1
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 1 of 247 PageID #: 2250
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`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
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`)C.A. No. 15-1159 (GMS)(SRF)
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`)CONSOLIDATED
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`ALCON RESEARCH, LTD.,
`Plaintiff,
`
`v.
`WATSON LABORATORIES, INC.,
`Defendant.
`
`ALCON RESEARCH, LTD.,
`Plaintiff,
`
`v.
`LUPIN LTD. and LUPIN
`PHARMACEUTICALS, INC.,
`Defendants.
`
`))
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`))
`
`))
`
`)
`
`))
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`)
`- - -
`Wilmington, Delaware
`Monday, October 2, 2017
`9:00 a.m.
`Bench Trial - Day 1
`- - -
`BEFORE: HONORABLE GREGORY M. SLEET, Senior Judge, U.S.
`District Court of DE
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`
`
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 1 of 247 PageID #: 2250
`
`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
`
`))
`
`))
`
`)
`- - -
`
`)C.A. No. 15-1159 (GMS)(SRF)
`)
`)CONSOLIDATED
`)
`
`ALCON RESEARCH, LTD.,
`Plaintiff,
`
`v.
`WATSON LABORATORIES, INC.,
`Defendant.
`
`ALCON RESEARCH, LTD.,
`Plaintiff,
`
`v.
`LUPIN LTD. and LUPIN
`PHARMACEUTICALS, INC.,
`Defendants.
`
`))
`
`))
`
`))
`
`)
`
`))
`
`)
`- - -
`Wilmington, Delaware
`Monday, October 2, 2017
`9:00 a.m.
`Bench Trial - Day 1
`- - -
`BEFORE: HONORABLE GREGORY M. SLEET, Senior Judge, U.S.
`District Court of DE
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
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`
`
`2
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 2 of 247 PageID #: 2251
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`APPEARANCES:
`MARYELLEN NOREIKA, ESQ.
`Morris Nichols Arsht & Tunnell LLP
`-and-
`CHRISTOPHER J. MANDERNACH, ESQ., and
`ADAM PERLMAN, ESQ.,
`JOELLE JUSTUS, ESQ., and
`CHRISTOPHER SUAREZ, ESQ.
`Williams & Connolly LLP
`(Washington, DC)
`Counsel for Plaintiff
`Alcon Research, Ltd.
`MELANIE K. SHARP, ESQ., and
`ROBERT VRANA, ESQ.
`Young Conaway Stargatt & Taylor LLP
`-and-
`MARK D. SCHUMAN, ESQ.,
`TODD S. WERNER, ESQ.,
`JENELL C. BILEK, ESQ.,
`SHELLEAHA JONAS, ESQ., and
`CAROLINE R. MARSILI, ESQ.
`Carlson Caspers
`(Minneapolis, MN)
`
`Counsel for Defendant
`Watson Laboratories, Inc.
`DOMINICK GATTUSO, ESQ.
`Heyman Enerio Gattuso & Hirzel LLP
`-and-
`IMRON T. ALI, ESQ.,
`JOHN K. HSU, ESQ., and
`CHRISTINE WILSON FELLER, ESQ.
`Schiff Hardin
`(Chicago, IL and New York, NY)
`Counsel for Lupin Limited and
`Lupin Pharmaceuticals, Inc.
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
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`
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`3
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`THE COURT: Good morning
`(Counsel respond "Good morning.")
`THE COURT: Please, take your seats everyone.
`Let's start out with introductions if we could
`from plaintiff.
`MS. NOREIKA: Good morning, Your Honor.
`THE COURT: Good morning, Ms. Noreika.
`MS. NOREIKA: For the plaintiffs, Maryellen
`Noreika from Morris Nichols Arsht & Tunnell.
`With me at counsel are Adam Perlman,
`Christopher Mandernach, Joelle Justus, and in the back is
`Christopher Suarez. They are all from Williams & Connolly.
`We also have a representative, Peter Waibel,
`here from Novartis, the parent of Alcon.
`THE COURT: Good morning.
`MS. SHARP: Good morning, Your Honor.
`For the Watson defendants, Melanie Sharp from
`Young Conaway, Rob Vrana also from Young Conaway.
`And my colleagues from Carlson Caspers seated at
`counsel are counsel table are Mark Schuman and Todd Werner.
`We also have Jennell Bilek, Caroline Marsili,
`and Shelleaha Jonas.
`I have my phonetics here to make sure nobody is
`mispronounced.
