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
`____________
`
`DECLARATION OF DR. JAMES RILEY
`IN SUPPORT OF PATENT OWNER’S PRELIMINARY RESPONSE
`
`SKI Exhibit 2002
`Page 1 of 111
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`
`____________
`
`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
`____________
`
`DECLARATION OF DR. JAMES RILEY
`IN SUPPORT OF PATENT OWNER’S PRELIMINARY RESPONSE
`
`SKI Exhibit 2002
`Page 1 of 111
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`I, James Riley, declare as follows:
`1.
`I am over the age of 21 years and am fully competent to make this
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`Declaration. I make the following statements based on personal knowledge and, if
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`called to testify to them, could and would do so.
`
`2.
`
`I understand these patents are being challenged in inter partes reviews
`
`in front of the Patent Trial and Appeal Board of the United States Patent and
`
`Trademark Office.
`
`3.
`
`I understand that U.S. Patent No. 7,541,179 (“the ‘179 Patent”) and
`
`U.S. Patent No. 8,058,061 (“the ‘061 Patent”) have been challenged in IPR2023-
`
`00070 and IPR2023-00073, respectively. I make this declaration in support of Patent
`
`Owner’s Preliminary Response in the above captioned inter partes review.
`
`I.
`
`Qualifications
`4.
`I received my B.S. from Vanderbilt University in Molecular Biology in
`
`1989. I received my Ph.D. from Emory University in Genetics and Molecular
`
`Biology in 1994 under the supervision of Dr. Jeremy Boss. I did my postdoctoral
`
`work at the Walter Reed Army Institute of Research in the Division of Retrovirology
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`under the supervision of Dr. Carl June.
`
`5.
`
`I am currently employed by the University of Pennsylvania’s Perelman
`
`School of Medicine, where I am a Professor of Microbiology. I am also a member
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`of the Immunology and Cell & Molecular Biology Graduate Groups as well as the
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`Institute for Immunology, Center for Cellular Immunotherapies, and Diabetes
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`Research Center. I also currently serve on Scientific Advisory Board at Johns
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`Hopkins Translational ImmunoEngineering Center.
`
`6.
`
`I have used recombinant DNA technology in the vast majority of my
`
`more than 120 peer reviewed research papers. I have also published approximately
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`10 papers that have examined how to best to control expression of inserted genes in
`
`lentiviral vectors or DNA plasmids.
`
`7.
`
`In 1999, I joined the faculty at the University of Pennsylvania School
`
`of Medicine, where I am currently still a professor.
`
`8.
`
`Since 2000, I have served as an editorial reviewer for the Human Gene
`
`Therapy publication. Around that time, and since then, I have also been an editorial
`
`reviewer for Cell, Science, and Nature and their more specialized sister journals,
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`Clinical Immunology, Journal of Clinical Investigation, the Journal of Immunology,
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`and Molecular Therapy, among others.
`
`9.
`
`Between 1992 and 1996, I published a series of articles that described
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`the promoter elements required to regulated MHC class II genes in a B cell specific
`
`manner:
`
`(cid:120)
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`In early 2001, I presented a lecture on the use of lentiviruses for
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`HIV-1 immunotherapy.
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`(cid:120)
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`In 2013, I presented a lecture on “Gene Therapy Approaches to
`
`Treat and Cure HIV-1 Infection" as part of Nobel Forum:
`
`Towards an HIV-1 Cure, Stockholm, Sweden.
`
`(cid:120)
`
`(cid:120)
`
`In 2015, I co-founded a cell and gene therapy called Tmunity
`
`Therapeutics which was recently acquired by Gilead/Kite.
`
`Since 2016, I have lectured on Genome Engineering as part of
`
`Cell and Gene Therapy course offered to University of
`
`Pennsylvania graduate students.
`
`(cid:120)
`
`In 2021, I coauthored a peer reviewed review entitled “Genetic
`
`engineering of T cells for immunotherapy” that was published
`
`in Nature Review Genetics.
`
`10. A copy of my current CV is attached as Appendix A.
`
`II. Relevant Field and Level of Ordinary Skill in the Art
`11.
