UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________
`
`
`
`EVERGREEN THERAGNOSTICS, INC.
`
`Petitioner
`
`– vs. –
`
`ADVANCED ACCELERATOR APPLICATIONS SA
`
`Patent Owner
`
`____________________
`
`CASE NO. PGR2021-00002
`
`
`
`PETITION FOR
`
`POST GRANT REVIEW OF U.S. PATENT NO. 10,596,278
`
`(ALL CLAIMS)
`
`
`
`
`
`
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`TABLE OF CONTENTS
`
`
`Page
`INTRODUCTION ........................................................................................... 1
`I.
`GROUNDS FOR STANDING (37 C.F.R. § 42.204(a)) ................................. 2
`II.
`III. OVERVIEW OF THE TECHNOLOGY AND THE ’278 PATENT ............. 2
`A.
`Background of the Technology ............................................................. 2
`B.
`The ’278 Patent ..................................................................................... 4
`1.
`Summary of the Specification of the ’278 Patent ....................... 4
`2.
`Summary of the Claims of the ’278 Patent ................................. 5
`3.
`Summary of the Relevant Portions of the Prosecution
`History ......................................................................................... 5
`IV. CLAIMS FOR WHICH PGR IS REQUESTED, PRECISE RELIEF
`REQUESTED, AND SPECIFIC STATUTORY GROUNDS ON WHICH
`THE CHALLENGE IS BASED (37 C.F.R. § 42.22(a) AND 37 C.F.R. §
`42.204(b)) ........................................................................................................ 8
`A.
`Prior Art Patents and Printed Publications Relied Upon ...................... 8
`B.
`Level of Ordinary Skill in the Art ....................................................... 13
`C.
`Claim Construction ............................................................................. 13
`D. Overview of the Prior Art .................................................................... 14
`1. Maus (Ex. 1009) ........................................................................ 14
`2.
`Kwekkeboom (Ex. 1010) .......................................................... 17
`3.
`Prior art disclosing routine use of an acetic acid/sodium
`acetate buffer to maintain pH during complexation ................. 17
`The ’536 Patent (Ex. 1013) ....................................................... 19
`de Blois (Ex. 1017) ................................................................... 19
`
`4.
`5.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`SEC Statement (Ex. 1018) ........................................................ 20
`6.
`Luna-Gutierrez (Ex. 1025) ........................................................ 21
`7.
`Scott (Ex. 1015) ........................................................................ 21
`8.
`Challenge 1: Independent Claim 1 and Dependent Claims 8-17 and
`19 Are Anticipated by Maus (Ex. 1009) ............................................. 22
`1.
`Independent Claim 1 ................................................................. 22
`2.
`Dependent Claims 8-17 and 19 ................................................. 26
`Challenge 2: Independent Claim 1 and Dependent Claims 8-17 and
`19 Would Have Been Obvious Over Maus (Ex. 1009) Alone or in
`View of Kwekkeboom (Ex. 1010) ...................................................... 29
`1.
`Independent Claim 1 ................................................................. 29
`2.
`Dependent Claims 8-17 and 19 ................................................. 32
`Challenge 3: Dependent Claims 2-4 Would Have Been Obvious
`Over Maus (Ex. 1009) Alone or in View of Kwekkeboom (Ex.
`1010) Further in View of the Knowledge of a POSA that Ascorbic
`Acid and Sodium Ascorbate Are Interchangeable as Radiolytic
`Stabilizers as Evidenced by Scott (Ex. 1015) ..................................... 34
`1.
`Claim 2 ...................................................................................... 34
`2.
`Claim 3 ...................................................................................... 36
`3.
`Claim 4 ...................................................................................... 36
`Challenge 4: Dependent Claim 15 Would Have Been Obvious
`Over Maus (Ex. 1009) Alone or in View of Kwekkeboom (Ex.
`1010) Further in View of de Blois (Ex. 1017) and SEC Statement
`(Ex. 1018) ............................................................................................ 37
`Challenge 5: Dependent Claim 18 Would Have Been Obvious
`Over Maus (Ex. 1009) Alone or in View of Kwekkeboom (Ex.
