Demonstratives of Petitioner bluebird bio, Inc.
`
`The United States Patent and Trademark Office – Before the Patent Trial and Appeal Board
`
`bluebird bio, Inc., Petitioner / Sloan Kettering Institute for Cancer Research, Patent Owner*
`
`*San Rocco Therapeutics responded on behalf of Patent Owner
`
`IPR2023-00070 (U.S. Patent No. 7,541,179)
`
`IPR2023-00074 (U.S. Patent No. 8,058,061)
`
`Oral Hearing: January 24, 2024
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`1
`
`Page 1 of 68
`
`BLUEBIRD EXHIBIT 1069
`bluebird v. SKI
`IPR2023-00074
`
`
`
`The United States Patent and Trademark Office – Before the Patent Trial and Appeal Board
`
`bluebird bio, Inc., Petitioner / Sloan Kettering Institute for Cancer Research, Patent Owner*
`
`*San Rocco Therapeutics responded on behalf of Patent Owner
`
`IPR2023-00070 (U.S. Patent No. 7,541,179)
`
`IPR2023-00074 (U.S. Patent No. 8,058,061)
`
`Oral Hearing: January 24, 2024
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`1
`
`Page 1 of 68
`
`BLUEBIRD EXHIBIT 1069
`bluebird v. SKI
`IPR2023-00074
`
`
`
`Representative Challenged Claims
`
`’179 Patent
`
`’061 Patent
`
`See, e.g., Ex. 1001 (00070), 11:55-65
`
`See, e.g., Ex. 1001 (00074), 11:56-67
`
`See, e.g., 00070, 00074 Pet. § VI.B
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`2
`
`Page 2 of 68
`
`
`
`Instituted Grounds
`
`’179 Patent
`(IPR2023-00070)
`
`Ground 1
`
`The May Thesis Anticipates Claims 1, 19, and 22
`
`Ground 2
`
`The May Article Anticipates Claims 1, 18, and 22
`
`Ground 3
`
`The May Article Renders Claims 1, 19, and 22 Obvious
`
`Ground 4
`
`The May Abstract Renders Claims 1, 10, 19, and 22 Obvious
`
`Ground 1
`
`The May Thesis Anticipates Claims 1, 2, 6-7, and 11
`
`Ground 2
`
`The May Thesis in View of Himanen Renders Claim 5 Obvious
`
`’061 Patent
`(IPR2023-00074)
`
`Ground 3
`
`The May Article Anticipates Claims 1, 2, 6-7, and 11
`
`Ground 4
`
`The May Article Renders Claims 1, 2, 6-7, and 11 Obvious
`
`Ground 5
`
`The May Article in View of Himanen Renders Claim 5 Obvious
`
`Ground 6
`
`The May Abstract Renders Claims 1, 2, 6-8, 11, and 15 Obvious
`
`Ground 7
`
`The May Abstract in View of Himanen Renders Claim 5 Obvious
`
`See, e.g., 00070, 00074 Pet. § V
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`3
`
`Page 3 of 68
`
`
`
`Agenda
`
` Lack of written description support in the provisional applications
`
` The May Article invalidity grounds
`
` The May Abstract invalidity grounds
`
` The May Thesis invalidity grounds
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`4
`
`Page 4 of 68
`
`
`
`Agenda
`
` Lack of written description support in the provisional applications
`
` The May Article invalidity grounds
`
` The May Abstract invalidity grounds
`
` The May Thesis invalidity grounds
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`5
`
`Page 5 of 68
`
`
`
`Challenged Claims Are Directed to a Vector
`with a Functional Globin and a Human β-globin LCR
`
`’179 Patent
`
`See, e.g., 00070, 00074 Pet. § VI.B
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`6
`
`See, e.g., Ex. 1001 (00070), 11:55-65, Fig. 1
`
`Page 6 of 68
`
`
`
`SRT Asserts That the Claimed Functional Globin Genus Includes “Any” Globin
`
`’179 Patent
`
`Patent Owner Response
`
`See, e.g., Ex. 1001 (00070), 11:55-65
`
`• α (alpha)
`
`• δ (delta)
`
`• Human and other mammals
`
`• β (beta)
`
`• ε (epsilon)
`
`• Mutations
`
`•
`
`γ (gamma)
`
`See, e.g., POR, 33; Ex.1052, 87:15-17
`
`See, e.g., Paper 27 (00070), 4
`
`See, e.g., 00070, 00074, Pet. § VI.C; POR § III.A; Reply § II; Ex. 1001
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`7
`
`Page 7 of 68
`
`
`
`Provisionals Describe Only the Human β-globin Species
`
`’861 Provisional
`filed Jun. 29, 2001
`
`’852 Provisional
`filed Jul. 2, 2001
`
`The term “functional globin” (or equivalent language) does not appear in the provisionals
`
`See, e.g., Ex. 1002 (00070) ¶ 55
`
`See, e.g., 00070, 00074, Pet. § VI.C; Reply § II; Ex. 10002 § VIII; Ex. 1034; Ex. 1035
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`8
`
`See, e.g., Exs. 1034, 1035
`
`Page 8 of 68
`
`
`
`Description of Claimed Functional Globin Genus
`Did Not Appear Until the ’221 Application (Filed July 1, 2002)
`
`’179 Prosecution History
`
`See, e.g., 00070, 00074, Pet. § VI.C, Reply § II; Decision § II.D; Ex. 1032
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`9
`
`See, e.g., Ex. 1032 at 241, 243, 245
`
`Page 9 of 68
`
`
`
`Description of Claimed Functional Globin Genus
`Did Not Appear Until the ’221 Application (Filed July 1, 2002)
`
`Page 3, lines 24-26 of the specification:
`
`This description of the functional globin genus has no counterpart in the provisionals
`See, e.g., Ex. 1002 (00070) ¶ 54
`
`See, e.g., 00070, 00074, Pet. § VI.C, Reply § II; Decision § II.D; Ex. 1032
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`10
`
`See, e.g., Ex. 1032 at 4-5
`
`Page 10 of 68
`
`
`
`SRT’s Expert Did Not Determine the Scope of this Functional Globin Genus
`
`SRT Expert Dr. Riley
`
`Q.
