`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
`
`_________________
`
`Patent No. 8,058,061
`_________________
`
`REPLY IN SUPPORT OF PETITION FOR INTER PARTES
`REVIEW OF U.S. PATENT NO. 8,058,061
`
`
`
`IPR2023-00074
`Patent No. 8,058,061
`
`I.
`II.
`
`B.
`
`TABLE OF CONTENTS
`
`Introduction ...................................................................................................... 1
`Claims 1, 2, 5-7, and 11 Are Not Entitled to the Priority Dates of the
`Provisional Applications .................................................................................. 2
`A. No Written Description Support for All Globins and Their
`Mutations Covered by the Genus of Claims 1, 2, 5, 7, and 11 ............. 2
`No Written Description Support for the Mutations and Non-
`human β-globin Covered by the Genus of Claim 7 .............................. 6
`III. The May Article Renders Claims 1, 2, 6-7, and 11 Obvious ........................10
`A.
`SRT Confirms the Significant Motivation to Make TNS9 .................10
`B.
`SRT Failed to Establish That the May Article Taught Away
`from Using Restriction Enzymes ........................................................13
`SRT Failed to Establish That Dr. Bungert’s Analysis Required
`Hindsight .............................................................................................15
`SRT Is Incorrect That Dr. Bungert’s Analysis Used Restriction
`Enzymes That a POSA Would Have Excluded ..................................17
`Dr. Riley’s Own Analysis Confirms the Claimed HS Fragments
`Would Have Been Obvious .................................................................18
`IV. The May Abstract Renders the Challenged Claims Obvious ........................24
`V.
`SRT’s Alleged Objective Indicia Only Confirms a POSA’s
`Motivation to Make TNS9 .............................................................................29
`VI. Conclusion .....................................................................................................30
`
`
`
`C.
`
`D.
`
`E.
`
`
`
`
`
`
`
`
`
`
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`IPR2023-00074
`Patent No. 8,058,061
`
`TABLE OF AUTHORITIES
`
`
`Cases
`Ajinomoto Co. v. ITC,
`932 F.3d 1342 (Fed. Cir. 2019) ............................................................................ 5
`Ariad Pharms., Inc. v. Eli Lilly & Co.,
`598 F.3d 1336 (Fed. Cir. 2010) ............................................................................ 5
`In re Fulton,
`391 F.3d 1195 (Fed. Cir. 2004) .......................................................................... 13
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 30
`Mexichem Amanco Holdings v. Honeywell International,
`IPR2013-00576, Paper 36 (P.T.A.B. Sept. 5, 2014)............................................. 9
`Novozymes A/S v. Dupont Nutrition Biosciences APS,
`723 F.3d 1336 (Fed. Cir. 2013) ............................................................................ 4
`Realtime Data, LLC v. Iancu,
`912 F.3d 1368 (Fed. Cir. 2019) .......................................................................... 29
`Schering Corp. v. Geneva Pharmaceuticals,
`339 F.3d 1373 (Fed. Cir. 2003) .......................................................................... 29
`
`
`
`
`ii
`
`
`
`IPR2023-00074
`Patent No. 8,058,061
`
`LIST OF EXHIBITS
`
`Ex.1001
`
`U.S. Patent No. 8,058,061 to Sadelain et al. (“the ’061 patent”)
`
`Ex.1002
`
`Declaration of Jörg Bungert, Ph.D.
`
`Ex.1003
`
`Curriculum Vitae of Jörg Bungert, Ph.D.
`
`Ex.1004
`
`Ex.1005
`
`Ex.1006
`
`Ex.1007
`
`Ex.1008
`
`Ex.1009
`
`Ex.1010
`
`May, “Therapeutic Hemoglobin Synthesis in Beta-Thalassemic
`Mice Expressing Lentivirus-Encoded Beta-Globin,” Cornell
`University (2001) (“the May Thesis”)
`
`May, et al., “Therapeutic Haemoglobin Synthesis in β-thalassaemic
`Mice Expressing Lentivirus-Encoded Human β-globin,” Nature,
`406:82-86 (2000) (“the May Article”)
`
`May, et al., “Lentiviral-Mediated Transfer of the Human β-Globin
`Gene and Large Locus Control Region Elements Permit Sustained
`Production of Therapeutic Levels of β-Globin in Long-Term Bone
`Marrow Chimeras,” Mol. Therapy, 1(5):S248-249 (2000) (“the May
`Abstract”)
`
`Perutz, et al., “Hemoglobin Structure and Respiratory Transport,”
`Sci. Am., 239(6): 92-125 (1978)
`
`Thein & Rochette, “Disorders of Hemoglobin Structure and
`Synthesis,” in Principles of Mol. Med. 179 (Jameson, ed., 1998)
`
`Bank, et. al, “Disorders of Human Hemoglobin,” Science,
`207:486-93 (1980)
`
`He & Russell, “Expression, Purification, and Characterization of
`Human Hemoglobins Gower-I (ζ2ε2), Gower-2 (α2ε2), and
`Portland-2 (ζ2β2) Assembled in Complex Transgenic-Knockout
`Mice, Blood, 97(4):1099-1105 (2001)
`
`Ex.1011
`
`Bunn, “Pathogenesis and Treatment of Sickle Cell Disease,” N.
