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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`____________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`____________
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`BLUEBIRD BIO, INC.,
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`Petitioner,
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`v.
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`SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH,
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`Patent Owner.
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`____________
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`Case No. IPR2023-00070
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`Patent No. 7,541,179
`____________
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`PATENT OWNER’S SUR-REPLY TO PETITIONER’S REPLY
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`Case No. IPR2023-00070
`Patent 7,541,179
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`TABLE OF CONTENTS
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`I.
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`INTRODUCTION ..................................................................................... 1
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`II. CLAIMS 1, 19, AND 20 ARE ENTITLED TO THE PRIORITY
`DATE OF THEIR PROVISIONAL APPLICATION FILING DATE ... 5
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`III. THE NATURE ARTICLE DOES NOT RENDER CLAIMS 1, 19,
`AND 20 OBVIOUS ...................................................................................12
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`(a)
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`(b)
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`(c)
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`(d)
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`Petitioner’s Arguments Should Be Rejected Because a POSA
`Would Not Have Used Restriction Enzymes to Generate the
`Claimed HS Fragments .....................................................................12
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`Petitioner’s Arguments Should Be Rejected Because a POSA
`Would Not Have Used Fig. 1a as a Precision Guide .........................13
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`Petitioner’s Arguments Should Be Rejected Because They Are
`Based on an Impermissible Hindsight-Driven Approach ...................14
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`Petitioner’s Arguments Should Be Rejected Because They Are
`Based on a Flawed Analysis .............................................................17
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`IV. THE MAY ABSTRACT DOES NOT RENDER THE
`CHALLENGED CLAIMS OBVIOUS ....................................................23
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`V.
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`IT IS UNDISPUTED THAT THE OBJECTIVE EVIDENCE
`SUPPORTS NON-OBVIOUSNESS OF THE CLAIMED
`INVENTION .............................................................................................25
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`VI. CONCLUSION .........................................................................................26
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`Patent 7,541,179
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`TABLE OF AUTHORITIES
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` Page(s)
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`Cases
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`Ajinomoto Co. v. Int’l. Trade Comm’n.,
`932 F.3d 1342 (Fed. Cir. 2019) .................................................................... 9, 11
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`Ariad Pharm. Inc. v. Eli Lilly & Co.,
`598 F.3d 1336 (Fed. Cir. 2010) .................................................................. 5, 6, 7
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`Elcommerce.com, Inc. v. SAP AG and SAP America, Inc.,
`745 F. 3d 490 (Fed. Cir. 2014) ......................................................................... 17
`
`Invitrogen Corp. v. Clontech Labs.,
`429 F.3d 1052 (Fed. Cir. 2005) ........................................................................ 17
`
`Medtronic, Inc. v. Teleflex Innovations S.A.R.L.,
`70 F.4th 1331 (Fed. Cir. 2023) ......................................................................... 26
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`ii
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`Case No. IPR2023-00070
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`I.
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`INTRODUCTION
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`San Rocco Therapeutics (“SRT”) provides this sur-reply to Petitioner’s
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`Reply (Paper 35, herein “Reply”) to Patent Owner’s Response to Petition (Paper
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`27, herein “POR”).
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`Petitioner’s Reply makes clear that Petitioner has effectively conceded
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`Grounds 1 and 2 of its Petition, namely, that the May Thesis is not prior art that
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`can anticipate claims 1, 19, and 22 of the ’179 patent (Ground 1), and that the
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`Nature Article does not anticipate these challenged claims (Ground 2). Moreover,
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`Petitioner never raised the Nature Article as a basis for challenging claim 10 of
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`the ’179 patent, leaving only claims 1, 19, and 22 as being challenged by this
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`reference.