`THE COURT: Very good.
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
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`
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`MS. SHARP: In-house counsel from Watson, Jim
`Mahanna, is also here.
`THE COURT: Good morning.
`MS. SHARP: Your Honor, if I may briefly
`introduce Ms. Michelle Ovanesian. She is new from Young
`Conaway, and here in fulfillment of her clerkship
`requirements.
`THE COURT: Congratulations.
`Good morning.
`MR. GATTUSO: Good morning, Your Honor.
`Dominick Gattuso from Enerio Heyman Gattuso and
`
`Hirzel.
`
`We are representing defendant Lupin
`Pharmaceuticals.
`We have several people in the courtroom with us
`
`today.
`
`From Schiff Hardin first, Imron Aly, John Hsu,
`and Ms. Christine Feller.
`THE COURT: Good morning.
`MR. GATTUSO: We also have a representative from
`Lupin, Your Honor, Catherine Jonas.
`THE COURT: Good morning, Ms. Jonas.
`MR. GATTUSO: Thank you, Your Honor.
`THE COURT: All right.
`Hopefully, we will be able to do something
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
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`5
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 5 of 247 PageID #: 2254
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`about the temperature.
`It's a little warm, it seems to me.
`You can blame GSA.
`I have no control over them.
`Counsel, I understand there might be an issue or
`two before we get going that needs to be discussed.
`MR. WERNER: Your Honor, the same issue we
`addressed on the pretrial order related to the unexpected
`results.
`
`We wanted to preserve our objection. We didn't
`want to interrupt anything during openings.
`THE COURT: The objection has been preserved.
`You can remind me what was second.
`MR. WERNER: Your Honor, we don't believe there
`should be any evidence of unexpected results at this trial
`as a result of failure of proof, as a result of a lack of
`exposure, in expert reports.
`THE COURT: I don't remember the discussion, but
`it's likely that I might have. We would see.
`MR. WERNER: Your Honor said we will see how it
`goes and I will rule at the time when the evidence comes in.
`THE COURT: Your objection is certainly noted.
`I am prepared to entertain opening statements.
`THE COURT: Counsel, we will break at about
`12:30 for lunch, we will take as-needed breaks for comfort.
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
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`
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`6
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 6 of 247 PageID #: 2255
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`I am getting old so I need a few more breaks.
`MR. SHUMAN: Your Honor, I understand. Some
`housekeeping.
`Can I pass up some copies of my slides?
`THE COURT: Yes.
`Mr. Buckson will take them from you.
`I am assuming the other side has them.
`THE COURT: Counsel, from time to time, also,
`you may notice that your screen, it's going to wash out
`because of the distance and the dome.
`If you want the lights, if there is something
`critical going on up there that you want me to see, Mr.
`Buckson will lower the lights.
`MR. SHUMAN: I appreciate that.
`I will see how it works.
`It's my first time in the courtroom. I
`appreciate the opportunity to be here. I will do my best to
`make things clear this. If you can't see something --
`THE COURT: I will let you know.
`MR. SCHUMAN: Your Honor, my name is Mark
`Schuman. I represent the defendant Watson Laboratories in
`this case. I will be handling the opening for both of the
`co-defendants, Watson Laboratories and Lupin
`Pharmaceuticals.
`This case involves a formulation patent for an
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
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`
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`7
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 7 of 247 PageID #: 2256
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`eyedrop, a particular formulation patent for an eyedrop.
`The drug in the patent is olopatadine. It has been known
`since the 1990s. And it has been known since the 1990s that
`you can use this drug in an eyedrop.
`The defendants will prove that the patent in
`this lawsuit, the '154 patent, is invalid because it would
`have been obvious to one of ordinary skill in the art.
`Now, the first slide is DDX-2. It is the
`patent-in-suit. It's the '154 patent.
`It is entitled High Concentration Olopatadine
`Ophthalmic Composition, which is essentially an eyedrop, a
`fancy name for an eyedrop.
`It has six inventors.
`On this slide, I have highlighted the inventors
`with some coloring. I have done this for a purpose.
`One inventor, Dr. Ghosh, is highlighted in
`yellow. This week you will hear Dr. Ghosh's testimony live
`in court.
`
`The other testimony, the three inventors that
`are highlighted in purple, you will hear by video
`deposition.
`
`The other two inventors you will not hear any
`testimony from at all this week.
`Lastly, at the bottom of the page of DDX-2, I
`have highlighted one of the applications that led to the
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
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`8
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 8 of 247 PageID #: 2257
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`patent-in-suit.
