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. PGR2021-00001
`
`
`
`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 ....................................................... 12
`C.
`Claim Construction ............................................................................. 12
`D. Overview of the Prior Art .................................................................... 13
`1.
`Strosberg (Ex. 1011) and Protocol (Ex. 1012) ......................... 13
`2.
`Prior Art Disclosing that it was Routine to Use an Acetic
`Acid/Sodium Acetate Buffer to Maintain the pH during
`Complexation ............................................................................ 16
`The ’536 Patent (Ex. 1013) ....................................................... 17
`Filice (Ex. 1028) ....................................................................... 18
`
`3.
`4.
`
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`E.
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`F.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`5. Maus (Ex. 1009) ........................................................................ 19
`6.
`Kwekkeboom (Ex. 1010) .......................................................... 20
`7.
`SEC Statement (Ex. 1018) ........................................................ 21
`Challenge 1: Independent Claims 1 and 20 and Dependent Claims
`2-5, 8-19, 21-22, and 24-25 of the ’278 Patent Are Anticipated by
`Protocol (Ex. 1012) ............................................................................. 21
`1.
`Independent Claim 1 ................................................................. 21
`2.
`Dependent Claims 2-5 and 8-19 ............................................... 26
`3.
`Independent Claim 20 ............................................................... 31
`4.
`Dependent Claims 21-22 and 24-25 ......................................... 33
`Challenge 2: Independent Claims 1 and 20 and Dependent Claims
`2-5, 8-19, 21-22, and 24-25 Would Have Been Obvious Over
`Protocol (Ex. 1012) in View of Maus (Ex. 1009) Further in View
`of SEC Statement (Ex. 1018) .............................................................. 35
`1.
`Independent Claim 1 ................................................................. 35
`2.
`Dependent Claims 2-5 and 8-19 ............................................... 40
`3.
`Independent Claim 20 ............................................................... 44
`4.
`Dependent Claims 21-22 and 24-25 ......................................... 47
`Challenge 3: Dependent Claims 6-7 of the ’278 Patent Would Have
`Been Obvious Over (i) Protocol (Ex. 1012) in View of De León-
`Rodríguez (Ex. 1014) and/or Banerjee (Ex. 1016) or (ii) Protocol
`(Ex. 1012) in View of Maus (Ex. 1009) Further in View of SEC
`Statement (Ex. 1018) Further in View of De León-Rodríguez (Ex.
`1014) and/or Banerjee (Ex. 1016) ....................................................... 49
`Challenge 4: Dependent Claim 23 of the’278 Patent Would Have
`Been Obvious Over Protocol (Ex. 1012) in View of Filice (Ex.
`1028) or Over Protocol (Ex. 1012) in View of Maus (Ex. 1009)
`Further in View of SEC Statement (Ex. 1018) Further in View of
`Filice (Ex. 1028) .................................................................................. 53
`
`G.
`
`H.
`
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`

`

`K.
`
`L.
`
`I.
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`J.
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`Challenge 5: If Dependent Claims 8-10 Are Not Construed as
`Product-by-Process Claims They Would Have Been Obvious Over
`Protocol (Ex. 1012) in View of the ’536 Patent (Ex. 1013) or Over
`Protocol (Ex. 1012) in View of Maus (Ex. 1009) Further in View
`of SEC Statement (Ex. 1018) Further in View of the ’536 Patent
`(Ex. 1013) ............................................................................................ 56
`Challenge 6: If Dependent Claims 11-14 Are Not Construed as
`Product-by-Process Claims, They Would Have Been Obvious Over
`Protocol (Ex. 1012) in View of the ’536 Patent (Ex. 1013) Further
`in View of Maus (Ex. 1009) or Over Protocol (Ex. 1012) in View
`of Maus (Ex. 1009) Further in View of SEC Statement (Ex. 1018)
`Further in View of the ’536 Patent (Ex. 1013) ................................... 60
`Challenge 7: If Dependent Claim 17 Is Not Construed as a Product-
`by-Process Claim It Would Have Been Obvious Over Protocol (Ex.
