Trials@uspto.gov
`571-272-7822
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`Paper No. 43
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`AQUESTIVE THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`NEURELIS, INC.,
`Patent Owner.
`_____________
`
`Case IPR2019-00451
`Patent 9,763,876 B2
`_____________
`
`Record of Oral Hearing
`Held: May 14, 2020
`__________
`
`
`
`
`Before ZHENYU YANG, JON B. TORNQUIST, and JAMIE T. WISZ,
`Administrative Patent Judges.
`
`
`
`
`
`
`
`
`
`
`
`
`571-272-7822
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`
`Paper No. 43
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`AQUESTIVE THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`NEURELIS, INC.,
`Patent Owner.
`_____________
`
`Case IPR2019-00451
`Patent 9,763,876 B2
`_____________
`
`Record of Oral Hearing
`Held: May 14, 2020
`__________
`
`
`
`
`Before ZHENYU YANG, JON B. TORNQUIST, and JAMIE T. WISZ,
`Administrative Patent Judges.
`
`
`
`
`
`
`
`
`
`
`
`
`
`IPR2019-00451
`Patent 9,763,876 B2
`
`
`
`APPEARANCES:
`
`ON BEHALF OF THE PETITIONER:
`
`
`DANIEL A. SCOLA, JR., ESQ.
`MICHAEL L. CHAKANSKY, ESQ.
`Hoffmann & Baron, LLP
`4 Century Drive
`Parsippany, New Jersey 07054-4406
`973-331-1700 (Scola)
`dscola@hbiplaw.com
`973-331-1700 (Chakansky)
`mchakansky@hbiplaw.com
`
`
`
`ON BEHALF OF THE PATENT OWNER:
`
`
`WENDY L. DEVINE, ESQ.
`Wilson Sonsini Goodrich & Rosati
`One Market Plaza
`Spear Tower, Suite 3300
`San Francisco, California 94105
`415-947-2027
`wdevine@wsgr.com
`
`JEFF GUISE, ESQ.
`Wilson Sonsini Goodrich & Rosati
`12235 El Camino Real
`San Diego, California 92130-3002
`858-350-2307
`jguise@wsgr.com
`
`
`
`
`The above-entitled matter came on for hearing on Thursday, May 14,
`
`2020, commencing at 1:00 p.m., EDT, via Video Teleconference.
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`IPR2019-00451
`Patent 9,763,876 B2
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`P R O C E E D I N G S
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`1:00 p.m.
`JUDGE WISZ: So, today we will hear arguments in IPR 2019-
`00451 concerning U.S. Patent Number 9763876. I am Judge Wisz and I'm
`joined today by Judge Tornquist and Judge Yang.
`So, let's start with appearances, beginning with Petitioner.
`MR. SCOLA: Daniel Scola representing Aquestive Therapeutics.
`And my partner, Mike Chakansky, is also here and will do some speaking.
`MR. CHAKANSKY: Yeah, Michael Chakansky here.
`JUDGE WISZ: Thank you. Patent Owner?
`MR. GUISE: For the Patent Owner, I'm Jeff Guise, lead counsel.
`Wendy Devine is going to be arguing today. We also have on the audio line
`several people from the client Neurelis. Craig Chambliss and Jenny
`Alonso. Thank you.
`JUDGE WISZ: Thank you. And we'd like to remind the parties
`that we each have a copy of the demonstrative exhibits you provided. But
`during your argument please identify clearly and specifically each
`demonstrative referenced by slide or screen number so that everyone can
`follow along and to ensure clarity and accuracy of the court reporter's
`transcript.
`On that note, we did receive some objection to the demonstrative
`exhibits from Patent Owner. We reviewed the demonstrative --
`MR. SCOLA: I'm sorry, Your --
`JUDGE WISZ: Yes?
`MR. SCOLA: There was some feedback, Your Honor, I apologize.
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`IPR2019-00451
`Patent 9,763,876 B2
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`
`JUDGE WISZ: Okay. So we've reviewed the demonstrative and
`the objections, and we have taken the objections into consideration.
`We note that the demonstratives are just here to guide the arguments
`and are not coming in as evidence. We also note that we will not consider
`any new arguments.