`Engl. J. Med., 337(11):762-69 (1997)
`
`iii
`
`
`
`IPR2023-00074
`Patent No. 8,058,061
`
`Ex.1012
`
`Ex.1013
`
`Hardison, et al., “Locus Control Regions of Mammalian β-globin
`Gene Clusters: Combining Phylogenetic Analyses and
`Experimental Results to Gain Function Insights, Gene, 205:73-94
`(1997)
`
`Civin, et al., “Sustained, Retransplantable, Multilineage
`Engraftment of Highly Purified Adult Human Bone Marrow Stem
`Cells In Vivo,” Blood, 88(11):4102-09 (1996)
`
`Ex.1014
`
`High, “Gene Therapy in Haematology and Oncology,” Lancet,
`356:S8 (2000)
`
`Ex.1015
`
`Ex.1016
`
`Ex.1017
`
`Ex.1018
`
`Ex.1019
`
`Ex.1020
`
`Ex.1021
`
`Ex.1022
`
`Ellis, et al., “Evaluation of β-globin Gene Therapy Constructs in
`Single Copy Transgenic Mice,” Nucleic Acids Res.,
`25(6):1296-1302 (1997)
`
`Li, et al., “Nucleotide Sequence of 16-Kilobase Pairs of DNA 5’ to
`the Human ε-Globin Gene,” J. Biol. Chem., 260(28):14901-10
`(1985)
`
`Mishima, et al., “The DNA Deletion in an Indian δβ-thalassaemia
`Begins One Kilobase From the Aγ Globin Gene and Ends in an L1
`Repetitive Sequence,” Br. J. Haemotol., 73:375-79 (1989)
`
`Vosberg, “Molecular Cloning of DNA: An Introduction Into
`Techniques and Problems,” Hum. Genet. 40(1):1-72 (1977)
`
`Roberts, “Restriction Enzymes and Their Isoschizomers,” Nucleic
`Acids Res., 15(Suppl.):r189-r217 (1987)
`
`Zufferey, et al., “Multiply Attenuated Lentiviral Vector Achieves
`Efficient Gene Delivery in Vivo,” Nature Biotech., 15:871-75
`(1997)
`
`Miyoshi, et al., “Transduction of Human CD34+ Cells that Mediate
`Long-Term Engraftment of NOD/SCID Mice by HIV Vectors,”
`Science, 283:682-86 (1999)
`
`Sadelain, et. al., “Generation of a High-titer Retroviral Vector
`Capable of Expressing High Levels of the Human β-Globin Gene,”
`Proc. Natl. Acad. Sci. USA, 92:6728-32 (1995)
`
`iv
`
`
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`IPR2023-00074
`Patent No. 8,058,061
`
`Ex.1023
`
`Ex.1024
`
`Ex.1025
`
`Ex.1026
`
`Ex.1027
`
`Ex.1028
`
`Ex.1029
`
`Ex.1030
`
`Ex.1031
`
`Ex.1032
`
`Ex.1033
`
`Bouhassira, et al., “Transcriptional Behavior of LCR Enhancer
`Elements Integrated at the Same Chromosomal Locus by
`Recombinase-Mediated Cassette Exchange,” Blood 90(9):3332-44
`(1997)
`
`Fraser, et al., “Each Hypersensitive Site of the Human β-Globin
`Locus Control Regions Confers a Different Developmental Pattern
`of Expression on the Globin Genes,” Genes Dev., 7:106-113 (1993)
`
`Engel, “Developmental Regulation of Human β-Globin Gene
`Transcription: A Switch of Loyalties?,” Trend. Genet., 9(9):304-09
`(1993)
`
`Roberts & Macelis, “REBASE – Restriction Enzymes and
`Methylases,” Nucleic Acids Res., 26(1):338-350 (1998)
`
`Roberts & Macelis, “REBASE – Restriction Enzymes and
`Methylases,” Nucleic Acids Res., 27(1):312-13 (1999)
`
`Roberts & Macelis, “REBASE – Restriction Enzymes and
`Methylases,” Nucleic Acids Res., 28(1):306-07 (2000)
`
`Roberts & Macelis, “REBASE – Restriction Enzymes and
`Methylases,” Nucleic Acids Res., 29(1):268-69 (2001)
`
`Sequence Manipulation Suite (last visited October 11, 2022)
`(Website)
`
`Restriction Mapper, April 20, 2001 Wayback Machine Capture (last
`visited October 11, 2022) (Website)
`
`Prosecution History of the ’179 patent
`(U.S. Patent Application No. 10/188,221)
`
`Prosecution History of the ’061 patent
`(U.S. Patent Application No. 12/433,412)
`
`Ex.1034
`
`U.S. Provisional Application 60/301,861 to Sadelain
`
`Ex.1035
`
`U.S. Provisional Application 60/302,852 to Sadelain
`
`v
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`
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`IPR2023-00074
`Patent No. 8,058,061
`
`Ex.1036
`
`Declaration by Ingrid Hsieh-Yee, Ph.D.
