`
`
`
`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`______
`
`
`ELI LILLY AND COMPANY,
`Petitioner,
`
`v.
`
`LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE AT
`HARBOR UCLA MEDICAL CENTER,
`Patent Owner.
`
`___________
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`___________
`
`Record of Oral Hearing
`Held: September 4, 2019
`____________
`
`
`
`
`Before FRANCISCO C. PRATS, SHERIDAN K. SNEDDEN, and
`SUSAN L. C. MITCHELL, Administrative Patent Judges.
`
`
`
`
`
`
`
`
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`
`
`
`APPEARANCES:
`
`ON BEHALF OF THE PETITIONR:
`
`
`
`
`
`
`MARK FELDSTEIN, ESQUIRE
`DREW CHRISTIE, ESQUIRE
`JOSHUA GOLDBERG, ESQUIRE
`Finnegan Henderson Farabow Garrett & Dunner LLP
`901 New York Avenue, N.W.
`Washington, D.C. 20001
`
`MARK STEWART, ESQUIRE
`Eli Lilly and Company
`
`
`
`
`
`BEHALF OF THE PATENT OWNER:
`
`
`DAVID TELLEKSON, ESQUIRE
`ELIZABETH HAGAN, ESQUIRE
`Fenwick & West LLP
`815 Connecticut Avenue, N.W.
`Suite 200
`Washington, D.C. 20006
`
`
`
`
`The above-entitled matter came on for hearing on Wednesday,
`September 4, 2019, commencing at 2:00 p.m., at the U.S. Patent and
`Trademark Office, 600 Dulany Street, Alexandria, Virginia, before Julie
`Souza, Notary Public.
`
`
`
`
`
`
`
`
` 2
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`
`
`
`
`
`
`
`
` P R O C E E D I N G S
`- - - - -
`JUDGE SNEDDEN: Please be seated. Good
`
`
`afternoon. This is the hearing in IPR 2014-00752. I'm Judge
`Snedden. I have with me on the panel Judges Mitchell and Prats.
`So we'll begin with appearances starting with Petitioner. Please
`stand and introduce yourself and who you have with you today.
`
`
`MR. FELDSTEIN: Thank you, Your Honor. Mark
`Feldstein with Finnegan Henderson on behalf of the Petitioner
`Eli Lilly. With me today is my co-counsel Drew Christie from
`Finnegal Henderson, Josh Goldberg from Finnegan Henderson
`and co- counsel Mark Stewart from Eli Lilly.
`
`
`JUDGE SNEDDEN: Thank you. Welcome.
`
`
`MR. TELLEKSON: Good afternoon, Your Honor.
`I'm David Tellekson from Fenwick & West and I represent Los
`Angeles Biomedical Research Institute, and with me is Liz
`Hagan, also of Fenwick & West.
`
`
`JUDGE SNEDDEN: Welcome. Per our order
`granting this oral hearing, each party will have 60 minutes of
`total time to present its arguments. Petitioner will open the
`hearing by presenting its case regarding the claims for which we
`instituted at trial. Patent Owner will then respond to Petitioner's
`argument. Each side may reserve time for rebuttal. Patent
`Owner is limited to five minutes of rebuttal time. I also note
`
`
`
`
` 3
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`that Judge Prats is joining us remotely today and so if the parties
`could remember to speak the slide number for both the benefit of
`the record and also for Judge Prats. Okay. Mr. Feldstein, you
`may begin when you're ready.
`
`
`MR. FELDSTEIN: Thank you, Your Honor. Can we
`hand out some hard copies of the demonstratives?
`
`
`JUDGE SNEDDEN: Sure.
`
`
`MR. FELDSTEIN: Can we do that here?
`
`
`JUDGE SNEDDEN: Yes, you may, and will you be
`reserving any rebuttal time today?
`
`
`MR. FELDSTEIN: My intent is to reserve 20 minutes
`of rebuttal time, Your Honor.
`
`
`JUDGE SNEDDEN: Mr. Feldstein, if you could pause
`and wait for Judge Prats to join us again.
`
`
`MR. FELDSTEIN: Sure.
`
`
`JUDGE PRATS: I'm back. Can you all hear me?
`
`
`JUDGE MITCHELL: Yes.
`
`
`JUDGE SNEDDEN: We can hear you.
