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. PGR2021-00003
`
`
`
`PETITION FOR
`
`POST GRANT REVIEW OF U.S. PATENT NO. 10,596,276
`
`(ALL CLAIMS)
`
`
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`TABLE OF CONTENTS
`
` Page
`I.
`INTRODUCTION ........................................................................................... 1
`II. GROUNDS FOR STANDING (37 C.F.R. § 42.204(a)) ................................. 2
`III. OVERVIEW OF THE TECHNOLOGY AND THE ’276 PATENT ............. 3
`A.
`Background of the Technology ............................................................. 3
`B.
`The ’276 Patent ..................................................................................... 4
`1.
`Summary of the Specification of the ’276 Patent ....................... 5
`2.
`Summary of the Claims of the ’276 Patent ................................. 5
`3.
`Summary of the Relevant Portions of the Prosecution
`History ......................................................................................... 6
`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.
`De León-Rodríguez (Ex. 1014)................................................. 17
`3.
`Banerjee (Ex. 1016) .................................................................. 18
`4.
`The ’536 Patent (Ex. 1013) ....................................................... 18
`5.
`de Blois (Ex. 1017) ................................................................... 19
`
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`6.
`7.
`8.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`SEC Statement (Ex. 1018) ........................................................ 20
`The ’365 Publication (Ex. 1019) ............................................... 20
`Strosberg (Ex. 1011) and Associated Supplemental Material
`(i.e., Protocol (Ex. 1012)) ......................................................... 21
`Scott (Ex. 1015) ........................................................................ 23
`9.
`Challenge 1: Independent Claim 1 and Dependent Claims 2-9 and
`12-14 Would Have Been Obvious Over Maus (Ex. 1009) in View
`of the ’536 Patent (Ex. 1013) .............................................................. 24
`1.
`Claim 1 ...................................................................................... 24
`2.
`Claims 2-9 and 12-14 ................................................................ 30
`Challenge 2: Claims 10, 11, and 17 Would Have Been Obvious
`Over Maus (Ex. 1009) in View of the ’536 Patent (Ex. 1013)
`Further in View of De León-Rodríguez (Ex. 1014) or Banerjee (Ex.
`1016) .................................................................................................... 39
`Challenge 3: Claim 16 Would Have Been Obvious Over Maus (Ex.
`1009) in View of the ’536 Patent (Ex. 1013) Further in View of
`Kwekkeboom (Ex. 1010) or Other Prior Art Disclosing the Use of
`177LuCl3 in an HCl Solution for Complexation ................................... 43
`Challenge 4: Claim 18 Would Have Been Obvious Over Maus (Ex.
`1009) in View of the ’536 Patent (Ex. 1013) Further in View of the
`Knowledge of a POSA of the Interchangeability of Ascorbic Acid
`and Sodium Ascorbate as Stabilizers as Evidenced by Scott (Ex.
`1015) .................................................................................................... 45
`Challenge 5: Claims 15 and 19 Would Have Been Obvious Over
`Maus (Ex. 1009) in View of the ’536 Patent (Ex. 1013) Further in
`View of Prior Art Disclosing Routine Storage of Radiolabeled
`Pharmaceuticals in a Stoppered Vial ................................................... 46
`Challenge 6: Claims 20-24 are Anticipated by Maus (Ex. 1009) ...... 49
`1.
`Claim 20 .................................................................................... 50
`2.
`Claims 21-24 ............................................................................. 50
`
`E.
`
`F.
`
`G.
`
`H.
`
`I.
`
`J.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`
`K.
`
`L.
`
`Challenge 7: Claim 24 Would Have Been Obvious Over Maus
`(Ex. 1009) ............................................................................................ 53
`Challenge 8: If Claims 20-24 Are Not Construed as Product-by-
`Process Claims, They Would Have Been Obvious Over Maus (Ex.
`1009) in View of the ’536 Patent (Ex. 1013) ...................................... 54
`M. Challenge 9: Independent Claim 1 and Dependent Claims 2-19
`Would Have Been Obvious Over Protocol (Ex. 1012) in View of
`Maus (Ex. 1009) Further in View of the ’536 Patent (Ex. 1013)
`Further in View of De León-Rodríguez (Ex. 1014) or Banerjee (Ex.
