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 PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`
`TABLE OF CONTENTS
`
`2. 
`
`Page
`INTRODUCTION ..................................................................................................... 1 
`Background ................................................................................................................ 3 
`A. 
`The ‘061 Patent and Cited Art. .............................................................. 7 
`1. 
`The Invention. ............................................................................. 7 
`a) 
`Conception and Reduction to Practice. ............................ 7 
`b) 
`The ‘061 Patent. ................................................................ 8 
`c) 
`Relevant Prosecution History of the ‘061 Patent. .......... 13 
`The Cited Art. ........................................................................... 15 
`a)  May Abstract (Ex. 1006). ............................................... 15 
`b) 
`The Nature Article (Ex. 1005). ....................................... 15 
`c) 
`The May Thesis (Ex. 1004). ........................................... 16 
`ARGUMENT ........................................................................................................... 17 
`I. 
`The Relied Upon Art Does Not Qualify as Invalidating Prior Art. ............... 18 
`A. 
`The May Thesis and Nature Article Do Not Meet the Statutory
`Requirements to Qualify as Prior Art. ................................................. 19 
`1. 
`The ‘061 Patent’s Priority Date Is June 29, 2001. .................... 19 
`a) 
`Petitioner Has Not Met Its Burden to Show the ‘061
`Patent Is Not Entitled to Its Claimed Priority Date. ....... 19 
`The Provisional Applications Provide Sufficient
`Support to Entitle the ‘061 Patent to a June 29, 2001
`Priority Date. ................................................................... 21 
`The May Thesis Does Not Qualify as Prior Art. ...................... 29 
`
`b) 
`
`2. 
`
`i
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`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`
`B. 
`
`C. 
`
`2. 
`
`3. 
`The Nature Article Does Not Qualify as Section 102(b) Art. .. 30 
`The May Thesis and Nature Article Cannot Serve as Invalidating
`Art Under Section 102(a). ................................................................... 30 
`1. 
`The May Thesis and Nature Article Describe the Inventive
`Work of the Inventors. .............................................................. 30 
`The ‘061 Invention Was Conceived and/or Reduced to
`Practice Before the Publication of the Cited References. ......... 33 
`Petitioner Has Not Shown the May Abstract Qualifies as Prior
`Art. ....................................................................................................... 39 
`Discretionary Denial Is Appropriate. ............................................................ 40 
`A. 
`The Cited Art Is the Same or Substantially Same as Art Previously
`Considered by the Examiner. .............................................................. 43 
`Petitioner Has Not Alleged Material Error by the Examiner. ............. 44 
`B. 
`Petitioner Has Failed to Show a Reasonable Likelihood that at Least One
`Claim Is Invalid. ............................................................................................ 45 
`A. 
`The Nature Article Does Not Render the Challenged Claims
`Anticipated. ......................................................................................... 45 
`The Nature Article and May Abstract Do Not Render the
`Challenged Claims Obvious. ............................................................... 49 
`1. 
`The Nature Article Does Not Render the Claims Obvious. ..... 52 
`2. 
`The May Abstract Does Not Render the Challenged Claims
`Obvious. .................................................................................... 57 
`CONCLUSION ........................................................................................................ 62 
`
`
`II. 
`
`III. 
`
`B. 
