PCT/US2010/040486 01.09.2010
`
`PATENT COOPERATION TREATY
`
`From the
`INTERNATIONAL SEARCHING AUTHORITY
`
`To: CATHERINE M. MCCARTY
`LANDO & ANASTASI, LLP
`ONE MAIN STREET, ELEVENTH FLOOR
`CAMBRIDGE, MA 02142
`
`Applicant's or agent's file reference
`C2081-7019WO
`
`PCT
`
`WRITTEN OPrNION OF THE
`rNTERNATIONAL SEARCHrNG AUTHORITY
`
`(PCT Rule 43bis.l)
`
`Date of mailing
`(day/month/year)
`
`01 SEP 2010
`
`FOR FURTHER ACTION
`See paragraph 2 below
`
`International application No.
`PCT/US 10/40486
`
`International filing dale (day/month/year)
`29 June 201 o (29.06.201 O)
`International Patent Classification (IPC) or both national classification and !PC
`IPC(B) - A61K 31/497 (2010.01)
`USPC - 514/252.12-252.13
`Applicant AGIOS PHARMACEUTICALS, INC.
`
`Priority date (day/month/year)
`29 June 2009 (29.06.2009)
`
`I. This opinion contains indications relating to the following items:
`
`Box No. I
`
`Basis of the opinion
`
`Box No. II
`
`Priority
`
`Box No. IV Lack of unity of invention
`
`~
`□
`181 Box No. Ill Non-establishment of opinion with regard to novelty, inventive step and industrial applicability
`□
`IZI Box No. V
`□
`□
`□
`
`Reasoned statement under Rule 43bis. l (a)(i) with regard 10 novelty, inventive step or industrial applicability; •
`citations and explanations supporting such statement
`
`Box No. VI Certain documents cited
`
`Box No. VII Certain defects in the international application
`
`Box No. VIII Certain observations on the international application
`
`2. FURTHER ACTION
`If a demand for international preliminary examination is made, this opinion will be considered to be a written opinion of the
`International Preliminary Examining Authority ("IPEA") except that this does not apply where the applicant chooses an Authority
`other than this one to be the IPEA and the chosen IPEA has notified the International Bureau under Rule 66.lbis(b) that written
`opinions of this International Searching Authority will not be so considered.
`If this opinion is, as provided above, considered to be a written opinion of the !PEA, the applicant is invited to submit to the IPEA
`a written reply together, where appropriate, with amendments, before the expiration ofJ months from the date of mailing ofForm
`PCT/ISA/220 or before the expiration of22 months from the priority dale, whichever expires later.
`For further options, see form PCT/ISA/220.
`
`3. For further details, see notes to Form PCT/ISA/220.
`
`Name and mailing address of the ISNUS Date of completion of this opinion
`Man Slop PCT, Attn: IS.AA.IS
`Commissioner for Palenls
`P.O. Box 1450, Alexandria, Virginia 22313•1450
`Facsimile No. 571-273-3201
`Form PCT/ISA/237 (cover sheet) (July 2009)
`
`23.08.2010 (23.08.2010)
`
`Authorized officer:
`
`LeeW. Young
`
`PCT Helpdosk: 571·272-4300
`PCT OSP: 571 •272-7TT4
`
`Rigel Exhibit 1020
`Page 427 of 1266
`
`

`

`PCT/US2010/040486 01.09.2010
`
`WRl'rl'EN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/US 10/40486
`
`Box No. I
`
`Basis of this opinion
`
`I. With regard to the language, this opinion has been established on the basis of:
`
`the international application in the language in which it was filed.
`
`l8J
`□ a translation of the international application into _ _ _ _ _ _ _ _ _ _ _ which is the language of a
`
`translation furnished for the purposes of international search (Rules I 2.3(a) and 23.1 (b)).
`
`2. □
`This opinion has been established taking into account the rectification of an obvious mistake authorized by or notified
`to this Authority under Rule 91 (Rule 43bis.1 (a))
`
`3. With regard to any nucleotide and/or amino acid sequence disclosed in the international application, this opinion has been
`established on the basis of a sequence listing filed or furnished:
`
`a.
`
`(means)
`
`D on paper
`D in electronic form
`
`b.
`
`(time)
`
`D in the international application as filed
`D together with the· international application in electronic form
`D subsequently to this Authority for the purposes of search
`4. D
`
`In addition, in the case that more than one version or copy of a sequence listing has been filed or furnished, the required
`statements that the information in the subsequent or additional copies is identical to that in the application as filed or
`does not go beyond the application as filed, as appropriate, were furnished.
`
`5. Additional comments:
`
`Form PCT/ISA/237 (Box No. I} (July 2009)
`
`Rigel Exhibit 1020
`Page 428 of 1266
`
`

