`
`CIVIL ACTION
`
`NO. 14-1453-LPS
`
`::
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`::
`
`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
`:
`:
`:
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`MEDA PHARMACEUTICALS, INC.,
`and CIPLA LTD.,
`Plaintiffs,
`
`v.
`APOTEX INC. and APOTEX CORP.,
`Defendants.
`
`- - -
`Wilmington, Delaware
`Wednesday, December 14, 2016
`Bench Trial - Volume B
`- - -
`HONORABLE LEONARD A. STARK, Chief Judge
`- - -
`
`BEFORE:
`APPEARANCES:
`
`RICHARDS LAYTON & FINGER, P.A.
`BY: FREDERICK L. COTTRELL, III, ESQ., and
`SELENA E. MOLINA, ESQ.
`and
`STERNE KESSLER GOLDSTEIN & FOX, LLP
`BY: UMA N. EVERETT, ESQ.,
`DENNIES VARUGHESE, ESQ.,
`RAMI BARDENSTEIN, ESQ.,
`ADAM C. LaROCK, ESQ.,
`JOSHUA I. MILLER, ESQ.,
`JOSEPHINE J. KIM, ESQ.,
`STEPHANIE NGUYEN, ESQ., and
`MARK FOX EVENS, ESQ.
`(Washington, District of Columbia)
`Counsel for Plaintiffs
`
`Valerie Gunning
`Official Court Reporter
`
`Brian P. Gaffigan
`Official Court Reporter
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`1
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`1
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`CIP2019
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
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`
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`APPEARANCES: (Continued)
`
`158
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`PROCTOR HEYMAN ENERIO, LLP
`BY: DOMINICK GATTUSO, ESQ.
`and
`WINSTON & STRAWN, LLP
`BY:
`GEORGE C. LOMBARDI, ESQ.,
`SAMUEL S. PARK, ESQ.,
`KEVIN E. WARNER, ESQ., and
`RYAN B. HAUER, ESQ.
`(Chicago, Illinois)
`and
`WINSTON & STRAWN, LLP
`BY: CHARLES B. KLEIN, ESQ., and
`ILAN WURMAN, ESQ.
`(Washington, District of Columbia)
`Counsel on behalf of Defendants
`
`- oOo -
`P R O C E E D I N G S
`(REPORTER'S NOTE: The following trial was held
`in open court, beginning at 3:08 p.m.)
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`THE COURT: Good afternoon.
`(The attorneys respond, "Good afternoon, Your
`
`Honor.")
`
`THE COURT: Do we have any issues we need to
`discuss before we continue with the examination?
`MR. LOMBARDI: We apparently have a technical
`issue, Judge, that they were working on resolving before you
`came down.
`
`THE COURT: Where do we stand?
`MR. ARANA: We're trying to get ahold of them
`
`again.
`
`MR. LOMBARDI: We need the courtroom people,
`something happened to the screen.
`THE COURT: Okay. Do you know if they have been
`called or do you need us to call them?
`MR. LOMBARDI: We need to recall them. They
`were here but I think we do need to recall them.
`THE COURT: We will do that.
`MR. EVENS: Your Honor, if I could approach?
`THE COURT: Wait one second.
`MR. EVENS: Evens.
`THE DEPUTY CLERK: He is on his way.
`THE COURT: In the meantime, is there something
`we should discuss while we're waiting for them to come back?
`MR. EVENS: Your Honor, Mark Evens again.
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`THE COURT: Yes.
`MR. EVENS: When we left yesterday, we had,
`plaintiffs had moved to introduce the four exhibits that we
`used to impeach Dr. Wedner. We're still trying to work out
`an accommodation with Apotex. We should be able to reach
`that certainly by the next break, we hope.
`THE COURT: All right. Thank you for the update
`
`on that.
`
`MR. EVENS: Thank you.
`THE COURT: Are there any issues from defendants
`other than the technical issue?
`MR. KLEIN: No issues, Your Honor.
`THE COURT: All right.
`MR. KLEIN: One logistical issue is yesterday we
`promised to given up updated openings slides so we do have
`those slides.
`THE COURT: Oh, okay. Please pass those up.
`MR. KLEIN: I don't know. How many do you need?
`THE COURT: Two, please.
`MR. KLEIN: Two?
`THE COURT: Yes. And, Mr. Klein, it is your
`witness I believe. I have your hard copy of the slides.
`Would we be able to get started or would you prefer to wait?
`MR. KLEIN: We can -- yes, we can do that.
`THE COURT: All right. Why don't we do that.
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`And if we need to stop to let the technical people do their
`thing, just let me know.
`MR. KLEIN: I can also try to put it on the
`Elmo, if that is easier.
`THE COURT: The old fashioned way, if you like,
`but you can pass up a hard copy.
`MR. KLEIN: A hard copy should be ...