`
`
`
`
`
`ii
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`Case IPR2023-00074
`Patent 8,058,061
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Abbott Labs. v. Sandoz, Inc.,
`544 F.3d 1341, 1352 (Fed. Cir. 2008) ................................................................ 55
`AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc.,
`759 F.3d 1285 (Fed. Cir. 2014) .............................................................. 25, 27, 28
`Advanced Bionics, LLC v. Med-El Elektromedizinische Geräte GMBH,
`IPR2019-01469, Paper 6 (P.T.A.B. Feb. 13, 2020) ...................................... 41, 44
`All Dental Prodx, LLC v. Advantage Dental Prods., Inc.,
`309 F.3d 774 (Fed. Cir. 2002) ............................................................................ 22
`Amgen Inc. v. F. Hoffman-La Roche Ltd,
`580 F.3d 1340 (Fed. Cir. 2009) .......................................................................... 50
`Apple Inc. v. Uniloc USA, Inc.,
`IPR2017-00224, Paper 7 (P.T.A.B. May 25, 2017) ........................................... 43
`Apple, Inc. v. DSS Tech. Mgmt., Inc.,
`IPR2015-00369, Paper 14 (P.T.A.B. Aug. 12, 2015) ......................................... 39
`Biogen Inv. B. Amgen Inc.,
`973 F.Supp. 39 (D. Mass. 1997) ......................................................................... 49
`Capon v. Eshhar,
`418 F.3d 1349 (Fed. Cir. 2005) .......................................................................... 21
`Continental Can Co. USA, Inc. v. Monsanto Co.,
`948 F.2d 1267 (Fed. Cir. 1991) .......................................................................... 48
`Cultec Inc. v. StormTech LLC,
`IPR2017-00777, Paper 7 (P.T.A.B. Aug. 22, 2017) ........................................... 43
`Cuozzo Speed Techs., LLC v. Lee,
`579 U.S. 261 (2016) ............................................................................................ 40
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Pat. Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 50
`
`iii
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`Patent 8,058,061
`
`Dorco Co. v. Gillette Co.,
`IPR2017-00500, Paper 7 (P.T.A.B. June 21, 2017) ........................................... 43
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) .................................................................... 17, 18
`Ecolochem, Inc. v. S. Cal. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) ..................................................51, 52, 60, 61, 62
`Falkner v. Inglis,
`448 F.3d 1357 (Fed. Cir. 2006) .......................................................................... 14
`Green Cross Corporation v. Shire Human Genetic Therapies Inc.,
`IPR2016-00258, Paper 89 (P.T.A.B. Mar. 22, 2017) ................................... 34, 35
`Harmonic Inc. v. Avid Tech., Inc.,
`815 F.3d 1356 (Fed. Cir. 2016) .......................................................................... 17
`Hybritech Inc. v. Monoclonal Antibodies, Inc.,
`802 F.2d 1367 (Fed. Cir. 1986) .......................................................................... 21
`InTouch Techs., Inc. v. VGO Commc'ns, Inc.,
`751 F.3d 1327 (Fed. Cir. 2014) .......................................................................... 51
`Intromedic Co., Ltd. v. Given Imaging, Ltd.,
`IPR2015-00579, Paper 9 (P.T.A.B. Aug. 5, 2015) ............................................. 42
`In re Katz,
`687 F.2d 450 (C.C.P.A. 1982) .......................................................... 22, 30, 31, 32
`Kennaetal, Inc. v. Ingersoll Cutting Tool Company,
`780 F.3d 1376 (Fed. Cir. 2015) .......................................................................... 49
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 50
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) .......................................................................... 51
`Lumenis Be Ltd. v. Btl Healthcare Techs. A.S.,
`IPR2021-01275, 2022 WL 433628 (P.T.A.B. Feb. 8, 2022) ............................. 40
`
`iv
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`

`Case IPR2023-00074
`Patent 8,058,061
`
`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) .................................................................... 34, 38
`Metalcraft of Mayville, Inc. v. The Toro Co.,
`848 F.3d 1358 (Fed. Cir. 2017) .................................................................... 50, 51
`Motorola Mobility LLC v. Arouse,
`IPR2013-00010, Paper 27 (P.T.A.B. Apr. 5, 2013) ............................................. 1
`Paice LLC v. Ford Motor Co.,
`881 F.3d 894 (Fed. Cir. 2018) ............................................................................ 19
`Paragon 28, Inc. v. Wright Med. Tech., Inc.,
`IPR2019-00896, 2020 WL 5848657 (P.T.A.B. Oct. 1, 2020) ................ 19, 20, 21
`Perfect Surgical Techniques, Inc. v. Olympus Am., Inc.,
`841 F.3d 1004 (Fed. Cir. 2016) .......................................................................... 33
