BLUEBIRD BIO, INC.,
`Petitioner,
`v.
`SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH,
`Patent Owner.
`IPR2023-00070 (U.S. Patent No. 7,541,179)
`IPR2023-00074 (U.S. Patent No. 8,058,061)
`
`January 24, 2024 Oral Hearing
`Patent Owner’s Demonstratives
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE IPR2023-00070 & 00074
`
`1
`
`
`Petitioner,
`v.
`SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH,
`Patent Owner.
`IPR2023-00070 (U.S. Patent No. 7,541,179)
`IPR2023-00074 (U.S. Patent No. 8,058,061)
`
`January 24, 2024 Oral Hearing
`Patent Owner’s Demonstratives
`
`DEMONSTRATIVE EXHIBIT - NOT EVIDENCE IPR2023-00070 & 00074
`
`1
`
`
`
`Challenged Claims And Asserted Grounds
`
`IPR2023-00070 (U.S. Patent No. 7,541,179)
`
`Ground Claims Challenged
`1
`1, 19, 22
`2
`1, 19, 22
`3
`1, 19, 22
`4
`1, 10, 19, 22
`
`35 U.S.C. § References
`§102
`May Thesis (Ex. 1004)
`§102
`Nature Article (Ex. 1005)
`§103
`Nature Article (Ex. 1005)
`§103
`May Abstract (Ex. 1006)
`
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`2
`
`See e.g. Paper 1 at 4-5.
`
`
`
`Challenged Claims And Asserted Grounds
`
`Ground
`
`1
`
`2
`
`3
`
`4
`
`§102 – May Thesis
`
`1, 19, 22
`
`§102 – Nature Article
`
`IPR2023-00070 (U.S. Patent No. 7,541,179)
`Claims
`Basis
`Petitioner’s Position After Completion of
`Challenged
`Briefing
`1, 19, 22
`No longer seriously advancing – As ID
`found, the May Thesis cannot be prior art to
`any of the Challenged Claims
`No longer seriously advancing – As ID
`found, Nature Article does not disclose all
`of the elements of the Challenged Claims
`Still at issue – but does not contest claim 10
`because its priority to Provisionals removes
`the Nature Article as prior art.
`Still at issue – even though ID found no
`obviousness based on the May Abstract
`See e.g. Paper 41 at 1-3.
`
`1, 19, 22
`
`§103 – Nature Article
`
`1, 10, 19, 22
`
`§103 – May Abstract
`
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`3
`
`
`
`Priority Date Of The ’179 Patent
`
`Claim Claim Element
`A recombinant vector comprising a nucleic acid encoding a
`1
`functional globin operably linked to a 3.2-kb nucleotide fragment
`which consists essentially of three contiguous nucleotide fragments
`obtainable from a human β-globin locus control region (LCR), the
`three fragments being a BstXI and SnaBI HS2-spanning nucleotide
`fragment of said LCR, a BamHI and HindIII HS3-spanning nucleotide
`fragment of said LCR and a BamHI and BanII HS4-spanning
`nucleotide fragment of said LCR, said vector providing expression of
`the globin in a mammal in vivo.
`The vector of claim 1, wherein the functional globin is human β-
`globin.
`The vector of claim 1, wherein the functional globin is a β-globin.
`The vector of claim 1, wherein the vector is a lentiviral vector.
`
`19
`22
`
`10
`
`Priority date
`Date of the filing of
`Provisional Application
`(Ex. 1035) – 6/29/2001
`
`Priority date not
`challenged (6/29/2001)
`6/29/2001
`6/29/2001
`
`See e.g. Paper 27 at 20-37
`
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`4
`
`
`
`Claim 19 Should Be Afforded The Same Priority Date As Claim 10
`
`Claim Claim Element
`
`Priority date
`
`10
`
`19
`
`The vector of claim 1, wherein the functional globin is human β-
`globin.
`The vector of claim 1, wherein the functional globin is a β-globin.
`
`Priority date not
`challenged (6/29/2001)
`6/29/2001
`
`“In order to satisfy the written description requirement, the disclosure as originally
`filed does not have to provide in haec verba support for the claimed subject matter at
`issue.” Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1323 (Fed. Cir. 2000).
`
`Instead, “the test for sufficiency is whether the disclosure of the specification relied
`upon reasonably conveys to a POSA that the inventors had possession of the claimed
`subject matter as of the filing date.” Ariad Pharms. Inc. v. Eli Lilly & Co., 598 F.3d 1336,
`1351 (Fed. Cir. 2010).