`1016) Further in View of the Knowledge of a POSA of the
`Interchangeability of Ascorbic Acid and Sodium Ascorbate as
`Stabilizers as Evidenced by Scott (Ex. 1015) ..................................... 56
`1.
`Claim 1 ...................................................................................... 56
`2.
`Claims 2-19 ............................................................................... 64
`Challenge 10: Claim 16 Would Have Been Obvious Over Protocol
`(Ex. 1012) in View of Maus (Ex. 1009) Further in View of the ’536
`Patent (Ex. 1013) Further in View of Kwekkeboom (Ex. 1010)
`Further in View of De León-Rodríguez (Ex. 1014) or Banerjee (Ex.
`1016) Further in View of the Knowledge of a POSA of the
`Interchangeability of Ascorbic Acid and Sodium Ascorbate as
`Stabilizers as Evidenced by Scott (Ex. 1015) ..................................... 72
`Challenge 11: Claims 20-24 Are Anticipated by Protocol (Ex.
`1012) .................................................................................................... 73
`1.
`Claim 20 .................................................................................... 74
`2.
`Claims 21-24 ............................................................................. 74
`Challenge 12: Claim 24 Would Have Been Obvious Over
`Protocol (Ex. 1012) ............................................................................. 77
`Challenge 13: If Claims 20-24 Are Not Construed as Product-by-
`Process Claims They Would Have Been Obvious Over Protocol
`(Ex. 1012) in View of Maus (Ex. 1009) Further in View of the ’536
`Patent (Ex. 1013) Further in View of De León-Rodríguez (Ex.
`1014) or Banerjee (Ex. 1016) Further in View of the Knowledge of
`
`N.
`
`O.
`
`P.
`
`Q.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
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`
`S.
`
`R.
`
`a POSA of the Interchangeability of Ascorbic Acid and Sodium
`Ascorbate as Stabilizers as Evidenced by Scott (Ex. 1015) ................ 78
`Objective Considerations of Non-Obviousness Do Not Affect
`Obviousness Challenges (1-5, 7-10, 12, and 13) ................................ 80
`Challenge 14: Claim 24 Is Not Enabled for its Full Scope if the
`Recited Stability Limitation Is Not an Inherent Property of the
`Pharmaceutical Aqueous Solutions Taught in the Prior Art ............... 81
`V.
`CONCLUSIONS ........................................................................................... 86
`VI. MANDATORY NOTICES ........................................................................... 86
`A.
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) ................................ 86
`B.
`Related Matters (37 C.F.R. § 42.8(b)(2)) ............................................ 86
`C.
`Designation of Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)) .. 87
`D.
`Service of Information (37 C.F.R. § 42.8(b)(4)) ................................. 87
`CERTIFICATE OF SERVICE ................................................................................ 89
`CERTIFICATE OF WORD COUNT ...................................................................... 90
`
`
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Amgen, Inc. v. Hoffmann-La Roche Ltd.,
`580 F.3d 1340 (Fed. Cir. 2009) .................................................................... 49, 74
`Atlas Powder Co. v. Ireco Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) .................................................................... 53, 77
`
`In re Best,
`562 F.2d 1252 (C.C.P.A. 1977) .................................................................... 53, 77
`
`Hulu, LLC,
`IPR2018-01039, Paper 29 ..................................................................................... 8
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) .......................................................................... 52
`Statutes
`35 U.S.C. § 102(a) ......................................................................................... 8, 11, 12
`35 U.S.C. § 103 ............................................................................................ 10, 11, 12
`35 U.S.C. § 112 ........................................................................................................ 12
`35 U.S.C. §§ 321-329 ................................................................................................ 1
`Other Authorities
`37 C.F.R. § 42 ............................................................................................................ 1
`37 C.F.R. § 42.8(b)(1) .............................................................................................. 86
`37 C.F.R. § 42.8(b)(2) .............................................................................................. 86
`37 C.F.R. § 42.8(b)(3) .............................................................................................. 87
`37 C.F.R. § 42.8(b)(4) .............................................................................................. 87
`37 C.F.R. § 42.22(a) ................................................................................................... 8
