`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`Lassen Therapeutics 1, Inc.
`
`Petitioner
`
`v.
`
`Singapore Health Services PTE LTD., and
`
`National University of Singapore
`
`Patent Owner
`
`
`
`CASE: Unassigned
`
`Patent No. 10,106,603
`
`PETITION FOR POST GRANT REVIEW
`
`

`

`TABLE OF CONTENTS
`
`
`Page
`
`
`
`GROUNDS FOR STANDING PURSUANT TO 37 C.F.R. §
`
`37 C.F.R. §§ 42.8(b)(3) AND (4): LEAD AND BACK-UP
`
`IDENTIFICATION OF CHALLENGED CLAIMS AND RELIEF
`
`
`INTRODUCTION ....................................................................................... 1
`I.
`II.
`42.104(A) .................................................................................................... 1
`III. MANDATORY NOTICES .......................................................................... 1
`A.
`37 C.F.R. § 42.8(b)(1): REAL PARTY-IN-INTEREST .................... 1
`B.
`37 C.F.R. § 42.8(b)(2): RELATED MATTERS ................................ 2
`C.
`COUNSEL AND SERVICE INFORMATION .................................. 2
`IV. PAYMENT OF FEES .................................................................................. 3
`TIME FOR FILING PETITION .................................................................. 3
`V.
`VI.
`SOUGHT ..................................................................................................... 3
`’603 PATENT OVERVIEW ........................................................................ 4
`VII.
`VIII. 37 C.F.R. § 42.104(b)(3): Claim Construction ............................................ 5
`A.
`“method of treating fibrosis” .............................................................. 5
`B.
`(IL-11Rα) antibody” .......................................................................... 7
`C.
`“Interleukin 11 receptor α (IL-11Rα) antibody” ................................. 8
`D.
`signaling”......................................................................................... 11
`E.
`eye” ................................................................................................. 12
`IX. Level of ordinary skill in the art ................................................................. 13
`X. DETAILED GROUNDS FOR UNPATENTABILITY .............................. 13
`State of the Art ................................................................................. 13
`A.
`
`“administering to the human subject in need of treatment a
`therapeutically effective amount of an Interleukin 11 receptor α
`
`“capable of inhibiting Interleukin 11 (IL-11) mediated
`
`“wherein the fibrosis is fibrosis of the heart, liver, kidney, or
`
`
`
`
`
`i
`
`
`
`

`

`TABLE OF CONTENTS
`
`
`
`
`Page
`
`State of the Art, Unpredictability of the Art, and the
`
`Lack of Direction or Guidance and the Absence of
`
`B.
`C.
`
`D.
`
`Lack of Written Description ............................................................. 22
`Lack of Enablement ......................................................................... 27
`1.
`The Nature of the Invention and Breadth of the Claims .......... 28
`2.
`Level of Ordinary Skill .......................................................... 31
`3.
`Working Examples ................................................................ 36
`4.
`Quantity of Experimentation Required ................................... 36
`Claims 1-4, 6 and 8-10 are anticipated by Edwards .......................... 37
`Claim 1 .................................................................................. 38
`1.
`2.
`Claim 2 .................................................................................. 42
`Claim 3 .................................................................................. 42
`3.
`4.
`Claim 4 .................................................................................. 43
`5.
`Claim 6 .................................................................................. 45
`6.
`Claims 8-10 ........................................................................... 46
`E.
`POSITA ........................................................................................... 48
`1.
`Claims 1-7 ............................................................................. 49
`2.
`Claims 8-10 ........................................................................... 53
`F.
`Wynn, and Chegini .......................................................................... 54
`1.
`Claims 1-7 ............................................................................. 54
`2.
`Claims 8-10 ........................................................................... 61
`XI. CONCLUSION ......................................................................................... 62
`
`Clams 1-10 are obvious over Edwards with the knowledge of
`
`Clams 1-10 are obvious over the combination of Edwards,
`
`
`
`
`
`
`
`
`ii
`
`
`
`

