pnas.org/content/72/10/4018.full.pdf



http://worldwide.espacenet.com/publicationDetails/biblio?CC=CA&NR=2156826A1&KC=A1&FT=D



http://worldwide.espacenet.com/publicationDetails/biblio?DB=EPODOC&II=11&ND=3&adjacent=true&locale=en_EP&FT=D&date=19800902&CC=JP&NR=S55113721A&KC=A

http://worldwide.espacenet.com/publicationDetails/biblio?CC=US&NR=5217974A&KC=A&FT=D

http://worldwide.espacenet.com/publicationDetails/biblio?DB=EPODOC&II=0&ND=3&at=19&locale=en_EP&FT=D&CC=EP&NR=0505640A1&KC=A1

http://worldwide.espacenet.com/publicationDetails/biblio?DB=worldwide.espacenet.com&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=19940920&CC=JP&NR=H06263639A&KC=A

http://worldwide.espacenet.com/publicationDetails/biblio?DB=worldwide.espacenet.com&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=19940920&CC=JP&NR=H06263639A&KC=A

The selective toxicity of antifolates for a variety of cancers can be improved, as illustrated by the combined administration of

N5-methyltetrahydrofolate and methotrexate in tissue culture. When a variety of neoplastic cell types characterized by a

deficiency of vitamin B12-dependent N5-methyltetrahydrofolate methyltransferase (5-methyltetrahydropteroyl-L-

glutamate:LIhomocysteine S-methyltransferase, EC 2.1.1.13) and normal adult cells are grown in media containing

methotrexate and either N5-methyltetrahydrofolate or N5-formyltetrahydrofolate, not only is the selective toxicity of

methotrexate demonstrated, but the advantage of using N5-methyltetrahydrofolate in place of N5-formyltetrahydrofolate is also

revealed. The implications and applications of this particular combination in the treatment of human cancer are discussed.

RELEVANT TEXT:

Page 2; Col 1; Paragraph 2Page 4; Col 1; Paragraph 3

Thus, when cells are presented with both MTX and N5mH4F, only those cells which possess sufficient vitamin B12-dependent

N5-methyltetrahydrofolate:homocysteine methyltransferase activity will thrive, whereas all cells which do not possess

adequate methyltransferase activity will succumb. All normal adult cells should thrive, whereas certain malignant cells should

die under these conditions. To test the thesis, the following tissue culture experiments were performed.

Both N5fH4F and N5mH4F have been reported to be competitive inhibitors at 10 times the concentration we have used of MTX

uptake by L-1210 and Ehrlich's ascites cells (34); however, it is difficult to reconcile the effect of N5fH4F and N5mH4F on

intracellular MTX with the fact that N5mH4F does not significantly interfere with the lethal effects of MTX in these two

malignant cells, whereas N5fH4F completely protects these same neoplastic cells. Both N5mH4F and N5fH4F counteract the

toxic effects of MTX on normal adult cells. The single metabolic difference so far demonstrated between the normal adult cells

and the malignant cells used in our experiments which can explain the difference in the effect of N5mH4F and N5fH4F is the

considerable disparity in the intracellular activity of the methyl-B12-dependent N5-methyltetrahydrofolate:homocysteine

methyltransferase (2).

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6.3 Detailed Analysis of Search Results

6.3.1 Patent ResultsPlease note that the list given is not comprehensive. The results given are for your reference.

Claim Limitation Representative Embodiment from Patent

Disclosure in Prior Art Comments

1.A method for administering pemetrexed disodium to a patient in need thereof comprising

Col 3, ll.1-6“Furthermore, the present invention relates to a method of administering an antifolate to a mammal in need thereof, comprising administering an effective amount of said antifolate in combination with a methylmalonic acid lowering agent and a FBP binding agent. A preferred FBP binding agent is folic acid.”