`1010) Further in View of the Knowledge of a POSA That the
`Volume of a Pharmaceutical Aqueous Solution Can Vary ................. 39
`
`E.
`
`F.
`
`G.
`
`H.
`
`I.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`J.
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`K.
`
`L.
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`Challenge 6: Dependent Claims 5-7 Would Have Been Obvious
`Over Maus (Ex. 1009) Alone or in View of Kwekkeboom (Ex.
`1010), Further in View of De León-Rodríguez (Ex. 1014) and/or
`Banerjee (Ex. 1016) ............................................................................. 40
`1.
`Claim 5 ...................................................................................... 41
`2.
`Claim 6 ...................................................................................... 44
`3.
`Claim 7 ...................................................................................... 45
`Challenge 7: Dependent Claims 5-7 Would Have Been Obvious
`Over Maus (Ex. 1009) Alone or in View of Kwekkeboom (Ex.
`1010), Further in View of the ’536 Patent (Ex. 1013), Further in
`View of De León-Rodríguez (Ex. 1014) and/or Banerjee (Ex. 1016)
` ............................................................................................................. 46
`1.
`Claim 5 ...................................................................................... 46
`2.
`Claim 6 ...................................................................................... 50
`3.
`Claim 7 ...................................................................................... 51
`Challenge 8: Independent Claim 20 Would Have Been Obvious
`Over Maus (Ex. 1009) alone or in View of Kwekkeboom (Ex. 1010)
`Further in View of Knowledge that Ascorbic Acid and Sodium
`Ascorbate Are Interchangeable as Radiolytic Stabilizers as
`Evidenced by Scott (Ex. 1015) Further in View of De León-
`Rodríguez (Ex. 1014) and/or Banerjee (Ex. 1016) ............................. 52
`1.
`A pharmaceutical aqueous solution .......................................... 53
`2.
`comprising: (a) a complex formed by (ai) the radionuclide
`177Lu (Lutetium-177) in a concentration that it provides a
`volumetric radioactivity of from 250 to 500 MBq/mL, and
`(aii) DOTA-TATE or DOTA-TOC .......................................... 53
`(b) the stabilizers against radiolytic degradation comprising
`(bi) gentisic acid in a concentration of from 0.5 to 1 mg/mL
`and (bii) ascorbic acid in a concentration of from 2.0 to 5.0
`mg/mL ....................................................................................... 53
`
`3.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`4.
`
`5.
`
`6.
`
`7.
`
`(c) diethylentriaminepentaacetic acid (DTPA) or a salt
`thereof in a concentration of from 0.01 to 0.10 mg/mL ........... 54
`(d) an acetate buffer composed of: (di) acetic acid in a
`concentration of from 0.3 to 0.7 mg/mL; and (dii) sodium
`acetate in a concentration from 0.4 to 0.9 mg/mL .................... 54
`wherein the pharmaceutical aqueous solution has less than
`1% ethanol ................................................................................. 55
`the radiochemical purity ( determined by HPLC) of the
`solution is maintained at ≥95% for at least 72 h when stored
`at 25° C. ..................................................................................... 55
`M. Challenge 9: Independent Claim 20 Would Have Been Obvious
`Over Maus (Ex. 1009) Alone or in View of Kwekkeboom (Ex.
`1010) Further in View of the ’536 Patent (Ex. 1013) Further in
`View of the Knowledge of a POSA that Ascorbic Acid and Sodium
`Ascorbate Are Interchangeable as Radiolytic Stabilizers as
`Evidenced by Scott (Ex. 1015) Further in View of De León-
`Rodríguez (Ex. 1014) and/or Banerjee (Ex. 1016) ............................. 56
`1.
`A pharmaceutical aqueous solution .......................................... 57
`2.