`

`
`
`Exhibit
`No.
`
`PETITIONER’S EXHIBIT LIST
`
`Description
`
`1001
`
`U.S. Patent No. 10,106,603 B2 (the ’603 patent”)
`
`1002
`
`Prosecution History of U.S. Patent No. 10,106,603 B2
`
`1003
`
`Declaration of Dr. Peter Bowers
`
`1004
`
`Declaration of Dr. Stephen Ledbetter
`
`1005
`
`U.S. Patent No. 8,182,814 B2 (“Baca”)
`
`1006
`
`Victoria A. Barton et al., Interleukin-11 Signals through the Formation
`of a Hexameric Receptor Complex, 275 THE J. OF BIOLOGICAL
`CHEMISTRY 36197 (2000)
`
`1007
`
`Qingsheng Chen et al., IL-11 Receptor α in the Pathogenesis of IL-13
`Induced Inflammation and Remodeling, 174 J. IMMUNOL 2305 (2005)
`
`1008
`
`U.S. Patent Publication No. 2014/0219919 A1 (“Edwards”)
`
`1009 Weiliang Tang et al., Targeted Expression of IL-11 in the Murine
`Airway Causes Lymphocytic Inflammation, Bronchial Remodeling, and
`Airways Obstruction, 98 THE J. OF CLINICAL INVESTIGATION 2845
`(1996)
`
`1010
`
`Thomas A. Wynn, Fibrotic Disease and the TH1/TH2 Paradigm, 4
`NATURE REVIEWS IMMUNOLOGY 583 (2004)
`
`1011
`
`U.S. Patent Publication No. 2018/0186872 A1 (“Cook”)
`
`1012
`
`1013
`
`
`
`
`
`Xiaoyu Yang et al., Developability studies before initiation of process
`development, 5 MABS 787 (2013)
`
`Ƚukasz Opaliński et al., High Affinity Promotes Internalization of
`Engineered Antibodies Targeting FGFR1, 19 INT. J. MOL. SCI. 1435
`(2018)
`
`iii
`
`
`
`

`

`Exhibit
`No.
`
`1014
`
`1015
`
`1016
`
`1017
`
`
`
`Description
`
`Ru Zhou & Rachel R. Caspi, Ocular immune privilege, F1000
`BIOLOGY REPORTS (2010)
`
`Chrystel Blanc et al., Monoclonal antibodies against the human
`interleukin-11 receptor alpha-chain (IL-11Rα) and their use in studies
`of human mononuclear cells; 241 J. OF IMMUNOLOGICAL METHODS 43
`(2000)
`
`Bryan Briney et al., Commonality despite exceptional diversity in the
`baseline human antibody repertoire,
`NATURE|www.nature.com/nature (2019)
`
`David J. Curtis et al., Recombinant Soluble Interleukin-11 (IL-11)
`Receptor α-Chain Can Act as an IL-11 Antagonist, 90 BLOOD 4403
`(1997)
`
`1018 Martin Friedlander, Fibrosis and diseases of the eye, 117 THE J. OF
`CLINICAL INVESTIGATION 576 (2007)
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`
`
`
`
`Christoph Garbers et al., Plasticity and cross-talk of Interleukin 6-type
`cytokines, 23 CYTOKINE & GROWTH FACTOR REVIEWS 85 (2012)
`
`Simon A. Jones & Brendan J. Jenkins, Recent insights into targeting
`the IL-6 cytokine family in inflammatory diseases and cancer, 18
`NATURE REVIEWS|IMMUNOLOGY 773 (2018)
`
`Sujin Kang et al., Therapeutic uses of anti-interleukin-6 receptor
`antibody, 27 INT’L IMMUNOLOGY 21 (2014)
`
`Rishi Matadeen et al., The Dynamics of Signal Triggering in a gp130-
`Receptor Complex; 15 STRUCTURE 441 (2007)
`
`Norihiro Nishimoto et al., Toxicity, Pharmacokinetics, and Dose-
`Finding Study of Repetitive Treatment with the Humanized Anti-
`Interleukin 6 Receptor Antibody MRA in Rheumatoid Arthritis. Phase
`I/II Clinical Study, 30 J. RHEUMATOL 1426 (2003)
`
`iv
`
`
`
`

`

`Exhibit
`No.
`
`1024
`
`
`
`Description
`
`Jean-François Rossi et al., Interleukin-6 as a Therapeutic Target; 21
`CLIN CANCER RES 1248 (2015)
`
`1025
`
`Valerie S. Salazar et al., BMP signalling in skeletal development,
`disease and repair, 12 NATURE REVIEWS|ENDOCRINOLOGY 203 (2016)
`
`1026 Michael Schiff et al., Efficacy and safety of tabalumab, an anti-BAFF
`monoclonal antibody, in patients with moderate-to-severe rheumatoid
`arthritis and inadequate response to TNF inhibitors: results of a
`randomised, double-blind, placebo-controlled, phase 3 study; RMD
`OPEN 1 (2015)
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`
`
`
`
`Sachdev S. Sidhu, Phage display in pharmaceutical biotechnology, 11
`CURRENT OPINION IN BIOTECHNOLOGY 610 (2000)
`
`Nese Unver et al., IL-6 Family Cytokines: Key inflammatory mediators
`as biomarkers and potential therapeutic targets; 41 CYTOKINE
`GROWTH FACTOR REV. 1 (2018)
`
`Daniel J. Wallace et al., Efficacy and safety of an interleukin 6
`monoclonal antibody for the treatment of systemic lupus
`erythematosus: a phase II dose-ranging randomised controlled trial;
`76 ANN RHEUM DIS 534 (2017)
`
`Nathaniel R. West, Coordination of Immune-Stroma Crosstalk by IL-6
`Family Cytokines, 10 FRONTIERS IN IMMUNOLOGY 1 (2019)
`
`Gennaro Ciliberto & Rocco Savino, Cytokine Inhibitors, Chapter 8,
`edited by Gennaro Ciliberto and Rocco Savino, MARCEL DEKKER, INC.
`(2001)
`
`Sara Carmen & Lutz Jermutus, Concepts in antibody phage display, 1
`BRIEF. FUNCT. GENOMICS & PROTEOMICS 189 (2002)
`
`Jefferson Foote & Greg Winter, Antibody Framework Residues
`Affecting the Conformation of the Hypervariable Loops, 224 J. MOL.
`BIOL. 487 (1992)
`
`v
`
`
`
`