`
`Ex.1037
`
`SciMago, Nature (last visited October 11, 2022) (Website)
`
`Ex.1038
`
`Ex.1039
`
`SciMago, Molecular Therapy (last visited October 11, 2022)
`(Website)
`
`SciMago, Journal of Biological Chemistry (last visited October 11,
`2022) (Website)
`
`Ex.1040
`
`Steele, “Editorial,” Mol. Therapy, 1(5):S1 (2000)
`
`Ex.1041
`
`Glorioso, “Highlights from the Third Annual ASGT Meeting,” Mol.
`Therapy, 2(2):96-100 (2000)
`
`Ex.1042
`
`“Author Index,” Mol. Therapy, 1(5):S345-61 (2000)
`
`Ex.1043
`
`Ex.1044
`
`Ex.1045
`
`Ex.1046
`
`Ex.1047
`
`San Rocco Therapeutics, LLC v. bluebird bio, Inc. et al., C.A. No.
`21-1478-RGA, D.I. 75 (D. Del. July 26, 2022)
`
`San Rocco Therapeutics, LLC v. bluebird bio, Inc. et al., C.A. No.
`21-1478-RGA, D.I. 76 (D. Del. July 26, 2022)
`
`San Rocco Therapeutics, LLC v. bluebird bio, Inc. et al., C.A. No.
`21-1478-RGA, D.I. 78 (D. Del. July 28, 2022)
`
`Vidal, “Interim Procedures for Discretionary Denials in AIA
`Post-Grant Proceedings with Parallel District Court Litigation (June
`21, 2022)
`
`Himanen, et. al., “A Recombinant Sickle Hemoglobin Triple
`Mutant With Independent Inhibitory Effects on Polymerization.” J.
`Biol. Chem. 271(41):25152-56 (1996) (“Himanen”)
`
`Ex.1048
`
`Declaration of K. Ho ISO Motion for Admission Pro Hac Vice
`
`Ex.1049
`
`Declaration of M. Yusem IOS Motion for Admission Pro Hac Vice
`
`Ex.1050
`
`Corrected Images for Paragraph 113 and 114 of Dr. Bungert’s
`October 18, 2022 Declaration (Ex. 1002)
`
`vi
`
`
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`IPR2023-00074
`Patent No. 8,058,061
`
`Ex.1051
`
`Transcript of Deposition of Dr. Stefano Rivella on September 25,
`2023
`
`Ex.1052
`
`Transcript of Deposition of Dr. James Riley on September 28, 2023
`
`Ex.1053
`
`Transcript of Deposition of Dr. Chad May on October 6, 2023
`
`Ex.1054
`
`Nature Guide to Authors, January 2000 Wayback Machine Capture
`(last visited October 23, 2023) (Website)
`
`Ex.1055
`
`Ex.1056
`
`Nature Portfolio, “Reporting Standards and Availability of Data,
`Materials, Code and Protocols,” (last visited October 23, 2023)
`(Website)
`
`Boulad, et.al., “Lentiviral Globin Gene Therapy With Reduced-
`Intensity Conditioning in Adults with β-Thalassemia: A Phase 1
`Trial.” Nature Medicine, 68:63-82 (2022)
`
`Ex.1057
`
`Sadelain, et. al., “Progress Towards the Genetic Treatment of the β-
`Thalassemias.” Ann. N.Y. Acad. Sci., 1054:78-91 (2005)
`
`Ex.1058
`
`Sadelain, “Recent Advances in Globin Gene Transfer for the
`Treatment of Beta-Thalassemia and Sickle Cell Anemia.” Curr.
`Opin. Hemtol., 13:142-48 (2006)
`
`Ex.1059
`
`American Society of Gene Therapy Website, May 11, 2000
`Wayback Machine Capture (last visited October 23, 2023)
`(Website)
`Ex.1060 Molecular Therapy Journal Abstracts, June 7, 2000 Wayback
`Machine Capture (last visited October 23, 2023) (Website)
`
`Ex.1061
`
`Ex.1062
`
`American Society of Gene Therapy General Meeting Information,
`June 15, 2000 Wayback Machine Capture (last visited October 23,
`2023) (Website)
`
`American Society of Gene Therapy, Abstracts of Scientific
`Presentations: The Third Annual Meeting of the American Society
`of Gene Therapy, August 18, 2000 Wayback Machine Capture (last
`visited October 23, 2023) (Website)
`
`vii
`
`
`
`IPR2023-00074
`Patent No. 8,058,061
`
`Ex.1063
`
`[intentionally omitted]
`
`Ex.1064
`
`Excerpts of SRT’s Initial Infringement Claim Charts from San
`Rocco Therapeutics, LLC v. Bluebird Bio, Inc. and Third Rock
`Ventures, C.A. No. 21:1478-RGA (D. Del.)
