UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________________________
`
`APOTEX INC.,
`Petitioner,
`
`v.
`
`CELGENE CORPORATION,
`Patent Owner
`
`____________________________________________
`
`Case IPR2023-00512
`Patent 8,846,628
`____________________________________________
`
`EXPERT DECLARATION OF WILLIAM G. BLUM, MD
`
`CELGENE 2053
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

`I.
`
`TABLE OF CONTENTS
`INTRODUCTION AND BACKGROUND ..................................................... 1
`A. Qualifications and Experience .......................................................................... 1
`B. Compensation ................................................................................................... 3
`II.
`PERSON OF ORDINARY SKILL IN THE ART ........................................... 3
`III. BASIS OF OPINIONS ..................................................................................... 4
`IV. BACKGROUND .............................................................................................. 4
`A. AML and MDS ................................................................................................. 4
`B. 5-Azacytidine Treatments ................................................................................ 6
`C. The ’628 Patent ................................................................................................. 7
`V. ONUREG®....................................................................................................... 8
`VI. ONUREG® EMBODIES THE ’628 PATENT’S CLAIMS............................ 9
`VII. A CLINICIAN WOULD NOT HAVE LOOKED TO PETITIONER’S
`references FOR TREATMENT OPTIONS IN DECEMBER 2008 .......................... 9
`A. Clinicians Would Not Have Pursued An Unproven Therapeutic Formulation9
`1.
`Ionescu (Ex.1004) .......................................................................................10
`2. Atadja (Ex.1005) .........................................................................................11
`3. Gibson (Ex.1006) ........................................................................................12
`4. Pharmion-PR (Ex.1010) ..............................................................................13
`VIII. AS OF DECEMBER 2008 THERE WAS A LONG-FELT BUT UNMET
`NEED FOR ONUREG® .........................................................................................14
`A. There Was an Unmet Need for A Therapeutically Effective Oral Formulation
`of 5-Azacytidine....................................................................................................14
`B. There Was a Long-Felt Unmet Need for a Continued Therapy for AML .....16
`C. The FDA Designated Oral 5-Azacytidine for Fast Track Status ...................18
`IX. THE MEDICAL INDUSTRY PRAISED ONUREG® .................................19
`X. AVAILABILITY FOR CROSS-EXAMINATION .......................................24
`XI. RIGHT TO SUPPLEMENT ...........................................................................25
`XII. JURAT ............................................................................................................26
`
`i
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`

`

`
`Blum Decl. IPR2023-00512
`
`
`I, William G. Blum, M.D., declare as follows:
`INTRODUCTION AND BACKGROUND
`I have been retained by counsel for Celgene Corporation (“Patent
`1.
`
`I.
`
`Owner”) as an expert in Apotex Inc. v. Celgene Corporation, No. IPR2023-00512,
`
`challenging claims 1, 2, 6-9, 11-28, 32-36, and 38-43 of U.S. Patent No. 8,846,628
`
`(“the ’628 patent”).
`
`2.
`
`I understand that Apotex Inc. (“Apotex”) have filed an Inter Partes
`
`Review (IPR) at the USPTO challenging claims 1, 2, 6-9, 11-28, 32-36, and 38-43
`
`of the ’628 patent.
`
`A. Qualifications and Experience
`I am a board-certified hematologist-oncologist specializing in
`3.
`
`treatment of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS),
`
`acute lymphoblastic leukemia and other myeloid malignancies. I have over 20
`
`years of experience treating patients in this field including 19 years treating
`
`patients with injectable 5-azacytidine (Vidaza®) and 3 years treating patients with
`
`oral 5-azacytidine (Onureg®).
`
`4.
`
`I am currently a professor in the Department of Hematology and
`
`Medical Oncology at Emory University School of Medicine. I serve as Director of
`
`the Acute Leukemia Program at Winship Cancer Institute and also serve on the
`
`clinical team in the Bone Marrow and Stem Cell Transplant Center at Winship. I
`
`
`
`1
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`