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`As to the remaining Ground 3, obviousness of claims 1, 19, and 22 over the
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`Nature Article, SRT maintains that the Nature Article is not prior art over these
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`claims because these claims have an effective filing date of their Provisional
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`Applications (“Provisionals”). Claim 19 is directed to the “β globin gene,” and
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`Petitioner does not dispute that this claim has in haec verba written description
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`support from the Provisionals. (Ex. 1034, 2; Ex. 1035, 2-4). Despite the fact that
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`the Provisionals consistently describe a “β globin gene,” Petitioner’s only reply is
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`that the POSA would recognize that “β globin gene” is merely “shorthand” for
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`“human β globin gene,” which is the subject of claim 10, and which Petitioner
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`concedes has priority and written description support from the Provisionals. But
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`Petitioner cannot have it both ways. If the POSA believed from reviewing the
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`Provisionals that the term “β globin gene” is merely “shorthand” for “human β
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`globin gene,” then that same POSA would also understand that the undisputed
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`working examples of the “human β globin gene” within the claimed expression
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`vector systems also indicated that the inventors were in possession of a vector
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`system that could express a “β globin gene,” including the many β globin gene
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`mutants that were known at the time. Indeed, despite taking the depositions of the
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`inventors of the ’179 patent, Petitioner failed to impeach their sworn declarations
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`submitted in these proceedings, which clearly state that by the filing dates of these
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`Provisionals, these inventors possessed a vector systems system which would
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`express not just β globin gene mutants, but other globin genes as well, such as the γ
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`globin gene, which confirms that claims 1, 19 and 22 also receive priority to their
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`provisional application filing dates, and thus removing the Nature Article as prior
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`art.
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`Even if the Nature Article is considered prior art against claims 1, 19, and
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`22, Petitioner fails to explain how the POSA would have been motivated to arrive
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`at the specific restriction enzyme fragments within the three hypersensitive regions
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`as claimed, when no such information is disclosed in the Nature Article. In fact, it
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`is undisputed that if the POSA used what was publicly known about the sequence
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`information of these hypersensitive regions, the size of these hypersensitive
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`regions disclosed in the Nature papers, and the known restriction enzymes that
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`were publicly available in the literature and commercial catalogs, the POSA would
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`not be able to arrive at any of claimed restriction enzyme fragments of the
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`Challenged Claims. This cannot be emphasized enough. The only way Petitioner
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`and its expert Dr. Bungert could arrive at their 6 choices of hypersensitive region
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`restriction enzyme fragments which allegedly render the Challenged Claims
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`obvious was to actually deviate from the teachings for the Nature Article by
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`assuming that when the Nature Article specifically identified a particular size of
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`these hypersensitive region, such as the “840-bp HS2 fragment,” this really meant
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`840 ± 20 base pairs. On Reply, Petitioner simply fails to account for this arbitrary
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`± 20 bp catch-all, which Petitioner concedes is not disclosed in the Nature Article
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`or anywhere else in the literature as providing a standard deviation for cloning, and
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`which clearly indicates that Petitioner and Dr. Bungert were improperly using
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`hindsight by working backwards from the claim language in order to somehow
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`make the Nature Article fit into the claims. Since restriction enzymes simply would
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`not have generated the claimed fragments (except if one arbitrarily accounted for a
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`± 20 bp difference), this should have foreclosed the POSA from using restriction
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`enzymes and consider other cloning options, such as the use of PCR. However,
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`Petitioner fails to explain why a POSA would not have used PCR—a widely used,
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`routine, and more efficient cloning technique that provides a POSA significant
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`flexibility to clone HS fragments of a desired size or incorporate desired flanking
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`restriction sites.
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`Even if restriction enzymes were used to generate the claimed HS fragments,
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`Petitioner also fails to explain why a POSA would use Fig. 1a as a precision guide
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`to map the restriction sites, when Fig. 1a was shown to contain over 200 bp size
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`discrepancies. In its Opposition, SRT, through its expert, Dr. Riley, demonstrated
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`that even assuming a number of Dr. Bungert’s flawed approaches at arriving at
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`potential restriction enzyme fragments (including the arbitrary ± 20 bp size
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`variability), there would have been many hundreds of possible combinations, and
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`not just the six (6) initially identified by Dr. Bungert. In Reply, Petitioner’s
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`attempts to undermine Dr. Riley’s methodology fail for a number of reasons,
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`foremost being that they are not supported by scientific evidence, but are nothing
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`more than attorney argument that should not be credited. As shown below, Dr.
