UNITED STATES PATENT AND TRADEMARK OFFICE
`
`APPLICATION
`NUMBER
`61/173,518
`
`FILING or
`37l(c)DATE
`04/28/2009
`
`GRPART
`UNIT
`
`FIL FEE REC'D
`220
`
`37462
`LOWRIE, LANDO & ANASTASI, LLP
`ONE MAIN STREET, SUITE 1100
`CAMBRIDGE, MA 02142
`
`Ul\TfED STATES DEPA RTME'IT OF COMMERCE
`United States Patent and Trademark Office
`Adiliess. COMMISSIO'JER FOR PATENTS
`PO Box 1450
`Alexandria, Virgmia 22313-1450
`\VVi\V.USpto.gov
`
`ATTY.DOCKET.NO
`C2081-701302
`
`TOT CLAIMS IND CLAIMS
`
`CONFIRMATION NO. 5577
`FILING RECEIPT
`
`1111111111111111111111 ll]~!l]!~l!~l!~IIJHI i111 jl] 111111111111111 IIII IIII
`
`Date Mailed: 05/22/2009
`
`Receipt is acknowledged of this provisional patent application. It will not be examined for patentability and will
`become abandoned not later than twelve months after its filing date. Any correspondence concerning the application
`must include the following identification information: the U.S. APPLICATION NUMBER, FILING DATE, NAME OF
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`to the Notice, the USPTO will generate another Filing Receipt incorporating the requested corrections
`
`Applicant( s)
`
`Stefan Gross, Brookline, MA;
`Shengfang Jin, Newton, MA;
`Shinsan Su, Cambridge, MA;
`Valeria Fantin, Cambridge, MA;
`Lenny Dang, Boston, MA;
`Katharine Yen, Wellesley, MA;
`Power of Attorney:
`Catherine McCarty--54301
`
`If Required, Foreign Filing License Granted: 05/14/2009
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61/173,518
`Projected Publication Date: None, application is not eligible for pre-grant publication
`Non-Publication Request: No
`Early Publication Request: No
`Title
`
`METHODS AND COMPOSITIONS FOR TREATING CANCER
`
`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
`
`Since the rights granted by a U.S. patent extend only throughout the territory of the United States and have no
`effect in a foreign country, an inventor who wishes patent protection in another country must apply for a patent
`in a specific country or in regional patent offices. Applicants may wish to consider the filing of an international
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`application under the Patent Cooperation Treaty (PCT). An international (PCT) application generally has the same
`effect as a regular national patent application in each PCT-member country. The PCT process simplifies the filing
`of patent applications on the same invention in member countries, but does not result in a grant of "an international
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`Almost every country has its own patent law, and a person desiring a patent in a particular country must make an
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`For information on preventing theft of your intellectual property (patents, trademarks and copyrights), you may wish
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`LICENSE FOR FOREIGN FILING UNDER
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`Title 35, United States Code, Section 184
`
`Title 37, Code of Federal Regulations, 5.11 & 5.15
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`GRANTED
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`The applicant has been granted a license under 35 U.S.C. 184, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" followed by a date appears on this form. Such licenses are issued in all applications where
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`This license is to be retained by the licensee and may be used at any time on or after the effective date thereof unless
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`The grant of a license does not in any way lessen the responsibility of a licensee for the security of the subject matter
`as imposed by any Government contract or the provisions of existing laws relating to espionage and the national
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`security or the export of technical data. Licensees should apprise themselves of current regulations especially with
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`State (with respect to Arms, Munitions and Implements of War (22 CFR 121-128)); the Bureau of Industry and
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`NOT GRANTED
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`No license under 35 U.S.C. 184 has been granted at this time, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" DOES NOT appear on this form. Applicant may still petition for a license under 37 CFR 5.12,
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`
`page 3 of 3
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`Rigel Exhibit 1045
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`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (04-07)
`Approved for use through 06/30/2010 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
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`Provisional Application for Patent Cover Sheet
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c)
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`lnventor(s)
`
`Inventor 1
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Stefan
`
`Inventor 2
`
`Gross
`
`Brookline
`
`MA
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Shengfang
`
`Inventor 3
`
`Jin
`
`Newton
`
`MA
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Shinsan
`
`Inventor 4
`
`Su
`
`Cambridge
`
`MA
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Valeria
`
`Inventor 5
`
`Fantin
`
`Cambridge
`
`MA
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Lenny
`
`Inventor 6
`
`Dang
`
`Boston
`
`MA
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Katharine
`
`Yen
`
`Wellesley
`
`MA
`
`All Inventors Must Be Listed -Additional Inventor Information blocks may be
`generated within this form by selecting the Add button.