`I have reviewed the ‘061 Patent and portions of its prosecution history
`
`with the United States Patent and Trademark Office. Specifically, I have reviewed
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`the ‘061 Patent and its prosecution history in relation to the asserted prior art and
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`arguments at issue in the present inter partes review.
`
`12.
`
`I have reviewed Dr. Jörg Bungert’s declaration, submitted in support of
`
`the Petition, which I understand to be Ex. 1002. I understand Dr. Bungert has taken
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`the position that a person of ordinary skill in the art at the time of the invention
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`(“POSA”) would have had at least an advanced degree (e.g., a Master’s or Ph.D.) in
`
`biochemistry, biotechnology, protein chemistry, genetics, molecular and structural
`
`biology, bioengineering, or similar disciplines. (Ex. 1002 at ¶ 14.) He also opines
`
`that a POSA would also have had several years of post-graduate training or related
`
`experience in one or more of these areas, which would have given them an
`
`understanding of vector design and the effect of LCR fragments on gene expression,
`
`including how the LCR regulates gene expression. (Id. at ¶ 14.) For the purpose of
`
`responding to the Petition in the Preliminary Patent Owner’s Response, I utilize this
`
`definition and do not take a position as to whether it is correct or not. However, I
`
`reserve all rights to set forth the proper education and experience of a POSA should
`
`institution be granted.
`
`13. Based on my experience described above and contained in my C.V., I
`
`have an established understanding of the relevant field in the relevant timeframe,
`
`and the knowledge that would have been known by a POSA, as defined above and
`
`during the relevant time frame (late 1990s to very early 2000s).
`
`III. Materials Reviewed
`14.
`I have reviewed the Petition and supporting evidence. I have also
`
`reviewed all challenged claims of the ‘061 Patent (Claims 1-2, 5-8, 11 and 15), as
`
`well as the ‘061 specification and parts of its file history. I have examined the prior
`
`art references asserted against the ‘061 Patent in the Petition. I will use the exhibit
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`4
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`numbers listed on the “List of Exhibits” on pages vii-x of the Petition and the exhibit
`
`numbers listed in Patent Owner’s exhibit list, which I have included for ease of
`
`reference below:
`
`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-
`
`5
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`SKI Exhibit 2002
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`Exhibit No.
`
`Description
`globin locus control region.” Domain opening and synergism
`between HS2 and HS3. J Biol Chem. 271:11871-8
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`Philipsen, et al. “The (cid:533)-globin dominant control region:
`hypersensitive site 2.” EMBO J. (1990) 9:2159-67
`
`Hardison, et. al., “Locus control regions of mammalian (cid:533)-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 (cid:533)-globin gene in
`erythroid cells of transgenic mice.” Nature. (1985) 314:377-80
`
`Townes, et al., “Expression of human (cid:533)-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 (cid:533)-
`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 (cid:533)-globin gene after retrovirus transfer into
`hematopoietic stem cells.” (1989) Mol Cell Biol. 9:1426-34
`
`6
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`SKI Exhibit 2002
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`Exhibit No.
`
`Description
`
`2024
`
`2025
`
`2026
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`2035
`
`2036
`
`2037
`
`2038
`
`Sadelain et al., Proc. Nat’l Acad. Sci. (USA) 92:6728-6732
`(1995)
`
`GenBank Accession No. Z84721 (March 19, 1997)
`
`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)
`
`7
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`SKI Exhibit 2002
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`Exhibit No.
`
`Description
`
`Physical mapping of the globin gene deletion in (cid:533)-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
`
`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 (cid:533)-
`like globin genes.” (1987) Prog Cin Biol Res. 251: 211-20
`
`2039
`
`2040
`
`2041
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`2042
`
`2043
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`2044
`
`2045
`
`
`
`15.
`
`I reserve the right to supplement this exhibit list.
`
`IV. The Understandings Applied to My Analysis
`16.
`I understand that in an IPR proceeding, claims should be construed as
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`having their ordinary and customary meaning as understood by a POSA at the time
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`of the invention. I understand that claims should be read in the context of the claim
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`language of which they are a part. I further understand that the specification and file
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`history can also inform the scope of the claims. If, after a review of this evidence,
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`the construction is not apparent, I understand that extrinsic evidence, such as
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`dictionary definitions, treatises, and trade journals, may be consulted to discern the
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`meaning of a term. For terms where no construction is necessary, I have simply read
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`the terms according to their ordinary and customary meaning. My understandings
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`herein are made in light of how a person of ordinary skill in the art in or around 2000
`
`would view the ordinary and customary meaning of the claim terms. I reserve the
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`right to supplement my declaration, should any claim terms be given different
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`constructions.
