`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`________________________________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`________________________________
`
`
`RIGEL PHARMACEUTICALS, INC.,
`
`Petitioner,
`
`v.
`
`SERVIER PHARMACEUTICALS LLC
`
`Patent Owner.
`____________________________
`
`Case IPR2022-01423
`U.S. Patent No. 10,610,125
`________________________________
`
`PETITION FOR INTER PARTES REVIEW
`
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`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`
`TABLE OF CONTENTS
`
`PETITIONER’S LIST OF EXHIBITS .................................................................... iii
`I.
`INTRODUCTION ............................................................................................... 1
`II. MANDATORY NOTICES ................................................................................. 2
`A. Real Party-In-Interest (37 C.F.R. §42.8(b)(1)) ........................................... 2
`B. Related Matters (37 C.F.R. §42.8(b)(2)) .................................................... 2
`C. Counsel (37 C.F.R. §42.8(b)(3)) and Service Information (37 C.F.R.
`§42.8(b)(3)-(4))........................................................................................... 2
`III. PAYMENT OF FEES ......................................................................................... 3
`IV. REQUIREMENTS FOR IPR .............................................................................. 3
`A. Grounds for Standing ................................................................................. 3
`B.
`Identification of Challenge ......................................................................... 4
`V. BACKGROUND ................................................................................................. 8
`A. Overview of Technology ............................................................................ 8
`B. The ’125 Patent ........................................................................................... 9
`C. Prosecution History of the ’125 Patent ..................................................... 15
`D. Asserted Prior Art ..................................................................................... 18
`VI. LEVEL OF ORDINARY SKILL IN THE ART .............................................. 23
`VII. CLAIM CONSTRUCTION .............................................................................. 24
`VIII. GROUNDS OF UNPATENTABILITY ......................................................... 24
`A. The Challenged Claims are not entitled to any priority date ................... 24
`B. Ground 1: PM’678 anticipates the Challenged Claims ............................ 57
`C. Ground 2: PM 2012 in view of PM’678 renders obvious the Challenged
`Claims ....................................................................................................... 63
`D. Ground 3: PM’678 (optionally together with PM 2012) in view of
`Dang’243 renders Challenged Claim 12 .................................................. 69
`E. Ground 4: Dang’243 Anticipates Claims 1-5 and 9-12 ........................... 69
`i
`
`
`
`

`

`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`IX. NO SECONDARY CONSIDERATIONS ........................................................ 75
`XI. CONCLUSION ................................................................................................. 75
`
`
`
`
`
`
`
`
`ii
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`
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`

`

`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`
`PETITIONER’S LIST OF EXHIBITS
`
`Exhibit Description
`
`1001
`1002
`1003
`1004
`1005
`1006
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`U.S. Patent No. 10,610,125 (“’125 Patent”)
`Excerpted Prosecution History of U.S. Patent No. 10,610,125
`Declaration of Professor David J. Sherman (“Sherman Dec.”)
`Curriculum Vitae of Professor David J. Sherman
`Declaration of Doctor Leslie Oleksowicz (“Oleksowicz Dec.”)
`Curriculum Vitae of Doctor Leslie Oleksowicz
`Mardis et al., Recurring Mutations Found by Sequencing an Acute
`Myeloid Leukemia Genome, 361 N. ENGL. J. MED. 1058 (2009).
`(“Mardis”)
`Vogelstein et al., U.S. Pat. App. Pub. No. 2011/0229479
`(“Vogelstein”)
`Dang et al., Int’l Pat. App. Pub. No. 2010/105243
`(“Dang ’243” or “2010 Application”)
`Popovici-Muller et al., Pat. App. Pub. No. 2012/009678
`(“PM ’678”)
`Popovici-Muller et al., Discovery of the First Potent Inhibitors of
`Mutant IDH1 That Lower Tumor 2-HG in Vivo, 3 ACS MED. CHEM.
`LETT. 850 (2012).
`(“PM 2012”)
`Zhao et al. Glioma-Derived Mutations in IDH1 Dominantly Inhibit
`IDH1 Catalytic Activity and Induce HIF-1α, 324 SCIENCE 261
`(2009).
`Tostmann et al., Protecting Chemistry Inventions: The Double-
`Edged Sword of Being an Unpredictable Art, 6 ACS MED. CHEM.
`LETT. 364-6 (2015).
`Golub et al., Mutant Isocitrate Dehydrogenase Inhibitors as
`Targeted Cancer Therapeutics, 9 FRONT. ONCOL. 417 (2019).
`(“Golub”)
`Parsons et al., An Integrated Genomic Analysis of Human
`Glioblastoma Multiform, SCIENCEXPRESS (2008). (“Parsons”)
`
`iii
`
`
`
`