`Just a few more reminders before we begin. I am getting some
`feedback. We request that you keep your line muted when you're not
`speaking, which might help some of the feedback.
`And also please keep in mind that the remote nature of this hearing
`may result in audio lags. So please pause prior to speaking so as to avoid
`speaking over others.
`So with that, consistent with our hearing order, each party has 60
`minutes to present their arguments. Petitioner, you'll proceed first. And
`you may reserve time for rebuttal. How much time would you like to
`reserve, if any?
`MR. SCOLA: Your Honor, we anticipate about 15 minutes for
`rebuttal. Approximately. But whatever we don't use in our argument, we'd
`like to reserve.
`JUDGE WISZ: Okay. We will keep track of the time and I'll give
`you a reminder with five minutes left. But we do encourage the parties to
`keep track of your own time as well.
`Petitioner, you can proceed whenever you're ready.
`MR. SCOLA: Okay, thank you, Your Honor. Good afternoon.
`My name is Daniel Scola, representing the Petitioner, Aquestive, along with
`my partner Michael Chakansky. And as I mentioned, each of us will do
`some talking during this hearing.
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`IPR2019-00451
`Patent 9,763,876 B2
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`
`The first issue I'd like to discuss is the lack of description about the
`glycosides in the 558 provisional application. Which means that Patent
`Owner cannot rely on the 558 provisional filing date for the 876 patent
`claims.
`The reason that the 558 provisional application lacks description of
`alkyl glycosides is because the Patent Owner didn't even have possession of
`alkyl glycosides when the provisional was filed.
`Now, the 876 patent claims recite alkyl glycoside as an essential
`element. All of the claims require alkyl glycosides.
`And alkyl glycosides are not disclosed, described or enabled in the
`priority 558 provisional. Dr. Peppas speaks to this in his declaration.
`That's Exhibit 1041 at Paragraphs 68 through 70. We raise the petition at
`Page 20.
`So once the Petitioner raises this issue, the burden then shifts to the
`Patent Owner to prove otherwise, as the PTAB recognizes in the decision.
`And they have not done so.
`The burden means that they must show that the alkyl glycoside is
`supported through the chain of priority. Now, there are several reasons why
`the incorporation by reference of the SIGMA Catalog, which is a non-patent
`document, is not proper.
`First, alkyl glycosides is an essential element through all the claims.
`This is in violation of 37 CFR 1.57.
`Incorporation of essential material from a non-patent document is
`improper. 37 CFR 1.57 is controlling. So that's the first reason.
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`IPR2019-00451
`Patent 9,763,876 B2
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`
`But in addition to being a -- having a proper incorporation by
`reference, you also have to satisfy the statute, Section 112. And the
`SIGMA is the general reference --
`JUDGE TORNQUIST: Counsel?
`MR. SCOLA: Yes.
`JUDGE TORNQUIST: I have a brief question on the 1.57. If we
`apply Rule 1.57, as you suggest, would we be in conflict with the MPEP
`instructions about incorporation by reference?
`MR. SCOLA: I don't believe so. To begin with, 1.57 relates to all
`applications, not just the applications that are being prosecuted.
`And number two, so that is -- 1.57 is controlling over the -- it's a
`regulation that controls the MPEP. The MPEP is -- or they don't have the
`force of law so regulations and statutes govern over them. And you're not
`bound by the MPEP.
`And when 1.57 is applied, it clearly indicates essential material
`cannot be to a non-patent document. So, I don't think you would be in
`contradiction to -- the whole purpose is public policy. And it would not be
`in conflict, so --
`JUDGE TORNQUIST: Okay. Let me ask you --
`MR. SCOLA: -- I think the answer is no.
`JUDGE TORNQUIST: -- one more question.
`MR. SCOLA: Yes.
`JUDGE TORNQUIST: We rely on Dynamic Drinkware for the
`burden shifting in our rehearing decision. Patent Owner has suggested that
`that decision actually supports their position. What do you think about
`that?
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`Patent 9,763,876 B2
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`MR. SCOLA: I don't think so, Your Honor. I think when it comes
`to incorporating essential material, the public policies, you have to let others
`know that -- the public know that in fact you have possession. And that's
`the whole purpose of 1.57.