Col.4, ll:28-43“The terms “antifolate” and “antifolate drug” refer to a chemical compound which inhibits at least one key folate-requiring enzyme of the thymidine or purine biosynthetic pathways, preferably thymidylate synthase (“TS”), dihydrofolate reductase (“DHFR”), or glycinamideribonucleotideformyltransferase (“GARFT”), by competing with reduced folates for binding sites of these enzymes. Preferred examples of antifolates include Tomudex®, as manufactured by Zeneca; Methotrexate®, as manufactured by Lederle; Lometrexol®, as manufactured by Tularik;

Reference V, Page 8, Claim 1-4

1. The use of a folate binding protein binding agent selected from folic acid, (6R)-5-methyl-5,6,7,8-tetrahydrofolic acid, and (6R)-5-formyl-5,6,7,8-tetrahydrofolic acid, or a physiologically-available salt or ester thereof, in the preparation of a medicament useful in lowering the mammalian toxicity of a GAR-transformylase inhibitor, or other antifolate which binds to a folate binding protein.

2. The use claimed in claim 1, wherein the binding agent is folic acid, or a physiologically-available salt or ester thereof.

3. The use claimed in claim 1 or 2, wherein the GAR-transformylase inhibitor is lomotrexol.

4. A combination of folic acid, or a physiologically-available salt or ester thereof, and lomotrexol, for use in cancer chemotherapy.

Also see

Reference VI, Claim 1,3, 4

1. A method of inhibiting the

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pyrido[2,3-d]pyrimidine derivatives described by Taylor et al in U.S. Pat. Nos. 4,684,653, 4,833,145, 4,902,796, 4,871,743, and 4,882,334; derivatives described by Akimoto in U.S. Pat. No. 4,997,838; thymidylate synthase inhibitors as found in EPO application 239,362; and most preferred, Pemetrexed Disodium (ALIMTA), as manufactured by Eli Lilly & Co.”

growth of GAR-transformylase-dependent tumors in mammals comprising administering to said mammals an effective amount of a GAR-transformylase inhibitor which binds to a folate binding protein in combination with a toxicity-reducing amount of a folate binding protein binding agent selected from folic acid, (6R)-5-methyl-5,6,7,8-tetrahydrofolic acid, and (6R)-5-formyl-5,6,7,8-tetrahydrofolic acid, or a physiologically-available salt or ester thereof.

2. The method of claim 1 wherein the GAR-transformylase inhibitor is a pyrido[2,3-d]pyrimidine.

3. The method of claim 2 wherein the GAR-transformylase inhibitor is lometrexol.

4. The method of claim 1 wherein the folate binding protein binding agent is folic acid.

administering an effective amount of folic acid

Col 3, ll.1-6“Furthermore, the present invention relates to a method of administering an antifolate to a mammal in need thereof, comprising administering an effective amount of said antifolatein combination with a methylmalonic acid lowering agent and a FBP binding agent. A preferred FBP binding agent is folic acid.”

Reference B Page 7, ll.7-19

“The organocobalt complex is any organic complex containing a cobalt atom having bound thereto 4-5 nitrogen and/or chalcogens such as oxygen, sulfur, etc., as part of a multiple unsaturated heterocyclic ring system. In accordance with the present invention, suitable organocobalt complexes include, but are not limited to, cobalamin, Co[SALEN], organo- (pyridine)bis(dimethylglyoximato)cobalt, corrinoids, derivatives

Reference B:Organocobalt (cobalamine derivative) can be complexed with folic acid

16

thereof and analogues thereof. The organocobalt complexes may be unsubstituted or substituted with conventional organic functional groups which will not alter the basic nature of the organocobalt complex. The basic nature of the organocobalt complex is to directly or indirectly bind the bioactive agent covalently to the cobalt such that the cobalt-bioactive agent bond is readily cleavable as described herein. The organocobalt complex may also be covalently bound directly or indirectly to a targeting molecule. The targeting molecule is a molecule for which the desired cell, tissue or organ has a requirement or a receptor, as described herein.”

Reference B Page 14 &15 , ll.1

“Targeting Molecule: a molecule which is bound by a receptor and transported into a cell by a receptor-mediated process. Examples of suitable targeting molecules include, but are not limited to. glucose, galactose. mannose. mannose 6-phosphate, transferrin. asialoglycoprotein, α-2-macroglobulins, insulin, a peptide growth factor, cobalamin. folic acid or derivatives, biotin or derivatives, YEE(GalNAcAH)3 or derivatives, albumin, texaphyrin. metallotexaphyrin, porphyrin, any vitamin, any coenzyme, an antibody, an antibody fragment (e.g., Fab) and a single chain antibody variable region (scFv). A skilled artisan will readily

17

recognize other targeting molecules (ligands) which bind to cell receptors and which are transported into a cell by a receptor-mediated process. The present invention is intended to include all such targeting molecules.”

