Trials@uspto.gov
`571-272-7822
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`Paper 46
`Entered: March 12, 2024
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`BLUEBIRD BIO, INC.,
`Petitioner,
`
`v.
`
`SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH,
`Patent Owner
`____________
`
`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
`____________
`
`Record of Oral Hearing
`Held: January 24, 2024
`____________
`
`
`Before JAMES A. WORTH, SHERIDAN K. SNEDDEN, and CYNTHIA
`M. HARDMAN, Administrative Patent Judges.
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`
`

`

`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
`
`
`APPEARANCES:
`
`ON BEHALF OF THE PETITIONER:
`
`
`MAX YUSEM, ESQUIRE
`Paul Hastings, LLP
`200 Park Avenue
`New York, New York 10166
`(212) 318-6000
`maxyusem@paulhastings.com
`
`
`
`
`ON BEHALF OF THE PATENT OWNER:
`
`
`HOWARD SUH, ESQUIRE
`Fox Rothschild LLP
`101 Park Avenue, 17th Floor
`New York, New York 10178
`(212) 878-7900
`hsuh@foxrothschild.com
`
`
`
`The above-entitled matter came on for hearing on January 24,
`2024, commencing at 9:00 a.m., at the U.S. Patent and Trademark
`Office, 600 Dulany Street, Alexandria, Virginia.
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`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
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`P R O C E E D I N G S
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`- - - - -
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`JUDGE SNEDDEN: Okay. Good morning. This is the consolidated
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`oral hearing in IPR2023-00070 and 00074. I'm Judge Snedden, and with me
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`on the panel today are Judges Worth and Hardman. We'll begin with
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`appearances. So starting with Petitioner, please stand and introduce
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`yourself, and who you have with you today.
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`MR. MODI: Good morning, Your Honors. Naveen Modi from Paul
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`Hastings on behalf of Petitioner Bluebird. With me I have my colleagues
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`Eric Dittmann, Krystina Ho, and Max Yusem. And Mr. Yusem will be
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`presenting the argument for Bluebird today.
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`JUDGE SNEDDEN: Okay. Thank you.
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`MR. YUSEM: And, Your Honors, I have copies of our
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`demonstratives. If I can approach, I provide them if you need them.
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`JUDGE SNEDDEN: Sure. I'll take one.
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`MR. YUSEM: Okay.
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`JUDGE SNEDDEN: Thank you.
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`MR. SUH: Good morning, Your Honors. My name is Howard Suh
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`from the law firm of Fox Rothschild, and we are representing San Rocco
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`Therapeutics on behalf of Patent Owner Sloan Kettering Institute. And with
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`me are my colleagues Dr. Joe Chen and Ms. Wanda French-Brown. We
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`also have, I believe, Dr. Michael Glynn calling in by remote.
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`JUDGE SNEDDEN: We welcome you. Thank you.
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`MR. SUH: Thank you.
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`

`

`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
`
`
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`JUDGE SNEDDEN: We, the judges, do have electronic versions of
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`each of the parties' slides. As you proceed through your presentations today,
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`we ask that -- remind you to refer to the slide number as you move through
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`your arguments today so we can more easily follow along, and also for the
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`benefit of the record.
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`As set forth in our hearing order, each party will have 90 minutes of
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`total time to present its arguments. Patent Owner is granted an additional 15
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`under our LEAP Program. Petitioner will open the hearing with its
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`argument. Patent Owner will have the opportunity to respond. And each
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`party may reserve time for rebuttal. Any questions before we begin?
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`MR. YUSEM: No, Your Honor.
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`JUDGE SNEDDEN: Okay. Very good. Sir, can you repeat your
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`name one more time?
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`MR. YUSEM: Max Yusem, Y-U-S-E-M.
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`JUDGE SNEDDEN: All right. Thank you, Ms. Yusem. When
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`you're ready, you may begin. And would you like to reserve time for
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`rebuttal?
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`MR. YUSEM: Thank you, Your Honor. Yes. If I can reserve 30
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`minutes for rebuttal.
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`JUDGE SNEDDEN: When you're ready.
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`MR. YUSEM: Good morning, Your Honors. May it please the
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`Board. My name is Max Yusem from Paul Hastings, LLP representing
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`Petitioner, Bluebird Bio. The patents at issue here, the 179 and 061 patent
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`relate to work that Memorial Sloan Kettering did in the mid to late 90s
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`regarding a vector that they call TNS9.