`This is the October 19th, 2011 application.
`This is the date the parties agree from which all of the
`prior art should be calculated from in the case.
`The next slide gives you the claims that the
`parties agree are in contention. They are Claims 8, 9, 21
`through 24.
`
`Of those claims, I have put on Slide DDX-4 the
`broadest claim, that is Claim 8. What I have done, it is a
`little hard to see on this slide, but I think your monitor
`shows it and so does the book -- I have color-coded the
`claim to help us understand the aspects of the claim and how
`the testimony will come in in the case at least from the
`defendants' standpoint.
`First of all, the preamble of the case kind of
`sets us up and tells us about what this claim covers. It's
`an aqueous ophthalmic solution for treatment of ocular
`allergic conjunctivitis.
`So it's an eyedrop that treats this condition
`called allergic conjunctivitis.
`What is that?
`If you have some pollen or some other matter
`that gets in your eye, your eye has a reaction to it. Gets
`itchy. It starts to water.
`That is allergic conjunctivitis.
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
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`
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`9
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 9 of 247 PageID #: 2258
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`You will hear more about that condition as the
`evidence comes in the case.
`That is what this eyedrop is meant to treat.
`So there is a specific formulation that is
`claimed in this patent for treating that condition.
`As I have color-coded, there is three aspects to
`the patent that we will be dealing with with the experts and
`with the evidence. The first is the purple portion. That
`is the active ingredient, which is olopatadine, and the
`amount of that ingredient claimed here in the invention is
`.67 to 1 percent weight-by-volume.
`Now, there is this weight-by-volume percentage.
`What does that mean? We are talking about solutions. You
`will hear evidence that means you weigh out a certain amount
`of powder, then you put it into a volume of solution.
`So when you see weight-by-volume, that's what
`that means. Sometimes we get lazy, sometimes you forget to
`say weight-by-volume because it's a lot to say, and people
`just say percentage, rather. But it often means the same
`thing.
`
`If you hear those two things in the case, often
`people are talking about the same thing.
`I may forget to say it in my opening, too, and I
`apologize if I do. But it happens often in this case. That
`is what people are talking about.
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
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`
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`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 10 of 247 PageID #: 2259
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`The second part of the claim, which I have in
`teal, is really how you get that amount of the active
`ingredient to dissolve into the eyedrop solution.
`In this claim there are three aspects to it.
`It's hard to see on the screen, but you can
`probably see it on yours. There is near the top an
`ingredient called PEG, PEG, in the first line. Then two
`lines down there is a second ingredient called polyvinyl
`pyrrolidone. And then the last two lines contain an
`ingredient called hydroxypropyl-gamma-cyclodextrin.
`So this patent uses three ingredients to
`dissolve the olopatadine into the solution that becomes the
`eyedrop.
`
`Then finally I have highlighted the last part of
`this invention in green. These are kind of the
`run-of-the-mill ingredients that you use to make it into an
`eyedrop, the things that make it thick enough so it doesn't
`run out of your eye when you drop it into your eye and
`preserve the eyedrop on the shelf so it doesn't spoil and
`things of that nature.
`Now, the next slide, which is DDX-5, is a more
`narrow claim, it is Claim 21. Just for illustration, I have
`also highlighted some of the green items, those more
`run-of-the-mill ingredients that form most eyedrops. You
`can see there is a preservative and some pH specifications,
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
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`
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`11
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 11 of 247 PageID #: 2260
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`etc. I won't cover those right now but I will cover them
`later in my opening. But I wanted to give an example that
`the narrower claims have these run-of-the-mill ingredients
`as part of the claims.
`On Slide 6, it turns out a lot of the prior art
`that you will hear evidence about this week comes from Alcon
`itself. It's probably not surprising. They have done a lot
`of work with olopatadine. What I have attempted to do is
`kind of summarize the prior art in a way that you might not
`see it come in from the evidence and the witnesses in this
`case and organize it in a different way so that as the
`evidence comes in this week you will be able to maybe put it
`in a different context, so you will put it in a timeline
`context. And I have organized it by products that are on
`the market.
`
`At the bottom of the screen or in the bottom of
`this exhibit in front of you, I have a timeline running from
`1993 through 2032. I have three products running from the
`left-hand side to the right-hand side. So the first product
`is blue. That is the Patanol product. This was approved in
`1996. It is an Alcon product. It is an olopatadine
`product.