Also See

Reference I, Column 26, Claims 1,2

1. A method for treating or preventing a deficiency in a host of at least one of cobalamin, folate or B6 comprising determining the level of at least one metabolite selected from the group consisting of homocysteine, cystathionine, and 2-methylcitric acid, and administering to the host a formulation containing cobalamin, folate and B6, only if the level of at least one of said metabolites is elevated.

2. The method of claim 1, wherein said administering step includes administering between 0.1 and 10.0 mg cobalamin, between 0.1 and 10 mg of folate, and between 5 and 75 mg B6.

Also See

Reference IV, Abstract

PURPOSE: To obtain an inexpensive medicine for improving precancerous symptoms.

18

CONSTITUTION: Elimination of precancerous change, especially precancerous change of bronchial tubes is confirmed by administration of a large amount of folic acid and vitamin B12. The amounts of folic acid and vitamin B12 per adult daily are about 100 times as much as those required for a healthy adult. The composition ratio of folic acid and vitamin B12 by weight is properly 5-30 of folio acid based on 1 of vitamin B12.

Also See

Reference V, Page 8, Claim 1,3,4

1. The use of a folate binding protein binding agent selected from folic acid, (6R)-5-methyl-5,6,7,8-tetrahydrofolic acid, and (6R)-5-formyl-5,6,7,8-tetrahydrofolic acid, or a physiologically-available salt or ester thereof, in the preparation of a medicament useful in lowering the mammalian toxicity of a GAR-transformylase inhibitor, or other antifolate which binds to a folate binding protein.

3. The use claimed in claim 1 or 2, wherein the GAR-transformylase inhibitor is lomotrexol.

4. A combination of folic acid, or a physiologically-available salt or

19

ester thereof, and lomotrexol, for use in cancer chemotherapy.

Also see

Reference VI, Claim 1- 4

1. A method of inhibiting the growth of GAR-transformylase-dependent tumors in mammals comprising administering to said mammals an effective amount of a GAR-transformylase inhibitor which binds to a folate binding protein in combination with a toxicity-reducing amount of a folate binding protein binding agent selected from folic acid, (6R)-5-methyl-5,6,7,8-tetrahydrofolic acid, and (6R)-5-formyl-5,6,7,8-tetrahydrofolic acid, or a physiologically-available salt or ester thereof.

2. The method of claim 1 wherein the GAR-transformylase inhibitor is a pyrido[2,3-d]pyrimidine.

3. The method of claim 2 wherein the GAR-transformylase inhibitor is lometrexol.

4. The method of claim 1 wherein the folate binding protein binding agent is folic acid.

and an effective amount of a methylmalonic

Col 3, ll.1-6“Furthermore, the present invention relates to a

Reference B Page 72 , Claims

“1. A bioconjugate of a bioactive

20

acid lowering agent (whereinthemethylmalonic acid lowering agent is selected from the group consisting of vitamin B12, hydroxycobalamin, cyano-10-chlorocobalamin, aquocobalamin perchlorate, aquo-10-cobalamin perchlorate, azidocobalamin, cobalamin, cyanocobalamin, or chlorocobalamin.)

method of administering an antifolate to a mammal in need thereof, comprising administering an effective amount of said antifolate in combination with a methylmalonic acid lowering agent and a FBP binding agent. A preferred FBP binding agent is folic acid.”

Col.4.ll: 47-50“The term “methylmalonic acid loWering agent” refers to asubstrate, Which loWers the concentration of methylmalonic acid in a mammal. A preferred example of such a substrate isvitamin B12.”

agent and an organocobalt complex wherein the bioactive agent is covalently conjugated to the cobalt atom through a non-reactive atom in the bioactive agent molecule.17. The bioconjugate of any one of claims 1 -16, wherein said organocobalt complex is cobalamin, a cobalamin derivative or a cobalamine analogue.