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`Riley’s conclusions remain intact and unrebutted on the record.
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`Finally, for the same reasons stated above with respect to Ground 3, Ground
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`4, which is based on obviousness in view of the May Abstract, should also be
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`rejected. The May Abstract discloses substantially less information than the
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`Nature Article and even under Dr. Bungert’s best case scenario, the May Abstract
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`would leave the POSA with at least hundreds of different restriction enzyme
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`possibilities, which the Board correctly decided could not support an obviousness
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`claim.
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`For at least the reasons discussed below, the Board should find the
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`Challenged Claims to be patentable over the Grounds alleged in the Petition.
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`II. CLAIMS 1, 19, AND 20 ARE ENTITLED TO THE PRIORITY DATE
`OF THEIR PROVISIONAL APPLICATION FILING DATE
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`Petitioner does not challenge the written description of the issued ’179
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`patent for support of claim 10. However, the only difference between the ’179
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`patent specification and the Provisionals for purposes of describing a “β globin
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`gene” (as opposed to a “human β globin gene”) is that the ’179 patent makes a
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`single statement describing a “mutant form of globin.” (’179 patent, col. 2:45-47
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`(“The functional globin gene…may be a mutant form of globin.”)). That Petitioner
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`argues that the Provisionals do not support a written description of a “β globin
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`gene” simply because the Provisionals do not explicitly describe that this gene can
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`be a “mutant” is both legally and scientifically flawed.
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`Under Ariad, a sufficient written description of a genus can be satisfied by
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`“structural features common to the members of the genus so that one of skill in the
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`art can ‘visualize or recognize’ members of the genus.” Ariad Pharm. Inc. v. Eli
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`Lilly & Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010) (internal citation omitted). It is
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`undisputed that the Provisionals describe a human β globin gene, and this human
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`gene clearly has structural features common to members of a mutant genus. As Dr.
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`Riley explains, human β globin is 147 amino acids long (Ex. 2056, ¶87; POR, 34),
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`and a single mutation along its length would be more than 99% identical to the
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`native protein, and two mutations would still be more than 98% identical. Clearly,
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`the POSA would be able to visualize members of this genus given this structural
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`similarity, and especially in view of the fact that mutations to the human β globin
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`gene were so well studied as of the time of the Provisionals. In Opposition, SRT
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`pointed out the that the human β globin gene described in the Provisionals is itself
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`a mutant because it contains the IVS2 deletion not found in native genes. In Reply,
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`Petitioner does not dispute that the human β globin gene is a mutant, but argues
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`that because the deletion occurs at the intron, the encoded protein would be the
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`same as one that was naturally occurring. But Petitioner misses the point. Mutant
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`human β globin genes were so well studied and published by the time of the
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`Provisionals that even the human β globin gene of the Challenged Claims (as
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`exemplified in the Provisionals) was a mutant, and SRT showed numerous
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`examples of these mutations in its Opposition resulting in mutant human β globin
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`proteins. (POR, 28-29; Ex. 2056, ¶95-96).
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`Moreover, the POSA would also have recognized that the inventors were in
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`possession of an expression vector system that could not just express human β
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`globin, but mutant human β globin as well, which was confirmed by the inventors’
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`declarations and testimony in this case, which remain unrebutted on the record.