`

`PCT/US2010/040486 01.09.2010
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/US 10/40486
`
`Box No. Ill Non-establishment of opinion with regard to novelty, inventive step and Industrial applicability
`
`The questions whether the claimed invention appears to be novel, to involve an inventive step (to be non obvious), or to be industrially
`applicable have not been examined in respect of:
`
`D the entire international application.
`~ claims Nos. 21·22 25 and 27-28
`
`because:
`
`□ the said international application, or the said claims Nos. _ _ _ _,,,..,...----------
`
`subject matter which does not require an international search (specify):
`
`relate to the following
`
`~ the description, claims or drawings (indicate particular elements below) or said claims Nos. 21-22, 25 and 27•28
`are so unclear that no meaningful opinion could be fonncd (specify):
`Claims 21-22, 25 and 27·28 are improper multiple dependent claims because they are dependent claims and are not drafted in
`accordance with the second and third sentences of Rule 6.4(a).
`
`□ the claims, or said claims Nos. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
`
`by the description that no meaningful opinion could be fonned (specljj~:
`
`arc so inadequately supported
`
`~ no international search report has been established for said claims Nos. _2_1._2_2_, _2_5_a_n_d_2_7_•28 _ _ _ _ _ _ _ _ _ _ _ _
`D a meaningful opinion could not be fonned without the sequence listing; the applicant did not, within the prescribed time limit:
`D furnish a sequence listing on paper complying with the standard provided for in Annex C of the Administrative
`
`Instructions, and such listing was not available to the International Searching Authority in a fonn and manner acceptable
`to it.
`furnish a sequence listing in electronic fonn complying with the standard provided for in Annex C of the Administrative
`Instructions, and such listing was not available to the International Searching Authority in a fonn and manner acceptable
`toit.
`pay the required late furnishing fee for the furnishing of a sequence listing in response to an invitation under
`Rule 13ter. l(a) or (b).
`
`□
`□
`D Sec Supplemental Box for further details.
`
`Fonn PCT/ISA/237 (Box No. Ill) (July 2009)
`
`Rigel Exhibit 1020
`Page 429 of 1266
`
`