21. A method of administering a bioactive agent to cells of a targeted tissue site of a subject which comprises administering to said subject an effective amount of said bioactive agent as the bioconjugate of any one of claims 1-20.

53. The method of any one of claims 21-52, wherein a bolus of vitamin B12 is administered prior to administration of said bioconjugate.”

Also See

Reference III, Abstract

FIELD: biology, medicine, oncology. SUBSTANCE: invention relates to methods of SUPPRESSION of malignant tumors growth. Method involves the use of the known cytostatics in combination with a mixture consisting of cobalt octacarboxyphthalocyanine or hydroxycoblamine and sodium ascorbate at molar ratio of components = 1:(20-40). EFFECT:

21

enhanced effectiveness of method, decreased toxicity. 6 tbl, 6 dwgo




Also See

Reference VII, Abstract

PURPOSE: An immunity regulator useful as a treating agent for cancers and infectious diseases due to the abnormal immunity function, comprising Mecobalamin.CONSTITUTION:An immunity regulator comprising Mecobalamin [alpha-(5,6-dimethylbenzimidazole)-Co-methyl-cobamide]. The Mecobalamin biochemically known as a co-enzyme B12 in

22

blood, has been found to exert an immunity regulatory action, and is effective against diseases, e.g. cancers, infectious, allergic or autoimmune diseases, and also for preventing side effects of drugs, particularly cancer chemotherapeutic agents which will cause the immune hypofunction.

Also See

Reference VIII, Page 46-47 , Claims 11, 12, 21, 22

11. A method for lowering levels of homocysteine or for the prophylaxis or treatment of elevated levels of homocysteine in a patient or of clinical conditions associated therewith, which comprises administration to such patient a combination comprising:

a) vitamin B6;b) folate or a suitable active metabolite of folate or a substance which releases folate in vivo;c) vitamin B12, with or without intrinsic factor.

12. A method as claimed in claim 11, wherein in the combination the ingredients a) - c) are present in the following ratios by weight calculated on the basis of pure unphosphorylated pyridoxal (PL), pure vitamin B12 and pure folic acid:

21. A method as claimed in claim

23

11, wherein the combination is parenterally administered.

22. A method as claimed in claim 21, wherein the combination is administered by infusion or intramuscular injection.

followed by administering an effective amount of pemetrexed disodium

Col 3, ll.1-6“Furthermore, the present invention relates to a method of administering an antifolate to a mammal in need thereof, comprising administering an effective amount of said antifolate in combination with a methylmalonic acid lowering agent and a FBP binding agent. A preferred FBP binding agent is folic acid.”

Col.4, ll:28-43“The terms “antifolate” and “antifolate drug” refer to a chemical compound which inhibits at least one key folate-requiring enzyme of the thymidine or purine biosynthetic pathways, preferably thymidylate synthase (“TS”), dihydrofolate reductase (“DHFR”), or glycinamideribonucleotideformyltransferase (“GARFT”), by competing with reduced folates for binding sites of these enzymes. Preferred examples of antifolates include Tomudex®, as manufactured by Zeneca; Methotrexate®, as manufactured by Lederle;

- We suggest a structure search on STN to cover this aspect

24

Lometrexol®, as manufactured by Tularik; pyrido[2,3-d]pyrimidine derivatives described by Taylor et al in U.S. Pat. Nos. 4,684,653, 4,833,145, 4,902,796, 4,871,743, and 4,882,334; derivatives described by Akimoto in U.S. Pat. No. 4,997,838; thymidylate synthase inhibitors as found in EPO application 239,362; and most preferred, Pemetrexed Disodium (ALIMTA), as manufactured by Eli Lilly & Co.”

2. The method of claim 1, wherein the methylmalonic acid lowering agent is vitamin B12.

Col.4.ll: 47-50“The term “methylmalonic acid loWering agent” refers to asubstrate, Which loWers the concentration of methylmalonic acid in a mammal. A preferred example of such a substrate isvitamin B12.”

Reference B Page 72 , Claims

“1. A bioconjugate of a bioactive agent and an organocobalt complex wherein the bioactive agent is covalently conjugated to the cobalt atom through a non-reactive atom in the bioactive agent molecule.

