`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`
`BLUEBIRD BIO, INC.,
`Petitioner,
`
`v.
`
`SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH,
`Patent Owner.
`____________
`
`Case No. IPR2023-00074
`Patent No. 8,058,061
`____________
`
`
`
`
`
`PATENT OWNER’S RESPONSE TO PETITION
`
`
`
`
`
`
`
`
`147940117.6
`
`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`
`TABLE OF CONTENTS
`
`
`I.
`
`INTRODUCTION AND SUMMARY OF THE ARGUMENT ..................... 1
`
`II.
`
`BACKGROUND AND FACTS ...................................................................... 7
`
`A.
`
`The ’061 Patent And The Challenged Claims ................................................. 7
`
`B.
`
`The Prior Art Raised By Petitioner................................................................ 11
`
`1.
`
`2.
`
`3.
`
`The May Abstract (Ex. 1006) .............................................................. 11
`
`The Nature Article ............................................................................... 12
`
`The May Thesis ................................................................................... 14
`
`C.
`
`The Board’s Institution Decision ................................................................... 15
`
`III. ARGUMENT ................................................................................................. 20
`
`A.
`
`The Challenged Claims Are Entitled To The Priority Date Of Their
`Provisional Application Filing Date .............................................................. 20
`
`1.
`
`2.
`
`Like Claim 8, Claim 7 Is Fully Described In The Provisional
`Application .......................................................................................... 24
`
`Like Claims 7, 8, and 15, Claims 1, 2, 5, 6, and 11 Are Also Fully
`Described In the Provisional Application ........................................... 29
`
`B.
`
`The Challenged Claims Are Not Anticipated By Or Obvious Over The
`Nature Article ................................................................................................ 37
`
`1.
`
`2.
`
`The Board Was Correct In Rejecting Petitioner’s Argument That
`The Nature Article Anticipates The Challenged Claims .................... 37
`
`Petitioner’s Obviousness Arguments Regarding The Nature
`Article Should Also Be Rejected ........................................................ 40
`
`C.
`
`The Challenged Claims Are Not Obvious Over The May Abstract ............. 52
`
`i
`
`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`D.
`
`There Is Compelling Objective Evidence Of Non-Obviousness Of The
`Challenged Claims ......................................................................................... 59
`
`1.
`
`2.
`
`3.
`
`Long-felt But Unsolved Needs and Failure of Others ........................ 60
`
`The Unexpected Results And Praise From Others .............................. 62
`
`The Copying Of Others ....................................................................... 64
`
`IV. CONCLUSION .............................................................................................. 65
`
`
`
`ii
`
`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`
`Cases
`
`TABLE OF AUTHORITIES
`
`
`
`Page(s)
`
`Ajinomoto Co. v. Int’l. Trade Comm’n.,
`932 F.3d 1342 (Fed. Cir. 2019)..............................................................................22, 23, 36, 37
`
`Ariad Pharms., Inc. v. Eli Lilly & Co.,
`598 F.3d 1336 (Fed. Cir. 2010)..........................................................................................22, 27
`
`Catalina Lighting, Inc. v. Lamps Plus, Inc.,
`295 F.3d 1277 (Fed. Cir. 2002)................................................................................................59
`
`Continental Can Co. USA, Inc. v. Monsanto Co.,
`948 F.2d 1267 (Fed. Cir. 1991)................................................................................................39
`
`Ecolochem, Inc. v. S. Cal. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000)..........................................................................................44, 56
`
`Kennametal, Inc. v. Ingersoll Cutting Tool Co.,
`780 F.3d 1376 (Fed. Cir. 2015)..........................................................................................38, 39
`
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009)................................................................................................44
`
`Leapfrog Enters., Inc. v. Fisher-Price, Inc.,
`485 F.3d 1157 (Fed. Cir. 2007)................................................................................................59