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`

`

`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
`
`
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`If we turn to Slide 2, you can see here representative claims from the
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`179 and 061 patents. Claim 1 from both. The named inventors published
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`their TNS9 work in 2000 but waited until mid-2001 to file very limited
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`provisional applications, only a few pages. They then waited another year to
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`file a non-provisional application, that's the 221 application, pursuing
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`broader claims. Publicizing their TNS9 work while seeking a longer patent
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`term resulted in the inventors' own work becoming invalidating prior art.
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`As seen here, the focus of these IPRs, the challenges in these IPRs is
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`the language seen in both Claim 1's functional globin highlighted here on
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`Slide 2. Functional globin lacks priority supports to provisional. The same
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`argument applies to both the 179 and 061 patent. The rest of the claim
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`language identified here, whether the HS2-, HS3-, and HS4-spanning
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`nucleotide fragments that are part of the claimed locus control region, or
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`LCR, whether or not those would have been obvious over the inventor's own
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`prior art is the other central focus of the arguments today.
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`And as I explained earlier, for the purpose of today's arguments, the
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`arguments for both the 179 and 061 patents are the same. As Patent Owner
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`noted, San Rocco Therapeutics or SRT is the one that responded on behalf
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`of the Patent Owner. So at times in our papers and today I might refer to
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`them as SRT. That also is the Patent Owner here.
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`Turning to Slide 3. Petitioner presented various invalidity grounds for
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`these two patents which you can see here on Slide 3, where Ground 3 for the
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`179 patent, and Ground 4 and 5 for the 061 patent are what resulted in the
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`institution of these two IPRs. As you can see for Ground 3, that's based on
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`an obviousness argument based on what we refer to as the May article which
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`is an article that the inventors published in Nature. And the background
`5
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`

`

`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
`
`renders Claims 1, 19, and 22 of the 179 patent obvious. And for the 061
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`patent, that's Ground 4. The May article renders Claims 1, 2, 6, 7, and 11
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`obvious. If you look at Ground 5 of the 061 patent, to the extent that the
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`May article renders those claims obvious, there's no dispute that it would
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`also render Claim 5 obvious in combination with Himanen, a secondary
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`reference.
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`So if time allows today, I'll also address the obviousness argument
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`based on the May abstract. That's an earlier published abstract that resulted
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`later in the publication of the May article. That's the basis of Ground 4 for
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`the 179 patent, which renders Claims 1, 19, and 22 obvious, the same
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`grounds from Ground 3, as well as Claim 10, an additional claim. And then
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`for the 061 patent, the May abstract, as you seen in Ground 6, renders
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`Claims 1, 2, 6, 7, and 8, as well 11 and 15 obvious. There, the additional
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`claims being Claim 15 and Claim 8.
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`Similar to Claim 5 -- sorry, similar to Ground 5, Ground 7, to the
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`extent the May abstract renders those claims obvious, Claim 5 is also
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`obvious in combination with Himanen. There's no dispute on that
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`combination with the secondary reference. And the key to these arguments
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`are -- is had the PTO or the examiner had originally considered either the
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`May Nature article or the May abstract prior art during the original
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`examination to claims that issued in the 179 -- the challenged claims at issue
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`in the 179 and 061 patents would not have issued.
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`Turning now to Slide 4 to take a look at the agenda. I'll address first
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`the lack of written description support in the provisional application, and
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`then I'll discuss the May article invalidity grounds. If time permits, I'll
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`also -- I can also discuss the May abstract and May thesis grounds.
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`

`

`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
`
`
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`Turning to Slide 5, we'll focus first on the lack of written description.
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`And just as a reminder, this is important for Grounds 3 of the 179 patent, and
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`Grounds 4 and 5 of the 061 patent, which make the May article prior art. So
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`let's turn to Slide 6.
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`So for ease today, because the -- so for ease today because the claims
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`are the same and the arguments are the same, I'm going to be referring to the
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`179 patent. If there's any differences, I'll note them. But just for ease of the
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`record and for reference today, I'll focus on the 179 patent. But the
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`arguments apply to both.
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`As you can see here, the claims are directed to what's referred to as a
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`vector with a functional globin and a human beta-globin locus control
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`region, or LCR. Vectors like this that are seen in the claim were known at
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`the time of these patents. Basically, they were known for being able to
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`deliver a gene to express in the human cell. Similar to a letter -- an envelope
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`delivering a letter. The envelope would be the vector, the letter would be the
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`functional globin that's being delivered.
