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
`________________________________
`
`DECLARATION OF DR. LESLIE OLEKSOWICZ
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
`U.S. PATENT NO. 10,610,125
`
`
`
`
`Rigel Exhibit 1005
`Page 1 of 63
`
`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`TABLE OF CONTENTS
`
`LIST OF EXHIBITS REFERENCED IN DECLARATION .................................. iii
`INTRODUCTION ............................................................................................... 1
`I.
`II. BACKGROUND AND QUALIFICATIONS .................................................... 2
`III. MATERIALS CONSIDERED ........................................................................... 5
`IV. MY UNDERSTANDING OF CERTAIN LEGAL STANDARDS ................... 6
`A. Ordinary Skill in the Art ............................................................................. 6
`B. Claim Construction ..................................................................................... 7
`C. Prior Art and Priority .................................................................................. 8
`V. BACKGROUND ............................................................................................... 10
`A. Overview of Technology .......................................................................... 10
`B. The ’125 Patent ......................................................................................... 17
`C. Technical Background and Prior Art ........................................................ 24
`1. Parsons .................................................................................................. 24
`2. Bleeker .................................................................................................. 25
`3. Kang ...................................................................................................... 26
`4. Yan ........................................................................................................ 27
`5. Zhao ...................................................................................................... 28
`6. Mardis ................................................................................................... 29
`7. Vogelstein ............................................................................................. 31
`8. Dang 2009............................................................................................. 33
`VI. A PERSON OF ORDINARY SKILL IN THE RELEVANT FIELD IN THE
`RELEVANT TIMEFRAME ............................................................................ 36
`VII. CLAIM CONSTRUCTION .............................................................................. 37
`VIII. SUMMARY OF MY OPINIONS ................................................................... 37
`IX. THE CHALLENGED CLAIMS ARE NOT ENTITLED TO ANY PRIORITY
`DATE EARLIER THAN JULY 11, 2013 ....................................................... 38
`i
`
`Rigel Exhibit 1005
`Page 2 of 63
`
`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`A. The state of the art as of March 2010 ....................................................... 38
`B. The scope of the Challenged Claims is broad .......................................... 42
`C. The disclosure of the 2010 Application does not provide sufficient
`information to demonstrate possession of methods for treating IDH1-
`mutant AML ............................................................................................. 44
`
`
`
`
`
`
`ii
`
`
`
`Rigel Exhibit 1005
`Page 3 of 63
`
`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`
`
`LIST OF EXHIBITS REFERENCED IN DECLARATION
`
`1008
`
`1009
`
`1010
`
`1011
`
`Exhibit Description
`1001
`U.S. Patent No. 10,610,125 (“’125 Patent”)
`1002
`Excerpted Prosecution History of U.S. Patent No. 10,610,125
`1005
`Declaration of Doctor Leslie Oleksowicz (“Oleksowicz Dec.”)
`1006
`Curriculum Vitae of Doctor Leslie Oleksowicz
`1007 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., Int’l 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).
`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”)
`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”)
`
`1012
`
`1014
`
`1015
`
`1016
`
`1017
`
`iii
`
`
`
`Rigel Exhibit 1005
`Page 4 of 63
`
`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`1024
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1022
`
`Exhibit Description
`1019
`Kang et al., Mutational Analysis of IDH1 Codon 132 in Glioblastomas
`and Other Common Cancers, 125 INT. J. CANCER 353 (2009).
`(“Kang”)
`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”)
`Dang et al., Cancer-associated IDH1 Mutations Produce 2-
`hydroxyglutarate, 462 NATURE 739 (2009).
`(“Dang 2009”)
`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%20
`in,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”)
`
`1057
`
`1058
`
`
`
`iv
`
`
`
`Rigel Exhibit 1005
`Page 5 of 63
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`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`I, Dr. Leslie Oleksowicz, declare as follows:
`
`I
`
`INTRODUCTION
`
`1.
`
`I have been retained by Petitioner Rigel Pharmaceuticals, Inc.
`
`(“Rigel”) as a technical expert witness to provide my independent opinions in
`
`connection with a petition for inter partes review (“IPR”) of U.S. Patent No.
`
`10,610,125 (“the ’125 Patent,” EX1001) before the Patent Trial and Appeal Board
`
`(“Board”). I understand that the ’125 Patent is currently assigned to Servier
`
`Pharmaceuticals LLC (“Patent Owner”).