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013)..........................................................................................51, 58
`
`Metalcraft of Mayville, Inc. v. Toro Co.,
`848 F.3d 1358 (Fed. Cir. 2017)................................................................................................44
`
`Novozymes A/S v. Dupont Nutrition Biosciences APS,
`723 F.3d 1336 (Fed. Cir. 2013)................................................................................................36
`
`Ortho-McNeil v. Mylan Lab,
`520 F.3d 1358 (Fed. Cir. 2008)....................................................................................51, 58, 59
`
`Paice LLC v. Ford Motor Co.,
`881 F.3d 894 (Fed. Cir. 2018)..................................................................................................21
`
`Paragon 28, Inc. v. Wright Med. Tech., Inc.,
`IPR2019-00896, 2020 WL 5848657 (P.T.A.B. Oct. 1, 2020) .................................................21
`
`iii
`
`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`In re Petering,
`301 F.2d 676 (CCPA 1962) .....................................................................................................39
`
`Pozen Inv. v. Par Pharm., Inc.,
`696 F.3d 1151 (Fed. Cir. 2012)................................................................................................21
`
`Purdue Pharma L.P. v. Faulding Inc.,
`230 F.3d 1320 (Fed. Cir. 2000)................................................................................................21
`
`SAS Institute Inc. v. Iancu,
`584 U.S. ___, 138 S.Ct. 1348 (2018) .......................................................................................16
`
`Schering Corp. v. Geneva Pharms., Inc.,
`339 F.3d 1373 (Fed. Cir. 2003)................................................................................................37
`
`Takeda Chemical v. Alphapharm,
`492 F.3d 1350 (Fed. Cir. 2007)..........................................................................................51, 58
`
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
`683 F.3d 1356 (Fed. Cir. 2012)................................................................................................39
`
`Zoho Corp. v. Sentius Int’l., LLC,
`494 F. Supp.3d 693 (N.D. Cal. 2020) ......................................................................................27
`
`Statutes
`
`35 U.S.C. §§ 112, 120 ....................................................................................................................21
`
`35 U.S.C. § 112(a) .........................................................................................................................21
`
`Other Authorities
`
`37 CFR § 42.6(e)............................................................................................................................67
`
`37 CFR § 42.24(d) .........................................................................................................................66
`
`M.P.E.P. § 2161 .............................................................................................................................26
`
`U.S. Patent No. 7,541,179....................................................................................................7, 11, 45
`
`U.S. Patent No. 8,058,061
`............................................1, 3, 7, 11, 13, 14, 15, 16, 17, 20, 29, 35, 37, 40, 43, 45, 52, 59, 65
`
`
`
`
`
`
`iv
`
`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`
`Exhibit
`No.
`2001
`
`2002
`2003
`2004
`
`2005
`2006
`2007
`2008
`2009
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`EXHIBIT LIST
`
`Description
`
`Exclusive Licensee Agreement Between Sloan Kettering Institute for
`Cancer Research and San Rocco Therapeutics, LLC
`January 2023 Declaration of Dr. James Riley
`October 2020 Declaration of Dr. Michel Sadelain
`Petitioner’s October 2020 Letter Submitting Dr. Sadelain’s October
`2020 Declaration in New York State Court
`Joint Defense Agreement
`January 2023 Declaration of Michel Sadelain
`January 2023 Declaration of Chad May
`January 2023 Declaration of Stefano Rivella
`January 2023 Declaration of Lucio Luzzatto
`Sorrentino, B., One Step Closer to Gene Therapy for
`Hemoglobinopathies, Blood (2004) 104(12):3419.
`Caterina J., et al., Human Beta-Globin Locus Control Region:
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`Judson, H., The Glimmering Promise of Gene Therapy, MIT Tech.
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`glimmering-promise-of-gene-therapy/.
`Jackson, J., et al. Role of DNA Sequences Outside the Cores of DNase
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`Biol. Chem. (1996) 271(20):11871-8.