`

`PCT/US2010/040486 01.09.2010
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`
`PCT/US 10/40486
`
`Box No. V
`
`Reasoned statement under Rule 436£1'.l(a)(i) with regard to novelty, inventive step or industrial applicability;
`citations and explanations supporting such statement
`
`I.
`
`Statement
`
`Novelty (N)
`
`Inventive step (IS)
`
`Industrial applicability (IA)
`
`Claims
`
`Claims
`
`Claims
`
`Claims
`
`Claims
`
`Claims
`
`1 ·20, 23-24, 26, 29-30
`
`None
`
`None
`
`1-20, 23-24, 26, 29-30
`
`1-20, 23-24, 26, 29-30
`None
`
`YES
`NO
`
`YES
`NO
`
`YES
`NO
`
`2.
`Citations and explanations:
`Claims 1-20, 23-24, 26 and 29-30 lack an Inventive step under PCT Artlcle 33(3) as being obvious over US 5,834,485 A to Dyke et al.
`(hereinafter 'Dyke') In view of US 2003/0095958 Al to Bhisetti et al. (hereinafter 'Bhisetti').
`
`As per claims 1-20, Dyke discloses a similar compound of formula I or a pharmaceutically acceptable salt thereof wherein W, X, Y and Z
`are each independently CH or N; D and 01 are independently a bond or NRb (col 1, In 35-45, wherein R6 is aryl or heteroaryl; additionally
`R6 is subsituted with R14 and R14 is CORl 1 and R11is a heterocycle corresponding to the plperazlne or diazepane ring), A Is optionally
`substitited bicyclic heteroaryl (col 1, In 35-45), g, m and hare 0, 1 or 2 and Lis a bond (col 1, In 35-45, col 2, In 10-15). Dyke does not
`explicitly disclose wherein Lis C(O), (CRcRc)m, OC(O), (CRcRc)m-OC(O) or NRbC(O) or Al is selected from alkyl, cycloalkyl, aryl,
`heteroaryl and heterocyclyl, each of which is substituted with 0-5 occurrences of Rd. However, Bhisetti discloses similar piperazine
`derivatives (para [0217)), wherein Lis a bond (para [0217), wherein mis O) or C(O), (CRcRc)m, OC(O), (CRcRc)m-OC(O) or NRbC(O)
`(para (0215), see L 1) and Al is aryl (para (0231), see M). Therefore, it would have been obvious to one of ordinary skill In the art at the
`time ol the invention to combine the substlluents of Bhisetti with the invention of Dyke to arrive at the claimed compounds without undue
`experimentation for the purpose of providing another conjugalable site on the molecule that is the least sterically hindered.
`
`As per claims 23-24, 26 and 29-30, Dyke discloses a similar compound used in a pharmaceutical composition in the manufacture of a
`medicament of formula I or a pharmaceutically acceptable salt thereof wherein W, X, Y and Z are each independently CH or N, D and 01
`are Independently a bond or NRb (col 1, In 35-45, wherein R6 ls aryl orheteroaryl; addilionally R6 is subsltuted with R14 and R14 is
`COR11 and R11 ls a heterocycle corresponding to the piperazine or diazepane ring), A Is optionally substltlled blcycllc heteroaryl (col 1, In
`35-45), g, m and hare 0, 1 or 2 and Lis a bond (col 1, In 35-45, col 2, In 10-15). Dyke does not explicitly disclose wherein Lis C(O),
`(CRcRc)m, OC(O), (CRcRc)m-OC(O) or NRbC(O) or R1 is selected from alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, each of which
`is substituted with 0-5 occurrences of Rd in the manufacture of a medicament for modulating PKM2 activity in a subject in need thereof or
`for treating cancer associated with PKM2 activity in said subject. However, Dyke discloses said compounds and composllions are useful
`in treating cancer and cancer related disorders (abstract). Addllioanlly, Bhisettl discloses similar piperazine derivatives (para (0217)),
`wherein L Is a bond (para (0217), wherein m is O) or C(O), (CRcRc)m, OC(O), (CRcRc)m-OC(O) or NRbC(O) (para [0215), see L 1) and
`R1 is aryl (para [0231), see M). Therefore, it would have been obvious to one of ordinary skill in the art at the time of the invention to
`combine the substituents of Bhiselli with the invention of Dyke to arrive at the claimed compositions and compounds without undue
`experimentation for the purpose of optimizing the treatment of cancer and cancer related diseases as these would have been known
`equivalents in the art with similar chemical and pharmacological properties.
`
`Claims 1-20, 23-24, 26 and 29-30 have industrial applicability as defined by PCT Article 33(4) because the subject matter can be made or
`used in industry.
`
`Fonn PCT/ISA/237 (Box No. V) (July 2009)
`
`Rigel Exhibit 1020
`Page 430 of 1266
`
`