`Personal Web Tech., LLC v. Apple, Inc.,
`848 F.3d 987 (Fed. Cir. 2017) ............................................................................ 50
`In re Petering,
`301 F.2d 676 (CCPA 1962) ................................................................................ 49
`Pozen Inv. vf. Par Pharmaceutical, Inc.,
`696 F.3d 1151 (Fed. Cir. 2010) .......................................................................... 19
`SAS Inst., Inc. v. Iancu,
`138 S. Ct. 1348 (2018) ........................................................................................ 17
`ServiceNow, Inc. v. Hewlett-Packard Co.,
`IPR2015-00716, Paper 13 (P.T.A.B. August 26, 2015) ..................................... 39
`Shds, Inc. v. Truinject Corp.,
`IPR2020-00935, 2020 WL 6750124 (P.T.A.B. Nov. 17, 2020) ......................... 42
`Taurus IP, LLC v. DaimlerChrysler Corp.,
`726 F.3d 1306 (Fed. Cir. 2013) .......................................................................... 33
`Unilever, Inc. v. Proctor & Gamble Co.,
`IPR2014-00506, Paper 17 (P.T.A.B. July 7, 2014) ............................................ 41
`
`v
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`

`

`Case IPR2023-00074
`Patent 8,058,061
`
`Unilever, Inc. v. Proctor & Gamble Co.,
`IPR2014-00628, Paper 21 (P.T.A.B. Oct. 20, 2014) .......................................... 43
`In re Vaidyanathan,
`381 F. App'x 985 (Fed. Cir. 2010) ...................................................................... 51
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
`683 F.3d 1356 (Fed. Cir. 2012) .......................................................................... 48
`Zoltek Corp. v. United States,
`815 F.3d 1302 (Fed. Cir. 2016) .......................................................................... 21
`Statutes
`35 U.S.C. § 102(a) ...........................................................................22, 29, 30, 31, 32
`35 U.S.C. § 102(b) ............................................................................................. 22, 29
`35 U.S.C. § 112 .................................................................................................. 13, 19
`35 U.S.C. § 120 ........................................................................................................ 19
`35 U.S.C. § 312(a)(3) ......................................................................................... 17, 58
`35 U.S.C. § 314(a) ................................................................................................... 40
`35 U.S.C. § 316(b) ................................................................................................... 42
`35 U.S.C. § 325(d) ............................................................................. 3, 40, 41, 42, 43
`Other Authorities
`37 C.F.R. § 1.131 ..................................................................................................... 35
`37 C.F.R. § 1.132 ............................................................................................... 31, 35
`37 C.F.R. § 42.1(b) .................................................................................................. 42
`37 C.F.R. § 42.22(a)(2) ............................................................................................ 58
`M.P.E.P. § 715.07 .................................................................................................... 33
`M.P.E.P. § 2132.01 ............................................................................................ 30, 31
`
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`Case IPR2023-00074
`Patent 8,058,061
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`
`EXHIBIT LIST
`
`Exhibit No.
`
`Description
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`
`Exclusive Licensee Agreement Between Sloan Kettering
`Institute for Cancer Research and San Rocco Therapeutics, LLC
`
`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
`
`Declaration of Chad May
`
`Declaration of Stefano Rivella
`
`Declaration of Lucio Luzzatto
`
`Sorrentino, “One step closer to gene therapy for
`hemoglobinopathies”
`
`Caterina et al., “Human beta-globin locus control region:
`analysis of the 5’ DNase I hypersensitive site HS2 in transgenic
`mice.” Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1626-30.
`doi: 10.1073/pnas.88.5.1626. PMID: 2000371; PMCID:
`PMC51077
`
`Judson, “Glimmering Promise of Gene Therapy”
`
`Jackson, et al., (1996), “Role of D N A sequences outside the
`cores of DNase hypersensitive sites (HSs) in functions of the p-
`globin locus control region.” Domain opening and synergism
`between HS2 and HS3. J Biol Chem. 271:11871-8
`
`2014
`
`Philipsen, et al. “The β-globin dominant control region:
`hypersensitive site 2.” EMBO J. (1990) 9:2159-67
`
`vii
`
`

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`Case IPR2023-00074
`Patent 8,058,061
`
`
`Exhibit No.
