Paper No. 61
`Trials@uspto.gov
`571-272-7822 Entered: March 3, 2023
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`____________
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`STRECK, INC.,
`Petitioner,
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`v.
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`RAVGEN, INC.,
`Patent Owner.
`____________
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`IPR2021-01577
`Patent 7,332,277 B2
`____________
`
`Record of Oral Hearing
`Held: January 24, 2023
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`____________
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`Before ZHENYU YANG, TIMOTHY G. MAJORS, and DAVID COTTA,
`Administrative Patent Judges.
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`Trials@uspto.gov
`571-272-7822 Entered: March 3, 2023
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
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`
`STRECK, INC.,
`Petitioner,
`
`v.
`
`RAVGEN, INC.,
`Patent Owner.
`____________
`
`IPR2021-01577
`Patent 7,332,277 B2
`____________
`
`Record of Oral Hearing
`Held: January 24, 2023
`
`____________
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`
`
`Before ZHENYU YANG, TIMOTHY G. MAJORS, and DAVID COTTA,
`Administrative Patent Judges.
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`IPR2021-01577
`Patent 7,332,277 B2
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`APPEARANCES:
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`ON BEHALF OF PETITIONER:
`
`
`SANDIP PATEL, ESQUIRE
`THOMAS BURNS, ESQUIRE
`THOMAS DUSTON, ESQUIRE
`Marshall, Gerstein & Borun, LLP
`233 South Wacker Drive
`Suite 6300
`Chicago, IL 60606
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`
`
`
`
`ON BEHALF OF PATENT OWNER:
`
`
`BRIAN MATTY, ESQUIRE
`GABRIELLE HIGGINS, ESQUIRE
`Desmarais LLP
`230 Park Avenue
`26th floor
`New York, NY 10169
`
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`The above-entitled matter came on for hearing 10:00 a.m., EDT on
`Tuesday, January 34, 2023, by video, before Chris Hofer, Notary Public.
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`IPR2021-01577
`Patent 7,332,277 B2
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`P R O C E E D I N G S
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`JUDGE MAJORS: All right. Good morning, everyone. This is
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`Judge Majors and here with me as part of the panel are Judges Yang and
`Cotta. This is the final oral hearing in IPR 2021-01577. Petitioner in this
`case is Streck, Inc. and the Patent Owner is Ravgen, Inc.
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`We have our court reporter present and we will issue a transcript for
`this case in due course after the transcript is ready. Counsel for Petitioner,
`would you identify who is present today on behalf of your client and who
`will be presenting?
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`MR. DUSTON: Certainly, Your Honor. This is Thomas Duston on
`behalf of Petitioner Streck with me as my colleague, Thomas Burns. Each
`of us will be presenting today.
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`JUDGE MAJORS: Okay. Welcome, Mr. Duston and Burns.
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`MR. DUSTON: Oh, I should -- Judge, I should also mention and in
`the room here with us is Sandip Patel who is listed as lead counsel on the
`petition as well.
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`JUDGE MAJORS: Okay. That's fine. Welcome, Mr. Patel.
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`For Patent Owner, counsel please identify yourself.
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`MR. MATTY: Good morning, Your Honor. Brian Matty,
`representing Patent Owner, Ravgen and appearing with me on video is my
`colleague, Gabby Higgins and listening in on the public line from Ravgen
`and our Dr. Ravinder Dhallan, who is the inventor on the patent we're going
`to discuss today and also John Varney from Ravgen.
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`And we'll also be splitting our argument today. So I will address
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`IPR2021-01577
`Patent 7,332,277 B2
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`Petitioner's Ground 1 which involves the Pertl and Granger references, and
`then Ms. Higgins will address secondary considerations of nonobviousness,
`Grounds that involve the Chiu and Lee references and also claim
`construction.
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`JUDGE MAJORS: Welcome to you all.
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`MR. HIGGINS: Can you hear me okay?
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`JUDGE MAJORS: Is this Ms. Higgins?
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`MR. MATTY: Yes.
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`MR. HIGGINS: Yes. Yes, Judge Majors.