`
`A.
`
`Sitting here today, do you have an estimate of
`how large that genus would be, the number of
`the members of the genus?
`
`Yeah. I -- I would not be able to find an exact
`number on that.
`
`Riley Declaration
`
`See, e.g., Ex. 2056, ¶ 90
`
`SRT Expert Dr. Riley
`
`See, e.g., Ex. 1052, 90:14-18
`
`Q.
`
`So is it your opinion that zeta-globin would also fall within the
`term "functional globin" for this case?
`
`A.
`
`I would say, I don't know.
`
`* * *
`
`See, e.g., Ex. 1052, 88:21-89:6
`
`See, e.g., 00070, 00074, Reply § II; Ex. 2056 § VIII.B; Ex. 1052
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`11
`
`Page 11 of 68
`
`
`
`Both Experts Agreed That There Are Structural Differences Between Globin
`
`Bungert Declaration
`
`See, e.g., Ex. 1002 (00070) ¶ 56;
`see also Ex. 2055, 193:3-25, 209:4-13
`(“you also have sequences in the protein that may interact with
`regulatory elements that could contribute different expression”)
`
`SRT Expert Dr. Riley
`
`Q. Do you know whether or not alpha-globin
`has a different regulator compared to
`beta-globin?
`
`A. Yeah, alpha-globin is in a different
`genomic locus and is -- does have a
`separate control region.
`
`* * *
`
`Q. You agree that alpha-globin is encoded on
`a separate chromosome than beta-globin,
`right?
`
`A.
`
`I said that a few seconds ago.
`
`See, e.g., Ex. 1052, 91:14-19, 92:1-11
`
`See, e.g., 00070, 00074, Pet. § VI.C, Reply § II; Ex. 1002 § VIII; Ex. 1052
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`12
`
`Page 12 of 68
`
`
`
`Changes Required to Potentially Express
`Other Globin Are Not Described in Provisionals
`
`SRT Expert Dr. Riley
`
`SRT Expert Dr. Riley
`
`Q.
`
`You recognize that changes would have to be made to the TNS9
`vector to get it to express a different type of globin, correct?
`
`A. At a minimum, you would certainly have to put in the correct
`coding sequence of the new globin.
`
`Q. And possibly the promoter?
`
`A. And possibly the promoter.
`
`Q. And maybe some other elements in certain situations that are
`undefined?
`
`Q. Or not? I mean, I'm asking your opinion here.
`
`A.
`
`It's unclear.
`
`See, e.g., Ex. 1052, 57:2-18
`
`Q. Okay. And to make sure I understand, these changes that we're
`describing, changing the coding sequence, changing the
`promoter, or these other potential changes that might need to
`be made, those are not described in the provisional application
`in this case?
`
`A.
`
`I would have to review the provisional application to give you an
`answer.
`
`(Whereupon, Exhibit 1034, US Patent Provisional Application 60-
`301861, was identified.)
`
`* * *
`
`I'm not asking if it would be obvious to make the changes. What
`I'm asking is: Is it described in the provisional application?
`
`If you don't know, that's fine.
`
`I will say I don't know then.
`
`Q.
`
`Q.
`
`A.
`
`See, e.g., Ex. 1052, 57:19-58:5, 62:11-17
`
`See, e.g., 00070, 00074, Reply § II; Ex. 2056 § VIII; Ex. 1052
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`13
`
`Page 13 of 68
`
`
`
`The Experts Agreed That a POSA Would Have
`Needed to Experiment to Potentially Express Other Globin
`
`Bluebird Expert Dr. Bungert
`
`SRT Expert Dr. Riley
`
`Q. Would you agree that if you substituted a
`different globin gene in for the ß-globin gene but
`left all of the rest of the sequence including the
`LCR, etc. the same, that you would get
`comparable levels of expression of that gene?
`
`A. No, I would not say so.
`
`* * *
`
`A.
`
`So I think scientifically, right scientifically we
`would have to test it. Scientifically you cannot
`make that prediction.
