Attorney Docket No. AGS-013C2
`
`NO:8 (see also FIG. 21), more specifically His, Ser, Cys, Gly, Val, or Leu. In an
`
`embodiment the allele encodes an IDHl having Cys at residue 132.
`
`In an embodiment the IDHl allele has a T (or any other nucleotide other than
`
`C) at nucleotide position 394. In an embodiment the allele is a C394T mutation
`
`according to the sequence of SEQ ID NO:5.
`
`In an embodiment the method comprises selecting a subject having ALL, e.g.,
`
`B-ALL or T-ALL, characterized by an IDHl allele described herein, e.g., an IDHl
`
`allele having Cys at residue 132 according to the sequence of SEQ ID NO:8.
`
`In an embodiment the method comprises selecting a subject ALL, e.g., B-ALL
`
`or T-ALL, on the basis of cancer being characterized by having an IDHl allele
`
`described herein, e.g., an IDHl allele having Cys at residue 132 (SEQ ID NO:8).
`
`In an embodiment the method comprises selecting a subject having ALL, e.g.,
`
`B-ALL or T-ALL, on the basis of the cancer being characterized by increased levels
`
`of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
`
`In an embodiment the cell proliferation-related disorder is acute myelogenous
`
`leukemia (e.g., an adult or pediatric form), e.g., wherein the acute myelogenous
`
`leukemia (sometimes referred to herein as AML) is characterized by an IDHl somatic
`
`mutant having alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a mutant
`
`described herein. In an embodiment the cancer is characterized by increased levels of
`
`an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, as compared to non(cid:173)
`
`diseased cells of the same type. E.g., in an embodiment, the IDHl allele is an IDHl
`
`having other than an Arg at residue 132 (SEQ ID NO:8). E.g., the allele encodes His,
`
`Ser, Cys, Gly, Val, Pro or Leu, or any residue described in Kang et al., at residue 132,
`
`according to the sequence of SEQ ID NO:8 (see also FIG. 21). In an embodiment the
`
`allele encodes an IDHl having Cys, His or Gly at residue 132, more specifically, Cys
`
`at residue 132.
`
`In an embodiment the IDHl allele has a T (or any other nucleotide other than
`
`C) at nucleotide position 394. In an embodiment the allele is a C394T mutation
`
`according to the sequence of SEQ ID NO:5.
`
`In an embodiment the method comprises selecting a subject having acute
`
`myelogenous lymphoplastic leukemia (AML) characterized by an IDHl allele
`
`described herein, e.g., an IDHl allele having Cys, His, or Gly at residue 132
`
`according to the sequence of SEQ ID NO:8, more specifically, Cys at residue 132.
`
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`Attorney Docket No. AGS-013C2
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`In an embodiment the method comprises selecting a subject having acute
`
`myelogenous lymphoplastic leukemia (AML) on the basis of cancer being
`
`characterized by having an IDHl allele described herein, e.g., an IDHl allele having
`
`Cys, His, or Gly at residue 132 (SEQ ID NO:8), more specifically, Cys at residue 132.
`
`In an embodiment the method comprises selecting a subject having acute
`
`myelogenous lymphoplastic leukemia (AML), on the basis of the cancer being
`
`characterized by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG,
`
`e.g., R-2HG.
`
`In an embodiment the method further comprises evaluating the subject for the
`
`presence of a mutation in the NRAS or NPMc gene.
`
`In an embodiment the cell proliferation-related disorder is myelodysplasia or
`
`myelodysplastic syndrome, e.g., wherein the myelodysplasia or myelodysplastic
`
`syndrome is characterized by having an IDHl somatic mutant having alpha hydroxy
`
`neoactivity, e.g., 2HG neoactivity, e.g., a mutant described herein. In an embodiment
`
`the disorder is characterized by increased levels of an alpha hydroxy neoactivity
`
`product, e.g., 2HG, e.g., R-2HG, as compared to non-diseased cells of the same type.
`
`E.g., in an embodiment, the IDHl allele is an IDHl having other than an Arg at
`
`residue 132 (SEQ ID NO:8). E.g., the allele encodes His, Ser, Cys, Gly, Val, Pro or
`
`Leu, or any residue described in Kang et a.l, according to the sequence of SEQ ID
`
`NO:8 (see also FIG. 21), more specifically His, Ser, Cys, Gly, Val, or Leu. In an
`
`embodiment the allele encodes an IDHl having Cys at residue 132.