`

`Exhibit
`No.
`
`1034
`
`
`
`Description
`
`David McKean et al., Generation of Antibody Diversity in the Immune
`Response of BALB/c Mice to Influenza Virus Hemagglutinin, 81 PROC.
`NATL. ACAD. SCI. USA 3180 (1984)
`
`1035 Mattia Pedotti et al., Computational Docking of Antibody-Antigen
`Complexes, Opportunities and Pitfalls Illustrated by Influenza
`Hemagglutinin, 12 INT. J. MOL. SCI. 226 (2011)
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`
`
`
`
`Julia V. Ponomarenko & Philip E. Bourne, Antibody-Protein
`Interactions: Benchmark Datasets and Prediction Tools Evaluation, 7
`BMC STRUCTURAL BIOL. 64 (2007)
`
`U.S. Patent No. 6,043,344 to Kenneth Jacobs et al., issued Mar. 28,
`2000 (“Jacobs”)
`
`Charles A. Janeway et al., IMMUNO BIOLOGY Ch. 3, 93 (Garland
`Publishing, 5th ed. 2001)
`
`Charles A. Janeway et al., IMMUNO BIOLOGY Ch. 4, 123 (Garland
`Publishing, 5th ed., 2001)
`
`Charles A. Janeway et al., IMMUNO BIOLOGY Ch. 9, 341 (Garland
`Publishing, 5th ed., 2001)
`
`Charles A. Janeway et al., IMMUNO BIOLOGY App. I, 613 (Garland
`Publishing, 5th ed., 2001)
`
`Bruce Alberts, et al., MOLECULAR BIOLOGY OF THE CELL Ch. 24, 1363
`(Garland Science, 4th ed. 2002)
`
`Ivan Roitt, ESSENIAL IMMUNOLOGY Ch. 3, 43 (Blackwell Science, 9th
`ed., 1997)
`
`Ivan Roitt, ESSENTIAL IMMUNOLOGY Ch. 5, 80 (Blackwell Science, 9th
`ed., 1997)
`
`Ivan Roitt, ESSENTIAL IMMUNOLOGY Ch. 6, 107 (Blackwell Science, 9th
`ed., 1997)
`
`vi
`
`
`
`

`

`Exhibit
`No.
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`
`
`Description
`
`Peter J. Hudson & Christelle Souriau, Engineered Antibodies, 9
`NATURE MED. 129 (2003)
`
`Paul Carter, Improving the Efficacy of Antibody-Based Cancer
`Therapies, 1 NAT. REV. CANCER 118 (2001)
`
`Catherine A. Kettleborough, Humanization of a Mouse Monoclonal
`Antibody by CDR-Grafting: The Importance of Framework Residues
`on Loop Conformation, 4 PROTEIN ENG’G, 773 (1991)
`
`Stefan Gerhardt et al., Structure of IL-17A in Complex with a Potent,
`Fully Human Neutralizing Antibody, 394 J. MOL. BIOL. 905 (2009)
`
`Felix F. Vajdos et al., Comprehensive Functional Maps of the Antigen-
`Binding Site of an Anti-ErbB2 Antibody Obtained with Shotgun
`Scanning Mutagenesis, 320 J. MOL. BIOL. 415 (2002)
`
`1051 Mei Sun et al., Antigen Recognition by an Antibody Light Chain, 269 J.
`BIOL. CHEM. 734 (1994)
`
`1052
`
`1053
`
`1054
`
`1055
`
`R. A. Mariuzza et al., The Structural Basis of Antigen-Antibody
`Recognition, 16 ANNU. REV. BIOPHYS. BIOPHYS. CHEM. 139 (1987)
`
`Kathryn E. Tiller & Peter M. Tessier, Advances in Antibody Design, 17
`ANNU. REV. BIOMED. ENG. 191 (2015)
`
`Kristin Reilly, Cardiac Fibrosis: New Treatments in Cardiovascular
`Medicine, 40 US PHARM. 32 (2015)
`
`Steven A. Frank, IMMUNOLOGY AND EVOLUTION OF INFECTIOUS
`DISEASE (Princeton University Press, 2002)
`
`1056 Marc H. V. Van Regenmortel, Specificity, Polyspecificity, and
`Heterospecificity of Antibody-Antigen Recognition, 27 J. MOL.
`RECOGNIT. 627 (2014)
`
`1057
`
`Ole Henrik Brekke & Inger Sandlie, Therapeutic Antibodies for
`Human Diseases at the Dawn of the Twenty-First Century, 2 NAT.
`REV. DRUG. DISCOV. 52 (2003)
`
`
`
`
`
`vii
`
`
`
`