`
`We will talk a little bit more about it in a
`
`few minutes.
`
`The second product to the right was improved
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`
`
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`12
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 12 of 247 PageID #: 2261
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`approved in 2004. It is also prior art. It is called
`Pataday. Pataday was sold around 2004.
`Finally, the third product that's on the market
`involving olopatadine is Pazeo. It was approved in 2015.
`Those are the three products.
`Associated with those products, each of those
`products comes with little package inserts that prescribe
`how the use the products, et cetera. They also have patent
`markings on them, what patents cover these products.
`It turns out that Patanol has what's called the
`Hayakawa patent that covers it. That is also prior art. It
`is JTX-55. I have color-coded that patent on this timeline
`in blue to correspond to the Patanol product.
`The Pataday product, the second product, the
`red product, has a patent called Castillo, JTX-54, that
`corresponds to it. Then the Pazeo product has a '154
`patent-in-suit that corresponds to it.
`For each of the patents, I have put the filing,
`the issue date, and the expiration date for those patents on
`the timeline.
`Now, as you can observe, the Hayakawa patent is
`expired, it's gone, and the Castillo patent will expire in
`2023.
`
`Now, this was not lost on Alcon. The
`olopatadine franchise, as I like to refer to it, was going
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
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`
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`to be lost, and they were looking for a way to expand that
`franchise. And to do that they needed to come up with
`another product to expand that franchise.
`That was to come up with another version of an
`olopatadine product and to get more protection for it. They
`came up with the high dosage olopatadine project. And the
`objective of that project, at least one of them, was to
`expand the olopatadine franchise. That is shown on Slide 6,
`DDX-6.
`
`Let's look at these Patanol products that were
`prior art a little more carefully than were on the screen.
`I have simplified the screen and taken them one by one.
`I will focus on the solutions that were
`available on the market, those patents.
`We will talk about them later. The Patanol
`product was the first one. On Slide 9 is the first product
`that was introduced by Alcon. The Patanol product. This
`was a solution of olopatadine at .1 percent.
`So a couple things that we learn about this. It
`contained olopatadine, and it was a solution, and it was not
`a suspension, it treated allergic conjunctivitis, this
`allergic condition in the eyes, and it was applied twice
`daily.
`
`The next product that was put on the market was
`called Pataday, I have a slide, Slide 11, showing Pataday.
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`
`
`
`14
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 14 of 247 PageID #: 2263
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`By the time Pataday was introduced in 2004, the
`concentration of olopatadine was doubled to .2. It was
`still a solution, not a suspension. And it still treated
`allergic conjunctivitis. But it was applied once a day
`rather than twice a day. That makes sense. It's a stronger
`solution, stronger concentration of the drug. So if you put
`it in your eye it's going to last longer than the
`concentration that's half as strong. So you put it in, it
`lasts twice a long. So you put it in once a day.
`Then we come to the current product, the product
`that's covered by the patent-in-suit, that is the Pazeo
`product, which has a concentration of olopatadine of 0.7
`percent.
`
`In this case, Your Honor, you are going to see
`evidence from defendants' experts. You are going to hear
`them testify. We have experts on the obviousness case. One
`is Dr. Modi, and one is Dr. Maurin. We have the pictures
`here on my demonstrative. They will start today.
`Dr. Modi will tell you about the selection of
`olopatadine and the percentages that one of skill in the art
`would have selected in forming a new selection or new
`product of olopatadine. And Dr. Maurin is a formulator. He
`will tell you how to formulate that amount of olopatadine
`into an eyedrop formulation.
`As far as the selection of olopatadine, you will
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`
`
`
`15
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 15 of 247 PageID #: 2264
`
`recall the first product that was put on the market was
`Patanol. It had a corresponding patent, the Hayakawa
`product here is the Hayakawa patent on Slide 15.
`This was issued in 1997. And an incredible
`amount about olopatadine was known way back in 1997. Let's
`see what this patent discloses to one of skill in the art.
`First of all, it is an Alcon patent, which I
`mentioned earlier. It discloses in the abstract the
`chemical formula for olopatadine. And I won't read that
`into the record, that is it.
`It says it is used for treating allergic eye
`diseases, including allergic conjunctivitis, which is the
`same indication that all of the products on the market are
`used to treat.
`So way back in 1997, already, that indication
`was known, and that's what's being used today in all the
`products.