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`Blum Decl. IPR2023-00512
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`have worked at Emory since 2017. Prior to working at Emory, I was a Professor in
`
`the Division of Hematology in the Department of Internal Medicine at The Ohio
`
`State University - James Cancer Hospital and Solove Research Institute from 2003-
`
`2017.
`
`5.
`
`I am a member of several professional organizations including
`
`American Society of Hematology, American Association of Cancer Research,
`
`American Society of Clinical Oncology, American Society of Bone Marrow
`
`Transplantation and Alliance Cooperative Group for Clinical Trials in Oncology.
`
`Additionally, I am a cadre member of the Alliance Leukemia Committee and
`
`principal investigator/study chair for The Leukemia & Lymphoma Society's Beat
`
`AML Master Trial. I have been an invited speaker at international meetings of the
`
`American Society of Hematology, American Society of Clinical Oncology,
`
`European Hematology Association, and the Tandem Transplant meetings of the
`
`Center for International Blood and Marrow Transplant Research/American Society
`
`of Blood and Marrow Transplantation, among others.
`
`6.
`
`I received my Medical Degree from the Medical School of Georgia in
`
`Augusta, Georgia, completed my residency at the University of Virginia in
`
`Charlottesville, Virginia, and completed my fellowship in medical oncology at
`
`Washington University in St. Louis, Missouri.
`
`2
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`

`

`7. My curriculum vitae, which lists my professional experience and
`
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`Blum Decl. IPR2023-00512
`
`
`qualifications in greater detail, is attached hereto as Appendix A.
`
`B. Compensation
`I am being compensated for my time in connection with this matter at
`8.
`
`my standard consulting rate, which is $1,000.00 per hour. My compensation is not
`
`dependent in any way upon the substance of my opinions or the outcome of this
`
`matter.
`
`II.
`
`PERSON OF ORDINARY SKILL IN THE ART
`I understand that a POSA relating to the subject matter of the ʼ628
`9.
`
`patent would have had (1) a Pharm.D., and/or a Ph.D. in pharmaceutical sciences,
`
`biomolecular engineering, chemical engineering, chemistry, or related discipline or
`
`an M.D.; and (2) at least two years of experience with oncology, medicine,
`
`pharmaceutical design, or formulation of oral dosage forms. As of December 2008
`
`I would have been a POSA.1
`
`
`1 I understand Petitioner’s experts, Drs. Buckton and Batchelor, each put forth
`
`identical definitions of a POSA, and that they both opine that a POSA as of
`
`December 5, 2008 would have had (1) a Pharm.D., or a Ph.D. in pharmaceutical
`
`sciences, chemical engineering, chemistry, or related discipline; and (2) at least
`
`two to four years of experience with pharmaceutical design, formulation,
`
`
`
`
`
`3
`
`

`

`III. BASIS OF OPINIONS
`In forming my opinions set forth in this Declaration, I have considered
`10.
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`Blum Decl. IPR2023-00512
`
`
`and relied on my education and experience in the fields of oncology and treating
`
`AML and MDS patients. I have also relied on the materials listed in Appendix B.
`
`IV. BACKGROUND
`A. AML and MDS
`In the early 2000s, doctors understood that “[t]he prognosis for
`11.
`
`patients with myelodysplastic syndrome (MDS) is grim[.]” Ex.2092(Kornblith),
`
`2441. Every year, more than 10,000 patients in the United States are diagnosed
`
`with MDS (Ex.2098(Ma), Abstract), which is a collection of blood cell disorders
`
`caused by malfunctioning bone marrow (Ex.2064(Altman), 197). Most MDS
`
`patients die from bleeding or infection sometimes with progression of MDS into
`
`acute myeloid leukemia (AML or acute myelogenous leukemia).
`
`
`development, and/or manufacturing of oral dosage forms. I further understand that
`
`Dr. Buckton states a POSA would have consulted with a team including at least a
`
`clinician. I am (and was since before the priority dates of the ’628 patent) a
`
`clinician that would have been consulted. My opinions would not change under
`
`this definition.
`
`
`
`4
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`