`
`In an embodiment the IDHl allele has a T (or any other nucleotide other than
`
`C) at nucleotide position 394. In an embodiment the allele is a C394T mutation
`
`according to the sequence of SEQ ID NO:5.
`
`In an embodiment the method comprises selecting a subject having
`
`myelodysplasia or myelodysplastic syndrome characterized by an IDHl allele
`
`described herein, e.g., an IDHl allele having Cys, His, or Gly at residue 132
`
`according to the sequence of SEQ ID NO:8, more specifically, Cys at residue 132.
`
`In an embodiment the method comprises selecting a subject having
`
`myelodysplasia or myelodysplastic syndrome on the basis of cancer being
`
`characterized by having an IDHl allele described herein, e.g., an IDHl allele having
`
`Cys, His, or Gly at residue 132 (SEQ ID NO:8), more specifically, Cys at residue 132.
`
`In an embodiment the method comprises selecting a subject having
`
`myelodysplasia or myelodysplastic syndrome, on the basis of the cancer being
`
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`characterized by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG,
`
`e.g., R-2HG.
`
`In an embodiment the cell proliferation-related disorder is a glioma,
`
`characterized by a mutation, or preselected allele, of IDH2 associated with an alpha
`
`hydroxy neoactivity, e.g., 2HG neoactivity. E.g., in an embodiment, the IDH2 allele
`
`encodes an IDH2 having other than an Arg at residue 172. E.g., the allele encodes
`
`Lys, Gly, Met, Trp, Thr, Ser, or any residue described in described in Yan et al., at
`
`residue 172, according to the sequence of SEQ ID NO: lO(see also Fig. 22), more
`
`specifically Lys, Gly, Met, Trp, or Ser. In an embodiment the allele encodes an IDH2
`
`having Lys at residue 172. In an embodiment the allele encodes an IDH2 having Met
`
`at residue 172.
`
`In an embodiment the method comprises selecting a subject having a glioma,
`
`wherein the cancer is characterized by having an IDH2 allele described herein, e.g.,
`
`an IDH2 allele having Lys, Gly, Met, Trp, Thr, or Ser at residue 172 (SEQ ID NO:10),
`
`more specifically Lys, Gly, Met, Trp, or Ser; or Lys or Met.
`
`In an embodiment the method comprises selecting a subject having a glioma,
`
`on the basis of the cancer being characterized by an IDH2 allele described herein, e.g.,
`
`an IDH2 allele having Lys, Gly, Met, Trp, Thr, or Ser at residue 172 (SEQ ID NO:10),
`
`more specifically Lys, Gly, Met, Trp, or Ser; or Lys or Met.
`
`In an embodiment the method comprises selecting a subject having a glioma,
`
`on the basis of the cancer being characterized by increased levels of an alpha hydroxy
`
`neoactivity product, e.g., 2HG, e.g., R-2HG.
`
`In an embodiment the cell proliferation-related disorder is a prostate cancer,
`
`e.g., prostate adenocarcinoma, characterized by a mutation, or preselected allele, of
`
`IDH2 associated with an alpha hydroxy neoactivity, e.g., 2HG neoactivity. E.g., in an
`
`embodiment, the IDH2 allele encodes an IDH2 having other than an Arg at residue
`
`172. E.g., the allele encodes Lys, Gly, Met, Trp, Tor, Ser, or any residue described in
`
`described in Yan et al., at residue 172, according to the sequence of SEQ ID
`
`NO:lO(see also Fig. 22), more specifically Lys, Gly, Met, Trp, or Ser. In an
`
`embodiment the allele encodes an IDH2 having Lys at residue 172. In an
`
`embodiment the allele encodes an IDH2 having Met at residue 172.
`
`In an embodiment the method comprises selecting a subject having a prostate
`
`cancer, e.g., prostate adenocarcinoma, wherein the cancer is characterized by having
`
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`Attorney Docket No. AGS-013C2
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`an IDH2 allele described herein, e.g., an IDH2 allele having Lys or Met at residue 172
`
`(SEQ ID NO: 10).