`

`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`
`Exhibit Description
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`1024
`
`1025
`
`1026
`
`1027
`
`Yan et al., IDH1 and IDH2 Mutations in Gliomas, 360 N. ENGL. J.
`MED. 765 (2009).
`(“Yan”)
`Bleeker et al., IDH1 Mutations at Residue p.R132 (IDH1R132) Occur
`Frequently in High-Grade Gliomas But Not in Other Solid Tumors,
`30 HUMAN MUTATION 7 (2009).
`(“Bleeker”)
`Zernicka-Goetz et al., U.S. Pat. App. Pub. No. US 2003/0027783
`(“Zernicka-Goetz”)
`Kang et al., Mutational Analysis of IDH1 Codon 132 in
`Glioblastomas and Other Common Cancers, 125 INT. J. CANCER 353
`(2009).
`(“Kang”)
`U.S. Pat. App. No. 13/939,519, Excerpted Prosecution History
`(“ ’519 FH”)
`U.S. Pat. App. No. 13/256,396, Excerpted Prosecution History
`(“ ’396 FH”)
`Gross et al., Cancer-associated Metabolite 2-hydroxyglutarate
`Accumulates in Acute Myelogenous Leukemia With Isocitrate
`Dehydrogenase 1 and 2 Mutations, 207 J. EXP. MED. 339 (2010).
`(“Gross”)
`Salituro et al., Int’l Pat. App. Pub. No. 2011/072174
`Dang et al., Cancer-associated IDH1 Mutations Produce 2-
`hydroxyglutarate, 462 NATURE 739 (2009).
`(“Dang 2009”)
`U.S. Provisional Pat. App. No. 61/229,689, filed July 29, 2009
`(“July 29, 2009 Provisional”)
`Gottlieb et al., Int’l Pat. App. Pub. no. 2006/016143
`(“Gottlieb”)
`Shin et al., Catechin Gallates are NADP+-competitive Inhibitors of
`Glucose-6-phosphate Dehydrogenase and Other Enzymes that
`Employ NADP+ as a Coenzyme, 16 Bioorganic & Medicinal
`Chemistry (2008), 16, 3580-86
`
`iv
`
`
`
`

`

`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`
`Exhibit Description
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`1033
`1034
`
`1035
`
`1036
`
`1037
`
`Lee & Park, Oxalomalate Regulates Ionizing Radiation-Induced
`Apoptosis in Mice, 42 FREE RADICAL BIO. & MED. 44-51 (2007).
`(“Lee & Park”)
`Korean Pat. App. Pub. no. 10-2005-0036293 A, provided with
`English-language abstract and translation
`Brock, Generation and Phenotypic Characterization of Aspergillus
`nidulans Methylisocitrate Lyase Deletion Mutants: Methylisocitrate
`Inhibits Growth and Conididation, 71 APPLIED & ENV’TAL
`MICROBIO. 5465-75 (2015).
`(“Brock”)
`Korean Pat. App. Pub. no. 10-2002-0095553 A, provided with
`English-language abstract and translation
`Einat et al., U.S. Pat. App. Pub. No. 2004/0067234
`Koh et al., Int’l Pub. No. WO 02/33063
`Pirrung et al., O-Alkyl Hydroxamates as Metaphors of Enzyme-
`Bound Enolate Intermediates in Hydroxy Acid Dehydrogenases.
`Inhibitors of Isopropylmalate Dehydrogenase, Isocitrate
`Dehydrogenase, and Tartrate Dehydrogenase, 61 J. ORG. CHEM.
`4527-4531 (1996).
`(“Pirrung”)
`Ingebretsen, Mechanism of the Inhibitory Effect of Glyoxylate Plus
`Oxaloacetate and Oxalomalate on the NADP-Specific Isocitrate
`Dehydrogenase, 452 BIOCHIMICA ET BIOPHYSICA ACTA 302-9
`Enzymology (1976).
`Plaut et al., α-Methylisocitrate: A Selective Inhibitor of TPN-Linked
`Isocitrate Dehydrogenase From Bovine Heart and Rat Liver, 250 J.
`BIOL. CHEM. 6351-4 (1975).
`(“Plaut”)
`Marr & Weber, Feedback Inhibition of an Allosteric
`Triphosphopyridine Nucleotide-specific Isocitrate Dehydrogenase,
`244 J. BIOL. CHEM. 5709-12 (1969).
`(“Marr & Weber”)
`
`v
`
`
`
`