`

`Ex.2018(Kaminskas), 181. For the highest risk patients, median survival rate is
`
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`Blum Decl. IPR2023-00512
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`between only six and twelve months. Ex.2092(Kornblith), 2441.
`
`12.
`
`In adults, AML is the most common type of acute leukemia with
`
`about 20,000 patients diagnosed in the United States each year. Ex.2072(Choi);
`
`Ex.2071(Carter), 1. It is an aggressive form of cancer that “has the lowest survival
`
`rate of all leukemia types….” Ex.2072(Choi), 1416; Ex.2142(European Medicines
`
`Report), 8. In children, it is the second most common acute leukemia.
`
`Ex.2064(Altman), 16; Ex.2071(Carter), 1. AML results in the growth of abnormal
`
`immature blood cells in the bone marrow. Ex.2064(Altman), 16-17. AML’s poor
`
`prognosis is stark: three-quarters of AML patients die within five years, and among
`
`older patients long-term survival is uncommon. Ex.2073(Cogle), 1405.
`
`13. As of December 2008, standard therapy for AML was intensive
`
`“induction” therapy designed to achieve remission followed by short-term
`
`intensive “consolidation” therapy to try to eradicate undetectable residual
`
`leukemia. Ex.2071(Carter), 2-3; Ex. 2111(Reville), 1. Risk of relapse, though,
`
`remained high, occurring in more than 50% of adults. Ex. 2111(Reville), 1. At
`
`that time, the FDA had only approved one oral therapy (lenalidomide) to treat
`
`MDS. Ex.2076(Curtiss), 573; Ex.2071(Carter). However, although low intensity,
`
`prolonged so-called maintenance therapy was established in acute lymphoblastic
`
`leukemia, there was no approved oral or maintenance therapies for AML.
`5
`
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`

`

`Blum Decl. IPR2023-00512
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`Ex.2076(Curtiss), 573; Ex.2071(Carter). Many different trials, including CALGB
`
`10503 of which I was the national study chair, tried to establish efficacy of various
`
`maintenance therapies with chemotherapy but were all ineffective. See e.g.,
`
`Ex.2136(Blum), Abstract.
`
`B.
`14.
`
`5-Azacytidine Treatments
`In 2004, the FDA first approved 5-azacytidine as the injectable drug,
`
`Vidaza®, to treat MDS. See Ex.1007(Vidaza Label 2004); Ex.2018(Kaminskas),
`
`176. Clinicians were hopeful that further development would result in “non-toxic
`
`therapies with convenient dose schedules, such as oral administration, [to] provide
`
`new tools for cancer prevention and maintenance.” Ex.2087(Grønbæk), 395.
`
`15.
`
`In 2007, the FDA granted Pharmion Fast Track designation for oral 5-
`
`azacytidine. See Ex.1011-0005(Pharmion-PR II). The Fast Track program seeks
`
`“to facilitate the development and expedite the review of new drugs that are
`
`intended to treat serious or life-threatening conditions” and have “the potential to
`
`address unmet medical needs.” Ex.1011-0005(Pharmion-PR II). Over a decade
`
`and a half after approving the injectable formulation of 5-azacytidine (Vidaza®),
`
`the FDA finally approved the first oral formulation of 5-azacytidine as Onureg® in
`
`September 2020. See Ex.2055 (FDA Approves Onureg®); Ex.1007(Vidaza®
`
`Label 2004); Ex.2062(Onureg® Label).
`
`6
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`

`

`Blum Decl. IPR2023-00512
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`16. Onureg® is an immediate release (i.e., non-enterically coated) (see
`
`Ex.2142(European Medicines Report, 15) tablet and is also the first FDA approved
`
`drug for maintenance treatment of patients with AML who achieved remission
`
`following intensive induction chemotherapy and are not able to complete intensive
`
`curative therapy such as allogeneic donor cell transplant. (Ex.2062(Onureg®
`
`Label), 1). Canada and Europe quickly followed suit, approving Onureg® in
`
`January and June 2021, respectively. Ex.2056(Canadian Product 200mg Onureg®
`
`Product Information); Ex.2057(Canadian Product 300mg Onureg® Product
`
`Information); Ex.2058(Canadian Product Monograph Onureg®);
`
`Ex.2059(European Commission Decision 17.6.21). The FDA also granted
`
`Onureg® Orphan Drug designation, which was set up to provide incentives for the
`
`research and development of drugs to treat uncommon diseases. See
`
`Ex.2140(Finkel), 313.
`
`C.
`17.
`
`The ’628 Patent
`The ’628 patent is directed to “pharmaceutical compositions
`
`comprising cytidine analogs,” specifically 5-azacytidine, “for oral administration,
`
`wherein the compositions release the cytidine analog…substantially in the
`
`stomach” as well as “methods of treating diseases and disorders using the oral
`
`formulations provided herein.” Ex.1001(’628 patent), Abstract. The patent
`
`includes two independent claims: claim 1 and claim 28.
`
`7
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`