`
`See e.g. Paper 27 at 24-29.
`
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`5
`
`
`
`Claim 19 Should Be Afforded The Same Priority Date As Claim 10
`
`Claim Claim Element
`
`Priority date
`
`10
`
`19
`
`The vector of claim 1, wherein the functional globin is human β-
`globin.
`The vector of claim 1, wherein the functional globin is a β-globin.
`
`Priority date not
`challenged (6/29/2001)
`6/29/2001
`
`•
`
`• “β-globin” has in haec verba support throughout the Provisional Applications
`•
`This would convey to the POSA that the inventors were in possession of vector system that could be
`used with not just human β-globin, but other β-globin, such as mutant β-globins.
`• By the time of the Provisional Applications, globin genes were among the most studied genes in
`history and the POSA knew of hundreds of different mutant human β-globins.
`Even the human β-globin disclosed in the Provisional Application is technically a mutant, even though
`its mutation lies in the intron (not in the coding region).
`• Can hardly be disputed that “human β-globin” is a good representative of the family of “β-globin”
`genes.
`• High structural similarity between “human β-globin” and “β-globin,” such as mutant human β-
`globins.
`See e.g. Paper 27 at 24-29.
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`6
`
`
`
`The ’861 Provisional (Filed 6/29/2001) Has Verbatim Support For “β
`Globin” of Claim 19
`
`Ex. 1034 (’861 Provisional, filed 6/29/2001) at 2
`Paper 27 at 24-29
`
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`7
`
`
`
`The ’861 Provisional (Filed 6/29/2001) Has Verbatim Support For “β
`Globin” of Claim 19
`“The stable introduction of a functional β-globin gene in haematopoietic stem cells could be a powerful
`approach to treat β-thalassemia and sickle-cell disease.” (Ex. 1034 (’861 Provisional) at 4)
`
`“Genetic approaches aiming to increase normal β-globin expression in the progeny of autologous
`haematopoietic stem cells might circumvent the risks of allogeneic cell transplants.” (Id.)
`
`“Studies in transgenic mice and deletional analysis support the view that coordinated interaction of
`several genetic elements including the LCR is required for physiologic β-globin gene expression.” (Id.)
`
`“We therefore thought that incorporation of large elements spanning HS2, HS3, and HS4 in a vector
`might enhance β-globin expression beyond the levels previously achieved using arrayed minimal core
`elements, and thus might diminish position effects and vector silencing.” (Id. at 5)
`
`“The combined effect of the high efficiency of gene transfer and the absence of vector rearrangements
`afforded by the recombinant lentivirus carrying the β-globin gene and LCR configuration adopted in
`TNS9 yielded levels of human βA expression in the therapeutic range.” (Id. at 5)
`
`Paper 27 at 24-29
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`8
`
`
`
`The Provisionals Have Verbatim Support For “β Globin”
`
`(Ex. 1034 (’861 Provisional, 6/29/2001), Fig. 1b, page 4; Paper 27 at 26)
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`9
`
`
`
`The Provisionals Have Verbatim Support For “β Globin”
`
`(Ex. 1035 (’852 Provisional, 7/2/2001), Fig. 4, page 10; Paper 27 at 26)
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`10
`
`
`
`Board’s Institution Decision, dated April 24, 2023
`
`“Similarly, the provisionals lack written description support for
`dependent claim 19. Claim 19 recites that “the functional globin is a
`β-globin,” which includes the human β-globin described in the
`provisionals, but also includes other β-globin, e.g., mutant β-globin.
`For the same reasons discussed regarding claim 1, we do not find
`that the provisionals adequately describe the scope of β-globins in a
`manner that would inform a POSA that the inventors possessed all
`recombinant vectors that can express a functional globin that is a β-
`globin from the claimed LCR in a mammal in vivo.”
`
`Institution Decision (Paper 8) at 24 (emphasis added).
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`11
`
`
`
`Board’s Institution Decision, dated April 24, 2023
`
`Paper 8 at 21.
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`12
`
`
`
`Just Because The Provisionals Do Not Recite The Words “Mutant Form of Globin,”
`Does Not Mean That A POSA Would Not Think The Inventors Also Had Possession Of
`Mutant Human β-Globin
`
`By June 2001 (provisional application filing), human β-globin was
`among the most studied human genes in scientific history.