`

`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`
`Exhibit Description
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`1044
`1045
`1046
`1047
`1048
`1049
`1050
`
`Duan et al., Discovery of DC_H31 as Potential Mutant IDH1
`Inhibitor Through NADPH-based High Throughput Screening, 27
`BIOORGANIC. & MEDICINAL CHEM. 3229-36 (2019).
`(“Duan”)
`Pelosi et al., Isocitrate Dehydrogenase Mutations in Human
`Cancers: Physiopathological Mechanisms and Therapeutic
`Targeting, 1 J. EXPL. RSCH. PHARMACOLOGY 20-34 (2016).
`(“Pelosi”)
`Chaturvedi et al., In Vivo Efficacy of Mutant IDH1 Inhibitor HMS-
`101 and Structural Resolution of Distinct Binding Site, 34 Leukemia
`416-26 (2020).
`(“Chaturvedi”)
`Heuser et al., Safety and Efficacy of BAY1436032 in IDH1-mutant
`AML: Phase 1 Study Results, 34 LEUKEMIA 2903-13 (2020).
`(“Heuser”)
`NAT’L CANCER INST., Pan-mutant-IDH1 Inhibitor BAY1436032,
`https://www.cancer.gov/publications/dictionaries/cancer-drug/
`def/pan-mutant-idh1-inhibitor-bay-1436032 (last visited Aug. 15,
`2022).
`(“NCI”)
`U.S. Provisional Pat. App. No. 61/160,253, filed March 13, 2009
`U.S. Provisional Pat. App. No. 61/160,664, filed March 16, 2009
`U.S. Provisional Pat. App. No. 61/173,518, filed April 28, 2009
`U.S. Provisional Pat. App. No. 61/180,609, filed May 22, 2009
`U.S. Provisional Pat. App. No. 61/220,543, filed June 25, 2009
`U.S. Provisional Pat. App. No. 61/227,649, filed July 22, 2009
`U.S. Provisional Pat. App. No. 61/253,820, filed October 21, 2009
`U.S. Provisional Pat. App. No. 61/266,929, filed December 4, 2009
`
`vi
`
`
`
`

`

`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`
`Exhibit Description
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`
`
`Matteo et al., Molecular Mechanisms of Isocitrate Dehydrogenase 1
`(IDH1) Mutations Identified in Tumors: The Role of Size and
`Hydrophobicity at Residue 132 on Catalytic Efficiency, 292 J. BIOL.
`CHEM. 7971-83 (2017).
`Frezza et al. IDH1 Mutations in Gliomas: When an Enzyme Loses its
`Grip, 17 Cancer Cell 7-9 (2010).
`(“Frezza”)
`FDA, GLEEVEC® PRESCRIBING INFORMATION (2022)
`https://www.accessdata.fda.gov/drugsatfda_docs/label/
`2008/021588s024lbl.pdf.
`Biomarkers, KIT Mutation, MY CANCER GENOME,
`https://www.mycancergenome.org/content/alteration/kit-
`mutation/#:~:text=KIT%20Mutation%20is%20present%20in,
`the%20greatest%20prevalence%20%5B4%5D. (last visited Aug. 14,
`2022).
`BRAFTOVI® Prescribing Information, PFIZER,
`https://labeling.pfizer.com/ShowLabeling.aspx?id=12990 (last
`visited Aug. 14, 2022).
`Turski et al., Genomically Driven Tumors and Actionability Across
`Histologies: BRAF-Mutant Cancers as a Paradigm, 15 MOL.
`CANCER. THER. 533-47 (2016).
`(“Turski”)
`Kumar et al. Genetic Abnormalities and Challenges in the Treatment
`of AML, 2 GENES & CANCER 95-107 (2011).
`(“Kumar”)
`Popovici-Muller et al., Discovery of AG-120 (Ivosidenib): A First-in-
`Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant
`Cancers, 9 ACS MED. CHEM. LETT. 300-5 (2018).
`(“PM 2018”)
`
`vii
`
`
`
`