`

`PATENT COOPERATION TREATY
`PCT
`
`INTERNATIONAL PRELIMINARY REPORT ON PATENTABILITY
`(Chapter I of the Patent Cooperation Treaty)
`
`(PCT Rule 44bis)
`
`FOR FURTHER ACTION
`
`See item 4 below
`
`Applicant's or agent's file reference
`C2081-7033WO
`
`International application No.
`PCT/US2010/053623
`
`International filing date (day/month/year)
`21 October 2010 (21.10.2010)
`
`International Patent Classification (8th edition unless older edition indicated)
`See relevant information in Form PCT/ISA/237
`
`Applicant
`AGIOS PHARMACEUTICALS, INC.
`
`I Priority date (day/month/year)
`
`21 October 2009 (21.10.2009)
`
`1.
`
`This international preliminary report on patentability (Chapter I) is issued by the International Bureau on behalf of the
`International Searching Authority under Rule 44 bis.l(a).
`
`2.
`
`This REPORT consists of a total of 6 sheets, including this cover sheet.
`
`In the attached sheets, any reference to the written opinion of the International Searching Authority should be read as a
`reference to the international preliminary report on patentability (Chapter I) instead.
`
`3.
`
`This report contains indications relating to the following items:
`
`~ Box No. I
`□ Box No. II
`~ Box No. III
`□ Box No. IV
`~ Box No. V
`□ Box No. VI
`□ Box No. VII
`□ Box No. VIII
`
`Basis of the report
`
`Priority
`
`Non-establishment of opinion with regard to novelty, inventive step and industrial
`applicability
`
`Lack of unity of invention
`
`Reasoned statement under Article 35(2) with regard to novelty, inventive step or
`industrial applicability; citations and explanations supporting such statement
`
`Certain documents cited
`
`Certain defects in the international application
`
`Certain observations on the international application
`
`4.
`
`The International Bureau will communicate this report to designated Offices in accordance with Rules 44bis.3(c) and 93bis.1
`but not, except where the applicant makes an express request under Article 23(2), before the expiration of 30 months from
`the priority date (Rule 44bis .2).
`
`The International Bureau of WIPO
`34, chemin des Colombettes
`1211 Geneva 20, Switzerland
`
`Facsimile No. +41 22 338 82 70
`
`Form PCT/IB/373 (January 2004)
`
`Date of issuance of this report
`24 April 2012 (24.04.2012)
`
`Authorized officer
`
`Nora Lindner
`
`e-mail: pt03.pct@wipo.int
`
`Rigel Exhibit 1020
`Page 431 of 1266
`
`

`

`PCT/US2010/053623 18.01.2011
`
`PATENT COOPERATION TREATY
`
`From the
`INTERNATIONAL SEARCHING AUTHORITY
`To: CATHERINE M. MCCARTY
`LANDO & ANASTASI, LLP
`ONE MAIN STREET, ELEVENTH FLOOR
`CAMBRIDGE, MA 02142
`
`Applicant's or agent's file reference
`C2081-7033WO
`
`PCT
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`(PCT Rule 43bis.1)
`
`Date of mailing
`( day/month/year)
`
`18 JAN ·2011
`
`FOR FURTHER ACTION
`See paragraph 2 below
`
`International application No.
`PCT /US 10/53623
`
`International filing date (day/month/year)
`21 October 2010 (21.10.201 O)
`
`Priority date (day/month/year)
`21 October 2009 (21.10.2009)
`
`International Patent Classification (IPC) or both national classification and IPC
`IPC(8) - C12Q 1/68; A61K 31/225 (2010.01)
`USPC - 435/6; 514/547
`Applicant AGIOS PHARMACEUTICALS, INC.
`
`Basis of the opinion
`
`Priority
`
`Non-establishment of opinion with regard to novelty, inventive step and industrial applicability
`
`Lack of unity of invention
`
`1. This opinion contains indications relating to the following items:
`~
`Box No. I
`□
`Box No. II
`~
`Box No. Ill
`□
`Box No. IV
`~ Box No. V
`D Box No. VJ Certain documents cited
`D Box No. VII Certain defects in the international application
`D Box No. VIII Certain observations on the international application
`
`Reasoned statement under Rule 43bis .1 (a)(i) with regard to novelty, inventive step or industrial applicability;
`citations and explanations supporting such statement
`
`2. FURTHER ACTION
`If a demand for international preliminary examination is made, this opinion will be considered to be a written opinion of the
`International Preliminary Examining Authority ("JPEA") except that this does not apply where the applicant chooses an Authority
`other than this one to be the IPEA and the chosen IPEA has notified the International Bureau under Rule 66.1 bis(b) that written
`opinions of this International Searching Authority will not be so considered.
`If this opinion is, as provided above, considered to be a written opinion of the IPEA, the applicant is invited to submit to the IPEA
`a written reply together, where appropriate, with amendments, before the expiration of3 months from the date of mailing of Form
`PCT/ISN220 or before the expiration of22 months from the priority date, whichever expires later.
`For further options, see Form PCT/ISN220.
`
`3. For further details, see notes to Form PCT/ISN220.
`
`Name and mailing address of the !SA/US Date of completion of this opinion
`Mail Stop PCT, Attn: ISA/US
`Commissioner for Patents
`P.O. Box 1450. Alexandria, Virginia 22313-1450
`Facsimile No. 571-273-3201
`Form PCT/ISN237 (cover sheet) (July 2009)
`
`31 December 201 O {31.12.2010)
`
`Authorized officer:
`LeeW. Young
`
`PCT Helpdesk: 571•272-4300
`PCT OSP: 571•272-7774
`
`Rigel Exhibit 1020
`Page 432 of 1266
`
`