`

`Exhibit
`No.
`
`1058
`
`1059
`
`1060
`
`1061
`
`
`
`Description
`
`Jennifer Maynard & George Georgiou, Antibody Engineering, 2 ANNU.
`REV. BIOMED. ENG. 339 (2000)
`
`Lisa Djavadi-Ohaniance et al., Measuring Antibody Affinity in Solution,
`ANTIBODY ENGINEERING: A PRACTICAL APPROACH, Ch. 4, 77 (J.
`McCafferty et al. eds., 1996)
`
`Cary Queen et al., A Humanized Antibody that Binds to the Interleukin
`2 Receptor, 86 PROC. NATL. ACAD. SCI. USA 10029 (1989)
`
`Elizabeth R. Tucker et al., Immunoassays for the quantification of ALK
`and phosphorylated ALK support the evaluation of on-target ALK
`inhibitors in neuroblastoma, 11 MOLECULAR ONCOLOGY 996 (2017)
`
`1062 Maximiliano Vásquez et al., Connecting the sequence dots: shedding
`light on the genesis of antibodies reported to be designed in silico, 11
`MABS 803 (2019)
`
`1063
`
`Ablynx Drug Fails Again in Mid-Stage Trial, BIOSPACE, March 26,
`2018
`
`1064
`
`U.S. FDA rejects J&J’s arthritis drug, REUTERS (2017)
`
`1065
`
`U.S. Patent Publication No. 2008/0300147 A1 (“Chegini et al.”)
`
`1066
`
`1067
`
`1068
`
`1069
`
`
`
`
`
`Sebastian Schafer et al., IL-11 is a crucial determinant of
`cardiovascular fibrosis, 552 NATURE 110 (2017)
`
`Benoît Lebeau et al., Reconstitution of two isoforms of the human
`interleukin-11 receptor and comparison of their functional properties,
`407 FEBS LETTERS 141 (1997)
`
`TA Wynn, Cellular and molecular mechanisms of fibrosis, 214 J.
`PATHOLOGY 199 (2008)
`
`Eleanor Minshall et al., IL-11 expression is increased in severe
`asthma: Association with epithelial cells and eosinophils; 105 J.
`ALLERGY CLIN. IMMUNOL 232 (2000)
`
`viii
`
`
`
`

`

`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
`
`
`I.
`
`INTRODUCTION
`
`Lassen Therapeutics 1, Inc. (“Lassen”) respectfully requests institution of a
`
`post-grant review (“PGR”) of claims 1-10 (“the Challenged Claims”) of U.S. Patent
`
`No. 10,106,603 (“the ’603 patent”) pursuant to 35 U.S.C. §§ 321-329 and 37 C.F.R.
`
`§ 42.200 et seq.
`
`For the reasons below, the Board should institute a PGR of the ’603 patent
`
`and cancel the Challenged Claims.
`
`II. GROUNDS FOR STANDING PURSUANT TO 37 C.F.R. § 42.204(A)
`
`Petitioner certifies that the ’603 patent is available for PGR and that Petitioner
`
`is not barred or estopped from requesting PGR on the grounds identified in this
`
`Petition. Specifically, neither Petitioner nor any of its privies own the ’603 patent;
`
`and neither Petitioner nor any of its privies have filed a U.S. civil action challenging
`
`the validity of any claim of the ’603 patent.
`
`The earliest priority date to which the ’603 patent claims are entitled is
`
`December 16, 2015. Accordingly, the ’603 patent is not entitled to a pre-AIA
`
`priority date, and thus is eligible for PGR. This Petition is filed within nine months
`
`of the issue date of the ’603 patent, which was October 23, 2018, or by July 23, 2019.
`
`III. MANDATORY NOTICES
`
`A.
`
`37 C.F.R. § 42.8(b)(1): REAL PARTY-IN-INTEREST
`
`Lassen is the real party-in-interest.
`
`
`
`