`1012) in View of the General Knowledge of a POSA or Over
`Protocol (Ex. 1012) in View of Maus (Ex. 1009) Further in View
`of SEC Statement (Ex. 1018) Further in View of the General
`Knowledge of a POSA ........................................................................ 67
`Objective Considerations of Non-Obviousness Do Not Affect
`Obviousness Challenges (2-7) ............................................................. 69
`M. Challenge 8: The Claims of the ’278 Patent Are Not Enabled for
`Their Full Scope if the Recited Stability Limitations Are Not
`Anticipate by (or Obvious over) the Pharmaceutical Aqueous
`Solution Disclosed in Protocol (Ex. 1012) .......................................... 70
`Challenge 9: Claim 24 is Invalid for Improper Dependency ............. 74
`N.
`CONCLUSIONS ........................................................................................... 75
`V.
`VI. MANDATORY NOTICES ........................................................................... 75
`A.
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) ................................ 75
`B.
`Related Matters (37 C.F.R. § 42.8(b)(2)) ............................................ 75
`C.
`Designation of Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)) .. 77
`D.
`Service of Information (37 C.F.R. § 42.8(b)(4)) ................................. 77
`
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`CERTIFICATE OF SERVICE ................................................................................ 79
`CERTIFICATE OF WORD COUNT ...................................................................... 80
`
`
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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) .................................................................... 29, 42
`
`Hulu, LLC,
`IPR2018-01039, Paper 29 ..................................................................................... 8
`
`Iron Grip Barbell Co., Inc. v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) .................................................................... 52, 53
`
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) .......................................................................... 26
`
`Uber Tech., Inc. v. X One, Inc.,
`957 F.3d 1334 (Fed. Cir. 2020) .......................................................................... 55
`Valeant Pharma. Inc. v. Mylan Pharma. Inc.,
`955 F.3d 25 (Fed. Cir. 2020) .............................................................................. 56
`Statutes
`35 U.S.C. § 102(a) ............................................................................................... 9, 10
`35 U.S.C. § 103 .................................................................................................. 10, 11
`35 U.S.C. § 112 ........................................................................................................ 11
`35 U.S.C. §§ 321-329 ................................................................................................ 1
`Other Authorities
`37 C.F.R. § 42 ............................................................................................................ 1
`37 C.F.R. § 42.8(b)(1) .............................................................................................. 75
`37 C.F.R. § 42.8(b)(2) .............................................................................................. 76
`37 C.F.R. § 42.8(b)(3) .............................................................................................. 77
`
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`37 C.F.R. § 42.8(b)(4) .............................................................................................. 77
`37 C.F.R. § 42.22(a) ................................................................................................... 8
`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 ................................................................................................... 79
`83 Fed. Reg. 197 (Oct. 11, 2018) ............................................................................. 12
`
`
`
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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
`
`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
`
`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)
`
`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”)
`
`1012
`
`Protocol associated with Strosberg (Ex. 1011) providing the protocol
`used in the clinical study reported in Strosberg (“Protocol”)
`
`
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`U.S. Patent No. 6,261,536 (“the ’536 patent”)
`
`1013
`
`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”)
`
`Number Not Used
`
`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”)
`
`- viii -
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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”)
`
`- ix -
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`

`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`
`1034
`
`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).
`
`
`
`- x -
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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 (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 a determination that all claims (1-25) of the ’278
`
`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 ’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.
`
`Pharmaceutical aqueous compositions containing complexes of 177Lu with
`
`DOTA-TATE were well-known in the prior art, and for most claims, the precise
`
`formulations claimed in the ’278 patent had previously been disclosed. See, e.g.,
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`composition disclosed in Protocol (Ex. 1012); see also Ex. 1006, Maus Declaration,
`
`¶¶97-210. 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. Evergreen 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
`
`Complexes of 177Lu with DOTA-TATE and DOTA-TOC were well-known in
`
`the art. Ex. 1006, ¶¶45-46; 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.