`
`2.
`
`I have been asked by Rigel to offer opinions on the ’125 Patent,
`
`including whether Claims 1-5 and 9-12 are entitled to their 2009 and 2010 Priority
`
`Dates. This Declaration sets forth the opinions I have reached to date regarding
`
`these matters.
`
`3.
`
`I am being compensated at my standard hourly consulting rate of $500
`
`for my time spent in this matter. My compensation is not contingent on the
`
`outcome of the IPR or on the substance of my opinions.
`
`4.
`
`I have no financial interest in Rigel or Patent Owner.
`
`5. My opinions and the bases for my opinions are set forth below.
`
`1
`
`
`
`Rigel Exhibit 1005
`Page 6 of 63
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`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`II. BACKGROUND AND QUALIFICATIONS
`
`6.
`
`I am a 33-year veteran of academic medicine, a key opinion leader in
`
`Medical Oncology, and a board-certified Hematologist/Oncologist, holding a rank
`
`of Professor of Medicine. I have served on the faculties of Mount Sinai Cancer
`
`Center in New York City, Montefiore/Albert Einstein College of Medicine,
`
`Roswell Park Cancer Institute, The University of Cincinnati Cancer Institute, Saint
`
`Louis University Cancer Center, and the Dana Farber Cancer Institute in Boston.
`
`7.
`
`I received a B.A. degree in biology from Amherst College in 1978 and
`
`an M.D. degree from Tufts University School of Medicine in 1982. I completed
`
`my residency in internal medicine at the Montefiore Hospital/Albert Einstein
`
`College of Medicine. I also completed fellowships in hematology and medical
`
`oncology at the Mount Sinai Medical Center. I am board certified in both internal
`
`medicine and medical oncology.
`
`8.
`
`I have worked as a professor of medicine and/or attending oncologist
`
`at the University of Cincinnati Hospital, Saint Louis University Medical Center,
`
`and the Dana Farber Cancer Institute, among other medical centers.
`
`9.
`
`I have been a member of the American Society of Clinical Oncology
`
`and the American Society of Hematology.
`
`2
`
`
`
`Rigel Exhibit 1005
`Page 7 of 63
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`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`10.
`
`I have worked on more than 100 clinical trials. I was the principal
`
`investigator for the following clinical trials focused on Acute Myeloid Leukemia
`
`(AML): Cytarabine and Daunorubicin in treating older patients with AML;
`
`Lenalidomide in Treating Older patients with AML; Studies in Leukemia Patients
`
`Ancillary; Leukemia Centralized Reference Laboratories and Tissue Repositories,
`
`Ancillary; A Phase II Study of Lenalidomide for Previously Untreated Non-M3,
`
`Deletion 5q Acute AML in Patients age 60 or Older Who Decline Remission
`
`Induction Chemotherapy; Azacitidine and Gemtuzumab in Treating Older Patients
`
`with Previously Untreated AML; A Phase II Trial of Azacitidine plus Gentuzumab
`
`as Induction and Post-Remission Therapy in Patients older than 60 and older with
`
`Previously Untreated non-M3 Acute Myeloid Leukemia; Study of Bone Marrow
`
`and Blood Samples from Patients with Leukemia or Other Hematopoietic cancers;
`
`. Additionally, I was co-investigator for the following clinical trials focused on
`
`AML: Cytarabine and Daunorubicin with or without Gemtuzumab followed by HD
`
`Cytarabine and either Gemtuzumab in de Novo AML; Lenalidomide in treating
`
`older patients with AML.
`
`11.
`
`I have delivered lectures on AML as well, such as “Characterizations
`
`of Immunorelated GPIb Expression by Myelogenous Leukemia Cells” at the
`
`National Leukemia Research Association Annual Meeting; “Review of novel
`3
`
`
`
`Rigel Exhibit 1005
`Page 8 of 63
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`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`Agents in AML” to the University of Cincinnati Division of
`
`Hematology/Oncology during Grand Rounds; and “Using genomic profiling in
`
`selecting optimal treatment in AML” to the University of Cincinnati Division of
`
`Hematology/Oncology during Grand Rounds.
`
`12. Additional information regarding my background, qualifications,
`
`publications, and presentations is included as part of my curriculum vitae (“CV”),
`
`which is included in EX1006.