`

`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
`
`37 C.F.R. § 42.8(b)(2): RELATED MATTERS
`
`B.
`
`To Petitioner’s best knowledge, the ’603 patent is not currently involved in
`
`any other judicial or administrative matters that would affect, or be affected by, a
`
`decision in this proceeding. However, Petitioner is aware that an EPO opposition
`
`was filed against European Patent No. 3 298 040 B1 (“EP ’040”), which is the
`
`European counterpart to the ’603 patent and claims priority to the same GB
`
`application. The specification of EP ’040 is substantively identical to that of the
`
`’603 patent.
`
`C.
`
`37 C.F.R. §§ 42.8(b)(3) AND (4): LEAD AND BACK-UP COUNSEL
`AND SERVICE INFORMATION
`
`Petitioner provides the following designation of counsel.
`
`Lead Counsel
`Christopher P. Bruenjes
`Reg. No. 62,941
`DRINKER BIDDLE &
`REATH LLP
`1500 K St. NW
`Suite 1100
`Washington, DC 20005
`
`Back-up Counsel
`Back-up Counsel
`William S. Foster, Jr.
`Mercedes K. Meyer
`Reg. No. 51,695
`Reg. No. 44,939
`DRINKER BIDDLE &
`DRINKER BIDDLE &
`REATH LLP
`REATH LLP
`1500 K St. NW
`1500 K St. NW
`Suite 1100
`Suite 1100
`Washington, DC 20005 Washington, DC 20005
`
`christopher.bruenjes@dbr.com mercedes.meyer@dbr.com william.foster@dbr.com
`
`
`
`Pursuant to 37 C.F.R. § 42.10(b), a Power of Attorney accompanies this
`
`Petition. Please address all correspondence to lead and back-up counsel at the
`
`2
`
`

`

`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
`
`addresses above. Petitioner also consents to electronic service by email at the email
`
`addresses listed above.
`
`IV. PAYMENT OF FEES
`
`The USPTO is authorized to charge the Petition fee of $38,000.00 required by
`
`37 C.F.R. §§ 42.203(a) and 42.15(a) to Deposit Account No. 50-0573, as well as any
`
`additional fees that might be necessary for this Petition.
`
`V. TIME FOR FILING PETITION
`
`The ’603 patent issued on October 23, 2018 and this Petition was timely filed
`
`on July 23, 2019, which is no later than the date that is nine months after the date of
`
`the grant of the patent. 37 C.F.R. § 42.202.
`
`VI.
`
`IDENTIFICATION OF CHALLENGED CLAIMS AND RELIEF
`SOUGHT PURSUANT TO 37 C.F.R. § 42.204(B)
`
`Petitioner respectfully requests post grant review of claims 1-10 of the ’603
`
`patent and cancellation of claims 1-10 as unpatentable under 35 U.S.C. §§ 112, 102,
`
`and/or 103. It is more likely than not that claims 1-10 are unpatentable in view of
`
`the following prior art references and grounds:
`
`Ground Claims Statutory Basis
`
`Prior Art References
`
`1
`
`1-10
`
`35 U.S.C.
`
`§
`
`112(a)
`
`
`
`Lack of Written Description
`
`3
`
`

`

`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
`
`112(a)
`
`35 U.S.C.
`
`§
`
`
`
`1-10
`
`2
`
`3
`
`4
`
`5
`
`Lack of Enablement
`
`1-4, 6,
`
`35
`
`U.S.C.
`
`§
`
`102
`
`Edwards (Ex. 1008)
`
`8-10
`
`Anticipation
`
`1-10
`
`35
`
`U.S.C.
`
`§
`
`103
`
`Edwards (Ex. 1008)
`
`Obviousness
`
`1-10
`
`35
`
`U.S.C.
`
`§
`
`103
`
`Edwards (Ex. 1008)
`
`Obviousness
`
`Wynn (Ex. 1010)
`
`Chegini (Ex. 1065)
`
`
`
`VII. ’603 PATENT OVERVIEW
`
`The ’603 patent issued on October 23, 2018, is titled “Treatment of Fibrosis”
`
`and contains 10 claims, one of which is independent and directed to a method of
`
`treating fibrosis. A Certificate of Correction issued on February 5, 2019 amended
`
`claim 1. Specifically, the claims recite a method of treating fibrosis in a human
`
`subject, the method comprising administering to the human subject in need of
`
`treatment a therapeutically effective amount of an Interleukin 11 receptor α (IL-
`
`11Rα) antibody which is capable of inhibiting Interleukin 11 (IL-11) mediated
`
`signaling, wherein the fibrosis is fibrosis of the heart, liver, kidney, or eye. Ex. 1001,
`
`Claim 1. Each of the claims requires an anti-IL-11Rα antibody defined only by its
`
`4
`
`