`

`Independent claim 1 of the ’628 patent is reproduced below:
`
`
`Blum Decl. IPR2023-00512
`
`
`1.
`A pharmaceutical composition for oral administration
`comprising a therapeutically effective amount of 5-azacytidine and at
`least one pharmaceutically acceptable excipient, wherein the
`composition is a non-enteric coated tablet.
`Independent claim 28 of the ’628 patent is reproduced below:
`
`18.
`
`19.
`
`28. A method for treating one or more symptoms of a disease
`associated with abnormal cell proliferation, comprising orally
`administering to a subject in need thereof a pharmaceutical
`composition comprising a therapeutically effective amount of 5-
`azacytidine and at least one pharmaceutically acceptable excipient,
`wherein the composition is a non-enteric coated tablet, and wherein
`the disease associated with abnormal cell proliferation is
`myelodysplastic syndrome or acute myelogenous leukemia.
`V. ONUREG®
`I understand that FDA-approved Onureg® is a pharmaceutical
`20.
`
`composition for oral administration comprising a therapeutically effective amount
`
`of 5-azacytidine and at least one pharmaceutically acceptable excipient, wherein
`
`the composition is a non-enteric coated tablet. See, e.g., Ex.2062(Onureg® Label).
`
`Additionally, I understand that the FDA-approved Onureg® for “continued
`
`treatment of adult patients with acute myeloid leukemia who achieved first
`
`complete remission (CR) or complete remission with incomplete blood count
`
`recovery (CRi) following intensive induction chemotherapy and are not able to
`
`complete intensive curative therapy.” Ex.2062(Onureg® Label).
`
`
`
`8
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`

`

`VI. ONUREG® EMBODIES THE ’628 PATENT’S CLAIMS
`I have spoken to Cory Berkland, Ph.D., who I understand analyzed the
`21.
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`Blum Decl. IPR2023-00512
`
`
`literature about Onureg® and the claims, and from this conversation I understand
`
`Onureg® embodies the claims of the ’628 patent.
`
`VII. A CLINICIAN WOULD NOT HAVE LOOKED TO PETITIONER’S
`REFERENCES FOR TREATMENT OPTIONS IN DECEMBER 2008
`I understand that Apotex relies on the following references:
`22.
`
`• Ionescu (Ex.1004)
`
`• Atadja (Ex.1005)
`
`• Gibson (Ex.1006)
`
`• Pharmion-PR (Ex.1010).
`
`23.
`
`I have reviewed these references and provide the following comments
`
`from the perspective of an oncologist treating MDS and/or AML patients with 5-
`
`azacytidine during the relevant time period.
`
`A. Clinicians Would Not Have Pursued An Unproven Therapeutic
`Formulation
`24. The route of administering a pharmaceutical compound influences its
`
`biological impact. “Bioavailability is highly dependent on both the route of
`
`administration and the drug formulation,” and factors including the absorption
`
`process and “metabolism [of the drug] prior to reaching the systemic circulation”
`
`may reduce a drug’s bioavailability. Ex.2075(Craig), 50. Indeed, by December
`
`
`
`9
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`

`

`2008 an oncologist would have been aware of many injectable chemotherapeutics
`
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`Blum Decl. IPR2023-00512
`
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`that were not approved for oral administration, several of which belong to the same
`
`class of nucleotide analogs as 5-azacytidine. See, e.g., Ex.2137(Cytarabine), 8
`
`(disclosing an injectable but not oral cytidine analog approved to treat acute
`
`nonlymphocytic leukemia that is acute myeloid leukemia); Ex.2138(Dacogen), 1, 6
`
`(disclosing a different injectable but not oral cytidine analog approved to treat
`
`MDS); Ex.2139(Mitoxantrone), 2, 14 (disclosing a non-nucleoside injectable but
`
`not oral formulation approved to treat acute nonlymphocytic leukemia). A
`
`clinician would have understood that the therapeutic effectiveness of a drug can
`
`depend on its administration route and is highly unpredictable when administered
`
`in a manner inconsistent with the established clinical data. Without more
`
`information, therapeutic effectiveness of a drug given intravenously or
`
`subcutaneously does not indicate that the same drug would be therapeutically
`
`effective if administered orally.
`
`25. None of Ionescu, Atadja, Gibson, and Pharmion-PR would have
`
`provided any reason for an oncologist to expect that an oral formulation of 5-
`
`azacytidine would have been tolerable and therapeutically effective for a patient.
`
`Ionescu (Ex.1004)
`1.
`Ionescu “relates to the isolation of crystalline polymorphic and
`
`26.
`
`pseudopolymorphic forms of 5-azacytidine….” Ex.1004-0003(Ionescu), 1:8-10. It
`
`
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`10
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`