`And they cited Section 1.57(h), but that provides for rectifying non-
`provisional applications. You can't correct a provisional application. If it's
`not there -- if the essential material is not there, you have to re-file the case.
`So I don't think that --
`JUDGE TORNQUIST: My question --
`MR. SCOLA: -- Drinkware --
`JUDGE TORNQUIST: My question was a little broader than that.
`Who had the initial burden to show that there wasn't written description
`support in that provisional?
`MR. SCOLA: Well, we had -- the burden was that we -- we
`actually shifted the burden. We raised it first.
`So, yes, Petitioner raised the issue when they said there was no
`disclosure, enablement or description in the ’558 application. Dr. Peppas
`raised this and it was in our reply. Once that's raised, then it shifts the
`burden.
`JUDGE TORNQUIST: Okay.
`MR. SCOLA: So, I'd like to now address the Section 112, the
`failure to meet the Section 112. So, Dr. Peppas had testified that alkyl
`glycosides are not disclosed, described or enabled by the 558 provisional. It
`does this at Paragraph 68.
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`IPR2019-00451
`Patent 9,763,876 B2
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`
`And then Dr. Wermeling said that when you look at the 558
`provisional application, there is 15 broad classes of enhancing agents. Only
`one of them is biological detergents listed in the SIGMA Catalog.
`And if you look to Slide 10, it shows you three paragraphs from the
`558 provisional. And the term enhancer there -- it's actually highlighted --
`the term enhancer there is very broad. And then also highlighted are the
`other categories.
`And Dr. Wermeling said that it actually shows the preferred
`enhancing material, directs one to lysophospholipids and also acyl carnitines
`as the alternative. So that's where it says the preferred enhancing materials.
`And then there is 15 total categories, only one of which is biological
`detergent. Now, biological detergent as listed in the SIGMA Catalog
`doesn't really tell you very much at all.
`But then he goes on to say, Dr. Wermeling, that there is no direction
`on choosing one candidate over another and no identification of specific
`biological detergents. In other words, there is no blaze marks through this -
`- if you look at the enhancers as a forest, there is no blaze marks to take the
`POSA through to show that alkyl glycosides is what is being indicated.
`And I would like to point out Dr. Gizurarson in his deposition agreed
`that Paragraph 152, which is -- you see in the Slide 10, Paragraph 152 did
`not associate non-ionic materials with biological detergents. He says this at
`Page 51, Line 18 to Page 52, Line 9. That's also in Slide 21.
`Now, Dr. Wermeling also points out -- this is Paragraph 175 of Dr.
`Wermeling -- that buried among -- in the SIGMA Catalog itself, buried
`among the 150 compounds, there is only six alkyl glycoside compounds.
`And he notes that there is also four categories of detergents -- and one of
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`IPR2019-00451
`Patent 9,763,876 B2
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`them is anionics, another cationics, a third is zwitterionics and a fourth non-
`ionics -- with no direction by the 558 provisional as to which ones are
`important or may be important.
`So, out of 150 total biological detergents -- and I might add that the
`SIGMA Catalog is a price list, that's what catalogs generally are, it's a price
`list of what's offered -- that out of 150, only about a dozen or so that we
`could identify are alkyl glycosides.
`So, Wermeling further goes on to say that a POSA would not have --
`would have to conduct and do experimentation to figure out which of the
`biological detergents were more useful or worked better than other
`biological detergents.
`So, for this reason we don't believe that the SIGMA Catalog is
`proper -- is sufficient to support written description or enablement. So there
`is two reasons why the incorporation by reference falls and that they
`shouldn't be entitled to that provisional date for alkyl glycosides, the first
`being it doesn't comply with Rule 1.57 and for -- because it puts a reference
`to a non-patent document. And second, even if it were properly
`incorporated, it's insufficient to provide proper written description and
`enablement.
`So we don't believe the Patent Owner had possession of the alkyl
`glycosides at the time of the 558 provisional's filing date. Because they're
`neither disclosed, described or enabled by the 558 provisional. This means
`that Gwozdz is prior art to the 876 patent.
`Now, I'd like to discuss the issue of criticality of alcohols next, if I
`may. There are two ways the alcohols are claimed. One is a combined
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`IPR2019-00451
`Patent 9,763,876 B2
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`amount in the claims and the other is individual, smaller ranges in the
`claims.
