`
`APPLICATION
`NUMBER
`61/160,253
`
`FILING or
`37l(c)DATE
`03/13/2009
`
`GRPART
`UNIT
`
`FIL FEE REC'D
`110
`
`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
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`\VVi\V.USpto.gov
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`ATTY.DOCKET.NO
`C2081-701300
`
`TOT CLAIMS IND CLAIMS
`
`CONFIRMATION NO.1380
`FILING RECEIPT
`
`11111111111111111 lllll ll]~!l]!~l!~l!~IIJHi~11 jl] 111111111111111 IIII IIII
`
`Date Mailed: 04/16/2009
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`Receipt is acknowledged of this provisional patent application. It will not be examined for patentability and will
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`
`Applicant( s)
`
`Stefan Gross, Brookline, MA;
`Shengfang Jin, Newton, MA;
`Shinsan Su, Cambridge, MA;
`Power of Attorney:
`Catherine McCarty--54301
`
`If Required, Foreign Filing License Granted: 04/14/2009
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61 /160,253
`Projected Publication Date: None, application is not eligible for pre-grant publication
`Non-Publication Request: No
`Early Publication Request: No
`** SMALL ENTITY **
`Title
`
`METHODS OF TREATING CANCER HAVING SOMATIC MUTATIONS OF THE ISOCITRATE
`DEHYDROGENASE GENE
`
`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
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`Doc Code: TR.PROV
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`lnventor(s)
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`Inventor 1
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`Given Name
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`Middle Name
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`Family Name
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`City
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`State
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`Stefan
`
`Inventor 2
`
`Gross
`
`Brookline
`
`MA
`
`Given Name
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`Middle Name
`
`Family Name
`
`City
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`State
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`I Remove I
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`us
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`I Remove I
`Country
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`Jin
`
`Newton
`
`MA
`
`us
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`Shengfang
`
`Inventor 3
`
`Given Name
`
`Middle Name
`
`Family Name
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`City
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`State
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`Shinsan
`
`Su
`
`Cambridge
`
`MA
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`i
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`Title of Invention
`
`METHODS OF TREATING CANCER HAVING SOMATIC MUTATIONS OF
`THE ISOCITRATE DEHYDROGENASE GENE
`
`Attorney Docket Number (if applicable)
`
`C2081-701300
`
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`37462
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`EFS - Web 1.0.1
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`Rigel Exhibit 1043
`Page 4 of 65
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`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
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`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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`Signature
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`Please see 37 CFR 1.4(d} for the form of the signature.
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`Signature
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`/Catherine M. McCarty/
`
`Date (YYYY-MM-DD)
`
`2009-03-13
`
`First Name
`
`Catherine
`
`Last Name
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`McCarty
`
`Registration Number
`(If appropriate)
`
`54301
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`Rigel Exhibit 1043
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`Rigel Exhibit 1043
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`C208 l -701300
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`METHODS OF TREATING CANCER HAVING SOMATIC MUTATIONS OF
`
`THE ISOCITRA TE DEHYDROGENASE GENE
`
`The invention relates to the treatment of proliferative disorders such as cancer as
`
`well as related methods, compounds and compositions.
`
`BACKGROUND
`
`Isocitrate dehydrogenase, also known as IDH, is an enzyme which participates in
`
`the citric acid cycle. It catalyzes the third step of the cycle: the oxidative decarboxylation
`
`of isocitrate, producing alpha-ketoglutarate (a-ketoglutarate or a-KG) and CO2 while
`
`converting NAD+ to NADH. This is a two-step process, which involves oxidation of
`
`isocitrate (a secondary alcohol) to oxalosuccinate (a ketone), followed by the
`
`decarboxylation of the carboxyl group beta to the ketone, forming alpha-ketoglutarate.
`
`Another isoform of the enzyme catalyzes the same reaction, however this reaction is
`
`unrelated to the citric acid cycle, is carried out in the cytosol as well as the mitochondrion
`
`and peroxisome, and uses NADP+ as a cofactor instead of NAD+.
`
`SUMMARY OF THE INVENTION
`
`The inventors have discovered novel methods for treating a proliferative disorder
`
`such as cancer. Described herein are methods, compounds and compositions for the
`
`treatment of a proliferative disorder such as cancer (e.g., a cancer of the nervous system
`
`such as glioblastoma).