`comprising: (a) a complex formed by (ai) the radionuclide
`177Lu (Lutetium-177) in a concentration that it provides a
`volumetric radioactivity of from 250 to 500 MBq/mL, and
`(aii) DOTA-TATE or DOTA-TOC .......................................... 57
`(b) the stabilizers against radiolytic degradation comprising
`(bi) gentisic acid in a concentration of from 0.5 to 1 mg/mL
`and (bii) ascorbic acid in a concentration of from 2.0 to 5.0
`mg/mL ....................................................................................... 57
`(c) diethylentriaminepentaacetic acid (DTPA) or a salt
`thereof in a concentration of from 0.01 to 0.10 mg/mL ........... 58
`(d) an acetate buffer composed of: (di) acetic acid in a
`concentration of from 0.3 to 0.7 mg/mL; and (dii) sodium
`acetate in a concentration from 0.4 to 0.9 mg/mL .................... 58
`
`3.
`
`4.
`
`5.
`
`
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`
`6.
`
`7.
`
`wherein the pharmaceutical aqueous solution has less than
`1% ethanol ................................................................................. 59
`the radiochemical purity ( determined by HPLC) of the
`solution is maintained at ≥95% for at least 72 h when stored
`at 25° C ...................................................................................... 59
`Challenge 10: Dependent Claims 21-25 Would Have Been
`Obvious Over Maus (Ex. 1009) Alone or in View of Kwekkeboom
`(Ex. 1010) Further in View of Knowledge that Ascorbic Acid and
`Sodium Ascorbate Are Interchangeable as Radiolytic Stabilizers as
`Evidenced by Scott (Ex. 1015) Further in View of De León-
`Rodríguez (Ex. 1014) and/or Banerjee (Ex. 1016), Optionally in
`View of the ’536 Patent (Ex. 1013) .................................................... 60
`1.
`Claim 21 .................................................................................... 60
`2.
`Claim 22 .................................................................................... 61
`3.
`Claim 23 .................................................................................... 61
`4.
`Claim 24 .................................................................................... 63
`5.
`Claim 25 .................................................................................... 64
`Challenge 11: If Claims 8 and 11-14 Are Not Construed as
`Product-By-Process Claims, They Would Have Been Obvious Over
`Maus (Ex. 1009), Optionally in View of Kwekkeboom (Ex. 1010),
`and in View of the ’536 Patent (Ex. 1013) .......................................... 65
`Challenge 12: If Claims 9 and 10 Are Not Construed as Product-
`By-Process Claims, They Would Have Been Obvious Over Maus
`(Ex. 1009) Optionally in View of Kwekkeboom (Ex. 1010), Further
`in View of the ’536 Patent (Ex. 1013) and Knowledge that Ascorbic
`Acid and Sodium Ascorbate Are Interchangeable as Radiolytic
`Stabilizers as Evidenced by Scott (Ex. 1015) ..................................... 71
`Challenge 13: If Claim 17 Is Not Construed as a Product-By-
`Process Claim, It Would Have Been Obvious Over Maus (Ex.
`1009) Alone or in View of Kwekkeboom (Ex. 1010) Further in
`View of Knowledge That Batch Size Can Vary as Evidenced by
`Luna-Gutierrez (Ex. 1025) .................................................................. 73
`
`N.
`
`O.
`
`P.
`
`Q.
`
`
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`

`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`
`S.
`
`R. Objective Considerations of Non-Obviousness Do Not Affect
`Obviousness Challenges (2-13) ........................................................... 75
`Challenge 14: If the Recited Stability Limitations Are Anticipated
`or Rendered Obvious by the Pharmaceutical Aqueous Solutions
`Taught in the Prior Art the Claims of the ’278 Patent Are Not
`Enabled for their Full Scope ................................................................ 75
`CONCLUSIONS ........................................................................................... 79
`V.
`VI. MANDATORY NOTICES ........................................................................... 79
`A.
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) ................................ 79
`B.
`Related Matters (37 C.F.R. § 42.8(b)(2)) ............................................ 79
`C. Designation of Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)) .. 81
`D.