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`And as you can see at the bottom, this image is from the -- is from the
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`patent itself, the 179 patent. But the same image also does appear in the
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`May article. And here is an exemplary image of a vector where you can see
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`on the left-hand side, the globin gene that's referred to and then the locus
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`control region on the right-hand side, which is made up as you can see of the
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`HS2, HS3, and HS4 regions connected there by the promoter which is
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`identified as a P.
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`So turning to Slide 7, what is the priority issue here. The priority
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`issue is focused on the term functional globin that you can see here
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`identified in Claim 1. And the issue is that the term functional globin in the
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`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
`
`claims is not presented anywhere in the provisional applications. It simply is
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`not there. SRT asserts that the genus functional globin actually includes any
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`globin. And what does that mean, right?
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`So we have beta-globin which is the focus of the provisional human
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`beta-globin. But there's also various other globins that existed and were
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`being tested and were known about at the time. This includes alpha-globin,
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`gamma-globin, delta-globin, epsilon-globin, and others. Not all of them are
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`listed here.
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`Not only does this term functional globin cover these other globins,
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`but it also covers mutations of these globins. Any mutation that might fall
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`within the scope of functional globin. Not only does it cover mutations of
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`all these globins, but it also covers non-human globin. Horse, mice, rat, any
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`other mammals are also covered by this term functional globin. So the exact
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`scope of this is not clear, and I'll talk about that in a second. But what we
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`can tell is that the claims that we see here, the functional globin, this scope is
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`clearly not explained or not provided in the provisional applications.
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`JUDGE WORTH: Is it true that you're not disputing the priority of
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`Claim 10?
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`MR. YUSEM: For the purpose of this IPR, that's correct, Your
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`Honor. We don't agree -- there is a parallel district court proceeding here,
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`and in that parallel district court proceeding SRT is taking a broader
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`understanding of Claim 10. So we don't agree with that broader
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`understanding, and we think that broader understanding also subjects it to a
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`lack of priority. However, here in this IPR proceeding, we're not
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`challenging that. But I just wanted to make that clear for the record.
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`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
`
`
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`JUDGE WORTH: And is that because human beta-globin is more
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`characterized?
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`MR. YUSEM: So from our reading, our understanding when we filed
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`these petitions was that the human beta-globin that's mentioned in Claim 10
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`is limited to human beta-globin, which you do see in the provisional
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`application. In the parallel proceeding, SRT is taking the position that
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`human beta-globin actually also includes mutants. If that's true, which we,
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`of course, disagree with, then it would also lack priority for the same reasons
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`that we explained for the other claims. But when we filed these petitions,
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`we were not aware of that reading of Claim 10 that they're taking in the
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`parallel proceeding.
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`JUDGE SNEDDEN: So the provisional actually states functional
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`beta-globin. And Patent Owner, I believe, is making the argument that the
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`beta-globin was well-known, well studied. Mutants were known, it was
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`known how to make the mutants. And so a person of ordinary skill in the art
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`would have understood functional beta-globin as disclosed in the provisional
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`to encompass other forms of the beta-globin, not just human beta-globin.
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`And they also mention that one of the beta-globins used -- or disclosed in the
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`provisional was actually a mutant. Can you respond to those?
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`MR. YUSEM: Yes, Your Honor. So a few points there, and I'll try to
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`take them in order. And if I miss any, please let me know. To the first
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`point, the verbatim disclosure of beta-globin. While the term beta-globin
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`does appear in the provisionals, it's used in a much different context than in
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`the claims.
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`If we take a look at Claim 10 -- the claims that actually use the beta-
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`globin terminology in the claims, those are defined by the specification. The
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`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
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`specification defines functional beta-globin to be much more expansive to
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`include mutants. So when you read the claims in light of the specification,
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`it's clear that that term beta-globin by itself includes mutants.
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`There's other claims like Claim 10 that are limited then to human beta-
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`globin, right, which would exclude these. In the provisional application,
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`however, only human beta-globin is discussed. In the examples they're
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`talking about expressing human beta-globin, and in the title itself it talks
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`about human beta-globin. So when you see the term beta-globin used in
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`other parts of the provisional, it's simply referring to human beta-globin.
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`The person of ordinary skill reading that in context would understand it to be
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`referring to be referring to human. Even though the term beta-globin is used
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`at times.