`
`I Remove I
`Country
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`us
`
`I Remove I
`Country
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`us
`
`I Remove I
`Country
`
`us
`
`I Remove I
`Country
`
`us
`
`I Remove I
`Country
`
`us
`
`I Remove I
`Country
`
`us
`
`I Add
`
`I
`
`i
`
`i
`
`i
`
`i
`
`i
`
`i
`
`Title of Invention
`
`METHODS AND COMPOSITIONS FOR TREATING CANCER
`
`Attorney Docket Number (if applicable)
`
`C2081-701302
`
`Correspondence Address
`
`Direct all correspondence to (select one):
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`® The address corresponding to Customer Number
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`0 Firm or Individual Name
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`EFS - Web 1.0.1
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`Rigel Exhibit 1045
`Page 4 of 106
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`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (04-07)
`Approved for use through 06/30/2010 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid 0MB control number
`
`Customer Number
`
`37462
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United
`States Government.
`0 No.
`0 Yes, the name of the U.S. Government agency and the Government contract number are:
`
`EFS - Web 1.0.1
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`Rigel Exhibit 1045
`Page 5 of 106
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`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (04-07)
`Approved for use through 06/30/2010 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid 0MB control number
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`Entity Status
`Applicant claims small entity status under 37 CFR 1.27
`0 Yes, applicant qualifies for small entity status under 37 CFR 1.27
`® No
`Warning
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`Petitioner/applicant is cautioned to avoid submitting personal information in documents filed in a patent application that may
`contribute to identity theft. Personal information such as social security numbers, bank account numbers, or credit card
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`Signature
`
`Please see 37 CFR 1.4(d} for the form of the signature.
`
`Signature
`
`/Catherine M. McCarty/
`
`Date (YYYY-MM-DD)
`
`2009-04-28
`
`First Name
`
`Catherine
`
`Last Name
`
`McCarty
`
`Registration Number
`(If appropriate)
`
`54301
`
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`form can only be used when in conjunction with EFS-Web. If this form is mailed to the USPTO, it may cause delays in handling
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`EFS - Web 1.0.1
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`Rigel Exhibit 1045
`Page 6 of 106
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`

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`Rigel Exhibit 1045
`Page 7 of 106
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`C2081-701302
`
`CLAIMS
`
`1. A method of treating a subject having a glioma or brain tumor characterized by a
`
`mutant IDHl or IDH 2 gene which encodes a mutant enzyme having a neoactivity,
`
`compnsmg:
`
`administering to said subject a therapeutically effective amount of an inhibitor of
`
`the neoactivity of said mutant enzyme, wherein said neoactivity is the ability to convert
`
`alpha ketoglutarate to 2-hydroxyglutarate,
`
`to thereby treat said subject.
`
`2. A method of treating a subject, e.g., a subject having a disorder characterized by
`
`unwanted cell proliferation, e.g., cancer, comprising:
`
`administering to said subject a therapeutically effective amount of an inhibitor of
`
`a neoactivity of a mutant enzyme encoded by a mutant gene, e.g., wherein the enzyme is
`
`in a metabolic pathway,
`
`to thereby treat said subject.
`
`3. The method of claim 2, wherein said metabolic pathway is selected from a metabolic
`
`pathway leading to fatty acid biosynthesis, glycolysis, glutaminolysis, the pentose
`
`phosphate shunt, nucleotide biosynthetic pathways, or the fatty acid biosynthetic pathway.
`
`4. The method of claim 2, wherein a non-mutant form of the mutant gene encodes IDHl
`
`or, IDH2.
`
`5. The method of claim 2, wherein a non mutant form of the mutant gene encodes a
`
`protein that modulates the flow of substrate into a metabolic pathway, e.g., a synthetic
`
`pathway, e.g., the fatty acid synthetic pathway.
`
`6. The method of claim 2, wherein the neoactivty reverses or diverts a metabolite of a
`
`first pathway (e.g., glycolysis) into a second pathway (e.g., the pentose phosphate shunt).
`
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`C2081-701302
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`7. The method of claim 2, wherein the neoactivity causes a metabolite, e.g., alpha
`
`ketoglutarate which would have been in the TCA cycle to go, e.g., directly, into another
`
`pathway, e.g., synthesis of fatty acid, or a metabolic pathway leading to fatty acid
`
`biosynthesis.
`
`8. The method of claim 2, wherein a non mutant form of the mutant gene encodes an
`
`enzyme that converts a substrate into a substance that feeds into fatty acid synthesis.