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`17.
`
`I understand that a claim is anticipated if a single prior art reference
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`discloses each and every limitation of the claimed invention. I understand that a
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`limitation can be expressly disclosed by the reference or be inherent. I further
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`understand that for a feature to be inherently disclosed, a POSA would understand
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`the inherent feature would necessarily and inevitably be present when the teaching
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`of the reference is practiced. That is, I understand that if a feature is not necessarily
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`and inevitably present, it is not inherently disclosed.
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`18.
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`I understand that a patent claim may be unpatentable for obviousness if
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`the difference between the claimed subject matter and the prior art is such that the
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`subject matter as a whole would have been obvious at the time the invention was
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`made to a person having ordinary skill in the art. I understand that a finding of
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`obviousness requires a determination of: (1) the scope and content of the prior art;
`
`(2) the difference(s) between the claimed invention and the prior art; (3) the level of
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`skill of the ordinary artisan in the pertinent art. I understand this analysis looks at
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`whether the differences are such that the claimed invention as a whole would have
`
`been obvious to one of ordinary skill in the art at the time the invention was made. I
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`further understand that any obviousness analysis must consider objective evidence
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`of non-obviousness, where such evidence is present.
`
`19.
`
`I understand that objective evidence of non-obviousness includes (1)
`
`copying, (2) long felt but unsolved need, (3) failure of others, (4) commercial success
`
`of the invention, (5) unexpected results created by the claimed invention, (6)
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`unexpected properties of the claimed invention, (7) licenses showing industry
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`respect for the invention, (8) skepticism of skilled artisans before the invention, (9)
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`recognition of invention’s advancement, and (10) contemporaneous invention by
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`others or absence thereof. In general, there must be a connection between the factor
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`and the claimed invention. For instance, the “commercial success” of a product
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`practicing the claimed invention is relevant to the obviousness analysis only if the
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`commercial success is attributable to advantages from the use of the invention that
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`were not available to the purchasing public before the invention was made.
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`20. My understanding is that the obviousness inquiry is not limited to just
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`the prior art references being applied, but includes the knowledge and understanding
`
`of one of ordinary skill in the art.
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`21. However, I understand that merely demonstrating that each element,
`
`independently, was known in the prior art is, by itself, insufficient to establish a
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`claim was obvious. My understanding is that the test for obviousness is not whether
`
`the features of one reference can be incorporated into the structure of another
`
`reference, but rather what the combined teachings would have suggested to those of
`
`ordinary skill in the art. I further understand that a party seeking to invalidate a patent
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`must show a person of ordinary skill in the art would have been motivated to
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`combine the teachings of the prior art references to achieve the claimed invention.
`
`22.
`
`It is my understanding that each prior art reference must be considered
`
`as a whole, including the portions that would lead away from the claimed invention.
`
`I have been informed that some prior art combinations are improper, or not
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`combinable. For instance, the reference cannot be non-analogous art. In order for a
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`reference to be used to show obviousness, the reference must be analogous art to the
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`claimed invention. I understand that to be analogous, the art must be from the same
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`field of endeavor or be reasonably pertinent to the problem – and therefore logically
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`would command the artisan’s attention in considering her/his problem. I also
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`understand that when (1) the combination of prior art references teaches away from
`
`the claimed invention or from each other, (2) the combination makes one invention
`
`unsatisfactory for its intended purpose, or (3) when the combination would change
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`the principle of operation of prior art reference, such a combination is improper and
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`does not show obviousness.
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`23.
`
`I understand that a combination of old, familiar, or known elements
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`according to known methods is likely to be obvious when it does no more than yield
`
`predictable results. Predictable variations of a work from one field are likely to be
`
`obvious, even if the variation is in another field. For example, where a technique has
`
`been used to improve a device, use of the same technique to improve similar devices
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`is a predictable variation and likely obvious. Likewise, if the use of prior art for
`
`improvements is simply done according to the prior art’s established functions, a
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`person of ordinary skill in the art has simply implemented a predictable variation. If
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`there existed at the time of invention a known problem for which there was an
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`obvious solution, a patent claim encompassing that solution is not patentable.