`Blum Decl. IPR2023-00512
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`notes that “5-azacytidine may be used in the treatment of disease, including the
`
`treatment of myelodysplastic syndromes” (Ex.1004-0003(Ionescu), 1:10-11), but
`
`only references working examples of injectable formulations of 5-azacytidine
`
`suspended in a water-based solution, i.e., Vidaza®. See, e.g., Ex.1004-0011.
`
`Otherwise, Ionescu provides only a general disclosure of other aspects of 5-
`
`azacytidine pharmaceutical compositions such as possible excipients
`
`(Ex.1004(Ionescu), 2:26-28), generic and hypothetical formulations
`
`(Ex.1004(Ionescu), 12:11-14:29), and broad ranges of potential dosages
`
`(Ex.1004(Ionescu), 14:22-25). Nowhere does Ionescu disclose a working oral
`
`formulation of 5-azacytidine (such as Onureg®); a safe, effective, tolerable, and
`
`non-hazardous dosage; or any data showing efficacy upon oral administration.
`
`Thus, a clinician would not have been motivated by Ionescu to treat a patient with
`
`AML or MDS with oral 5-azacytidine, nor would they have had any expectation of
`
`success using such a treatment.
`
`Atadja (Ex.1005)
`2.
`27. Atadja discloses over 130 various chemotherapeutics to be combined
`
`with histone deacetylase inhibitors. Ex.1005-0002-0028(Atadja). Atadja provides
`
`a blanket statement that any of “the compounds or the pharmaceutically acceptable
`
`salts thereof, are administered as an oral pharmaceutical formulation in the form of
`
`a tablet, capsule or syrup; or as parenteral injections if appropriate.” Ex.1005-
`
`11
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`

`Blum Decl. IPR2023-00512
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`0028(Atadja) (emphasis added). An oncologist confronted with the over 130
`
`chemotherapeutics disclosed in Atadja would have understood that each
`
`chemotherapeutic agent would be administered based on the clinical data and FDA
`
`approvals for each respective drug at the time. For example, an oncologist would
`
`have understood the FDA had approved certain agents listed in Atadja as tablets.
`
`See, e.g., Ex.1005-0004-0005(Atadja); Ex.2133(Exemestane);
`
`Ex.2134(Anastrozole), 1; Ex.2135(Letrozole), 1. On the other hand, an oncologist
`
`in December 2008 would have recognized that the disclosure of “parenteral
`
`injections [would have been] appropriate” for 5-azacytidine since the only FDA-
`
`approved formulation of 5-azacytidine was injectable Vidaza®. Ex.1005-
`
`0028(Atadja); Ex.1007(Vidaza® Label 2004); Ex.1008(Vidaza® Label 2007). An
`
`oncologist would have understood Atadja’s blanket disclosure of formulations in
`
`the specific context of the existing data for each of the dozens of agents listed and
`
`applied that understanding to determine which formulation was appropriate for
`
`which agent.
`
`Gibson (Ex.1006)
`3.
`28. Gibson is a general formulation textbook without mention of 5-
`
`azacytidine, MDS, or AML. Gibson would not have provided a clinician with
`
`information on how to administer 5-azacytidine in a therapeutically effective
`
`amount to treat a patient.
`
`12
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`