21. A method of administering a bioactive agent to cells of a targeted tissue site of a subject which comprises administering to said subject an effective amount of said bioactive agent as the bioconjugate of any one of claims 1-20.

53. The method of any one of claims 21-52, wherein a bolus of vitamin B12 is administered prior to administration of said bioconjugate.”

25

Also See




Also See

Reference VII, Abstract

PURPOSE: An immunity regulator useful as a treating agent for cancers and infectious diseases due to the abnormal immunity function, comprising Mecobalamin.CONSTITUTION: An immunity regulator comprising Mecobalamin [alpha-(5,6-dimethylbenzimidazole)-Co-methyl-cobamide]. The Mecobalamin biochemically known as a co-enzyme B12 in blood, has been found to exert an immunity regulatory action, and is effective against diseases, e.g.

26

cancers, infectious, allergic or autoimmune diseases, and also for preventing side effects of drugs, particularly cancer chemotherapeutic agents which will cause the immune hypofunction.Also See



a) vitamin B6;b) folate or a suitable active metabolite of folate or a substance which releases folate in vivo;c) vitamin B12, with or without intrinsic factor.12. A method as claimed in claim 11, wherein in the combination the ingredients a) - c) are present in the following ratios by weight calculated on the basis of pure unphosphorylated pyridoxal (PL), pure vitamin B12 and pure folic acid:

21. A method as claimed in claim 11, wherein the combination is parenterally administered.22. A method as claimed in claim 21, wherein the combination is administered by infusion or intramuscular injection.

27

3. The method of claim 2, wherein the vitamin B12 is administered as an intramuscular injection of about 500 μg to about 1500 μg.

Col. 5,ll:4-10“The term “vitamin B12” refers to vitamin B12 and itspharmaceutical derivatives, such as hydroxocobalamin,cyano-10-chlorocobalamin, aquocobalamin perchlorate,aquo-10-chlorocobalamin perchlorate, aZidocobalamin,chlorocobalamin, and cobalamin. Preferably the term refers to vitamin B12, cobalamin, and chlorocobalamin.”

Col. 5,ll: 25-27“Preferably, cobalamin Will be dosed as an intramuscularinjection of about 500 µg to about 1500 µg administered from about every 24 hours to about every 1680 hours”

Reference B Page 48 , ll:5-10

“It is preferred that 0.1 mg to 100 mg, more preferably 1.0 mg to 10 mg, of vitamin B12 be administered prior to the administration of the bioconjugate containing cobalamin. In addition, vitamin BI2 can be administered, preferably intravenously, following the selective cleavage of bioconjugate to wash out all bioconjugate which has not been cleaved, and thus further reduce potential systemic effects. It is preferred that 0.1 mg to 100 mg, more preferably 10 mg to 100 mg, of vitamin B12 in saline be administered intravenously over 4-5 hrs”

Also See



a) vitamin B6;b) folate or a suitable active metabolite of folate or a substance which releases folate in vivo;c) vitamin B12, with or without intrinsic factor.

Reference B:Vitamin B12 is administered intravenously

28

12. A method as claimed in claim 11, wherein in the combination the ingredients a) - c) are present in the following ratios by weight calculated on the basis of pure unphosphorylated pyridoxal (PL), pure vitamin B12 and pure folic acid:

21. A method as claimed in claim 11, wherein the combination is parenterally administered.22. A method as claimed in claim 21, wherein the combination is administered by infusion or intramuscular injection.

4. The method of claim 2, wherein the vitamin B12 is administered as an intramuscular injection of about 1000 μg.

Col. 5,ll: 25-33“Preferably, cobalamin Will be dosed as an intramuscularinjection of about 500 µg to about 1500 µg administered fromabout every 24 hours to about every 1680 hours. Preferably, itis an intramuscular injection of about 1000 µg administeredinitially from about 1 to about 3 Weeks prior to administrationof the antifolate and repeated from about every 24 hours toabout every 1680 hours, regardless of When treatment With the antifolate is started and continued until the administrationof the antifolate is discontinued.