`
`In some embodiments, the methods described herein can result in reduced side
`
`effects relative to other known methods of treating cancer.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 depicts DNA sequence verification of pET41a-IDH1 and alignment against
`
`published IDHl CDS.
`
`FIG. 2 depicts DNA sequence verification of IDHr132s and IDHr132h mutants.
`
`FIG. 3 depicts separation of wild type IDHl protein on Ni-Sepharose column.
`
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`FIG. 4 depicts protein analysis of wild type IDHl on SDS gel pre and post Ni column
`
`fractionation. T: total protein; I: insoluble fractions; S: soluble fraction; L: sample for
`
`loading on Ni-column. The numbers in the figure indicates the fraction numbers.
`
`Fractions #17 ~ #27 were collected for further purification.
`
`FIG. SA depicts separation of wild type IDHl protein through SEC column S-200.
`
`FIG. SB depicts protein analysis of wild type IDHl on SDS gel pre and post S-200
`
`column fractionation. M: molecular weight marker; Ni: nickel column fraction prior to S-
`
`200; S200: fraction from SEC column.
`
`FIG. 6 depicts separation of mutant IDH1R132S protein on Ni-Sepharose column.
`
`FIG. 7 depicts protein analysis of mutant IDH1R132S on SDS gel pre and post Ni
`
`column fractionation. M: protein marker (KDa): 116, 66.2, 45, 35, 25, 18.4, 14.4; T: total
`
`cell protein; So: soluble fraction; In: insoluble fraction; Ft: flow through. #3-#7 indicate
`
`the corresponding eluted fraction numbers.
`
`FIG. SA depicts separation of mutant IDH1R132S protein through SEC column S-200.
`
`FIG. 8B depicts protein analysis of mutant IDH1R132S on SDS gel post S-200 column
`
`fractionation. M: molecular weight marker; IDHR1325 : fraction from SEC column.
`FIG. 9 depicts separation of mutant IDH1R132H protein on Ni-Sepharose column.
`
`FIG. 10 depicts protein analysis of mutant IDH1R132H on SDS gel pre and post Ni
`
`column fractionation. M: protein marker (KDa): 116, 66.2, 45, 35, 25, 18.4, 14.4; T: total
`
`cell protein; So: soluble fraction; In: insoluble fraction; Ft: flow through; #5-#10 indicate
`
`the corresponding eluted fraction numbers; Ni: sample from Ni-Sepharose column, pool
`
`#5-#10 together.
`
`FIG. llA depicts separation of mutant IDH1R132H protein through SEC column S-200.
`
`FIG. 11B depicts protein analysis of mutant IDH1R132H on SDS gel post S-200 column
`
`fractionation. M: molecular weight marker; IDHR132H: fraction from SEC column.
`
`FIG. 12A depicts Michalis-Menten plot of IDHl wild-type in forward reaction.
`
`FIG. 12B depicts Michalis-Menten plot of IDH1R132H mutant enzyme in forward
`
`reaction.
`
`FIG. 12C depicts Michalis-Menten plot of IDH1R132S mutant enzyme in forward
`
`reaction.
`
`FIG. 13A depicts a-KG inhibition of IDHl wild-type.
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`FIG. 13B depicts a-KG inhibition of IDH1R132H mutant enzyme.
`
`FIG. 13C depicts a-KG inhibition of IDH1R132S mutant enzyme.
`
`FIG. 14 depicts IDHl wt, IDH R132H, and IDH R132S in the reverse reaction.
`
`FIG. lSA depicts Substrate-Concentration velocity plot for IDH R132H mutant enzyme.
`
`FIG. 15B depicts Substrate-Concentration velocity plot for IDH R132S mutant enzyme.
`
`FIG. 16 depicts IDHl wt, IDH R132H, and IDH R132S in the reverse reaction with
`
`NADH.
`
`FIG. 17A depicts oxalomalate inhibition to IDHl wt.
`
`FIG. 17B depicts oxalomalate inhibition to IDH1R132H.
`
`FIG. 17C depicts oxalomalate inhibition to IDH1R132S.
`
`DETAILED DESCRIPTION
`
`The inventors have discovered that certain mutated forms of an enzyme (e.g.,
`
`IDHl or IDH2) have a gain of function, which can be targeted in the treatment of a
`
`proliferative disorder such as cancer. Described herein are methods and compositions for
`
`the treatment of a proliferative disorder such as cancer.