`
`13.
`
`I have served as an expert witness in several Intellectual Property
`
`matters spanning form 2014 through 2020. Specifically, in 2014, I served as an
`
`expert witness in Par Sterile Products LLC/Accord Health Care Inc. v. Novartis, on
`
`the side of the patent owner involving a dispute over Zomenta®. In 2015 through
`
`2016, I served as an expert witness retained by Perkins Coie LLP, to submit expert
`
`declarations in two patent disputes, one between Mylan Pharmaceuticals Inc. and
`
`AstraZeneca and the other between Dr. Reddy’s Laboratories and Celgene. In
`
`2017 I served as an expert witness for Genentech in a matter involving the drug
`
`Herceptin® against Hospira and Amgen. In 2018 I was retained by Springings
`
`Intellectual Property Law Firm to opine in a patent dispute between Celgene and
`
`Dr. Reddy’s Laboratories involving the drug Revlamid® used to treat a variety of
`
`hematologic malignancies. In 2018, I also was retained by Irell and Manella LLP,
`4
`
`
`
`Rigel Exhibit 1005
`Page 9 of 63
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`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`to provide a declaration regarding the drug Rituxan® to treat B-cell malignancies
`
`in a dispute between Genentech/Biogen and Pfizer. More recently, in 2020 I was
`
`retained by Kasowitz, Benson and Torres LLP, to provide expert reports regarding
`
`ibrutinib for the treatment of Mantel cell lymphoma in a dispute between Zydus
`
`Pharmaceuticals and Pharmacyclics (now AbbVie).
`
`14. Based on my experiences described above, and as indicated in my
`
`CV, I am qualified to provide the following opinions regarding the ’125 Patent.
`
`III. MATERIALS CONSIDERED
`
`15.
`
`In forming my opinions, in addition to my education, knowledge, and
`
`experience, I have reviewed and considered the ’125 Patent and each of the
`
`documents and items listed in the List of Exhibits above and the other documents
`
`cited in my Declaration.
`
`16. The opinions I have set forth in this Declaration are not exhaustive of
`
`my opinions regarding the Challenged Claims of the ’125 Patent. Thus, the fact
`
`that I do not address a particular point should not be understood to indicate that any
`
`issued claim of the ’125 Patent is patentable and/or complies with the requirements
`
`of any applicable patent law, patent rule, or any other applicable statute, case law,
`
`or rule.
`
`5
`
`
`
`Rigel Exhibit 1005
`Page 10 of 63
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`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`17.
`
`I reserve the right to amend and supplement this Declaration based on
`
`consideration of additional evidence, arguments, or testimony presented during this
`
`IPR or during any other proceedings related to the ’125 Patent.
`
`IV. MY UNDERSTANDING OF CERTAIN LEGAL STANDARDS
`
`18.
`
`I am not a legal expert and offer no opinions on the law. However, I
`
`have been informed by counsel of the various legal standards that apply, some of
`
`which I have set forth my understanding below, and I have applied these standards
`
`in arriving at my conclusions.
`
`19.
`
`I understand that for a claim to be found unpatentable in this
`
`proceeding, Petitioner must prove that the claim is unpatentable by a
`
`preponderance of the evidence. Put another way, Petitioner must show the claim is
`
`more likely than not anticipated or obvious in light of prior art.
`
`A. Ordinary Skill in the Art
`
`20. My opinions in this Declaration are based on, and applied from the
`
`perspective of, an understanding of a person of ordinary skill in the art, which I
`
`understand is typically referred to by the acronym “POSA.”
`
`21.
`
`I understand that a POSA is a hypothetical person who is presumed to
`
`be aware of the relevant information that is considered prior art at the time of
`
`6
`
`
`
`Rigel Exhibit 1005
`Page 11 of 63
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`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`invention. By “relevant,” I mean relevant to the Challenged Claims of the ’125
`
`Patent.
`
`22.
`
`I understand that, in assessing the level of skill of a POSA, one should
`
`consider the type of problems encountered in the art, the solutions to those
`
`problems, the pace of innovation in the field, the sophistication of the technology,
`
`the level of education of active workers in the field, and my own experience
`
`working with those of skill in the art at the time of the invention.
`
`B. Claim Construction
`
`23.