`
`
`JUDGE PRATS: Thank you. Sorry about that.
`
`
`JUDGE SNEDDEN: All right, Mr. Feldstein. You
`may begin.
`
`
`MR. FELDSTEIN: Thank you. We'll start on slide 1.
`I'd just like to note this is a relatively unique case that we have.
`We have the Federal Circuit decision with claim construction.
`
`
`
`
` 4
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`We have the Board's decision for ground one on remand and in
`view of those prior decisions, we are able to focus our argument
`today to really hone in on what's undisputed or minimize
`disputes at least, and so we're going to hone in, we're going to
`focus on the obviousness of treating Peyronie's disease plaque is
`one of the three populations that are addressed in the petition
`and by doing so I think we can avoid a lot of argument, a lot of
`Patent Owner's argument relating to claim construction, a lot of
`Patent Owner's argument related to the populations of the
`Rochira and Zippe petitions references.
`
`
`So if we go to slide 3, I'd like to start with just a little
`background on the patent and the NO/cGMP pathway as well as
`PDE5 inhibitors. Going to slide 4, slide 4 is a quote from Patent
`Owner response paper 20 where Patent Owner early in the case
`admitted that the discovery at the heart of their invention, the
`903 patent, was that iNOS, inducible nitric oxide synthase,
`serves too protect penile tissue from fibrosis and that this
`discovery paved the way for the invention itself.
`
`
`So we think that that was actually a true statement,
`that that was the heart of the invention and it did pave the way.
`If we go to slide 6. That discovery however is fully disclosed in
`Ferrini reference 1091, which is one of the four references in the
`ground, that is confirmed 102(b) prior art at this point, the patent
`having lost its claim to the provisional filing date.
`
`
`
`
` 5
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`So if we go to slide 7, what Ferrini 2002 teaches
`
`
`among other things is that having reviewed the background, the
`science up to the time suggests that NO nitric oxide is a potent
`antifibrotic agent and it acts through one of several possible
`mechanisms. Those possible mechanisms include inhibition of
`collagen synthesis, so inhibiting the ability of the body to build
`up more collagen which is the primary component of fibrosis or
`increasing how much the collagen has degraded because there are
`natural enzymes in the body that degrade collagen naturally. So
`it can be any fibrotic by decreasing synthesis, increasing
`degradation or other mechanisms including by neutralizing this
`reactive oxygen species ROS.
`
`
`If we go to slide 8, slide 8 is a further teaching of the
`reference and it's based on the observation relying on the prior
`art that nitric oxide, NO donors, the NOS substrate, and cGMP
`analogs have been observed -- this is not hypothetical, this is
`actual reporting prior observation -- had been observed to
`ameliorate, i.e., prove, experimental fibrosis and that supports
`they say the role of nitric oxide as an antifibrotic agent. This
`discovery, this report leads directly to the use of PD5 inhibitors
`for the same antifibrotic purpose.
`
`
`If we go to slide 10. So slide 10 is an admission from
`LA Biomed's inventors, among others, in September 2003 which
`is before the filing date of the patent. The admission is that their
`
`
`
`
` 6
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`results for PDE5 inhibitors, which are basically the same results
`that are in the patent, are a natural extension of the previous
`work demonstrating the antifibrotic effects of NO and so what
`they're saying, in other words, that once you know that nitric
`oxide is antifibrotic the natural extension of that is to consider
`PDE5 inhibitors for the same purpose. If we go to slide 11.
`
`
`JUDGE PRATS: Counsel, if I could interject there?
`
`
`MR. FELDSTEIN: Yes, Your Honor.
`
`
`JUDGE PRATS: That LAB 2003 publication, and I've
`been informed that you all can't see me but hopefully you can
`hear me, that LAB 2003 publication that's cited on slide 10,
`that's not in the ground, correct?
`
`
`MR. FELDSTEIN: No. That's not a part of the
`ground, that is in the reference itself is not prior art but it's an
`admission from the inventors and it's reflective of, because it's
`from the prior art time period -- even though the document itself
`is not a prior art printed publication, it was drafted and received
`by September 2003 -- it's reflective of level of skill and the
`understanding of a person at the relevant time.
`
`
`JUDGE PRATS: Well actually if it's the inventors,
`how can it be a level of ordinary skill?