`Service of Information (37 C.F.R. § 42.8(b)(4)) ................................. 81
`CERTIFICATE OF SERVICE ................................................................................ 83
`CERTIFICATE OF WORD COUNT ...................................................................... 84
`
`
`
`
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`

`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Amgen, Inc. v. Hoffmann-La Roche Ltd.,
`580 F.3d 1340 (Fed. Cir. 2009) .................................................................... 27, 32
`Atlas Powder Co. v. Ireco Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) .............................................................. 26, 28, 33
`
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) ............................................................................ 23
`
`In re Best,
`562 F.2d 1252 (C.C.P.A. 1977) .............................................................. 26, 28, 33
`
`Hulu, LLC,
`IPR2018-01039, Paper 29 ..................................................................................... 8
`
`Iron Grip Barbell Co., Inc. v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) ........................................................ 44, 45, 50, 52
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) .................................................................... 26, 27
`
`Uber Tech., Inc. v. X One, Inc.,
`957 F.3d 1334 (Fed. Cir. 2020) .......................................................................... 62
`Valeant Pharma. Inc. v. Mylan Pharma. Inc.,
`955 F.3d 25 (Fed. Cir. 2020) ........................................................................ 62, 63
`Statutes
`35 U.S.C. § 102 .......................................................................................................... 9
`35 U.S.C. § 102(a) ..................................................................................................... 8
`35 U.S.C. § 103 ............................................................................................ 10, 11, 12
`35 U.S.C. § 112 ........................................................................................................ 12
`35 U.S.C. §§ 321-329 ................................................................................................ 1
`- vii -
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`

`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`Other Authorities
`37 C.F.R. § 42 ............................................................................................................ 1
`37 C.F.R. § 42.8(b)(1) .............................................................................................. 79
`37 C.F.R. § 42.8(b)(2) .............................................................................................. 79
`37 C.F.R. § 42.8(b)(3) .............................................................................................. 81
`37 C.F.R. § 42.8(b)(4) .............................................................................................. 81
`37 C.F.R. §42.24(a) .................................................................................................. 84
`37 C.F.R. § 42.103 ..................................................................................................... 1
`37 C.F.R. § 42.204 ..................................................................................................... 1
`37 C.F.R. § 42.204(a) ................................................................................................. 2
`37 C.F.R. § 42.204(b) ................................................................................................ 8
`37 C.F.R. § 42.22(a) ................................................................................................... 8
`37 C.F.R. § 42.205 ................................................................................................... 83
`83 Fed. Reg. 197 (Oct. 11, 2018) ............................................................................. 13
`
`
`
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`- viii -
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`

`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`PETITIONER’S EXHIBIT LIST
`
`Exhibit
`1001
`
`Number Not Used
`
`Description
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`U.S. Patent No. 10,596,278 (“the ’278 patent”)
`
`Number Not Used
`
`Prosecution History of U.S. Patent No. 10,596,278 (Application
`Serial No. 16/175,239) (“the ’239 application”)
`
`Number Not Used
`
`Number Not Used
`
`Declaration of Stephan Maus Under 37 C.F.R. § 1.68 in Support of
`Petition for Post Grant Review of U.S. Patent No. 10,596,278 (All
`Claims)
`
`Expert Declaration of Ingrid Hsieh-Yee, Ph.D. Under 37 C.F.R.