`
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`
`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. § 42.205 ................................................................................................... 89
`83 Fed. Reg. 197 (Oct. 11, 2018) ............................................................................. 13
`
`
`
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`PETITIONER’S EXHIBIT LIST
`
`Description
`
`U.S. Patent No. 10,596,276 (“the ’276 patent”)
`
`Number Not Used
`
`Prosecution History of U.S. Patent No. 10,596,276 (Application
`Serial No. 16/175,261) (“the ’261 application”)
`
`Number Not Used
`
`Declaration of Stephan Maus Under 37 C.F.R. § 1.68 in Support of
`Petition for Post Grand Review of U.S. Patent No. 10,596,276 (All
`Claims)
`
`Number Not Used
`
`Number Not Used
`
`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”)
`
`Exhibit
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`Protocol associated with Strosberg (Ex. 1011) providing the protocol
`used in the clinical study reported in Strosberg (“Protocol”)
`
`
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`- vii -
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`

`
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`U.S. Patent No. 6,261,536 (“the ’536 patent”)
`
`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”)
`
`United States Security and Exchange Commission Form F-1 for
`Advanced Accelerator Applications S.A., 2014 (“SEC Statement”)
`
`U.S. Published Patent Application No. US 2012/0065365 (“the ’365
`publication”)
`
`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”)
`
`
`
`- viii -
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`

`

`
`
`1023
`
`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`S. Liu et al., Stabilization of 90Y-Labeled DOTA-Biomolecule
`Conjugates Using Gentisic Acid and Ascorbic Acid, Bioconjugate
`Chem., 12:554-558, 2001 (“Liu”)
`
`1024
`
`Lutetium 177 – LuMark® Lu-177 Chloride product page,
`https://www.idb-holland.com/our-products/lutetium-177-lumark/
`
`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
`
`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”)
`
`J. Chen et al., Synthesis, stabilization and formulation of [177Lu]Lu-
`AMBA, a systemic radiotherapeutic agent for Gastrin Releasing
`Peptide receptor positive tumors, Applied Radiation and Isotopes,
`66(4):497–505, Apr. 2008 (“Chen”)
`
`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”)
`
`
`
`- ix -
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`

`
`
`1032
`
`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`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
`
`1034
`
`Number Not Used
`
`Number Not Used
`
`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).
`
`
`
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`Evergreen Theragnostics, Inc. (“Petitioner”) petitions for Post Grant Review
`
`of claims 1-24 of U.S. Patent No. 10,596,276 (Ex. 1001), 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 a determination that all claims (1-24) of the ’276
`
`patent be canceled 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 claims of the ’276 patent are primarily directed to methods of making
`
`pharmaceutical aqueous solutions containing (1) 177Lu complexed with a
`
`somatostatin receptor binding peptide (“SRBP”) linked to the chelating agent DOTA
`
`and (2) including two stabilizers, such as gentisic and ascorbic acids (or salts
`
`thereof). Additionally, there are five product-by-process claims (claims 20-24).
`
`While there are a number of grounds below given the 24 claims in issue, there
`
`are two primary arguments as to why the claims are invalid. The first argument
`
`involves an article authored by Petitioner’s expert Stephan Maus which discloses a
`
`process for making 177Lu-DOTA-TATE solutions. That article anticipates the
`
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`
`product-by-process claims and, in conjunction with other art, renders obvious the
`
`process claims.
`
`The second reference is Strosberg and its published Protocol. That Protocol
`
`relates to a Phase III trial of the commercial embodiment of a product claimed by
`
`the product-by-process claims and anticipates them. Additionally, a POSA would
`
`have used the process disclosed in the Maus article (as modified by other prior art)
`
`to make the product disclosed in the Protocol. Thus, the process claims would have
`
`been obvious.
`
`Because claims 1-24 of the ’276 patent are not novel and/or would have been
`
`obvious in view of the prior art, Petitioner respectfully requests the Board cancel
`
`claims 1-24.
`
`II. GROUNDS FOR STANDING (37 C.F.R. § 42.204(a))
`
`The undersigned and Petitioner certify that the ’276 patent is available for post
`
`grant review. The ’276 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. 1001. Petitioner also certifies that it is not barred or estopped from
`
`requesting this post grant review on the grounds identified herein.