`
`In an embodiment the method comprises selecting a subject having a prostate
`
`cancer, e.g., prostate adenocarcinoma, on the basis of the cancer being characterized
`
`by an IDH2 allele described herein, e.g., an IDH2 allele having Lys or Met at residue
`
`172 (SEQ ID NO: 10).
`
`In an embodiment the method comprises selecting a subject having a prostate
`
`cancer, e.g., prostate adenocarcinoma, on the basis of the cancer being characterized
`
`by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
`
`In an embodiment the cell proliferation-related disorder is ALL, e.g., B-ALL
`
`or T-ALL, characterized by a mutation, or preselected allele, of IDH2 associated with
`
`an alpha hydroxy neoactivity, e.g., 2HG neoactivity. E.g., in an embodiment, the
`
`IDH2 allele encodes an IDH2 having other than an Arg at residue 172. E.g., the allele
`
`encodes Lys, Gly, Met, Trp, Thr, Ser, or any residue described in described in Yan et
`
`al., at residue 172, according to the sequence of SEQ ID NO: lO(see also Fig. 22). In
`
`an embodiment the allele encodes an IDH2 having Lys at residue 172. In an
`
`embodiment the allele encodes an IDH2 having Met at residue 172.
`
`In an embodiment the method comprises selecting a subject having ALL, e.g.,
`
`B-ALL or T-ALL, wherein the cancer is characterized by having an IDH2 allele
`
`described herein, e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID
`
`N0:10).
`
`In an embodiment the method comprises selecting a subject having ALL, e.g.,
`
`B-ALL or T-ALL, on the basis of the cancer being characterized by an IDH2 allele
`
`described herein, e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID
`
`N0:10).
`
`In an embodiment the method comprises selecting a subject having ALL, e.g.,
`
`B-ALL or T-ALL, on the basis of the cancer being characterized by increased levels
`
`of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
`
`In an embodiment the cell proliferation-related disorder is AML, characterized
`
`by a mutation, or preselected allele, of IDH2 associated with an alpha hydroxy
`
`neoactivity, e.g., 2HG neoactivity. E.g., in an embodiment, the IDH2 allele encodes
`
`an IDH2 having other than an Arg at residue 172. E.g., the allele encodes Lys, Gly,
`
`Met, Trp, Tor, Ser, or any residue described in described in Yan et al., at residue 172,
`
`according to the sequence of SEQ ID NO: lO(see also Fig. 22), more specifically Lys,
`
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`Attorney Docket No. AGS-013C2
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`Gly, Met, or Ser. In an embodiment the allele encodes an IDH2 having Lys at residue
`
`172. In an embodiment the allele encodes an IDH2 having Met at residue 172. In an
`
`embodiment the allele encodes an IDH2 having Gly at residue 172.
`
`In an embodiment the method comprises selecting a subject having AML,
`
`wherein the cancer is characterized by having an IDH2 allele described herein, e.g.,
`
`an IDH2 allele having Lys, Gly or Met at residue 172 (SEQ ID NO: 10), more
`
`specifically Lys or Met.
`
`In an embodiment the method comprises selecting a subject having AML, on
`
`the basis of the cancer being characterized by an IDH2 allele described herein, e.g., an
`
`IDH2 allele having Lys, Gly, or Met at residue 172 (SEQ ID NO: 10), more
`
`specifically Lys or Met.
`
`In an embodiment the method comprises selecting a subject having AML, on
`
`the basis of the cancer being characterized by increased levels of an alpha hydroxy
`
`neoactivity product, e.g., 2HG, e.g., R-2HG.
`
`In an embodiment the cell proliferation-related disorder is myelodysplasia or
`
`myelodysplastic syndrome, characterized by a mutation, or preselected allele, of
`
`IDH2. E.g., in an embodiment, the IDH2 allele encodes an IDH2 having other than
`
`an Arg at residue 172. E.g., the allele encodes Lys, Gly, Met, Trp, Thr, Ser, or any
`
`residue described in described in Yan et al., at residue 172, according to the sequence
`
`of SEQ ID NO:lO(see also Fig. 22), more specifically Lys, Gly, Met, Trp or Ser. In
`
`an embodiment the allele encodes an IDH2 having Lys at residue 172. In an
`
`embodiment the allele encodes an IDH2 having Met at residue 172. In an
`
`embodiment the allele encodes an IDH2 having Gly at residue 172.