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`There is no mention of mutants. There is no mention of mutant beta-
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`globin. It's not discussed. Other mutants are not discussed. And, you know,
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`this verbatim argument that they're making, to be clear, only applies to beta-
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`globin. There is no argument that there is a verbatim disclosure of
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`functional globin including animals, for example.
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`There is no argument that animals are being disclosed as part of a
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`provisional. And I'll talk soon about why that's important because of the
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`changes that need to be made and the experimentation that's required to even
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`know whether those are going to work. To be clear, even today, the vector
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`that is claimed in this patent has never been tested with mutants, has never
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`been tested with other animals.
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`To our knowledge we've seen no evidence of that. Whether it has or
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`hasn't, is unknown to us. It's not in the specification. We haven't seen any
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`evidence of it. We don't know whether this vector would work with
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`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
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`mutants. We don’t know whether this vector would work with other globin.
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`We don't know whether this vector would work with other animal globin.
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`JUDGE SNEDDEN: Before you move on from there, the
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`provisional -- and I think at Page 5, you know, of the provisional, I believe
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`this could be essentially the Nature article or the May article just, you know,
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`attached to the back of the specification that was provided with the
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`provisional. But the date in the first sentence of that page, there's a mention
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`of this -- you basically as I read it, the stable introduction of a functional
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`beta-globin gene and hematopoietic cells could be a powerful approach to
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`treat, and I won't mention these diseases. Well, I'll try. Beta Thalassemia
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`and sickle cell disease.
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`Now in that sentence, importantly, they mention functional beta-
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`globin, and it's in a general sense. And I think the question there would be
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`how would a person of ordinary skill in the art understand what functional
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`beta-globin is describing there?
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`MR. YUSEM: Yeah. That's a good question, Your Honor. And let
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`me -- if I can just pull that up to make sure I have it. Yeah. So that's a good
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`question, Your Honor. And as you pointed out, the terminology that's used
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`there is functional beta-globin. To our understanding, I think both experts in
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`this case talked about this in their expert reports. Functional means that it's
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`going to work. It's going to work to deliver a therapeutic level of expression
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`of the gene, right, of the functional gene that's being discussed.
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`Here, as seen in the May Nature article, which is attached, as you
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`mentioned to the provisional, it's talking about beta-globin, right? And it's
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`not clear in that first sentence what type of beta-globin is being discussed.
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`But if you read further into the examples, including in Figure 1, it makes
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`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
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`very clear that what's being encoded is human beta-globin. That's explained
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`in Figure 1A and Figure 1B that even though they use the terminology
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`human -- sorry, they use the terminology beta-globin, human beta-globin is
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`what's being encoded by the vector. And here, the claims are focused on
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`what is encoded, right?
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`So to your point, functional is being discussed there. What we
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`understand the inventors to be saying also, the co-authors here on this
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`article, is that they found a vector that can deliver a human beta-globin gene
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`to a human cell, and it's going to provide a therapeutic level of expression.
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`That's what the claims are talking about as well. That's different from the
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`definition that's provided in the specification itself.
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`If you turn to slide -- if we turn to Slide 10, we can see here, this is the
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`definition of a functional globin that was actually linked to the specification,
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`which defines it differently than you would understand it -- a person of
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`ordinary skill would understand it from reading the May Nature article.
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`Here, it's not only talking about the human beta-globin that's referred to in
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`the May Nature article, but also mutant forms of globin. Other mammalian
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`individuals
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`It's talking about alpha-globin. It's talking about gamma-globin. But
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`it does have the common thread that I talked about which is what it's going
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`to produce -- it's not going to produce a hemoglobinopathy phenotype. And
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`it's going to provide, quote, therapeutic benefits to an individual. That's the
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`functional globin aspect that I think is being referred to in the May Nature
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`article. This other expansion on functional globin to include other animals
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`besides human, mutant forms that provide superior properties, for example
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`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
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`superior oxygen properties, alpha-globin, gamma-globin, those are simply
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`not discussed in the media.
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`JUDGE SNEDDEN: Yeah. I understand. But here we have
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`functional beta-globin, and if we, you know, read that in the context of
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`claim -- I believe it's 19. Yes. Claim 19, which is just specific to beta-
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`globin, I think it -- and I think what's important is how you understand what
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`the language in the provisional states, which is functional beta-globin and
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`how a person of ordinary skill in the art would read that. And I understand
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`how the specification of the patent, how that is described. But really what
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`we need to consider is the meaning a person of ordinary skill in the art
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`would subscribe to beta-globin in the provisional, compare that to Claim 19
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`which has alluded to beta-globin.