`
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`
`III. OVERVIEW OF THE TECHNOLOGY AND THE ’276 PATENT
`A. Background of the Technology
`
`Complexes of 177Lu with DOTA-TATE and DOTA-TOC were well-known in
`
`the art. Ex. 1005, Maus Declaration at ¶¶44-45; see also, Ex. 1009, Maus; Ex. 1016,
`
`Banerjee at 2941-2942, 2951-2953; Ex. 1017, de Blois at 29; Ex. 1020, Breeman
`
`2003 at 917-918; Ex. 1027, Breeman 2016 at 8-9. Those complexes were formed
`
`by reacting DOTA-TATE or DOTA-TOC with 177LuCl3 in an aqueous solution. Ex.
`
`1005, ¶46; see also Ex. 1009; Ex. 1010, Kwekkeboom; Ex. 1017; Ex. 1021, Das 1
`
`at 301; Ex. 1022, Das 2 at 1391; Ex. 1027.
`
`The prior art taught that the optimal pH for complexation was between 5 and
`
`6, usually maintained with a buffer. Ex. 1005, ¶46; see also Ex. 1014, De León-
`
`Rodríguez at 395; Ex. 1016 at 2941; Ex. 1022 at 1391. A pH of 5-6 is optimal
`
`because, while the rate of complex formation increases with increasing pH, the
`
`solubility of Lu3+ decreases above pH 6. Ex. 1005, ¶46; see also Ex. 1014 at 395.
`
`The buffer that was routinely used to maintain the optimum pH was acetic
`
`acid/sodium acetate, which advantageously does not interfere with complexation.
`
`Ex. 1005, ¶47; see also Ex. 1014 at 395; Ex. 1017 at 29; Ex. 1020 at 918; Ex. 1016
`
`at 2941; Ex. 1026, Sosabowski at 973; Ex. 1022 at 1391.
`
`177Lu DOTA-TATE-
`
`and DOTA-TOC-containing
`
`pharmaceutical
`
`compositions were vulnerable to radiolysis, resulting in decreased radiochemical
`
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`
`purity (“RCP”) over time. Ex. 1005, ¶48; see also Ex. 1009 at Abstract; Ex. 1017 at
`
`29; Ex. 1023, Liu at 556. Stabilizers, such as gentisic and/or ascorbic acids, were
`
`used to minimize radiolytic degradation. Ex. 1005, ¶48; see also Ex. 1009; Ex. 1017
`
`at 29; Ex. 1016 at 2942; Ex. 1025, Luna-Gutierrez at 2182, 2187; Ex. 1026 at 973.
`
`Although ascorbic acid (or its salts) was used as a stabilizer, it was known to
`
`interfere with the reaction to form the complex. Thus, adding the ascorbic acid after
`
`complexation was preferable. See Ex. 1005, ¶49; see also Ex. 1013, ’536 patent.
`
`Additionally, it was routine to include a sequestering agent, such as
`
`diethylentriaminepentaacetic acid (DTPA), in the compositions to chelate free 177Lu
`
`ions remaining after complexation. Ex. 1005 , ¶50; see also Ex. 1009 at 8; Ex. 1017
`
`at 29; Ex. 1027 at 11. Free 177Lu ions were known to cause severe radiotoxic effects.
`
`Id. Chelating the free 177Lu ions facilitated renal excretion and minimized adverse
`
`radiotoxic effects. Id.; see also Ex. 1035, Breeman 2003B at 312; Ex. 1017 at 29;
`
`Ex. 1027 at 11.
`
`B.
`
`The ’276 Patent
`
`The ’276 patent, entitled “Stable, Concentrated Radionuclide Complex
`
`Solutions,” issued on March 24, 2020, from Application No. 16/175,261, filed on
`
`October 30, 2018, as a continuation-in-part of Application No. 16/140,962, filed on
`
`September 25, 2018, which is a continuation-in-part of Application No. 16/045,484,
`
`filed on July 25, 2018.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
`
`1.
`Summary of the Specification of the ’276 Patent
`The ’276 patent is generally directed to pharmaceutical aqueous compositions
`
`containing a complex of (ai) a radionuclide and (aii) a cell receptor binding organic
`
`moiety linked to a chelating agent and (b) at least one stabilizer against radiolytic
`
`degradation (Ex. 1001 at 2:58-64) and to methods of making such compositions (Ex.