`
`In an embodiment the method comprises selecting a subject having
`
`myelodysplasia or myelodysplastic syndrome,wherein the cancer is characterized by
`
`having an IDH2 allele described herein, e.g., an IDH2 allele having Lys, Gly, or Met
`
`at residue 172 (SEQ ID NO: 10), in specific embodiments, Lys or Met.
`
`In an embodiment the method comprises selecting a subject having
`
`myelodysplasia or myelodysplastic syndrome, on the basis of the cancer being
`
`characterized by an IDH2 allele described herein, e.g., an IDH2 allele having Lys, Gly,
`
`or Met at residue 172 (SEQ ID NO: 10), in specific embodiments, Lys or Met.
`
`In an embodiment the method comprises selecting a subject having
`
`myelodysplasia or myelodysplastic syndrome, on the basis of the cancer being
`
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`Attorney Docket No. AGS-013C2
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`characterized by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG,
`
`e.g., R-2HG.
`
`In an embodiment a product of the neoactivity is 2HG (e.g., R-2HG) which
`
`acts as a metabolite. In another embodiment a product of the neoactivity is 2HG (e.g.,
`
`R-2HG) which acts as a toxin, e.g., a carcinogen.
`
`In some embodiments, the methods described herein can result in reduced side
`
`effects relative to other known methods of treating cancer.
`
`Therapeutic agents and methods of subject evaluation described herein can be
`
`combined with other therapeutic mocalities, e.g., with art-known treatments.
`
`In an embodiment the method comprises providing a second treatment, to the
`
`subject, e.g., surgical removal, irradiation or administration of a chemotherapeutitc
`
`agent, e.g., an administration of an alkylating agent. Administration ( or the
`
`establishment of therapeutic levels) of the second treatment can: begin prior to the
`
`beginning or treatment with ( or prior to the establishment of therapeutic levels of) the
`
`inhibitor; begin after the beginning or treatment with ( or after the establishment of
`
`therapeutic levels of) the inhibitor, or can be administered concurrently with the
`
`inhibitor, e.g., to achieve therapeiutc levels of both concurrently.
`
`In an embodiment the cell proliferation-related disorder is a CNS tumor, e.g., a
`
`glioma, and the second therapy comprises administration of one or more of: radiation;
`
`an alkylating agent, e.g., temozolomide, e.g., Temoader®, or BCNU; or an inhibitor
`
`of HERl/EGFR tyrosine kinase, e.g., erlotinib, e.g., Tarceva®.
`
`The second therapy, e.g., in the case of glioma, can comprise implantation of
`
`BCNU or carmustine in the brain, e.g., implantation of a Gliadel® wafer.
`
`The second therapy, e.g., in the case of glioma, can comprise administration of
`
`imatinib, e.g., Gleevec®.
`
`In an embodiment the cell proliferation-related disorder is prostate cancer and
`
`the second therapy comprises one or more of: androgen ablation; administration of a
`
`microtubule stabilizer, e.g., docetaxol, e.g., Taxotere®; or administration of a
`
`topoisomerase II inhibitor, e.g., mitoxantrone.
`
`In an embodiment the cell proliferation-related disorder is ALL, e.g., B-ALL
`
`or T-ALL, and the second therapy comprises one or more of:
`
`induction phase treatment comprising the administration of one or more of: a
`
`steroid; an inhibitor of microtubule assembly, e.g., vincristine; an agent that reduces
`
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`
`the availability of asparagine, e.g., asparaginase; an anthracycline; or an
`
`antimetabolite, e.g., methotrexate, e.g., intrathecal methotrexate, or 6-mercaptopurine;
`
`consolidation phase treatment comprising the administration of one or more of:
`
`a drug listed above for the induction phase; an antimetabolite, e.g., a guanine analog,
`
`e.g., 6-thioguanine; an alkylating agent, e.g., cyclophosphamide; an anti-metabolite,
`
`e.g., AraC or cytarabine; or an inhibitor of topoisomerase I, e.g., etoposide; or
`
`maintenance phase treatment comprising the administration of one or more of
`
`the drugs listed above for induction or consolidation phase treatment.
`
`In an embodiment the cell proliferation-related disorder is AML and the
`
`second therapy comprises administration of one or more of: an inhibitor of
`
`topoisomerase II, e.g., daunorubicin, idarubicin, topotecan or mitoxantrone; an
`
`inhibitor of topoisomerase I, e.g., etoposide; or an anti-metabolite, e.g., AraC or
`
`cytarabine.