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`24.
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`I understand that claims must be enabled by the original disclosure of
`
`the patent. For the claims to be enabled, the information contained in the disclosure
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`must be sufficient to inform those skilled in the relevant art how to make and use the
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`claimed invention without undue experimentation. I also understand the original
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`disclosure must contain a written description of the claimed invention. I understand
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`that the written description requirement is separate and distinct from the enablement
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`requirement. To satisfy the written description requirement, the original disclosure
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`must describe (in writing or drawings) the claimed invention in sufficient detail that
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`one skilled in the art can reasonably conclude the inventor had possession of the
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`claimed invention. I understand that a genus can find written description support
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`when the disclosure includes representive species of the genus and/or when one
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`skilled in the art would understand that the species disclosed had a correlation
`
`between the structure and function of other species within the genus. In other words,
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`the question is whether one of skill in the art can discern or visualize, from the
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`original disclosure, that the named inventor actually invented the subject matter later
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`claimed.
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`25. The following background and analysis is based on my own
`
`experiences, education, and opinions. I have provided citations in support of this
`
`understanding. Although the following analysis cites to particular pages, lines,
`
`paragraphs, or figures of many of the references discussed, these citations are
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`intended to assist in understanding the various bases of my conclusions, and prior
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`art teachings used to reach them. These citations are not intended to be an exhaustive
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`recitation of every page, line number, or paragraph in which these teachings may be
`
`found. Similar teachings or disclosures may be found at other pages, lines, or
`
`paragraphs, as well as in other references, and it is to be understood that my opinions
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`and statements are made in view of all of the references and teachings I have
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`reviewed.
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`V.
`
`State of the Art
`26. A gene is a region of DNA located on a chromosome. In fact, genes are
`
`located at a specific locus or fixed position on a chromosome. Classically, a gene
`
`encodes for a particular trait. We find genes scattered throughout the genome. Genes
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`are the basic physical and functional units of our DNA, which are passed from
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`parents to their offspring. They act as a sort of template or instruction to make
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`molecules or proteins, which determines different physical traits and usually
`
`provides for normal physiological functions. When there is a flaw in a gene or the
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`gene is missing, it can result in one or more diseases or disorders.
`
`27.
`
`In general, the amount of DNA used to encode the information to make
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`these genes is a very small percentage of the DNA present in a cell. In contrast, the
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`amount DNA whose job it is to ensure proper regulation of a gene is much larger
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`and can present millions of base pairs away from the gene it regulates.
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`Understanding how DNA regulates when a gene is transcribed has been a major
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`research focus since the early 1980s.
`
`28. Gene therapy is a technique that alters the genome of a cell to treat,
`
`prevent, or cure a disease or medical disorder. (Ex. 2036 at 1-8; Ex. 2037 at 1.) The
`
`technique usually involves altering genes to begin, increase, decrease, or stop
`
`expression of certain genes, which may result in the normal expression and function
`
`of one or more proteins. (Id.)
`
`29. Gene therapy often involves packaging one or more genes into a vector
`
`and administering this vector to the patient. (Id.) The vector, usually comprised of a
`
`modified virus, would infect certain cells with the packaged genes, which would fix,
`
`replace, or supplement the expression of other genes. (Id.) The packaged genes
`
`would be incorporated into the host’s DNA. (Id. (explaining the DNA packaged in
`
`the virus would be permanently integrated into chromosomal DNA).) The plan being
`
`that the packaged genes would then be transcribed, resulting in the expression of one
`
`or more proteins that would treat or cure the disease or disorder. (Ex. 2036 at 1-2;
`
`Ex. 2037 at 2.)
`
`30.