`

`PCT/US2010/053623 18.01.2011
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/US 10/53623
`
`Box No. I
`
`Basis of this opinion
`
`l. With regard to the language, this opinion has been established on the basis of:
`
`the international application in the language in which it was filed.
`a translation of the international application into _____________ which is the language of a
`translation furnished for the purposes of international search (Rules 12.3( a) and 23. l (b)).
`
`2. □
`This opinion has been established taking into account the rectification of an obvious mistake authorized by or notified
`to this Authority under Rule 91 (Rule 43bis.l(a))
`
`3. With regard to any nucleotide and/or amino acid sequence disclosed in the international application, this opinion has been
`established on the basis of a sequence listing filed or furnished:
`
`a. (means)
`
`D
`D
`
`onpaper
`
`in electronic form
`
`in the international application as filed
`
`together with the international application in electronic form
`
`subsequently to this Authority for the purposes of search
`
`b. (time)
`
`D
`D
`D
`4. D
`
`In addition, in the case that more than one version or copy ofa sequence listing has been filed or furnished, the required
`statements that the information in the subsequent or additional copies is identical to that in the application as filed or
`does not go beyond the application as filed, as appropriate, were furnished.
`
`5. Additional comments:
`
`Form PCT/ISN237 (Box No. I) (July 2009)
`
`Rigel Exhibit 1020
`Page 433 of 1266
`
`

`

`PCT/US2010/053623 18.01.2011
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/US 10/53623
`
`Box No. III Non-establishment of opinion with regard to novelty, inventive step and industrial applicability
`
`The questions whether the claimed invention appears to be novel, to involve an inventive step (to be non obvious), or to be industrially
`applicable have not been examined in respect of:
`
`D the entire international application.
`IZ!
`claims Nos. 14-35 -~~---------------------------------------
`because: D the said international application, or the said claims Nos.
`
`subject matter which does not require an international sea_rc_h-(s_p_e_c_ify,_,J_: __________ _
`
`relate to the following
`
`IZ!
`
`the description, claims or drawings (indicate particular elements below) or said claims Nos. _1_4_-3_5 _________ _
`are so unclear that no meaningful opinion could be formed (specijj,):
`Claims 14-35 are not drafted in accordance with the second and third sentences of Rule 6.4 (a). These claims are improper multiple
`dependent claims.
`
`□ the claims, or said claims Nos. _______________________ _
`
`by the description that no meaningful opinion could be formed (specijj,):
`
`are so inadequately supported
`
`Instructions, and such listing was not available to the International Searching Authority in a form and manner acceptable
`
`Instructions, and such listing was not available to the International Searching Authority in a form and manner acceptable
`
`__ IZ! no international search report has been established for said claims Nos. _1_4_-35 __________________ _
`D a meaningful opinion could not be formed without the sequence listing; the applicant did not, within the prescribed time limit:
`D furnish a sequence listing on paper complying with the standard provided for in Annex C of the Administrative
`to it. D furnish a sequence listing in electronic form complying with the standard provided for in Annex C of the Administrative
`to it. D pay the required late furnishing fee for the furnishing of a sequence listing in response to an invitation under
`
`Rule 13ter. l(a) or (b).
`
`D See Supplemental Box for further details.
`
`Form PCT/ISA/237 (Box No. Ill) (July 2009)
`
`Rigel Exhibit 1020
`Page 434 of 1266
`
`