- Numeric Property Searching on STN recommended

5. The method of claim

Col. 5,ll: 25-38“Preferably, cobalamin Will

- Dosage regime not

29

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 of the pemetrexed disodium is discontinued.

be dosed as an intramuscularinjection of about 500 µg to about 1500 µg administered fromabout every 24 hours to about every 1680 hours. Preferably, itis an intramuscular injection of about 1000 µg administeredinitially from about 1 to about 3 Weeks prior to administrationof the antifolate and repeated from about every 24 hours toabout every 1680 hours, regardless of When treatment With the antifolate is started and continued until the administrationof the antifolate is discontinued.Most preferred is an intramuscular injection of about 1000 µg administered initiallyfrom about 1 to about 3 Weeks prior to the first administrationof the antifolate and repeated every 6 to 12 Weeks, preferably about every 9 Weeks, and continued until the discontinuation of the antifolate administrations.”

found

6. The method of claim 5 wherein the folic acid is administered 1 to 3 weeks prior to the first

Col. 5,ll: 25-38“Preferably, cobalamin Will be dosed as an intramuscularinjection of about 500 µg to about 1500 µg administered fromabout every 24 hours to

Reference VI, Col 6; Lines 29-36

The FBP binding agent is administered to the subject mammal prior to treatment with the GAR-transformylase inhibitor or other antifolate. Pretreatment

30

administration of the pemetrexed disodium.

about every 1680 hours. Preferably, itis an intramuscular injection of about 1000 µg administeredinitially from about 1 to about 3 Weeks prior to administrationof the antifolate and repeated from about every 24 hours toabout every 1680 hours, regardless of When treatment With the antifolate is started and continued until the administrationof the antifolate is discontinued.Most preferred is an intramuscular injection of about 1000 µg administered initiallyfrom about 1 to about 3 Weeks prior to the first administrationof the antifolateand repeated every 6 to 12 Weeks, preferably about every 9 Weeks, and continued until the discontinuation of the antifolate administrations.”

with the suitable amount of FBP binding agent from about 1 to about 24 hours is usually sufficient to substantially bind to and block the folate binding protein prior to administration of the GAR-transformylase inhibitor or other antifolate. Although one single dose of the FBP binding agent, preferably an oral administration of folic acid, should be sufficient to load the folate binding protein, multiple dosing of the FBP binding agent can be employed for periods up to weeks before treatment with the active agent to ensure that the folate binding protein is sufficiently bound in order to maximize the benefit derived from such pretreatment.

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.

Col. 6, ll:35-41“In the especially preferred embodiment of this invention,about 0.1 mg to about 30 mg, most preferably about 0.3 mg to about 5 mg, of folic acid is administered orally to a mammal about 1 to 3 Weeks post administration of the methylmalonic acid loWering agent and about 1 to about 24 hours prior to the


In the especially preferred embodiment of this invention, about 1 mg to about 5 mg of folic acid is administered orally to a mammal about 1 to about 24 hours prior to the parenteral administration of the amount of lomotrexol which is normally required to attain the desired therapeutic benefit. Although greater or additional doses of folic

31

parenteral administration of the amount of an antifolate.”

acid or another FBP binding agent are also operable, the above parameters will usually bind the folate binding protein in an amount sufficient to reduce the toxicity effects normally seen upon lomotrexol administration above.

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.

Col. 6, ll:35-41“In the especially preferred embodiment of this invention,about 0.1 mg to about 30 mg, most preferably about 0.3 mg to about 5 mg, of folic acid is administered orally to a mammal about 1 to 3 Weeks post administration of the methylmalonic acid loWering agent and about 1 to about 24 hours prior to the parenteral administration of the amount of an antifolate.”


In the especially preferred embodiment of this invention, about 1 mg to about 5 mg of folic acid is administered orally to a mammal about 1 to about 24 hours prior to the parenteral administration of the amount of lomotrexol which is normally required to attain the desired therapeutic benefit. Although greater or additional doses of folic acid or another FBP binding agent are also operable, the above parameters will usually bind the folate binding protein in an amount sufficient to reduce the toxicity effects normally seen upon lomotrexol administration above.

9. The method of claim 8 wherein about 350 μg to about 1000 μg of folic acid is administered.

Col. 9, ll: 7-13“Folic acid Will be supplied as one of the following options,With preference in order from option #1 to option #3:1. 350-600 µg folic acid.2. A multivitamin containing folic acid in the range of 350µg to 600 µg is acceptable if option #1 is not available.3. A dose of folic acid betWeen 350 µg and 1000 µg isacceptable if neither option


32

#1 or option # 2 is available.”10. The method of claim 9 wherein 350 μg to 600 μg of folic acid is administered.