`
`
`MR. FELDSTEIN: Well it's the inventors --
`
`
`JUDGE PRATS: We're not talking about what the
`inventors know. We're talking about what an ordinary artisan
`
`
`
`
` 7
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`knew and the inventors meet this leap. My question is, how is
`this leap that we're seeing here in this undisputedly non- prior art
`reference being made in the reference that you cite in your
`ground?
`MR. FELDSTEIN: So I will explain and I can explain
`
`
`how, you know, independent of the inventor's admission PDE5
`becomes the obvious follow-on to nitric oxide being an
`antifibrotic. But it does have evidentiary weight, it should have
`evidentiary weight as an admission from the inventors and
`because the publication is from not just the inventors, it's also
`through the other authors reflective of skill in the art at the time.
`I can and I will explain --
`
`
`JUDGE PRATS: Thank you.
`
`
`MR. FELDSTEIN: -- how, you know, independently
`of this admission -- this admission doesn't stand alone, this is
`just one piece of our evidence.
`
`
`JUDGE PRATS: I guess what I'm saying is that can
`we fairly characterize this as an admission?
`
`
`MR. FELDSTEIN: That's how I read it. I see the
`statement a natural extension of our previous work and that's
`exactly what we've said from the beginning from our petition
`that once you know that nitric oxide is an antifibrotic, the natural
`thing to do is a PDE5 inhibitor. If you're looking for what is
`available out there in the part in 2003 that's going to increase
`
`
`
`
` 8
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`nitric oxide in the body, and human especially, the answer is
`Viagra. Viagra was approved in 1998. It was what Rochira or
`Zippe deemed the Viagra error by 2003 and it directly, as LA
`Biomed further admits, it's going to increase nitric oxide.
`Rochira teaches that PDE5 is going to increase nitric oxide. LA
`Biomed admits that fibrosis should go the same direction, both
`from nitric oxide and PDE5 inhibitors, and so really this is sort
`of icing, this statement from the inventors. It's actually entirely
`consistent with the art as a whole that says where you want to
`increase nitric oxide, a PDE5 inhibitor is what comes to mind
`immediately.
`
`
`JUDGE PRATS: Thank you. I guess maybe let me
`clarify a little bit. You're saying it's an admission but to me it
`almost seems like when I read this statement in reply it seems
`like it's hindsight. We're saying well, this is what the inventors
`did and therefore it's obvious, so you're looking at what the
`inventors did and you're looking at it as opposed to being an
`admission, it seems almost like hindsight. Where reconstructing
`the past the inventor took -- the inventors took it so therefore it
`must be obvious, if you understand my position there.
`
`
`MR. FELDSTEIN: I do.
`
`
`JUDGE PRATS: Or my concern there.
`
`
`MR. FELDSTEIN: Yes. I do understand your
`position. I do understand your concern. I read it and I think it's
`
`
`
`
` 9
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`a fair, in view of how other admissions from inventors have been
`used to show obviousness like Pfizer, Inc., v. Apotex, Inc., that
`it was straightforward to go stream for salts, this is likewise
`admission not that we came up with some further discovery to be
`able to extend it to PDE5 inhibitors but that it's the natural
`extension.
`JUDGE PRATS: Thank you.
`
`
`MR. FELDSTEIN: Okay. Thank you. Going to slide
`
`
`11. I think the admissions from Dr. Bivalacqua who is LA
`Biomed's expert on slide 11. He I think consistently testified
`with the document that we just saw that the discovery that
`iNOS's antifibrotic brings you to PDE5 inhibitors where all you
`really have to do is test and confirm that they are likewise going
`to work.
`And if we jump to slide 75, basically you find that the
`
`
`teachings that the PDE5 inhibitor would have been obvious based
`on Ferrini 2002 in the reference grounds as a whole is that
`functionally a PDE5 inhibitor does everything that the cGMP
`analogs that Ferrini 2002 specifically points to do, and so
`functionally biologically like a cGMP analog which is prior art
`referenced in that portion of the Ferrini 2002 patent where it
`ameliorated experimental experimental fibrosis, like a cGMP
`analog, a PDE5 inhibitor was known to be antifibrotic. It was
`known to functionally resist the effects of the PDE5 enzyme. It
`
`
`
`
` 10
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`was functionally and biologically equivalent. The difference
`between a cGMP analog and a PDE5 inhibitor is that at the time
`in 2003 a cGMP analog was a laboratory chemical used in invitro
`experiments and animal experiments. It wasn't an approved drug
`for doing that.