`

`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
`
`binding function rather than by any sequence or structure. Ex. 1003 ¶ 95; Ex. 1004
`
`¶ 29
`
`VIII. 37 C.F.R. § 42.204(b)(3): Claim Construction
`
`The claim terms are to be construed under the same claim construction
`
`standard as civil actions in federal district court. Accordingly, the claims are
`
`generally given their ordinary and customary meaning as understood by a person of
`
`ordinary skill in the art at the time of the invention (“the POSITA”) in the context of
`
`the entire claim and in the context of the entire patent, as well as the prosecution
`
`history. Further, the inventor can be its own lexicographer, where a clear definition
`
`is provided in the specification. Astrazeneca AB v. Mutual Pharmaceutical Co., Inc.,
`
`384 F.3d1333, 1337 (Fed. Cir. 2004). For this proceeding only, without conceding
`
`their correctness for litigation and unless otherwise noted below, Petitioner proposes
`
`the following construction:
`
`A.
`
`“method of treating fibrosis”
`
`This phrase occurs in the preamble of the claims. Preambles of claims are
`
`only limiting when they provide life and vitality to the claim. Intirtool, Ltd., v. Texar
`
`Corp., 369 F.3d 1289, 1295 (Fed. Cir. 2004) (quoting Pitney Bowes, Inc. v. Hewlett
`
`Packard Co., 182 F.3d 1298, 1305 (Fed. Cir. 1999)). Preambles have been found
`
`to be limiting when the preamble was relied upon for patentability during
`
`prosecution. Intirtool, at 1295. In this case, the Examiner clearly relied upon the
`
`5
`
`

