UNITED STATES PATENT AND TRADEMARK OFFICE
`
`APPLICATION
`NUMBER
`61/220,543
`
`FILING or
`37l(c)DATE
`06/25/2009
`
`GRPART
`UNIT
`
`FIL FEE REC'D
`490
`
`37462
`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
`C2081-701304
`
`TOT CLAIMS IND CLAIMS
`
`CONFIRMATION NO. 6623
`FILING RECEIPT
`
`111111111111111111111111]~!1]i~1i~1i~1i!ui!1m11111111111111111111111111
`
`Date Mailed: 07/24/2009
`
`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
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`
`Applicant( s)
`
`Stephan 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: 07/15/2009
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61 /220,543
`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
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`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
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`LICENSE FOR FOREIGN FILING UNDER
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`Title 35, United States Code, Section 184
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`Title 37, Code of Federal Regulations, 5.11 & 5.15
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`GRANTED
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`LICENSE GRANTED" followed by a date appears on this form. Such licenses are issued in all applications where
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`security or the export of technical data. Licensees should apprise themselves of current regulations especially with
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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 1047
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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)
`
`lnventor(s)
`
`Inventor 1
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Stephan
`
`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)
`
`C2081-701304
`
`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 1047
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`

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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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`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 1047
`Page 5 of 170
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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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`Signature
`
`Please see 37 CFR 1.4(d} for the form of the signature.
`
`Signature
`
`/Catherine M. McCarty/
`
`Date (YYYY-MM-DD)
`
`2009-06-25
`
`First Name
`
`Catherine
`
`Last Name
`
`McCarty
`
`Registration Number
`(If appropriate)
`
`54301
`
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`Rigel Exhibit 1047
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`Rigel Exhibit 1047
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`METHODS AND COMPOSITIONS FOR TREATING CANCER
`
`C208 l -701304
`
`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, identifying, diagnosing
`
`and staging a disorder, e.g., 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 central nervous system such as a glioma or brain tumor).
`
`Accordingly, in one aspect, the invention features, a method of treating a subject
`
`having a disorder characterized by unwanted cell proliferation, e.g., cancer. The method
`
`comprises: administering to the subject a therapeutically effective amount of an inhibitor,
`
`of a neoactivity of an enzyme (the neoactive enzyme), encoded by a selected or mutant
`
`allele of a gene, to thereby treat the subject.
`
`In an embodiment the subject has a cancer characterized by the selected or mutant
`
`allele.
`
`In an embodiment the enzyme is in a metabolic pathway.
`
`- 1 -
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`C208 l -701304
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`In one embodiment, the 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.
`
`In an embodiment the inhibitor reduces the amount of neoactive enzyme or
`
`mRNA. In an embodiment the inhibitor interacts directly with, e.g., binds to, the
`
`neoactive enzyme or mRNA. In an embodiment, the inhibitor is a small molecule. In an
`
`embodiment the inhibitor is a nucleic acid-based inhibitor, such as a double stranded
`
`RNA (dsRNA) or antisense RNA that targets neoactive enzyme mRNA.
`
`In an embodiment the method comprises selecting a subject having a cancer
`
`characterized by the selected or mutant allele.
`
`In an embodiment the method comprises selecting a subject having a cancer on
`
`the basis of the cancer being characterized by the selected or mutant allele.
`
`In an embodiment the method comprises confirming or determining, e.g., by
`
`direct examination or evaluation of the subject, or sample therefrom, (e.g, by DNA
`
`sequencing, immuno analysis, or assay for enzymatic activity), or receiving such
`
`information about the subject, that the cancer is characterized by the selected or mutant
`
`allele.
`
`In an embodiment the method comprises administering a second anti-cancer agent
`
`or therapy to the subject, e.g., surgical removal or administration of a chemotherapeutic.
`
`In another aspect, the invention features, a method of treating a subject having
`
`cancer, wherein the cancer is characterized by a preselected allele, or mutant allele, of an
`
`IDH, e.g., IDHl. The method comprises administering to the subject a therapeutically
`
`effective amount of an inhibitor of an IDH gene, e.g., IDHl, e.g., a mutant IDHl gene,
`
`for example having a neoactivity.