`Philipsen, S., et al. The β-globin Dominant Control Region:
`Hypersensitive Site 2, EMBO J. (1990) 9(7):2159-67.
`Hardison, R., et. al., Locus Control Regions of Mammalian β-globin
`Gene Clusters: Combining Phylogenetic Analyses and Experimental
`Results to Gain Functional Insights, Gene (1997) 205(1-2):73-94.
`Persons, D. & Nienhuis, A., Gene Therapy for the Hemoglobin
`Disorders: Past, Present, and Future, Proc. Nat’l. Acad. Sci. USA
`(2000) 97(10):5022-24.
`Kafri, T. et al., Lentiviral Vectors: Regulated Gene Expression,
`Molecular Therapy (2000) 1(6): 516-521.
`
`v
`
`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`
`Exhibit
`No.
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`2025
`2026
`
`2027
`
`2028
`
`2029
`2030
`
`Description
`
`Amado, R. & Chen, I., Lentiviral Vectors — the Promise of Gene
`Therapy within Reach? Science. (1999) 285(5428):674-76.
`Chada, K., et al., Specific Expression of a Foreign β-globin Gene in
`Erythroid Cells of Transgenic Mice, Nature (1985) 314(6009):377-80.
`Townes, T., et al., Expression of Human β-globin Genes in Transgenic
`Mice: Effects of a Flanking Metallothionein-Human Growth Hormone
`Fusion Gene, Mol. Cell. Biol. (1985) 5(8):1977-83.
`Dzierzak, E., et al., Lineage-Specific Expression of a Human β-globin
`Gene in Murine Bone Marrow Transplant Recipients Reconstituted
`with Retrovirus-Transduced Stem Cells, Nature (1988) 331(6151):35-
`41.
`Bodine, D., et. al., Combination of Interleukins 3 and 6 Preserves
`Stem Cell Function in Culture and Enhances Retrovirus-Mediated
`Gene Transfer into Hematopoietic Stem Cells, Proc. Nat’l. Acad. Sci.
`USA (1989) 86(22):8897-901.
`Bender, M., et al., A Majority of Mice Show Long-Term Expression of
`a Human β-globin Gene After Retrovirus Transfer into Hematopoietic
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`Sadelain, M., et al., Generation of a High-Titer Retroviral Vector
`Capable of Expressing High Levels of the Human B-globin Gene,
`Proc. Nat’l Acad. Sci. (USA) (1995) 92(15):6728-32.
`GenBank Accession No. Z84721 (Mar. 19, 1997).
`NCBI RefSeq Gene HBA2, RefSeq:NM_000517.6 (data last updated
`Oct. 28, 2022).
`Hardison, R., et al., Sequence and Comparative Analysis of the Rabbit
`α-Like Globin Gene Cluster Reveals a Rapid Mode of Evolution in a G
`+ C-rich Region of Mammalian Genomes, J. Mol. Biol. (1991)
`222(2):233-49.
`Huisman, T., et al., A Syllabus of Human Hemoglobin Variants
`(1996), published by The Sickle Cell Anemia Foundation in Augusta,
`Georgia,
`GenBank Accession No. J00179 (1993).
`Tagle, D., et al., The β Globin Gene Cluster of the Prosimian Primate
`Galago crassicaudatus: Nucleotide Sequence Determination of the 41-
`kb Cluster and Comparative Sequence Analyses, Genomics (1992)
`13(3):741-60.
`
`vi
`
`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`
`Exhibit
`No.
`2031
`
`2032
`
`2033
`2034
`2035
`2036
`
`2037
`
`2038
`
`2039
`
`2040
`
`2041
`
`2042
`
`2043
`
`2044
`
`2048
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`Description
`
`Li, Q. et al., Development of Viral Vectors for Gene Therapy of β-
`Chain Hemoglobinopathies: Optimization of a γ-Globin Gene
`Expression Cassette, Blood (1999) 93(7):2208-16.
