UNITED STATES PATENT AND TRADEMARK OFFICE
`
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__
`
`APOTEX INC.,
`Petitioner
`
`v.
`
`CELLGENE CORPORATION,
`Patent Owner
`__
`
`Case IPR2023-00512
`U.S. Patent No. 8,846,628
`Issued: September 30, 2014
`
`Title:
`ORAL FORMULATIONS OF CYTIDINE ANALOGS AND METHODS OF USE THEREOF
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`INTRODUCTION ......................................................................................... 1 
`I. 
`II.  MANDATORY NOTICES ........................................................................... 4 
`A. 
`Real Party-In-Interest ............................................................................ 4 
`B. 
`Related Matters ...................................................................................... 4 
`C. 
`Designation of Lead and Back-Up Counsel .......................................... 5 
`D.  Notice of Service Information ............................................................... 5 
`III.  REQUIREMENTS FOR INTER PARTES REVIEW............................... 5 
`A.  Grounds for Standing ............................................................................ 5 
`B. 
`Identification of Challenge .................................................................... 6 
`IV.  BACKGROUND ............................................................................................ 6 
`A.  Knowledge in the Prior Art Would Have Led a POSA to the
`Claimed Invention ................................................................................. 6 
`5-Azacytidine Was a Long-Known Therapeutic
`Compound for Treating One or More Symptoms of a
`Disease Associated With Abnormal Cell Proliferation
`Such As Myelodysplastic Syndrome and Acute
`Myelogenous Leukemia .............................................................. 6 
`Oral Administration of 5-Azacytidine Was Known and
`Preferred at the Time of Invention .............................................. 8 
`NEC Tablets of 5-Azacytidine Were Known and
`Preferred .................................................................................... 10 
`It Would Have Been Routine to Use Well-Known and
`Conventional In Silico Modeling to Determine the
`Pharmacokinetics of Oral 5-Azacytidine Dosage Forms .......... 13 
`The ’628 Patent ................................................................................... 15 
`The Specification ...................................................................... 15 
`
`B. 
`
` 
`
` 
`
` 
`
`
`
`- i -
`
` 
`
` 
`
`

`

`The Prosecution History: The Examiner Was Missing
`Key Disclosures and Was Led to Error by Erroneous
`Arguments of Unexpected Results ........................................... 16 
`The Challenged Claims ............................................................. 18 
`Effective Filing Date of the Challenged Claims ....................... 19 
` 
`Claim Construction ............................................................................. 20 
`C. 
`V.  DETAILED EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY ................................................................................ 20 
`A.  Ground 1: Claims 1, 2, 6-8, 11, 13-18, 20-23, 28, 32-35, 38, 40,
`42, and 43 Are Anticipated by Ionescu ............................................... 20 
`Independent Claims 1 and 28: Ionescu Discloses NEC
`Tablets of 5-Azacytidine to Treat One or More
`Symptoms of a Disease Associated With Abnormal Cell
`Proliferation Such as MDS ....................................................... 21 
`a. 
`[1a] “A pharmaceutical composition for oral
`administration comprising” ............................................ 21 
`[1b] “a therapeutically effective amount of 5-
`azacytidine” .................................................................... 21 
`[1c] “at least one pharmaceutically acceptable
`excipient” ........................................................................ 22 
`[1d] “wherein the composition is a non-enteric
`coated tablet” .................................................................. 22 
`Claim 28 .......................................................................... 23 
`e. 
`Dependent Claims 2, 6, 7, 13-15, 32, and 34 Reciting
`Formulation Limitations: Ionescu Discloses a Sugar-
`Coated Tablet of 5-Azacytidine Comprising Mannitol,
`Microcrystalline Cellulose, Crospovidone, and
`Magnesium Stearate .................................................................. 24 
`a. 
`Dependent Claims 2 and 34 Reciting
`Pharmaceutically Acceptable Excipients ....................... 24 
`
`b. 
`
`c. 
`
`d. 
`
` 
`
` 
`
` 
`
` 
`
`
`
`- ii -
`
`