`
`See, e.g., Ex. 2055, 188:14-21, 202:22-25;
`see also Ex. 2055, 193:3-25, 209:4-13
`
`Q. Would the person of ordinary skill need to make
`other -- any other change apart from changing
`the globin in the vector?
`
`A.
`
`It's hard to know. That's a speculative.
`
`Q. And why is that?
`
`A. Well, you wouldn't know until you did the
`experiment.
`
`See, e.g., Ex. 1052, 49:8-15
`
`See, e.g., 00070, 00074, Reply § II; Ex. 2056 §V III; Ex. 2055; Ex. 1052
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`14
`
`Page 14 of 68
`
`
`
`SRT’s Expert Emphasized the Unpredictability of Making Changes to the Vector
`
`Riley Declaration
`
`See, e.g., Ex. 2056 ¶¶ 89, 153
`
`Changing the promoter and globin coding sequence implicates 1,800 bp of the vector
`
`See, e.g., Ex. 1001 (00070), Fig. 1
`
`See, e.g., Ex. 1022, 2
`
`See, e.g., 00070, 00074, Reply § II; Ex. 2056 § VIII; Ex. 1052; Ex. 1001; Ex. 1022
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`15
`
`Page 15 of 68
`
`
`
`SRT’s Own Evidence Demonstrates the Difficulty of
`Attempting to Express Other Globin with β-Globin Regulatory Elements
`
`McCune
`
`See, e.g., 00070, 00074, Reply § II; POR § III.A; Ex. 2056 § VIII; Ex. 2079
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`16
`
`See, e.g., Ex. 2079, 1
`
`Page 16 of 68
`
`
`
`SRT’s Expert Could Not Comment on Specific Therapies
`
`Bungert Declaration
`
`See, e.g., Ex. 1002 (00070) ¶¶ 56-57
`
`SRT Expert Dr. Riley
`
`Q. Do you agree that a POSA would not have viewed a vector expressing alpha-globin as a therapy for beta thalassemia or
`sickle cell disease?
`
`A. Yeah, I'm not a physician, so I'm hesitant to comment on specific therapies, but I --
`
`Q.
`
`If you don't know, that's fine?
`
`A. Yeah, I don't know.
`
`See, e.g., 00070, 00074, Reply § II; Ex. 1002 § VIII; Ex. 2056 §VIII; Ex. 1052
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`17
`
`See, e.g., Ex. 1052, 92:24-93:9
`
`Page 17 of 68
`
`
`
`Challenged Claims to “β-globin” Also Lack Priority Because
`Provisionals Do Not Describe Mutants or Non-Human β-globin
`
`’179 Patent
`
`’061 Patent
`
`See, e.g., Ex. 1001 (00070), 14:6-7
`
`See, e.g., Ex. 1001 (00074), 12:14-15
`
`Dependent claims cover functional genus of mutant and non-human β-globin
`
`See, e.g., Decision, 24; POR, 28
`
`See, e.g., 00070, 00074, Pet. § VI.C; Reply § II; Ex. 10002 § VIII; Decision § II.D; POR § III.A; Ex. 1001
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`18
`
`Page 18 of 68
`
`
`
`SRT’s Expert Could Not Determine Scope of Claimed “β-globin” Genus
`
`Bungert Declaration
`
`Riley Declaration
`
`See, e.g., Ex. 2056, (00070) ¶ 95
`
`See, e.g., Ex. 1002 (00070) ¶ 58
`
`SRT Expert Dr. Riley
`
`Q. Out of these literally hundreds of reported mutations to the human beta-globin gene, how many fall within the scope of functional
`globin as described in the patent; if you made that determination?
`
`A. Yeah. I would have to know which -- which of the mutations resulted in a functional globin and which ones did not.
`
`See, e.g., Ex. 1052, 104:8-15
`
`See, e.g., 00070, 00074, Pet. § VI.C, Reply § II; Ex. 1002 § VIII; Ex. 2056 § VIII; Ex. 1052
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`19
`
`Page 19 of 68
`
`
`
`Provisionals Describe Only Expression of Human (Not Mutant) β-globin
`
`’852 Provisional
`filed Jul. 2, 2001
`
`* * *
`
`Bungert Declaration
`
`See, e.g., Ex. 1035, 2-3
`
`See, e.g., Ex. 1002 (00070) ¶ 54
`
`See, e.g., 00070, 00074, POR § III.A, Reply § II; Ex. 1002 § VIII; Ex. 1035
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`20
`
`Page 20 of 68
`
`
`
`Inventors’ Publications Confirm TNS9 Encodes Human (Not Mutant) β-globin
`
`Sadelain 2022
`
`Sadelain 2009
`
`Sadelain 2006
`
`See, e.g., Ex. 1056, 71
`TNS9.3.55 and TNS9 encode the same “functional globin” (Ex.1066, 114:14-24)
`
`See, e.g., Ex. 1057, 86, Table 1
`
`See, e.g., Ex. 1058, 144
`
`See, e.g., 00070, 00074, Reply § II; Ex. 1056; Ex. 1057; Ex. 1058
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`21
`
`Page 21 of 68
`
`
`
`Agenda
`
` Lack of written description support in the provisional applications
`
` The May Article invalidity grounds
`
` The May Abstract invalidity grounds
`
` The May Thesis invalidity grounds
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`22
`
`Page 22 of 68
`
`
`
`A POSA Would Have Been Motivated to
`Make the Vector Described in the May Article
`
`May Article
`
`SRT Response
`
`See, e.g., Ex. 1005, 82, Fig. 1(b)
`
`SRT Expert Dr. Riley
`
`See, e.g., Paper 27 (00070), 62-63
`
`Q.