`
`
`On the other hand, in contrast PDE5 inhibitor
`Sildenafil was approved and so basically part of the obviousness
`is one path is that you're basically upgrading for a cGMP analog
`that is shown to ameliorate experimental fibrosis. If you're
`going to use it therapeutically you can't use a cGMP analog
`therapeutically in 2003 because it wasn't approved, but the
`functional equivalent Sildenafil, Viagra, was approved.
`
`
`JUDGE PRATS: Counsel, do we have evidence of the
`equivalence in the references cited in your ground? Do we have
`evidence of the equivalence of these two things, the cGMP
`analog and the PDE5 inhibitor?
`
`
`MR. FELDSTEIN: I think we do. I think slide 75 is
`showing how functionally they all do the same thing and there's
`actually not a dispute that a PDE5 inhibitor, like a cGMP analog,
`is going to increase the endogenous level of cGMP. It's
`functionally the same thing, and if we jump ahead to --
`
`
`JUDGE PRATS: Right. But just to interject there,
`my concern is I understand the argument but I'm seeing a lot of
`the references of pieces of the record that are cited here on slide
`
`
`
`
` 11
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`75, I don't remember them being in the original ground so I'm
`trying to figure out where in the references the link between
`cGMP analogs and one of the claimed therapeutic agents is being
`made in the references that are cited and the ground that we're
`looking at.
`
`
`MR. FELDSTEIN: So substantially you see Exhibit
`1089, that's the Goldstein declaration that was part of the
`original -- it's not one of the prior art references obviously but
`it's part of the original petition argument that explains the idea
`that where you have cGMP, the very next thing to do is to
`consider a PDE5 inhibitor.
`
`
`JUDGE PRATS: Which portion of that slide is --
`which cite to the, the top right --
`
`
`MR. FELDSTEIN: The top right, for example Exhibit
`1089, all the exhibits to 1089 are the original declaration of Dr.
`Goldstein. We also have, it's not part of the original petition
`because it hadn't happened yet, but we have Exhibit 1183 which
`is LA Biomed's Federal Circuit briefing. At page 19 they
`indicate that nitric oxide and PDE5 inhibitors have the same
`effect on increasing cGMP and would be expected to have the
`same effect on fibrosis.
`
`
`JUDGE PRATS: Actually wasn't that argument made
`with respect to I think it was Ferrini 2001 posited that nitric
`oxide would actually promote fibrosis and at that point in their
`
`
`
`
` 12
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`brief I think Patent Owner was saying well, we'd expect these
`things to do the same thing, i.e., promote fibrosis. They weren't
`-- I don't see that page of the brief as conceding that basically
`what you're showing me at slide 75, if you get what I'm saying.
`
`
`MR. FELDSTEIN: It's true that in Exhibit 1183 the
`Federal Circuit briefing, they're saying that NO and PDE5
`inhibitors would be expected to both be profibrotic but it's
`because mechanistically they're saying that at the time iNOS was
`thought to be antifibrotic and so now that we have Ferrini 2002
`-- I said that backwards. They argued that when people thought
`that iNOS was profibrotic you would expect that nitric oxide and
`PDE5 inhibitors would both be profibrotic as well. Ferrini 2002
`clarified and confirmed that iNOS is antifibrotic. It confirms
`that NO is antifibrotic and it follows from what they said to the
`Federal Circuit too that if nitric oxide and PDE5 inhibitors point
`in the same direction for fibrosis, once you know that nitric
`oxide is pointing antifibrotic, PDE5 inhibitors are going to point
`antifibrotic too.
`
`
`We also have, even in the current briefing surreply in
`this round of briefing at page 16 from LA Biomed, they agree
`that nitric oxide and PDE5 inhibitors both amplify cGMP and so
`--
`
`
`Sorry.
`
`
`
`
`JUDGE PRATS: Could you give me that cite again?
`
` 13
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`MR. FELDSTEIN: Sure. It's the surreply which is
`
`
`paper 80 at page 16 and they're referring back to the same
`testimony from Exhibit 1183, page 19, the Federal Circuit
`briefing.
`JUDGE PRATS: Thank you.