`

`
`
`b. 
`
`c. 
`
`b. 
`
`Dependent Claims 6, 7, and 32 Reciting
`“Essentially Free” of Cytidine Deaminase
`Inhibitor, Like THU ........................................................ 24 
`Dependent Claims 13-15 Reciting Film Coatings
`Like HPMC, HPC, or MC .............................................. 25 
`Dependent Claims 8, 16, 17, 23, 33, and 35 Reciting
`Dosage Limitations: Ionescu Discloses Tablets
`Containing “About 5 mg to 200 mg, More Usually About
`100 mg” of 5-Azacytidine ......................................................... 26 
`a. 
`Dependent Claims 8, 16, 17, and 35 Reciting
`Various Dosage Amounts ............................................... 26 
`Dependent Claim 23 Reciting Dosage Amount of
`“120 to 480 mg”.............................................................. 27 
`Dependent Claim 33 Reciting a “Single Unit
`Dosage Form” ................................................................. 28 
`Dependent Claims 11, 18, 20-22, 38, 40, 42, and 43:
`Ionescu Inherently Discloses the Claimed PK Properties
`(AUC, Cmax, and Tmax) ............................................................... 28 
`a. 
`The PK Claims Are Inherently Anticipated
`Because They Are Natural Results of
`Administering a Prior Art Formulation .......................... 29 
`In Silico Modelling Further Demonstrates Inherent
`Anticipation of the PK Claims........................................ 29 
`Ground 2: Claims 1, 2, 6-9, 11-28, 32-36, and 38-43 Would
`Have Been Obvious Over Ionescu in View of Atadja, Gibson,
`and the Knowledge of a POSA ........................................................... 31 
`Independent Claims 1 and 28 Would Have Been Obvious ...... 31 
`a. 
`A POSA Would Have Been Motivated to Pursue
`an Oral, NEC Tablet of 5-Azacytidine ........................... 32 
`
` 
`
` 
`
` 
`
`c. 
`
`b. 
`
`B. 
`
`- iii -
`
`

`

`
`
`i. 
`
`ii. 
`
`b. 
`
`A POSA Would Have Been Motivated to Pursue
`and Select an Oral Dosage Form of 5-Azacytidine
`From the Dosage Forms Ionescu .......................... 32 
`A POSA Would Have Been Motivated to Pursue
`and Select a NEC Tablet of 5-Azacytidine From
`the Oral Dosage Forms of Ionescu ....................... 36 
`A POSA Would Have Had a Reasonable
`Expectation of Arriving at the Claimed
`Compositions and Methods of Treatment ...................... 38 
`Dependent Claims 2, 6, 7, 13-15, 32, and 34 Reciting
`Formulation Limitations Would Have Been Obvious .............. 38 
`a. 
`Dependent Claims 2 and 34 Reciting
`Pharmaceutically Acceptable Excipients ....................... 39 
`Dependent Claims 6, 7, and 32 Reciting
`“Essentially Free” of Cytidine Deaminase
`Inhibitor, Like THU ........................................................ 39 
`Dependent Claims 13-15 Reciting Film Coatings
`Like HPMC, HPC, or MC .............................................. 41 
`A POSA Would Have Had a Reasonable
`Expectation of Arriving at Claims 2, 6, 7, 13-15,
`32, and 34 ........................................................................ 43 
`Dependent Claims 8, 9, 16, 17, 23-27, 33, 35, and 36
`Reciting Dosage Limitations Would Have Been Obvious ....... 43 
`a. 
`Dependent Claims 8, 9, 16, 17, 23-27, 35, and 36
`Reciting Various Dosage Amounts ................................ 43 
`Dependent Claim 33 Reciting a “Single Unit
`Dosage Form” ................................................................. 47 
`A POSA Would Have Had a Reasonable
`Expectation of Arriving at Claims 8, 9, 16, 17, 23-
`27, 33, 35, and 36 ........................................................... 47 
`
`b. 
`
`c. 
`
`d. 
`
`b. 
`
`c. 
`
` 
`
` 
`
`- iv -
`
`

`

` 
`
` 
`
`C. 
`
`Dependent Claims 11, 12, 18-22, and 38-43 Reciting PK
`Limitations Would Have Been Obvious ................................... 48 
`Patent Owner Failed to Show Unexpected Results
`Sufficient to Rebut the Strong Showing of Obviousness
`of Claims 1, 2, 6-9, 11-28, 32-36, and 38-43 ............................ 53 
`Ground 3: Claims 1, 2, 6-9, 11-28, 32-36, and 38-43 Would
`Have Been Obvious Over Ionescu in View of Pharmion-PR,
`Atadja, Gibson, and the Knowledge of a POSA ................................. 58 
`D.  Grounds 1-3 Present New References and Disclosures That
`Were Not Properly Evaluated or Applied by the Examiner ................ 62 
`Part One: The Petition Presents New Art and Arguments ........ 62 
`Part Two: The Examiner Erred in a Manner Material to
`Patentability by Not Substantively Considering and
`Applying Ionescu, and New Evidence Warrants
`Reconsideration ......................................................................... 63 
`VI.  CONCLUSION ............................................................................................ 64 
`CERTIFICATE OF COMPLIANCE .................................................................. 66 
`CERTIFICATE OF SERVICE ............................................................................ 67 
`
`
`
` 
`
` 
`
`
`
`- v -
`
`