`
`This -- this article, the Exhibit 1005, represents a major advancement towards the genetic treatment of disorders such as hemoglobinopathies.
`Do you agree with that?
`Yes.
`A.
`Q. And do you agree this article, 1 -- Exhibit 1005, describes results that are nothing short of outstanding?
`A.
`I -- I would describe these results as outstanding.
`
`See, e.g., Ex. 1052, 134:5-15, 135:16-136:9
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; POR § III.D; Ex. 1052
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`23
`
`Page 23 of 68
`
`
`
`SRT Disputes Prior Art Disclosure of Only the Restriction Enzyme Limitations
`
`’179 Patent
`
`Claim element
`
`Taught in May Article
`
`Recombinant vector
`
`Functional globin
`
`3.2-kb LCR
`
`HS2, HS3 and HS4
`spanning fragments
`
`See, e.g., Ex. 1001 (00070), 11:55-65
`
`Providing expression in vivo
`
`See, e.g., 00070, 00074 Pet. § VI.B; Ex. 1001
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`24
`
`Page 24 of 68
`
`
`
`A POSA Would Have Used Figure 1a as a
`Guide to Arrive at the Claimed HS Fragments
`
`May Article
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; POR § III.B; Ex. 1002 §§ XI-XII; Ex. 2056 § XII.1; Ex. 1005
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`25
`
`See, e.g., Ex. 1005, 82, Fig. 1(a)
`See also Ex. 1002 (00070) ¶113
`
`Page 25 of 68
`
`
`
`Figure 1a Provided the Proper Proportionality of the HS Fragments
`
`May Article
`
`Inventor Dr. Sadelain
`
`Q. So what is it intended to convey?
`A.
`It shows the proportionality between the fragment in
`RNS1 and the fragment in TNS9.
`Q. The proper what?
`A. Proportionality.
`
`See, e.g., Ex. 1066, 95:13-16, 98:24-99:13
`
`See, e.g., Ex. 1005, 82, Fig. 1(a)
`
`SRT Expert Dr. Riley
`
`Q. Do you agree at best that the Figure 1a could provide a
`rough guideline to a person of ordinary skill to make
`the TNS9 vector?
`A. As a -- sure.
`
`See, e.g., Ex. 2052, 144:6-10
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; POR § III.B; Ex. 1002 §§ XI-XII; Ex. 2056 § XII.1; Ex. 1005
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`26
`
`Page 26 of 68
`
`
`
`A POSA Would Have Been Able to Map
`All Possible Restriction Sites for HS2, HS3, and HS4
`
`’179 Prosecution
`History
`
`Bungert Declaration
`
`See, e.g., Ex. 1032, 302
`
`See, e.g., Ex. 1002 (00070) ¶ 107
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; Ex. 1002 §§ XI-XII; Ex. 1016; Ex. 1019; Ex. 1032
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`27
`
`Page 27 of 68
`
`
`
`Restriction Enzymes Were Well Characterized and Commercially Available
`
`* * *
`
`* * *
`
`* * *
`
`Roberts 1987
`
`See, e.g., 00070, 00074, Pet. § VI.A; Ex. 1002 § V; Ex. 1019
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`28
`
`See, e.g., Ex. 1019, r192-93, r198-99, r207, 22
`
`Page 28 of 68
`
`
`
`A POSA Would Have Been Able to Replicate the Results of the May Article
`
`SRT Expert Dr. Riley
`
`Q. Do you agree or disagree that one of the goals of a scientific article is to provide information such that
`others in the field can reproduce or build on what's described in the paper?
`* * *
`A. Stated that way -- yes, I mean, a goal of publication is to provide a base from which people can move
`the field forward.
`
`See, e.g., Ex. 1052, 140:14-22
`
`Nature Reporting
`Standards
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III.A; Ex. 1052; Ex. 1066; Ex. 1055
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`29
`
`See, e.g., Ex. 1055, 1
`
`Page 29 of 68
`
`
`
`Nature Requires Authors to Identify Conditions for Use of Methods and Materials
`
`Inventor Dr. Sadelain
`
`Q. Do you believe that you complied with the Nature guidelines when submitting your Nature article for
`publication in 2000?
`
`A. Yes, because the -- if I didn't, reviewers or editors would have pointed that out to me.
`
`See, e.g., Ex. 1052, 140:14-22
`
`Nature Guide
`to Authors
`
`See, e.g., Ex. 1054, 7
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III.A; Ex. 1052; Ex. 1066; Ex. 1054
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`30
`
`Page 30 of 68
`
`
`
`SRT’s Expert Confirmed Testing Would Not
`Have Been Needed for a Reasonable Expectation of Success
`
`Q.