`
`I understand that claims, including the Challenged Claims, are
`
`generally interpreted according to their ordinary and customary meaning taking
`
`into consideration the so-called “intrinsic evidence” of the patent consisting of (1)
`
`the claim language; (2) the specification and drawings; and (3) the prosecution
`
`history. I understand that the Board has discretion to take into consideration so-
`
`called “extrinsic evidence” including references (prior art and non-prior art) as well
`
`as definitions from dictionaries and treatises.
`
`24.
`
`I understand that claim terms may be explicitly defined in the patent
`
`specification or they may be implicitly defined through consistent usage in the
`
`specification. I also understand that the scope of claim terms may be limited by
`
`7
`
`
`
`Rigel Exhibit 1005
`Page 12 of 63
`
`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`statements in the specification or prosecution history where the application clearly
`
`disavows or disclaims subject matter in a clear and unmistakable manner.
`
`25.
`
`I understand that antecedent basis in a claim is a recitation of words or
`
`phrases that makes clear (e.g., introduces) a limitation in the claim. For example, I
`
`understand “a lever” recited at the beginning of the claim provides antecedent basis
`
`for “the lever” recited later in the claim.
`
`26.
`
`I understand that for purposes of this IPR, the standards for claim
`
`construction are the same as the standards used in the federal district courts.
`
`C.
`
`27.
`
`Prior Art and Priority
`
`I understand that “prior art” for the purposes of determining
`
`anticipation and obviousness includes material published before the effective filing
`
`date of a Challenged Claim. The effective filing date is judged on a claim-by-
`
`claim basis. I understand that the filing date of the application underlying the ’125
`
`Patent is May 8, 2017, but that there are claims to priority to a parent application
`
`filed July 11, 2013; a grandparent application filed March 12, 2010 (“the 2010
`
`Application”); and nine provisional patent applications filed in 2009. I understand,
`
`however, that a Challenged Claim may be entitled to an earlier effective filing date
`
`of an earlier filed application only if the disclosure of the earlier application
`
`8
`
`
`
`Rigel Exhibit 1005
`Page 13 of 63
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`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`provides support for the claims of the later application as required by the “written
`
`description” requirement of 35 U.S.C. §112.
`
`28.
`
`I understand that in order to satisfy the written description
`
`requirement, the patent specification must contain a written description of the
`
`invention sufficient to reasonably convey to a POSA that the inventors had
`
`possession of their claimed invention at the time of the filing of their patent
`
`application.
`
`29.
`
`I understand that written description and “enablement” are separate
`
`requirements for patentability; whereas written description is about whether the
`
`skilled reader of the patent disclosure can recognize that what was claimed
`
`corresponds to what was described, it is not about whether the patentee has proven
`
`to the skilled reader that the invention works, or how to make it work, which is an
`
`enablement issue.
`
`30.
`
`I understand that when a genus is claimed, the specification must
`
`describe the invention in a way that makes it clear that the genus has been
`
`invented, not just a species of the genus. I understand that a patentee can satisfy
`
`the written description of a genus either (1) by describing a representative number
`
`of species falling within the scope of the genus or (2) by describing structural
`
`9
`
`
`
`Rigel Exhibit 1005
`Page 14 of 63
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`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`features common to the members of the genus so that a POSA can visualize and/or
`
`recognize the members of the genus.
`
`31.
`
`I understand that a wish or plan for obtaining the claimed invention is
`
`not adequate to satisfy the written description requirement. And I understand that
`
`to satisfy the written description requirement, the patent specification must do
`
`more than claim something might work when a POSA would not have thought that
`
`it would work. Rather, the specification must provide evidence that the inventors
`
`had possessed the invention claimed.
`
`32. However, I understand that a patent specification is written for a
`
`POSA; thus, it is not necessary for the patent specification to spell out every detail
`
`of the invention in the specification because the POSA would read the
`
`specification with the knowledge of what has come before.
`
`V.
`
`BACKGROUND
`
`A. Overview of Technology
`
`33.
`
`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.
`
`10
`
`
`
`Rigel Exhibit 1005
`Page 15 of 63
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`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`34. 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; EX1016, 1, 4; EX1017,
`
`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 now understood to be an early and critical contributor to oncogenesis. EX1014,
`
`2.
`
`35.