`So, we don't believe the Patent Owner has demonstrated criticality
`with respect to the combined amounts or the individual amounts of benzyl
`alcohol and ethanol.
`Now, in the decision, the claims -- which directed combined amounts
`-- the Board seemed to understand our position that there was no criticality.
`But the Board was skeptical, however, about certain claims that were more
`narrow regarding the alcohol and ethanol ranges. So, for example, Claims 8
`to 10, 15, 28 and 30 to 33. These recite smaller ranges of alcohols.
`We maintain the position that the Patent Owner has not demonstrated
`any criticality in the separate ranges for benzyl alcohol and ethanol. Or
`dehydrated ethanol, as recited in those claims.
`Now, Dr. Peppas testified there is no criticality shown for the
`amounts and types of alcohols. He did this in Paragraphs 52 to 57. You
`could refer to Slide 33 if you wanted to see that exact portion.
`Now, I believe the skepticism in the decision might have been
`because the European Patent Office considered the issue of criticality and
`yet still allowed the patent to be granted.
`But when you look at this closely -- as we did and Dr. Wermeling
`confirmed this -- shows the EPO was in fact wrong. Because what
`happened was, when the issue of criticality came up, the Patent Owner
`pivoted away from showing the criticality of alcohols and compared a
`solution to a suspension instead.
`Now, Dr. Wermeling gives several reasons why there is no criticality
`shown in the 876 patent. The first is that there is an apples and oranges
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`IPR2019-00451
`Patent 9,763,876 B2
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`comparison between a solution -- which is in 11-1 in the table of 876 -- and
`the suspension, which is 11-2.
`Now, apples and oranges means comparing one form of solution to
`another form, a suspension. So, comparing dosage forms is not a test of
`criticality of one ingredient within the claim. Dosage form certainly.
`Number two, they use diazepam. Now, a solution, Dr. Wermeling
`says, would be expected to work better than a suspension. One would
`expect that it's not surprising that the solution worked better than the
`suspension because it's easier for the body to absorb the solution. It has to
`deal with -- a suspension has to deal with particles more so it takes longer,
`so you would expect that you would get better results from the solution.
`Now, another point is that the ingredients in the solution are very
`different than the ingredients in the suspension. I mean, the only real
`commonalities is the fact that they both have diazepam in it and they both
`have Intravail A3, which is -- they both have the alkyl glycoside in it.
`Now, if you look to Slide 43 there is a table -- comparison table that
`was in Dr. Wermeling's declaration. And that would be Page 110 of his
`declaration.
`And you can see that the solution that they use to compare had
`alcohol in it. It had alcohol, benzyl alcohol and ethanol in it. And it also
`had a high degree of tocopherol, 56 percent.
`Now, you compare that to the suspension solution and that had 78
`percent water. So even the comparison, it's apples and oranges. It's not a
`fair comparison to say a criticality when you're comparing something that's
`very different.
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`IPR2019-00451
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`And it had one percent of a synthetic vitamin E. And so it was, you
`know, compared to the solution, extremely different. So different forms
`and totally different compositions. So it's, again, apples and oranges, and
`not a test for criticality.
`JUDGE TORNQUIST: Counsel?
`MR. SCOLA: He also gives another reason -- yes?
`JUDGE TORNQUIST: Counsel, this is Judge Tornquist. If I
`could just ask a question to orient myself.
`Did Patent Owner argue criticality in the Patent Owner response?
`MR. SCOLA: I don't believe they did.
`JUDGE TORNQUIST: Okay. And did Patent Owner adopt or
`reiterate any of the arguments they made in the EPO, in their Patent Owner
`response or sur-reply?
`MR. SCOLA: We pointed to the -- no, I don't believe -- let's see.
`In the decision it was referenced. But we raised it in our petition.
`JUDGE TORNQUIST: I understand you guys raised it, and we
`raised it in our decision. I was wondering if Patent Owner has adopted
`these in their Patent Owner response.
`MR. SCOLA: I don't believe so but I don't have recollection at the
`moment.
`JUDGE TORNQUIST: Okay. Okay, thank you.