`§ 1.68 (“Hsieh-Yee Declaration”)
`
`S. Maus, et al., Aspects on radiolabeling of 177Lu-DOTA-TATE: After
`C18 purification re-addition of ascorbic acid is required to maintain
`radiochemical purity, Int. J. Diagnostic Imaging, 1(1):5-12, 2014
`(“the Maus article”)
`
`D. Kwekkeboom et al., [177Lu-DOTA0,Tyr3]octreotate: comparison
`with [111In-DTPA0]octreotide in patients, Eur. J. Nucl. Med.,
`28(9):1319-1325, Sept. 2001 ( “Kwekkeboom”)
`
`J. Strosberg et al., Phase 3 Trial of 177Lu-Dotatate for Midgut
`Neuroendocrine Tumors, N. Engl. J. Med., 376(2):125–135, Jan. 12,
`2017 (“Strosberg”)
`
`Number Not Used
`
`U.S. Patent No. 6,261,536 (“the ’536 patent”)
`
`
`
`- ix -
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`

`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`
`1014
`
`1015
`
`1016
`
`1017
`
`L. De León-Rodríguez et al., The Synthesis and Chelation Chemistry
`of DOTA−Peptide Conjugates, Bioconjugate Chem., 19(2):391-402,
`Feb. 2008 (“De León-Rodríguez”)
`
`P. Scott et al., Studies into Radiolytic Decomposition of Fluorine-18
`Labeled Radiopharmaceuticals for Positron Emission Tomography,
`Appl. Radiat. Isot., 67(1): 88-94 Jan. 2009 (“Scott”)
`
`S. Banerjee et al., Lutetium-177 Therapeutic Radiopharmaceuticals:
`Linking Chemistry, Radiochemistry, and Practical Applications,
`Chem. Rev., 115:2934−2974, 2015 (“Banerjee”)
`
`E. de Blois et al., Application of single-vial ready-for-use formulation
`of 111In- or 177Lu-labelled somatostatin analogs, Applied Radiation
`and Isotopes, 85:28-33, 2014 (“de Blois”)
`
`1018
`
`United States Security and Exchange Commission Form F-1 for
`Advanced Accelerator Applications S.A., 2014 (“SEC Statement”)
`
`1019
`
`Number Not Used
`
`1020 W. Breeman et al., Optimising conditions for radiolabelling of
`DOTA-peptides with 90Y, 111In and 177Lu at high specific activities,
`Eur. J, Nuc. Med. and Molecular Imaging, 30(6):917-920, June 2003
`(“Breeman 2003”)
`
`1021
`
`1022
`
`T. Das et al., Formulation of Patient Dose of 177Lu-DOTA-TATE in
`Hospital Radiopharmacy in India: Preparation Using In Situ
`Methodology Vis-a-Vis Freeze-Dried Kit, Cancer Biotherapy and
`Radiopharmaceuticals, 29(7):301-302, 2014 (“Das 1”)
`
`T. Das et al., Preparation of DOTA-TATE and DOTA-NOC freeze-
`dried kits for formulation of patient doses of 177Lu-labeled agents and
`their comparison for peptide receptor radionuclide therapy
`application, J. Radioanal. Nucl. Chem., 299:1389-1398, 2014 (“Das
`2”)
`
`1023
`
`S. Liu et al., Stabilization of 90Y-Labeled DOTA-Biomolecule
`Conjugates Using Gentisic Acid and Ascorbic Acid, Bioconjugate
`Chem., 12:554-558, 2001 (“Liu”)
`
`
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`
`1024
`
`Number Not Used
`
`1025 M. Luna-Gutiérrez et al., Freeze-dried multi-dose kits for the fast
`preparation of 177Lu-Tyr3-octreotide and 177Lu-PSMA(inhibitor)
`under GMP conditions, J. Radioanal. Nucl. Chem., pp. 2181-2188,
`published on-line Nov. 2, 2017 (“Luna-Gutierrez”)
`
`1026
`
`J. Sosabowski et al., Conjugation of DOTA-like chelating agents to
`peptides and radiolabeling with trivalent metallic isotopes, Nature
`Protocols, 1(2):972-976, 2006 (“Sosabowski”)
`
`1027 W. Breeman et al., Overview of Development and Formulation of
`177Lu-DOTA-TATE for PRRT, Current Radiopharmaceuticals, 9:8-18,
`2016 (“Breeman 2016”)
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`A. Filice et al., Radiolabeled Somatostatin Analogues Therapy in
`Advanced Neuroendocrine Tumors: A Single Centre Experience, J.
`Oncology, 2012:1-10, Aug. 9, 2012 (“Filice”)
`
`Number Not Used
`
`Guidance for Industry, Q1A(R2) Stability Testing of New Drug
`Substances and Products, U.S. Department of Health and Human
`Services, Food and Drug Administration, Center for Drug Evaluation
`and Research (CDER), Center for Biologics Evaluation and Research
`(CBER), Nov. 2003 (“FDA Guidance”)
`
`T. Das et al., On the preparation of a therapeutic dose of 177Lu-
`labeled DOTA–TATE using indigenously produced 177Lu in medium
`flux reactor, Applied Radiation and Isotopes, 65:301-308, 2007 (“Das
`3”)
`
`A. Aslani et al., Lutetium-177 DOTATATE Production with an
`Automated Radio-pharmaceutical Synthesis System, Asia Oceania J.