`
`In recent times, two mutant IDH inhibitors, ivosidenib (mutant IDH1
`
`inhibitor) and enasidenib (mutant IDH2 inhibitor), have been FDA-approved for
`
`IDH-mutant relapsed or refractory acute myeloid leukemia (AML) based on phase
`
`1 safety and efficacy data and continue to be studied in trials in hematologic
`
`malignancies, as well as in glioma, cholangiocarcinoma, and chondrosarcoma.
`
`EX1014, 9.
`
`36. AML comprises a heterogeneous group of aggressive blood
`
`neoplasms that arise from clonal expansion of malignant hematopoietic precursors
`
`as a result of DNA mutations. Although in a given leukemic blast cell, there are
`
`multiple oncogenic signaling pathways leading to unfettered cellular proliferation,
`
`tissue invasion and loss of the ability to undergo apoptosis (natural cell death), the
`11
`
`
`
`Rigel Exhibit 1005
`Page 16 of 63
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`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`foremost property of AML blasts is their inability to differentiate into mature blood
`
`cells. In all subtypes of acute myeloid leukemia, a differentiation block prevents
`
`hematopoietic precursors from maturing into normal neutrophils, red blood cells
`
`and platelets and these undifferentiated, immature blast cells accumulate in the
`
`bone marrow and interfere with the production of normal healthy blood cells
`
`37. The first systematic classification of acute leukemia dates back to
`
`1978 and was based primarily on the morphologic appearance of the blast cells.
`
`This classification was designated as “FAB”, an acronym from French, American
`
`and British collaboration. See the table below which illustrates the 9 “FAB”
`
`subtypes of AML.
`
`12
`
`
`
`Rigel Exhibit 1005
`Page 17 of 63
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`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`
`
`38. AML “blasts” are immature granulocytic/myeloid precursors arrested
`
`at a very early stage in development when the malignant cell is recognizably
`
`committed to the myeloid cell line. The most common subtypes are the
`
`myeloblastic leukemias, M1 and M2, which define leukemias with some degree of
`
`granulocytic differentiation. M0, however, describes an undifferentiated leukemia.
`
`Typically, M0 blasts have very low levels of cytochemical staining for myeloid
`
`markers and as such M0 defines a very poorly differentiated myeloid leukemias
`
`with no evidence of lymphoid markers. Erythroblasts (M6) are blocked from
`
`13
`
`
`
`Rigel Exhibit 1005
`Page 18 of 63
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`

`

`Declaration of Dr. Leslie Oleksowicz
`U.S. Patent No. 10,610,125
`
`differentiating into mature red cells, while acute megakaryoblast leukemia (M7)
`
`evolves from megakaryoblasts which are platelet precursors.
`
`39. All of these blasts are derived from myeloid progenitors and are
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`contained in an intrinsic proliferative state. Additionally, these leukemic clones
`
`suppress the production of normal blood cells resulting in decreased RBCs,
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`neutrophils and platelets which lead to symptoms of shortness of breath, fever,
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`infection and bleeding.
`
`40. As technology evolved, M0 blasts could be interrogated by flow
`
`cytometry or otherwise assayed for immunophenotypic myeloid-related surface
`
`markers. Whereas the diagnosis of M3 or APML was solely based on tumor
`
`morphology in the earliest FAB classifications, in the 1990s, investigators found a
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`unique translocation, t(15, 17), in virtually all patients with APML by FAB
`
`criteria. This translocation between chromosome 15 and 17, resulted in an
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`abnormal fusion protein called PML/RARα: promyelocytic leukemia/retinoic acid
`
`receptor alpha and these leukemias were found to be highly sensitive to all-trans
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`retinoic acid (ATRA) and arsenic trioxide. Soon after its recognition as a driver of
`
`APML, efforts to pharmacologically target PML/RARa were found to be highly
`
`effective. With the use of ATRA and arsenic trioxide, over 90% of APML patients
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`can now be cured and APML represents one of the first leukemias where a novel
`
`treatment strategy was based on a molecular understanding of the disease.
`
`41. As illustrated in the table below, in the WHO 2010 classification of
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`AML, 9 types of AML are classified as having recurrent genetic abnormalities.
`
`Although the FAB morphologic classification had been useful in many regards, it
`
`lacked rigor and was limited by the absence of genomic profiling, cytogenetics and
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`immuno-phenotyping. As technology evolved, the more comprehensive WHO
`
`classification focused on molecular profiling at a time when medicinal chemistry
`
`was also moving forward with viable compounds which could effectively target
`
`these molecular aberrations. The more comprehensive 2010 WHO classification
`
`and its associated publication provided recommendations for first line treatment,
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`consolidation and maintenance for both “fit” and “unfit” (more frail) patients.