`Slightom, J., et al., Human Fetal Gγ- and Aγ-Globin Genes: Complete
`Nucleotide Sequences Suggest that DNA Can Be Exchanged Between
`These Duplicated Genes, Cell (1980) 21(3):627-38.
`Excerpts from Inventor Notebooks
`Excerpts from Inventor Notebooks
`October 2020 Affidavit of Dr. Isabelle Rivière
`Verma, I. & Weitzman, M., Gene Therapy: Twenty-First Century
`Medicine, Annu. Rev. BioChem. (2005) 74:711-38.
`Blau, H. & Springer, M., Molecular Medicine, Gene Therapy – A
`Novel Form of Drug Delivery, N. Engl. J. Med. (1995) 333(18):1204-
`07.
`Morris, A., et al., MHC Class II Gene Silencing in Trophoblast Cells
`is Caused by Inhibition of CIITA Expression, Am. J. Reproductive
`Immunology (1998) 40(6):385-94.
`Bernards, R., et al. Physical Mapping of the Globin Gene Deletion in
`β-thalassemia, Gene (1979) 6(3):265-80.
`Ryan, T., et al., A Single Erythroid-Specific DNase I Super-
`Hypersensitive Site Activates High Levels of Human β-globin Gene
`Expression in Transgenic Mice, Genes & Dev. (1989) 3(3): 314-23.
`Pasceri, P., et al., Full Activity from Human β-globin Locus Control
`Region Transgenes Requires 5'HS1, Distal β-globin Promoter, and 3’
`β-globin Sequences, Blood (1998) 92(2):653-63.
`Hardison, R., et al., Locus Control Regions of Mammalian β-globin
`Gene Clusters: Combining Phylogenetic Analyses and Experimental
`Results to Gain Functional Insights, Gene (1997) 205(1-2):73-94.
`Hacein-Bey-Abina, S., et al., “A Serious Adverse Event after
`Successful Gene Therapy for X-Linked Severe Combined
`Immunodeficiency, N. Engl. J. Med. (2003) 348(3):255-256.
`Pfeifer, A., & Verma, I., Gene Therapy: Promises and Problems,
`Annu. Rev. Genomics Hum. Genet. (2001) 2:177-211.
`Joseph Caputo, Cell Press Selected to Publish Molecular Therapy
`Family of Journals, Elsevier (Oct. 31, 2016),
`
`vii
`
`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`
`Exhibit
`No.
`
`Description
`
`2049
`
`2050
`2051
`
`2052
`
`2053
`2054
`
`2055
`2056
`2057
`
`2058
`
`2059
`
`2060
`
`2061
`
`2062
`
`https://www.prnewswire.com/news-releases/cell-press-selected-to-
`publish-molecular-therapy-family-of-journals-599337931.html
`Molecular Therapy MARC Tags, Library of Congress,
`https://catalog.loc.gov/vwebv/staffView?searchid=19014&recPointer=
`0&recCount=25&bibId=13190243
`CrossRef, https://api.crossref.org/v1/works/10.1006/mthe.2000.0176
`Global Tel*Link Corp. v. Securus Tech. Inc., IPR2017-01435,
`Declaration of Dr. Leonard J. Forys in Support of Petition for Inter
`Partes Review of U.S. Patent No. 7,529,357 (PTAB May 15, 2017)
`Bungert, J., et al., Synergistic Regulation of Human β-globin Gene
`Switching by Locus Control Region Elements HS3 and HS4, Genes
`and Development (1995) 9:3083-3096
`Duplicate of Ex. 2014.