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`(Ex. 1051, 145:12-16; POR, 27-29). Given this glaring structural similarity
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`between human β globin and its mutants, it is not surprising that the inventors
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`chose to use the term “β globin” when describing their expression system in the
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`Provisionals no less than 10 times. While Petitioner attempts to casually discount
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`this clear in haec verba support as mere “shorthand” for human β globin, by doing
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`so, Petitioner just underscores how representative human β globin is to the β globin
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`genus. See Ariad, 598 F.3d at 1350 (sufficient written description of a genus can be
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`shown by “a representative number of species falling within the scope of the
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`genus.”).
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`Regarding claims 1 and 22, Petitioner characterizes “functional globin” as a
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`“vast genus” (Reply at 3). But again, the ’179 patent specification defines
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`“functional globin gene” as either mutants or wild-type in the form of three known
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`globin genes, “α-globin, β-globin, or γ-globin.” SRT and Dr. Riley have
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`conclusively shown the similar structural characteristics between β-globin and γ-
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`globin (POR, 33-34; Ex. 2056, ¶¶87-88), which Petitioner does not dispute on
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`Reply. Even Dr. Bungert admitted that he “expected” expression of other globin
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`genes apart from human β-globin. (Ex. 2055, 212:8-19; POR, 36). And while he
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`testified that expression of γ-globin is not necessarily straightforward and might
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`not provide a therapeutic level of expression, the Challenged Claims do not require
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`therapeutic levels of expression but merely require some level of “expression of
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`the globin in vivo.”
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`While the Provisionals clearly describe the invention as providing “a
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`paradigm for any stem cell therapy requiring stable and regulated expression of a
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`tissue-specific transgene,” Petitioner relegates this in its Reply as “no more than a
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`wish” that does not demonstrate possession by the inventors. (Reply at 5).
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`However, the living inventors all submitted declarations in these proceedings
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`clearly indicating that at the time of the Provisionals, they believed that their
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`lentivirus expression system could express globin genes other than human β-
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`globin, and none of their opinions were rebutted by Petitioner at deposition. See
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`Sadelain Decl., ¶30 (“Once you solved two big issues: (1) levels of expression that
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`are high enough to be therapeutic [with human β-globin] and (2) stable transfer of
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`genetic material and good efficiency [with human β-globin], it would be apparent
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`that you can use this design as a recipe for other vectors. Instead of the beta-globin
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`gene, you could use an animal globin gene, a fetal gene [γ-globin] etc., and
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`reasonably expect expression of that gene.”) (See also May Decl., ¶15; Rivella
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`Decl., ¶17).
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`Ajinomoto supports SRT, not Petitioner. There, the Federal Circuit
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`confirmed that a “a patentee may rely on information that is well-known in the art
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`for purposes of meeting the written description requirement, because the
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`specification is viewed from the perspective of one of skill in the relevant art.”
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`Ajinomoto Co. v. Int’l. Trade Comm’n., 932 F.3d 1342, 1359 (Fed. Cir. 2019)
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`(internal quotations omitted). Ajinomoto was one of those circumstances, where the
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`written description for “more potent promoters” was evaluated using both the
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`content of the specification and the knowledge of a POSA. In particular, “the
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`genus of more potent promoters was already well explored in the relevant art by
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`the time of the ’655 patent’s invention” and “the Commission permissibly found in
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`the specification, read in light of the background knowledge in the art, a
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`representative number of species for the genus of more potent promoters.” That is
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`the same circumstance here: the Provisionals disclosed, inter alia, “[t]he vector of
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`the invention is used in therapy for treatment of individuals suffering from
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`hemoglobinopathies,” gave the example of a “β-globin gene,” and expressly did
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`not limit this to a β-globin gene: “the principles underlying inclusion of multiple
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`genetic elements within this vector provide a paradigm for any stem cell therapy
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`requiring stable and regulated expression of a tissue-specific transgene.” It was
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`well known in the art that “hemoglobinopathies” are disorders that result from
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`mutations in one or more functional globin genes, which includes, e.g., the alpha,
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`beta, epsilon, or gamma globin genes, (Ex. 2056 at ¶85) and it was not necessary to
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`convert the Provisionals into remedial training for a POSA with “at least an
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`advanced degree,… several years of post-graduate training… [and] an
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`understanding of vector design and the effect of LCR fragments on gene
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`expression, including experience with how the LCR regulates gene expression.”