`
`1001 at 3:19-36). The ’276 patent discloses that the radionuclide can be 177lutetium,
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`the cell receptor binding organic moiety linked to a chelating agent can be DOTA-
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`TATE or DOTA-TOC, and the stabilizers against radiolytic degradation can be a
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`combination of gentisic and ascorbic acids (or salts thereof). Ex. 1001 at 3:5-18.
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`The ’276 patent asserts
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`that
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`the composition “is 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 it can be produced on commercial scale and supplied as [a]
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`ready-to-use radiopharmaceutical product.” Ex. 1001 at 2:50-55.
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`2.
`Summary of the Claims of the ’276 Patent
`The ’276 patent includes one independent claim (claim 1) and 23 dependent
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`claims (claims 2-24). The claims of the ’276 patent generally relate to a process for
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`making a pharmaceutical aqueous solution that comprises a complex of 177lutetium
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`and a somatostatin receptor binding peptide linked to the chelating agent DOTA.
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`The solutions include a first stabilizer (e.g., gentisic acid or a salt thereof) and a
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`second stabilizer (e.g., ascorbic acid or a salt thereof). The method of making
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
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`involves forming the 177lutetium complex in the presence of the first stabilizer and
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`adding the second stabilizer after the complex has formed.
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`3.
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`Summary of the Relevant Portions of the Prosecution
`History
`In a first Office Action, the Examiner found the then-pending claims obvious
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`over US 2007/0269375Al (“Chen”) in view of Maus. Ex. 1003, File History of the
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`’276 patent, Office Action, Feb. 12, 2019, at 2-4. Original claim 1 is representative:
`
`1. A process for manufacturing a pharmaceutical
`aqueous solution, comprising:
`providing a solution comprising a complex of
`the radionuclide 177Lu (Lutetium-177) and a
`somatostatin receptor binding peptide linked to the
`chelating agent DOTA; a first stabilizer against
`radiolytic degradation, and optionally a second
`stabilizer against radiolytic degradation different
`from the first stabilizer; and
`diluting the solution comprising the complex
`with an aqueous dilution solution optionally
`comprising at least one stabilizer against radiolytic
`degradation to obtain the pharmaceutical aqueous
`solution;
`wherein if the solution comprising the
`complex comprises only the first stabilizer and not
`the second stabilizer, then the aqueous dilution
`solution comprises at least one stabilizer that is
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
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`different from the first stabilizer, and in the obtained
`pharmaceutical aqueous solution, the radionuclide
`177Lu is present in a concentration that it provides
`a volumetric radioactivity of from 250 to 500
`MBq/mL and the stabilizers are present in a total
`concentration of from 0.2 to 20.0 mg/ml.
`Id., Original Claims, filed Oct. 30, 2018.
`
`In response, Applicants argued that a person of ordinary skill in the art would
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`not have been motivated to combine Chen and Maus and, even if there was a
`
`motivation to combine, they would not have had a reasonable expectation of success
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`because of the unpredictability in selecting stabilizers and the amount of
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`stabilizer(s). Id., Response to Office Action, May 13, 2019, at 6-10. Applicants
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`further argued that Chen and Maus each taught stabilizers concentrations that are
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`higher than the concentrations recited in the claims. Id.
`
`In a second Office Action, dated June 6, 2019, the Examiner found the claims
`
`obvious over de Blois in view of Singh et al., Ind. J. Nucl. Med., 26:135-138, 2014
`
`(“Singh”), and Stip. Republic of Macedonia, October 1-5, 2012 (“RCM Meeting”),
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`further in view of Maus and Chen. Ex. 1003, File History of the ’276 patent, Office
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`Action, June 6, 2019, at 4-12.
`
`In response, Applicants argued that de Blois does not disclose the recited
`
`stabilizer concentration and volumetric radioactivity or diluting the complex
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`solution with a solution that includes at least one stabilizer, and that the secondary
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
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`references do not remedy these deficiencies. Id., Response to Office Action, Sept.
`
`6, 2019, at 6-10.