`Liu, Q., et al., Mutation of Gene-proximal Regulatory Elements
`Disrupts Human ε-, γ-, and β-globin Expression in Yeast Artificial
`Chromosome Transgenic Mice, Proc. Natl. Acad. Sci. USA (1996)
`94:169-174
`Transcript of Deposition of Dr. Jӧrg Bungert on July 10, 2023
`August 2023 Declaration of Dr. James Riley
`McInerney, J., et al. Slow and Steady Wins The Race? Progress in the
`Development of Vectors for Gene Therapy of β-Thalassemia and
`Sickle Cell Disease, Hematology (2000) 4(5):437-455.
`Grosveld, F., et al., The Dynamics of Globin Gene Expression
`and Gene Therapy Vectors, Ann. NY Acad. Sci. (1998) 850:18-27.
`Fraser, P., et al., DNaseI Hypersensitive Sites 1, 2 and 3 of the Human
`β-globin Dominant Control Region Direct Position-Independent
`Expression, Nucleic Acids Res. (1990) 18(12):3503-8.
`Fraser, P., et al., Each Hypersensitive Site of the Human β- globin
`Locus Control Region Confers a Different Developmental Pattern of
`Expression on the Globin Genes, Genes & Dev. (1993) 7(1):106-13.
`Kulozik, A., et al., The Proximal Element of the β Globin Locus
`Control Region Is Not Functionally Required In Vivo, J. Clin. Invest.
`(1991) 87(6):2142-46.
`Milot, E., et al., Heterochromatin Effects on the Frequency and
`Duration of LCR-Mediated Gene Transcription, Cell (1996)
`87(1):105-14.
`
`viii
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`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`
`Exhibit
`No.
`2063
`
`2064
`
`2065
`
`2066
`
`2067
`
`2068
`
`2069
`
`2070
`
`2071
`
`2072
`
`2073
`
`2074
`
`Description
`
`Peterson, K., et al., Effect of Deletion of 5’HS3 or 5’HS2 of the Human
`β-globin Locus Control Region on the Developmental Regulation of
`Globin Gene Expression in β-globin Locus Yeast Artificial
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`93(13):6605-09.
`Bungert, J., et al., Hypersensitive Site 2 Specifies a Unique Function
`within the Human β-Globin Locus Control Region To Stimulate
`Globin Gene Transcription, Mol. Cell. Biol. (1999) 19(4):3062–3072.
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`Independent Enhancer far Upstream of the Human “β-like Globin”
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`Collis, P., et al., Definition of the Minimal Requirements Within the
`Human β-globin Gene and the Dominant Control Region for High
`Level Expression, EMBO J. (1990) 9(1): 233-40.
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`span.org/video/?155137-1/safety-gene-therapy.
`
`Press Briefing by Scott McClellan, The White House (Aug. 9, 2001),
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`Cures for Blood Diseases, Newsday (July 6, 2000),
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`Experiments-point-to-2714623.php.
`Malik, P., Toward Gene Therapy for β-thalassemia; New Models, New
`Approaches, Blood (2003) 101(8): 2902-03.
`Stamatoyannopoulos, M., Prospects for Developing a Molecular Cure
`for Thalassemia, Hematology (2005) 10 (Supplement 1): 255-57.
`Malech, H., et al., Evolution of Gene Therapy, Historical Perspective,
`Hematol. Oncol. Clin. N. Am. (2022) 36(4):627-45.
`
`ix
`
`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`
`Exhibit
`No.
`2075
`
`2076
`
`2077
`
`2078
`
`2079
`
`2080
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`
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`Description
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`Genes by LCR Element HS3 When Linked to β-Globin Gens and LCR
`Element HS2 in MEL Cells, Am. J. Hematology (1996) 51(3):220-28.
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`Therapeutics, LLC v. Bluebird Bio, Inc. and Third Rock Ventures,
`C.A. No. 21-1478-RGA (D. Del.)
`
`x
`
`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`
`San Rocco Therapeutics (“SRT”), responding on behalf of Patent Owner
`
`Sloan Kettering Institute For Cancer Research, submits this Response to Bluebird
`
`bio, Inc.’s Petition for Inter Partes Review of claims 1, 2, 5-8, 11, and 15 (the
`
`“Challenged Claims”) of U.S. Patent No. 8,058,061 (Ex. 1001, “the ’061 patent”).