`
`
`MR. FELDSTEIN: And if you want there's another
`
`
`cite. LA Biomed paper 51 which is from the first remand. LA
`Biomed, their paper on remand, paper 51 at page 9, they again I
`think agree that NO and PDE5 inhibitors point the same way for
`cGMP.
`JUDGE PRATS: Did you argue that in the briefing in
`
`
`this round, that is was that cited in the briefing in this round?
`
`
`MR. FELDSTEIN: I don't know if that's cited. It's
`redundant in fact with 1183 though.
`
`
`JUDGE PRATS: And my concern would be to -- I
`know we want to look at the whole record -- my concern would
`be if you're not arguing it in these papers that, you know, if
`we're going to cite that in an opinion it wouldn't be fair to Patent
`Owner so.
`MR. FELDSTEIN: Understood. I can assure that
`
`
`1183 is cited and argued. I'd have to check back on paper 51.
`
`
`JUDGE PRATS: Thanks.
`
`
`MR. FELDSTEIN: So if we go to slide 14. I want to
`talk through some of the claim elements now. The claim
`
`
`
`
` 14
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`elements include administering to an individual with Peyronie's
`disease plaque. We've put together the language from claim 1
`and dependent claim 3 to pull that quote together. Peyronie's
`disease, as we've already seen and we're going to reiterate now,
`is a focus of Ferrini 2002 and there's really no basis but to
`conclude, and I don't think there's any dispute, that Peyronie's
`disease is a claimed fibrosis
`
`
`So what Ferrini 2002 says about Peyronie's disease
`among other things is that they were testing it and that their
`results can have therapeutic implications, obviously bringing
`into the human, for both Peyronie's disease, PD, plaque and
`fibrosis in general and that interventions aimed at reducing
`collagen deposition. The input side of the fibrosis may be
`beneficial because endogenous metalloproteinase, those are the
`enzymes that degrade the fibrosis as it exists, would tend to
`reduce growth arrested plaque and so a key teaching of Ferrini
`2002 having Peyronie's disease you have a plaque, a fibrotic
`plaque, that's growth arrested -- it's neither growing nor
`shrinking in size -- but it is in a state of dynamic balance
`(phonetic) and flux where there's an input side of new collagen
`being generated and collagen being degraded at the same time, a
`flux back and forth, and what Ferrini is teaching is that if you
`reduce the input side because it's being naturally consumed by
`enzymes is going to be reduced.
`
`
`
`
` 15
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`So put slide 16. This is one of the things that
`
`
`distinguishes ground two from ground one as it was decided on
`remand. Part of the basis for ground one on remand finding
`nonobviousness was that Montorsi and Whitaker didn't limit its
`patient population to those with a recognized underlying fibrosis.
`Respectfully we think that the right question is whether the
`reference points to an obvious cell population, but regardless for
`Ferrini there can be no question that Ferrini 2002 is pointing to a
`population with a recognized fibrosis and so it overcomes that
`reason for denial of ground one, the rejection of ground one
`previously.
`
`
`If we move on to slide 17. In terms of arresting or
`regressing, we know regressing has been construed as halting or
`reversing. Ferrini 2002 repeatedly tells you that especially
`Peyronie's disease plaque is amenable to being reduced. It's
`something that can be achieved. It's something that in fact has
`been achieved. That type of plaque has been reduced in the past.
`
`
`If we go to slide 18. Ferrini 2002 is building on
`Ferrini 2001. Ferrini 2001 had recognized that iNOS may be a
`defense mechanism against collagen deposition. Again, the input
`side and that's in agreement they say with inhibitory effects of
`nitric oxide on collagen synthesis and so again Ferrini 2002
`doesn't come out of nowhere. It builds on Ferrini 2001 and
`consistently pointing to nitric oxide being antifibrotic by
`
`
`
`
` 16
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`inhibiting collagen synthesis and/or increasing collagen
`degradation.
`
`
`If we go to slide 52. This is from Dr. Goldstein's
`reply declaration Exhibit 1153, paragraph 25. He is explaining
`sort of putting formulaically for those who see the world in a
`sort of math perspective, that when you have a stable plaque
`that's neither growing nor decreasing what that means is that the
`amount of collagen coming in and the amount of collagen coming
`out are balanced, collagen being the primary component of the
`extracellular matrix of fibrosis and so when you have a growth
`arrested plaque, like Ferrini refers to, what that means is that
`you've still got collagen synthesis but the collagen synthesis is
`completely offset by collagen degradation. They offset each
`other. The ratio, just as a matter of math, would be one.