`

`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`
`I.
`
`INTRODUCTION
`
`Petitioner respectfully requests inter partes review (“IPR”) of Claims 1-5
`
`and 9-12 (the “Challenged Claims”) of U.S. Patent No. 10,610,125 (EX1001, “the
`
`’125 Patent”).
`
`The ’125 Patent purports to claim the use of any IDH1 inhibitor in the
`
`treatment of IDH1-mutant Acute Myeloid Leukemia (“AML”). However, the
`
`Challenged Claims of the ’125 Patent are not entitled to the claims of priority to
`
`applications filed in 2010 and earlier, because the applications filed at those times
`
`do not provide sufficient written description to support the broad Challenged
`
`Claims. Accordingly, because the Challenged Claims of ’125 Patent cannot be
`
`entitled to any priority dates before July 11, 2013, they are invalid over 2012
`
`publications by Popovici-Muller, and over a 2011 publication to Dang (which is
`
`the publication of the international application of which the ’125 Patent is a
`
`grandchild continuation).
`
`The Board should institute trial and cancel the Challenged Claims.
`
`1
`
`
`
`

`

`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`
`II. MANDATORY NOTICES
`
`A. Real Party-In-Interest (37 C.F.R. §42.8(b)(1))
`
`The petitioner in this proceeding is Rigel Pharmaceuticals, Inc. (“Rigel” or
`
`“Petitioner”) and Rigel is the real party-in-interest. There are no other real parties-
`
`in-interest.
`
`B. Related Matters (37 C.F.R. §42.8(b)(2))
`
`Petitioner identifies U.S. Provisional Patent Applications Nos. 61/160,253;
`
`61/160,665; 61/173,518; 61/180,609; 61/220,543; 61/227,649; 61/229,689;
`
`61/253,820; and 61/266,929 (all lapsed); International Patent Application no.
`
`PCT/US2010/027253 (lapsed); and U.S. Patent Applications No. 13/256,396
`
`(abandoned); 13/443,012 (abandoned); 13/939,519 (abandoned); and 16/790,860
`
`(pending) as related administrative matters.
`
`There are no district court or other inter partes review proceedings currently
`
`involving the ’125 Patent or its Related Matters.
`
`C. Counsel (37 C.F.R. §42.8(b)(3)) and Service Information (37
`C.F.R. §42.8(b)(3)-(4))
`
`Petitioner designates Paul H. Berghoff (Reg. No. 30,243) as lead counsel for
`
`this matter, and designates James L. Lovsin (Reg. No. 69,550) and James V. Suggs
`
`(Reg. No. 50,419) as back-up counsel for this matter.
`
`2
`
`
`
`

`

`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`Post mailings and hand deliveries for lead and back-up counsel should be
`
`addressed to: McDonnell Boehnen Hulbert and Berghoff LLP, 300 South Wacker
`
`Drive, Chicago, IL, 60606. (Telephone: 312-913-0001; Fax: 312-913-0002).
`
`Pursuant to 37 C.F.R. §42.8(b)(4), Petitioner consents to e-mail service at:
`
`docketing@mbhb.com, and RigelIPR@mbhb.com.
`
`For compliance with 37 C.F.R. §42.10(b), a Power of Attorney is filed
`
`concurrently herewith.
`
`III. PAYMENT OF FEES
`
`The undersigned authorizes the Office to charge the fee required by 37
`
`C.F.R. §42.15(a) and any additional fees to Deposit Account 132490.
`
`IV. REQUIREMENTS FOR IPR
`
`A. Grounds for Standing
`
`Petitioner certifies that the ’125 Patent is available for IPR and that
`
`Petitioner is not barred or estopped from requesting IPR on the following grounds.
`
`3
`
`
`
`