`
`I.
`
`INTRODUCTION AND SUMMARY OF THE ARGUMENT
`
`The Challenged Claims are directed to recombinant vector systems
`
`incorporating a functional globin gene and large portions of the β-globin locus
`
`control region (“LCR”). The only prior art Petitioner raised as grounds for
`
`invalidating the Challenged Claims are publications mainly authored by the
`
`inventors reporting the work described in the ’061 patent in varying levels of
`
`detail.
`
`While SRT respectfully believes that the Board was led into error by
`
`Petitioner in granting institution of this IPR based on the preliminary record, the
`
`Board’s decision does make clear that at least claims 8 and 15 of the ’061 patent,
`
`which is limited to the vector of claim 1, “wherein said functional globin is human
`
`β-globin,” is free and clear of all of the prior art raised in the Petition. This
`
`conclusion is based on the Board’s findings that: (1) claims 8 and 15 are afforded
`
`priority to the June 29, 2001 filing date of its provisional application; (2) as a result
`
`of this priority date, the Nature Article is neither prior art under Section 102(b),
`
`because it is not a statutory bar, nor prior art under Section 102(a), because it is the
`
`1
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`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`work of the inventors; (3) that the May thesis does not qualify as prior art because
`
`it was deemed published more than one year after the June 2001 priority date and
`
`also constituted the work of the inventors; and (4) that the May Abstract contained
`
`so little information that a person of ordinary skill in the art (“POSA”) would not
`
`have been motivated with a reasonable expectation of success to use it in arriving
`
`at the Challenged Claims. As to findings 1-3, Petitioner never disputed these with
`
`respect to claims 8 and 15 prior to Institution and is therefore precluded from
`
`challenging these findings now.
`
`SRT believes that based upon this more complete Record, the Board should
`
`make these same findings against the other three Challenged Claims, claims 1, 2,
`
`5-7, and 11, which will result in affirming the validity of the Challenged Claims.
`
`Claim 7 is virtually the same as claim 8, except that instead of being limited
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`to “human” β-globin, claim 7 is directed to a functional globin that is a “β-globin.”
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`As detailed below, the provisional application (Appl. No. 60/302,852, filed on July
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`2, 2001 (“the ’852 Provisional” or the “provisional application”) and the Nature
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`Article (which is reproduced as part of the disclosure of the provisional
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`application) describe the use of “functional-β-globin” repeatedly as part of the
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`invention. (See, e.g., Ex. 1035 at 2 (emphasis added) (“Thus, in one aspect of the
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`invention, there is provided a lentiviral vector which combines a β-globin gene, an
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`RRE element and large portions of the locus control region which includes DNase
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`I hypersensitive sites HS2, HS3, and HS4.”)) This in haec verba support
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`throughout the provisional application fully supports written description of claim 7,
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`and clearly would have conveyed to a POSA that the inventors were in possession
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`of not just “human” β-globin, but also other β-globins, for use in their expression
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`vector system.
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`In its Institution Decision, the Board suggested that claim 7’s recitation of a
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`β-globin gene was not supported by the provisional application because it did not
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`disclose a “mutant β-globin.” (Paper No. 8 at 24.) However, as detailed below by
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`SRT’s supporting declaration of Dr. James L. Riley, a POSA would immediately
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`recognize that the provisional application’s repeated use of the term “β-globin” in
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`the context of the claimed vector system would of course include mutant forms of
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`β-globin. (Ex. 2056 at ¶¶92-98.) After all, by this time, point mutations to the
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`human β-globin gene were routine, and hundreds of mutations of the human β-
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`globin gene had been reported in the literature, including mutations to the human
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`β-globin gene that were specifically designed to treat the hemoglobinopathies that
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`are the subject of the ’061 patent. (Ex. 2056 at ¶¶95-96; see also Ex. 2079 at 9852,
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`Ex. 2080 at 9562. Ex. 1047 at 8, Ex. 2081 at 13885.) Moreover, the “human” β-
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`globin gene within the claimed TNS9 vector reported in the provisional application
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`and the Nature Article is itself a mutant, since it contains the IVS2 deletion that
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`does not exist in the native human β-globin gene. (Ex. 1035 at 5 (Fig. 1).) Thus,
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`like claim 8, claim 7 (which is directed to a functional β-globin) also has written
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`description support in the provisional application, resulting in a priority date that
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`removes the Nature Article and May Thesis as prior art.