`
`
`If we go to slide 59, if you do something like what
`Ferrini is telling you to decrease collagen synthesis or increase
`collagen degradation you end up with this ratio being less than
`one. You're making less collagen than you're destroying. So
`you're destroying more collagen than you're making and when
`you go from growth arrested stable plaque and you either
`decrease collagen synthesis or increase collagen degradation, the
`expectation is you can only go one way. You can only go
`towards reduction, amelioration, involution of the plaque as
`Ferrini describes.
`
`
`
`
` 17
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`Can we have slide 19, if we could? Slide 19 is a
`
`
`schematic of the NO/cGMP pathway as it relates to inhibiting
`collagen synthesis being antifibrotic. This also is from Exhibit
`1153, Dr. Goldstein's reply declaration. The solid lines in here
`are all teachings of Ferrini 2002 and Ferrini 2001 that nitric
`oxide synthase increases nitric oxide which in turn can be
`antifibrotic or go through cGMP to be antifibrotic by reducing
`collagen synthesis and/or increasing collagen breakdown.
`
`
`The dotted line of increasing oxygenation, that's an
`express teaching from the Rochira reference which teaches that
`Sildenafil, for example, is an oxygenating therapy and
`oxygenating therapies stimulate nitric oxide synthase which then
`makes more NO and then basically it cycles around.
`
`
`So if we go to slide 20. In terms of -- there were
`questions earlier about how do you end up at PDE5 inhibitors
`from the teachings of Ferrini 2002 and the other references in the
`ground. So again we have this important sentence, important
`statement from Ferrini 2002 that NO donors and cGMP analogs
`among other things can ameliorate experimental fibrosis and so
`you know that NO donors -- NO is an antifibrotic, you know that
`cGMP is an antifibrotic and the question is did you want to apply
`that therapeutically, where do you go?
`
`
`Just as an aside with this sentence, you know, we have
`comments from LA Biomed that oh, this is one sentence, one
`
`
`
`
` 18
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`sentence, we're relying on one sentence. You know, it's true of
`course it's quoted as a full sentence beginning with a capital and
`a period but it's not one sentence that's inconsistent with the art.
`It's not one sentence that comes out of nowhere. It's in fact one
`sentence that builds on expressly cited other publications where
`they actually observed a reduction in experimental fibrosis and if
`we go to slide 63, it builds on and is consistent with the art as a
`whole where since at least the 1990s researchers have viewed the
`NO/cGMP pathway as a key target in antifibrotic treatment and
`there are more than a dozen references all cited back with the
`petition for the state of the art showing that this pathway, the
`N/cGMP pathway, was a known antifibrotic pathway and that's
`what Ferrini 2002 is confirming along with its finding about
`iNOS.
`So if you go to slide 21, please. Once you know that
`
`
`the pathway is antifibrotic what does that tell you? That tells
`you, as Dr. Goldstein testified on cross-examination to LA
`Biomed, it tells you -- this is a reference to Ferrini 2002 -- when
`Ferrini said NO donor, NO substrate and cyclic GMP analogs, it
`opened the door to Viagra. It opened the door to Viagra to do
`the same thing because it is an NO therapy, it is increasing a
`cGMP analog.
`
`
`If we go to slide 22, Zippe is directed to antifibrotic
`oxygenating therapies and one of the things that Zippe teaches
`
`
`
`
` 19
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`you can use as an antifibrotic oxygenating therapy is Sildenafil,
`Viagra, and Zippe teaches that administering it for three months
`following radical prostatectomy was actually successful in a high
`degree of spontaneous recovery and what that means is that in a
`radical prostatectomy you have nerve damage, hopefully not
`complete nerve loss, but there's nerve damage at the beginning
`where the cells are not getting signals and you're not getting
`erections naturally that would then provide oxygenating therapy
`and if you do nothing, you're in a condition where the penis is in
`a fibrotic condition and you're going to get fibrosis and if you do
`nothing, the spontaneous recovery rate according to Zippe is
`around 20 percent. You end up with so much fibrosis that you
`never recover erectile function.