`
`In the late 1990s, there was a hope that scientists could use gene therapy
`
`to treat various diseases and disorders associated with multiple different genes,
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`including the globin genes. (See, e.g., Exs. 1004-1006; Ex. 1009 at 7.) For example,
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`the (cid:533)-globin gene is located on the short arm of chromosome 11. (Ex. 1004 at 24;
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`Ex. 1009 at 1.) The (cid:533)-globin gene is a protein that acts as a subunit to hemoglobin,
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`which is a macro-protein used by the blood to carry and distribute oxygen. (See, e.g.,
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`Ex. 1004 at 21.) By at least the 1970s, scientists understood where the (cid:533)-globin gene
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`was located and that certain deletions of the gene were associated with blood
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`diseases and disorders (“hemoglobinopathies”), which included (cid:533)-thalassemia,
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`sickle-cell disease, and others. (See, e.g., Ex. 2039.) Researchers also understood
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`that upstream of the (cid:533)-globin gene was a 20-kb region that affected the expression
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`thereof and the nearby HBE1, hemoglobin subunit epsilon, hemoglobin subunit
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`gamma-2, hemoglobin subunit gamma-1, hemoglobin subunit delta, hemoglobin
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`subunit beta ((cid:533)-globin). (See, e.g., Ex. 1004 at 23, 38.) Because this 20-kb region
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`impacted the expression of the (cid:533)-globin and functionally related genes, it was coined
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`the locus control region (“LCR”). (See id.)
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`31. The LCR contained at least five minimal DNA sequences having sites
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`of strong Deoxyribonuclease I (“DNase I”) cleavage, meaning DNase I effectively
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`cut the DNA in this region. (Id.) These five sequences each are referred to as
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`hypersensitive sites (“HS”), and were numbered HS1, HS2, HS3, HS4, and HS5
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`(collectively herein “HS sites”). The HS sites were understood to be capable of
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`conferring high level expression of the (cid:533)-globin gene. (Ex. 1004 at 23, 28, and 37.)
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`It was also understood that proteins were capable of binding with the HS sites to
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`form a holocomplex to effect gene activation. (Ex. 1004 at 37.)
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`32. However, knowing where genes were located and what caused diseases
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`and disorders was just the start. Effectively treating genetic diseases and disorders
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`has taken, and continues to take, significant time and effort. Indeed, by the 1990s,
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`researchers had been working for years to find a way to insert one or more gene
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`sequences into a patient to treat a patient of a genetic disorder, but had yet to be
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`successful. (See, e.g., Ex. 1036 at 128-129 (citing commentary from Molecular
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`Therapy noting “frustration of the past 12 years” in globin gene therapy was replaced
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`with optimism based on Michel Sadelain and his research teams results in the Nature
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`Article).) As one observer noted in 2006, “[t]he history of gene therapy can be told
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`as the repeatedly frustrated search for viruses that work well as envelopes for gene
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`delivery, paralleled by the increasingly baffling realization that far more than a few
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`simple genes are needed to produce the desired proteins successfully.” (Ex. 2012
`
`at 3.)
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`33. There were so many optimization problems with the gene delivery
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`systems that, in a December 1995 report, the National Institutes of Health called for
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`researchers to working on gene vectors and vector design to “return to the drawing
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`board.” (Ex. 2018 at 1.) In 1999, a patient named Jesse Gelsinger died after being
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`subjected to one of the first gene therapy experiments. (See https://www.c-
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`span.org/video/?155137-1/safety-gene-therapy.) Congress held a hearing on the
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`“Safety of Gene Therapy,” where it was announced there were hundreds of reports
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`of serious, adverse effects to experimental gene therapy studies, including over 650
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`previously unreported incidents that had just been submitted. (Id. at 6:00) Shortly
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`thereafter, President Bush prohibited the use of federal funding for research on new
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`stem cell lines. (See https://georgewbush-whitehouse.archives.gov/news/releases/
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`2001/08/20010809-2.html.)
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`34. The problems plaguing gene therapy treatment extended to the
`
`treatment of hemoglobinopathies. Indeed, the cited prior art states, “the prospect of
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`gene therapy using the (cid:533)-globin gene has proven to be exceedingly difficult to attain
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`due to many factors.” (Ex. 1004 at 32.) Indeed, it was recognized in 2000 that vector
`
`design was still a “major barrier” in the successful treatment of hemoglobin disorders
`
`using gene therapy. (Ex. 2016 at 3.) In addition, it was not enough to simply find a
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`way to transfer genes. To be effective, researchers needed to effectively transfer the
`
`right genes in a way that would result in globin gene expression of at least 10-20%
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`to be therapeutically relevant. (Id.) But studies at the time resulted in (cid:533)-globin
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`expression of less than 1%. (See Exs. 2019-2023.)