`
`Can a person of ordinary skill have a reasonable expectation of expression in
`vivo according to Claim 1 without testing the vector?
`
`SRT Expert Dr. Riley
`
`A.
`
`Yeah. I think a POSA could expect that it would work.
`
`* * *
`
`See, e.g., Ex. 1052, 66:16-22
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; Ex. 1052
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`31
`
`Page 31 of 68
`
`
`
`Dr. Bungert’s Analysis Confirmed That a POSA
`Would Have Been Able to Arrive at the Claimed HS Fragments
`
`Bungert Declaration
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; Ex. 1002 §§ XI-XII
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`32
`
`See, e.g., Ex. 1002 (00070) ¶ 117
`
`Page 32 of 68
`
`
`
`Dr. Bungert’s Analysis Confirmed That a POSA
`Would Have Been Able to Arrive at the Claimed HS Fragments
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; Ex. 1002 §§ XI-XII; Ex. 1050
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`33
`
`See, e.g., Ex. 1050, 1
`
`Page 33 of 68
`
`
`
`Dr. Bungert’s Analysis Confirmed That a POSA
`Would Have Been Able to Arrive at the Claimed HS Fragments
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; Ex. 1002 §§ XI-XII; Ex. 1050
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`34
`
`See, e.g., Ex. 1050, 2
`
`Page 34 of 68
`
`
`
`Dr. Bungert’s Analysis Confirmed That a POSA
`Would Have Been Able to Arrive at the Claimed HS Fragments
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; Ex. 1002 §§ XI-XII; Ex. 1050
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`35
`
`See, e.g., Ex. 1002 (00070) ¶115
`
`Page 35 of 68
`
`
`
`SRT Failed to Establish That the May Article
`Taught Away from Using Restriction Enzymes
`
`SRT Expert Dr. Riley
`
`Q. So it's silent on whether or not the construct was made using PCR or
`restriction enzymes?
`A. I thought that's what I just said but, yes.
`* * *
`Q. Right. So the person of ordinary skill could make it either using PCR or with
`restriction enzymes if they wanted to make it
`A. Sure
`
`See, e.g., Ex. 1052, 78:10-14; 78:20-23
`
`“[M]ere disclosure of alternative designs does not teach away”
`See, e.g., In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004)
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; Decision § II.H.1; Ex. 1052
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`36
`
`Page 36 of 68
`
`
`
`Prior Art Demonstrated Preference for Using
`Restriction Enzymes When Creating Expression Constructs
`
`Sadelain 1995
`
`Ellis 1997
`
`See, e.g., Ex. 1022, 2
`
`See, e.g., Ex. 1022, 3
`
`bluebird Expert Dr. Bungert
`
`A. With respect to this particular situation, a POSA, or a person of ordinary skill in the art, would have looked at this
`publication, would have looked at previous publications and would have assumed that in this particular
`situation restriction enzymes were used.
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; POR § III.B; Ex. 2055; Ex. 1022
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`37
`
`See, e.g., Ex. 2055, 12:18-13:13, 88:20-89:11
`
`Page 37 of 68
`
`
`
`A POSA Would Have Been Discouraged from Using PCR
`
`Inventor Dr. Sadelain
`
`Bluebird Expert Dr. Bungert
`
`A. My recollection is that Stefano, in particular,
`liked PCR, which made me nervous because
`we always have to sequence to make sure
`there's no PCR mistake.
`* * *
`A. Because it's notorious that PCR imperfect
`and can make a mistake.
`
`See, e.g., Ex. 1066, 40:14-17, 41:3-4
`
`A. The advantage of restriction enzymes is that
`you don't introduce mutations. If you use
`PCR there’s a possibility that you introduce
`mutations. Nucleotide changes.
`
`See, e.g., Ex. 2055, 32:24-33:4
`
`SRT Expert Dr. Riley
`
`Q. Okay. And my question is: When it comes to
`Vent DNA polymerase, did that eliminate the
`concern of mutations?
`A. No.
`
`See, e.g., Ex. 1052, 72:1-4
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; POR § III.B; Ex. 2055; Ex. 1066; Ex. 1052; Ex. 2055
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`38
`
`Page 38 of 68
`
`
`
`A POSA Would Have Been Discouraged from Using PCR
`
`Patent Owner Response
`
`See, e.g., Paper 27 (00070), 42, n.4
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; POR § III.B; Decision § H.1; Ex. 1052
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`39
`
`Page 39 of 68
`
`
`
`SRT’s Expert Had No Experience Designing
`LCR Fragments at the Time of the Invention
`
`SRT Expert Dr. Riley
`
`Q. Have you -- as of 2000/2001, have you ever had hands-on experience designing
`LCR fragments for expression constructs?
`
`A. At the time of the invention. Is that what -- could you clarify that?
`
`Q. Yes.
`
`A. No. I had -- had not used, you know, specific LCRs.