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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
`
`formed by reacting DOTA-TATE or DOTA-TOC with 177LuCl3 in an aqueous
`
`solution. Ex. 1006, ¶47; see also Ex. 1009; Ex. 1010, Kwekkeboom; Ex. 1017; Ex.
`
`1021, Das 1 at 301; Ex. 1022, Das 2 at 1391; Ex. 1027.
`
`It was known in the prior art that the optimal pH for the reaction was a pH of
`
`between 5 and 6, usually with a buffer. Ex. 1006, ¶48; see also Ex. 1014, De León-
`
`Rodríguez at 395; Ex. 1016 at 2941; Ex. 1022 at 1391. A pH of between 5 and 6 is
`
`optimal because, while the rate of formation of Lu3+-DOTA complexes increases
`
`with increasing pH, the solubility of Lu3+ decreases above a pH of 6. Ex. 1006, ¶48,
`
`see also Ex. 1014 at 395. An acetic acid/sodium acetate buffer was routinely used
`
`as a buffer because it could achieve the desired balance without interfering with the
`
`complexation reaction. Ex. 1006, ¶48; 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
`
`purity (“RCP”) of the radiopeptide. Ex. 1006, ¶49; see also Ex. 1009 at Abstract;
`
`Ex. 1017 at 29; Ex. 1023, Liu at 556. Therefore, stabilizers, such as gentisic acid
`
`and/or ascorbic acid, were routinely used to minimize radiolytic degradation. Ex.
`
`1006, ¶49; see also Ex. 1009; Ex. 1017 at 29; Ex. 1016 at 2942; Ex. 1025, 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
`
`diethylentriaminepentaacetic acid (DTPA) to chelate free 177Lu ions that did not
`
`complex. Ex. 1006, ¶51; see also Ex. 1009 at 8; Ex. 1017 at 29; Ex. 1027 at 11.
`
`Free 177Lu ions were known to cause severe radiotoxic effects upon administration.
`
`Id. Chelating the free 177Lu ions facilitates their renal excretion and minimizes the
`
`adverse radiotoxic effects. Id; see also Ex. 1035, Breeman 2003B at 312; Ex. 1017
`
`at 29; Ex. 1027 at 11.
`
`B.
`
`The ’278 Patent
`
`The ’278 patent, entitled “Stable, Concentrated Radionuclide Complex
`
`Solutions,” issued on March 24, 2020, from Application No. 16/175,239, filed on
`
`October 30, 2018, as a continuation 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 Jul. 25, 2018.
`
`1.
`Summary of the Specification of the ’278 Patent
`The ’278 patent is generally directed to pharmaceutical aqueous solutions
`
`containing complexes formed by radionuclides and cell receptor binding organic
`
`moieties linked to chelating agents with at least one stabilizer against radiolytic
`
`degradation. Ex. 1002 at 2:58-64. The ’278 patent discloses that the radionuclide
`
`can be 177lutetium, the moiety linked to a chelating agent can be DOTA-TATE
`
`(oxodotreotide) or DOTA-TOC (edotreotide), and the stabilizers against radiolytic
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`Petition for Post Grant Review of U.S. Patent No. 10,596,278
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`degradation can be gentisic and ascorbic acids or salts thereof. Id. at 3:5-18. The
`
`’278 patent also discloses methods for making the aqueous pharmaceutical
`
`composition. Id. at 3:19-36.
`
`The ’278 patent asserts that the compositions are “chemically and
`
`radiochemically very stable even if stored at ambient or short term elevated
`
`temperatures so that [they] can be produced on commercial scale and supplied as
`
`ready-to-use radiopharmaceutical product[s].” Id. at 2:50-55.
`
`2.