`
`Description
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`Hardison, et. al., “Locus control regions of mammalian β-globin
`gene clusters: combining phylogenetic analyses and experimental
`results to gain functional insights.” (1997) Gene. 205:73-94.
`
`Persons, D. A., A. W. Nienhuis. 2000. “Gene therapy for the
`hemoglobin disorders: past, present, and future.” Proc Natl Acad
`Sci U S APNAS. 97:5022-4
`
`Kafri, “Lentiviral Vectors: Regulated Gene Expression”
`
`Amado, “Lentiviral Vectors — the Promise of Gene Therapy
`within Reach?”
`
`Chada, et al., “Specific expression of a foreign β-globin gene in
`erythroid cells of transgenic mice.” Nature. (1985) 314:377-80
`
`Townes, et al., “Expression of human β-globin genes in
`transgenic mice: effects of a flanking metallothionein-human
`growth hormone fusion gene.” (1985) Mol Cell Biol. 5:1977-83
`
`Dzierzak, et al., “Lineage-specific expression of a human β-
`globin gene in murine bone marrow transplant recipients
`reconstituted with retrovirus-transduced stem cells.” (1988)
`Nature. 331:35-41
`
`Bodine, et. al., “Combination of interleukins 3 and 6 preserves
`stem cell function in culture and enhances retrovirus-mediated
`gene transfer into hematopoietic stem cells.” (1989) Proc Natl
`Acad Sci USA. 86: 8897-901
`
`Bender, et al., “A majority of mice show long-term expression of
`a human β-globin gene after retrovirus transfer into
`hematopoietic stem cells.” (1989) Mol Cell Biol. 9:1426-34
`
`Sadelain et al., Proc. Nat’l Acad. Sci. (USA) 92:6728-6732
`(1995)
`
`2025
`
`GenBank Accession No. Z84721 (March 19, 1997)
`
`viii
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`Patent 8,058,061
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`
`Exhibit No.
`
`Description
`
`2026
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`2035
`
`2036
`
`2037
`
`2038
`
`2039
`
`2040
`
`GenBank Accession No. NM_ 000517 (October 31, 2000)
`
`Hardison et al., J. Mol. Biol. (1991) 222(2):233-249
`
`A Syllabus of Human Hemoglobin Variants (1996), by Titus et
`al., published by The Sickle Cell Anemia Foundation in Augusta,
`Georgia (available online at http://globin.cse.psu.edu)
`
`GenBank Accession No. JOO179 (August 26, 1993)
`
`Tagle et al., Genomics (1992) 13(3):741-760
`
`Li et al., Blood (1999) 93(7):2208-2216
`
`Slightom et al., Cell (1980) 21(3):627-638
`
`Excerpts from Inventor Notebooks
`
`Excerpts from Inventor Notebooks
`
`October 2020 Declaration of Dr. Isabelle Rivière
`
`Verma et al., “Gene Therapy: Twenty-First Century Medicine,”
`Annu Rev. BioChem (2005). 74:711-38
`
`Blau, et al., “Moleular Medicine, Gene Therapy – A Novel Form
`of Drug Delivery,” The New England Journal of Medicine
`(1995).
`
`Morris et al., “MHC class II gene silencing in trophoblast cells is
`caused by inhibition of CIITA expression,” American Journal of
`Reproductive Immunology (1998)
`
`Physical mapping of the globin gene deletion in β-thalassemia,
`Benards (1979)
`
`Ryan, T. M., R. R. Behringer, N. C. Martin, T. M. Townes, R. D.
`Palmiter, R. L. Brinster. 1989. A single erythroid-specific DNase
`I super-hypersensitive site activates high levels of human beta-
`globin gene expression in transgenic mice. Genes Dev. 3: 314-23
`
`ix
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`Patent 8,058,061
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`
`Exhibit No.