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`As to claims 1, 2, 5, 6, and 11, these too find written description support in
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`the provisional application and Nature Article. While the scope of these claims is
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`broader since functional globin is not limited to β-globin but includes any globin
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`gene, the purpose of the invention disclosed in the provisional application was to
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`provide a vector system that consistently expresses certain genes in patients to treat
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`hemoglobinopathies “including β-thalassemia and sickle cell disease.” (See Ex.
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`1035 at 2.) At the time of filing of the provisional application, globin genes other
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`than β-globin were being extensively studied to enhance their expression as a
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`means to treat β-thalassemia and sickle cell disease. (Ex. 2056 at ¶93; Ex. 2075 at
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`221; Ex. 2076 at 873, 875; Ex. 2077 at 7258; Ex. 2078 at 2076.) Thus, a POSA,
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`having reviewed the provisional application’s goal of using gene therapy to treat β-
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`thalassemia and sickle cell disease, readily would have recognized that the
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`inventors were in possession of not just an expression vector system that could
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`enhance the expression of β-globin, but other globin genes, such as γ (gamma)-
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`globin. (Id.) In fact, the provisional application explicitly states that “recombinant
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`lentiviruses bearing large fragments of the human β-globin gene and its LCR
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`represent” not only “an advancement towards the genetic treatment of severe
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`haemoglobinopathies,” but also provides the “paradigm for any stem cell therapy
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`requiring stable and regulated expression of a tissue-specific transgene.” (Ex. 1035
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`at 7 (emphasis added).)
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`Even if claims 1-2, 5-8, 11, and 15 are not afforded priority to the filing of
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`the provisional application, these claims would still not be rendered obvious over
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`the Nature Article. While the Board initially determined that these claims were
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`obvious over the Nature Article, SRT believes that this finding was largely based
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`on the Board’s misplaced crediting of the conclusion of Petitioner’s expert, Dr.
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`Jӧrg Bungert. Dr. Bungert submitted a declaration in support of the Petition that
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`surmised, upon reviewing the Nature Article, there were only six possible
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`combinations of restriction enzyme fragments that a POSA needed to choose from
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`to arrive at the claimed inventions. However, based on the more complete Record
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`established below, Dr. Bungert’s original opinion cannot withstand scientific
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`scrutiny. Dr. Bungert admitted at deposition that he did not account for many other
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`known restriction enzymes that a POSA would have considered and that his
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`“preferred” approach of discounting numerous other possible restriction enzymes
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`was not supported by the Record. (Ex. 2055 at 59:17-61:2.) By the very nature of
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`Dr. Bungert’s analysis and the variability of trying to guess the restriction enzyme
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`sites of three hypersensitive regions, Dr. Bungert’s failure to account for even just
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`one restriction enzyme site pair in one HS fragment, such as HS2, would increase
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`the possible combinations from 6 to 12, and a failure to account for 2 restriction
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`enzyme site pairs would increase that combination to 24. Here, when Dr. Riley
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`takes into consideration many of the other commercially known restriction
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`enzymes that Dr. Bungert inexplicably and conveniently ignores – at least 8
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`restriction enzyme site pairs for HS2, 3 restriction enzyme site pairs for HS3, and 8
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`restriction enzyme site pairs for HS4 – Dr. Riley concludes that a POSA would be
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`confronted with not just six options, but at least 540 possible combinations of
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`restriction enzymes for the HS fragments. (Ex. 2056 at ¶¶169-175.) Clearly, having
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`to choose from among these hundreds of combinations is not a sufficient teaching,
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`suggestion, or motivation to combine the Nature Article with what was known in
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`the art to arrive at the Challenged Claims.