`Nucl. Med. Biol., 3(2):107-115, 2015 (“Aslani”)
`
`1033 W. Lambert, Considerations in Developing a Target Product Profile
`for Parenteral Pharmaceutical Products, AAPS Pharm. Sci. Tech.,
`11(3):1476-1481, Sept. 2010 (“Lambert”)
`
`
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`
`1034
`
`J. Zakun et al., The joint IAEA, EANM, and SNMMI practical
`guidance on peptide receptor radionuclide therapy (PRRNT) in
`neuroendocrine tumours, Eur J Nucl Med Mol Imaging, 40:800-816,
`Feb. 2013 (“Zakun”)
`
`1035 W. Breeman et al., The addition of DTPA to [177Lu-DOTA0,
`Tyr3]octreotate prior to administration reduces rat skeleton uptake of
`radioactivity, Eur. J. Nucl. Med. Mol. Imaging, 30(2):312-315, Feb.
`2003 (“Breeman 2003B”)
`
`1036
`
`A. Frilling et al., Treatment with 90Y- and 177Lu-DOTATOC in
`patients with metastatic neuroendocrine tumors, Surgery,140(6):968-
`977, 2006 (“Frilling”)
`
`
`Note Regarding Citations
`
`For patent exhibits, Petitioner’s citations will be to the figure or the column and
`
`line numbers of the specification. For all other exhibits, Petitioner’s citations are
`
`to the original page numbers and not to the page numbers added for compliance
`
`with 37 C.F.R. § 42.63(d)(2)(i).
`
`
`
`- xii -
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`Evergreen Theragnostics, Inc. (“Petitioner”) petitions for Post Grant Review
`
`of claims 1-25 of U.S. Patent No. 10,596,278 (“the ’278 patent”) (Ex. 1002), which
`
`is assigned to Advanced Accelerator Applications SA (“Patent Owner”), under 35
`
`U.S.C. §§ 321-329 and 37 C.F.R. § 42 and seeks cancellation of all claims (1-25) of
`
`the ’278 patent as unpatentable.
`
`This Petition is filed in accordance with 37 C.F.R. § 42.204. Filed herewith
`
`is a power of attorney and exhibit list per § 42.10(b) and § 42.63(e). Pursuant to 37
`
`C.F.R. § 42.203, the fee set forth in § 42.15(b) accompanies this Petition. The
`
`undersigned authorizes the Office to charge any additional fees that may be due in
`
`connection with this Petition from EFT Account No. 536.
`
`I.
`
`INTRODUCTION
`
`The ’278 patent purports to disclose novel pharmaceutical aqueous solutions
`
`containing (1) 177Lu complexed with a somatostatin receptor binding peptide linked
`
`to the chelating agent DOTA, such as DOTA-TATE, and (2) the stabilizers gentisic
`
`and ascorbic acids (or their salts) in recited amounts. The solutions also include a
`
`functional limitation regarding maintenance of radiochemical purity for 72 hours.
`
`Such pharmaceutical solutions are not novel.
`
`The prior art disclosed a composition that meets each and every limitation
`
`recited in various claims of the ’278 patent, either literally or inherently. See, e.g.,
`
`
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`- 1 -
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`

`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`composition disclosed in Maus (Ex. 1009) at 7, section 2.2; see also Ex. 1007, Maus
`
`Declaration, ¶¶105-138. Thus, certain claims are anticipated by the prior art.
`
`Those claims that are not anticipated recite that the composition includes
`
`minor additional limitations that the prior art taught were routine in relation to 177Lu-
`
`containing solutions, and, thus, those claims would have been obvious over the prior
`
`art. Alternatively, if it is determined that any claim is novel and nonobvious, then
`
`that claim lacks enablement for its full scope.
`
`Thus, Petitioner respectfully requests the Board cancel claims 1-25.