`THE COURT: Our assistant is here.
`MR. KLEIN: It might not be worth trying. In
`the meantime ...
`(Witness retakes the witness stand.)
`THE COURT: You do not need to be sworn. You
`are under oath.
`And are there hard copies of your presentation
`
`up there?
`
`THE WITNESS: I will take a look. Yes.
`THE COURT: Mr. Klein, do you think we can do
`this with the witness and me having a hard copy?
`MR. KLEIN: I do think so, Your Honor.
`THE COURT: All right. I don't know if there is
`something you all can be helped with in the background while
`we're doing this, but if there is, I promise it won't
`distract me.
`
`MR. KLEIN: Okay.
`THE COURT: All right. Why don't you go ahead
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`Schleimer - direct
`
`162
`
`then.
`
`... ROBERT P. SCHLEIMER, having been previously
`sworn as a witness, was examined and testified as follows ...
`DIRECT EXAMINATION (Continued)
`
`BY MR. KLEIN:
`Q.
`Welcome back, Dr. Schleimer.
`A.
`Thank you.
`Q.
`Now, yesterday I forgot to ask you something. Have
`you done work for Apotex in the past?
`A.
`I have.
`Q.
`What type of work?
`A.
`I met with a couple lawyers representing Apotex a
`couple times in order to explore whether I would be an
`expert witness for them.
`Q.
`When was that?
`A.
`In April of 2010.
`Q.
`And was that in connection with the litigation?
`A.
`Yes.
`Q.
`And were you compensated for your time?
`A.
`I was.
`Q.
`About how much did you make during that period?
`A.
`About $7500.
`Q.
`Did you end up serving as an expert witness?
`A.
`I did not.
`Q.
`Now, let's go back to DDX-4.20, which is where I
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`163
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`Schleimer - direct
`believe we left off last night. Do you have that in front
`of you?
`I do.
`A.
`We were talking about intranasal antihistamines. How
`Q.
`many intranasal antihistamines were FDA approved in the 2002
`time frame?
`A.
`There were two, azelastine and Levocabastine.
`Q.
`Can you compare those two products?
`A.
`Well, there were only a couple of studies that
`compared them, and the one that I have as an example on the
`slide is by Falser from 2001, and they concluded that
`Azelastine was statistically superior in efficacy as judged
`by both physicians and patients themselves.
`Q.
`And were you referring to Falser 2001, which is
`PTX-266, as well as Küsters, which is DTX-85?
`A.
`Yes.
`Q.
`If we go to DDX-4.21, were steroids successfully
`combined with antihistamines before 2002?
`A.
`Yes. In fact, it was probably the most common
`combination prescribed since antihistamines and intranasal
`steroids were both exceedingly popular drugs. In this slide
`I have excerpted a study by Drouin, et al, where they tested
`the effects of the combination and found that it was -- that
`it improved the treatment of patients with seasonal allergic
`rhinitis compared to the monotherapies.
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`Schleimer - direct
`And what drugs were at issue in that study?
`Q.
`Loratadine and beclomethasone dipropionate.
`A.
`Are you referring to PTX-333?
`Q.
`Yes.
`A.
`If we go to the next slide, DDX-4.22. Were there
`Q.
`other studies before 2002 combining steroids with
`antihistamines?
`A.
`Yes. Many. And this is one example of them. This
`is Brooks in 1996, and they confirmed the overall
`effectiveness of the combination of a steroid and
`antihistamine and they concluded that it will provide very
`satisfy level of comfort for most seasonal allergic rhinitis
`patients and would be preferred, and they also suggested
`that there were additive suppression symptoms with a
`combination.
`Q.
`And are we referring to PTX-332?
`A.
`Yes.
`Q.
`If we go to the next slide, which is DDX-4.23, did
`you also review a reference published by Berger in 1999?
`A.
`Yes.
`Q.
`And does Berger teach anything with regard to
`Azelastine combination therapy?
`A.
`Yes. And, in fact, Berger in this paper actually
`comes out and proposes that Azelastine could be used in
`combination with intranasal corticosteroids as his
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`There were, and I think we'll discuss them a little
`
`Schleimer - direct
`recommendation to physicians.
`Q.
`That is DTX-26; right?
`A.
`Yes.
`Q.
`And there were other studies combining oral
`antihistamines with intranasal steroids before 2002; is that
`right?
`A.
`later.
`Let's go to DDX-4.24. Was fluticasone ever
`Q.
`co-formulated with another drug before 2002?
`A.
`Yes. And this slide I think is a very important one
`because it covers the precedent that was already in the
`literature, which was to take the steroid drug, which is the
`superior drug, but acts slowly, and combine it with a
`rapidly acting drug, because steroids in asthma were the
`best drugs available, but the problem was patients got
`impatient. They didn't feel the effect and they would
`sometimes not use it.