`
`9. The method of claim 2, wherein the neoactivity reduces the flow of substrate into a
`
`metabolic pathway, e.g., fatty acid synthesis.
`
`10. The method of claim 2, wherein the neoactivity increases the flow of substrate into a
`
`metabolic pathway.
`
`11. The method of claim 2, wherein a non-mutant form of the enzyme, e.g., a wild type
`
`form, converts product A (e.g., isocitrate) to product B (e.g., alpha ketoglutarate) and the
`
`neoactivity converts product B to product C (e.g., 2-hydroxyglutarage).
`
`12. The method of claim 2, wherein the neoactivity is substantially absent from wild type
`
`or non-mutant eznzyme.
`
`13. The method of claim 2, wherein a non mutant form of the mutant gene encodes an
`
`enzyme that converts isocitrate to alpha ketoglutarate.
`
`14. The method of claim 2, wherein the gene encodes IDHlor IDH2.
`
`15. The method of claim 2, wherein the gene encodes IDHl and the mutant neoactivity is
`
`the conversion of alpha ketoglutarate to 2-hydroxyglutarate.
`
`16. The method of claim 2, wherein the mutation is a mutation in the active site of the
`
`enzyme encoded by the gene.
`
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`C2081-701302
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`17. The method of claim 2, wherein the mutation is in the active site of IDHl, e.g., is at
`
`residue 132.
`
`18. The method of claim 17, wherein the mutant IDHl has a His, Ser, Cys, Gly, Val or
`
`Leu, or any other mutations described in Yan H et al., N Engl J Med. 2009 Feb
`
`19;360(8):765-73, at residue 132.
`
`19. The method of claim 2, wherein the mutation is in the active site of IDH2, e.g., is at
`
`residue 172.
`
`20. The method of claim 19, wherein the mutant IDH2 has a Gly, Met or Lys, or any
`
`other mutations described in Yan H et al., N Engl J Med. 2009 Feb 19;360(8):765-73 at
`
`residue 172.
`
`21. The method of claim 2, wherein the cancer is selected from a cancer described herein.
`
`22. The method of claim 2, wherein the mutant is in IDHl and the cancer is brain tumor,
`
`e.g., glioma, e.g., glioblastoma.
`
`23. The method of claim 2, wherein the mutant is in IDH2 and the cancer is brain tumor,
`
`e.g., glioma, e.g., glioblastoma.
`
`24. The method of claim 2, wherein said inhibitor is an siRNA, aptomer, or anti-sense
`
`molecule, which, e.g., specifically inhibits the product of the mutant gene as compared to
`
`the product of a non mutant gene, e.g., a wild type gene.
`
`25. The method of claim 24, wherein the inhibitor targets mutant IDHl or IDH2.
`
`26. The method of claim 1, wherein said inhibitor is a polypetide, e.g., an antibody
`
`which binds, e.g., specifically binds, the mutant protein and inhibits its neoactivity.
`
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`C2081-701302
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`26. The method of claim 1, wherein said inhibitor is a small molecule, e.g., specifically
`
`binds, the mutant protein and inhibits its neoactivity.
`
`27. The method of claim 2, wherein:
`
`said subject is selected on the basis of the subject having a mutant gene having a
`
`neoactivity, e.g., a mutant IDHl or IDH2; and/or
`
`said inhibitor is selected on the basis of being able to inhibit the neoactivity ( e.g.,
`
`conversion of alpha-ketoglutarate to 2-hydroxyglutarate) (selecting as used herein can
`
`mean selecting in whole or part on said basis).
`
`28. The method of claim 2, further comprising,
`
`evaluating the subject for the presence of a mutant gene encoding a mutant gene
`
`product having the neoactivity, a mutant gene product having the neoactivity, or the
`
`neoactivity, and
`
`optionally, selecting a patient and or a drug on the basis of the result of the
`
`evaluation.
`
`29. The method of claim 2, further comprising, evaluating the subject for the presence of
`
`a mutant IDHl gene, e.g., which encodes a mutant gene product having a mutation at
`
`amino acid residue 132 and, optionally, selecting a patient and or a drug on the basis of
`
`the result of the evaluation ( e.g., wherein the mutant IDHl has a neoactivity described
`
`herein such as the conversion of alpha-ketoglutarate to 2-hydroxyglutarate).
`
`30. The method of claim 2, further comprising, evaluating the subject for the presence of
`
`a mutant IDH2 gene, e.g., which encodes a mutant gene product having a mutation at
`
`amino acid residue 172 and, optionally, selecting a patient and or a drug on the basis of
`
`the result of the evaluation.