`Ex. 2036 (Riley Declaration) at ¶¶31-35; Paper 27(POR) at 27.
`
`Making point mutations at any position within human β-globin
`gene was routine lab work.
`Ex. 2082 ; Paper 27(POR) at 27-28.
`
`James L. Riley,
`Ph.D.
`
`“By June 2001, there were literally hundreds of reported mutations for the human β-
`globin gene. These did not just observe ‘defective’ genes that resulted in disease, but
`also demonstrated researchers’ efforts to intentionally mutate human β-globin genes
`for improved properties (e.g., higher expression levels) to develop treatment for
`diseases (e.g., sickle cell disease).” Ex. 2036 at ¶¶ 95-96; ; Paper 27(POR) at 28.
`
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`13
`
`
`
`By June 2001, Researchers Were Intentionally Mutating Human β-Globin Genes
`For Purposes Of Treating Diseases Like Sickle Cell Disease
`
`• E22A and Q80K mutations and E22A and T87Q mutations “designed to inhibit
`the polymerization of sickle hemoglobin.” (Ex. 2079 at 9852; Paper 27 (POR) at 28)).
`• E6V and T87Q mutations generated for the inhibition of hemoglobin S
`polymerization by hemoglobin. (Ex. 2080 at 9562; Paper 27 (POR)at 28)).
`• E6V/L88A/K95I mutations generated as an anti-sickling agent. (Ex. 1047 at 25152; Paper
`27 (POR) at 28)).
`• Lys 95 (β) has a very important role in the aggregation process and is a good
`candidate site for the design of a therapeutic agent for sickle cell anemia.” (Ex. 2081
`at 13885; Paper 27 (POR) at 28)).
`
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`14
`
`
`
`Even The Human β-globin Gene In the TNS9 Vector Described In The Provisionals
`Is A Mutant Human β-globin Gene
`
`The IVS2 deletion is a deletion to intron 2
`(constituting deletions of hundreds of base
`pairs of DNA) of the endogenous human
`gene which was found to improve stability
`and expression. Ex. 2036 at ¶ 97, Ex. 2024; Paper 41 at 6-7.
`
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`15
`
`See e.g., Paper 27 at 28-29.
`
`
`
`“β-globin” Of Claim 19 Is Adequately Described In Provisionals
`
`“We held that a sufficient description of a genus instead
`requires the disclosure of either a representative number of
`species falling within the scope of the genus or structural
`features common to the members of the genus so that one of
`skill in the art can ‘visualize or recognize’ the members of the
`genus.” Ariad, 598 F.3d at 1350
`
`Here, human β-globin is representative to β-globin.
`
`As to “mutant human β-globin” genes, the human β-globin
`gene represents that genus.
`
`Even Petitioner states that “β-globin” is “shorthand” for
`“human β-globin.”
`
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`16
`
`See e.g., Paper 41 at 6-7.
`
`
`
`“β-globin” Of Claim 19 Is Adequately Described In Provisionals
`
`“We held that a sufficient description of a genus instead requires the disclosure
`of either a representative number of species falling within the scope of the
`genus or structural features common to the members of the genus so that one
`of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad,
`598 F.3d at 1350
`
`Human β-globin is 147 amino acids long. Ex. 2056
`at ¶ 87.
`
`Single mutation along its length would be more
`than 99% identical to the native protein.
`
`Two mutations would still be more than 98%
`identical.
`
`See e.g., Paper 41 at 5-6.
`
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`17
`
`
`
`“Functional Globin” In Claims 1 and 22
`Is Adequately Described In Provisionals
`Claim Element
`
`Claim
`
`1
`
`22
`
`A recombinant vector comprising a nucleic acid encoding a functional globin operably linked
`to a 3.2-kb nucleotide fragment which consists essentially of three contiguous nucleotide
`fragments obtainable from a human β-globin locus control region (LCR), the three fragments
`being a BstXI and SnaBI HS2-spanning nucleotide fragment of said LCR, a BamHI and HindIII
`HS3-spanning nucleotide fragment of said LCR and a BamHI and BanII HS4-spanning
`nucleotide fragment of said LCR, said vector providing expression of the globin in a mammal in
`vivo.
`The vector of claim 1, wherein the vector is a lentiviral vector.