`Blum Decl. IPR2023-00512
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`Pharmion-PR (Ex.1010)
`4.
`29. An oncologist would not have understood Pharmion-PR to disclose a
`
`therapeutically effective oral formulation of 5-azacytidine, such as Onureg®.
`
`Pharmion-PR merely reports “preliminary results” of a pilot study “designed to
`
`assess the safety, tolerability, and pharmacokinetics” of administration of an
`
`undescribed oral formulation of 5-azacytidine. Ex.1010-0005, -0006(Pharmion-
`
`PR). An oncologist would have understood that these results do not indicate that
`
`the formulation is therapeutically effective but merely that it was “well-tolerated
`
`and quantifiable in plasma.” See Ex.1010-0005(Pharmion-PR). Indeed, the
`
`preliminary study concludes that the undescribed formulation results in only 18%
`
`bioavailability relative to that of subcutaneously administered Vidaza® (Ex.1010-
`
`0005(Pharmion-PR)), and the reference provides no evidence that the administered
`
`dose was therapeutically effective. In fact, a clinician would have understood that
`
`“the relationship between drug intake and a clinical response is highly complex,”
`
`and “deviations between drug response within or between individuals may be
`
`ascribed either to product bioavailability…, drug pharmacokinetics…, or the
`
`particular concentration-effect relationship.” Ex2141(Martinez), 620. A clinician
`
`would have understood that bioavailability is not necessarily an indication of
`
`therapeutic effectiveness as other factors may affect clinical responses. For
`
`example, a clinician would have looked to dose escalation studies that evaluate an
`
`13
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`

`

`efficacious dose to ascertain whether the dose also has an acceptable toxicity
`
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`Blum Decl. IPR2023-00512
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`profile at that dose.
`
`30. Additionally, a clinician would have recognized that Pharmion-PR’s
`
`“preliminary results” “involve a number of known and unknown risks and
`
`uncertainties that could cause the final results to differ significantly from the
`
`results summarized….” Ex.1010-0006(Pharmion-PR). A clinician would have
`
`understood and agreed that Pharmion-PR’s “preliminary results may not be
`
`confirmed upon the full analysis of the detailed results of a trial and additional
`
`information relating to the safety, efficacy or tolerability of oral azacitidine[.]”
`
`Ex.1010-0006(Pharmion-PR) (emphasis added).
`
`31. An oncologist in December 2008 would not have pursued an oral non-
`
`enteric coated tablet of 5-azacytidine as a therapeutic for a subject with AML or
`
`MDS based on the prior art at least because at that time there was no data to
`
`establish that an oral tablet of the drug could be given at an efficacious dose in a
`
`safe manner.
`
`VIII. AS OF DECEMBER 2008 THERE WAS A LONG-FELT BUT
`UNMET NEED FOR ONUREG®
`A. There Was an Unmet Need for A Therapeutically Effective Oral
`Formulation of 5-Azacytidine
`32. As of 2008, clinicians were desirous of “more specific and non-toxic
`
`therapies with convenient dose schedules, such as oral administration, [to] provide
`
`
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`14
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`

`new tools for cancer prevention and maintenance.” Ex.2087(Grønbæk), 395.
`
`
`Blum Decl. IPR2023-00512
`
`
`Clinicians and researchers understood that 5-azacytidine was potentially useful in
`
`treating cancers as soon as it was first synthesized. See, e.g., Ex.2012(Čihák),
`
`2100. However, for many decades, clinicians believed the development of an oral
`
`formulation was fraught with difficulty. See Ex.2029(Stresemann), 8 (disclosing
`
`difficulty in formulating 5-azacytidine “interferes with [its] potential oral
`
`administration”); see also Ex.1014(Chan), 807 (disclosing 5-azacytidine’s “proper
`
`formulation [was] a problem in its clinical use”); Ex.2003(Aparicio), 631
`
`(disclosing its “significant restrictions on dosing schedule adjustments” inhibited
`
`the creation of a “dramatically successful” formulation of 5-azacytidine). The
`
`FDA approved Vidaza®, an injectable formulation of 5-azacytidine, in 2004
`
`(Ex.1007(Vidaza Label 2004)), but injection protocols dictated by 5-azacytidine’s
`
`instability had been associated with “severe gastrointestinal toxicity….”
`
`(Ex.2004(Beisler), 281). See also Ex.2125(Vigil), 227 (injectable 5-azacytidine
`
`caused discomfort and other injection-site reactions in patients);
`
`Ex.2118(Sorrentino), 20.
`
`33. Thus, for over forty years clinicians wanted for a therapeutically
`
`effective, oral formulation of 5-azacytidine that was only realized by Onureg®.
`
`
`
`15
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`