`
`31. The method of claim 2, wherein the cancer is brain tumor, e.g., glioma, e.g.,
`
`glioblastoma and the gene is IDHl or IDH2, further comprising, evaluating the subject
`
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`C2081-701302
`
`for the presence of a second mutant gene, e.g., a p53 mutation, and optionally, selecting a
`
`patient and or a drug on the basis of the result of the evaluation.
`
`32. The method of claim 2, further comprising, administering a second anti-cancer agent
`
`or therapy to the subject.
`
`33. The method of claim 2, wherein the cancer is brain tumor, e.g., glioma, e.g.,
`
`glioblastoma, the gene is IDHl or IDH2, further comprising, administering a second anti(cid:173)
`
`cancer agent or therapy to the subject, e.g., surgical removal, administration of an
`
`alkylating agent, administration of temoader, or administration of Gleevec.
`
`34. A method of evaluating a candidate compound, e.g., for use as an anti-proliferative
`
`or anti-cancer agent, comprising:
`
`optionally supplying said candidate compound;
`
`contacting said candidate compound with an enzyme having the activity of a
`
`mutant enzyme having a neoactivity;
`
`evaluating the ability of the candidate compound to inhibit the activity,
`
`thereby evaluating the compound.
`
`35. The method of claim 34, comprising contacting the candidate compound with a
`
`mutant enzyme in the metabolic pathway having a neoactivity.
`
`36. The method claim 34, comprising:
`
`contacting said candidate compound with a mutant IDHl enzyme having a
`
`neoacivity wherein the neoactivity is the ability to convert alpha ketoglutarate to 2-
`
`hydroxyglutarate; and
`
`evaluating the ability of the candidate compound to inhibit the neoactivity,
`
`thereby evaluating the compound.
`
`34. A method of evaluating a candidate compound, e.g., for use as an anti-proliferative
`
`or anti-cancer agent, comprising:
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`optionally supplying said candidate compound;
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`contacting said candidate compound with an enzyme having a wild type or non(cid:173)
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`mutant activity;
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`evaluating the ability of the candidate compound to inhibit the wild type or non(cid:173)
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`mutant activity,
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`correlating the wild-type or non-mutant activity with the presence or absence of a
`
`neoactivity
`
`thereby evaluating the compound.
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`36. The method claim 34, comprising:
`
`contacting said candidate compound with an IDHl enzyme having activity of the
`
`ability to convert isocitrate to alpha ketoglutarate; and
`
`evaluating the ability of the candidate compound to inhibit the activity,
`
`thereby evaluating the compound.
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`37. A pharmaceutical composition of an inhibitor described herein.
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`37 .1 A method of treating a subject having a glioma or brain tumor characterized
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`by a mutant IDHl or IDH2 gene which encodes a mutant enzyme having a neoactivity,
`
`compnsmg:
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`administering to said subject a therapeutically effective amount of a alpha
`
`ketogluterate, a prodrug thereof, a compound that increases the level of alpha
`
`ketogluterate in a subject, a compound that activates HIP-la hydroxylase, or a compound
`
`that inhibits HIP-la,
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`to thereby treat said subject.
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`37 .2 A method of treating a subject, e.g., a subject having a disorder characterized by
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`unwanted cell proliferation, e.g., cancer, comprising:
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`administering to said subject a therapeutically effective amount of a substance, or
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`a compound that induces activity of said substance or a compound that increases the level
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`of said substance in vivo, wherein said subject has a mutation giving rise to a neoactivity
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`and the endogenous level of the substance in cancer cells of said subject is reduced as
`
`compared to a cell not having the mutation, e.g., wherein the enzyme is in a metabolic
`
`pathway,
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`to thereby treat said subject.
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`37 .3 The method of claim 37 .2, wherein the substance is a substrate of the mutant
`
`enzyme.
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`38. A method of treating cancer, e.g., brain tumor, e.g., glioma, e.g., glioblastoma, in a
`
`subject, comprising:
`
`identifying a cancer having a mutant gene encoding a mutant gene product having
`
`a neoactivity, a mutant gene product having a neoactivity, or a neoactivity; and
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`administering to said subject a therapeutic effective amount of alpha-ketoglutarate,
`
`an alpha-ketoglurarate prodrug, a compound that increases the level of alpha(cid:173)
`
`ketoglurarate in a subject, or a compound that activates HIP-la hydroxylase.
`
`39. The method of claim 38, wherein said metabolic pathway is selected from a metabolic
`
`pathway leading to fatty acid biosynthesis, glycolysis, glutaminolysis, the pentose
`
`phosphate shunt, nucleotide biosynthetic pathways, or the fatty acid biosynthetic pathway.