`• Based on words and figures of the provisional applications
`• Based on what the POSA knew about the invention disclosed in the provisional
`applications
`• Based on Inventor’s unrebutted opinions regarding that they believed they
`possessed as of the provisional applications (Paper 41 at 7)
`
`See e.g., Paper 27 at 30-37.
`
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`18
`
`
`
`“Functional Globin” In Claims 1 and 22 Is
`Supported By The Provisionals
`“This application relates to a vector encoding the human beta-globin gene and
`to the use thereof in treatment of hemoglobinopathies, including β-
`thalassemia and sickle-cell disease.” (Ex. 1035 at 1)
`
`“The vector of the invention is used in therapy for treatment of individuals
`suffering from hemoglobinopathies.” (Ex. 1035 at 3)
`
`“The stable introduction of a functional β-globin gene in haematopoietic stem
`cells could be a powerful approach to treat β-thalassemia1 and sickle-cell
`disease2.” (Ex. 1035 at 5)
`
`“We have shown that recombinant lentiviruses bearing large fragments of
`the human β-globin gene and its LCR represent an advancement towards the
`genetic treatment of severe haemoglobinopathies. Lentiviral vectors appear
`to be well suited for the stable transduction of human CD34+ cells25 and are
`expected to be available for therapeutic applications once safety concerns ar
`fully addressed26. Furthermore, the principles underlying inclusion of
`multiple genetic elements within this vector provide a paradigm for any
`stem cell therapy requiring stable and regulated expression of a tissue-
`specific transgene.” (Ex. 1035 at 7)
`
`See e.g., Paper 27 at 30-37.
`
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`19
`
`
`
`“Hemoglobinopathies” Are Disorders That Result In Mutations To
`Various Globin Genes, Including α, β, ε, or γ
`
`Ex. 1034 (’861 Provisional, filed 6/29/2001), page 3
`It was well known in the art that “hemoglobinopathies” are disorders that result
`from mutations in one or more functional globin genes, which includes, e.g.,
`the alpha, beta, epsilon, or gamma globin genes.
`(Ex. 2056 (Dr. Riley 8/2023 Decl.) at ¶85)
`
`Paper 41 at 9-11; Paper 27, 35-37
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`20
`
`
`
`LCRs Control Expression Of Not Just β-globin But Also ε-globin, γ-
`globin, and δ-globin
`
`Ex. 2058 at 19, Figure 1
`
`Paper 27 at 33.
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`21
`
`Ex. 1035, Figure 1
`
`
`
`Human β-globin LCR Was Essential For High Level Expression of ε-
`globin, γ-globin, and β-globin
`
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`22
`
`Ex. 2011 at 1.
`
`See e.g., Paper 5 at 24.
`
`
`
`As of the Provisionals, POSAs Were Overexpressing γ-globin Using LCR
`Expression Vectors For Treatment Of β-thalassemia and Sickle-Cell Disease
`
`“Ryan et al. tested expression of γ-globin on a 22-kb DNA fragment encompassing the
`human-globin locus control region (LCR) linked to a 9.7-kb DNA fragment containing
`a 4.1 kb β-globin gene and a 5.65 kb γ-globin gene. (Ex. 2076 at 873, 875.) Walsh et
`al. investigated expression of the human γ-globin gene linked to HS2 from the LCR of
`the β-globin gene cluster, which was subcloned into a plasmid (psub201) containing
`AAV inverted terminal repeats. (Ex. 2077 at 7258.) Arcasoy et al. analyzed γ-globin
`expression in expression in six hereditary persistence of fetal hemoglobin (HPFH)
`transgenic lines and demonstrated persistence of γ-globin mRNA and peptides in
`erythrocytes of adult HPFH transgenic mice. (Ex. 2078 at 2076.)”
`
`
`
`
`
`
`
`
`
`
`
`
`Ex. 2056 (Riley Declaration) at ¶93
`
`
`James L. Riley, Ph.D.
`
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`23
`
`See e.g., Paper 27 at 34-35.
`
`
`
`Petitioner’s Expert Dr. Bungert Admitted That You Would Get Expression of
`Gamma Globin In The Claimed Expression System
`
`Jorg Bungert, Ph.D.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Ex. 2055 at 212:8-19
`See Paper 41 at 8.