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`JUDGE MAJORS: I can hear you fine. Thank you.
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`MR. HIGGINS: Thank you.
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`JUDGE MAJORS: I was going to say this at the end, but just for
`everyone's benefit, please, when you are not presenting, please make sure
`that your line is muted and this includes the judges unless we're going to ask
`a question. It just keeps the transcript cleaner and avoids the background
`noise.
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`Before we get going today for the parties, any questions or issues that
`we need to talk about before we start? Everybody is okay? Technical
`issues, no, so far? Fingers crossed.
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`MR. MATTY: This is Brian Matty for a Patent Owner, Your Honor.
`We're okay here.
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`JUDGE MAJORS: Okay? All right. Well, on behalf of the Board
`and the panel, we thank everyone for participating today, especially doing it
`via video. With any of these video hearings, we do advise the parties that if
`at any time during the course of today's proceeding, that you feel that there's
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`a technical issue that arises that prevents you from adequately representing
`your client's interests, please speak up. And if you can't do that, please
`phone enter the PTAB team member who helped you access the meeting
`today and we'll see if we can make an accommodation should something
`arise.
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`We understand, Petitioner, that you have filed motions to strike and a
`motion to exclude. It's unlikely that we're going to rule on those motions
`today. You are, however, welcome to argue that, those motions, during your
`presentation, if you choose.
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`So that all being said, as we set forth in our oral hearing order, each
`side has 60 minutes to present its case. I will try and do my best to keep
`track of time, but I would suggest that the parties try to do that as well. I
`also will generally try to give you a heads up if it's, you know, five or so
`minutes before your time is up.
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`Petitioner, you're going to be --
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`MR. DUSTON: Judge Majors, I apologize. For some reason, my
`video has frozen. I may need to log back on.
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`JUDGE MAJORS: Okay. It this Mr. Duston.
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`MR. DUSTON: It is, Your Honor.
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`JUDGE MAJORS: Okay. We'll take a brief moment. See if you can
`log out and log back in.
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`MR. DUSTON: Okay. Thank you, Your Honor. And one other
`thing. Your Honor, we were not connected for the last few minutes, so I'm
`not sure if there's anything that we need to address, but it sounds like you
`were doing the preliminaries.
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`JUDGE MAJORS: Yeah. I'll circle back very quickly. I don't think
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`there was anything that you missed that was that significant.
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`JUDGE MAJORS: I can see you, Mr. Duston. So can you hear me?
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`MR. DUSTON: Is that speaker off?
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`MR. BURNS: Yeah.
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`MR. DUSTON: Okay. Yes, Your Honor, I apologize. We had a
`little technical glitch here on our end.
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`JUDGE MAJORS: That's okay. That's perfectly fine. It was actually
`a good test case. What I was saying before, I'm not sure exactly when you
`dropped off, but I was emphasizing that if a technical issue comes up and it's
`preventing you from adequately representing your side of the case, please let
`us know either, you know, orally or calling into the number if for some
`reason you drop off completely.
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`We may notice, of course, if somebody drops off, but just want to
`make sure everybody has the opportunity to be heard today. Let's see I think
`that was the most important thing that you may have missed out on. As far
`as presenting your case, Petitioner you're going to go first as you have the
`burden. You have 60 minutes. Would you like to reserve any time for
`rebuttal?
`
`MR. DUSTON: We would, Your Honor. We'd like to reserve the full
`fifteen that the order allows. If you could give us a heads up at, say, 40
`minutes in just so that we know that we're coming up to that? We'll keep our
`own time too to try and pay attention to it.
`
`JUDGE MAJORS: Okay. Yeah, I'll do my best to give you some
`notice when you're getting close on time.
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`And Patent Owner, would you like to reserve rebuttal time as well?
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`MR. MATTY: Yes, please, Your Honor. Fifteen minutes.
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`JUDGE MAJORS: All right.
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`JUDGE MAJORS: The panel has the entire record, including the
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`demonstratives. So when you're presenting -- this goes for both parties.
`When you're presenting your case, please direct us to the page number of
`your presentation and just give us a second or two to get there, particularly if
`you are jumping around in the presentation.