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`(Petition, 17). A POSA would have understood that the Provisionals disclosed a
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`vector for any stem cell therapy requiring stable and regulated expression of a
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`tissue-specific transgene, was specifically useful for hemoglobinopathies (i.e.,
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`replacement of defective globin), and therefore would deliver a replacement (i.e.,
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`working) globin gene. Against this backdrop, the “functional globin” makes
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`perfect sense: a working globin. There was no need to list out every possible globin
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`where the field was already well explored in the relevant art. (POR, 32-36). It is
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`not “obviousness” to look to how a POSA would understand those disclosures, as
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`Petitioner suggests. (POR, 21-23). Notably, citation 9 of the Provisionals was a
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`1995 article by named inventor Sadelain discussing “Recombinant Human β-
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`Globin Genes.” (Ex. 1022, 2; cf. Ajinomoto, 932 F.3d 1359-60 (discussing articles,
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`including one cited in the specification, in the written description analysis)).
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`Moreover, the fact that Ajinomoto disclosed examples is inapposite where the
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`Provisionals also contained examples of natural and mutant globin genes (β-globin
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`gene with IVS2 deletion) (Ex. 1035, 5, Fig. 1; POR, 8, 29).
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`Here, the claimed invention is directed to a vector having a particularly
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`novel aspect that involves the three larger contiguous nucleotide fragments from a
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`human β-globin LCR. (POR, 7; Ex. 1001, 2:54-56). Petitioner does not dispute the
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`LCR and the HS2, HS3, and HS4 fragments contained therein are sufficiently
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`described in the Provisionals. (Reply, 2-6). The Provisionals make clear that the
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`application of the novel LCR for expression of a functional globin was
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`contemplated by the inventors for “treatment of individuals suffering from
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`hemoglobinopathies.” (POR, 24-36; Ex. 1005, 6; Ex. 1034, 2). As Dr. Riley
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`explained, “[hemoglobinopathies] is an encompassing term[] [including] alpha,
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`gamma, and beta-globin.” (POR, 33-35; Ex. 1052, 60:13-17). Indeed, the
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`Provisionals state that “the principles underlying inclusion of multiple genetic
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`elements within this vector provide a paradigm for any stem cell therapy requiring
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`stable and regulated expression of a tissue-specific transgene.” (POR, 32-33; Ex.
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`1035, 7).
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`Therefore, the Provisionals meet the written description requirement, and
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`claims 1, 19, and 20 are entitled to the priority date of their provisional application
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`filing date.
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`III. THE NATURE ARTICLE DOES NOT RENDER CLAIMS 1, 19, AND
`20 OBVIOUS
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`(a) Petitioner’s Arguments Should Be Rejected Because a POSA
`Would Not Have Used Restriction Enzymes to Generate the
`Claimed HS Fragments
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`Petitioner does not dispute that even though the entire map of the LCR
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`region was available at that time, a POSA would have recognized that there were
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`no combinations of restriction enzymes that can provide the claimed HS2, HS3,
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`and HS4 LCR fragments with the actual fragment size (i.e., 840 bp for HS2, 1308
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`bp for HS3, and 1069 bp for HS4, respectively) disclosed in the Nature Article.
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`(See, e.g., Ex. 2055, 155:4-155:8). Even assuming a POSA would disregard such
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`clear teaching away and follow Dr. Bungert’s criteria (e.g., excluding frequent
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`cutters such as BanII), Petitioner admits that a POSA would have a “lack of other
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`options for HS4 fragment.” (Reply, 17; POR, 45).