`
`Neoactivity of an enzyme
`
`Neoactivity, as used herein, means an activity that arises as a result of a mutation,
`
`e.g., a point mutation, e.g., a substitution, e.g., in the active site of an enzyme. In an
`
`embodiment the neoactivity is substantially absent from wild type or non-mutant enzyme.
`
`This is sometimes referred to as first degree neoactivity. An example of a first degree
`
`neoactivity is a "gain of function" wherein the mutant enzyme gains a new catalytic
`
`activity. In an embodiment the neoactivity is present in wild type or non-mutant enzyme
`
`but at a level which is less than 10, 5, 1, 0.1, 0.01 or 0.001 % of what is seen in the
`
`mutant enzyme. This is sometimes referred to as second degree neoactivity. An example
`
`of a second degree neoactivity is a "gain of function" wherein the mutant enzyme has a
`
`100 fold increase in the rate of a catalytic activity possessed by the enzyme when lacking
`
`the mutation.
`
`In some embodiments, a non-mutant form the enzyme, e.g., a wild type form,
`
`converts product A (e.g., isocitrate) to product B (e.g., a-ketoglutarate), and the
`
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`neoactivity converts product B (e.g., a-ketoglutarate) to product A (e.g., isocitrate). In
`
`some embodiments, the enzyme is in a metabolic pathway, e.g., a metabolic pathway
`
`leading to fatty acid biosynthesis, glycolysis, glutaminolysis, the pentose phosphate shunt,
`
`the nucleotide biosynthetic pathway, or the fatty acid biosynthetic pathway, e.g., IDHl or
`
`IDH2.
`
`Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of
`
`isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of
`
`which utilizes NAD( +) as the electron acceptor and the other NADP( + ). Five isocitrate
`
`dehydrogenases have been reported: three NAD( + )-dependent isocitrate dehydrogenases,
`
`which localize to the mitochondrial matrix, and two NADP( + )-dependent isocitrate
`
`dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic.
`
`Each NADP( + )-dependent isozyme is a homodimer.
`
`IDHl (isocitrate dehydrogenase 1 (NADP+), soluble) is also known as IDH; IDP;
`
`IDCD; IDPC or PICD. The protein encoded by this gene is the NADP( + )-dependent
`
`isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1
`
`peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes
`
`suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the
`
`conversion of 2, 4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions
`
`that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The
`
`cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production. Human
`
`IDHl gene encodes a protein of 414 amino acids. The nucleotide and amino acid
`
`sequences for human IDHl can be found as Genebank entries NM_005896.2 and
`
`NP _005887.2 respectively. The nucleotide and amino acid sequences for IDHl are also
`
`described in, e.g., Nekrutenko et al., Mol. Biol. Evol. 15:1674-1684(1998); Geisbrecht et
`
`al., J. Biol. Chem. 274:30527-30533(1999); Wiemann et al., Genome Res. 11:422-
`
`435(2001); The MGC Project Team, Genome Res. 14:2121-2127(2004); Lubec et al.,
`
`Submitted (DEC-2008) to UniProtKB; Kullmann et al., Submitted (JUN-1996) to the
`
`EMBL/GenBank/DDBJ databases; and Sjoeblom et al., Science 314:268-274(2006).
`
`IDH2 (isocitrate dehydrogenase 2 (NADP+ ), mitochondrial) is also known as
`
`IDH; IDP; IDHM; IDPM; ICD-M; or mNADP-IDH. The protein encoded by this gene is
`
`the NADP( + )-dependent isocitrate dehydrogenase found in the mitochondria. It plays a
`
`- 4 -
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`C208 l -701300
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`role in intermediary metabolism and energy production. This protein may tightly
`
`associate or interact with the pyruvate dehydrogenase complex. Human IDH2 gene
`
`encodes a protein of 452 amino acids. The nucleotide and amino acid sequences for IDH2
`
`can be found as Genebank entries NM_002168.2 and NP _002159.2 respectively. The
`
`nucleotide and amino acid sequence for human IDH2 are also described in, e.g., Huh et
`
`al., Submitted (NOV-1992) to the EMBL/GenBank/DDBJ databases; and The MGC
`
`Project Team, Genome Res. 14:2121-2127(2004).