`
`The next slide, DDX-16, not only was it known
`what it treated, it was known how it treated it. The
`biology of it was known. At the top slide there, the cutout
`I have, I am not going to go into the biology of it, you
`will hear evidence about the fact that olopatadine works in
`two ways. There are cells in the eye called mast cells.
`When you have this allergic conjunctivitis, they have a
`breakdown that secretes certain products. What the
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`
`
`
`16
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 16 of 247 PageID #: 2265
`
`olopatadine does is stabilizes that secretion. That is one
`way that olopatadine works to prevent this allergic
`reaction.
`
`The second way is as an antihistamine type of
`
`product.
`
`So it was known that the biology worked in two
`different ways.
`Not only did they know that it just works, they
`knew how it worked. Furthermore, they knew that it had, in
`the second part, it had concentration dependence. What does
`that mean? That means the more of the product you give, the
`better therapeutic effect you get. The more you give, the
`better effect you get. So they were telling the world about
`that in this patent in 1997.
`And finally, they said that their preferred
`formulation of olopatadine was topical "formulations that
`were solutions," not suspensions but solutions.
`Finally, they claimed, so that no one else could
`practice, they claimed in their patent on Slide DDX-17, they
`claimed solutions, not suspensions, of this product from
`practically zero percent up to five 5 percent, the actual
`amount is .0001 weight percent to 5 percent.
`Not only did they claim it, but the public
`records show that they sued people on this patent and
`protected their market on this patent.
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`
`
`
`17
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 17 of 247 PageID #: 2266
`
`What else would one of skill in the art know
`about olopatadine?
`You will recall that the Hayakawa patent said
`that olopatadine was dose dependent. But that is not the
`only evidence, or not the only record of that that the
`evidence will show. There was also this article by Vogelson
`that we have on DDX-18.
`One of skill in the art would also understand
`that olopatadine was dose dependent based upon this Vogelson
`article. This Vogelson article was written by a number of
`authors. Interestingly, one of those authors I have
`highlighted in pink or purple, and it is Dr. Gamache. Dr.
`Gamache is one of the inventors of the patent-in-suit. He
`is one of the inventors you will hear by video deposition
`this week.
`
`Pardon me, Your Honor.
`In the Vogelson article, there is a table, Table
`2, which I have on Slide 19. What they do here is they are
`looking at various concentrations of olopatadine and seeing
`what effect it has. On the left side of this table, they
`have what's called a vehicle, which is basically a water
`solution with no olopatadine in it. Then they add more
`concentration of olopatadine up to a hundred percent down at
`the bottom. And then on the right side, you can see the
`percent change from vehicle. And you get no change at
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`
`
`
`18
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 18 of 247 PageID #: 2267
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`vehicle down to minus 86 percent change with the 1 percent
`solution.
`
`The more you give -- let's see if I can get my
`laser pointer -- the more you give on this column, on the
`left, the more effect you get on the right. And you get a
`plateau right about here at .75 percent. It goes 61, 83,
`88. Then it goes just a little, but probably plateaus
`around 88 percent, and that's where it stops. You see
`increasing activity all the way up to about here, dose
`dependence.
`
`The Vogelson article, interestingly, the .1
`percent corresponds to Patanol and Vogelson even tells you
`that in the article, the .2 percent corresponds to the
`Pataday product and this article was published about the
`same day that Pataday was put on the market. The .75
`percent corresponds roughly to the current Pazeo product.
`This article lays the whole blueprint for the
`olopatadine franchise that Alcon has, right here.
`Now, not only was olopatadine known by those
`skilled in the art to be dose dependent, but it was also
`known that you if you gave a greater concentration or a
`greater dosage of olopatadine, you would get a longer
`duration of action. That is shown on Slide DDX-20.
`So there was a prior art article of evidence of
`what I call the Yanni 1996 article. Again, it was written
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`
`
`
`19
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 19 of 247 PageID #: 2268
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`by a number of authors. One of those authors was Dr.
`Gamache, an inventor of the patent who you will hear by
`video testimony.
`Here on this chart, in Yanni, the data is
`presented in tabular form, which is sometimes hard to read.
`So you will hear from our expert that she put it into a
`graphical form and she will present this evidence, as you
`see it on the screen here. So I will use that as an opening
`for you.
`
`What they have in Yanni is they give a 1 percent
`version of this drug and a .1 percent. So one a more
`concentrated or a higher dose than the other. They track it
`from four hours to 24 hours. And the 1 percent has very
`little diminution in its effectiveness where the, .1 drops
`off at 24 hours. So you get a longer duration of action.