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`With these apparent obstacles, Petitioner refused to consider PCR—a widely
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`used, routine, and more efficient cloning technique that provides a POSA
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`significant flexibility to clone HS fragments of a desired size and/or incorporate
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`desired flanking restriction sites. (Ex. 2056, 32; POR, 42). Petitioner cannot deny
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`that while “PCR is imperfect and can make a mistake,” such mistake is rare when a
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`high-fidelity polymerase is used, and if any, can be ruled out by sequencing. (Ex.
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`2056, ¶142). Indeed, Dr. Sadelain further explained that “if we use PCR, we will
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`run sequenc[ing].” (Ex. 1066, 41:3-4). In fact, Dr. Bungert himself routinely used
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`PCR to clone LCR fragments to study globin genes and many others did so as well.
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`(See, e.g., Ex. 2056, ¶141).
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`Instead, Dr. Bungert, struggling to arrive at the claimed invention, relies on
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`Fig. 1a in the Nature Article as a precision guide and his hindsight-driven
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`approach.
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`(b) Petitioner’s Arguments Should Be Rejected Because a POSA
`Would Not Have Used Fig. 1a as a Precision Guide
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`Dr. Bungert’s reliance on Fig. 1a as a precision guide is misplaced. As Dr.
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`Sadelain explained, Fig. 1a is a cartoon merely to show proportionality between
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`the HS fragments of the RNS1 vector and those of the TNS9 vector. (Ex. 1066,
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`98:24-99:3). In this regard, Petitioner ignores his explanation that “[Fig. 1a] is not
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`intended to be … a road map.” (Ex. 1066, 99:9-10). Consistently, Dr. May stated,
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`“These aren’t data figures. These are illustrations or cartoons. So I wouldn’t say
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`they are a map. A map would be an actual series of the base pairs that you’re
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`looking at.” (Ex. 1053, 51:23-52:1). Dr. Riley also explained that Fig. 1a is only a
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`“cartoon” and “due to the substantial size discrepancies of over 200 bp in Fig. la,
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`a POSA would at best view Fig. la as provid[ing] a … rough guideline” (emphasis
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`added). (Ex. 1052, 143:3-4, 9-13). Petitioner cannot deny that it is not reasonable
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`to use a cartoon as depicted in Fig. 1a that has “substantial size discrepancies of
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`over 200 bp” to identify HS fragments within ± 20 bp – an unsupported, arbitrary
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`size variability set by Dr. Bungert.
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`(c) Petitioner’s Arguments Should Be Rejected Because They Are
`Based on an Impermissible Hindsight-Driven Approach
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`Petitioner’s arbitrary selection of ± 20 bp size variability of the HS
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`fragments disclosed in the Nature Article and inconsistent application of rules for
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`selecting restriction enzymes demonstrate Petitioner’s hindsight driven approach.
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`Because the length of the three HS fragments in the Nature Article are
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`different than the length between restriction sites of the claimed HS fragments,
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`Petitioner arbitrarily awards itself some leeway, ± 20 bp, to the sizes disclosed in
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`the Nature Article—just enough to cover through hindsight the 17 bp size
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`discrepancy of the claimed the HS2 fragment. Of course, a larger size variability
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`would create more possible combinations for the six restriction sites for HS
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`fragments. Conveniently, Dr. Bungert only considers a ± 20 bp size variability
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`while providing no support and no reasonable explanation as to why a POSA
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`would not instead use a ± 21 bp, ± 22 bp, or more size variability. (POR, 43-44;
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`Ex. 2056, ¶157). Petitioner’s reliance on the prosecution history of the ’179 patent
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`to justify the Dr. Bungert’s arbitrary (and hindsight driven) selection of ± 20 bp is
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`unavailing because the file wrapper was not available to a POSA at the time that
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`the claimed invention was made.