`

`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
`
`preamble in finding the claim to overcome a possible 35 U.S.C. § 101 rejection, as
`
`indicated in the notice of allowance. Ex. 1002 at 42. Applicant did not dispute this
`
`interpretation by the Examiner. Id.
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`Also, claim preambles have been found to be limiting when the preamble
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`provides antecedent basis for limitations in the body of the claim. Pacing Techs.,
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`LLC v. Garmin Int’l, Inc., 778 F.3d 1021, 1023-24 (Fed. Cir. 2015). The phrase
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`“administering to the human subject” found in the body of claim 1 finds antecedent
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`basis in the preamble phrase “a method of treating fibrosis in a human subject.” For
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`at least being relied upon for purposes of patentability and providing antecedent
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`basis to limitations in the body of the claim, the preamble should limit the scope of
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`claim 1.
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`The ’603 patent specification provides a clear definition of “fibrosis” as
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`follows:
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`As used herein, “fibrosis” refers to the formation of excess fibrous
`connective tissue as a result of the excess deposition of extracellular
`matrix components, for example collagen. Fibrous connective tissue is
`characterised by having extracellular matrix (ECM) with a high
`collagen content. The collagen may be provided in strands or fibers,
`which may be arranged irregularly or aligned. The ECM of fibrous
`connective tissue may also include glycosaminoglycans. As used
`herein, “excess fibrous connective tissue” refers to an amount of
`connective tissue at a given location (e.g. a given tissue or organ, or
`part of a given tissue or organ) which is greater than the amount of
`connective tissue present at that location in the absence of fibrosis, e.g.
`under normal, non-pathological conditions. As used herein, “excess
`deposition of extracellular matrix components” refers to a level of
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`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
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`deposition of one or more extracellular matrix components which is
`greater than the level of deposition in the absence of fibrosis, e.g. under
`normal, non-pathological conditions.
`
`
`
`Ex. 1001, col. 33, ll. 26-44.
`
`Accordingly, the ’603 patent defines “fibrosis” as referring to “the formation
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`of excess fibrous connective tissue as a result of the excess deposition of
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`extracellular matrix components,” as those terms are defined above. Ex. 1003 ¶ 99;
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`Ex. 1004 ¶¶ 35-36.
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`Therefore, for purposes of this Petition, the phrase “method of treating
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`fibrosis” should be interpreted as “method of treating the formation of excess fibrous
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`connective tissue as a result of the excess deposition of extracellular matrix
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`components.” Ex. 1003 ¶ 100; Ex. 1004 ¶ 37.
`
`B.
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`“administering to the human subject in need of treatment a
`therapeutically effective amount”
`
`The ’603 patent specification provides a clear definition of “therapeutically
`
`effective amount” as referring to “an amount sufficient to show benefit to the human
`
`subject.” Ex. 1001, col. 33, ll. 11-13.
`
`Because the phrase “therapeutically effective amount” is used in conjunction
`
`with a method of treating fibrosis, the therapeutic benefit to be shown must be related
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`to treatment of fibrosis. Ex. 1004 ¶ 39. Neither the ’603 patent nor anything within
`
`the prosecution history limits the extent of the benefit to the human subject. Id. ¶
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`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
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`40. Accordingly, any benefit would fall within the scope of a “therapeutically
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`effective amount,” and thus would fall within the scope of the phrase “method of
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`treating fibrosis” to which the “therapeutically effective amount” phrase is further
`
`defining. Id.
`
`Therefore, for purposes of this Petition, the phrase “administering to a human
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`subject in need of treatment a therapeutically effective amount” should be
`
`interpreted as “administering a human subject in need of treatment for fibrosis an
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`amount sufficient to show benefit to the human subject regarding the subject’s
`
`fibrosis.” Id. ¶ 41; Ex. 1003 ¶ 103.
`
`C.
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`“Interleukin 11 receptor α (IL-11Rα) antibody”
`
`The ’603 patent broadly describes agents that bind to an IL-11 receptor (IL-
`
`11R) and in preferred embodiments, the IL-11R is IL-11Rα. Ex. 1001, col. 17, ll.
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`27-34. The IL-11R binding agents can be an anti-IL-11R antibody. Id. col. 17, ll.
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`35-37. The ’603 patent includes many different proteins in the definition of an “IL-
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`11R antibody” which they set forth at col. 18 as follows:
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`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
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`Ex. 1001, col. 18, ll. 14-46.
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`No further limitation on the breadth of the term was provided during
`
`
`
`prosecution history.
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`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
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`Based on the description in the ’603 patent, the scope of an “IL-11Rα
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`antibody” may include any kind of antibody that binds to IL-11Rα and may be an
`
`antagonist antibody or a neutralizing antibody. Ex. 1003 ¶ 104. Further, nothing in
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`the ’603 patent or its prosecution history limits the antibodies to human antibodies.
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`Id. ¶ 105. In fact, the ’603 patent indicates that non-human antibodies are included
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`by explicitly mentioning that human antibodies are preferable. Id.; Ex. 1001, col.
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`18, ll. 14-15. Accordingly, other animal anti-IL-11Rα antibodies fall within the full
`
`scope of an “IL-11Rα antibody”, including antibodies directed against other animal
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`IL-11R and IL-11Rα antigens. Ex. 1003 ¶ 105.
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`Further, the description of antibodies included in the ’603 patent includes
`
`fragments or derivatives of an antibody, a monoclonal antibody, and even a
`
`polyclonal antibody. Ex. 1001, col. 20, ll. 38-col. 21, ll. 64; Ex. 1003 ¶¶ 106-107;