`
`See, e.g., Ex. 1052, 30:22-31:4
`
`See, e.g., 00070, 00074, Reply § III.B; Ex. 1002 § I; Ex. 2002 § I; Ex. 2056 § I; Ex. 1052
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`40
`
`Page 40 of 68
`
`
`
`A POSA Would Have Been Aware of Variations in Reported Fragment Lengths
`
`Bungert Declaration
`
`bluebird Expert Dr. Bungert
`
`See, e.g., Ex. 1002 (00070) ¶ 113, n. 6
`
`Q. Right, but didn't do five or ten, right, you did plus or minus 20?
`A. I mentioned before, just to be conservative I just added five extra base pairs because there could be other circumstances where you allow this
`window. So this is how I analyzed these fragments and identified fragments that were similar to the ones drawn to scale by the May, et al. article.
`* * *
`
`Q. So within 20, 15 plus 5 is 20?
`A. Yes, in the May article where we had the positional information and we were able to generate a limited number of fragments based on that
`information.
`
`See, e.g., Ex. 2055, 133:8-14, 136:5-11, 138:20-25, 169:5-13
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; Ex. 1002 §§ XI-XII; Ex. 2055
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`41
`
`Page 41 of 68
`
`
`
`The Named Inventors Recognized Variations of Reported Fragment Lengths
`
`Inventor Dr. May
`
`Inventor Dr. Sadelain
`
`A. You run that on a gel, and you get an approximate size
`of that fragment, not a specific size of that fragment,
`but you know that you're in the ballpark.
`
`Q. So depending on who is reporting the length, you could
`get slight variations?
`A. You could get these tiny, tiny, tiny variations, yes.
`
`See, e.g., Ex. 1053, 56:1-4
`
`See, e.g., Ex. 1066, 95:13-16
`
`Q.
`
`If you asked two researchers in your lab to measure a
`HS2 fragment of the human beta-globin LCR, would you
`expect them to get the exact same lengths, or is it
`possible they would have slightly different lengths even
`though they are looking at the exact same fragment?
`A. Depending on how you measure it, there's that
`potential.
`
`See, e.g., Ex. 1053, 71:8-17
`
`Inventor Dr. Rivella
`
`A. Different labs may have different results. The same lab
`may have the same results or different results in two
`different experiments.
`
`See, e.g., Ex. 1051, 77:8-10
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; Ex. 1051; Ex. 1053; Ex. 1066
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`42
`
`Page 42 of 68
`
`
`
`The Applicant Even Reported Different Lengths
`for the Same HS Fragments (Within +/– 20 bp)
`
`See, e.g., Ex. 1001 (00070), 3:23-26
`
`’179 Patent
`
`’179 Prosecution
`History
`
`HS2 is 17 bp shorter –– HS3 is 13 bp longer –– HS4 is 11 bp shorter
`
`See, e.g., Ex.1032, 309 (citing Ex.1032, 322-23, ¶¶38, 44, and 46)
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; Ex. 1002 §§ XI-XII; Ex. 1001; Ex. 1032
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`43
`
`Page 43 of 68
`
`
`
`Restriction Enzymes That Cleave Outside the Restriction Site
`Lead to Unwieldly Fragments, Which a POSA Would Have Avoided
`
`Roberts
`
`* * *
`
`SRT Expert Dr. Riley
`
`Q. You previously agreed when discussing
`with your counsel that the BsgI restriction
`enzyme cleaves the DNA outside
`the restriction site; is that correct?
`
`A.
`
`I did.
`
`* * *
`
`See, e.g., Ex.1026, 341
`
`Q. Okay. And do you agree that [AclWI]
`restriction enzyme also cleaves the
`DNA outside the restriction site?
`
`A.
`
`I do.
`
`See, e.g., Ex. 1052, 154:25-155:4, 156:1-4
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; Ex. 1002 §§ XI-XII; Ex. 1050; Ex. 1026; Ex. 1052
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`44
`
`Page 44 of 68
`
`
`
`Restriction Enzymes That Cleave Outside the Restriction Site Lead to
`Unwieldly Fragments, Which a POSA Would Have Avoided
`
`Bluebird Expert Dr. Bungert
`
`Bluebird Expert Dr. Bungert
`
`Q. Okay. But you wouldn't have
`excluded them?
`
`Q. And why would they have excluded
`them?
`
`A.
`
`I would -- I cannot recall ever
`having used enzymes that cut
`outside the restriction enzyme site.
`
`See, e.g., Ex. 2055, 53:10-12
`
`A. Because of the undefined
`sequences that you may get into or
`additional sequences that you may
`not want to include.