`MR. SCOLA: But we were -- yes. Okay. So, just to pick up
`where I was, Your Honor. So, different dosage forms, different
`compositions, but it goes further than that.
`Now, I want to point out that both experts -- Dr. Peppas and Dr.
`Wermeling -- in their declarations said that there is only one data point.
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`And one data point is insufficient to criticality. But one data point meaning
`the table in 11-1 shows one data point for a solution and that the
`bioavailability is in 11 -- Table 11-3.
`And they both say, in order to properly test criticality of a range,
`several data points are required. And the data points should be inside and
`outside the range in order to actually demonstrate that the range
`encompasses critical amounts. We mention these in Slides 40 through 42.
`So we do not believe, I also want to mention one thing about 11-3
`table. Both experts, well, our expert, Dr. Wermeling, and their expert, Dr.
`Gizurarson, if I pronounce that correctly, Wermeling says that Paragraph
`204, he mentions that 11-1, the solution, 11-1, which is also shown in Table
`11-3, that solution is a nasoral solution.
`In other words, you administer, whatever you administer nasally it
`goes down. And Wermeling says, almost always when you nasally
`administer something, what doesn't get completely into the membrane here it
`goes down the gut.
`So, nas-oral is also admitted by, that 11-3 relates to nas-oral
`bioavailability. Dr. Gizurarson in his deposition also says that. He
`confirms that. His exhibit is 1149. It's at Page 124, Lines 4 to 12. Or
`begins at Lines 12 to 42. I can't read my own writing. I can't read my own
`writing, but it's on Page 124. I apologize.
`So, we believe that Patent Owner has not demonstrated any
`criticality in the separate ranges for benzyl alcohol and ethanol at Claims 8
`through 10, 15, 28 and 30 to 33.
`And where there is a range disclosed in the prior art and the claim
`invention falls within that range, and the burden of production falls on the
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`patentee to show some unexpected results or criticality. And this was stated
`in our reply.
`So, we believe the Patent Owner has never proven criticality for any
`ranges of alcohols. Has never shown any data comparing differing amounts
`of ethanol and benzyl alcohol inside and outside the ranges and therefore no
`criticality is being shown.
`Now, I want to also make a mention about bioavailability. Those
`are Claims 34 to 36. And also, I want to speak to Claim 28.
`With respect to Claim 28, that's almost like a picture claim, right? It
`has diazepam. We don't think there is any criticality in choosing that
`formula either, even though it's a very, it's a picture claim, narrow claim.
`Because Dr. Wermeling and also Dr. Gizurarson, their expert, they
`both say that 11-1, which the solution for 11-1, which is, appears to be
`similar to 28, gives you 100 percent nas-oral availability. So, the
`formulation itself falls within the prior art broad ranges. But for them to
`show some kind of unexpected results they would have to show something
`like, some unexpected results regard to bioavailability.
`But that's not really possible because diazepam, which is the
`ingredient there, is 100 percent bioavailable. It doesn't go through first
`pass.
`
`So, if you administer it nas-orally, whatever doesn't get into the nasal
`passage membranes is going to the gut and then it will be eventually, close
`to 100 percent, if not 100 percent.
`And in fact, with respect to these claims, 34 to 36, they don't specify
`any particular benzodiazepines, number one. And number two, diazepam
`falls within those claims. So the criticality data, which they rely on, which
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`is the tables 1-1, 1 dash, 11 dash, sorry, 11-1, 11-2 and 11-3, 11-3 being the
`bioavailability of the two compositions, doesn't support criticality, it's one
`data point.
`Now, the PTAB has asked us to explain why Meezan's absorption
`improvement, which is attributable to the alpha glycosides and peptides and
`proteins, would also apply to benzodiazepine.
`So, Dr. Wermeling says, and if I quote "if a penetration enhancer
`increases penetration for a large molecule, such as calcitonin, it will also be
`expected to increase the penetration for small molecules, such as benzyls
`and diazepam in particular. And the reason for that is because molecular
`size is the primary constraint for passing between epithelial cells.
`Now, Meezan talks about non-aqueous solution and it talks about
`using anti-seizure drugs. And it gives two specific anti-seizure drugs, small
`molecules.