`

`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`
`Identification of Challenge
`
`B.
`
`1.
`
`The Specific Art on Which the Challenge is Based
`
`This Petition relies on the prior art identified below.1 This Petition also
`
`relies on expert declarations of Professor David J. Sherman (EX1003; CV of
`
`Professor Sherman provided as EX1004) and Doctor Leslie Oleksowicz (EX1005;
`
`CV of Doctor Oleksowicz provided as EX1006).
`
`Name
`
`Exhibit
`
`Relevant Date(s)
`
`Prior Art category
`
`Dang’243
`
`PM’678
`
`PM 2012
`
`1009
`
`1010
`
`1011
`
`September 2010
`
`§102(a)(1)
`
`January 2012
`
`§102(a)(1)
`
`September 2012
`
`§102(a)(1)
`
`2.
`
`Statutory Grounds on Which the Challenge is Based
`
`The above-identified prior art renders the Challenged Claims unpatentable
`
`based on the following grounds:
`
`
`
`
`1 These references have publication dates after March 13, 2009, the earliest priority
`
`date claimed by the ’125 Patent. Petitioner describes in Section VII, infra, that the
`
`Challenged Claims are not entitled to the 2009 and 2010 priority dates.
`
`4
`
`
`
`

`

`Ground
`
`Statute
`
`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`
`Art Cited
`
`Claims Challenged
`
`1
`
`2
`
`3
`
`4
`
`35 U.S.C. §102
`
`PM’678
`
`35 U.S.C. §103
`
`35 U.S.C. §102
`
`PM 2012 in view
`of PM’678
`
`PM’678, or PM
`2012 in view of
`PM’678, in view of
`Dang’243
`
`35 U.S.C. §102 Dang’243
`
`
`1-5 and 6-12
`
`1-5 and 6-12
`
`12
`
`1-5 and 6-12
`
`3.
`
`Discretionary Denial is Not Warranted
`
`Petitioner respectfully submits that the Board should not exercise its
`
`discretion under 35 U.S.C. §§314(a) or 325(d) to deny this Petition.
`
`a)
`
`No prior petitions or parallel litigation
`
`The ’125 Patent has not been challenged in any prior IPR petition, and
`
`Patent Owner has not asserted the ’125 Patent against Petition in any co-pending
`
`litigation. As such, none of the discretionary factors in General Plastic Indus. Co.,
`
`Ltd. v. Canon Kabsuhiki Kaisha, IPR2016-01357, Paper 19 at 16 (PTAB Sep., 6,
`
`2016) (Section II.B.4.i precedential) or in Apple Inc. v. Fintiv, Inc., IPR2020-0019,
`
`Paper 11 (PTAB Mar. 20, 2020) applies to this Petition, therefore discretionary
`
`denial under §§314 and 325(d) is not warranted.
`
`5
`
`
`
`

`

`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`
`The Advanced Bionics test favors institution
`
`b)
`
`The Petition satisfies the two-part test of Advanced Bionics, LLC v. Med-El
`
`Elektromedizinische Gerate GMBH, IPR2019-01469, Paper 6 at 8 (PTAB Feb. 13,
`
`2020) (precedential). First, none of the evidence and arguments in the Petition that
`
`the Challenged Claims are not entitled to any priority date was previously presented
`
`to or otherwise considered by the Office. The ’125 Patent issued from U.S. Patent
`
`Application No. 15/589,615 (“the ’615 Application”). The Examiner never
`
`addressed the ’615 Application’s priority claim on the record during examination
`
`and there is “no basis to presume” that the ’615 Application is “necessarily entitled
`
`to the filing date of its provisional application.” Dynamic Drinkware, LLC v.
`
`National Graphics, Inc., 800 F.3d 1375, 1380 (Fed. Cir. 2015).
`
`Moreover, while U.S. Patent Application Publication 2013/0184222 was cited
`
`during prosecution, the corresponding international publication, Popovici-Muller et
`
`al., WO 2012/009678 (“PM’678”) was not; this difference is critical, as the
`
`publication date of the document cited during prosecution was after the July 11,
`
`2013 Application filing date, while the PM’678 publication was more than a year
`
`before. Accordingly, the Grounds raised by this Petition are not the same or
`
`substantially the same as the arguments raised during the prosecution of the ’125
`
`Patent.
`
`6
`
`
`
`