`
`
`If you treat with an oxygenating therapy for six
`months, either three months with this PG1 therapy followed by
`three months with Sildenafil, you end up with a 70 percent
`spontaneous recovery indicating that it was successful in
`arresting fibrosis that would have happened or caused by the
`neuropraxia that's present up to nine, twelve, even twenty four
`months.
`JUDGE SNEDDEN: May I interrupt?
`
`
`MR. FELDSTEIN: Please.
`
`
`JUDGE SNEDDEN: I have a question. When we look
`
`
`back at the history of this case and we look at ground one and
`
`
`
`
` 20
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`our decision there, one of the problems we had we understand
`there's a connection between erectile dysfunction and the fibrotic
`diseases, Statini's (phonetic) disease, but I think the problem we
`keep running against is how then do we get to the specific
`patient population that gets us to the method of treating the
`fibrotic diseases. I understand there's this common biological
`mechanism but what we've seen before and what was guided by
`the Federal Circuit is that we have to actually get to the specific
`patient population and so how do we do that with the evidence of
`record?
`MR. FELDSTEIN: The easiest path there, Your
`
`
`Honor, is through Peyronie's disease. Peyronie's disease is a
`fibrotic condition. The Ferrini 2002 is teaching therapy to treat
`Peyronie's disease. Peyronie's disease means you are a fibrotic
`population.
`
`
`JUDGE SNEDDEN: And what are they using in
`Ferrini to treat PD or the fibrotic diseases?
`
`
`MR. FELDSTEIN: So Ferrini itself, the research they
`do is lab scale. They are actually not administering any drugs to
`humans. They refer back to other treatments that were
`successful for treating Peyronie's disease including vitamin E
`and antioxidants. Their teaching is that nitric oxide is an
`antifibrotic pathway that would be useful for treating Peyronie's
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`
`
`
`
`
` 21
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`disease. They, in Ferrini 2002, they don't yet get to the step of
`actually administering a drug to humans.
`
`
`JUDGE SNEDDEN: And so the teaching is to use,
`and I think you brought it up in a previous slide, they use the
`cGMP analogs might be beneficial in the treatment of fibrotic
`diseases and might have antifibrotic effects ameliorate the
`diseases?
`MR. FELDSTEIN: Basically, if we go back to slide
`
`
`20, Ferrini is referring to basically all the points in the
`NO/cGMP pathway as supporting the role of nitric oxide as being
`an antifibrotic agent. NO directly can do it, cGMP analogs can
`do it and so anything that's going to stimulate the NO/cGMP
`pathway is going to be antifibrotic based on these teachings.
`
`
`JUDGE SNEDDEN: Okay. And then we know that
`the compound then in the claims has this effect and plays a role
`in this pathway, stimulates the pathway.
`
`
`MR. FELDSTEIN: Correct.
`
`
`JUDGE SNEDDEN: And that's the link.
`
`
`MR. FELDSTEIN: I'm sorry?
`
`
`JUDGE SNEDDEN: And that's the link, that's the
`connection between the use of the drug and the fibrotic effects.
`
`
`MR. FELDSTEIN: Absolutely. You have Ferrini
`2002 teaching that the pathway is an active antifibrotic pathway.
`You have them teaching it to arrest or regress in a fibrotic
`
`
`
`
` 22
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case IPR2014-00752
`Patent 8,133,903 B2
`
`
`
`population, Peyronie's disease, and then you have other
`references that point you to PD E5 inhibitors as a way to amplify
`the NO/cGMP pathway.
`
`
`JUDGE SNEDDEN: I mean now then how do we get
`to treating an individual with a specific dose that's in the claim?
`
`
`MR. FELDSTEIN: Okay. So if we go to slide 24.
`Zippe again is intending to be on antifibrotic treatment, the
`abstract of Zippe itself is referring to oxygenating therapy for
`antifibrotic purposes. The dose that Zippe uses, that purports
`using --
`JUDGE SNEDDEN: This is in the context of erectile
`
`
`dysfunction though?
`
`
`MR. FELDSTEIN: No. This is in the context of post-
`radical prostatectomy where you have neuropraxia that is going
`to be causing fibrosis. The whole context of Zippe is that
`fibrosis is going to result from neuropraxia and so you have a
`dose, what does is actually taught
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