`So what Advair was is a combination of a rapidly
`acting bronchodilator that would allow patients to have
`improved breathing immediately, and it was combined with a
`steroid, and over many days or weeks the steroid would
`progressively improve the disease. And so this was due to
`the same type of complementary mechanisms of action,
`combining a drug that worked quickly and a drug that worked
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`166
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`Schleimer - direct
`effectively, but with a delay.
`And by putting it in a single product, they also
`believed that it improved adherence, which is another way of
`saying compliance. Ultimately, this drug Advair ended up
`being the largest selling respiratory drug of all time, I
`believe.
`Q.
`And was the drug well-known as of June 2002 as well?
`A.
`Yes. It was well on its way to being a very popular
`drug.
`Okay. And for this slide, are you referring to
`Q.
`DTX-77 and DTX-68?
`A.
`Yes.
`Q.
`Okay. If we go to the next slide, this is 4.25.
`Let's now turn to your next background topic, which is the
`patents-in-suit; right?
`A.
`Yes.
`Q.
`And let's go to DDX-4.26. Have you reviewed the '620
`and '428 patents-in-suit which are DTX-136 and DTX-253?
`A.
`Yes.
`Q.
`And do you understand that these patents are held by
`Cipla?
`Yes.
`A.
`Do all of the asserted '620 patent claims require a
`Q.
`pharmaceutical formulation comprising Azelastine and
`fluticasone in a nasal spray?
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`Schleimer - direct
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`167
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`Yes.
`A.
`And do you understand that Apotex has a formulation
`Q.
`expert who will testify about the excipients required by
`that patent?
`A.
`Yes. Dr. Donovan.
`Q.
`And do all the asserted '428 patent claims cover
`methods of treating seasonal allergic rhinitis with
`basically the '620 patent formulation?
`A.
`Yes.
`Q.
`And what's the difference between seasonal and
`non-seasonal allergic rhinitis?
`A.
`Well, as I believe Dr. Accetta testified, seasonal
`allergic rhinitis occurs seasonally. For instance, if a
`patient were only allergic to birch pollen, they would only
`have symptoms when the birch trees are booming whereas
`perennial allergic rhinitis is typically when the person is
`allergic to an allergen that's always in their environment.
`It could be a cat or mold or something like that. So they
`always have symptoms.
`But mechanistically, they both work the same way
`and they respond similarly to drugs.
`Q.
`What date do you use for determining prior art?
`A.
`June 14th, 2002.
`Q.
`And, by the way, are the patent specifications for
`the two patents materially similar for purposes of this
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`Schleimer - direct
`
`168
`
`case?
`Yes.
`A.
`Let's go to DDX-4.27. Now, do you recognize this
`Q.
`demonstrative to be a portion of the '428 patent
`specification?
`A.
`Yes.
`Q.
`Did the listed inventors claim to have invented
`fluticasone?
`A.
`No.
`Q.
`And did they claim to have invented a method of using
`fluticasone to treat seasonal allergic rhinitis?
`A.
`No.
`Q.
`Did they claim to have invented Azelastine?
`A.
`No.
`Q.
`And did they claim to have invented a method using
`Azelastine to treat seasonal allergic rhinitis?
`A.
`No.
`Q.
`And is this confirmed by the snapshot on DDX-4.27
`from DTX-253?
`A.
`Yes.
`Q.
`Now, if we go to 4.28, what did the inventors say
`about treatment with fluticasone combined with Azelastine?
`A.
`Well, they said what I believe was already clear at
`that time, which was that it would be highly desirable to
`combine an antihistamine with a steroid.
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`Schleimer - direct
`In a pharmaceutically acceptable formulation?
`Q.
`Yes.
`A.
`And does the patent disclose any new clinical data to
`Q.
`support combining Azelastine with fluticasone?
`A.
`No. There are no clinical data.
`Q.
`Did the patent disclose testing as to whether these
`drugs are compatible or incompatible with one another?
`A.
`No.
`Q.
`Do the patents disclose any recommended dosing
`information for the combination?
`A.
`No.
`Q.
`If we go to the next slide, which is DDX-4.29.
`How does the '428 patent describe the
`therapeutic effect of combining the two drugs, Azelastine
`and fluticasone?
`A.
`Well, interestingly, it states that the two
`therapeutic agents could be administered simultaneously
`either in the same or different formulations and either
`separately or sequentially. And in those cases, would
`obtain a synergistic therapeutic effect.
`Q.
`So according to the patent, do you need a
`co-formulation of the two drugs to achieve what they called
`a synergistic therapeutic effect?
`A.
`No.
`Q.
`And, by the way, does the patent provide any data
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`Schleimer - direct
`that shows synergy when combining these two agents?
`A.
`No.
`Q.