`
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`24
`
`
`
`“Paradigm for any stem cell therapy requiring stable and regulated
`expression of a tissue-specific transgene”
`
`Ex. 1035., page 6
`
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`25
`
`Paper 27 at 32-33
`
`
`
`Living Inventors All Swore That Other Globin Genes Could Also Be
`Expressed In The Claimed Expression Vector System
`
`…Once you solved two big issues: (1) levels of expression that are high
`enough to be therapeutic and (2) stable transfer of genetic material
`and good efficiency, it would be apparent that you can have this
`design as a recipe for other vectors. Instead of the beta-globin gene,
`you could use an animal globin gene, a fetal globin gene [gamma-
`globin], etc. and reasonably expect expression of that gene.”
`
`
`
`
`
`Ex. 1066 (Sadelain Declaration) and ¶ 30.
`
`Dr. Michel Sadelain
`
`See e.g., Paper 41 at 8-9.
`
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`26
`
`
`
`Living Inventors All Swore That Other Globin Genes Could Also Be
`Expressed In The Claimed Expression Vector System
`
`“Through this process, we were able to create a vector, which we coined the TNS9
`vector, that we believed was capable of being successfully transferred into
`hematopoietic stems cells to achieve therapeutic expression levels of the beta-globin
`gene. While we focused on trying to express the beta-globin gene, we continued to
`discuss the use of our vector design with other globin genes, which included
`discussions of fetal or gamma-globin as well as alpha- and beta-globins. I
`remember talking to Drs. Sadelain and Rivella about the potential of using our vector
`design with other globin genes.”
`
`
`
`
`
`
`
`Ex. 2007 (May Declaration) at ¶ 15.
`
`Dr. Chad May
`
`
`
`“While each of the TNS vectors included the beta-globin gene, we did discuss the use
`of our vector design with other globin genes, i.e., fetal or gamma globin, as well as
`alpha-globins. We understood the potential of using our vector designs with other
`globin genes to address other hemoglobinopathies.”
`
`
`
`
`
`Ex. 2008 (Rivella Declaration) at ¶ 17.
`See e.g., Paper 41 at 8-9.
`
`Dr. Stefano Rivella
`
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`27
`
`
`
`Claim 1 of the ’179 Patent Does Not Require Therapeutic Levels Of
`Expression
`
`Claim
`
`Claim Element
`
`1
`
`10
`19
`22
`
`A recombinant vector comprising a nucleic acid encoding a functional globin
`operably linked to a 3.2-kb nucleotide fragment which consists essentially of
`three contiguous nucleotide fragments obtainable from a human β-globin
`locus control region (LCR), the three fragments being a BstXI and SnaBI HS2-
`spanning nucleotide fragment of said LCR, a BamHI and HindIII HS3-spanning
`nucleotide fragment of said LCR and a BamHI and BanII HS4-spanning
`nucleotide fragment of said LCR, said vector providing expression of the
`globin in a mammal in vivo.
`
`The vector of claim 1, wherein the functional globin is human β-globin.
`The vector of claim 1, wherein the functional globin is a β-globin.
`The vector of claim 1, wherein the vector is a lentiviral vector.
`
`See e.g., Paper 41 at 8.
`
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`28
`
`
`
`“Functional Globin” Was Not Known As A Vast Genus
`
`Paper 8 at 21.
`
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`29
`
`
`
`During Prosecution, PO Overcame A Similar Written Description
`Rejection Over “Functional Globin”
`Under Falkner v. Inglis, 448 F.3d 1357, 1379 (Fed. Cir. 2006):
`
`Ex. 1032 at 247.
`
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`30
`
`
`
`During Prosecution, PO Overcame A Similar Written Description
`Rejection Over “Functional Globin”
`
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`31
`
`See e.g., Ex. 1032 at 247-248
`
`
`
`β And γ Globins Share High Sequence Identity And Regulated By The
`Same LCR
`
`Ex. 2056 (Dr. Riley 8/2023 Decl.) at ¶87; Paper 27, 34
`β And γ Globins
`
`ε (embryonic), γ (fetal), and β (adult) globins are regulated by the same LCR
`
`Ex. 2056 (Dr. Riley 8/2023 Decl.) at ¶32; Ex. 2058 at 19 (Fig. 1); Ex. 2011 at 1; Paper 27 at 33
`
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`32
`
`
`
`POSA Believed That The Significance Of The Provisionals Applied To Hemoglobin
`Disorders, i.e., Functional Globins, Not Just Human β-globin
`
`“This is a significant achievement for the research team lead by
`Michel Sadelain and brings to an end more than a decade of
`frustration regarding a critical step in the development of gene
`therapy for hemoglobin disorders. Hemoglobinopathies are
`relatively common disorders, allowing gene therapy to now be
`proposed for a large number of patients…
`
`….Sadelain hypothesized that the presence of rev would prevent
`splicing of the LCR/globin cassette….