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`Ex. 1004 ¶ 43. Accordingly, both monoclonal and polyclonal antibodies, antibody
`
`fragments, a synthetic antibody or a synthetic antibody fragment all fall within the
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`scope of the term “antibody.” Ex. 1003 ¶¶ 106-107.
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`Therefore, for purposes of this Petition, the phrase “Interleukin 11 receptor α
`
`(IL-11Rα) antibody” should be interpreted at least as “any natural or synthetic,
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`monoclonal or polyclonal antibody made using any animal system including phage,
`
`or fragment or derivative thereof, that binds to IL-11Rα of any species.” Id. ¶ 108;
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`Ex. 1004 ¶ 46.
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`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
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`“capable of inhibiting Interleukin 11 (IL-11) mediated signaling”
`
`D.
`
`The ’603 patent specification recites that antibodies that bind to an IL-11R for
`
`example “may inhibit IL-11 mediated signaling by blocking the binding of IL-11 to
`
`an IL-11R or by preventing signal transduction via the gp130 co-receptors.” Ex.
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`1001, col. 17, ll. 27-30; Ex. 1004 ¶ 47. In “preferred embodiments the IL-11R is IL-
`
`11Rα and suitable binding agents may bind the IL-11Rα polypeptide and may be
`
`inhibitors or antagonists of IL-11Rα.” Ex. 1001, col. 17, ll. 31-34; Ex. 1004 ¶ 47.
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`Such antibodies may also “inhibit or prevent association of IL-11Rα with gp130 to
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`form a functional receptor complex capable of productive signaling, e.g. in response
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`to IL-11 binding.” Ex. 1001, col. 18, ll. 29-32; Ex. 1004 ¶ 47. It is unclear what the
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`difference is between IL-11R and IL-11Rα. Ex. 1004 ¶ 47. IL-11Rα is the receptor
`
`on the cell surface responsible for binding to IL-11 and involved with producing a
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`signal in the cell downstream. Id. There is an IL-11Rα2, which is produced by the
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`proteolytic cleavage of IL-11Rα (also known as IL-11Rα1) from the surface of the
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`cell. Id. The human form results from two different cDNAs produced by alternative
`
`splicing, which yields a 80 kD protein and a 82 kD protein. Ex. 1067 at 141; Ex.
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`1004 ¶ 47. However, IL-11Rα2 can produce no signal as it is not on the cell surface.
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`Id. Thus, IL-11Rα to be the form that is on the cell’s surface and provides the signal.
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`Id. However, because claim 1 specifically recites IL-11Rα, the broader genus of IL-
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`11 receptor antigens characterized by “IL-11R” are excluded.
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`11
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`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
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`Therefore, for purposes of this Petition, the phrase “capable of inhibiting
`
`Interleukin 11 (IL-11) mediated signaling” should be interpreted as any antibody
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`within the definition above that is “capable of blocking the binding of IL-11 to an
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`IL-11Rα or preventing signal transduction via the gp130 co-receptors.” Id. ¶ 48; Ex.
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`1003 ¶ 110.
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`E.
`
` “wherein the fibrosis is fibrosis of the heart, liver, kidney, or eye”
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`The ’603 patent states that the fibrosis can be any of the following from col.
`
`3, lines 46-56 (Ex. 1001):
`
`Ex. 1004 ¶ 50.
`
`By specifically reciting fibrosis of heart, liver, kidney, or eye, claim 1 limits
`
`the fibrosis to be treated in one of the recited organs. Id. ¶ 49; Ex. 1003 ¶ 111.
`
`
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`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
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`
`Plain and Ordinary Meaning
`
`Petitioner proposes that all other terms of the Challenged Claims be construed
`
`in accordance with their plain and ordinary meanings.
`
`IX. Level of ordinary skill in the art
`
`A person of ordinary skill in the art at the time (“POSITA”) of the alleged
`
`invention in 2016 would typically have had a Ph.D. in immunology, molecular
`
`biology, cellular biology, or a similar field, or an M.D. with similar experience in
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`one of the listed fields. POSITA would typically have had at least about five years
`
`of experience with antibodies and antibody engineering, or access to other
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`individuals with that knowledge and experience. Ex. 1003 ¶ 113; Ex. 1004 ¶ 53.
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`Likewise, a person of ordinary skill in the art would have had knowledge and
`
`experience in fibrosis, or access to a person with that knowledge and experience.
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`Ex. 1003 ¶ 113; Ex. 1004 ¶ 53.
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`X. DETAILED GROUNDS FOR UNPATENTABILITY
`
`A.
`
`State of the Art
`
`Around December 2015, it was thought that IL-11 binds with low nanomolar
`
`affinity to IL-11Rα on the cell surface. Ex. 1003 ¶ 32. The IL-11/ IL-11Rα complex
`
`is not competent for cell signaling, whereas heterodimerization IL-11/IL-11Rα with
`
`GP130 results in a higher affinity complex that is capable of intracellular signaling
`
`Id. (citing Ex. 1017 at 4403-12). These complex and temporal set changes involve
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`PETITION FOR POST GRANT REVIEW
`U.S. Patent No. 10,106,603
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`transitions in receptor homo- and hetero-dimerization, conformational changes,
`
`interactions between IL-11 and IL-11Rα, interactions between IL-11 and GP130 and
`
`between IL-11Rα and GP130. Id. The functional signaling complex of IL-11, IL-
`
`11Rα and gp130 contains two molecules of each of the three proteins. Id. IL-11Rα
`
`is an ~420 amino acid protein possessing multiple domains that have been shown to
`
`interact with IL-11. Id. Likewise, GP130 is large multisubunit, ~870 amino acid
`
`protein containing multiple interaction domains that facilitate signaling with diverse
`
`binding partners across the IL-6 receptor family. Id.
`
`Accordingly, antibodies against IL-11Rα could (i) inhibit IL-11Rα but not
`
`GP130 binding, (ii) inhibit IL-11Rα but not IL-11 binding; (iii) inhibit
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`heterodimerization of IL-11RΑ/GP130; (iv) drive IL-11Rα internalization of IL-
`
`11RΑ; and (v) modulate expression of IL-11RΑ among other things. Id. ¶ 34.
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`Therefore, characterizing the binding, structure and activity of an anti-IL-11Rα
`
`antibody would be necessary to identify which anti-IL-11Rα antibody would also
`
`have the function of an anti-fibrotic effect. Id.
`
`Because of the unpredictability of antibody sequences, to understand
`
`antibodies that bind IL-11Rα, POSITA would have to screen from the vast pool of
`
`potential antibodies, to identify ones having the desired activity, and then have to
`
`determine their stru