`
`II. GROUNDS FOR STANDING (37 C.F.R. § 42.204(a))
`
`The undersigned and Petitioner certify that the ’278 patent is available for post
`
`grant review. The ’278 patent issued on March 24, 2020, less than nine months ago,
`
`and has an earliest possible effective filing date of July 25, 2018. See section III.B,
`
`below; Ex. 1002. Petitioner also certifies that it is not barred or estopped from
`
`requesting this post grant review on the grounds identified herein.
`
`III. OVERVIEW OF THE TECHNOLOGY AND THE ’278 PATENT
`A. Background of the Technology
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`Complexes of 177Lu with DOTA-TATE and DOTA-TOC were well-known in
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`the art. Ex. 1007, ¶45; see also, Ex. 1009, Maus; Ex. 1016, Banerjee at 2941-2942
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`and 2951-2953; Ex. 1017, de Blois at 29; Ex. 1020, Breeman 2003 at 917-918; Ex.
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`1027, Breeman 2016 at 8-9.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`The complex of 177Lu and DOTA-TATE- or DOTA-TOC was typically
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`formed by reacting DOTA-TATE or DOTA-TOC with 177LuCl3 in an aqueous
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`solution. Ex. 1007, ¶47; see also Ex. 1009; Ex. 1010, Kwekkeboom; Ex. 1017; Ex.
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`1021, Das 1 at 301; Ex. 1022, Das 2 at 1391; Ex. 1027.
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`It was known in the prior art that the optimal pH for the reaction was a pH of
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`between 5 and 6, usually with a buffer. Ex. 1007, ¶47; see also Ex. 1014, De León-
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`Rodríguez at 395; Ex. 1016 at 2941; Ex. 1022 at 1391. A pH of between 5 and 6 is
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`optimal because, while the rate of formation of Lu3+-DOTA complexes increases
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`with increasing pH, the solubility of Lu3+ decreases above a pH of 6. Ex. 1007, ¶47,
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`see also Ex. 1014 at 395. An acetic acid/sodium acetate buffer was routinely used
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`as a buffer because it could achieve the desired balance without interfering with the
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`complexation reaction. Ex. 1007, ¶48; see also Ex. 1014 at 395; Ex. 1017 at 29; Ex.
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`1020 at 918; Ex. 1016 at 2941; Ex. 1026, Sosabowski at 973; Ex. 1022 at 1391.
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`177Lu DOTA-TATE-
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`and DOTA-TOC-containing
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`pharmaceutical
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`compositions were vulnerable to radiolysis, resulting in decreased radiochemical
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`purity (“RCP”) of the radiopeptide. Ex. 1007, ¶49; see also Ex. 1009 at Abstract;
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`Ex. 1017 at 29; Ex. 1023, Liu at 556. Therefore, stabilizers, such as gentisic acid
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`and/or ascorbic acid, were routinely used to minimize radiolytic degradation. Ex.
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`1007, ¶49; see also Ex. 1009; Ex. 1017, de Blois at 29; Ex. 1016 at 2942; Ex. 1025,
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`Luna-Gutierrez at 2182 and 2187; Ex. 1026 at 973.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`Additionally, it was routine to include a sequestering agent, such as
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`diethylentriaminepentaacetic acid (DTPA) to chelate free 177Lu ions that did not
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`complex. Ex. 1007, ¶51; see also Ex. 1009 at 8; Ex. 1017 at 29; Ex. 1027 at 11.
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`Free 177Lu ions were known to cause severe radiotoxic effects upon administration.
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`Id. Chelating the free 177Lu ions facilitates their renal excretion and minimizes the
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`adverse radiotoxic effects. Id; see also Ex. 1035, Breeman 2003B at 312; Ex. 1017
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`at 29; Ex. 1027 at 11.
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`B.
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`The ’278 Patent
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`The ’278 patent, entitled “Stable, Concentrated Radionuclide Complex
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`Solutions,” issued on March 24, 2020, from Application No. 16/175,239, filed on
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`October 30, 2018, as a continuation of Application No. 16/140,962, filed on
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`September 25, 2018, which is a continuation-in-part of Application No. 16/045,484,
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`filed on Jul. 25, 2018.