`
`40. The method of claim 38, wherein a non-mutant form of the mutant gene encodes
`
`IDHl or, IDH2.
`
`41. The method of claim 38, wherein a non mutant form of the mutant gene encodes a
`
`protein that modulates the flow of substrate into a metabolic pathway, e.g., a synthetic
`
`pathway, e.g., the fatty acid synthetic pathway.
`
`42. The method of claim 38, wherein the neoactivty reverses or diverts a metabolite of a
`
`first pathway (e.g., glycolysis) into a second pathway (e.g., the pentose phosphate shunt).
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`43. The method of claim 38, wherein the neoactivity causes a metabolite, e.g., alpha
`
`ketoglutarate which would have been in the TCA cycle to go, e.g., directly, into another
`
`pathway, e.g., synthesis of fatty acid, or a metabolic pathway leading to fatty acid
`
`biosynthesis.
`
`44. The method of claim 38, wherein a non mutant form of the mutant gene encodes an
`
`enzyme that converts a substrate into a substance that feeds into fatty acid synthesis.
`
`45. The method of claim 38, wherein the neoactivity reduces the flow of substrate into a
`
`metabolic pathway, e.g., fatty acid synthesis.
`
`46. The method of claim 38, wherein the neoactivity increases the flow of substrate into
`
`a metabolic pathway.
`
`47. The method of claim 38, wherein a non-mutant form of the enzyme, e.g., a wild type
`
`form, converts product A (e.g., isocitrate) to product B (e.g., alpha ketoglutarate) and the
`
`neoactivity converts product B to product C (2-hydroxyglutarate).
`
`48. The method of claim 38, wherein the neoactivity is substantially absent from wild
`
`type or non-mutant eznzyme.
`
`49. The method of claim 38, wherein a non mutant form of the mutant gene encodes an
`
`enzyme that converts isocitrate to alpha ketoglutarate.
`
`50. The method of claim 38, wherein the gene encodes IDHlor IDH2.
`
`51. The method of claim 38, wherein the gene encodes IDHl and the mutant neoactivity
`
`is the conversion of alpha ketoglutarate to 2-hydroxyglutarate.
`
`52. The method of claim 38, wherein the mutation is a mutation in the active site of the
`
`enzyme encoded by the gene.
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`53. The method of claim 38, wherein the mutation is in the active site of IDHl, e.g., is at
`
`residue 132.
`
`54. The method of claim 53, wherein the mutant IDHl has a His, Ser, Cys, Gly, Val or
`
`Leu, or any other mutations described in Yan H et al., N Engl J Med. 2009 Feb
`
`19;360(8):765-73, at residue 132.
`
`55. The method of claim 38, wherein the mutation is in the active site of IDH2, e.g., is at
`
`residue 172.
`
`56. The method of claim 55, wherein the mutant IDH2 has a Gly, Met or Lys, or any
`
`other mutations described in Yan H et al., N Engl J Med. 2009 Feb 19;360(8):765-73 at
`
`residue 172.
`
`57. The method of claim 38, wherein the cancer is selected from a cancer described
`
`herein.
`
`58. The method of claim 38, wherein the mutant is in IDHl and the cancer is brain tumor,
`
`e.g., glioma, e.g., glioblastoma.
`
`59. The method of claim 38, wherein the mutant is in IDH2 and the cancer is brain tumor,
`
`e.g., glioma, e.g., glioblastoma.
`
`60. The method of claim 38, wherein:
`
`said subject is selected on the basis of the subject having a mutant gene having a
`
`neoactivity, e.g., a mutant IDHl or IDH2;
`
`(selecting as used herein can mean selecting in whole or part on said basis).
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`61. The method of claim 38, further comprising, identifying the cancer having a mutant
`
`IDHl gene, e.g., which encodes a mutant gene product having a mutation at amino acid
`
`residue 132.
`
`62. The method of claim 38, further comprising, identifying the cancer having a mutant
`
`IDH2 gene, e.g., which encodes a mutant gene product having a mutation at amino acid
`
`residue 172 and, optionally, selecting a patient and or a drug on the basis of the result of
`
`the evaluation.
`
`63 The method of claim 38, wherein the cancer is brain tumor, e.g., glioma, e.g.,
`
`glioblastoma and the gene is IDHl or IDH2, further comprising, identifying the cancer
`
`having a second mutant gene, e.g., a p53 mutation, and optionally, selecting a patient and
`
`or a drug on the basis of the result of the evaluation.
`
`64. The method of claim 38, further comprising, administering a second a