`
`Description
`
`2041
`
`2042
`
`2043
`
`2044
`
`2045
`
`Pasceri, P., D. Pannell, X. W u, J. Ellis. 1998. Full activity from
`human beta-globin locus control region transgenes requires
`5'HSl, distal beta-globin promoter, and 3’ beta-globin sequences.
`Blood. 92:653-63
`
`Hardison, R., J. L. Slightom , D. L. Gumucio, M. Goodman, N .
`Stojanovic, W. Miller. 1997. Locus control regions of
`mammalian beta-globin gene clusters: combining phylogenetic
`analyses and experimental results to gain functional insights.
`Gene. 205: 73-94
`Hacein-Bey-Abina, et. al., “Vector mediated
`transformation,” (2003) N. Engl. J. Med. 348:255-256.
`[PubMed])
`
`Pfeifer, Gene Therapy: Promises and Problems
`
`Tuan, et al., “Identification of regulatory elements of human β-
`like globin genes.” (1987) Prog Cin Biol Res. 251: 211-20
`
`x
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`Patent 8,058,061
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`
`Sloan Kettering Institute for Cancer Research (“SKI”) is the owner by
`
`assignment of U.S. Patent No. 8,058,061 (“the ‘061 Patent”). SKI has granted San
`
`Rocco Therapeutics LLC (“SRT”) an exclusive but assignable license to — and for
`
`the entire term of — the ‘061 Patent, entitling SRT to make, use, and sell the claimed
`
`invention, commence litigation for infringement, and obtain past damages. (See Ex.
`
`2001 at 1-2.) Pursuant to the agreement, SRT has the “sole responsibility” to defend
`
`any challenge to the validity of the ‘061 Patent. (Id. at 3.) SKI has also entered into
`
`a joint defense agreement with SRT to assist in defending any validity challenge.
`
`(Ex. 2005.) Because SRT has all substantial rights, including the obligation to defend
`
`against Petitioner’s baseless challenge, this Preliminary Patent Owner Response is
`
`submitted by SRT. See Motorola Mobility LLC v. Arouse, IPR2013-00010, Paper 27
`
`at 3-5 (P.T.A.B. Apr. 5, 2013). SKI and SRT are referred to herein, collectively, as
`
`“Patent Owner.”
`
`INTRODUCTION
`The Petition should be denied because the asserted art — the May Thesis,
`
`May Article (referred to herein as the Nature Article), and May Abstract — is the
`
`work of the inventors of Claim 1-2, 5-8, 11, and 15 (“the Challenged Claims”) and
`
`fails to disclose each limitation thereof. The inventors’ own work cannot act as a
`
`statutory bar and indeed evidence that the inventions were conceived of and reduced
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`to practice before the publication of the asserted art.1 During prosecution of the
`
`Challenged Claims, the Office removed the Nature Article as anticipatory art after
`
`all of the inventors submitted Rule 132 affidavits attesting to the fact that the work
`
`contained in that reference was the inventors’ work. Declarations by the surviving
`
`inventors corroborate the same with respect to all of the prior art of Record and
`
`detail the inventors’ earlier conception and reduction to practice over the asserted
`
`art. The Petition should be denied because the references cannot act as invalidating
`
`art, as a matter of law.
`
`Also, the Office has substantively addressed Petitioner’s sole argument that
`
`the claim term “a functional globin gene” is not adequately described in the
`
`provisional applications. The Office already determined that this term had support
`
`based on the disclosed human β-globin gene and the fact that more than a dozen
`
`alpha and gamma globin sequences were known in the art and publicly accessible.
`
`Critically, all of these same circumstances apply to the provisional applications since
`
`they too disclose the same human β-globin gene and all of these other globin genes
`
`were available and known to skilled workers as of the filing of the provisional
`
`applications. Contrary to Petitioner’s arguments, the Challenged Claims are fully
`
`described and enabled by the disclosure of their provisional applications, and
`
`
`1 “May” refers to Chad May, an inventor of the Challenged Claims.