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`I don't think there's any confidential information in this case. Yeah,
`that's right. Great. All right. As far as objections are concerned, ordinarily
`parties don't object during the other side's presentation and we would
`suggest that both parties observe that unless it's absolutely necessary to jump
`in on some matter.
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`With that all being said, unless there are any questions from the
`parties, Petitioner we’ll open the floor to you and you have you have 45
`minutes. And again, I'll try to let you know when you're getting about five
`minutes close to your rebuttal time.
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`MR. DUSTON: All right. Your Honor, if you give me a few minutes
`just to get the Slides up here and then I'll be ready to roll. Hopefully those
`are visible to people.
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`JUDGE MAJORS: Yes.
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`MR. DUSTON: Okay. All right. So with further ado, good morning,
`Your Honors. Thomas Duston on behalf of Petitioner, we acknowledge that
`the present IPR is one of several that have been argued to this panel,
`however, none of the other petitions have presented the particular
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`IPR2021-01577
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`combination of Pertl and Granger that you'll hear from us today nor has the
`panel heard from the manufacturer of the accused collection tube itself.
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`As the Board has yet to rule on Petitioner's challenges to Patent
`Owner's arguments and evidence, I will be addressing them but Petitioner
`does not waive its objections in doing so.
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`Let's skip to Slide 3. The IPR challenges the claims of the '277 patent,
`whose priority date is March 1, 2002.
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`Slide 4. Three Grounds are presented in the petition. Given the
`limited time, I will initially address Ground 1 and arguments concerning
`secondary factors and Mr. Burns will later address Ground 3 and arguments
`relating to ACD, time permitting. Let's go to Slide 8.
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`Ground 1 relies --
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`JUDGE MAJORS: Mr. Duston, can I interrupt you just for a second?
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`MR. DUSTON: Yes, sir.
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`JUDGE MAJORS: Sorry to do this so quickly, but I know there's a
`lot of argument in this case surrounding the priority date and in particular
`some of the references related to formaldehyde. My question, though, is
`why should the Board simply presume that these claims are entitled to a
`priority going back to early 2002, the provisional filings?
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`MR. DUSTON: Oh, we're not disputing the priority date, Your
`Honor. We're arguing based upon the March 2002 priority date. I know that
`there have been petitions which have challenged that priority date, but our
`references all antedate that priority date, Your Honor.
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`JUDGE MAJORS: No, understood. I'm simply saying for purposes
`of this proceeding, I don't think either party has attempted to make a
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`showing that these claims are, in fact, entitled to the provisional filing dates
`back in 2002
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`MR. DUSTON: I'm not aware of a particular presentation made by
`Petitioner on that. You're correct, Your Honor. I mean, by --
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`JUDGE MAJORS: Okay.
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`MR. DUSTON: -- Patent Owner rather, I should say.
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`JUDGE MAJORS: And my question, I guess, is simply, when you
`read the Federal Circuit law on this question, especially when you have CIPs
`that are involved in the priority chain, as we do here. I'm thinking of cases
`like Dynamic Drinkware and Power Oasis. Those cases, to my reading,
`seem to say, well, we don't just simply assume that whatever the earliest
`application in the chain is the priority date for claims in a later applied for
`and issued patent.
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`MR. DUSTON: So Your Honor, I think you are correct that the
`Patent Owner has the burden of proving a priority date earlier than the actual
`filing date of its application. It has claimed a priority date of March 2002.
`We've assembled our petition based upon that assertion that they were
`entitled to that priority date and have presented arguments using art that
`predates the March 2002 date.
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`JUDGE MAJORS: Okay. Thank you, Mr. Duston.
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`MR. DUSTON: Now, on Slide 8, Your Honor, Ground 1 is an
`obviousness argument involving the combination of Pertl and Granger,
`which together disclose every element of the claim. Granger discloses an
`agent that inhibits the lysis of cells, while Pertl discloses all the remaining
`limitations of the independent and other dependent claims. Slide 9?