`So, small molecules, anti-seizure drugs. And two specific anti-
`seizure drugs that it does give is topiramate and zonisamide. And the
`reason it gives those because it gives you molecular weights. That's
`referring to the size, small molecules.
`So, the small molecules, the size of benzodiazepine is right in the
`range of these. So that's the reason why you would look to Meezan because
`you would clearly expect it to work.
`Now, further, with respect to these bioavailability claims, and this
`was not, by the way, this was not challenged by the Patent Owner.
`Obtaining 100 percent bioavailability with diazepam is not only obvious, it's
`expected.
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`IPR2019-00451
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`Because certain nas-oral administration gives you 100 percent. And
`if you give it nas-orally, because giving 11-1 to the nose and membrane has
`been said to give nas-orally, you will also get some down the throat so you
`would expect 100 percent bioavailability. No first pass in the metabolism.
`When you spray it in the nose, some goes down the throat. And
`therefore you would expect 100 percent bioavailability.
`Furthermore, there are known references, which we refer to the
`Ritschel reference. Slides 45 and 46 give the standard reference books
`which talk about the bioavailability being 100 percent for diazepam.
`Now, POSA would expect to achieve bioavailabilities of
`approaching 100 percent. A hundred percent when exposed to diazepam.
`And the claims are not limited to any particular, let's say benzodiazepine.
`Sorry, benzodiazepines.
`So, one data point about the claims, that you would expect to get 100
`percent bioavailability and the claims encompass all benzodiazepines.
`So, basically it's very easy to obtain 100 percent bioavailability with
`diazepam. And one would know this and so would expect that alkyl
`glycosides would even be further ensured about getting 100 percent
`bioavailability for diazepam.
`And for this reason we don't think that these claims are valid when
`you make the combination of the references.
`Now, if there are no questions, Your Honors, I would like to pass
`this to Mr. Chakansky who will deal with several other issues.
`MR. CHAKANSKY: Good afternoon, Your Honors. My name is
`Michael Chakansky and I represent Petitioner Aquestive Therapeutics.
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`And I would like to address, among other things, the grounds of our
`petition, as well as discuss the motivation a POSA would have to combine
`the references. And also, a slight discussion of secondary considerations.
`To begin, our references are Gwozdz, Meezan and Cartt. And with
`Gwozdz, as my partner said, we said it was proper prior art in the
`provisional application. It was entitled to a provisional date.
`And that it was also good prior art because the 876 patent was not
`entitled to its provisional date for the lack of a disclosure of alkyl glycosides
`in the 558 patent. That was our initial burden as Mr. Scola said.
`Then Patent Owner came back and said, no, notwithstanding Rule
`1.57, that incorporation by reference was proper of essential materials. And
`furthermore that, Patent Owner argued that the 558, that the SIGMA Catalog
`that was incorporated by reference, complies with Section 112.
`We then went ahead and offered what I think is persuasive evidence
`in declarations from Dr. Wermeling to the effect that even if incorporation
`by reference was proper, it was insufficient to comply with 112. So we
`think we satisfied the Drinkware obligations in that respect.
`To begin, and then one thing that is, a lot of what we have to say
`deals with overlapping ranges in the references. And, Your Honors,
`brought up the question of criticality and who argued it.
`And I think it was quite clear that we were addressing, that as
`Petitioner was addressing the comments made in the institution decision by
`the Board. And in accordance with the PTAB trial guides, consolidated
`trial guides on Page 73, Petitioner is allowed to address those arguments.
`Especially in light of SAS.
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`Now, in the discussion of the grounds we like to start with the
`claims. At least I do. And basically I direct the attention of the Board to
`Slide 3, Claim 1.
`And that claim is the only independent claim. It goes throughout,
`obviously, the rest of the patent claims. And it's the method for treating a
`patient with the administration of benzodiazepine solution intra-nasally,
`which the solution consists of four major components. The benzodiazepine
`drug, one or more natural synthetic tocopherols and tocotrienols, including
`Vitamin E, or any combinations thereof. An amount of about 30 percent to
`95 percent. That's a pretty big range.
`The next component is ethanol and benzyl alcohol. In a combined
`amount from about ten percent to about 70 percent. And then finally, an
`alkyl glycoside that is an enhancing agent.