`

`PCT/US2010/053623 18.01.2011
`
`WRI1TEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`
`PCT/US 10/53623
`
`Box No. V
`
`Reasoned statement under Rule 43bis.l(a)(i) with regard to novelty, inventive step or industrial applicability;
`citations and explanations supporting such statement
`
`I.
`
`Statement
`
`Novelty (N)
`
`Inventive step (IS)
`
`Industrial applicability (IA)
`
`Claims
`Claims
`
`Claims
`Claims
`
`Claims
`Claims
`
`1-13
`none
`
`none
`
`1-13
`
`1-13
`none
`
`YES
`NO
`
`YES
`NO
`
`YES
`NO
`
`2. Citations and explanations:
`Claims 5-7 lack inventive step under PCT Article 33(3) as being obvious over the article titled "Hydroxyglutaric aciduria and malignant
`brain tumor: a case report and literature review• by Aghili et al. (hereinafter 'Aghili') in view of the article titled "Mutations in the D-2-
`hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria" by Struys et al. (hereinafter 'Struys '05')
`
`Regarding claim 5, Aghili discloses a method of treating a subject having a cell proliferation-related disorder (abstract, ependymoma)
`characterized by ii) elevated levels of 2HG {abstract, pg 233, right col, para 1, elevated levels of L-2-OHG in urine and CSF) the method
`comprising radiotherapy (pg 234, left col, para 1 ).
`Aghili does not specifically disclose a treatment method of administering to the subject in need thereof a therapeutically effective amount
`of a compound that degrades, sequesters, metabolizes, increases the metabolic conversion of 2HG.
`Struys '05 discloses that low activity of D-2-hydroxyglutarate dehydrogenase in cells from patients of D-2-hydroxyglutaric aciduria
`{abstract and pg 359, right col, para 4) is due disease causing gene mutations in D-2-hydroxyglutarate dehydrogenase {abstract). It
`would have been obvious to one of ordinary skill in the art, at the time the invention was made, to have applied a commonly practiced
`replacement therapy of D-2-hydroxyglutarate dehydrogenase of Struys '05 to the method of treating a subject having a cell proliferation(cid:173)
`related disorder of Aghili, and thus to have increases the metabolic conversion of 2HG, without undue experimentation.
`
`Regarding claim 6, Aghili, in view of Struys '05, discloses the method of claim 5, wherein the compound metabolizes 2HG (Struys '05,
`abstract).
`
`Regarding claim 7, Aghili, in view of Struys '05, discloses the method of claim 6, wherein the compound is 2-HG dehydrogenase (Struys
`'05, abstract).
`
`Claims 8 and 11 lack inventive step under PCT Article 33(3) as being obvious over Aghili, as above, in view of US 6,979,675 B2
`(lidmarsh).
`
`Regarding claim 8, Aghili discloses a method of treating a subject having a cell proliferation-related disorder (abstract, ependymoma)
`characterized by ii) elevated levels of 2HG (abstract, pg 233, right col, para 1, elevated levels of L-2-0HG in urine and CSF) the method
`comprising radiotherapy (pg 234, left col, para 1 ).
`Aghili does not specifically disclose a treatment method of administering to the subject in need thereof a therapeutically effective amount
`of an anti-glycolytic compound, to thereby treat the subject.
`Tidmarsh discloses a method of treating ependymoma with anti-glycolytic compound {col 3, In 26-44 and col 19, In 13-41). It would have
`been obvious to one of ordinary skill in the art, at the time the invention was made, to have applied the anti-glycotic compound of Tidmarsh
`to treat the ependymoma of Aghili, because Tidmarsh teaches that anti-glycolytic compound is effective in treating ependyrnoma
`
`Regarding claim 11, Aghili, in view of Tidmarsh, discloses the method of claim 8, wherein the anti-glycolytic compound is 2 deoxyglucose
`{Tidmarsh, col 3, In 26-44).
`
`Claims 12-13 lack inventive step under PCT Article 33(3) as being obvious over Aghili, as above, in view of US 5,984,882 A to
`Rosenschein et al. (hereinafter 'Rosenschein').
`
`Regarding claim 12, Aghili discloses a method of treating a subject having a cell proliferation-related disorder (abstract, ependymoma)
`characterized by ii) elevated levels of 2HG (abstract, pg 233, right col, para 1, elevated levels of L-2-OHG in urine and CSF) the method
`comprising radiotherapy (pg 234, left col, para 1 ).
`Aghili does not specifically disclose a treatment method of administering to the subject in need thereof a therapeutically effective amount
`of an antioxidant, to thereby treat the subject.
`Rosenschein discloses a method of applying antioxidant to treat ependymoma (col 2, In 46-53 and col 6, In 36-66). It would have been
`obvious to one of ordinary skill in the art, at the time the invention was made, to have applied the antioxidant of Rosenschein to treat the
`ependymoma of Aghili, because Rosenschein teaches that antioxidant is effective in treating ependymoma.
`
`Regarding claim 13, Aghili, in view of Rosenschein, discloses the method of claim 12, wherein the antioxidant is ascorbic acid
`(Rosenschein, col 2, In 46-53).
`
`---------<-:o-ntinued in Supplemental Bo x - - - - - - - - - - -
`
`Form PCT/JSA/237 (Box No. V) (July 2009)
`
`Rigel Exhibit 1020
`Page 435 of 1266
`
`