Col. 9, ll: 7-13“Folic acid Will be supplied as one of the following options,With preference in order from option #1 to option #3:1. 350-600 µg folic acid.2. A multivitamin containing folic acid in the range of 350µg to 600 µg is acceptable if option #1 is not available.3. A dose of folic acid betWeen 350 µg and 1000 µg isacceptable if neither option #1 or option # 2 is available.”


11. The method of claim 1 further comprising the administration of cisplatin to the patient.

Col. 9, ll: 14-17“For purposes of this study, patients should take oral folicacid daily beginning approximately 1 to 3 Weeks before treatment With ALIMTA plus cisplatin or cisplatin alone and continuing daily until discontinuation from study therapy.”

Reference IX , Page 24 , Claim 1

1. A composition of matter for the treatment of non-melanoma cancers, wherein said composition comprises a combination of a platinum anti-neoplastic compound and tamoxifen, wherein said platinum antineoplastic compound and tamoxifen exert a synergistic anti-tumor effect on said non-melanoma cancer.

3. The composition of claim 1, wherein said platinum anti-neoplastic compound is selected from the group consisting of cisplatin and carboplatin.

12. An improved method for administering pemetrexed disodium to a patient in need

Col. 8,ll: 39-42In a typical clinical evaluation involving cancer patients, allof Whom have histologically or cytologically confirmed diaganosis of cancer, an antifolate is administered in

- Structure Search on STN recommended

33

of chemotherapeutic treatment, wherein 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;

combinationWith vitamin B12

Col. 9,ll: 4-13“Method of Administration and Dosing Procedures:1. Folic Acid:Folic acid Will be supplied as one of the following options,With preference in order from option #1 to option #3:1. 350-600 µg folic acid.2. A multivitamin containing folic acid in the range of 350µg to 600 µg is acceptable if option #1 is not available.3. A dose of folic acid betWeen 350 µg and 1000 µg isacceptable if neither option #1 or option # 2 is available.”

b) administration of about 500 μg to about 1500 μg of vitamin B12, prior to the first administration of pemetrexed disodium; and

Col. 5, ll:25-27“Preferably, cobalamin Will be dosed as an intramuscularinjection of about 500 µg to about 1500 µg administered fromabout every 24 hours to about every 1680 hours.”

Col. 9, ll: 20-24“Vitamin B12 Will be obtained and administered as a 1000µg intramuscular injection. A vitamin B12 injection must beadministered approximately 1 to 3 Weeks before treatmentWith ALIMTA and should be repeated approximately every 9 Weeks until the patient discontinues from


34

study therapy.”c) administration of pemetrexed disodium.

Col. 9, ll: 20-24“Vitamin B12 Will be obtained and administered as a 1000µg intramuscular injection. A vitamin B12 injection must beadministered approximately 1 to 3 Weeks before treatmentWith ALIMTA and should be repeated approximately every 9 Weeks until the patient discontinues from study therapy.”

- Structure Search Recommended on STN



- Cis-Platin in combination with specific drug not found.

14. The method of claim 12, wherein vitamin B12 is administered as an intramuscular injection of about 500 μg to about 1500 μg.

Col. 5,ll:4-10“The term “vitamin B12” refers to vitamin B12 and itspharmaceutical derivatives, such as hydroxocobalamin,cyano-10-chlorocobalamin, aquocobalamin perchlorate,aquo-10-chlorocobalamin perchlorate, aZidocobalamin,chlorocobalamin, and cobalamin. Preferably the term refers to vitamin B12, cobalamin, and chlorocobalamin.”

Col. 5,ll: 25-27“Preferably, cobalamin Will be dosed as an intramuscularinjection of about 500 µg to


35

about 1500 µg administered from about every 24 hours to about every 1680 hours”

15. The method of claim 14, wherein vitamin B12 is administered as an intramuscular injection of about 1000 μg.

Col. 8,ll: 39-46“In a typical clinical evaluation involving cancer patients, allof Whom have histologically or cytologically confirmed diaganosis of cancer, an antifolate is administered in combinationWith vitamin B12. Vitamin B12 is administered as a 1000 µgintramuscular injection 1-3 Weeks prior to treatment With theantifolate, and 1000 µg intramuscular injection of vitaminB12 is made approximately every 9 Weeks until the patientdiscontinues from therapy..