`
`In another aspect, the invention features, a method of evaluating, e.g.
`
`diagnosing, a subject, e.g., a subject not having, or not diagnosed as having, 2-
`
`hydroxyglutaric aciduria. The method comprises analyzing a parameter related to the
`
`neoactivity genotype or phenotype of the subject, e.g., analyzing one or more of:
`
`a) the presence, distribution, or level of a neoactive product, e.g., the product
`
`of an alpha hydroxy neoactivity, e.g., 2HG, e.g., R-2HG, e.g., an increased level of
`
`product, 2HG, e.g., R-2HG (as used herein, an increased level of a product of an alpha
`
`hydroxy neoactivity, e.g., 2HG, e.g., R-2HG, or similar term, e.g., an increased level
`
`of neoactive product or neoactivity product, means increased as compared with a
`
`reference, e.g., the level seen in an otherwise similar cell lacking the IDH mutation,
`
`e.g., IDHl or IDH2 mutation, or in a tissue or product from a subject noth having the
`
`mutation (the terms increased and elevated as refered to the level of a product of alpha
`
`hydroxyl neoactivity as used herein, are used interchangably);
`
`b) the presence, distribution, or level of a neoactivity, e.g., alpha hydroxy
`
`neoactivity, e.g., 2HG neoactivity, of an IDHl or IDH2, mutant protein;
`
`c) the presence, distribution, or level of a neoactive mutant protein, e.g., an
`
`IDH, e.g., an IDHl or IDH2, mutant protein which has a neoactivity, e.g., alpha
`
`hydroxy neoactivity, e.g., 2HG neoactivity, or a corresponding RNA; or
`
`d) the presence of a selected somatic allele or mutation conferring neoactivity,
`
`e.g., an IDH, e.g., IDHl or IDH2, which encodes a protein with a neoactivity, e.g.,
`
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`alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., an allele disclosed herein, in
`
`cells characterized by a cell proliferation-related disorder from the subject,
`
`thereby evaluating the subject.
`
`In an embodiment analyzing comprises performing a procedure, e.g., a test, to
`
`provide data or information on one or more of a-d, e.g., performing a method which
`
`results in a physical change in a sample, in the subject, or in a device or reagent used
`
`in the analysis, or which results in the formation of an image representative of the data.
`
`Methods of obtaining and analyzing samples, and the in vivo analysis in subjects,
`
`described elsewhere herein, e.g., in the section entitled, "Methods of evaluating
`
`samples and/or subjects," can be combined with this method. In another embodiment
`
`analyzing comprises receiving data or information from such test from another party.
`
`In an embodiment the analyzing comprises receiving data or information from such
`
`test from another party and, the method comprises, responsive to that data or
`
`information, administering a treatment to the subject.
`
`As described herein, the evaluation can be used in a number of applications,
`
`e.g., for diagnosis, prognosis, staging, determination of treatment efficacy, patent
`
`selection, or drug selection.