`
`These findings have made gene therapy for thalassemia a realistic
`goal that will be aggressively pursued.”
`
`Bodine (August 2000) (Ex.
`1036 at 128-129)
`
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`33
`
`See e.g., Paper 27 at 63-64.
`
`
`
`
`
`GROUND 1: ANTICIPATION OF CLAIMS 1, 19, AND 22 OVER
`GROUND 1: ANTICIPATION OF CLAIMS 1, 19, AND 22 OVER
`THE MAY THESIS
`THE MAY THESIS
`
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`34
`
`
`
`May Thesis Is Not Prior Art For The Challenged Claims
`
`(Paper 8, 15)
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`35
`
`
`
`
`
`GROUND 2: ANTICIPATION OF CLAIMS 1, 19, AND 22 OVER
`GROUND 2: ANTICIPATION OF CLAIMS 1, 19, AND 22 OVER
`THE NATURE ARTICLE
`THE NATURE ARTICLE
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`36
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`
`
`The Challenged Claims Are Not Anticipated By Or Obvious Over The
`Nature Article
`Disclosure of Nature Article (Ex. 1005) (also referred to as
`the “May Article”
`
`Claim 1 of ’179 Patent
`
`1. A recombinant vector comprising a nucleic acid encoding a functional
`globin operably linked to a 3.2-kb nucleotide fragment which consists
`essentially of three contiguous nucleotide fragments obtainable from a
`human β-globin locus control region (LCR), the three fragments being a
`BstXI and SnaBI HS2-spanning nucleotide fragment of
`said LCR, a BamHI and HindIII HS3-spanning nucleotide
`fragment of said LCR and a BamHI and BanII HS4-
`spanning nucleotide fragment of said LCR, said vector
`providing expression of the globin in a mammal in vivo.
`
`BstXI
`BamHI
`
`BamHI
`
`HS2
`HS3
`
`HS4
`
`SnaBI
`HindIII
`
`BanII
`
`(Paper 27 (POR), 10; Ex. 2056, ¶¶ at 149-151)
`
`“TNS9 was generated by replacing the core HS2
`element of RNS1 with an 840-bp HS2 fragment, the core
`HS3 element with a 1,308-bp HS3 fragment, and the
`core HS4 element with a 1,069-bp HS4 fragment”
`(Ex. 1005 at 3, Figs. 1a and 1b)
`
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`37
`
`
`
`The Nature Article Fails To Disclose All The Claimed Features
`
`BstXI
`BamHI
`
`BamHI
`
`HS2
`HS3
`
`HS4
`
`SnaBI
`HindIII
`
`BanII
`
`(Paper 8 (Institution Decision), 38)
`
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`38
`
`
`
`There Is No Inherency For The Claimed Features
`
`1. Multiple different ways available for constructing
`LCR (e.g., PCR, restriction enzyme cutting, etc.)
`(Paper 8, 40; Ex. 2056, ¶136)
`
`2. Restriction enzyme method cannot provide HS
`fragments with lengths disclosed by the Nature
`Article. (Paper 27 (POR), 40-44; Ex. 2056, ¶145)
`
`3.
`
`Even if the unsupported assumptions of Petitioner’s
`expert Dr. Bungert are applied, there are at least
`hundred of possible HS combination. (Paper 27
`(POR), 46-47; Ex. 2056, ¶168)
`
`BstXI
`BamHI
`
`BamHI
`
`HS2
`HS3
`
`HS4
`
`SnaBI
`HindIII
`
`BanII
`
`(Paper 8, 40)
`
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`39
`
`
`
`
`
`GROUND 3: OBVIOUSNESS OF CLAIMS 1, 19, AND 22 OVER
`GROUND 3: OBVIOUSNESS OF CLAIMS 1, 19, AND 22 OVER
`THE NATURE ARTICLE
`THE NATURE ARTICLE
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`40
`
`
`
`Nature Article Does Not Renders Claims 1, 19, And 22 Obvious
`
`Claim 1 of ’179 Patent
`
`Disclosure of Nature Article (Ex. 1005) (also referred to as
`the “May Article”
`
`1. A recombinant vector comprising a nucleic acid encoding a functional
`globin operably linked to a 3.2-kb nucleotide fragment which consists
`essentially of three contiguous nucleotide fragments obtainable from a
`human β-globin locus control region (LCR), the three fragments being a
`BstXI and SnaBI HS2-spanning nucleotide fragment of said
`LCR, a BamHI and HindIII HS3-spanning nucleotide
`fragment of said LCR and a BamHI and BanII HS4-
`spanning nucleotide fragment of said LCR, said vector
`providing expression of the globin in a mammal in vivo.