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`Petitioner cannot dispute that its own expert provided criteria that a POSA
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`would use to select restriction enzymes and then ignored those criteria when it was
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`convenient. Dr. Bungert stated that “a POSA would exclude those restriction
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`enzymes that: (1) cleave the DNA outside the restriction site as it would lead to
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`unwieldy fragments that are difficult to integrate into a vector; and (2) cleave the
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`LCR too frequently, which would prevent one from generating fragments of
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`sufficient length.” (Ex. 1002 at ¶149, emphasis added.) Dr. Bungert further stated
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`that a POSA would avoid using restriction enzymes that (i) have undefined
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`nucleotides as part of their recognition sequence (including the claimed BstXI)
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`(Reply, 18; POR, 45; Ex. 2055, 54:9-14), or (ii) generate blunt ends (including the
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`claimed SnaBI). (POR, 45; Ex. 2055, 59:11-16).
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`Petitioner and Dr. Bungert then ignore Dr. Bungert’s stated exclusions and
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`preferences in order to select the claimed HS fragments. The claimed HS4
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`fragment recites an enzyme, BanII (a frequent cutter) that, according to Dr.
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`Bungert, a POSA would “exclude.” Petitioner admits that without including BanII,
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`a POSA would “lack [] other options for HS4 fragment.” (Reply, 17; POR, 45; Ex.
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`1002, ¶154). Yet, guided by the ’179 patent, Dr. Bungert conveniently violates his
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`own criteria to include BanII. (POR, 45; Ex. 1002, ¶154).
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`The claimed HS2 fragment uses two enzyme that, according to Dr. Bungert,
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`a POSA would avoid, namely BstXI (recognition sequence with undefined
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`nucleotides) and SnaBI (blunt end cutter). (POR, 45; Ex. 2055, 59:11-16). Further,
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`Petitioner argues that “a POSA would have considered these types of restriction
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`enzymes” (Reply, 18), even though Dr. Bungert fails to consider such enzymes in
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`his analysis, for example, Bpu10I and BlpI in the analysis of HS3. (Ex. 1002,
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`¶153).
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`In an attempt to reduce the hundreds of possible combinations of HS
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`fragments identified by Dr. Riley, Petitioner simply eliminated the possible HS
`
`fragments having restriction sites that have undefined nucleotides as part of their
`
`recognition sequence, cut outside the recognition site, or cut frequently unless such
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`an enzyme is recited in the claims. (Reply, 20-23). Clearly, Dr. Bungert’s arbitrary
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`application of his own criteria to arrive at the claimed invention is hindsight-
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`driven.
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`(d) Petitioner’s Arguments Should Be Rejected Because They Are
`Based on a Flawed Analysis
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`Dr. Bungert’s criteria to exclude restriction enzymes not only was applied
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`arbitrarily as discussed above, but they are also flawed because they are not
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`supported by credible scientific evidence. While SRT and its expert, Dr. Riley,
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`conclusively showed in Opposition that the Nature Article would have presented
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`the POSA with upwards of 560 combinations of restriction enzyme choices,
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`Petitioner attempts to pare down these options without supporting their attorney
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`arguments with a declaration by their scientific expert, Dr. Bungert. As such,
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`Petitioner’s attorney arguments on Reply should not be credited. See Invitrogen
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`Corp. v. Clontech Labs., 429 F.3d 1052, 1068 (Fed. Cir. 2005) (“unsubstantiated
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`attorney argument regarding the meaning of technical evidence is no substitute for
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`competent substantiated expert testimony”; Elcommerce.com, Inc. v. SAP AG and
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`SAP America, Inc., 745 F. 3d 490, 506 (Fed. Cir. 2014) (“Without evidence, [a
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`court cannot] decide whether, for a specific function, the description in the
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`specification is adequate from the viewpoint of a [POSITA] . . . . The burden was
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`on [defendant] to prove its case, and in the absence of evidence provided by
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`technical experts . . . there is a failure of proof. Attorney argument is not
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`evidence.”).
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`Petitioner’s conclusion that after removing fragments from Dr. Riley’s
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`analysis “only 8 combinations” remain is based on Petitioner’s faulty analysis that
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`arbitrarily eliminates commercially available restriction enzymes. (Reply, 18;
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`POR, 45; Ex. 1002, ¶149).