`

`PCT/US2010/053623 18.01.2011
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`
`PCT/US 10/53623
`
`Supplemental Box
`
`In case the space in any of the preceding boxes is not sufficient.
`Continuation of:
`Box V2. Citations and explanation
`
`Claims 1-4 lack inventive step under PCT Article 33(3) as being obvious over Aghili, as above, in view of the article titled "Investigations by
`mass isotopomer analysis of the formation of 0-2-hydroxyglutarate by culutred tymphoblasts from two patients with D-2-hydroxyglutaric
`aciduria" by Struys et al. (hereinafter 'Struys '03') and the article titled "Metabolic enzymes as oncogenes or tumor suppressors• by
`Thompson (hereinafter "Thompson").
`
`Regarding claim 1, Aghili discloses a method of treating a subject having a cell proliferation-related disorder (abstract, ependymoma)
`characterized by ii) elevated levels of 2HG (abstract, pg 233, right col, para 1, elevated levels of L-2-OHG in urine and CSF) the method
`comprising radiotherapy (pg 234, left col, para 1).
`Aghili does not specifically disclose a treatment method of administering to the subject in need thereof a therapeutically effective amount of
`a treatment that decreases the ability of 2HG to compete with a cellular structural analog of the 2HG.
`Struys '03 discloses that mitochondrial 2-KG interconverts rapidly to D-2-HG in cultured lymphoblast from patients with D-2-HG aciduria
`(abstract) and the three components, citrate, 0-2-HG and 2-KG, are part of a metabolic sequence (pg 119, left col, para 2).
`Thompson discloses that mutated IDH1, arginine 132, is found in 12% of glioblastomas (pg 1, para 3) and maybe resulted from its loss of
`capacity to be regulated by its end-product alpha-ketoglutarate (pg 2, para 1 ). One skilled in the art.at the time the invention was made,
`would have been motivated to combine the observations that isocitrate and 2-KG are precursors of elevated D-2-HG of Stuys '03 with
`dysregulated IDH1 mutant of Thompson, and to have applied the end-product alpha-ketoglutarate as an inhibitor of IDH1 to treat the cell
`proliferation disorder of Aghili, by reducing the level of D-2-HG precursors.
`
`Regarding claim 2, Thompson further discloses increasing the cellular concentration of the cellular structural analog of the 2HG relative to
`the concentration of the 2HG (pg 2, para 1, alpha-ketoglutarate).
`
`Regarding claim 3, Thompson further discloses that the cellular structural analog has the following formula as disclosed: wherein;
`each Ra and Rb are independently H;
`Re is a hydrogen bond acceptor, and can be bound to the caribon chain by way of a single or double bond, as indicated by the dashed line;
`and
`n is 1 (pg 2, para 1, alpha-ketoglutarate).
`
`Regarding claim 4, Aghili, in view of Struys '03 and Thompson, discloses the method of claim 3, wherein the cellular structural analog is
`alpha ketoglutarate (Thompson, pg 2, para 1).
`
`Claims 9-10 lack inventive step under PCT Article 33(3) as being obvious over Aghili, as above, in view of Tidmarsh and Thompson.
`
`Regarding claim 9, Aghili, in view of Tidmarsh, discloses the method of claim 8, but does not specifically disclose that wherein the anti(cid:173)
`glycolytic compound is a compound, which upon administration, turns a PET positive cancer into a PET negative cancer. Thompson
`discloses that cancer cells preferentially metabolize glucose in PET positive cancer (pg 1, para 1 ). It would have been obvious to one of
`ordinary skill in the art, at the time the invention was made, to have applied the anti-glycolytic compound of Aghili and Tidmarsh to treat the
`PET positive cancer of Thompson, because Thompson teaches that cancer cells preferentially metabolize glucose.
`
`Regarding claim 10, Aghili, in view of lidmarsh and Thompson, discloses the method of daim 9, wherein the PET positive cancer is a
`tumor (Thompson, pg 1, para 1-2).
`
`Claims 1-13 have industrial applicability as defined by PCT Article 33(4) because the subject matter can be made or used in industry.
`
`Fonn PCT/ISN237 (Supplemental Box) (July 2009)
`
`Rigel Exhibit 1020
`Page 436 of 1266
`
`