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`In 2000, Pertl reported initial studies concerning non gender specific
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`analysis of cell-free fetal DNA, and Pertl reported varying success with
`samples taken from late term mothers, but cautioned that due to the
`nonselective nature of PCR amplification, maternal background cell-free
`DNA might outcompete less predominant cell-free fetal DNA for
`amplification. Slide 10?
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`This was a particular concern, Your Honors, for testing at more
`clinically relevant stages early in pregnancy when the quantity of cell-free
`fetal DNA was expected to be lower. Slide 11?
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`A year later, Chiu reported that background maternal cell-free DNA
`could be reduced if maternal cell lysis was prevented. Chiu addressed
`concerns that results reported in previously published research on cell-free
`DNA were not comparable due to differences in the reported pre-analytic
`protocols used. Slide 12?
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`From experiments, Chiu concluded that the background maternal cell-
`free DNA about which Pertl was concerned, was the consequence of the
`lysis of maternal cells. Slide 13?
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`Now, Chiu reported that when the effects of maternal cell lysis were
`largely eliminated, the percentage of fetal cell-free DNA could be increased
`to as much as 25 percent. Patent Owner's, expert Dr. Van Ness confirmed
`Chiu's measurements of both the total and fetal cell-free DNA fractions from
`the report that you provided. And here is some testimony on fourteen from
`Dr. Van Ness, confirming that the total CF DNA measured by Chiu was 800
`and that the total fetal DNA, go back to 13, was reported as 100 based upon
`just one half of the fetal chromosomes which, according to Dr. Van Ness,
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`properly should be doubled in order to make this calculation.
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`This was similar in Slide 15 to the calculation that Dr. Dhallan made
`himself in assessing the percentage of fetal DNA in his samples and the
`resulting equation here on Figure -- Slide 16 shows that SRY which is the --
`its measure, one half of the male fetal cell-free DNA and B globin, which is
`a surrogate for all of the cell-free DNA in the sample, maternal and fetal,
`results in a measurement as Chiu reported from his results of 25 percent.
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`Now --
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`JUDGE MAJORS: Mr. Duston, if I could interrupt you again? Chiu
`doesn't actually recite 25 percent recovery in its method, does it?
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`MR. DUSTON: Chiu does not does not do this calculation, which I
`just put up on the screen on Slide 16. You are correct, Your Honor. But the
`but the results that they reported here on Slide 13 are in -- the results that
`Chiu reported on Slide 13 are that in a method which largely illuminated
`maternal cells, the fraction of the sample that was represented by the fetal
`cell-free DNA was roughly 25 percent. And as I said, on Slide 14, Patent
`Owner's own expert agreed with this with this calculation.
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`Now --
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`JUDGE MAJORS: If I could interject again? I just want to probe on
`that just for a moment. It does strike me as a bit odd, however, that if, in
`fact, Chiu had detected the fetal relative to total DNA and in the realm of 25
`percent or even 12.5 percent, if you didn't double it based on what you're
`showing me here, that that would not have been recognized by others in the
`field to say, in effect, "Hey, what Chiu determined in 2001, they got 12.5
`percent or they got 25 percent."
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`Instead, on this record, I think what we see is you see papers from,
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`including Chiu and others, in 2004, 2008, 2012, 2013, that keep coming
`back to this 3 to 6 percent recovery Figure. And maybe that's -- maybe it's a
`statement more than a question to you, but I'm struggling how to reconcile
`this position being advanced here that Chiu discloses 25 percent with what
`those in the arts recognized, first Chiu, because I'm not aware of any
`evidence in the record here where anyone raised their hand and said, "Well,
`hold on a second. We actually got one 12.5 or 25 percent in Chiu in 2001."
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`MR. DUSTON: I understand, Your Honor. Many of -- certain of the
`articles that you referring to did not cite to Chiu, so it's not a surprise that
`they didn't cite Chiu's results. But to the extent that you're referring to, for
`example, later Chiu articles and other articles, let me skip to Slide 18. What
`those articles are talking about is correctly measuring the cell-free fetal DNA
`fraction in a maternal blood sample prior to any efforts made to enhance the
`percentage of cell-free DNA through lysis inhibition.