`
`Ex.1065
`
`[intentionally omitted]
`
`Ex.1066
`
`Transcript of Deposition of Dr. Michel Sadelain on October 20,
`2023
`
`Ex.1067
`
`Transcript excerpts of YouTube video of Patrick Girondi TrialSite
`interview (uploaded to YouTube on May 18, 2023), available at:
`https://www.youtube.com/watch?v=EsJ29bT7t8M
`
`Ex.1068
`
`Email Correspondence re. Dr. Luzzatto Deposition Availability,
`September 20, 2023
`
`
`
`viii
`
`
`
`IPR2023-00074
`Patent No. 8,058,061
`Introduction
`I.
`After designing, making, and testing TNS9 by the late-1990s, the named
`
`inventors published their TNS9 work in 2000, but waited until mid-2001 to file
`
`limited provisional applications. They then waited another year to file a
`
`non-provisional application pursing broader claims. Publicizing their TNS9 work
`
`while also seeking a longer patent term has resulted in the inventors’ own
`
`publications qualifying as invalidating prior art references.
`
`Had the PTO considered either the May Abstract or May Article as prior art,
`
`challenged claims 1, 2, 5-8, 11, and 15 would not have issued. The Petition
`
`demonstrates the challenged claims are unpatentable, and, as explained below,
`
`SRT’s responsive arguments either further confirm unpatentability or are
`
`contradicted by the record, their own expert, or the inventors. This Reply focuses
`
`primarily on Grounds 4 and 6, but Petitioner maintains the May Thesis is “by
`
`others” for purposes of §102(a) (Petition, 19 n.7; Ex.1053, 40:23-42:9; Ex.1066,
`
`117:21-120:17), and that the May Article anticipates (Petition, 35-45; infra III).
`
`1
`
`
`
`IPR2023-00074
`Patent No. 8,058,061
`II. Claims 1, 2, 5-7, and 11 Are Not Entitled
`to the Priority Dates of the Provisional Applications
`A. No Written Description Support for All Globins and
`Their Mutations Covered by the Genus of Claims 1, 2, 5, 7, and 11
`SRT asserts the claimed “functional globin” genus includes “any” globin,
`
`including mutant forms of globin.1 (POR, 4-5.) The provisionals, however, do not
`
`provide written description for this genus because they describe only the human β-
`
`globin species, and do not describe (1) other globin types or (2) mutations of those
`
`globins. (Petition, 15-19 (citing Samsung Elecs. Co. v. Acorn Semi, LLC,
`
`IPR2020-01206, Paper 49 at 18, 24 (P.T.A.B. Jan. 12, 2022)); Ex.1002, ¶¶52-60;
`
`Reply to POPR, 1-5; Decision, 22-23.)
`
`With respect to mutated globins, SRT does not provide written description
`
`support for the countless mutations covered by the claimed globin genus. Instead,
`
`SRT simply asserts making such mutations was “routine.” (POR, 35.) This is
`
`insufficient as a matter of law. (Petition, 13 (citing PowerOasis, Inc. v. T-Mobile
`
`USA, Inc., 522 F.3d 1299, 1310 (Fed. Cir. 2008)); Reply to POPR, 4-5; Ex.1002,
`
`
`1 According to SRT, the genus is not limited to the α-, β-, and γ-globin discussed in
`
`the specification, but also includes other globins, such as ε- and δ-globin. (POR,
`
`33; Ex.1052, 87:15-17.)
`
`2
`
`
`
`IPR2023-00074
`Patent No. 8,058,061
`¶¶55-58; Decision, 23-24 (citing Lockwood v. Am. Airlines, 107 F.3d 1565, 1572
`
`(Fed. Cir. 1997)).)
`
`Regarding globin types other than β-globin, SRT attempts to demonstrate
`
`possession by pointing to prior art outside of the four corners of the provisionals
`
`discussing alleged “common structural similarity” between β-globin and γ-globin.
`
`(POR 34, 37.) But this ignores differences with other globins in the vast genus.
`
`(Petition, 18; Ex.1002 ¶¶57-59). For example, SRT’s expert, Dr. Riley, agreed “α‐
`
`globin has a different regulator compared to β‐globin,” is “encoded on a separate
`
`chromosome,” and has a separate LCR. (Ex.1052, 91:14-19, 92:1-11, 92:19-23,
`
`94:23-95:5.) In fact, Dr. Riley was not even “able to find an exact number” of
`
`species within the genus (Ex.1052, 90:14-18), and did not know if certain globin
`
`would fall within it (Ex.1052, 88:21-89:6). (Petition, 16-17 (citing AbbVie
`
`Deutschland GmbH v. Janssen Biotech, 759 F.3d 1285, 1299-1300 (Fed. Cir.