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`Finally, for many of the same reasons, the Board was correct to hold that the
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`May Abstract also doesn’t render the Challenged Claims obvious. Like the
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`hundreds of combinations deduced by Dr. Riley for the Nature Article, the 135
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`possible combinations of restriction enzyme fragments that Dr. Bungert arrives at
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`based on his review of the May Abstract fall woefully short of the reasonable
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`expectation of success standard of obviousness. In fact, because Dr. Bungert also
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`employed a seriously flawed approach and disregarded many commercially
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`available restriction enzymes in his analysis of the May Abstract (just as he did
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`with the Nature Article), the number of possible combinations is many times larger
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`than 135, as confirmed by Dr. Riley. (Ex. 2056 at ¶¶183-90.)
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`As this Response demonstrates, along with the August Declaration of Dr.
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`James L. Riley (“Riley Decl.,” Ex. 2056), Petitioner has not shown a reasonable
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`likelihood of prevailing on its assertion that the Challenged Claims of the ’061
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`patent are anticipated by, or obvious over, the prior art of record.
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`II. BACKGROUND AND FACTS
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`A. The ’061 Patent And The Challenged Claims
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`The ’061 patent is a divisional of U.S. Patent No. 7,541,179 and claims
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`priority to both Provisional Application No. 60/301,861, filed on June 29, 2001
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`and the ’852 Provisional.
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`The ’061 patent discloses and claims an innovative vector to treat
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`hemoglobinopathies. (Ex. 1001 at 1:24-27; Ex. 2002 at ¶¶48-56; Ex. 1036 at 128-
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`129.) Specifically, it claims a recombinant vector capable of providing expression
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`of a globin gene in vivo (Ex. 1001 at 11:56-14:8; Ex. 2002 at ¶¶55-56) and having
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`a region comprising a functional globin gene that is linked to a 3.2-kb Locus
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`Control Region (“LCR”). (Ex. 1001 at 3:26-28.)
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`A novel aspect of the claimed invention involves the three larger contiguous
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`nucleotide fragments from a human β-globin LCR. (Ex.1001 at 2:57-59.) While
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`prior art publications taught using a 1.0-kb LCR containing smaller nucleotide
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`fragments spanning the core portions of HS regions, including HS2, HS3, and
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`HS4. (Ex. 1001 at 2:59-62 (citing Ex. 2024)), the inventors envisioned using
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`certain larger regions — a BstXI and SnaBI DNA fragment (“HS2”), a BamHI and
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`HindIII DNA fragment (“HS3”), and a BamHI and BanII DNA fragment (“HS4”)
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`— that are included in the linked 3.2-kb LCR. (Id. at 2:63-3:28 (explaining other
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`length fragments may provide the same functionality).)
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`
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`(Id. at FIG. 1 (depicting genomic structure of one vector embodiment, TNS9).)
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`This embodiment used restriction enzymes SnaBI-BstXI, HindIII-BamHI,
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`and BamHI-BanII to obtain the HS2, HS3, and HS4 fragments of the LCR shown
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`above. (Id. at 3:26-28.) Notably, TNS9 employs a beta-globin gene. As disclosed
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`in the earliest provisional, this beta-globin gene is a “human β-globin gene
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`(including the IVS2 deletion).” (Ex. 1034 at 4.) The IVS2 deletion is a genetically
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`engineered mutation in the β-globin gene, for which the provisional cites a 1995
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