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`MR. YUSEM: Right. Yeah. No. So that's a good point, Your
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`Honor. So let me address two things.
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`JUDGE SNEDDEN: 19, sir.
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`MR. YUSEM: Sorry, go ahead.
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`JUDGE SNEDDEN: Claim 19, sir.
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`MR. YUSEM: Yes. Claim 19. Yeah. Why don't we turn to Slide
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`18? So I think this is the term, the patent, the claim that you're referring to,
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`Claim 19 in the 179 and Claim 7 in the 061, Your Honor.
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`JUDGE SNEDDEN: Yes.
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`MR. YUSEM: Yeah. So here, what we're talking about is the
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`functional globin is beta-globin, right? So it’s not even using the same term
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`that's being discussed in the provisional, which is functional beta-globin.
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`That term is actually not discussed by SRT. That has not been sort of
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`defined as part of this argument. What we see here is just the term beta-
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`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
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`globin, right? And what we're talking about here is whether the definition of
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`this term, as defined by the specification, is supported by the earlier
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`provisional application.
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`So one of the things I think you mentioned earlier is the possibility
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`that this TNS9 vector, in and of itself, is mutant. And I'll address that
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`shortly. But what we can tell from all of the information, including from the
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`inventors themselves, is TNS9 encodes a human beta-globin, right? And if
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`we turn to Slide 21, we can see here, the inventors' own publications from
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`2006, 2009, and 2020, all talk about TNS9 encoding the wild type beta-
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`globin or encoding the human beta-globin. This is the same TNS9 that's
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`being discussed in the May Nature article. So while the term functional
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`globin is used, there is no encoding of a mutant globin. That's simply not
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`discussed. That aspect is not discussed. And I'll explain why -- and I can
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`explain why that's important.
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`If we turn to Slide 19, we can see here, Dr. Bungert explained in his
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`declarations, that's the -- Dr. Bungert is the expert for Petitioner, that these
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`mutations that are covered by functional globin, it can include a vast number
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`of potential mutants. The possibilities are almost -- are near endless degree
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`of different potential mutations.
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`And in SRT's expert, Dr. Riley's declaration, he discussed hundreds of
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`reported mutations, right, hundreds of potential mutations that were known.
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`Most importantly about these though, is that the effect of these mutations on
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`the vector itself on expression was not known. Replacing the human beta-
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`globin with a mutated form of the globin to try to encode some sort of
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`mutated globin, the effect of that simply was not known.
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`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
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`And you can see here from Dr. Riley's admission at his deposition,
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`that whether a mutation did or did not fall within the scope of this beta-
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`globin claim would need to be tested because he didn't know whether it
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`would be a mutation or not unless it resulted in a functional globin.
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`And what does that mean? That means that you would actually have
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`to test the vector with the new mutated globin to determine, one, does it
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`produce a hemoglobinopathy, and two, does it provide therapeutic benefit.
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`And this is important, you'll hear -- and SRT might make this argument,
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`which is that the mutations ended up -- the cells are very, very structurally
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`similar to human beta-globin itself. 98 percent, 99 percent similar. But
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`these types of mutations are not about -- that's a very superficial way of
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`looking at it.
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`These types of mutations are not just about the structural similarity.
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`It's about their function. And we can see that very clearly in the diseases
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`themselves. Beta Thalassemia and sickle cell disease, these are diseases that
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`are being tried to treat with this vector. Both of those diseases can result
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`from a single mutation, right? So 99 percent similar to human beta-globin,
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`but one single mutation can result in beta-thalassemia, sickle cell disease.
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`So the percentage of structural similarity between these is simply a
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`superficial way of looking at this.
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`As Dr. Riley admitted at deposition, the only way to know whether a
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`mutant beta-globin is or is not a functional globin within the scope of the
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`claim is to test it. That's really the only -- some of them he said maybe you
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`might be able to tell, but he didn't know all of them. And without being able
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`to recognize or visualize the full scope of the genus, this lacks priority to the
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`provisional application, concluding, because the provisional provides no
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`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
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`information for how to identify that, and doesn't even define functional
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`globin to include mutants, which did not occur until later in the 221
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`application, the non-provisional.
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`JUDGE SNEDDEN: Okay. Thank you.
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`JUDGE WORTH: I think you're going to get there, but I would like
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`to hear about the number of possible combinations and to get to the
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`obviousness claim.