`
`In some embodiments, non-mutant, e.g., wild type, IDHl catalyzes the oxidative
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`decarboxylation of ioscitrate to a-ketoglutarate thereby reducing NAD+ (NADP+) to
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`NADP (NADPH), e.g., in the forward reaction:
`
`Isocitrate + NAD+ (NADP+)-----+ a-KG+ CO2 + NADH (NADPH) + H+
`
`In some embodiments, the neoactivity of a mutant IDHl can have the ability to
`
`convert a-ketoglutarate to isocitrate, e.g., in the reverse reaction:
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`a-KG + CO2 + NADH (NADPH) + H+ -----+ Isocitrate + NAD+ (NADP+)
`
`In some embodiments, the neoacitivty of a mutant IDHl can arise from a mutant
`
`IDHl having a His, Ser, Cys or Lys, or any other mutations described in Yan H et al., N
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`Engl J Med. 2009 Feb 19;360(8):765-73, at residue 132. In some embodiments, the
`
`neoactivity of a mutant IDH2 can arise from a mutant IDH2 having 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.
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`Methods of treating a proliferative disorder
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`Described herein are methods of treating cancer, e.g., by inhibiting a neoactivity
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`of a mutant enzyme, e.g., an enzyme in a metabolic pathway, e.g., a metabolic pathway
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`leading to fatty acid biosynthesis, glycolysis, glutaminolysis, the pentose phosphate shunt,
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`the nucleotide biosynthetic pathway, or the fatty acid biosynthetic pathway, e.g., IDHl or
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`IDH2. The cancer can be characterized by the presence of a neoactivity, such as a gain of
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`function in one or more mutant enzymes (e.g., an enzyme in the metabolic pathway, e.g.,
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`a metabolic pathway leading to fatty acid biosynthesis, glycolysis, glutaminolysis, the
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`pentose phosphate shunt, the nucleotide biosynthetic pathway, or the fatty acid
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`biosynthetic pathway e.g., IDHl or IDH2).
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`- 5 -
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`Rigel Exhibit 1043
`Page 11 of 65
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`C208 l -701300
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`Proliferative disorders
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`The disclosed methods are useful in treating proliferative disorders, e.g. treating
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`solid tumors, soft tissue tumors, and metastases thereof wherein the solid tumor, soft
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`tissue tumor or metastases thereof is a cancer described herein. Exemplary solid tumors
`
`include malignancies ( e.g., sarcomas, adenocarcinomas, and carcinomas) of the various
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`organ systems, such as those of brain, lung, breast, lymphoid, gastrointestinal (e.g.,
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`colon), and genitourinary (e.g., renal, urothelial, or testicular tumors) tracts, pharynx,
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`prostate, and ovary. Exemplary adenocarcinomas include colorectal cancers, renal-cell
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`carcinoma, liver cancer, non-small cell carcinoma of the lung, and cancer of the small
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`intestine. The disclosed methods are also useful in treating non-solid cancers.
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`The methods described herein can be administered with any cancer, for example
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`those described by the National Cancer Institute. A cancer can be evaluated to determine
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`whether it is using a method described herein. Exemplary cancers described by the
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`National Cancer Institute include: Acute Lymphoblastic Leukemia, Adult; Acute
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`Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical
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`Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS(cid:173)
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`Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma,
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`Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer,
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`Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem
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`Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood;
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`Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral
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`Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood;
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`Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive
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`Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic
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`Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and
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`Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial
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`Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor,
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`Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of
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`Unknown Primaiy; Central Nervous System Lymphoma, Primary; Cerebellar
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`Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical
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`Rigel Exhibit 1043
`Page 12 of 65
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`C208 l -701300
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`Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous
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`Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths;
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`Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma;
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`Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal
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`Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ
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`Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer;
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`Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer;
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`Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal
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`Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor,
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`Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma,
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`Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy
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`Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary);
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`Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult;
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`Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy;
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`Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood;
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`Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma;
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`Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute
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`Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute
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`Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic;
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`Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer;
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`Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non(cid:173)
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`Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute;
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`Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic;
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`Lymphoma, AIDS- Related; Lymphoma, Central Nervous System (Primary); Lymphoma,
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`Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood;
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`Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult;
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`Lymphoma, Non- Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy;
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`Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male
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`Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood;
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`Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular;
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`Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer
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`C208 l -701300
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`with Occul