`

`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`Second, even if one assumes arguendo that the arguments in the Petition were
`
`previously presented or substantially the same (they were not), the Examiner erred in
`
`a manner material to the patentability of the Challenged Claims. As a critical
`
`example, the Examiner committed errors of law by misapplying Federal Circuit case
`
`law regarding the lack of written description of genus claims with respect to these
`
`genus applications in determining the proper effective filing date of the claims,
`
`including Idenix Pharm. LLC v. Gilead Sci. Inc., 941 F.3d 1149 (Fed. Cir. 2019)
`
`and Abbvie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285
`
`(Fed. Cir. 2014). During prosecution of the ’125 Patent, the Examiner also did not
`
`have the benefit of Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330
`
`(Fed. Cir. 2021) (invalidating genus claims for lack of written description).
`
`Accordingly, the Examiner did not properly assess the content of the disclosure of
`
`the 2009 and 2010 priority applications in comparison to the claims and failed to
`
`determine that the claims were not entitled to early priority dates.
`
`Without an understanding of any proper priority date, the Office did not
`
`properly consider the teachings of Dang’243, PM’678 and PM 2012 from among the
`
`hundreds references cited. Thus, the Board should not exercise its discretion to deny
`
`institution of this Petition under §325(d).
`
`7
`
`
`
`