`Blum Decl. IPR2023-00512
`
`B.
`
`34.
`
`There Was a Long-Felt Unmet Need for a Continued Therapy for
`AML
`Since at least 1968, clinicians have recognized that “[m]ost patients
`
`with AML… will relapse….” Ex.2073(Cogle), 1409; Ex.2080(Ellison), 509; see
`
`also Ex.2110(Récher), 828-829 (“Preventing relapse after induction and
`
`consolidation therapy in AML has long been a major challenge[.]”). The outcomes
`
`for recovering AML patients that experience early relapse “are dismal.”
`
`Ex.2125(Vigil), 224); see also Ex.2082(Frisch), 683. Clinicians understood that
`
`“[t]o improve outcomes, there is a need to prolong remissions” through
`
`maintenance therapies. Ex.2073(Cogle), 1409; see also Ex.2118(Sorrentino), 20
`
`(“An oral formulation [of 5-azacytidine] is clinically desired due to the opportunity
`
`of delivering at lower systemic doses over a more prolonged schedule.”). At the
`
`time of the invention of the claims at issue here, “there was an unmet need for a
`
`therapy to maintain remission in such patients” because “a convenient, safe and
`
`effective option with proven capacity to improve survival was not available.”
`
`Ex.2119(Southall), 1.
`
`35.
`
`The search for an effective therapy for AML patients in remission had
`
`been ongoing for about 40 years before the invention of the ’628 patent and nearly
`
`50 years before the FDA approved Onureg® in 2020. See, e.g., Ex.2080(Ellisson)
`
`(studying the effects of subcutaneous arabinosyl cytosine maintenance treatments
`
`16
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`

`

`
`Blum Decl. IPR2023-00512
`
`in AML patients after remission); see also Ex.2108(Preisler), 1442-1443 (assessing
`
`subcutaneous cytosine arabinoside in rotating combination with 6-thioguanine,
`
`prednisone and vincristine, and daunorubicin in AML patients after remission);
`
`Ex.2097(Lӧwenberg) (evaluating effects of cytarabine as a maintenance therapy in
`
`AML patients after remission).
`
`36. Before the invention of the claims at issue and the launch of Onureg®,
`
`clinicians had not made substantial progress in identifying a maintenance therapy
`
`for AML. “For decades, although several trials with different strategies of
`
`maintenance therapy have been conducted to reduce the relapse of disease in
`
`patients, these trials have failed to show the improvement of outcomes.
`
`Consequentially, maintenance chemotherapy is not a standard therapy for AML
`
`except for acute promyelocytic leukemia (APL).” Ex.2072(Choi), 1416; see also
`
`Ex.2073(Cogle), 1410 (noting in 2015 that “there is an unmet need for additional
`
`low-intensity treatment options for patients with MDS or AML….”). Clinicians
`
`recognized a need for a therapeutic agent approved for “continuing therapy beyond
`
`the time of first response….” Ex.2093(Lammers), 1196.
`
`37. With the launch of Onureg®, such a long-desired continuous therapy
`
`was realized for the first time. Onureg® fulfilled this previously unmet need,
`
`“bec[oming] the first FDA approved drug specifically as maintenance treatment for
`
`AML patients….” Ex.2095(Liu), 13. With its approval, clinicians “[a]t last, [had]
`17
`
`
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`

`

`an effective treatment that can be given in the post-remission setting to help keep
`
`AML patients in remission and improve their survival.” Ex.2130(Weill Cornell),
`
`Blum Decl. IPR2023-00512
`
`2.
`
`38.
`
`Thus, a multidecade search for a continued therapy for AML finally
`
`came to fruition with Onureg®.
`
`C.
`39.
`
`The FDA Designated Oral 5-Azacytidine for Fast Track Status
`In 2007, the FDA granted to Pharmion Fast Track designation for oral
`
`5-azacytidine. See Ex.1011-0005(Pharmion-PR II). Fast Track designation is
`
`“designed to facilitate the development and expedite the review of new drugs that
`
`are intended to treat serious or life-threatening conditions and that demonstrate the
`
`potential to address unmet medical needs.” Ex.1011-0005(Pharmion-PR II). This
`
`designation provided “[t]he opportunity to explore the biological and clinical
`
`consequences of continuous oral dosing of Azacitdine” for the first time. Ex.1011-
`
`0005(Pharmion-PR II); see also id. at -0006 (“An oral dosage formulation of
`
`Azacitidine… would enable the evaluation of a low-dose regimen… [and] long-
`
`term or maintenance therapy.”). With this designation the FDA formally
`
`recognized what clinicians had previously understood—an unmet need for oral 5-
`
`azacytidine treatments. Section VIII.A.
`
`40.
`
`It took over four decades to develop Onureg®, the much-desired oral
`
`formulation of 5-azacytidine. These extended efforts reflected the desires of
`
`18
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`