`Summary of the Claims of the ’278 Patent
`The ’278 patent includes two independent claims (claims 1 and 20). Claims
`
`2-19 depend directly or indirectly from claim 1 and claims 21-25 depend directly
`
`from claim 20. The claims generally relate to pharmaceutical aqueous solutions
`
`comprising a complex of 177lutetium with a somatostatin receptor binding peptide
`
`linked to the chelating agent DOTA and a combination of gentisic and ascorbic acids
`
`(or their salts) as stabilizers.
`
`3.
`
`Summary of the Relevant Portions of the Prosecution
`History
`In a first Office Action, the Examiner found the then-pending claims
`
`unpatentable as obvious over US 2007/0269375Al (“Chen”) in view of Maus. Ex.
`
`1004, File History of the ’278 Patent, Office Action, Jan. 25, 2019, at 2-4. Original
`
`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.
`
`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.
`
`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
`
`taught higher stabilizer concentrations than those claimed. Id., Response to Office
`
`Action, Apr. 24, 2019, at 6-10.
`
`- 6 -
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`In a second Office Action, the Examiner found the claims unpatentable as
`
`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”),
`
`further in view of Maus and Frilling. Id., Office Action, June 5, 2019, at 4-11.
`
`In response, Applicants amended the independent claims to recite an aqueous
`
`pharmaceutical solution “substantially free of ethanol” and to recite that “the
`
`radiochemical purity (determined by HPLC) of the solution is maintained at ≥ 95%
`
`for at least 72 h when stored at 25 °C.” Id., Response to Office Action, Sept. 5,
`
`2019, at 2, 5. Applicants argued that de Blois did not disclose a formulation that is
`
`both ethanol-free and met the required purity. Applicants further argued that the
`
`secondary references did not remedy this deficiency. Applicants also argued that it
`
`was unexpected that an ethanol-free formulation would exhibit the required stability.
`
`Id., Response to Office Action, Sept. 5, 2019, at 6-10.
`
`In a third Office Action, the Examiner maintained the rejection of the claims
`
`as obvious over de Blois, Singh, RCM Meeting, Maus, and Frilling. Id., Office
`
`Action, Nov. 4, 2019, at 3-6.
`
`After an Interview with Applicants’ representative, the Examiner canceled
`
`claim 2 and amended the independent claims to recite that the claimed solutions
`
`contained “less than 1% ethanol.” Id., Notice of Allowance, Feb. 5, 2020, at 2; id.,
`
`Examiner Interview Summary Record, Feb. 5, 2020, at 1. The claims were allowed
`
`- 7 -
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`on February 5, 2020. According to the Examiner, “the prior art does not teach of the
`
`combination of gentisic acid, ascorbic acid and less than 1% ethanol to provide
`
`stabilization of the 177Lu-somatostatin complex wherein the gentisic acid and
`
`ascorbic acid are in low concentrations but the complex maintains a radiochemical
`
`purity (RCP) of ≥ 95% for at least 72h.” Id., Notice of Allowance, Feb. 5, 2020, at
`
`2.
`
`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
`
`1-25 of the ’278 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 ’278 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.
`
`- 8 -
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`Strosberg (Ex. 1011) published on January 12, 2017, before the earliest
`
`1.
`
`priority date to which the ’278 patent could be entitled. Ex. 1008,
`
`Hsieh-Yee Declaration, ¶¶19-36.2
`
`2.
`
`Protocol (Ex. 1012) published on January 12, 2017, before the earliest
`
`priority date to which the ’278 patent could be entitled. Ex 1008, ¶¶19-
`
`36.
`
`3.
`
`De León-Rodríguez (Ex. 1014) published in 2008, before the earliest
`
`priority date to which the ’278 patent could be entitled. Ex 1008, ¶¶37-
`
`57.
`
`4.
`
`Banerjee (Ex. 1016) published in 2015, before the earliest priority date
`
`to which the ’278 patent could be entitled.
`
`5.
`
`The ’536 patent (Ex. 1013) issued on July 17, 2001, before the earliest
`
`priority date to which the ’278 patent could be entitled.
`
`6.
`
`Filice (Ex. 1028) published on August 9, 2012, before the earliest
`
`priority date to which the ’278 patent could be entitled. Ex. 1008, ¶¶79-
`
`97.