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`So these statements are a correct statement of what a maternal blood
`sample would contain in the way of cell-free fetal DNA if one did not
`undertake any efforts to eliminate the result or the effects of maternal cell
`lysis and that's all those articles are referring to, Your Honor.
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`The reality is that this calculation by Chiu was in the prior art a year
`after Pertl. Pertl is quoting 3 to 6 percent. A year later, Chiu, in his or her
`experimentation, it reveals that the fetal fraction can be increased
`significantly if you eliminate maternal cell lysis.
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`Now, even the Patent Owner does not dispute that Chiu reports a
`significant increase over what -- the 3 to 6 percent reported by Pertl and Lo
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`earlier. In their surreply, the Patent Owner concedes Chiu's measurements.
`They take issue with whether or not the SRY component should be doubled,
`but even if you didn't double SRY component, even under the amount of
`fetal DNA that the Patent Owner itself concedes Chiu discloses, that that
`disclosure is 12.5 percent, a significant increase over the 3 to 6 percent.
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`These measurement, these measures, to limit or inhibit maternal cell
`lysis were known to increase the cell-free fetal fraction before the date of
`this invention, Your Honor.
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`JUDGE MAJORS: One more point on this and then I'll move on, but
`since you brought it up, I, myself, was curious and looking at the evidence of
`record here Patent Owner submitted, and you may not have it readily
`available, but Exhibit 2271, which is a paper by Chiu, and Lo and others in
`2004.
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`And if you'll get there, if you want to pull it up, looking at page 1 of
`this paper and again, it reports the fetal DNA analysis of roughly 3 to 6
`percent, interestingly in this paper, if you go down to page 2, it appears that
`the materials and methods here that they're actually modeling, I guess what
`I'll proffer, the Chiu method with centrifugation, followed by a micro
`centrifugation and they say cite citation 21, which is the Chiu paper.
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`And yet even in that context, going on now to page 5, they go on and
`they say it because the paternal specific fetal allele exists at roughly 3 to 6
`percent and total maternal (indiscernible), et cetera, et cetera.
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`So again, I hear you loud and clear about what you say Chiu -- can be
`derived from Chiu, but in terms of what others in the field recognize from
`Chiu, it seems to stand in tension with this idea that Chiu you would have
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`recognized somehow, you know, 12.5 or 25 percent recovery from its
`experiment when you have Chiu, him or herself, here three years later saying
`something different.
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`MR. DUSTON: Well, Your Honor, I don't think there's any dispute
`about the disclosures made in the Chiu article in 2001 and what those would
`have taught a person of skill in the art. Disclosures made an article
`subsequent to the invention that, I think what you're suggesting, tried to walk
`back some of those comments in the in the pre-application articles really
`don't have that much relevance.
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`I hear what you're saying about possibly maybe a revision of, or a
`rethinking of the of the data that was in the in the Chiu article, but the fact
`remains the Chiu article was prior art and it disclosed a significant increase
`in the cell-free fetal DNA fraction accomplished by maternal cell lysis
`inhibition and that would have been what a person of skill in the art at the
`time of the invention would have been aware of, not later commentary that
`that continued to repeat. Again, 3 to 6 percent was a measure in the absence
`of these extraordinary efforts to try and reduce maternal cell lysis, Your
`Honor.
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`If I may continue on Slide 20, and if there are further questions, Your
`Honor, I'm happy to answer them, but I wanted to make sure that we have
`enough time to address formaldehyde and some of the other issues that are
`that are presented in the petition and the Patent Owner response.
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`With respect to Slide 20, it was known that the move from research
`facilities which Pertl and Chiu are talking -- well, particularly Chiu is talking
`about to clinical applications would require transporting samples to distance
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`IPR2021-01577
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`labs, introducing processing delays and physical stress for the sample.
`
`Complicated Centrifugation research protocols discussed in Chiu
`required added equipment and trained personnel and were unsuitable for low
`volume points of collection such as doctor's offices and as Slide 21 indicates
`in the Petitioner's expert's declaration, even if Chiu's analytical processes,
`pre-analytical processes were used, cell lysis could be expected to occur
`before centrifugation or, in fact, as a consequence of it.