`
`In an embodiment the cancer is: a cancer of the CNS, e.g., a glioma; prostate
`
`cancer, e.g., prostate adenocarcinoma; or a hematological cancer, e.g., B-acute
`
`lymphoplastic leukemia (B-ALL).
`
`In an embodiment the inhibitor inhibits one or more of the following: the ability
`
`of IDHl to catalyze the conversion of isocitrate to alpha ketoglutarate; a first degree
`
`neoactivity, e.g., the conversion of alpha-ketoglutarate to 2-hydroxyglutarate, e.g., R-2-
`
`hydroxyglutarate; or a second degree neoactivity. In an embodiment, 2-hydroxyglurarate
`
`- 2 -
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`C208 l -701304
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`(e.g., R-2-hydroxyglutarate) is a metabolite. In another embodiment, 2-hydroxyglutarate
`
`(e.g., R-2-hydroxyglutarate) is a toxin, e.g., a carcinogen.
`
`In an embodiment the inhibitor reduces the amount of an IDH, e.g., IDHl, protein
`
`or mRNA. In an embodiment the inhibitor interacts directly with, e.g., binds to, the
`
`IDHl proteinor IDHl mRNA. In an embodiment, the inhibitor is a small molecule. In an
`
`embodiment the inhibitor is a nucleic acid-based inhibitor, such as a double stranded
`
`RNA (dsRNA) or antisense RNA that targets an IDH, e.g., IDHl.
`
`In an embodiment the cancer, e.g., a glioma, is characterized by a mutation, or
`
`preselected allele, of an IDH gene, e.g., IDHl. E.g., in an embodiment, the IDHl allele
`
`encodes an IDHl having other than an Arg at residue 132. E.g., the allele can have His,
`
`Ser, Cys, Gly, Val, Pro or Leu, or any residue described in Yan et al., N. Eng. J. Med.
`
`360:765-73, 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 His at residue 132. In an
`
`embodiment the allele encodes an IDHl having Ser at residue 132. In an embodiment the
`
`allele is an Arg132His mutation, or an Arg132Ser mutation, according to the sequence of
`
`SEQ ID NO:8 (see FIGs. 2 and 21).
`
`In an embodiment the IDHl allele has an A ( or any other nucleotide other than C)
`
`at nucleotide position 394, or an A (or any other nucleotide other than G) at nucleotide
`
`position 395. In an embodiment the allele is a C394A or a G395A mutation according to
`
`the sequence of SEQ ID NO:5.
`
`In an embodiment the method comprises selecting a subject having cancer, e.g., a
`
`glioma, wherein the cancer is characterized by having an IDH, e.g., IDHl, allele
`
`described herein, e.g., an IDHl allele having His or Ser at residue 132 (SEQ ID NO:8).
`
`In an embodiment the method comprises selecting a subject having a cancer, e.g.,
`
`a glioma, on the basis of the cancer being characterized by an IDH, e.g., IDHl, allele
`
`described herein, e.g., an IDHl allele having His or Ser at residue 132 (SEQ ID NO:8).
`
`In an embodiment the method comprises confirming or determining, e.g., by
`
`direct examination or evaluation of the subject, or sample therefrom, (e.g, by DNA
`
`sequencing, immuno analysis, evaluation of the presence, distribution or level of 2-
`
`hydroxyglutarate, e.g., R-2-hydroxyglutarate, or evaluation of the presence, distribution
`
`or level of alpha ketoglutarate, e.g., from MRI measurement, spinal cord fluid analysis, or
`
`- 3 -
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`C208 l -701304
`
`by analysis of surgical material, e.g., by mass-spectroscopy), or receiving such
`
`information about the subject, that the cancer is characterized by an IDH, e.g., IDHl,
`
`allele described herein, e.g., an IDHl allele having His or Ser at residue 132. In an
`
`embodiment, 2-hydroxyglurarate (e.g., R-2-hydroxyglutarate) is a metabolite. In another
`
`embodiment, 2-hydroxyglutarate (e.g., R-2-hydroxyglutarate) is a toxin, e.g., a
`
`carcmogen.
`
`In an embodiment, the nucleic acid-based inhibitor is a dsRNA that targets IDHl,
`
`e.g., an IDHl having an A at nucleotide position 394 or 395, e.g., a mutant allele carrying
`
`a C394A mutation or a G395A mutation according to the IDHl sequence of SEQ ID
`
`NO:5.