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`In a third Office Action, dated November 4, 2019, the Examiner maintained
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`the rejection of the claims as obvious over de Blois, Singh, RCM Meeting, Maus,
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`and Chen. Id., Office Action, Nov. 4, 2019, at 2-7.
`
`After an Interview with Applicants’ representative, the Examiner amended
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`independent claim 1 to recite that the aqueous pharmaceutical solution contains “less
`
`than 1% ethanol.” Id., Interview Summary, Feb. 11, 2020. The claims were allowed
`
`on February 11, 2020. Id., Notice of Allowance, Feb. 11, 2020.
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`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))
`
`Petitioner respectfully requests post grant review and cancellation of claims
`
`1-24 of the ’276 patent on the grounds set forth below.
`
`A.
`
`Prior Art Patents and Printed Publications Relied Upon
`
`Petitioner relies upon the following patents and printed publications, which
`
`are prior art to the ’276 patent under 35 U.S.C. § 102(a)1:
`
`
`1 To the extent the Patent Owner challenges the prior art status of any of these
`references, Petitioner expressly reserves the right to submit any additional evidence
`necessary to support its argument that a reference qualifies as prior art. See Hulu,
`LLC, IPR2018-01039, Paper 29 at 15.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
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`1. Maus (Ex. 1009) published on February 21, 2014, before the earliest
`
`priority date to which the ’276 patent could be entitled.
`
`2.
`
`Kwekkeboom (Ex. 1010) published in September 2001, before the
`
`earliest priority date to which the ’276 patent could be entitled.
`
`3.
`
`De León-Rodríguez (Ex. 1014) published in 2008, before the earliest
`
`priority date to which the ’276 patent could be entitled. Ex 1008,
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`Hsieh-Yee Declaration, ¶¶37-57.2
`
`4.
`
`Banerjee (Ex. 1016) published in 2015, before the earliest priority
`
`date to which the ’276 patent could be entitled.
`
`5.
`
`The ’536 patent (Ex. 1013) issued on July 17, 2001, before the earliest
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`priority date to which the ’276 patent could be entitled.
`
`6.
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`de Blois (Ex. 1017) published in 2014, before the earliest priority date
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`to which the ’276 patent could be entitled.
`
`7.
`
`SEC Statement (Ex. 1018) published in 2014, before the earliest
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`priority date to which the ’276 patent could be entitled.
`
`8.
`
`The ’365 publication (Ex. 1019) published on March 15, 2012, before
`
`the earliest priority date to which the ’276 patent could be entitled.
`
`
`2 Dr. Hsieh-Yee, a librarian with more than 25 years of experience, declares that
`various prior art references are authentic and were publicly available early enough
`to constitute prior art.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,276
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`9.
`
`Strosberg (Ex. 1011) published on January 12, 2017, before the
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`earliest priority date to which the ’276 patent could be entitled. Ex.
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`1008, ¶¶19-36.
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`10. Protocol (Ex. 1012) published on January 12, 2017, before the earliest
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`priority date to which the ’276 patent could be entitled. Ex. 1008,
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`¶¶19-36.
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`11. Scott (Ex. 1015) published in January 2009, before the earliest priority
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`date to which the ’276 patent could be entitled. Ex. 1008, ¶¶58-78.
`
`Challenge 1: Independent claim 1 and dependent claims 2-9 and 12-14 are
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`rendered obvious under 35 U.S.C. § 103 by Maus (Ex. 1009) in view of the ’536
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`patent (Ex. 1013);
`
`Challenge 2: Dependent claims 10, 11, and 17 are rendered obvious under
`
`35 U.S.C. § 103 by Maus (Ex. 1009) in view of the ’536 patent (Ex. 1013) further in
`
`view of De León-Rodríguez (Ex. 1014) or Banerjee (Ex. 1016);
`
`Challenge 3: Dependent claim 16 is rendered obvious under 35 U.S.C. § 103
`
`by Maus (Ex. 1009) in view of the ’536 patent (Ex. 1013) further in view of
`
`Kwekkeboom (Ex. 1010) or other prior art disclosing the use of 177LuCl3 in an HCl
`
`solution for complexation;
`
`Challenge 4: Dependent claim 18 is rendered obvious under 35 U.S.C. § 103
`
`by Maus (Ex. 1009) in view of the ’536 patent (Ex. 1013) further in view of the
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