`
`BstXI
`BamHI
`
`BamHI
`
`HS2
`HS3
`
`HS4
`
`SnaBI (857 bp)
`HindIII (1295 bp)
`
`BanII (1080 bp)
`
`(Paper 27 (POR) at 10; Ex. 2056, ¶¶ at 149-151)
`
`“TNS9 was generated by replacing the core HS2
`element of RNS1 with an 840-bp HS2 fragment, the core
`HS3 element with a 1,308-bp HS3 fragment, and the
`core HS4 element with a 1,069-bp HS4 fragment”
`(Ex. 1005 at 3, Figs. 1a and 1b)
`
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`41
`
`
`
`From Nature Article To The Claimed Vector
`Multiple different methods
`PCR
`
`Nature Article (840-
`bp HS2, 1308-bp
`HS3, 1069-bp HS4)
`
`Claimed Vector
`
`Paper 27 at 38; Paper 8 at 40; Ex. 2002 at ¶¶ 89, 106-115
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`42
`
`Restriction Enzyme
`
`
`
`PCR – “The Method Of Choice”
`
`James L. Riley, Ph.D.
`
`(Paper 27 (POR) at 41; Ex. 2056 at ¶46)
`
`Dr. Riley: “By virtue of the speed, sensitivity,
`specificity, and inherent simplicity of the
`PCR, it has become the method of choice for
`the above applications in most laboratories.
`(Ex. 2068 at 9-10.)” (Paper 27 (POR), 41; Ex.
`2056, ¶45)
`
`“[PCR] allows the ordinarily skilled artisan to
`include any restriction enzyme recognition
`sequence so that the fragment(s) generated
`by PCR can be easily assembled. (Paper 27
`(POR), 41; Ex. 2056, ¶48)
`
`“Moreover, PCR provides convenient and
`efficient ways to assemble multiple
`segments of DNA.” (Ex. 2056, ¶46)
`
`(Ex. 2068)
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`43
`
`
`
`PCR – “The Method Of Choice”
`
`High fidelity DNA polymerases, such as Vent DNA polymerase,
`less prone to introducing mutations were available. (Paper 41
`(Sur-reply) at 13; Ex. 2056 (Riley decl.), ¶52).
`
`James L. Riley, Ph.D.
`
`“Vent polymerase at least 5-fold greater fidelity than Taq
`polymerase.” (Id.)
`
`Dr. Sadelain: “[I]f we use PCR, we will run sequenc[ing].” (Ex.
`1066 (Sadelain dep. tr.) at 41:3-4; Paper 41 (Sur-reply) at 13).
`
`Dr. Michel Sadelain
`(co-inventor)
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`44
`
`
`
`Dr. Bungert Routinely Uses PCR to Clone LCR And HS Fragments
`
`Dr. Bungert used PCR:
`•
`To clone HS3 and HS4 fragments
`•
`To replace one restrict site (SacI) with another (XbaI)
`
`He also verifies the constructs by sequencing
`(Paper 27 (POR) at 41; Ex. 2052)
`
`(Ex. 2052)
`
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`45
`
`
`
`PCR – “The Method Of Choice”
`
`“Using PCR, a POSA would understand that he/she could obtain a fragment with
`any desired location by using custom-designed forward and reverse primers.
`Thus, for each fragment, hundreds, if not thousands, of different options
`existed. A POSA would also understand that to make all three fragments,
`thousands, if not millions, of different options existed.”
`(Paper 27 (POR) at 43; Ex. 2056 at ¶137)
`
`Restriction site 1
`
`Restriction site 3
`
`Restriction site 5
`
`HS2
`
`HS3
`
`HS4
`
`HS5
`
`Restriction site 2
`
`Restriction site 4
`
`Restriction site 6
`
`James L. Riley,
`Ph.D.