`

`
`
`LIST OF EXHIBITS
`
`
`Exhibit No. Description
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`U.S. Patent No. 8,846,628 (the “’628 patent”)
`
`Declaration of Dr. Graham Buckton (“Buckton Decl.”)
`
`Declaration of Dr. Hannah K. Batchelor (“Batchelor Decl.”)
`
`WO 2004/082619 (“Ionescu”)
`
`WO 2004/103358 (“Atadja”)
`
`Gibson, M., Ch. 11, Oral Solid Dosage Forms, PHARMA.
`PREFORMULATION AND FORMULATION, CRC Press (2001) (“Gibson”)
`
`Vidaza Label 2004
`
`Vidaza Label 2007
`
`WO 2004/082822 (“Ionescu ʼ822”)
`
`Press Release, Pharmion, “Clinical Data Presented on Pilot
`Pharmacokinetic Study of Oral Azacitidine” (June 2, 2007)
`(“Pharmion-PR”)
`
`Press Release, Pharmion, “Pharmion’s Oral Azacitidine Granted Fast
`Track Status for Myelodysplastic Syndromes” (August 29, 2007)
`(“Pharmion-PR II”)
`
`Pharmion Corporation, Form 10-K (February 29, 2008) (“Pharmion
`10-K”)
`Excerpts from Rowe, R.C., et al., Handbook of Pharma. Excipients,
`Pharma. Press, 5th ed. (2006) (“Handbook”)
`
`- vi -
`
`

`

`
`
`Exhibit No. Description
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`Chan et al., “5-Azacytidine Hydrolysis Kinetics Measured by High-
`Pressure Liquid Chromatography and 13C-NMR Spectroscopy,”68
`(7) J Pharma. Scis. 807 (1979) (“Chan”)
`
`Kelley et al., “Furanose-Pyranose Isomerization of Reduced
`Pyrimidine and Cyclic Urea Ribosides,” 29 J. Med. Chem. 2351
`(1986) (“Kelley”)
`
`U.S. Patent No. 3,817,980 (“Vorbruggen”)
`
`Marcucci, G., et al., “Bioavailability of Azacitidine Subcutaneous
`Versus Intravenous in Patients With the Myelodysplastic
`Syndromes,” 45 J. Clin. Pharmacology 597 (2005) (“Marcucci”)
`
`Thomson, A., “Back to basics: pharmacokinetics,” 272 Pharma. J
`769 (2004) (“Thomson”)
`
`U.S. Patent Publication No. 2006/0074046 (“Redkar”)
`
`Dintaman, et al., Pharmaceutical Research, 1999, 16(10), 1550-1556
`(“Dintaman”)
`
`U.S. Patent Publication No. 2004/0162263 (“Sands”)
`
`Application File History for the ʼ628 Patent, U.S. App. No.
`12/466,213 (“File History”)
`
`U.S. Patent No. 3,350,388
`
`Piskala, A. and Sorm, F., Collect. Czech. Chem. Commun., 29,
`2060-2076 (1964)
`
`Piskala, A. and Sorm, F., GB 1227691 (1971)
`
`U.S. Publication No. 2008/0057086 (“ʼ086 Publication”) (filed as
`U.S. Application No. 11/849,958 (“ʼ958 application”))
`
`- vii -
`
`

`

`
`
`Exhibit No. Description
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`GastroPlus version 5.2 Manual (“GP5.2 manual”)
`
`Exhibit number not used
`
`Kotke, M.K. and Rudnic, E.M, Ch. 10, Tablet Dosage Forms,
`MODERN PHARMACEUTICS, 4th ed. (2002) (“Modern Pharmaceutics”)
`
`Ch. 45, Oral Solid Dosage Forms, and Ch. 46, Coating of
`Pharmaceutical Dosage Forms, REMINGTON, THE SCIENCE AND
`PRACTICE OF PHARMACY, 20th ed., Lippincott Williams & Wilkins
`(2000) (“Remington”)
`
`Dover, G.J., et al., 5-Azacytidine Increases HbF Production and
`Reduces Anemia in Sickle Cell Disease: Dose-Response Analysis of
`Subcutaneous and Oral Dosage Regimens, Blood, 66(3): 527-532
`(Sep. 1985) (“Dover”)
`
`Hardy et al., Drug Delivery to the Gastrointestinal Tract, 1989 Ch. 7,
`83-96 (“Hardy”)
`
`Ewe et al., Digestive Diseases and Science, 1991, 36(2) 146-152
`(“Ewe”)
`
`Stoltz et al., Development of an Oral Dosage Form of Azacitidine:
`Overcoming Challenges in Chemistry, Formulation, and
`Bioavailability, Blood 108:4850 (2006) (“Stoltz”)
`
`Exhibit number not used
`
`U.S. Provisional Application No. 61/053,609 (“ʼ609 provisional”)
`
`Schwarz et al., Gastrointestinal Transit Times in Mice and Humans
`Measured With 27Al and 19F Nuclear Magnetic Resonance, Magnetic
`Resonance in Medicine 48:255-261, 260 (2002) (“Schwarz”)
`
`- viii -
`
`