`
`Thus, in an embodiment method further comprises, e.g., responsive to the
`
`analysis of one or more of a-d:
`
`diagnosing the subject, e.g., diagnosing the subject as having a cell
`
`proliferation-related disorder, e.g., a disorder characterized by unwanted cell
`
`proliferation, e.g., cancer, or a precancerous disorder;
`
`staging the subject, e.g., determining the stage of a cell proliferation-related
`
`disorder, e.g., a disorder characterized by unwanted cell proliferation, e.g., cancer, or
`
`a precancerous disorder;
`
`providing a prognosis for the subject, e.g., providing a prognosis for a cell
`
`proliferation-related disorder, e.g., a disorder characterized by unwanted cell
`
`proliferation, e.g., cancer, or a precancerous disorder;
`
`determining the efficacy of a treatment, e.g., the efficacy of a
`
`chemotherapeutic agent, irradiation or surgery;
`
`determining the efficacy of a treatment with a therapeutic agent, e.g., an
`
`inhibitor, described herein;
`
`selecting the subject for a treatment for a cell proliferation-related disorder,
`
`e.g., a disorder characterized by unwanted cell proliferation, e.g., cancer, or a
`
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`precancerous disorder. The selection can be based on the need for a reduction in
`
`neoactivity or on the need for amelioration of a condition associated with or resulting
`
`from neoactivity. For example, if it is determined that the subject has a cell
`
`proliferation-related disorder, e.g., e.g., cancer, or a precancerous disorder
`
`characterized by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG,
`
`e.g., R-2HG, or by a mutant IDHl or IDH2, having alpha hydroxyl neoactivity, e.g.,
`
`2HG, neaoctivity, selecting the subject for treatment with a therapeutic agent
`
`described herein, e.g., an inhibitor (e.g., a small molecule or a nucleic acid-based
`
`inhibitor) of the neoactivity of that mutant (e.g., conversion of alpha-ketoglutarate to
`
`2HG, e.g., R-2HG);
`
`correlating the analysis with an outcome or a prognosis;
`
`providing a value for an analysis on which the evaluation is based, e.g., the
`
`value for a parameter correlated to the presence, distribution, or level of an alpha
`
`hydroxyl neoactivity product, e.g., 2HG, e.g., R-2HG;
`
`providing a recommendation for treatment of the subject; or
`
`memorializing a result of, or ouput from, the method, e.g., a measurement
`
`made in the course of performing the method, and optionally transmitting the
`
`memorialization to a party, e.g., the subject, a healthcare provider, or an entity that
`
`pays for the subject's treatment, e.g., a government, insurance company, or other third
`
`party payer.
`
`As described herein, the evaluation can provide information on which a
`
`number of decisions or treatments can be based.
`
`Thus, in an embodiment the result of the evaluation, e.g., an increased level of
`
`an alpha hydroxyl neoactivity product, e.g., 2HG, e.g., R-2HG, the presence of an
`
`IDH, e.g., IDHl or IDH2, neoactivity, e.g., alpha hydroxyl neoactivity, e.g., 2HG
`
`neoactivity, the presence of an IDH, e.g., IDHl or IDH2, mutant protein (or
`
`corresponding RNA) which has alpha hydroxyl neoactivity, e.g., 2HG neoactivity, the
`
`presence of a mutant allele of IDH, e.g., IDHl or IDH2, having alpha hydroxyl
`
`neoactivity, 2HG neoactivity, e.g., an allele disclosed herein, is indicative of:
`
`a cell proliferation-related disorder, e.g., cancer, e.g., it is indicative of a
`
`primary or metastatic lesion;
`
`the stage of a cell proliferation-related disorder;
`
`a prognosis or outcome for a cell proliferation-related disorder, e.g., it is
`
`indicative of a less aggressive form of the disorder, e.g., cancer. E.g., in the case of
`
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`
`glioma, presence of an alpha hydroxyl neoactivity product, e.g., 2HG, e.g., R-2HG,
`
`can indicate a less aggressive form of the cancer;
`
`the efficacy of a treatment, e.g., the efficacy of a chemotherapeutic agent,
`
`irradiation or surgery;
`
`the need of of a therapy disclosed herein, e.g., inhibition a neoactivity of an
`
`IDH, e.g., IDHl or IDH2, neoactive mutant described herein. In an embodiment
`
`relatively higher levels ( or the presence of the mutant) is correlated with need of
`
`inhibition a neoactivity of an IDH, e.g., IDHl or IDH2, mutant described herein; or
`
`responsiveness to a treatment. The result can be used as a noninvasive
`
`biomarker for clinical response. E.g., elevated levels can be predictive on better
`
`outcome in glioma patients (e.g., longer life expectancy).
`
`As described herein, the evaluation can provide for the selection of a subject.