`

`PATENT COOPERATION TREATY
`PCT
`
`INTERNATIONAL PRELIMINARY REPORT ON PATENTABILITY
`(Chapter I of the Patent Cooperation Treaty)
`
`(PCT Rule 44bis)
`
`FOR FURTHER ACTION
`
`See item 4 below
`
`Applicant's or agent's file reference
`C2081-7021WO
`
`International application No.
`PCT/US2010/053624
`
`International filing date (day/month/year)
`21 October 2010 (21.10.2010)
`
`International Patent Classification (8th edition unless older edition indicated)
`See relevant information in Form PCT/ISA/237
`
`Applicant
`AGIOS PHARMACEUTICALS, INC.
`
`I Priority date (day/month/year)
`
`21 October 2009 (21.10.2009)
`
`1.
`
`This international preliminary report on patentability (Chapter I) is issued by the International Bureau on behalf of the
`International Searching Authority under Rule 44 bis.l(a).
`
`2.
`
`This REPORT consists of a total of 7 sheets, including this cover sheet.
`
`In the attached sheets, any reference to the written opinion of the International Searching Authority should be read as a
`reference to the international preliminary report on patentability (Chapter I) instead.
`
`3.
`
`This report contains indications relating to the following items:
`
`~ Box No. I
`□ Box No. II
`~ Box No. III
`
`~ Box No. IV
`~ Box No. V
`□ Box No. VI
`□ Box No. VII
`□ Box No. VIII
`
`Basis of the report
`
`Priority
`
`Non-establishment of opinion with regard to novelty, inventive step and industrial
`applicability
`
`Lack of unity of invention
`
`Reasoned statement under Article 35(2) with regard to novelty, inventive step or
`industrial applicability; citations and explanations supporting such statement
`
`Certain documents cited
`
`Certain defects in the international application
`
`Certain observations on the international application
`
`4.
`
`The International Bureau will communicate this report to designated Offices in accordance with Rules 44bis.3(c) and 93bis.1
`but not, except where the applicant makes an express request under Article 23(2), before the expiration of 30 months from
`the priority date (Rule 44bis .2).
`
`The International Bureau of WIPO
`34, chemin des Colombettes
`1211 Geneva 20, Switzerland
`
`Facsimile No. +41 22 338 82 70
`
`Form PCT/IB/373 (January 2004)
`
`Date of issuance of this report
`24 April 2012 (24.04.2012)
`
`Authorized officer
`
`Nora Lindner
`
`e-mail: pt03.pct@wipo.int
`
`Rigel Exhibit 1020
`Page 437 of 1266
`
`

`

`PCT/US2010/053624 07.04.2011
`
`PATENT COOPERATION TREATY
`
`From the
`INTERNATIONAL SEARCHING AUTHORITY
`To: CATHERINE M. MCCARTY
`LANDO & ANASTASI, LLP
`ONE MAIN STREET, ELEVENTH FLOOR
`CAMBRIDGE, MA 02142
`
`Applicant's or agent's file reference
`C2081-7021WO
`
`PCT
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`(PCT Rule 43bis.1)
`
`Date of mailing
`(day/month/year)
`
`07 APR 2011
`
`FOR FURTHER ACTION
`See paragraph 2 below
`
`International application No.
`PCT /US 10/53624
`International Patent Classification (IPC) or both national classification and IPC
`IPC(8) - A61 K 31/00 (2011.01)
`USPC- 514/1 ; 435/6
`Applicant AGIOS PHARMACEUTICALS, INC.
`
`International filing date (day/month/year)
`21 October 201 0 (21.10.2010)
`
`Priority date (day/month/year)
`21 October 2009 (21.10.2009)
`
`I. This opinion contains indications relating to the following items:
`
`Box No. I
`
`Basis of the opinion
`
`Box No. II
`
`Priority
`
`IZI
`□
`IZI Box No. III
`IZI Box No. IV
`IZI Box No. V
`Reasoned statement under Rule 43bis. l (a)(i) with regard to novelty,