`

`
`
`Exhibit No. Description
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`Amidon et al., A theoretical basis for a Biopharmaceutic Drug
`Classification - The correlation of in vitro drug product dissolution
`and in vivo bioavailability. Pharm. Res., 12:413-420 (1995)
`(“Amidon”)
`Buck et al., Prediction of Human Pharmacokinetics Using
`Physiologically Based Modeling: A Retrospective Analysis of 26
`Clinically Tested Drugs, Drug Metabolism & Disposition,
`35(10):17661780 (2007) (“Buck”)
`Dannenfelser et al., Development of Clinical Dosage Forms for a
`Poorly Water Soluble Drug I: Application of Polyethylene Glycol–
`Polysorbate 80 Solid Dispersion Carrier System, J Pharma. Sci.,
`93(5):1165(cid:31)1175 (2004) (“Dannenfelser”)
`Press Release, Simulations Plus, Inc., “Simulations Plus Releases
`GastroPlus(™) 5.2” (Nov. 30, 2006) (“GP5.2 PR”)
`IARC Monographs on the Evaluation of Carcinogenic Risks to
`Humans, Pharmaceutical Drugs, Vol. 50, 1990 (“IARC”)
`Israili et al., The Disposition and Pharmacokinetics in Humans of 5-
`Azacytidine Administered Intravenously as a Bolus or by Continuous
`Infusion, Cancer Res. 36:14531461 (1976) (“Israili”)
`Kuentz et al., A strategy for preclinical formulation development
`using GastroPlusTM as pharmacokinetic simulation tool and a
`statistical screening design applied to a dog study, Euro. J. Pharma.
`Sci., 27:9199 (2006) (“Kuentz”)
`Li et al., IV-IVC Considerations in the Development of Immediate-
`Release Oral Dosage Form, J Pharma. Sci. 94(7):13961417 (2005)
`(“Li”)
`Obach et al., The Prediction of Human Pharmacokinetic Parameters
`from Preclinical and In Vitro Metabolism Data, J. Pharma. & Exp.
`Thera., 283(1):4658 (1997) (“Obach”)
`Parrott & Lavé, Prediction of intestinal absorption: comparative
`assessment of gastroplus™ and idea™, Euro. J. Pharma. Sci.,
`17:5161 (2002) (“Parrott”)
`Simulations Plus, Inc., Form 10-QSB (January 16, 2007) (“SLP 10-
`QSB”)
`
`- ix -
`
`

`

`
`
`1049
`
`Exhibit No. Description
`FDA Guidance for Industry, Guideline for the Format and Content of
`the Human Pharmacokinetics and Bioavailability Section of an
`Application, February 1987 (“PK Guideline”)
`U.S. Provisional Application No. 61/157,875 (“ʼ875 provisional”)
`
`1050
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`1059
`
`
`
`U.S. Provisional Application No. 61/201,145 (“ʼ145 provisional”)
`
`The SDF file for the PubChem compound entry for Azacitidine
`(PubChem CID 9444) (September 16, 2004)
`(“Conformer3D_CID_9444 (1).sdf”), printed to PDF
`ADMET Predictor Output file (“Azacitidine ADMET.txt”), printed
`to PDF
`CDD file for 200 mg dose (“Azacitidine 200 mg.cdd”), printed to
`PDF
`IV plasma concentration-time data file for 200 mg dose
`(“Azacitidine 200 mg.ipd”), printed to PDF
`Result data file for 200 mg dose (“Azacitidine 200 mg All Data.txt”),
`printed to PDF
`CDD file for 400 mg dose (“Azacitidine 400 mg.cdd”), printed to
`PDF
`IV plasma concentration-time data file for 400 mg dose
`(“Azacitidine 400 mg.ipd”), printed to PDF
`Result data file for 400 mg dose (“Azacitidine 400 mg All Data.txt”),
`printed to PDF
`
`
`- x -
`
`