`
`2014)); Reply to POPR, 5.)
`
`Further, despite the alleged similarity between certain globin that SRT
`
`references, Dr. Riley confirmed changes would need to be made to the vector to
`
`allow for possible expression of other globin—changes not described in the
`
`provisional applications. (Ex.1052, 53:17-25, 55:1-5, 62:11-17; Reply to POPR, 5;
`
`Ex.1002, ¶55.) And he recognized a POSA “wouldn’t know until [they] did the
`
`experiment” if additional changes were needed. (Ex.1052, 49:8-15, 57:2-58:2.)
`
`3
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`
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`IPR2023-00074
`Patent No. 8,058,061
`Thus, the provisionals lack written description support because they did not
`
`describe making and testing “individual variants or at least identifying subclasses
`
`of variants that could be expected to possess the claimed properties,” as SRT’s
`
`cited case demonstrates. Novozymes v. Dupont Nutrition Biosciences, 723 F.3d
`
`1336, 1350 (Fed. Cir. 2013) (cited in POR, 36 n.2).
`
`SRT asserts Dr. Bungert agreed that a POSA would have “expected”
`
`expression of globin apart from human β-globin (POR, 35), but he repeatedly
`
`explained that a POSA “cannot make that prediction” (Ex.2055, 202:22-25; id.,
`
`188:14-21, 211:10-15, 212:5-19). Even SRT’s own cited references support
`
`Dr. Bungert’s opinion that trying to express γ-globin using β-globin regulatory
`
`elements (which is any event insufficient to demonstrate written description for the
`
`entire genus) is “not necessarily straightforward and might not provide a
`
`therapeutic level of expression.” (Ex.2079, 1; Ex.2055, 193:3-25, 209:4-13.)
`
`Dr. Riley emphasized this unpredictability, arguing that “something as small as 1-
`
`bp or even up to 100-bp could be the difference between the vector working or not
`
`working.” (Ex.2056, ¶91.) And altering “the promoter and the coding sequence,”
`
`as Dr. Riley says was required (Ex.1052, 53:17-25), would change 1,800-bp of the
`
`vector (Ex.1022, 2)—significantly more than 100-bp.
`
`SRT also argues that, because the provisionals discussed therapies for
`
`diseases like β-thalassemia and sickle-cell, a POSA would “appreciate
`
`4
`
`
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`IPR2023-00074
`Patent No. 8,058,061
`straightaway that the inventors possessed an expression system for” other globins.
`
`(POR, 34.) The description of those diseases, however, is consistent with the
`
`remainder of the provisionals, which is limited to vectors “capable of providing
`
`therapeutically meaningful levels of human β-globin.” (Petition, 16-17; Reply to
`
`POPR, 3; Ex.1002, ¶56; Ex.2055, 193:3-25, 207:21-208:21, 209:4-20; Decision,
`
`22-23.) And Dr. Riley could not support SRT’s assertion, as he was “hesitant to
`
`comment on specific therapies.” (Ex.1052, 92:24-93:9.)
`
`SRT also relies on the May Article’s statement that “the principles”
`
`underlying their lentiviral vector “provide a paradigm for any stem cell therapy.”
`
`(POR, 32-33.) But this description amounts “to no more than a wish” that does not
`
`demonstrate possession (Ex.1002, ¶¶57-59; Ex.2055, 188:14-21, 193:3-25, 202:22-
`
`25, 207:21-208:22, 209:4-20, 211:10-15, 212:5-19). Ariad Pharms., Inc. v. Eli
`
`Lilly & Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010) (en banc).
`
`Finally, SRT asserts Ajinomoto v. ITC “is particularly instructive” (POR,
`
`22), but overlooks that the claimed “more potent promoters” genus in that case was
`
`specifically described in the specification, which included various examples. 932
`
`F.3d 1342, 1359 (Fed. Cir. 2019). Here, by contrast, the provisionals do not even
`
`recite the term “functional globin” and describe only one species (i.e., human β-
`
`globin) of that genus. (Petition, 16-19; Reply to POPR, 2; Ex.1002, ¶¶54-55;
`
`Ex.2055, 211:10-15; Decision, 21-22.)
`
`5
`
`
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`IPR2023-00074
`Patent No. 8,058,061
`At best, SRT is attempting to rely on an obviousness standard to capture
`
`other globin and mutations of these globin, which “simply is not enough” to
`
`demonstrate written description. (Petition, 13 (quoting PowerOasis, 522 F.3d at
`
`1310); Reply to POPR, 4-5; Ex.1002, ¶¶56-59; Decision, 23 (citing Lockwood, 107
`
`F.3d at 1572).)