`
`Now, if we skip to 12, Granger --
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`JUDGE MAJORS: Mr. Duston?
`
`MR. DUSTON: Yes, sir?
`
`JUDGE MAJORS: Let me jump in again. I'll give you a little bit of
`time back, since I've asked a number of questions. Can you clarify for me
`what modifications precisely Petitioner is proposing be made to Pertl? And
`I'll preface that by saying, Pertl doesn't talk about this idea of, at least I don't
`believe, this idea of taking the blood somewhere remote in a doctor's office
`and then you ship it off to a lab where, I guess, the centrifugation and
`processing of the plasma and amplification, and so forth is going to take
`place.
`
`But my question is, so what in terms of the actual modification of the
`art being proposed here, are you simply proposing to take Pertl's method and
`add in the formaldehyde or paraformaldehyde of Granger or are you
`suggesting some other change be made to the Pertl process where you have
`this sort of shipment in a remote collection and shipment of the blood?
`
`MR. DUSTON: So Your Honor, our proposal is that the Granger
`solution for preserving blood samples would be would be employed in the
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`IPR2021-01577
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`Pertl methodology.
`
`My mention of the Chiu centrifugation filtration protocols was really
`just simply to address the Patent Owner's argument that one would have
`adopted those rather cumbersome and costly procedures in in lieu of the
`more simple and straightforward solution that Granger proposed. And what
`I'm saying is that that you don't necessarily have to have either or. Granger
`solution would be it would be a natural adjunct to Pertl would provide for
`the transportation of samples, which is expected in -- once these types of
`analyses reach their clinical application, commercial application.
`
`You're moving blood in, in these circumstances from doctor's offices
`and clinics to central laboratories. You wouldn't use Chiu's procedures at
`the doctor's office. You would do that at the central lab. You would want to
`preserve the sample in transit. Granger provides that. Whether you do
`further processing as Chiu suggests later on, would not prevent you from
`using the solution that Granger proposes to prevent lysis in the interim.
`
`JUDGE MAJORS: Okay. So just for absolute clarity then, but you're
`not proposing that Pertl will be changed such that the blood is collected at
`doctor's office, at point A, it's shipped somewhere else for a clinical lab or
`some lab that's capable of actually doing the centrifugation and further
`processing at some other remote location? This is rather that's just
`something you're suggesting might have been of clinical relevance later on?
`
`MR. DUSTON: Well, no. Your Honor, what I'm saying is that Pertl
`is talking about -- Pertl is conducting research in a laboratory, but it's
`conducting research in a laboratory directed to a potential clinical solution
`down the road. That clinical solution is going to involve the collection of
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`IPR2021-01577
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`blood samples and their transport to laboratories. If lysis were to occur
`during transport, then hurdles, concern about background maternal DNA
`would be would be increased. So Granger prevents that from happening.
`
`Whether -- you know, whether Pertl treats their sample with
`formaldehyde and then goes ahead and does the laboratory analysis that they
`described doing in their own lab, or whether they shipped the sample to a
`central lab, as would be expected to be the case when these when these
`processes are rolled out clinically and commercially, you would be you
`would be benefiting from adding that formaldehyde early in the process to
`prevent lysis from the earliest possible moment.
`
`So what I'm saying is Pertl could use it in the method that Chiu
`describes using for research, but the ultimate goal of Pertl's method is to
`provide something for clinical use and that would certainly be something
`that would involve transportation of a sample, Your Honor.
`
`JUDGE MAJORS: Yeah, and I'll just cut to the chase. I guess the
`reason I'm asking this, and this won't come as a surprise to you, because I'm
`sure you're familiar with the other matters, is in other cases where it was
`suggested that you would collect it at Point A and ship it somewhere else to
`Point B, that raises some other differences and concerns relative to how long
`the sample is going to be exposed to formaldehyde.
`
`And I'm not trying to bring in the records in those other cases, but that
`-- if that is the motivation, I think that does -- for modifying Pertl, I think
`that does raise some other issues and it wasn't clear to me that that was being
`advocated in the papers, apart from, as I think you said initially, this was
`simply pointing out a basis on which a person might not have engaged in the
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`micro centrifugation, et cetera; the research methodology of Chiu.