`

`
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte
`GmbH,
`IPR2019-01469, Paper 6 (P.T.A.B. Feb. 13, 2020) ...................................... 62, 63
`Almirall, LLC v. Amneal Pharms. LLC,
`28 F.4th 265 (Fed. Cir. 2022) ....................................................................... 25, 26
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8 (P.T.A.B. Dec. 15, 2017) ..................................... 63, 64
`In re De Blauwe,
`736 F.2d 699 (Fed. Cir. 1984) ............................................................................ 57
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) .......................................................................... 19
`Genentech, Inc. v. Hospira, Inc.,
`946 F.3d 1333 (Fed. Cir. 2020) .............................................................. 27, 28, 44
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 56
`King Pharms., Inc. v. Eon Labs, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) .......................................................................... 29
`Kyocera Wireless Corp. v. Int’l Trade Comm’n,
`545 F.3d 1340 (Fed. Cir. 2008) .......................................................................... 58
`Lyft, Inc. v. Rideshare Displays, Inc.,
`IPR2021-01601, Paper 7 (P.T.A.B. April 11, 2022) .......................................... 63
`Monsanto Tech. LLC v. E.I. DuPont de Nemours & Co.,
`878 F.3d 1336 (Fed. Cir. 2018) .......................................................................... 29
`Ohio Willow Wood Co. v. Alps S., LLC,
`735 F.3d 1333 (Fed. Cir. 2013) .......................................................................... 53
`Persion Pharms. LLC v. Alvogen Malta Operations Ltd.,
`945 F.3d 1184 (Fed. Cir. 2019) .................................................................... 49, 50
`
`- xi -
`
`

`

`
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) .......................................................................... 44
`Wabco Holdings Inc., et al., v. Transtex Composite Inc.,
`IPR2018-00737, Paper 8 (P.T.A.B. at Sept. 27, 2018) ....................................... 64
`Other Authorities
`Simulations Plus (https://www.simulations-plus.com/) .......................................... 14
`
`- xii -
`
`

`

`
`
`I.
`
`INTRODUCTION
`
`Petitioner Apotex Inc. requests inter partes review and cancellation of
`
`Claims 1, 2, 6-9, 11-28, 32-36, and 38-43 of U.S. Patent No. 8,846,628 (“’628
`
`patent”). The independent claims are generally directed to non-enteric coated
`
`(“NEC”) tablets of 5-azacytidine and methods of treatment of certain cancers using
`
`such tablets. Prior to the filing of the ’628 patent, non-enteric dosage forms of 5-
`
`azacytidine and its use to treat cancers were long known. Similarly, the dependent
`
`claims add no patentable value. They are simply directed to known formulation
`
`aspects, routine dosing parameters, and inherent pharmacokinetic properties.
`
`Specifically, the ’628 Patent claims are anticipated and obvious in view of
`
`the grounds below.
`
`Ground 1: Anticipation based on Ionescu. Ionescu anticipates Claims 1, 2,
`
`6-8, 11, 13-18, 20-23, 28, 32-35, 38, 40, 42, and 43 of the ʼ628 patent. (See infra
`
`V.A.) Specifically, Ionescu discloses a NEC tablet of 5-azacytidine and its use to
`
`treat one or more symptoms of a disease associated with abnormal cell
`
`proliferation such as MDS as recited in Claims 1 and 28. With respect to
`
`dependent claims, Ionescu discloses formulation and dosage limitations expressly,
`
`and PK limitations inherently (as confirmed by in silico modeling using GastroPlus
`
`software).
`
`- 1 -
`
`

`

`
`
`Ground 2: Obviousness over Ionescu in view of Atadja, Gibson, and the
`
`knowledge of a person of ordinary skill in the art (“POSA”). Claims 1, 2, 6-9,
`
`11-28, 32-36, and 38-43 would have been obvious over Ionescu in view of Atadja,
`
`Gibson, and the knowledge of a POSA. (See infra V.B.) Atadja discloses
`
`formulations of 5-azacytidine to treat one or more symptoms of a disease
`
`associated with abnormal cell proliferation with an oral tablet and according to the
`
`dependent dosage limitations. And Gibson—described by the ʼ628 patent as a
`
`“pertinent textbook[]” “in the field of pharmaceutical formulations”—teaches that
`
`oral dosage forms and, more specifically, that oral NEC tablets having film
`
`coatings like hydroxypropyl methyl-cellulose (“HPMC”), hydroxypropyl cellulose
`
`(“HPC”), or methyl-cellulose (“MC”) were the default and most preferred dosage
`
`form.
`
`Based on the foregoing and other knowledge, a POSA would have been
`
`motivated to pursue an oral, NEC tablet of 5-azacytidine from the dosage forms of
`
`Ionescu, including to treat one or more symptoms of a disease associated with
`
`abnormal cell proliferation such as MDS. A POSA would also have been
`
`motivated to pursue the formulation and dosage limitations recited in various
`
`dependent claims. Further, the dependent PK limitations are the inherent, natural
`
`results of administering the obvious formulation. The foregoing was further
`
`confirmed by in silico simulation using then-available GastroPlus software.
`
`- 2 -
`
`