`
`B. No Written Description Support for the Mutations and
`Non-human β-globin Covered by the Genus of Claim 7
`SRT agrees claim 7 covers a functional genus of “other β-globin, e.g.,
`
`mutant β-globin” (Decision, 24; POR, 28), and is not limited to “human β-globin”
`
`like claim 10.2 The provisionals, however, do not provide written description
`
`support for this genus because they describe only the human β-globin species, and
`
`not mutated β-globin or non-human β-globin. (Petition, 16-17 (citing AbbVie, 759
`
`F.3d at 1299-1300; Samsung, IPR2020-01206 at 18, 24); Reply to POPR, 4-5;
`
`Ex.1002, ¶¶56-59; Decision, 24-25.)
`
`Regarding mutations of human β-globin, Dr. Riley admitted that, “[b]y
`
`2001[,] there were literally hundreds of reported mutations” (POR, 28; Ex.1052,
`
`103:11-104:15), the vast majority of which would have unknown effects on
`
`expression (Ex.1002, ¶59). None of these mutations were disclosed in the
`
`
`2 Petitioner does not agree with SRT’s characterization that “the Board expressly
`
`recognized” that claims 8 and 15 “are entitled to the priority date.” (POR, 20.)
`
`6
`
`
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`IPR2023-00074
`Patent No. 8,058,061
`provisionals. Nor were non-human β-globin, which Dr. Riley asserted are
`
`additional distinct species within the β-globin genus of claim 19. (Ex.2056, ¶91.)
`
`SRT resorts to reliance on obviousness by arguing that making mutations
`
`was “routine.” (POR, 3, 27-28; POR, 29 (arguing mutant β-globin “expression
`
`systems could be employed”).) But, again, obviousness “simply is not enough” to
`
`establish possession of this functional genus. (Petition, 13 (quoting PowerOasis,
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`522 F.3d at 1310); Reply to POPR, 4-5; Ex.1002, ¶¶56-59; Decision, 24.) Indeed,
`
`Dr. Riley was unable to recognize which “mutants” are covered by the claim
`
`(Ex.1052, 100:19-101:7, 103:11-104:15, 105:15-106:15, 107:7-21), which further
`
`demonstrates lack of written description (Petition, 14-15 (citing AbbVie, 759 F.3d
`
`at 1299-1300; Samsung, IPR2020-01206 at 18, 24); Reply to POPR, 5).
`
`SRT also argues “the term ‘β-globin’” in the provisionals is somehow
`
`“explicit support” for the genus (POR, 24-26),3 but overlooks that the β-globin
`
`terms it cites are shorthand references to “human β-globin.” For example, SRT
`
`cites Figure 4, which states “the β-globin are the same as in TNS9.” (POR, 24.)
`
`But the provisionals explain TNS9 “incorporates human β-globin.” (Ex.1035, 2.)
`
`SRT also points to “β-globin” in Figure 1b (POR, 24), but the description again
`
`
`3 SRT asserts Dr. Riley “detailed” and “further explained” this argument (POR, 3,
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`27), but provides no citation to his declaration.
`
`7
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`
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`IPR2023-00074
`Patent No. 8,058,061
`makes clear the figure shows “human β-globin” (Ex.1035, 5). SRT further ignores
`
`the provisionals are titled “Vectors Encoding Human β-globin,” define “[t]he
`
`present invention” as a vector providing “levels of human β-globin,” and contain
`
`examples that all discuss expression of “human β-globin.” (Ex.1035, 1-2 (Figs.5-
`
`6); Petition, 18; Reply to POPR, 2; Ex.1002, ¶56; Ex.2055, 211:10-15.) It was not
`
`until the later-filed specification that the Applicant defined “functional globin”
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`broadly such that the term “β-globin” included “mutant forms of globin.”
`
`(Petition, 16; Reply to POPR, 2; Decision, 21-22 (“[T]hat does not appear and has
`
`no counterpart in the provisional.”).)
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`Finally, SRT argues the TNS9 vector is actually “a mutant, since it contains
`
`the IVS2 deletion.” (POR, 3, 28-29.) But this overlooks that the claimed
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`“functional globin” is what is “encoded” by the vector, which is accomplished
`
`through “expression of the globin” in vivo. (Ex.1001, Claim 1.) The “β-globin” of
`
`claim 7 is, therefore, what the vector encodes in vivo, not the globin-encoding
`
`portion of the vector itself.4 As Dr. Bungert explained (Ex.1002, ¶55), and as
`
`
`4 The “IVS2 deletion” SRT references is a partial deletion of a non-coding region
`
`(POR, 28-29; Ex.1022, 2, Fig.5), which in any event is not part of the “globin”
`
`referenced in the claims that is encoded in vivo (Ex.1052, 112:20-113:6).