16. The method of claim 15, wherein between 0.3 mg to about 5 mg of folic acid is administered orally.

Col. 6, ll:35-41“In the especially preferred embodiment of this invention,about 0.1 mg to about 30 mg, most preferably about 0.3 mg to about 5 mg, of folic acid is administered orally to a mammal about 1 to 3 Weeks post administration of the methylmalonic acid lowering agent and about 1 to about 24 hours prior to the parenteral administration of the amount of an antifolate.”


17. The method of claim 16 wherein

Col. 9, ll: 7-13“Folic acid Will be supplied as one of the following

- Numeric Property Searching on

36

about 350 μg to about 1000 μg of folic acid is administered.

options,With preference in order from option #1 to option #3:1. 350-600 µg folic acid.2. A multivitamin containing folic acid in the range of 350µg to 600 µg is acceptable if option #1 is not available.3. A dose of folic acid betWeen 350 µg and 1000 µg isacceptable if neither option #1 or option # 2 is available.”

STN recommended

18. The method of claim 17 wherein 350 μg to 600 μg of folic acid is administered.

Col. 9, ll: 7-13“Folic acid Will be supplied as one of the following options,With preference in order from option #1 to option #3:1. 350-600 µg folic acid.2. A multivitamin containing folic acid in the range of 350µg to 600 µg is acceptable if option #1 is not available.3. A dose of folic acid betWeen 350 µg and 1000 µg isacceptable if neither option #1 or option # 2 is available.”


19. The method of claim 18 wherein folic acid is administered 1 to 3 weeks prior to the first administration of the pemetrexed disodium.

Col. 5,ll: 25-38“Preferably, cobalamin Will be dosed as an intramuscularinjection of about 500 µg to about 1500 µg administered fromabout every 24 hours to about every 1680 hours. Preferably, itis an intramuscular injection of about 1000 µg administeredinitially from about 1 to about 3 Weeks prior to administration

- Dosage regime not found

37

of the antifolate and repeated from about every 24 hours toabout every 1680 hours, regardless of When treatment With the antifolate is started and continued until the administrationof the antifolate is discontinued.Most preferred is an intramuscular injection of about 1000 µg administered initiallyfrom about 1 to about 3 Weeks prior to the first administrationof the antifolateand repeated every 6 to 12 Weeks, preferably about every 9 Weeks, and continued until the discontinuation of the antifolate administrations.”

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 disodium.

Col. 6, ll:35-41“In the especially preferred embodiment of this invention,about 0.1 mg to about 30 mg, most preferably about 0.3 mg to about 5 mg, of folic acid is administered orally to a mammal about 1 to 3 Weeks post administration of the methylmalonic acid loWering agent and about 1 to about 24 hours prior to the parenteral administration of the amount of an antifolate.”

- Dosage Regime Not found

21. The method of claim 12, 18, or 19, wherein the vitamin B12 administration is repeated about every 6

Col. 5,ll: 25-38“Preferably, cobalamin Will be dosed as an intramuscularinjection of about 500 µg to about 1500 µg administered fromabout every 24 hours to

- Dosage Regime Not Found

38

to about every 12 weeks following the administration of vitamin B12 until administration of pemetrexed disodium is discontinued.

about every 1680 hours. Preferably, itis an intramuscular injection of about 1000 µg administeredinitially from about 1 to about 3 Weeks prior to administrationof the antifolate and repeated from about every 24 hours toabout every 1680 hours, regardless of When treatment With the antifolate is started and continued until the administrationof the antifolate is discontinued.Most preferred is an intramuscular injection of about 1000 µg administered initiallyfrom about 1 to about 3 Weeks prior to the first administrationof the antifolate and repeated every 6 to 12 Weeks, preferably about every 9 Weeks, and continued until the discontinuation of the antifolate administrations.”



-Cis-Platin in combination with specific drug not found.

39

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