`

`
`
`Overall, a POSA would have been motivated to arrive at the claimed inventions of
`
`Claims 1, 2, 6-9, 11-28, 32-36, and 38-43 with a reasonable expectation of success.
`
`Ground 3: Obviousness over Ionescu in view of Pharmion-PR, Atadja,
`
`Gibson, and the knowledge of a POSA. Claims 1, 2, 6-9, 11-28, 32-36, and 38-43
`
`would have been obvious over Ionescu in view of Pharmion-PR, Atadja, Gibson,
`
`and the knowledge of a POSA. (See infra V.C.) Building on Ground 2, Pharmion-
`
`PR additionally discloses a clinical study where patients with MDS were orally
`
`administered 5-azacytidine. The drug was well tolerated and sufficiently orally
`
`bioavailable. Based on the foregoing, a POSA would have been motivated to
`
`pursue and administer an oral, NEC tablet of 5-azacytidine, as claimed by the ’628
`
`patent, with a reasonable expectation of success.
`
`Secondary considerations of non-obviousness are unavailing. Secondary
`
`considerations, even if argued here, are insufficient to overcome such a strong
`
`prima facie case of obviousness. Moreover, Applicants’ purported results –
`
`“superior pharmacokinetic properties” (Cmax, Tmax, AUC, and relative oral
`
`bioavailability) of the NEC dosage forms of 5-azacytidine compared to enteric-
`
`coated dosage forms – were fully expected, not unexpected. Specifically, a POSA
`
`would have expected NEC oral dosage forms of 5-azacytidine to have higher Cmax,
`
`faster Tmax, and potentially greater overall bioavailability than enteric-coated oral
`
`dosage forms. Applicants’ comparative tests also fail to compare the claimed
`
`- 3 -
`
`