`
`7. Maus (Ex. 1009) published on February 21, 2014, before the earliest
`
`priority date to which the ’278 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.
`
`- 9 -
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`Kwekkeboom (Ex. 1010) published in September 2001, before the
`
`8.
`
`earliest priority date to which the ’278 patent could be entitled.
`
`9.
`
`SEC Statement (Ex. 1018) published in 2014, before the earliest
`
`priority date to which the ’278 patent could be entitled.
`
`Challenge 1: Independent claims 1 and 20 and dependent claims 2-5, 8-19,
`
`21-22, and 24-25 are anticipated under 35 U.S.C. § 102(a) by Protocol (Ex. 1012);
`
`Challenge 2: Independent claims 1 and 20 and dependent claims 2-5, 8-19,
`
`21-22, and 24-25 are rendered obvious under 35 U.S.C. § 103 by Protocol (Ex. 1012)
`
`alone or in view of Maus (Ex. 1009) further in view of SEC Statement (Ex. 1018);
`
`Challenge 3: Dependent claims 6-7 are rendered obvious under 35 U.S.C.
`
`§ 103 by (i) Protocol (Ex. 1012) in view of De León-Rodríguez (Ex. 1014) and/or
`
`Banerjee (Ex. 1016) or (ii) Protocol (Ex. 1012) in view of Maus (Ex. 1009) further
`
`in view of SEC Statement (Ex. 1018) further in view of De León-Rodríguez (Ex.
`
`1014) and/or Banerjee (Ex. 1016);
`
`Challenge 4: Dependent claim 23 is rendered obvious under 35 U.S.C. § 103
`
`by (i) Protocol (Ex. 1012) in view of Filice (Ex. 1028) or (ii) Protocol (Ex. 1012) in
`
`view of Maus (Ex. 1009) further in view of SEC Statement (Ex. 1018) further in
`
`view of Filice (Ex. 1028);
`
`Challenge 5: If dependent claims 8-10 are not construed as product-by-
`
`process claims, they are rendered obvious under 35 U.S.C. § 103 by (i) Protocol (Ex.
`
`- 10 -
`
`

`

`Petition for Post Grant Review of U.S. Patent No. 10,596,278
`
`1012) in view of the ’536 patent (Ex. 1013) or (ii) Protocol (Ex. 1012) in view of
`
`Maus (Ex. 1009) further in view of SEC Statement (Ex. 1018) further in view of the
`
`’536 patent (Ex. 1013);
`
`Challenge 6: If dependent claims 11-14 are not construed as product-by-
`
`process claims, they are rendered obvious under 35 U.S.C. § 103 by Protocol (Ex.
`
`1012) in view of the ’536 patent (Ex. 1013) further in view of Maus (Ex. 1009);
`
`Challenge 7: If dependent claim 17 is not construed as a product-by-process
`
`claim, it is rendered obvious under 35 U.S.C. § 103 by (i) Protocol (Ex. 1012) in
`
`view of the general knowledge of a POSA or (ii) Protocol (Ex. 1012) in view of
`
`Maus (Ex. 1009) further in view of SEC Statement (Ex. 1018) further in view of the
`
`general knowledge of a POSA;
`
`Challenge 8: If the recited stability limitations are not anticipated or rendered
`
`obvious by the pharmaceutical aqueous solutions disclosed in Protocol, the claims
`
`of the ’278 patent are unpatentable under 35 U.S.C. § 112 because they are not
`
`enabled for their full scope; and
`
`Challenge 9: Claim 24 is invalid for improper dependency.
`
`Petitioner’s full statement of the reasons for the requested relief is set forth
`
`below. In support of these grounds for unpatentability, Petitioner submits the expert
`
`declaration of Stephan Maus, i.e., Maus Declaration (Ex. 1006), and also relies on
`
`other Exhibits set forth in the concurrently filed Listing of Exhibits.
`
`-