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`35.
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`In the late 1990s and early 2000s, researchers did not have a full
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`understanding of what gene sequences would be required to achieve therapeutically
`
`relevant levels of expression of the (cid:533)-globin gene. Some studies suggested that
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`certain HS sites were critical to include in order to achieve expression of the (cid:533)-globin
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`gene. For instance, at least one study suggested a lack of HS1 results in sensitivity
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`to position effects and that full expression is “obtained only when a 1.0 kb HS1
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`fragment” is combined with an HS2-HS4 sequence. (Ex. 2045.)
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`36. Studies suggested the size and presence of certain HS fragments
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`mattered to overall gene expression but were divided on what was required. For
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`example, studies suggested that “larger HS2 fragments,” which were identified as
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`being between 1.5 kb to 1.9 kb, “conferred increased levels of use of (cid:533)-globin
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`expression” as compared to the HS2 core, which was only 215 bp. (Exs. 2013, 2040.)
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`At least one other study concluded that a full complement of the HS1, HS2, HS3,
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`and HS4 segments, which could be approximately 4.0kb in length, in combination
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`with a (cid:533)-globin promoter and enhancer were required for sufficient expression of the
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`(cid:533)-globin gene. (Ex. 2041.) It was also suggested that the “large number of conserved
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`sequences lying between the hypersensitive core elements [were] thought to play a
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`crucial role in LCR function.” (Ex. 2042.) However, in at least one study, the HS3
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`core alone, which is only 225 bp, was found to be a significant driver of (cid:533)-globin
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`expression. (Ex. 2014.)
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`37.
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`In and around 2000, vector design was also a problem. For one, most
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`of the vectors being used at the time could not carry more than a couple thousand
`
`base pairs. That is, after inclusion of the globin gene, there would only be a few
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`hundred to a thousand base pair capacity remaining, which was far short of the 20-
`
`kb LCR or even the 4-kb “full complement” of the HS1-HS4 segments. (See, e.g.,
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`Ex. 2046.)
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`38. There were also known “limitations and risks of allogenic cell
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`transplants,” as well as “position effects, and transcriptional silencing” that
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`hampered effectiveness of viral transduction of the human (cid:533)-globin gene when it
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`was linked to minimal regulatory sequences. (See Ex. 1005 at 3.) For example, onco-
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`retroviral-mediated transfer into mouse haematopoietic stem cells (HSCs) resulted
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`in low expression of the human (cid:533)-globin, which was further limited by chromosomal
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`position effects. (See Ex. 1005 at 3 (also noting problems in stability and
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`transduction of large genomic fragments); Ex. 1004 at 13; see also Ex. 2043 (noting
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`a serious adverse event after successful gene therapy for X-linked severe combined
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`immunodeficiency).)
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`VI. Vector Making and Testing is Slow
`39. Recombinant construction of a vector suitable for delivery and in vivo
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`expression of a cargo gene (e.g., globin) in an animal model is a slow process in the
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`late 1990s and early 2000s. It is particularly challenging to recombinantly construct
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`vectors having multiple inserts (e.g., globin, HS2, HS3, HS4, DHFR, etc.) as in the
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`cells and recombinant vectors defined in claims 1 and 11 of the ‘061 Patent. Based
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`on my experience and education, the understanding at the time was there was a lot
`
`of uncertainty in how long it would take to make a construct. Indeed, while it was
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`possible to get lucky and make a construct quicker, it was also understood that it
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`could easily take a very skilled artisan several months to actually make a single
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`construct. It was also understood that different methods to make the construct could
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`be used.
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`40. An example of one such process involves first producing and isolating
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`a sufficient amount of each insert, typically by polymerase chain reaction (PCR)
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`using a primer pair designed specifically for each insert. The primer pair consists of
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`a forward primer and reverse primer, each of which contains a restriction site of
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`choice. Upon completion of PCR amplification for each insert, the amplified insert
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`is subject to purification. Next, restriction digestion of the insert is performed using
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`a pair of restriction enzymes to create ends for ligation, matc
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