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`MR. YUSEM: Yes. Yes, Your Honor. I can turn to that next.
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`Unless there's any other questions on the broader scope, we've focused
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`primarily so far for the priority argument on the narrower claims that are
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`only to beta-globin. Of course, the broader functional globin claims do not
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`have verbatim support. If there's any questions, I can answer that. But if
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`not, I can move on to the May article.
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`JUDGE HARDMAN: It's Judge Hardman. Just a quick question
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`before you talk about the content of the May article. There is some
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`argument in the briefing or some discussion that the work of the May article
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`is buy another, and I don't see that Petitioner is disputing that. Is that
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`something you're disputing?
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`MR. YUSEM: Petitioner is disputing? No. Sorry. If I understand
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`correctly, that's our argument, and I don't believe that's being disputed by
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`Patent Owner.
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`JUDGE HARDMAN: Right. Okay. I got that backwards. Thank
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`you.
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`MR. YUSEM: Thank you, Your Honor. And I'll move on to the May
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`article in just a moment, I just wanted to cover one last thing on priority
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`before I did that. If you take a look at Slide 12 quickly, there are a multitude
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`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
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`of structural differences between the different globin and the different
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`mutations that both experts recognize. Alpha-globin, for example, different
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`regulator, different locus control region, different expression patterns.
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`And then if we take a look at Slide 12 -- sorry, Slide 13, both Riley
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`specifically admitted that the changes are going to need to be made to this
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`vector, right? So it is trying to express other globin, whether it's other globin
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`or mutated versions of the globin, changes are going to need to be made,
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`whether it's to the coding sequence, the promoter, potentially other elements.
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`He did not know, it was unclear to him. He needed to experiment more.
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`There's two important parts about this I just want to mention before I
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`move on. One, none of these changes are described in the provisional
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`application. All right? So that just doesn't appear. I gave Riley an
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`opportunity in his deposition to find support for that. He was unable to find
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`support during the deposition.
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`And the second part that's important here is that if we take a look at --
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`take a look at Slide 15, this is an argument Dr. Riley made in his
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`obviousness arguments, which is something as small as1 base pair, or even
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`100 base pairs could be the difference between the vector working or not
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`working. The changes that Dr. Riley was talking about to get these vectors
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`to express other globin can result in changes to up to 1,800 base pairs of a
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`vector, much larger than the 1 base pair or 100 base pairs he's talking about.
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`So the unpredictability of making these changes is evident in Dr.
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`Riley's own arguments, and that brings us back to this idea that it's routine to
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`make these changes. It's routine to swap in gamma-globin for beta-globin,
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`or it's routine to make a mutation change as we were discussing earlier. That
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`is really an obviousness argument, and obviousness is simply not enough for
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`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
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`written description support. So whether these changes would have been
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`obvious is not the question. The question is, would the POSA have
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`understood possession of this vast scope when reading the provisional
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`application that just mentions human beta-globin. Unless there's any other
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`questions on the priority argument, I can move on to the May article.
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`JUDGE SNEDDEN: I have none.
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`MR. YUSEM: So let's turn to Slide 23. I'd like to address the -- I'll
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`focus on Dr. Bungert and Dr. Riley's actual analysis of the specific
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`combination, but before I do, just to take a quick look, the May article was
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`published in Nature, which is obviously a leading, peer-reviewed, scientific
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`publication. And as SRT argues in their own papers, within months, you
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`know, in a very short period of time within a month, the scientific
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`community, as well as newspapers, immediately after the publication were
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`recognizing the inventors' significant achievement.
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`Dr. Riley himself during deposition said that the May Nature article
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`represented a major advance and provided outstanding results. So there's
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`really no dispute here that a person of ordinary skill would have had a very
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`good reason to try to reproduce the results of the May Nature article. That
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`shouldn't be any dispute considering the outstanding results, major
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`achievement, significant advancement that SRT themselves are putting
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`forward.
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`And if we take a look at Slide 24, so as you can see here, there's really
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`no dispute about the majority of elements of the claim, recombinant vector,
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`functional globin, 3.2-kb LCR, the HS2-, 3-, and 4-spanning fragments
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`providing expression in vivo. All these elements are met. The only
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`elements that SRT is disputing are the highlighted ones that we see here, the
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`IPR2023-00070 (Patent 7,541,179 B2)
`IPR2023-00074 (Patent 8,058,061 B2)
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`specific restriction enzymes that define the ends of eac