`This is similar to the difference between the
`Pataday and the Patanol products.
`Recall the Patanol products you had to put in
`twice a day because they were weaker, at .1 percent, and the
`Pataday you put in once a day because they had .2
`concentration of olopatadine. They were stronger and they
`lasted longer.
`So this confirms, again, that longer duration of
`action with a higher concentration of olopatadine.
`So there was a strong -- you will hear evidence
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`
`
`
`20
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 20 of 247 PageID #: 2269
`
`of this -- there was a strong motivation in the prior art so
`use .67 to 1 weight volume percent of olopatadine.
`The Yanni reference showed that you had a strong
`motivation because of the longer duration of action. The
`Vogelson reference showed a strong motivation of action due
`to the increasing dose-response curves. And the Hayakawa
`reference showed you you could make solution up to 1 percent
`and it would be useful for allergic conjunctivitis.
`So it would have clearly been obvious to make an
`eyedrop formulation according to the claims of the patents
`in suit.
`
`In fact, according to Hayakawa, that claimed
`eyedrop formulation already existed and was claimed before
`2010.
`
`Moving to the formulation of that eyedrop,
`looking at Slide DDX-24, you will hear evidence that one of
`the first things a formulator will look at in formulating an
`eyedrop is whether you would want to make it a solution or
`suspension. The first thing a particular formulator wants
`to do is kind of see what people are doing. You don't want
`to reinvent the wheel.
`So you would look to see what are people doing
`with olopatadine for eyedrops. And the first thing you
`would see is they are all solutions. Hayakawa says, and
`claims, solutions. Patanol is a solution and Pataday is a
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`
`
`
`21
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 21 of 247 PageID #: 2270
`
`solution. So you would think immediately solutions.
`But you wouldn't stop there, because you want to
`use your own independent judgment. And you will hear
`evidence, which is shown on DDX-25, that generally solutions
`are preferred over suspensions anyway because they are
`easier to develop and manufacture, they are less irritating
`to the eye. In this case, when you're talking about an
`eyedrop for allergic eye conditions, the eye is already
`irritated and you don't want to further irritate it. They
`have better bioavailability. And you get a more consistent
`dosage. You don't rely on the patient having to shake the
`bottle up to get that stuff back into a consistent
`suspension before they apply it to the eye.
`So solutions are a preferred way of doing these
`
`eyedrops.
`
`The next thing one skilled in the art would try
`to figure out is what generally you do to make an eyedrop.
`You need a solubilizing agent -- you will hear evidence of
`this -- a viscosity increasing agent and all of these other
`things that make a run-of-the-mill eyedrop. That is kind of
`your game plan for making one of these things.
`But you would start with a solubilizing agent,
`because that is the most important thing. You want to get
`your drug into solution to start with.
`And on Slide 27, the first thing you would to do
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`
`
`
`22
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 22 of 247 PageID #: 2271
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`again is do a survey of the prior art. You would want to
`think about, you are making an eyedrop, not some other type
`of drop, you are making an eyedrop. One of the design
`considerations, you will hear evidence about this, you are
`putting it into an eye. You don't want to make it too
`acidic or too basic. If you drop an acidic solution into
`the eye it is going to sting. And it's already inflamed
`from the allergy, et cetera.
`So you are kind of constrained to this neutral
`pH, 6.8 to 7.2. That is one consideration. It turns out
`that at that pH, olopatadine, the drug, exists in a chemical
`form called a zwitterion. I am not going to go into the
`chemistry of that. You will hear evidence about that. It
`is a unique form of chemical ion, and to dissolve a
`zwitterion they prefer nonionic solvents.
`So you already have limited your universe of
`solvents that you want to use the dissolve that zwitterion.
`So you will start to search and say, well, I
`don't want to reinvent the wheel. People have dissolved
`olopatadine. They obviously used these zwitterions. What
`do they use and can I use those? So you will do a
`literature search and see what people have done.
`You will learn that essentially there are three
`types of nonionic solvents that have been used in eyedrops
`and have been used specifically with olopatadine. You will
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`Novartis AG Exhibit 2005
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`
`
`
`23
`Case 1:15-cv-01159-GMS-SRF Document 145 Filed 10/27/17 Page 23 of 247 PageID #: 2272
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`investigate those. Here is what you will find.
`Cyclodextrin. Cyclodextrins are sometimes
`abbreviated CDs, so when you see them in the
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