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`2
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`therefore are entitled to an effective filing date of no later than June 29, 2001, which
`
`is less than one year after the publication date of the Nature Article and May Thesis.
`
`Petitioner has further failed to demonstrate that the Office erred in a matter
`
`material to the patentability of the Challenged Claims when it addressed the same or
`
`substantially same arguments previously presented to the Office. Therefore, the
`
`Board should exercise its discretion to deny this frivolous Petition under Section
`
`325(d).
`
`Against this Record, and for the reasons explained herein and in the attached
`
`Declaration of Dr. Riley, Patent Owner respectfully requests that the Board deny
`
`institution of the Petition.
`
`BACKGROUND
`Many facts here are undisputed. In fact, Petitioner has and continues to rely
`
`upon a declaration from inventor Michel Sadelain, a medical doctor with three
`
`decades experience on gene therapy-based treatments, in various prior and current
`
`litigation. (See Ex 2003 (prior Sadelain declaration) at ¶¶6, 23; Ex. 2004 (Petitioner’s
`
`2020 letter submitting Sadelain’s declaration); see also Ex. 2006 (current Sadelain
`
`declaration attesting to same).) Petitioner recently relied on Sadelain’s 2020
`
`declaration during a January 17, 2023 arbitration hearing in San Rocco Therapeutics,
`
`LLC v. bluebird bio, Inc. et al., AAA Case No. 01-22-0003-6927. The uncontested
`
`declaration sets forth the state of gene therapy at the time of the invention and the
`
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`conception and reduction to practice of the ‘061 Patented invention. (Ex. 2003 at
`
`¶¶8-23 (explaining work on the vector took 11 years and conception and initial
`
`reduction to practice occurred prior to Nature publication).)
`
`In the late 1990s and early 2000s, various hemoglobinopathies, or blood
`
`disorders like β-thalassemia, were treated using blood transfusions or bone marrow
`
`transplantation. (See Ex. 2002 at ¶¶30, 91; Ex. 1004 at 30-31; Ex. 2010.) However,
`
`such treatments were temporary, expensive, uncomfortable, ineffective or limited to
`
`a select number of matched donors, and/or unsafe. (See Ex. 2002 at ¶91; see also Ex.
`
`1001 at 1:24-33.) While gene therapy offered a potential solution, the still-emerging
`
`technology was plagued with known problems and limitations. (Ex. 2002 at ¶¶26-
`
`38.) The invention described in the ‘061 Patent offered a solution. (Ex. 1036 at 128-
`
`129.)
`
`Prior to the invention, researchers knew the location of the various globin
`
`genes but were just beginning to understand aspects affecting expression thereof.
`
`(Ex. 2002 at ¶¶30-36.) For instance, researchers knew that a 20-kb regulatory region
`
`termed the locus control region (“LCR”) contained at least five minimal DNA
`
`sequences having sites of strong DNase I cleavage — regions referred to as
`
`hypersensitive sites (“HS”) or core elements — at least some of which were required
`
`for globin gene activation. (Ex. 2002 at ¶¶30-31 (further identifying location of
`
`globin genes); Ex. 1004 at 37; Ex. 2011 (disclosing that the β-globin LCR helped to
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`express epsilon, gamma, and beta-globin genes).)
`
`However, for several years, none of the “research groups [] conducting this
`
`research had success in designing a vector that could both be transduced at high
`
`efficiency and express therapeutic levels of the beta-globin protein.” (Ex. 2003 at
`
`¶21.) As Petitioner’s cited art notes, “the prospect of gene therapy using the β-globin
`
`gene has proven to be exceedingly difficult to attain due to many factors.” (Ex. 1004
`
`at 32.) The lack of success was due at least to the following challenges.