`
`In an embodiment, the nucleic acid-based inhibitor is a dsRNA that targets IDHl,
`
`e.g., an IDHl having a C at nucleotide position 394 or a G at nucleotide position 395,
`
`according to the IDHl sequence of SEQ ID NO:5.
`
`In an embodiment, the dsRNA targets an IDHl having an A at nucleotide position
`
`394 or 395 (e.g., a mutant) and an IDHl having a C at nucleotide position 394 or a G at
`
`nucleotide position 395 (e.g., a wildtype), e.g., by targeting a region of the IDHl mRNA
`
`that is identical between the wildtype and mutant transcripts. In yet another embodiment,
`
`the dsRNA targets a particular mutant or polymorphism (such as a single nucleotide
`
`polymorphism (SNP)), but not a wildtype allele. In this case, the nucleic acid based
`
`inhibitor, e.g., a dsRNA, targets the region of the IDHl containing the mutation.
`
`As used herein, a "SNP" is a DNA sequence variation occurring when a single
`
`nucleotide (A, T, C, or G) in the genome (or other shared sequence) differs between
`
`members of a species (or between paired chromosomes in an individual).
`
`In one embodiment, the nucleic acid based inhibitor decreases or inhibits
`
`expression of an IDHl having His, Ser, Cys, Gly, Val, Pro or Leu, or any residue
`
`described in Yan et al., N. Eng. J. Med. 360:765-73, at residue 132, according to the
`
`sequence of SEQ ID NO:8 (see also FIG. 21). In one embodiment, the nucleic acid
`
`based inhibitor decreases or inhibits expression of an IDHl enzyme having His at residue
`
`132, e.g., an Arg132His mutation, or an Arg at residue 132, e.g., an Arg132Ser mutation,
`
`according to the sequence of SEQ ID NO:8 (see FIGs. 2 and 21).
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`In some embodiments, the nucleic acid based inhibitor, e.g., a dsRNA
`
`preferentially or specifically inhibits the product of a mutant IDHl as compared to the
`
`product of a wildtype IDHl. For example, in one embodiment, a dsRNA targets a region
`
`of an IDHl mRNA that carries the mutation (e.g., a C394A or a G395A mutation
`
`according to SEQ ID NO:5).
`
`In an embodiment, the nucleic acid based inhibitor is delivered to the brain, e.g.,
`
`directly to the brain, e.g., by intrathecal or intraventricular delivery. In an embodiment,
`
`the nucleic acid-based inhibitor is delivered by infusion using, e.g., a catheter, and
`
`optionally, a pump.
`
`In one embodiment, the nucleic acid-based inhibitor is a dsRNA including a sense
`
`strand and an antisense strand having a primary sequence presented in Tables 7, 8, 9, 10,
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`11, 12, 13 and 14. In another embodiment, the nucleic acid based inhibitor is an
`
`antisense oligonucleotide that includes all or a part of an antisense primary sequence
`
`presented in Tables 7, 8, 9, 10, 11, 12, 13 and 14 or which targets the same or
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`substantially the same region as does a dsRNA from Tables 7, 8, 9, 10, 11, 12, 13 and 14.
`
`In some embodiments, the methods described herein can result in reduced side
`
`effects relative to other known methods of treating cancer.
`
`In an embodiment the method comprises administering a second anti-cancer agent
`
`or therapy to the subject, e.g., surgical removal, administration of an alkylating agent,
`
`administration of temoader, or administration of Gleevec.
`
`In an embodiment the cancer, e.g., prostate cancer, e.g., prostate adenocarcinoma,
`
`is characterized by a mutation, or preselected allele, of an IDH gene, e.g., IDHl. E.g., in
`
`an embodiment, the IDHl allele encodes an IDHl having other than an Arg at residue
`
`132. E.g., the allele can have His, Ser, Cys, Gly, Val, Pro or Leu, or any residue
`
`described in Kang et al, 2009, Int. J. Cancer, 125: 353-355 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 His or Cys at residue 132. In an embodiment the allele is an Arg132His
`
`mutation, or an Arg132Cys mutation, according to the sequence of SEQ ID NO:8 (see
`
`FIGs. 2 and 21).