`

`U.S. Patent No. 10,610,125
`Petition for Inter Partes Review – IPR2022-01423
`
`
`V. BACKGROUND
`
`A. Overview of Technology
`
`Isocitrate dehydrogenase 1 (“IDH1,” found in the cytosol and peroxisomes)
`
`and isocitrate dehydrogenase 2 (“IDH2,” found in mitochondria) are homodimeric
`
`isoenzymes involved in a major pathway for cellular NADPH generation through
`
`the oxidative decarboxylation of isocitrate to α-ketoglutarate (“αKG”). EX1014, 2.
`
`Sherman Dec., ¶ 55.
`
`Mutations of IDH1 and IDH2 were identified in various brain tumors in
`
`2008 and early 2009, and in August 2009 mutations of IDH1 were identified in
`
`AML patient samples. See, e.g., EX1007, 7-8; EX1015, 1; 1017, 1, 4; 1016, 1-2.
`
`The mutation in IDH generates an oncometabolite product, 2-hydroxyglutarate
`
`(“2HG”), which has more recently been linked to the disruption of metabolic and
`
`epigenetic mechanisms responsible for cellular differentiation and is understood to
`
`be an early and critical contributor to oncogenesis. Id. at 2. Sherman Dec., ¶ 56.
`
`In recent times, two mutant IDH inhibitors ivosidenib, (mutant IDH1
`
`inhibitor) and enasidenib (mutant IDH2 inhibitor), have been FDA-approved for
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`IDH-mutant relapsed or refractory acute myeloid leukemia (AML) based on phase
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`1 safety and efficacy data and continue to be studied in clinical trials in relating to
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`malignancies, as well as in glioma, cholangiocarcinoma, and chondrosarcoma.
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`EX1014, 9. Sherman Dec., ¶ 57.
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`B.
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`The ’125 Patent
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`The ’125 Patent relates generally to “[m]ethods of treating and evaluating
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`subjects having neoactive mutants.” EX1001, Abstract. The inventors assert that
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`they “have discovered, inter alia, a neoactivity associated with IDH [i.e., isocitrate
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`dehydrogenase] mutants and that the product of the neoactivity can be significantly
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`elevated in cancer cells.” Id. at 1:52-54. They further assert the discovery “that
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`certain mutated forms of an enzyme (e.g., IDH1 or IDH2) have a gain of function,
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`referred to as a neoactivity, which can be targeted in the treatment of a cell
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`proliferation-related disorder such as cancer.” Id. at 38:29-33. The lone
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`independent claim recites:
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`1. A method of treating a subject having acute myelogenous leukemia
`(AML) characterized by the presence of a mutant isocitrate
`dehydrogenase 1 enzyme (IDH1) or a mutant isocitrate dehydrogenase
`2 enzyme (IDH2), wherein the mutant IDH1 or mutant IDH2 has the
`ability to convert alpha-ketoglutarate to 2-hydroxyglutarate (2HG),
`the method comprising administering to the subject a therapeutically
`effective amount of a small molecule inhibitor of said mutant IDH1 or
`mutant IDH2.
`
` Id. at 431:57-67. Sherman Dec., ¶ 58.
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`U.S. Patent No. 10,610,125
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`The ’125 Patent specification begins with a single paragraph background
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`section that identifies the biochemical role of isocitrate dehydrogenases. EX1001,
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`1:30-45. The Summary of the Invention section begins with a statement that “[t]he
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`inventors have discovered, inter alia, a neoactivity associated with IDH mutants
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`and that the product of the neoactivity can be significantly elevated in cancer
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`cells.” Id. at 1:52-54. Generally, “[d]isclosed herein are methods and
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`compositions for treating, and methods of evaluating, subjects having or at risk for
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`a disorder, e.g., a cell proliferation-related disorder characterized by a neoactivity
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`in a metabolic pathway enzyme, e.g., IDH neoactivity.” Id. at 1:55-59. The
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`inventors surmise a general underlying mechanism:
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`While not wishing to be bound by theory it is believed that the
`balance between the production and elimination of neoactive product,
`e.g., 2HG, e.g., R-2HG, is important in disease. Neoactive mutants, to
`varying degrees for varying mutations, increase the level of neoactive
`product, while other processes, e.g., in the case of 2HG, e.g., R-2HG,
`enzymatic degradation of 2HG, e.g., by 2HG dehydrogenase, reduce
`the level of neoactive product. An incorrect balance is associated with
`disease. In embodiments, the net result of a neoactive mutation at
`IDH1 or IDH2 result in increased levels, in affected cells, of neoactive
`product, 2HG, e.g., R-2HG,
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`Id. at 2:29-40. Sherman Dec., ¶ 59.
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`Columns 2-33 provide a series of repetitive “embodiments” and “aspects”
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`that set out various methods of treatment and methods for diagnosis of cell-
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`proliferation disorders characterized by a somatic mutation in a metabolic pathway
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`enzyme. This section begins with:
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`Accordingly, in one aspect, the invention features, a method of
`treating a subject having a cell proliferation-related disorder, e.g., a
`disorder characterized by unwanted cell proliferation, e.g., cancer, or a
`precancerous disorder. The cell proliferation-related disorder is
`characterized by a somatic mutation in a metabolic pathway enzyme.
`The mutation is associated with a neoactivity that results in the
`production of a neoactivity product. The method comprises:
`administering to the subject a therapeutically effective amount of a
`therapeutic agent described herein, e.g., a therapeutic agent that
`decreases the level of neoactivity product encoded by a selected or
`mutant somatic allele, e.g., an inhibitor of a neoactivity of the
`metabolic pathway enzyme (the neoactive enzyme), a therapeutic
`agent that ameliorates an unwanted affect [sic] of the neoactivity
`product, or a nucleic acid based inhibitor, e.g., a dRNA which targets
`the neoactive enzyme mRNA, to thereby treat the subject.
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`EX1001, 4157. The “embodiments” following this recite a number of metabolic
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`pathways, mutations, mutant IDH1 and IDH2 species, general types of therapeutic
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`agents, and disorders to be treated. Id. at 2:58-33:54. Sherman Dec., ¶ 60.
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`The Detailed Description section focuses on mutant IDH1 and mutant IDH2
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`that have a particular “neoactivity” – the ability to convert αKG to 2HG. EX1001,
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`38:29-40:52. Detection of 2HG in patients is described as a way to diagnose,
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`prognose, select an inhibitor or monitor treatment efficacy. Id. at 40:53-43:31.
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`Sherman Dec., ¶ 61.
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`Methods of treatment are described:
`
`Described herein are methods of treating a cell proliferation-related
`disorder, e.g., a cancer, e.g., a glioma, e.g., by inhibiting a neoactivity
`of a mutant enzyme, e.g., an enzyme 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.,
`IDH1 or IDH2. The cancer can be characterized by the presence of a
`neoactivity, such as a gain of function in one or more mutant enzymes
`(e.g., an enzyme in the 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., IDH1 or IDH2). In some
`embodiments, the gain of function is the conversion of α-ketoglutarate
`to 2-hydroxyglutarate, e.g., R-2-hydroxyglutarate.
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`EX1001, 43:31-48. Sherman Dec., ¶ 62.
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`The specification then purports to describe suitable compounds for
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`therapeutic use. A number of general methods for identifying suitable compounds
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`are provided. EX1001, 43:49-44:51. “Compounds that inhibit a neoactivity, e.g., a
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`neoactivity described herein, can include, e.g., small molecule, nucleic acid,
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`protein and antibody.” Id. at 44:52-54. Small molecules are described:
`
`Exemplary small molecules include, e.g, small molecules that bind to
`enzymes and decrease their activity, e.g., a neoactivity described
`herein. The binding of an inhibitor can stop a substrate from entering
`the enzyme's active site and/or hinder the enzyme from catalyzing its
`reaction. Inhibitor binding is either reversible or irreversible.
`Irreversible inhibitors usually react with the enzyme and change it
`chemically. These inhibitors can modify key amino acid residues
`needed for enzymatic activity. In contrast, reversible inhibitors bind
`non-covalently and different types of inhibition are produced
`depending on whether these inhibitors bind the enzyme, the enzyme-
`substrate complex, or both.
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`Id. at 44:55-67. The specification exemplifies micromolar-range inhibition of
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`enzyme αKG2HG activity by five compounds of four different structural
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`classes; and provides a measurement of isocitrateαKG activity by oxalomalate.
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`Id. at 72:30-54, 122:38-125:29. Oxalosuccinate and oxalofumarate are also
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`suggested as inhibitors, as are two chemical genera and 92 compounds apparently
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`falling into one of the genera. Id. at 45:1-67, 125:30-148:67. Moreover, a list of
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`references disclosing several wild-type IDH inhibitors is provided; these are said to
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`be “[e]xemplary candidate compounds, which can be tested for inhibition of a
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`neoactivity described herein (e.g., a neoactivity associated with mutant IDH1).”
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`Id. 46:16-31. However, no such testing is provided. Nucleic acids are also
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`described. Id. at 49:51-56:44. Sherman Dec., ¶ 63.
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`A general discussion of pharmaceutical formulations and combination
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`therapies are provided. EX1001, 56:45-66:39, 69:36-47. Sherman Dec., ¶ 64.
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`The specification suggests that a wide variety of disorders can be treated or
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`evaluated by the methods described, including virtually any kind of cancer.
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`EX1001, 66:40-69:35. Sherman Dec., ¶ 65.
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`The specification concludes with a number of examples. Examples 1 and 2
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`explore the biochemistry of mutant IDH1, including the identification of the
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`“neoactivity” of the conversion of αKG to 2HG. EX1001, 69:51-84:26. Example
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`3 provide suggestions for metabolomics analysis of IDH1 and for evaluation of
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`IDH1 as a cancer target. Id. at 84:28-61. Example 5 describes a variety if siRNAs
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`that “can be evaluated” for the ability to silence a mutated IDH. Id. at 84:63-
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`113:17. Example 6 describes the solving of a crystal structure of IDH1R132H
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`bound to αKG, NADPH and Ca2+. Id. at 113:18-122:35. Example 9 provides
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`U.S. Patent No. 10,610,125
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`compounds as described above. Id. at 122:37-144:67. Example 10 describes the
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`NADPH catalytic activity of IDH2R172K. Id. at149:1-16. Example 11 describes
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`that 2HG accumulates in AML with IDH mutations. Id. at 149:17-155:17; 156:1-
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`17. The rest of the specification is a sequence listing. Id. at cols. 156-432.
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`Sherman Dec., ¶ 66.
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`C.
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`Prosecution History of the ’125 Patent
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`1.
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`Prosecution History of the ’125 Patent Itself
`
`A copy of the file history of the ’125 Patent is provided as EX1002. The
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`underlying patent application was filed on May 8, 2017. EX1002, 1238, 274,
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`1472. It is a great-grandchild through two intervening continuations of a U.S.
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`National Stage entry of a PCT application filed in 2010, which in turn claims
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`priority to nine provisional applications going back to an earliest claimed priority
`
`date of March 13, 2009. EX1002, 1468.
`
`The originally-filed claims were similar to claim 1 of the ’125 Patent as
`
`issued, but recited treatment of “a cancer” instead of AML, using “an inhibitor”
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`instead of “a small molecule inhibitor.” Id. at 1460. In the first Office Action, the
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`Examiner rejected most of the claims as being obvious, primarily over Zernicka-
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`Goetz (provided as EX1018), which teaches therapy of cancers having mutated
`
`genes by inhibiting gene expression with a double-stranded RNA inhibitor, in view
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`U.S. Patent No. 10,610,125
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`of Yan, which teaches that mutant IDH1, present in certain cancers like certain
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`gliomas, has the ability to convert alpha-ketoglutarate to 2-hydroxyglutarate
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`(“2HG”). EX1002, 165-170.
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`In response, the Applicant amended the claims to recite the use of “small
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`molecule” inhibitors, noting that the definition in the text limited “small
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`molecules” to less than 1000 Da in molecular weight. Id. at 156, 158-160.
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`In a second Office Action, the Examiner based prior art reje