`
`MR. DUSTON: Well, Your Honor, I don't know of anything in the
`record that relates to the time spent on formaldehyde by a blood sample, not
`in not in this IPR and there's been no argument made to that effect by the
`Patent Owner in this particular IPR. So I don't think any of the parties have
`addressed what Your Honor is noting. I think that there are -- I mean, if
`there are issues with respect to the length of time formaldehyde is in contact
`with a blood sample, those issues can be dealt with pre-shipment. For
`example, some preliminary centrifugation just to create a plasma sample
`could be done without necessarily having to engage in Chiu's much more
`time intensive and complicated centrifugation and micro centrifugation
`process.
`
`Your Honor, I see that I'm now 22 minutes into my time, and I would
`like to have an opportunity to spend a little time on the formaldehyde issues,
`if I could.
`
`JUDGE MAJORS: Yes. Go ahead.
`
`MR. DUSTON: All right. So let's just talk about -- let's skip to Slide
`25. So Granger talks about applying formaldehyde to their sample and to
`your point, Your Honor, this sample was put on formaldehyde for five to
`seven days and then was processed at a central lab and it was stable during
`that time, and cellular integrity was maintained, as Granger reports, for that
`entire length of time despite the presence of formaldehyde in the sample for
`as much as a week's time.
`
`And not only did Granger report that the sample was -- maintained its
`cellular integrity over that period of time, but that, in fact, nucleic acids that
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`IPR2021-01577
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`were in contact or would have been in contact with formaldehyde for that
`length of time remained stable for up to five days after collection and could
`be successfully analyzed using PCR analytic techniques on Slide 26.
`
`Slide 27, this is, in fact, conceded by the Patent Owner itself who
`notes that Granger reports that its stabilization fluid preserves a cellular
`integrity of DNA for far longer in the stabilized samples than was the case in
`the unstabilized samples.
`
`So Granger's solution, Slide 29, was an aliphatic aldehyde combined
`with heavy metal salts and --
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`JUDGE MAJORS: Mr. Duston?
`
`MR. DUSTON: Yes, sir?
`
`JUDGE MAJORS: I'm sorry. I'm on Granger, however, what they're
`doing, they're actually -- those are cells that are fixed from which they're
`extracting the DNA, right, or the RNA in this case?
`
`MR. DUSTON: It's intercellular DNA, which is ultimately analyzed.
`Yes, Your Honor.
`
`JUDGE MAJORS: Okay. And I know you have an answer to that,
`but one other point. If I'm reading Granger correctly, they're also looking at
`the RNA that's -- that they're looking at. If I'm looking at Table 1, Figure
`10, for example, we're literally talking about billions of cells from which this
`RNA can be extracted, right?
`
`MR. DUSTON: If Your Honor will bear with me, let me get Granger
`up so we're on the same page. All right. So Your Honor is looking at Table
`1?
`
`
`JUDGE MAJORS: So Table 1, Figure 10. For example, if I'm
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`reading this correctly, you know, 4.8 times 10 to the ninth per liter. I think
`that's what they're telling me here.
`
`MR. DUSTON: White cell differential over a five-day period; is that
`the table we're speaking of?
`
`JUDGE MAJORS: Correct.
`
`MR. DUSTON: Okay.
`
`JUDGE MAJORS: And then my question, I guess, is so in Granger
`though they're literally dealing with billions of cells from which you can
`extract RNA. Granger is not dealing with a scenario where you're dealing
`with a rare target sequence of nucleotides that they're trying to detect?
`
`MR. DUSTON: I'm not sure that the difference matters, Your Honor,
`because what Granger reports is that there is relatively little or certainly less
`degradation in the RNA caused by the stabilization of the sample with
`formaldehyde than in the alternative. I think that would be true whether you
`were dealing with a large number of RNA fragments or a smaller number of
`RNA fragments.
`
`And I would also point out that the evidence here, too, is that RNA
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