`
`First, researchers were still at the early stage of understanding the roles the
`
`cis-acting regulatory regions or elements, such as their presence and size, could play
`
`in globin gene expression. (Ex. 2002 at ¶¶35-36; see also Ex. 2003 at ¶12; Ex. 2012
`
`at 3 (describing “increasingly baffling realization that far more than a few simple
`
`genes are needed”).)
`
`Studies suggested the size and presence of the HS fragments mattered to
`
`overall gene expression, but researchers did not know what size or what combination
`
`of HS fragments would efficiently drive expression. (Ex. 2002 at ¶¶35-36.) Some
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`studies suggested HS1 was crucial. (Ex. 2002 at ¶35; Ex. 1004 at 39.) Other studies
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`suggested large HS2 fragments (1.5 kb -1.9 kb) conferred increased expression over
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`the HS core, where still others found the HS2 alone could significantly drive
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`expression. (Ex. 2002 at ¶36 (citing Exs. 2013-2014).) Still others thought a “full
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`complement of HS1-HS4” segments (~4.0kb) in combination with a promoter and
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`enhancer was required. (Ex. 2002 at ¶37; Ex. 1004 at 49.) Others believed the “large
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`number of conserved sequences lying between the hypersensitive core elements
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`[were] thought to play a crucial role in LCR function.” (Ex. 1004 at 49 (citing Ex.
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`2015).)
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`Second, vector design around 2000 was still considered a “major barrier to
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`successful gene therapy for [] hemoglobin disorders.” (Ex. 2002 at ¶34 (citing Ex.
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`2016 at 3).) Onco-retroviral-mediated transfer into hematopoietic stem cells (HSCs)
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`resulted in low expression of the human β-globin, which was further limited by
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`chromosomal position effects. (See Ex. 1005 at 3 (also noting problems in stability
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`and transduction of large genomic fragments); Ex. 1004 at 33-34; Ex. 2003 at ¶21
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`(describing need to effectively transfer).) Most vectors could not hold large DNA
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`sequences and lentiviral vectors, introduced in the 1990s, were a type of retroviral
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`vector that most researchers had concluded “could not serve” as a successful vector.
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`(Ex. 2003 at ¶¶15, 21; Ex. 2017; Ex. 2018 (describing concerns with use of lentiviral
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`vectors).)
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`Third, researchers needed vectors capable of producing a substantial amount
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`of functional globin to be therapeutically relevant, which meant globin gene
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`expression of at least 10-20%. (Ex. 2002 at ¶34; Ex. 2003 at ¶21; Ex. 2006 at ¶24.)
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`However, studies suggested that gene therapy treatments at the time could not
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`achieve even 1% expression. (Ex. 2002 at ¶34 (citing Exs. 2019-2023); see also Ex.
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`2002 at ¶38 (describing other problems, e.g., transcriptional silencing and position
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`effects).)
`
`A. The ‘061 Patent and Cited Art.
`1.
`The Invention.
`a)
`Conception and Reduction to Practice.
`Dr. Sadelain began his gene therapy work in 1989. (Ex. 2003 at ¶8; Ex. 2006
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`at ¶11.) Throughout the 1990s and early 2000s, SKI’s labs employed him, Dr.
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`Stefano Rivella, Dr. Joseph Bertino, and a doctoral candidate and then post-doctorate
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`fellow, Chad May. (Ex. 2006 at ¶11; Ex. 2007 at ¶11; Ex. 2008 at ¶12.) These
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`individuals worked on transferring genes to HSCs to treat hemoglobinopathies. (Ex.
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`2006 at ¶11.)
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`Specifically, these individuals worked to and did identify DNA regions —
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`three nucleotide segments — that could be successfully transferred into a patient and
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`begin expressing β-globin, which they accomplished no later than 1999. (Ex. 2006
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`at ¶¶12-30 (discussing 1999 in vivo testing); Ex. 2007 at ¶¶12-18; Ex. 2008 at ¶¶13-
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`19.) Initially, the team could not verify their theory due to an inability to successfully
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`transfer these segments — packaged together into a locus control region (“LCR”)
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`— into a hematopoietic stem cell. (Ex. 2006 at ¶¶12-16, 20-22 (explaining repeated
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`problems with incomplete transfers or instability); Ex. 2003 at ¶¶12, 16 (Sadelain
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`explaining earlier vectors could not hold team’s designed sequence of genetic
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`material ).) Around 1996-1997, the inventors began to look to lentiviral vectors as a
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`solution to their transfer problem, which resulted in the creation of the TNS9 vector.