`clinicians, researchers, and the U.S. government to provide a therapeutically
`
`
`Blum Decl. IPR2023-00512
`
`
`effective oral formulation for the continued treatment of AML patients in
`
`remission. Only once the inventors developed the claimed invention, which was
`
`launched as Onureg®, was this long-felt need for a maintenance therapy for AML
`
`met. Section VIII.B.
`
`IX. THE MEDICAL INDUSTRY PRAISED ONUREG®
`41. Clinicians recognized Onureg® as a major development in the field of
`
`oncology even before its FDA-approval. Ex.2104(Perl), 2287;
`
`Ex.2068(Bankhead), 2. They praised oral 5-azacytidine, approved as Onureg®, as
`
`a “transformative” and “very significant advance” that “represent[s] a potential
`
`new standard of care for patients” and would “change practice once [it became]
`
`available.” Ex.2103(Oral CC-486), 2; Ex.2114(Slater), 2. Clinical results using
`
`the non-enteric coated tablets of 5-azacytidine provided clinicians with a tool to
`
`“improve[] relapse-free survival and overall survival” in older AML patients for
`
`the “first time.” Ex.2103(Oral CC-486), 4. This led clinicians to hail Pharmion’s
`
`non-enteric coated oral 5-azacytidine tablets, which would be approved as
`
`Onureg®, as “practice-changing” (Ex.2103(Oral CC-486), 4) and recommending
`
`doctors “strongly consider” treating patients with Onureg® (Ex.2129(Wei), E86).
`
`In fact, clinicians recognized Onureg®’s approval as ushering in a “period of
`
`breakthrough drug approvals for AML….” Ex.2094(Lin 2022), 1; see also
`
`
`
`19
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`

`

`Blum Decl. IPR2023-00512
`
`Ex.2089(Kantarjian), 581 (“We are witnessing an ongoing ‘slow-motion’
`
`revolution in AML research and therapy, with the approval of 9 agents for different
`
`AML indications since 2017” including “the oral [hypomethylating agent]
`
`azacitdine[.]”).
`
`42. As noted above, these breakthroughs extended to providing continued
`
`therapy to patients. Section IV.B. “Historically, maintenance therapy with various
`
`agents consistently failed to demonstrate [an overall survival] advantage.”
`
`Ex.2082(Frisch), 683; see also Ex.2150(Huls), 1457, 1458 (noting that
`
`subcutaneous 5-azacytidine administered as a maintenance therapy did not improve
`
`overall survival in patients). Indeed, clinicians long recognized that the major
`
`issue for the treatment of AML was the lack of effective maintenance therapies.
`
`See Ex.2094(Lin 2022), 13; see also, Ex.2110(Récher), 828-829. Onureg®
`
`changed this, “bec[oming] the first FDA approved drug specifically as
`
`maintenance treatment for AML patients….” Ex.2095(Liu), 13. Clinicians noted
`
`its success as “[t]he biggest advance in AML maintenance currently….”
`
`Ex.2111(Reville), 1. Further, clinicians recognized Onureg®’s approval as
`
`potentially paradigm-changing. See Ex.2111(Reville), 7 (stating that the post-
`
`complete remission care “paradigm maybe [sic] set to change” thanks to the
`
`approval of Onureg®); Ex.2081-0001(FDA Approves Oral Azacitidine) (clinician
`
`stating that the approval of Onureg® “should help establish continued treatment
`20
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`

`

`with azacitidine as a standard component of AML therapy for adults who achieved
`
`
`Blum Decl. IPR2023-00512
`
`
`first complete remission” but cannot proceed to intensive curative therapy or
`
`transplantation).
`
`43. The success of Onureg® highlights the potential for routes of
`
`administration that facilitate new protocols including low, continuous dosing of