`
`LCR
`
`HS1
`
`Paper 27 at 43
`
`Nature Article
` (840-bp HS2, 1308-bp HS3, 1069-bp HS4)
`
`PCR
`
`Thousands, if not millions, possible
`combinations of 6 restriction sites
`
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`46
`
`
`
`PCR
`
`Nature Article (840-
`bp HS2, 1308-bp
`HS3, 1069-bp HS4)
`
`Claimed Vector
`
`Paper 27 (POR) at 38; Ex. 2002 at ¶¶89, 106-115
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`47
`
`Restriction Enzyme
`
`
`
`Many Problems In Petitioner And Its Expert’s Approach
`
`85 possible HS2
`fragments
`
`81 possible HS3
`fragments
`
`65 possible HS4
`fragments
`
`No HS2 fragment has the length of 840 bp
`
`No HS3 fragment has the length of 1,308 bp
`
`No HS4 fragment has the length of 1,069 bp
`
`Paper 27 (POR) at 40-43; Ex. 1002 (Bungert decl.) at Appendices A-C; Ex. 2055 (Bungert dep. tr.) at 155:4-155:8
`
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`48
`
`
`
`Problem #1: Fail To Consider PCR When The Restriction Enzyme
`Method Is Not Feasible
`
`Teaching away #1:
`
`The restriction enzyme method cannot obtain
`the fragment lengths as disclosed in the Nature
`Article
`(Paper 27 (POR) at 40-43; Paper 41 (Sur-reply) at 12)
`
`Teaching away #2:
`
`Petitioner admits that “a POSA would have a
`lack of other options for HS4 fragment,” when
`BanII is excluded based on Dr. Bungert’s criteria
`for selecting restriction enzymes.
`(Paper 35 (Reply) at 17; Paper 27 (POR) at 45; Paper 41 (Sur-
`reply at 12).
`
`Teaching away #1
`
`Teaching away #2
`
`Paper 27 at 42; Paper 41 at 12
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`49
`
`
`
`Problem #1: Fail To Consider PCR When The Restriction Enzyme
`Method Is Not Feasible
`
`James L. Riley, Ph.D.
`
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`50
`
`Paper 27 (POR) at 41; Ex. 2056 at ¶136
`
`
`
`Problem #1: Fail To Consider PCR When The Restriction Enzyme
`Method Is Not Feasible
`Petitioner’s expert Dr. Bungert did not consider PCR, while he routinely used PCR to
`clone LCR and HS fragments. (Ex. 2055)
`
`(Ex. 2052)
`
`(Ex. 2054)
`
`Dr. Bungert used PCR:
`
`•
`
`•
`
`To clone HS3 and HS4 fragments (Ex.
`2052) or β globin locus (Ex. 2054)
`
`To replace one restrict site (e.g., SacI)
`with another (e.g., XbaI) (Ex. 2052),
`or incorporate new restriction sites
`(e.g., ClaI and XhoI) (Ex. 2054)
`
`(Paper 27 (POR) at 41; Ex. 2052)
`
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`51
`
`
`
`Problem #2: Use Of Unsupported, Hindsight-based ± 20 bp Size
`Variability
`
`± 20 bp Size Variability
`• ± 20 bp Size Variability not disclosed in the Nature Article or any literature, and is a
`deviation from the teaching of the Nature Article (Ex. 1002 at ¶152; Paper 27 (POR) at 43)
`• Just enough to cover the size discrepancies (see table below) (Paper 41 at 14)
`
`Claimed HS fragments of ’179 Patent
`
`HS fragment length disclosed by
`Nature Article (Ex. 1005)
`
`Difference
`
`BstXI
`
`BamHI
`
`BamHI
`
`HS2
`
`HS3
`
`HS4
`
`SnaBI (857 bp)
`
`840-bp HS2 fragment
`
`HindIII (1295 bp)
`
`1,308-bp HS3 fragment
`
`BanII (1080 bp)
`
`1,069-bp HS4 fragment
`
`+17 bp
`
`+13 bp
`
`-11 bp
`
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`52
`
`
`
`Problem #2: Use Of Unsupported, Hindsight-based ± 20 bp Size
`Variability
`• Only considered ± 20 bp
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