`
`8
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`
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`IPR2023-00074
`Patent No. 8,058,061
`confirmed by the named inventors, TNS9 encodes the “wild-type human beta
`
`globin” (Ex.1056, 715; Ex.1057, 98, Table 1; Ex.1058, 144). Regardless, even
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`SRT’s founder/president distinguished vectors having “a mutant gene” from TNS9,
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`which he explained “use[s] the wild-type beta-globin gene.” (Ex.1067, 6:22-25.)
`
`*
`
`
`
`*
`
`
`
`*
`
`The provisionals fail to provide written description support for the claimed
`
`functional globins, whether through any structure-function relationship between
`
`the claimed vector and the claimed functional globins or otherwise. (Petition, 15-
`
`19; Ex.1002, ¶¶52-60; Reply to POPR 1-5; Decision, 16-24.)6
`
`
`5 Ex.1056 discusses TNS9.3.55, but TNS9 encodes the same “functional globin.”
`
`(Ex.1066, 114:14-24.)
`
`6 SRT’s attempt to establish an earlier conception date is irrelevant to the May
`
`Abstract and May Article, which qualify as 102(b) prior art. (Petition, 20-23.)
`
`Regardless, the inventor declarations provide no reliable contemporaneous
`
`evidence (Ex.1051, 38:19-39:3, 39:22-40:11, 50:24-51:7, 93:3-21; Ex.1053, 22:10-
`
`15, 25:9-24, 25:25-26:3; Ex.1066, 37:7-15, 63:17-19, 65:5-11, 67:2-6; Decision, 26
`
`n.13), and SRT did not make the only purportedly corroborating witness available
`
`for deposition (Ex.1068). E.g., Mexichem Amanco Holdings v. Honeywell
`
`International, IPR2013-00576, Paper 36, 2-3 (P.T.A.B. Sept. 5, 2014).
`
`9
`
`
`
`IPR2023-00074
`Patent No. 8,058,061
`III. The May Article Renders Claims 1, 2, 6-7, and 11 Obvious
`SRT Confirms the Significant Motivation to Make TNS9
`A.
`SRT does not dispute a POSA would have had a good reason to make TNS9
`
`based on the May Article. (Petition, 47; Decision, 44.) In fact, SRT argues that,
`
`“[i]mmediately after the publication” of the May article, newspapers and the
`
`“scientific community” were “recognizing the inventor’s significant achievement.”
`
`(POR, 62-63; Ex.1052, 134:5-15, 135:14-136:9.)
`
`SRT also does not dispute the May Article teaches all of the claim
`
`limitations except for the restriction enzymes associated with the three recited
`
`HS fragments. (Petition, 45-48; Decision, 42-43.) But SRT cannot deny that a
`
`POSA would have known that “the entire map of the LCR region was available,”
`
`and that the restriction enzymes “were commercially available.” (Petition, 39, 45-
`
`48; Ex.1002, ¶145, 192-195; Ex.2056, ¶¶33, 38, 170; Ex.1052, 118:21-119:11;
`
`Decision, 43.) Further, SRT cannot dispute a POSA “would have used the known
`
`restriction-site LCR map as a tool for engineering the vector disclosed by the May
`
`Article” (Ex.1002 ¶¶146-156, 192-195; Decision, 44), including because the
`
`Applicant explained during prosecution that “it was within the skill in the art to
`
`map all of the possible restriction sites in the regions flanking the cores of HS2,
`
`HS3, and HS4” (Ex.1032, 301-3; Petition, 38-39, 46-48; Ex.1002, ¶¶147-48, 192;
`
`Decision, 45-46).
`
`10
`
`
`
`IPR2023-00074
`Patent No. 8,058,061
`SRT also cannot dispute a POSA could have selected HS fragments “with
`
`relative positions closely matching those shown in Fig. 1a of the [May] Article”
`
`(POR, 47; Petition, 37-38; Ex.1002, ¶152):
`
`
`
`(Ex.1005, Fig.1a (“Boxes represent HS fragments drawn to scale”).)7 Confirming
`
`a POSA’s use of Figure 1a (Ex.1002, ¶113), Dr. Sadelain testified that it was
`
`intended to convey “the [proper] proportionality between the fragment[s] in RNS1
`
`and the fragment[s] in TNS9” (Ex.1066, 98:24-99:3), and Dr. Riley admitted it
`
`“provide[d] a rough guideline to a [POSA] to make” TNS9 (Ex.1052, 144:6-10).
`
`Thus, a POSA would have understood how to create the May Article vector with
`
`the recited HS2, HS3, and HS4 fragments with a reasonable expectation of success,
`
`as it involved merely combining known elements to yield a predictable result.
`
`(Petition, 47-48; Decision, 45-46.)8
`
`
`7 The inventors confirmed they reviewed Figure 1a for accuracy (e.g., Ex.1066,
`
`87:22-89:1; Ex.1053, 92:1-93:2; Ex.1051, 107:4-18).