`And if, I direct your attention to 54, Slide 54, will be a summary of
`where the main, the main limitations of the claims can be found. And
`basically, I'll start with the fact that we believe that there is great motivation
`to combine these references because they all relate to optimizing the
`intranasal administration of drugs.
`Gwozdz is the pharmaceutical solutions and method for solubilizing
`therapeutic agents. Meezan is absorption enhancers for drug
`administration. And Cartt 784, and we use the 784 because the 876 patent
`has acquired the same inventor in. That is addressing the nasal
`administration of benzodiazepine.
`Going on to Gwozdz. Gwozdz discloses just about everything in
`Claim 1 except for the alkyl glycosides. It discloses the tocopherols, the
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`tocotrienols, solutions of benzodiazepines, including diazepam. It notes and
`discloses that its solutions increase the bioavailability of the benzodiazepine.
`It discloses the use of alcohols. In particular, ethanol and benzyl
`alcohol, in order to reduce the viscosity of the tocopherol to allow the
`solution to be sprayable and thereby able to be use in an intranasal
`administration of the drug.
`Additionally, it comments on the fact that the diazepam solutions,
`with ethanol alone, approach the ten percent level of concentration. If it's
`noteworthy, and something that Patent Owner discusses, there could be no
`reason to add benzyl alcohol. In fact, the reasons not to add benzyl alcohol
`to such a solution.
`One of the reasons for adding benzyl alcohol would be to have what
`Dr. Wermeling calls a ternary co-balance, co-solvent system. And Patent
`Owner objects to the term, ternary co-solvent system. That happens to be
`the way that Dr. Wermeling refers to systems with three ternary solvents.
`Tocopherol, ethanol and benzyl alcohol.
`Dr. Peppas did not call it ternary, he just referred to it as
`tocopherol, ethanol and benzyl alcohol. So there is nothing new here, we're
`talking about the three of them.
`And it turns out that a POSA would have expected that the addition
`of this third solvent may have increased the solubility of the drug. That's a
`reason for adding the benzyl alcohol to it.
`I'm not going to go over the actual disclosures in Gwozdz, other than
`to note that the primary ones are laid out in Slides 58 through Slides 60.
`They give the various ratios of tocopherols to ethanols, tocopherols to
`alcohols.
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`Slide 61 talks about the routine experimentation that any POSA
`would expect would be successful. And, excuse me, Your Honors.
`Additionally, and this is an important factor. And I direct your
`attention to Slide 64 I believe. And that is the second bullet point. Which
`is a quote straight out of Gwozdz.
`Combinations of tocopherols and alcohols are much less irritating to
`the mucus membranes than pure alcohol solutions. And this is important.
`What it's saying is, there is not so much of a worry about alcoholic
`irritations of the nasal lining when you have it as a component together with
`a tocopherol.
`One of the arguments that Patent Owner makes is that people, that a
`POSA wouldn't add benzyl alcohol because it's an irritant. Well, it's not
`going to be as much of an irritant as it would be by itself. And that's one of
`the teachings of Gwozdz.
`Okay. Now, going on to Meezan, Exhibit 1011, discloses alkyl
`glycosides to improve bioavailability. By the way, Gwozdz also says that
`its solutions with tocopherols and alcohols would increase bioavailability.
`And that's pointed out in Slide 59.
`But Meezan also improves bioavailability and solubility of drug
`molecules. Including small organic drug molecules delivered nasally. And
`that the active drugs include anti-seizure agents. And in particular,
`topiramate and zonisamide.
`Both of which have molecular weights, about the same as diazepam.
`And therefore, that is a disclosure in Meezan of what a small molecule might
`be as far as molecular weight. And certainly diazepam would fall within
`that.
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`Now, comments have been made by the Board and by Patent Owner
`regarding the effect of the alkyl glycosides with respect to small molecules.
`In particular, benzodiazepines.
`But if I direct your attention to Slide 69, and in fact, moving on to
`Slide 70. I apologize.
`In the middle Dr. Wermeling, Dr. Wermeling testifies in his
`declaration that in connection with the alkyl glycosides, if a penetration
`enhancer increases penetration for a large molecule, such as calcitonin,
`which was in Figure 1 of the M
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