`
`See, e.g., Ex. 2055, 54:9-14
`
`See, e.g., 00070, 00074, Pet. § X.C; Reply § III; Ex. 1002 §§ XI-XII; Ex. 1050; Ex. 2055
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`45
`
`Page 45 of 68
`
`
`
`Dr. Riley’s Analysis Confirmed That a POSA
`Would Have Been Able to Identify the Claimed HS4 Fragment
`
`Petitioner Reply
`
`See, e.g., Paper 35 (00070), 20
`
`See, e.g., 00070, 00074, Reply § III.E; POR § III.B; Ex. 2056 § XI.A
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`46
`
`Page 46 of 68
`
`
`
`After Removing Omitted Restriction Enzymes, Only 2 HS4 Fragments Remain
`
`Petitioner Reply
`
`BsgI and AclWI cleave outside restriction site, and PstI and BanII are frequent cutters
`
`See, e.g., Paper 35 (00070), 20
`
`See, e.g., 00070, 00074, Reply § III.E; POR § III.B; Ex. 2056 § XI.A
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`47
`
`Page 47 of 68
`
`
`
`Dr. Riley’s Analysis Confirmed That a POSA
`Would Have Been Able to Identify the Claimed HS3 Fragment
`
`Petitioner Reply
`
`See, e.g., Paper 35 (00070), 21
`
`See, e.g., 00070, 00074, Reply § III.E; POR § III.B; Ex. 2056 § XI.A
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`48
`
`Page 48 of 68
`
`
`
`After Removing Omitted Restriction Enzymes, Only 4 HS3 Fragments Remain
`
`Petitioner Reply
`
`Duplicative HindIII-BamHI entry, and BsgI cuts outside the restriction site
`
`See, e.g., Paper 35 (00070), 21
`
`See, e.g., 00070, 00074, Reply § III.E; POR § III.B; Ex. 2056 § XI.A
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`49
`
`Page 49 of 68
`
`
`
`Dr. Riley’s Analysis Confirmed That a POSA
`Would Have Been Able to Identify the Claimed HS2 Fragment
`
`Petitioner Reply
`
`See, e.g., Paper 35 (00070), 23
`
`See, e.g., 00070, 00074, Reply § III.E; POR § III.B; Ex. 2056 § XI.A
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`50
`
`Page 50 of 68
`
`
`
`After Removing Omitted Restriction Enzymes, Only 1 HS2 Fragment Remains
`
`Petitioner Reply
`
`MaeII, TaeI, and SnaBI cut in the same position, EcoICRI and SacI cut in the same position
`
`See, e.g., Paper 35 (00070), 23
`
`See, e.g., 00070, 00074, Reply § III.E; POR § III.B; Ex. 1002 §§ XI-XII
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`51
`
`Page 51 of 68
`
`
`
`Isoschizomers Cut In the Same Location
`
`Roberts
`
`See, e.g., 00070, 00074, PO Sur-reply § III; Ex. 1052; Ex. 1026
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`52
`
`See, e.g., Ex.1026, 8-10
`
`Page 52 of 68
`
`
`
`Agenda
`
` Lack of written description support in the provisional applications
`
` The May Article invalidity grounds
`
` The May Abstract invalidity grounds
`
` The May Thesis invalidity grounds
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`53
`
`Page 53 of 68
`
`
`
`The May Abstract Taught a Lentiviral Vector With
`a β-Globin and 3.2 kb LCR with HS2, HS3, and HS4 Fragments
`
`May Abstract
`
`See, e.g., Ex. 1006, 248
`
`See, e.g., 00070, 00074, Pet. § X.D; Reply § IV; POR § III.C
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`54
`
`Page 54 of 68
`
`
`
`The May Abstract Taught a Lentiviral Vector With
`a β-Globin and 3.2 kb LCR with HS2, HS3, and HS4 Fragments
`
`May Abstract
`
`Inventor Dr. Sadelain
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`But you did disclose that you had used a lentivirus to create your vector?
`
`Correct.
`
`And you did describe in the May abstract that you used human beta-
`globin gene linked to an LCR?
`
`Correct.
`
`And you did describe in the May abstract that the LCR is 3.2 kilobase in
`length?
`
`Correct.
`
`And you did describe in the May abstract that the LCR includes
`hypersensitive sites 2, 3, and 4?
`
`A.
`
`Correct.