`
`Thus, in an embodiment the method comprises, e.g., responsive to the analysis
`
`of one or more of a-d, selecting a subject, e.g., for a treatment. The subject can be
`
`selected on a basis described herein, e.g., on the basis of:
`
`said subject being at risk for, or having, higher than normal levels of an alpha
`
`hydroxy neoactivity product, e.g., 2-hydroxyglurarate (e.g., R-2HG) in cell having a
`
`cell proliferation-related disorder, e.g., a leukemia such as AML or ALL, e.g., B-ALL
`
`or T-ALL, or a tumor lesion, e.g., a glioma or a prostate tumor;
`
`said subject having a proliferation-related disorder characterized by a selected
`
`IDH, e.g., IDHl or IDH2 allele, e.g., an IDHl or IDH2 mutation, having alpha
`
`hydroxyl neoactivity, e.g., 2HG neoactivity;
`
`said subject having a selected IDH allele, e.g., a selected IDHl or IDH2 allele;
`
`having alpha hydroxyl neoactivity, e.g., 2HG neoactivity;
`
`said subject having a proliferation-related disorder;
`
`said subject being in need of, or being able to benefit from, a therapeutic agent
`
`of a type described herein;
`
`said subject being in need of, or being able to benefit from, a compound that
`
`inhibits alpha hydroxyl neoactivity, e.g., 2HG neoactivity;
`
`said subject being in need of, or being able to benefit from, a compound that
`
`lowers the level of an alpha hydroxyl neoactivity product, e.g., 2HG, e.g., R-2HG.
`
`In an embodiment evaluation comprises selecting the subject, e.g., for
`
`treatment with an anti-neoplastic agent, on the establishment of, or determination that,
`
`the subject has increased alpha hydroxyl neoactivity product, e.g., 2HG, e.g., R-2HG,
`
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`Attorney Docket No. AGS-013C2
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`or increased alpha hydroxyl neoactivity, e.g., 2HG neoactivity, or that the subject is in
`
`need of inhibition of a neoactivity of an IDH, e.g., IDHl or IDH2, mutant described
`
`herein.
`
`As described herein, the evaluations provided for by methods described herein
`
`allow the selection of optimal treatment regimens.
`
`Thus, in an embodiment the method comprises, e.g., responsive to the analysis
`
`of one or more of a-d, selecting a treatment for the subject, e.g., selecting a treatment
`
`on a basis disclosed herein. The treatment can be the administration of a therapeutic
`
`agent disclosed herein. The treatment can be selected on the basis that:
`
`it us useful in treating a disorder charcterized by one or more of alpha
`
`hydroxyl neoactivity, e.g., 2HG neoactivity, an IDHl or IDH2, mutant protein having
`
`alpha hydroxyl neoactivity, e.g., 2HG neoactivity (or a corresponding RNA);
`
`it is useful in treating a disorder characterized by a selected somatic allele or
`
`mutation of an IDH, e.g., IDHl or IDH2, which encodes a protein with alpha
`
`hydroxyl neoactivity, e.g., 2HG neoactivity, e.g., an allele disclosed herein, in cells
`
`characterized by a cell proliferation-related disorder from the subject;
`
`it reduces the level of an alpha hydroxyl neoactivity product, e.g., 2HG, e.g.,
`
`R-2HG;
`
`it reduces the level of alpha hydroxyl neoactivity, e.g., 2HG neoactivity.
`
`In an embodiment evaluation comprises selecting the subject, e.g., for
`
`treatment.
`
`In embodiments the treatment is the administration of a therapeutic agent
`
`described herein.
`
`The methods can also include treating a subject, e.g, with a treatment selected
`
`in response to, or on the basis of, an evaluation made in the method.
`
`Thus, in an embodiment the method comprises, e.g., responsive to the analysis
`
`of one or more of a-d, administerin a treatment to the subject, e.g., the administration
`
`of a therapeutic agent of a type described herein.
`
`In an embodiment the therapeutic agent comprises a compound from Table
`
`24a or Table 24b or a compound having the structure of Formula (X) or (XI)
`
`described below.
`
`In an embodiment the therapeutic agent comprises nucleic acid, e.g., dsRNA,
`
`e.g., a dsRNA described herein.
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`In an embodiment the the therapeutic agent is an inhibitor, e.g., a polypeptide,
`
`peptide, or small molecule (e.g., a molecule of less than 1,000 daltons), or aptomer,
`
`that binds to an IDHl or IDH2 mutant (e.g., an aptomer that binds to an IDHl mutant)
`
`or wildtype subunit and inhibits neoactivity, e.g., by inhibiting formation of a dimer,
`
`e.g., a homodimer of mutant IDHl or IDH2 subunits (e.g., a homodimer of mutant
`
`IDHl subunits) or a heterodimer of a mutant and a wildype subunit. In an
`
`embodiment the inhibitor is a polypeptide. In an embodiment the polypeptide acts as
`
`a dominant negative with respect to the neoactivity of the mutant enzyme. The
`
`polypeptide can correspond to full length IDHl or IDH2 or a fragment thereof (e.g.,
`
`the polypeptide correspondes to full length IDHl or a fragment thereof). The
`
`polypeptide need not be indentical with the corresponding residues of wildtype IDHl
`
`or IDH2 (e.g., wildtype IDHl), but in embodiments has at least 60, 70, 80, 90 or 95 %
`
`homology with wildtype IDHl or IDH2 (e.g., wildtype IDHl).