`
`In an embodiment the IDHl allele has a T (or any other nucleotide other than C)
`
`at nucleotide position 394, or an A (or any other nucleotide other than G) at nucleotide
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`position 395. In an embodiment the allele is a C394T or a G395A mutation according to
`
`the sequence of SEQ ID NO:5.
`
`In an embodiment the method comprises selecting a subject, e.g., a subject having
`
`cancer, e.g., prostate cancer, e.g., prostate adenocarcinoma, wherein the cancer is
`
`characterized by an IDH, e.g., IDHl, allele described herein, e.g., an IDHl allele having
`
`His or Cys at residue 132 (SEQ ID NO:8).
`
`In an embodiment the method comprises selecting a subject, e.g., a subject having
`
`cancer, e.g., prostate cancer, e.g., prostate adenocarcinoma, on the basis of the cancer
`
`being characterized by an IDH, e.g., IDHl, allele described herein, e.g., an IDHl allele
`
`having His or Ser at residue 132 (SEQ ID NO:8).
`
`In an embodiment the method comprises confirming or determining, e.g., by
`
`direct examination or evaluation of the subject, or sample therefrom, (e.g, by DNA
`
`sequencing, immuno analysis, evaluation of the presence, distribution or level of 2-
`
`hydroxyglutarate, e.g., R-2-hydroxyglutarate, or evaluation of the presence, distribution
`
`or level of alpha ketoglutarate), or receiving such information about the subject, that the
`
`cancer is characterized by an IDH, e.g., IDHl, allele described herein, e.g., an IDHl
`
`allele having His or Ser at residue 132 (SEQ ID NO:8). In an embodiment, 2-
`
`hydroxyglurarate (e.g., R-2-hydroxyglutarate) is a metabolite. In another embodiment, 2-
`
`hydroxyglutarate (e.g., R-2-hydroxyglutarate) is a toxin, e.g., a carcinogen.
`
`In an embodiment, the nucleic acid-based inhibitor is a dsRNA that targets IDHl,
`
`e.g., an IDHl having an T (or a nucleotide other than C) at nucleotide position 394 or an
`
`A (or a nucleotide other than G) at nucleotide position 395, e.g., a mutant allele carrying
`
`a C394T mutation or a G395A mutation according to the IDHl sequence of SEQ ID
`
`NO:5.
`
`In an embodiment, the nucleic acid-based inhibitor is a dsRNA that targets IDHl,
`
`e.g., an IDHl having a Cat nucleotide position 394 or a G at nucleotide position 395
`
`(SEQ ID NO:5).
`
`In an embodiment, the dsRNA targets an IDHl having an Cat nucleotide position
`
`394 or a G at 395 (e.g., a wildtype) and an IDHl having a Tat nucleotide position 394 or
`
`an A at nucleotide position 395 (e.g., a mutant) according to the sequence of SEQ ID
`
`NO:5, e.g., by targeting a region of the IDHl mRNA that is identical between the
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`wildtype and mutant transcripts. In yet another embodiment, the dsRNA targets a
`
`particular mutant or polymorphism (such as a single nucleotide polymorphism (SNP)),
`
`but not a wildtype allele. In this case, the nucleic acid based inhibitor, e.g., a dsRNA,
`
`targets the region of the IDHl containing the mutation.
`
`In one embodiment, the nucleic acid based inhibitor decreases or inhibits
`
`expression of an IDHl having His, Ser, Cys, Gly, Val, Pro or Leu, at residue 132,
`
`according to the sequence of SEQ ID NO:8 (see also FIG. 21). In one embodiment, the
`
`nucleic acid based inhibitor decreases or inhibits expression of an IDHl enzyme having
`
`His at residue 132, e.g., an Arg132His mutation, or an Cys at residue 132, e.g., an
`
`Arg132Cys mutation, according to the sequence of SEQ ID NO:8 (see FI Gs. 2 and 21).
`
`In some embodiments, the nucleic acid based inhibitor, e.g., a dsRNA
`
`preferentially or specifically inhibits the product of a mutant IDHl as compared to the
`
`product of a wildtype IDHl. For example, in one embodiment, a dsRNA targets a region
`
`of an IDHl mRNA that carries the mutation (e.g., a C394T or a G395A mutati