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`Petitioner supports the exclusion of commercially available restriction
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`enzymes that cut outside the restriction site by pointing to Dr. Bungert’s
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`unsupported statement that they “lead to unwieldy fragments that are difficult to
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`integrate into a vector.” (Ex. 1002, ¶149). Dr. Bungert’s explanation, however, for
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`why such fragments would be “unwieldy” simply does not make sense—he
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`explains that by unwieldy he means that “the end of the fragments are better
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`defined when you use enzymes that cut within the recognition site.” (Ex. 2055,
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`57:8-12). But, Dr. Bungert then admits that because the sequence of the LCR was
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`known, the sequence of the generated fragment would, in fact, be defined. (Id.
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`57:13-19; see also id., 50:7-51:3 and 55:4-56:7). Further, Dr. Bungert stated that
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`such fragments would be difficult to integrate into a vector, “unless you blunt
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`them.” (Id. 58:13-16). But, Dr. Bungert admits that it would be routine for a POSA
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`to create a blunt end. (Id. 58:22-59:5). Further, creating a blunt end cannot be
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`problematic, otherwise a POSA would also not use restriction enzymes like SnaBI
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`(recited in claim 1), which always creates a blunt end. Simply put, Dr. Bungert
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`provides no rationale for excluding restriction enzymes that cut outside of their
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`recognition sequences, except his unsupported belief that “a POSA would have
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`preferred enzymes that don’t cut outside the recognition site.” (Id. 65:6-8).
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`Likewise, Dr. Bungert and Petitioner arbitrarily exclude restriction enzymes
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`that cut the HS fragment into multiple pieces (“frequent cutters”), except when the
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`frequent cutter is a claimed restriction enzyme (i.e., BanII for HS4). Dr. Bungert
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`cites to no support for his exclusion of such enzymes, and his only rationale for
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`excluding them is that use of such enzymes would require some additional steps.
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`(Id. 75:18-24). But, Petitioner cannot have it both ways—if the additional steps
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`would have dissuaded a POSA from using frequent cutters, then the POSA would
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`also not have selected a HS4 fragment generated using BanII.
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`Petitioner cites the statement “Dr. Riley strictly followed the same
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`methodology as Dr. Bungert” to suggest that Dr. Riley contradicted himself in his
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`analysis by including more restriction enzymes. (Reply, 18). However, Petitioner
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`ignores the preceding statement “[t]he only difference is that Dr. Riley accounted
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`for additional commercially available restriction enzymes that Dr. Bungert
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`inexplicably ignored.” (POR, 47). Again, for the sole purpose of comparison with
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`Dr. Bungert’s analysis, Dr. Riley “more rigorously applied the criteria asserted by
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`Dr. Bungert” (“(a) with fragment sizes of 840 ± 20 bp for HS2, 1308 ± 20 bp for
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`HS3, and 1069 ± 20 bp for HS4, respectively, and (b) with relative positions
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`closely matching those shown in Fig. 1a of the Nature Article”). (Ex. 2056, ¶¶168-
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`169; POR, 47). In fact, Dr. Riley’s “Restriction Site Map Analysis” lists additional
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`HS fragments (colored in grey) that could have been added to possible
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`combinations of HS fragments, such as the PstI-SpeI HS3 fragment identified by
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`Dr. Bungert. (Ex. 2056, Figs. 17-19; Ex. 1002, ¶153).
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`Petitioners unsupported analysis of the HS fragments identified by Dr. Riley,
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`in addition to eliminating HS fragments by arbitrarily excluding restriction
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`enzymes, also makes numerous errors. For HS2 fragments, Petitioner is incorrect
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`that “SnaBI-SacI is 819-bp.” (Reply, 21). SnaBI cleaves at position 804, and SacI
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`cleaves at position 1631, resulting in a fragment of 828 bp, which is within ± 20 bp
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`size variability as applied
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