`
`In an embodiment the therapeutic agent decreases the affinity of an IDH, e.g.,
`
`IDHl or IDH2 neoactive mutant protein for NADH, NADPH or a divalent metal ion,
`+ or Mn2
`e.g., Mg2
`+, or decreases the levels or availability of NADH, NADPH or
`divalent metal ion, e.g., Mg2+ or Mn2+, e.g., by competing for binding to the mutant
`
`
`enzyme. In an embodiment the enzyme is inhibited by replacing Mg2
`
`Ca2+.
`
`+ or Mn2+ with
`
`In an embodiment the therapeutic agent is an inhibitor that reduces the level a
`
`neoactivity of an IDH, e.g., IDHl or IDH2, e.g., 2HG neoactivity.
`
`In an embodiment the therapeutic agent is an inhibitor that reduces the level of
`
`the product of a mutant having a neoactivity of an IDH, e.g., IDHl or IDH2 mutant,
`
`e.g., it reduces the level of 2HG, e.g., R-2HG.
`
`In an embodiment the therapeutic agent is an inhibitor that:
`
`inhibits, e.g., specifically, a neoactivity of an IDH, e.g., IDHl or IDH2, e.g., a
`
`neoactivity described herein, e.g., 2HG neoactivity; or
`
`inhibits both the wildtype activity and a neoactivity of an IDH, e.g., IDHl
`
`orIDH2, e.g., a neoactivity described herein, e.g, 2HG neoactivity.
`
`In an embodiment the therapeutic agent is an inhibitor that is selected on the
`
`basis that it:
`
`inhibits, e.g., specifically, a neoactivity of an IDH, e.g., IDHl or IDH2, e.g., a
`
`neoactivity described herein e.g., 2HG neoactivity; or
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`Attorney Docket No. AGS-013C2
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`inhibits both the wildtype activity and a neoactivity of an IDHl, e.g., IDHl or
`
`IDH2, e.g., a neoactivity described herein, e.g., 2HG neoactivity.
`
`In an embodiment the therapeutic agent is an inhibitor that reduces the amount
`
`of a mutant IDH, e.g., IDHl or IDH2, protein or mRNA.
`
`In an embodiment the therapeutic agent is an inhibitor that interacts directly
`
`with, e.g., it binds to, the mutant IDH, e.g., IDHl or IDH2 mRNA.
`
`In an embodiment the therapeutic agent is an inhibitor that interacts directly
`
`with, e.g., it binds to, the mutant IDH, e.g., IDHl or IDH2, protein.
`
`In an embodiment the therapeutic agent is an inhibitor that reduces the amount
`
`of neoactive enzyme activity, e.g., by interacting with, e.g., binding to, mutant IDH,
`
`e.g., IDHl or IDH2, protein. In an embodiment the inhibitor is other than an antibody.
`
`In an embodiment the therapeutic agent is an inhibitor that is a small molecule
`
`and interacts with, e.g., binds, the mutant RNA, e.g., mutant IDHl mRNA.
`
`In an embodiment the therapeutic agent is an inhibitor that interacts directly
`
`with, e.g., binds, either the mutant IDH, e.g., IDHl or IDH2, protein or interacts
`
`directly with, e.g., binds, the mutant IDH mRNA, e.g., IDHl or IDH2 mRNA.
`
`In an embodiment the therapeutic agent is administered.
`
`In an embodiment the treatment: inhibits, e.g., specifically, a neoactivity of
`
`IDHl or IDH2 (e.g., a neoactivity of IDHl), e.g., a neoactivity described herein; or
`
`inhibits both the wildtype and activity and a neoactivity of IDHl or IDH2 (e.g., a
`
`neoactivity of IDHl), e.g., a neoactivity described herein In an embodiment, the
`
`subject is subsequently evaluated or monitored by a method described herein, e.g., the
`
`analysis of the presence, distribution, or level of an alpha hydroxy