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`(Ex. 2006 at ¶23; Ex. 2003 at ¶16.) Thereafter, an in vitro study followed by a two-
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`part in vivo study using mice was initiated. (Ex. 2006 at ¶¶23-26 ; Ex. 2003 at ¶¶18-
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`19 (describing in vivo study).) By 2000, 11 years after the inventors started to design
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`a vector to overcome the above noted problems, the team believed they had a
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`possible solution. (Ex. 2003 at ¶¶21-22; Ex. 2006 at ¶32-33 (stating the solution has
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`since become the “foundation” for certain gene therapies).)
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`Noting safety concerns yet to be addressed, the team reported the results of
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`their initial testing showing a “proof of concept” in Nature in 2000. (Ex. 2003 ¶¶11,
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`22; Ex. 2006 at ¶¶28-32; Ex. 1005.) This led to “significant interest in both the
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`academic community and general press.” (Ex. 2003 at ¶23 (noting worldwide calls,
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`speaking engagements, etc.).)
`
`b)
`The ‘061 Patent.
`The ‘061 Patent, titled “Vector Encoding Human Globin Gene and Use
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`Thereof in Treatment of Hemoglobinopathies,” is a divisional of U.S. Patent No.
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`7,541,179 and claims priority to both Provisional Application Nos. 60/301,861, filed
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`on June 29, 2001 (“the ‘861 Provisional”), and 60/302,852, filed on July 2, 2001
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`(“the ‘852 Provisional”).
`
`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. (See id. at 11:56-14:8; Ex. 2002 at ¶¶55-56.) Embodiments
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`of the claimed vector include a region comprising a functional globin gene that is
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`linked to a 3.2-kb LCR. (Id.)
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`A particularly novel aspect of the claimed invention involves the three larger
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`contiguous nucleotide fragments or DNase I HS. (Id. at 2:57-59.) In fact, testimony
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`previously relied upon by Petitioner recognized that designing the genetic material
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`to be used in the vector was the “most innovative.” (Ex. 2003 at ¶12.) Prior art used
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`a 1.0-kb LCR containing smaller nucleotide fragments spanning the core portions of
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`HS regions, including HS2, HS3, and HS4. (Ex. 1001 at 2:59-62 (citing Ex. 2024).)
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`The inventors envisioned using larger regions — a BstXI and SnaBI DNA fragment
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`(“HS2”), a BamHI and HindIII DNA fragment (“HS3”), and a BamHI and BanII
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`DNA fragment (“HS4”) — that are included in the linked 3.2-kb LCR. (Id. at 2:63-
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`3:28 (explaining other length fragments may provide same functionality).)
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`(Id. at FIG. 1 (depicting genomic structure of one vector embodiment, TNS9).)
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`By exchanging and replacing the globin gene coding sequences, the vectors
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`can be used to treat various hemoglobinopathies, including sickle-cell disease and
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`thalassemia. (Id. at 1:24-27, 3:29-53, 4:25-36 (explaining that vectors can be used to
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`treat hematopoietic progenitor or stem cells ex vivo before restoring those cells to
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`the patient or through introduction of the vector directly into the patient, e.g., using
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`a lentiviral vector).)
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`When compared against a control (GFP) and a vector containing just the core
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`HS2, HS3, and HS4 fragments (RNS1), an embodiment of the ‘061 Patent — the
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`TNS9 vector — showed substantially increased expression of human β-globin. (See
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`id. at 5:21-60; FIG. 3 (showing expression over 70% for TNS9 vector, compared to
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`less than 15% for RNS1 vector).)
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