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`Treatment with induction chemotherapy, followed by consolidation with high dose
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`ARA-C or with an allo-HSCT (hematopoietic cell transplant) was and remains the
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`standard of care for curative therapy in a fit patient. For “unfit” patients, “low
`
`intensity” therapies are utilized to suppress the malignant myeloid clone, but not
`
`necessarily eradicate it, for the purpose of maintaining a good quality of life for as
`
`long as possible.
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`42. Despite advances in understanding the pathogenesis of AML, standard
`
`first line induction therapy has remained nearly unchanged over the past three
`
`decades. By early 2010, for most fit AML patients, 7&3 induction chemotherapy
`
`remained the standard of care for M0-M2; M4-M7 subtypes. “7&3” is an
`
`abbreviation for induction therapy which consists of cytarabine administered as a
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`7-day continuous infusion while daunorubicin is given as an infusion daily for 3
`
`days, hence, “7&3”.
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`43.
`
`In 2010, there were several circumstances where a different induction
`
`therapy was recommended. For patients carrying the diagnosis APML/M3, an
`
`entirely different treatment was administered which consisted of all trans retinoic
`
`acid (ATRA) together with an anthracycline-based chemotherapy or arsenic
`
`trioxide, as discussed above. AML patients with leukemia of ambiguous lineage
`
`associated with t(9,22) translocation resulting in the BCR-ABL fusion protein
`
`would require a BCR-ABL tyrosine kinase inhibitor (TKI) such as Imatinib
`
`administered with induction 7&3 chemotherapy.
`
`44. Finally, it is noted in the WHO guidelines that patients who were
`
`elderly and/or unfit, possessing a poor performance status and/or patients with
`
`major comorbidities, should not be treated with standard induction 7&3 therapy.
`
`Rather, these patients were and remain at present, candidates for low intensity
`
`hypomethylating agents, in particular Azacytidine or low dose ARA-C. Although
`
`these agents are non-curative, they provide good tumor control over long periods
`
`of time. Elderly patients treated with these agents will achieve a median overall
`
`survival between one and two years and for most, a good quality of life.
`
`B.
`
`The ’125 Patent
`
`45. The ’125 Patent relates generally to “[m]ethods of treating and
`
`evaluating subjects having neoactive mutants.” EX1001, Abstract. The inventors
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`assert that they “have discovered, inter alia, a neoactivity associated with IDH [i.e.,
`
`isocitrate dehydrogenase] mutants and that the product of the neoactivity can be
`
`significantly elevated in cancer cells.” EX1001, 1:52-54. They further assert the
`
`discovery “that certain mutated forms of an enzyme (e.g., IDH1 or IDH2) have a
`
`gain of function, referred to as a neoactivity, which can be targeted in the treatment
`
`of a cell proliferation-related disorder such as cancer.” EX1001, 38:29-33. The
`
`lone independent claim recites:
`
`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.
`
`EX1001, 431:57-67.
`
`46. The ’125 Patent specification begins with a single paragraph
`
`background section that identifies the biochemical role of isocitrate
`
`dehydrogenases. EX1001, 1:30-45. The Summary of the Invention section begins
`
`with a statement that “[t]he inventors have discovered, inter alia, a neoactivity
`
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`associated with IDH mutants and that the product of the neoactivity can be
`
`significantly elevated in cancer cells.” EX1001, 1:52-54. Generally, “[d]isclosed
`
`herein are methods and compositions for treating, and methods of evaluating,
`
`subjects having or at risk for a disorder, e.g., a cell proliferation-related disorder
`
`characterized by a neoactivity in a metabolic pathway enzyme, e.g., IDH
`
`neoactivity.” EX1001, 1:55-59. The inventors surmise a general underlying
`
`mechanism:
`
`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,
`
`EX1001, 2:29-40.
`
`47. Columns 2-33 provide a series of repetitive “embodiments” and
`
`“aspects” that set out various methods of treatment and methods for diagnosis of
`
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`cell-proliferation disorders characterized by a somatic mutation in a metabolic
`
`pathway enzyme. This section