`

`
`
`inventions to the NEC tablets of Ionescu, the closest prior art. Applicants’
`
`comparisons, therefore, provide no meaningful information about the obviousness
`
`of the challenged claims.
`
`Institution Under § 325(d) Should Not Be Denied. Because Grounds 1-3
`
`present new references and/or disclosures not previously considered by the
`
`Examiner, institution should not be denied. Indeed, as to all grounds, (1) Ionescu
`
`was not substantively considered during prosecution and (2) in silico modeling
`
`using GastroPlus software, confirming inherency of recited PK limitations, was not
`
`before the examiner. As to Grounds 2 and 3, Atadja, Gibson, and Pharmion-PR
`
`were not before the Examiner.
`
`II. MANDATORY NOTICES
`
`A. Real Party-In-Interest
`
`Petitioner Apotex Inc. is a real party-in-interest. Additional real parties-in-
`
`interest are Apotex Corp., Apotex Pharmaceutical Holdings Inc., and Aposherm
`
`Delaware Holdings Corp. Out of an abundance of caution, Petitioner additionally
`
`identifies SK Capital Partners, LP as a potential real party-in-interest in view of it
`
`being a potential acquiror of Apotex entities.
`
`B. Related Matters
`
`Petitioner identifies the following related matters involving the ’628 patent:
`
`Celgene Corp. v. Accord Healthcare Inc., 1-21-cv-01795 (D. Del.).
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`C. Designation of Lead and Back-Up Counsel
`
`Petitioner identifies the following:
`
` Lead counsel:
`
`Vishal Gupta (Reg. No. 67,284)
`
` Back-up counsel: John J. Molenda (Reg. No. 47,804)
`
` Back-up counsel: Tyler Doh (Reg. No. 80,274)
`
` Back-up counsel: Robert Kappers (Reg. No. 70,202)
`
`The Office is authorized to charge all fees due in connection with this mater
`
`to Deposit Account No. 19-4293.
`
`D. Notice of Service Information
`
`Petitioner identifies the following:
`
` Email address:
`
` Mailing address:
`
`
`
`
`
`Azacitidine@Steptoe.com
`
`STEPTOE & JOHNSON LLP
`1114 Avenue of the Americas
`New York, NY 10036
`
`
`
`
`
`
`
`
`
`
`
` Telephone number:
`
`212-506-3900
`
` Fax number:
`
`
`
`212-506-3950
`
`Please address all correspondence to lead counsel at the address shown
`
`above. Petitioner consents to electronic service at the above-listed email address.
`
`III. REQUIREMENTS FOR INTER PARTES REVIEW
`
`A. Grounds for Standing
`
`Petitioner certifies that (1) the ’628 patent is available for inter partes review
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`and (2) Petitioner is not barred or estopped from requesting review of any claim on
`
`the grounds identified in this Petition.
`
`B.
`
`Identification of Challenge
`
`Petitioner requests review and cancellation of the ’628 patent claims
`
`pursuant to the following statement of precise relief requested:
`
`Ground
`
`1
`
`2
`
`3
`
`Claims
`1, 2, 6-8, 11, 13-18, 20-23,
`28, 32-35, 38, 40, 42, and 43 § 102(b)
`
`Basis
`
`References
`
`Ionescu (EX-1004)
`
`1, 2, 6-9, 11-28, 32-36, and
`38-43
`
`§ 103(a)
`
`1, 2, 6-9, 11-28, 32-36, and
`38-43
`
`§ 103(a)
`
`Ionescu (EX-1004) in
`view of Atadja (EX-1005)
`and Gibson (EX-1006)
`
`Ionescu (EX-1004) in
`view of Pharmion-PR
`(EX-1010), Atadja (EX-
`1005), and Gibson (EX-
`1006)
`
`
`IV. BACKGROUND
`
`A. Knowledge in the Prior Art Would Have Led a POSA to the
`Claimed Invention
`
`
`
`5-Azacytidine Was a Long-Known Therapeutic Compound
`for Treating One or More Symptoms of a Disease
`Associated With Abnormal Cell Proliferation Such As
`Myelodysplastic Syndrome and Acute Myelogenous
`Leukemia
`
`As of the earliest effective filing date, December 5, 2008 (see infra IV.B.4),
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`
`
`5-azacytidine was a well-known compound that had been used for treating one or
`
`more symptoms of a disease associated with abnormal cell proliferation such as
`
`myelodysplastic syndrome (“MDS”) and acute myelogenous leukemia (“AML”).
`
`5-azacytidine was first synthesized in the 1960s. (EX-1023; EX-1024; EX-1025.)
`
`It is an analogue of the natural cytidine nucleoside (found in DNA and RNA), and
`
`has the following structure:
`
`
`
`(EX-1001 at 2:33-61.)
`
`5-azacytidine was known to treat one or more symptoms of MDS, which
`
`“refers to a diverse group of hematopoietic stem cell disorders,” i.e., disorders that
`
`affect bone marrow. (EX-1001 at 1:39-67, 2:14-26.) Symptoms of MDS may
`
`include anemia, infections, bleeding, fatigue, and bruising, among others. (Id. at
`
`1:55-67.)
`
`The FDA approved 5-azacytidine for the treatment of symptoms of MDS by
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`

`
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`subcutaneous (“SC”) and intravenous (“IV”) administration in 2004 and 2007,
`
`respectively, under the trade name, Vidaza®. (See EX-1007; EX-1008; EX-1001 at
`
`3:48-50.) As approved, the recommended starting daily subcutaneous dose of 5-
`
`azacytidine was 75 mg/m2 (142.5 mg, on average), which may increase after two
`
`cycles to 100 mg/m2 (190 mg, on average). (EX-1007; EX-1008.) Other dosage
`
`forms and amounts were known and varied. (EX-1004 at 14:22-24; EX-1005 at
`
`27; EX-1009 at 10:35-37; EX-1016 at 4:53-54.)
`
` Oral Administration of 5-Azacytidine Was Known and
`Preferred at the Time of Invention
`
`Oral administration of 5-azacytidine was both known and preferred. Prior
`
`art examples describing the oral administration of 5-azacytidine are provided in the
`
`following table:
`
`Prior Art
`
`Vorbruggen
`(EX-1016)
`
`Ionescu
`(EX-1004)
`
`Atadja
`(EX-1005)
`
`Disclosure
`
`In 1974, Vorbruggen disclosed 5-Azapyrimidine
`nucleosides, including 5-azacytidine, for “oral
`administration.” (EX-1016 at Abstract, 1:4-18, 4:23-31,
`4:52-53, 7:21-31.)
`In 2004, Ionescu disclosed dosage units of 5-azacytidine
`for oral administration, including “coated tablets,
`capsules, or pulvules.” (EX-1004 at 13:11-12; id. at
`13:16-19, 13:28-14:7; see also EX-1009 at 9:19-10:16.)
`In 2004, Atadja disclosed that 5-azacytidine was
`“[p]referably, . . . administered as an oral pharmaceutical
`formulation in the form of a tablet, capsule or syrup . . . .”
`(EX-1005 at 27.)
`
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`