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`1.
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`Summary of the Specification of the ’278 Patent
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`The ’278 patent is generally directed to pharmaceutical aqueous compositions
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`containing complexes of radionuclides with cell receptor binding organic moieties
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`linked to chelating agents and having at least one stabilizer. Ex. 1002 at 2:58-64.
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`The ’278 patent discloses that the radionuclide can be 177lutetium, the moiety linked
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`to a chelating agent can be a somatostatin receptor binding organic moiety linked to
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`DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide), and the stabilizers
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`against radiolytic degradation can be gentisic and ascorbic acids (or salts thereof).
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`Ex. 1002 at 3:5-18. The ’278 patent also discloses methods for making the
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`compositions. Ex. 1002 at 3:19-36.
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`The ’278 patent asserts that the compositions are “chemically and
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`radiochemically very stable even if stored at ambient or short term elevated
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`temperatures so that [they] can be produced on commercial scale and supplied as
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`ready-to-use radiopharmaceutical product[s].” Ex. 1002 at 2:50-55.
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`2.
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`Summary of the Claims of the ’278 Patent
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`The ’278 patent includes two independent claims (claims 1 and 20). Claims
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`2-19 depend directly or indirectly from claim 1 and claims 21-25 depend directly
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`from claim 20. The claims generally relate to pharmaceutical aqueous solutions
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`comprising a complex of 177lutetium with a somatostatin receptor binding peptide
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`linked to the chelating agent DOTA and a combination of gentisic and ascorbic acids
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`(or their salts) as stabilizers.
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`3.
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`Summary of the Relevant Portions of the Prosecution
`History
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`In a first Office Action, the Examiner found the then-pending claims
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`unpatentable as obvious over US 2007/0269375A1 (“Chen”) in view of Maus. Ex.
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`1004, File History of the ’278 patent, Office Action, Jan. 25, 2019, at 2-4. Original
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`claim 1 is representative:
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`1. A pharmaceutical aqueous solution comprising:
`(a) a complex formed by
`(ai) the radionuclide 177Lu (Lutetium-177), and
`(aii) a somatostatin receptor binding peptide linked
`to the chelating agent DOTA; and
`(b) at least two different stabilizers against radiolytic
`degradation;
`wherein
`said radionuclide is present in a concentration that
`it provides a volumetric radioactivity of from 250 to
`500 MBq/mL; and
`said stabilizers are present in a total concentration
`of from 0.2 to 20.0 mg/mL.
`
`Id., Original Claims, filed Oct. 30, 2018.
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`In response, Applicants amended the claims to require “(bi) gentisic acid or a
`
`salt thereof; and (bii) ascorbic acid or a salt thereof” as stabilizers in the solution.
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`Id., Response to Office Action, Apr. 24, 2019, at 2. Applicants argued that a person
`
`of ordinary skill in the art would not have been motivated to combine Chen and
`
`Maus and that even if there was a motivation to combine, the claimed compositions
`
`achieved unexpected stability. Applicants further argued that Chen and Maus each
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`taught higher stabilizer concentrations than those claimed. Id., Response to Office
`
`Action, Apr. 24, 2019, at 6-10.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`In a second Office Action, the Examiner found the claims unpatentable as
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`obvious over de Blois in view of Singh et al., Ind. J. Nucl. Med., 26:135-138, 2014
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`(“Singh”), and Stip. Republic of Macedonia, October 1-5, 2012 (“RCM Meeting”),
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`further in view of Maus and Frilling. Id., Office Action, June 5, 2019, at 4-11.
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`In response, Applicants amended the independent claims to recite an aqueous
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`pharmaceutical solution “substantially free of ethanol” and to recite that “the
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`radiochemical purity (determined by HPLC) of the solution is maintained at ≥ 95%
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`for at least 72 h when stored at 25 °C.” Id., Response to Office Action, Sept. 5,
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`2019, at 2, 5. Applicants argued that de Blois did not disclose a formulation that is
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`both ethanol-free and met the required purity. Applicants further argued that the
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`secondary references did not remedy this deficiency. Applicants also argued that it
`
`was unexpected that a