`
`8 Although testing would not have been necessary for a POSA to have had a
`
`reasonable expectation of success (Ex.1052, 66:16-22, 48:1-21), a POSA could
`
`11
`
`
`
`IPR2023-00074
`Patent No. 8,058,061
`A POSA would have had a reasonable expectation of success from such an
`
`“impressive” article published in Nature (a “top tier” prestigious journal) because,
`
`as Dr. Riley admitted, “one of the goals of a scientific article is to provide
`
`information such that others in the field can reproduce or build on what’s described
`
`in the paper.” (Ex.1052, 140:14-22, 138:11-18; Ex.1055, 1 (“An inherent principle
`
`of publication is that others should be able to replicate and build upon the authors’
`
`published claims.”).) And Dr. Sadelain testified that he “complied with the Nature
`
`guidelines when submitting” the May Article (Ex.1066, 100:18-22), which
`
`required the authors to identify any “conditions for use of methods and materials”
`
`(Ex.1054, 7).
`
`For these reasons, and those discussed in the Petition and Sections III.B-E
`
`and V below, a POSA would have been motivated to arrive at the claims with a
`
`reasonable expectation of success.9
`
`
`have “quickly measure[d]” expression within a matter of weeks using the assays
`
`described in the May Article (Ex.1053, 36:8-37:5; Ex.1051, 163:21-164:21;
`
`Ex.2008, ¶18; Petition, 39-41; Ex.1002, ¶¶40-42, 194-195, 232; Ex.1066, 32:5-8).
`
`9 SRT does not separately dispute that claim 5 is obvious in further view of
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`Himanen. (Petition, 48-49; Ex. 1002 ¶¶198-204; Decision, 47.)
`
`12
`
`
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`IPR2023-00074
`Patent No. 8,058,061
`SRT Failed to Establish That the May Article
`B.
`Taught Away from Using Restriction Enzymes
`SRT argues the May Article “would have taught away from the use of
`
`restriction enzymes.” (POR, 41.) But Dr. Riley admitted the May Article is
`
`“silent on whether or not the construct was made using PCR or restriction
`
`enzymes” (Ex.1052, 78:10-14), and a reference that is silent does not teach away,
`
`see, e.g., In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004). Further, SRT now
`
`asserts a POSA would have been somehow “foreclos[ed]” from using restriction
`
`enzymes to make TNS9 (POR, 42), but Dr. Riley confirmed a POSA “could make
`
`[that vector] either using PCR or with restriction enzymes” (Ex.1052, 78:20-23,
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`67:13-20; Petition, 39-41; Ex.1002, ¶¶156-57; Decision, 46 (“Patent Owner has
`
`acknowledged that a skilled artisan would have known that the fragments disclosed
`
`in the May Article could be made in different ways, including cutting from
`
`genomic DNAs using restriction enzymes.”)).
`
`If anything, a POSA would have been discouraged from attempting to use
`
`PCR to recreate TNS9 based on the May Article because, as SRT argues, the
`
`number of possible fragments would have been “astronomical.” (POR, 42, n.4.)
`
`On the other hand, the POSA had a clear understanding of the restriction enzymes
`
`that would have been, at a minimum, obvious to try. (Petition, 46-47; Ex.1002,
`
`¶¶156-57.)
`
`13
`
`
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`IPR2023-00074
`Patent No. 8,058,061
`SRT relies on Dr. Riley to argue “PCR was a preferred method” (POR, 40),
`
`but he admitted he had no “hands-on experience designing LCR fragments” at the
`
`time of the invention (Ex.1052, 30:22-31:4).10 In contrast, Dr. Bungert was at least
`
`a POSA at the time of the invention, and his opinion regarding a POSA’s
`
`preference for restriction enzymes was based on relevant prior art. (Ex.2055,
`
`12:18-13:13, 88:20-89:11; Ex.1002, ¶¶36-42 (citing Ex.1022 and Ex.1015).)
`
`Dr. Sadelain agreed, explaining that PCR made him “nervous” because “it’s
`
`notorious that PCR is imperfect and can make a mistake.” (Ex.1066, 40:14-17,
`
`41:3-4; Ex.2055, 32:24-33:25, 34:13-35:6, 42:3-43:12, 44:25-45:15; Ex.1052,
`
`72:1-4.)11
`
`
`10 SRT argues “Bungert himself used PCR technology to clone LCR fragments”
`
`(POR, 41-42), but he explained his constructs were in a different context and not
`
`for LCR expression (Ex.2055, 78:5-14, 79:3-19, 81:8-12, 84:15-21, 85:4-10, 88:5-
`
`15, 91:15-92:2, 111:6-12), which Dr. Riley did not consider (Ex.1052, 76:9-18).
`
`11 Dr. Sadelain recalled that Dr. Rivella used PCR (Ex.1066, 40:14-17), but
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`Dr. Rivella did not remember using PCR for “any of the steps” (Ex.1051, 60:5-18),
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`and the research documents SRT submitted in t
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