`
`See, e.g., 00070, 00074, Pet. § X.D; Reply § IV; POR § III.C
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`55
`
`See, e.g., Ex. 1066, 79:18-80:6
`
`Page 55 of 68
`
`
`
`SRT Disputes Prior Art Disclosure of Only the Restriction Enzyme Limitations
`
`’179 Patent
`
`Claim element
`
`Taught in May Abstract
`
`Recombinant vector
`
`Functional globin
`
`3.2-kb LCR
`
`HS2, HS3 and HS4
`spanning fragment
`
`See, e.g., Ex. 1001 (00070), 11:55-65
`
`Providing expression in vivo
`
`See, e.g., 00070, 00074 Pet. § VI.B
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`56
`
`Page 56 of 68
`
`
`
`SRT Describes the Invention as the Use of a
`Lentiviral Vector, Which the May Abstract Taught
`
`SRT Response
`
`See, e.g., Paper 27 (00070), 32
`
`See, e.g., Paper 27 (00070), 64
`
`See, e.g., 00070, 00074, Pet. § X.D; Reply § IV; POR § III.C
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`57
`
`Page 57 of 68
`
`
`
`Dr. Bungert’s Analysis Confirms the
`Claimed HS Fragments Would Have Been Obvious
`
`Bungert Declaration
`
`Ellis 1997
`
`See, e.g., Ex. 1022, 2
`
`Bouhassira 1997
`
`See, e.g., Ex. 1002 (00070) ¶¶ 150-51
`
`See, e.g., 00070, 00074, Pet. § X.D; Reply § IV; Ex. 1002 § XIII
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`58
`
`See, e.g., Ex. 1023, 2
`
`Page 58 of 68
`
`
`
`Dr. Bungert Shows 13 Possible HS2 Fragments a POSA Would Have Considered
`
`See, e.g., 00070, 00074, Pet. § X.D; Reply § IV; Ex. 1002 § XIII
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`59
`
`See, e.g., Ex. 1002 (00070) ¶154
`
`Page 59 of 68
`
`
`
`Dr. Bungert Shows 11 Possible HS3 Fragments a POSA Would Have Considered
`
`See, e.g., 00070, 00074, Pet. § X.D; Reply § IV; Ex. 1002 § XIII
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`60
`
`See, e.g., Ex. 1002 (00070) ¶154
`
`Page 60 of 68
`
`
`
`Dr. Bungert Shows 11 Possible HS4 Fragments a POSA Would Have Considered
`
`See, e.g., 00070, 00074, Pet. § X.D; Reply § IV; Ex. 1002 § XIII
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`61
`
`See, e.g., Ex. 1002 (00070) ¶154
`
`Page 61 of 68
`
`
`
`SRT Asserts Literal Infringement of Prior Art
`HS Fragments That Do Not Have the Claimed Restriction Sites
`
`SRT’s Infringement Contentions:
`
`Ellis 1997
`
`See, e.g., Ex. 1064, 4
`
`See, e.g., Ex. 1015, 2
`
`“That which infringes, if later, anticipates, if earlier”
`See, e.g., Schering Corp. v. Geneva Pharmaceuticals, 339 F.3d 1373, 1379-80 (Fed. Cir. 2003)
`
`See, e.g., 00070, 00074, Reply § IV; POR § III.C; Ex. 1064
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`62
`
`Page 62 of 68
`
`
`
`The Inventors Could Not Confirm That TNS9
`Was Made Using the Claimed Restriction Enzymes
`
`Inventor Dr. May
`
`Inventor Dr. Rivella
`
`Inventor Dr. Sadelain
`
`A.
`
`Q. Are you aware of any evidence to
`show the claimed restriction
`enzymes were used to create
`TNS9?
`I don't have any recollection of
`how these were put together.
`Q. Were the claimed restriction
`enzymes that we see in Claim 1 of
`your '179 patent used to make the
`LCR fragment of the TNS9 vector?
`* * *
`I don't -- I don't recall.
`
`A.
`
`Q. What I'm asking is: The TNS9 vector
`that's described in your May
`Nature article, sitting here today,
`do you know whether or not that
`was made using the claimed
`restriction enzymes that are
`claimed in your patent?
`I don't remember.
`
`A.
`
`See, e.g., Ex.1051, 122:8-14
`
`Q. The claimed restriction enzymes
`for HS2, do you know whether or
`not those claimed restriction
`enzymes were used to make the
`HS2 fragment of the TNS9 vector?
`A. They likely were, as I said, because
`there's sometimes PCR, sometimes
`this. I don’t remember if -- on the
`day where the first TNS9 was
`constructed at some point in '90s,
`how that was performed.
`
`See, e.g., Ex. 1066, 37:7-15
`
`See, e.g., Ex.1053, 61:3-12
`
`See, e.g., 00070, 00074, Reply § IV; POR § III.C; Ex. 1064
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`63
`
`Page 63 of 68
`
`
`
`Agenda
`
` Lack of written description support in the provisional applications
`
` The May Article invalidity grounds
`
` The May Abstract invalidity grounds
`
` The May Thesis invalidity grounds
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`64
`
`Page 64 of 68
`
`
`
`The May Thesis Anticipates the Challenged Claims
`
`May Thesis
`
`See, e.g., Ex. 1004, 54
`
`See, e.g., Ex. 1004, 40
`
`See, e.g., 00070, 00074, Pet. § X.A; Ex. 1002 § X; Ex. 1004; Ex. 1001
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`65
`
`Page 65 of 68
`
`
`
`It Is Undisputed that the May Thesis Is “by Others”
`
`’179 Petition
`
`See, e.g., Paper 1 (00070), 18, n.7
`
`See, e.g., 00070, 00074, Pet. § X.A; Ex. 1002 § X
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`66
`
`Page 66 of 68
`
`
`
`The May Thesis is dated May 2001
`
`Inventor Dr. May
`
`Inventor Dr. Sadelain
`
`Q. Okay. And you stated before you defended
`your thesis in January of 2001?
`
`Q. Chad May went on to publish his thesis after the
`defense; is that common practice?
`
`A. Yes.
`
`* * *
`
`Q. You submitted your thesis for publication
`prior to your graduation in May 2001?
`
`A.
`
`I believe so.
`
`See, e.g., Ex. 1053, 40:23-25, 42:7-9
`
`A.
`
`It is the practice, after the defense, the thesis
`needs to be approved which takes a certain
`amount of time, variable, weeks to months.
`Then it is forwarded to the University, which in
`this case is Cornell. They have some processing
`to do. And at some point it is forwarded, I
`believe, to the National Lib
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