`

`
`
`Prior Art
`
`Disclosure
`
`Pharmion-PR
`(EX-1010)
`
`Pharmion-PR II
`(EX-1011)
`
`Pharmion 10-K
`(EX-1012)
`
`On June 2, 2007, Pharmion disclosed “data from a pilot
`study that demonstrated the bioavailability of the
`Company’s oral dosage formulation of Azacitidine.”
`(EX-1010 at -0005.) “In each case, Azacitidine was well-
`tolerated and quantifiable in plasma.” (Id.)
`On August 29, 2007, Pharmion disclosed: “The
`opportunity to explore the biological and clinical
`consequences of continuous oral dosing of Azacitidine is
`particularly exciting, since we know that DNA
`remethylation occurs between cycles of intermittent
`parenteral therapy.” (EX-1011 at -0005.)
`On February 29, 2008, Pharmion reported on its oral
`formulation of azacytidine and the “significant body of
`evidence showing that the biological effects of
`demethylating agents may be improved or extended
`through sustained DNA demethylation, which could most
`effectively be provided through oral delivery.” (EX-1012
`at 7.)
`
`5-azacytidine was known to be readily soluble in water across physiological
`
`pH. (EX-1042, IARC at 48 (40 mg/ml in warm water and 28 mg/ml in 0.1N
`
`HCl).) Accordingly, a POSA would have been motivated to formulate 5-
`
`azacytidine as an oral dosage form using a conventional formulation. (EX-1002,
`
`Buckton Decl. ¶43.) Oral dosage forms of 5-azacytidine were also preferred over
`
`SC and IV dosage forms, at least to improve patient convenience and compliance
`
`and to eliminate injection-site reactions. (EX-1010 at -0005; EX-1011 at -0005;
`
`EX-1004; EX-1005 at 27; EX-1006 at 379; EX-1029 at Ch. 10, I.-II.A; EX-1030 at
`
`- 9 -
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`
`
`858.)
`
`Oral dosage forms of 5-azacytidine were also preferred over parenteral
`
`dosage forms to “maximize demethylation and gene re-expression,” thereby
`
`improving the biological effect of 5-azacytidine. (EX-1010 at -0005.) It was
`
`known, for example, “that DNA remethylation occurs between cycles of
`
`intermittent parenteral therapy” causing cells to again proliferate abnormally. (EX-
`
`1011 at -0005 (emphasis added); see also EX-1012.) On the other hand, oral
`
`dosage forms provided a new opportunity for continuous, low-dose regimens of 5-
`
`azacytidine, which could improve its biological effect by sustaining and
`
`maximizing demethylation and gene re-expression. (EX-1010 at -0005; EX-1011
`
`at -0005; EX-1012.)
`
`
`
`NEC Tablets of 5-Azacytidine Were Known and Preferred
`
`NEC tablets of 5-azacytidine were known and were the preferred
`
`formulation at the time of invention. The ʼ628 patent teaches that its oral
`
`formulations “may be prepared using conventional methods known to those skilled
`
`in the field of pharmaceutical formulation, as described, e.g., in pertinent
`
`textbooks.” (EX-1001 at 37:20-32.) Conventional oral dosage forms (e.g., tablets)
`
`of 5-azacytidine were well known. (See generally EX-1001 at 37:20-32; EX-1006;
`
`EX-1029; EX-1004 at 13:16-19; EX-1030; EX-1005 at 27; EX-1021 [0033]; EX-
`
`1019 [0128].) Tablets were most preferred. (EX-1006 at 379, 380, Table 11.1; see
`
`- 10 -
`
`

`

`
`
`also EX-1029 at Ch. 10, II.A; EX-1030 at 858; EX-1026 at [0033].)
`
`Ionescu (EX-1004), for example, teaches NEC tablets of 5-azacytidine, i.e.,
`
`tablets that “do[] not comprise a coating intended to release the active ingredient(s)
`
`beyond the stomach (e.g., in the intestine).” (EX-1001 at 11:42-48.) Specifically,
`
`Ionescu teaches that pharmaceutical compositions of 5-azacytidine may comprise
`
`sugar-coated tablets. (EX-1004 at 13:16-19.) At a minimum, the sugar-coated
`
`tablets of Ionescu are NEC and “provide quick . . . release