`Could you go to the next slide, which is 4.30. Are
`you generally familiar with the prosecution history?
`A.
`Yes.
`Q.
`And did the examiner initially find the
`co-formulations claimed by the '620 patent to be obvious or
`not obvious?
`A.
`Obvious.
`Q.
`And are you referring to DTX-137?
`A.
`Yes.
`Q.
`Now, if you go to slide 4.31, did Cipla respond to
`that action by the PTO by submitting arguments and
`declarations?
`A.
`Yes. They submitted something called a Chopra
`declaration, which argued that there was commercial
`success and an unmet need and unexpected superiority of the
`product.
`Q.
`Okay. For the unexpected superiority, was that
`declaration by Dr. Rajan and Maus?
`A.
`Yes.
`Q.
`All right. And, again, we're at DTX-137; is that
`right?
`A.
`Q.
`
`Yes.
`Now, we were just talking about the prosecution
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`Schleimer - direct
`history for the '620 patent. If we go to DDX-4.32, why did
`the examiner allow the '428 patent?
`A.
`The same reason.
`Q.
`And is that DTX-307?
`A.
`Yes.
`Q.
`All right. Now, let's turn to your obviousness
`opinions. And on DDX-4.33, we have your outline here.
`Is the first several level of ordinary skill in
`
`the art?
`A.
`Yes.
`Q.
`All right. Let's talk about that. It's on DDX-4.34.
`What is the relevant art?
`A.
`The relevant art is the study and the treatment of
`allergic rhinitis.
`Q.
`And were you asked to define a person of ordinary
`skill in the art from a clinical perspective?
`A.
`I was.
`Q.
`And what is your definition?
`A.
`My definition is that it would be a person with an
`advanced degree, an M.D., a Ph.D. or a pharm D in that
`field, the field of allergy immunology or pharmacology or an
`equivalent field as well as three additional years in either
`treatment or the research for treatments of allergic
`rhinitis, preferably with experience with steroids and
`antihistamines.
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`Schleimer - direct
`Do you understand that a person of ordinary skill in
`Q.
`the art for these patents could also be a formulator and
`Apotex has another expert who will talk about that?
`A.
`Yes.
`Q.
`Now, were you a person of ordinary skill in the art
`as of June 2002 under your definition?
`A.
`Yes.
`Q.
`Do you understand that Meda's experts have a
`different definition?
`A.
`Yes. They think that an M.D. is required for a
`person of skill in the art.
`Q.
`Okay. Do you agree?
`A.
`No.
`Q.
`Do you -- have you taught M.D.s how to treat allergic
`rhinitis?
`A.
`Yes. As I testified earlier, I regularly teach
`clinical fellows learning to practice allergy about the
`pathologic mechanisms and the treatments of allergic
`diseases, including allergic rhinitis.
`Q.
`And do you actually supervise individuals who satisfy
`the definition of a person of ordinary skill in the art
`under Meda's definition?
`A.
`Yes. Our clinic, which is one of the largest
`academic clinics in the country, is one that I'm ultimately
`responsible for administratively.
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`173
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`Schleimer - direct
`And have you published about allergic rhinitis?
`Q.
`I have.
`A.
`Now, most scientists in pharmaceutical companies who
`Q.
`work on drug development for allergic rhinitis drugs, do
`they have an M.D.?
`A.
`Probably not. I can't tell you precisely, but in my
`experience, some have an M.D., some who are in industry and
`developing drugs. Most do not.
`Q.
`All right. And did either of the listed inventors
`have an M.D.?
`A.
`No.
`Q.
`So do you think a person of ordinary skill in the art
`as of 2002 would need to have an M.D. in order to understand
`the patents-in-suit and the issues in this case?
`A.
`I do not.
`Q.
`Would your opinions in this case change if a person
`of ordinary skill in the art were defined to require an
`M.D.?
`No. I think as long as the M.D. was treating
`A.
`patients with allergic disease and had experience in that,
`it would be obvious to them that combining these two drugs
`was desirable.
`Q.
`Let's turn to the key prior art on which you relied.
`The table of contents is DDX-4.35, but let's move to
`DDX-4.36.
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`174
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`Schleimer - direct
`Can you describe the prior art that you relied
`on and is reflected in this slide?
`A.
`Yes. One important piece of prior art is the
`approval by the FDA of Flonase, which contains fluticasone
`in 1994.
`Q.
`And what was Flonase indicated for?
`A.
`Flonase was approved for the management of nasal
`symptoms of seasonal and perennial allergic and non-allergic
`rights.
`You're referring to DTX-33?
`Q.
`Yes.
`A.
`So let's go to DDX-4.37. What's the next prior art
`Q.
`reference that you are relying on?
`A.
`This is the approval in 1996 of Astelin, which
`contains Azelastine. It was approved by the FDA for
`intranasal administration for the treatment of the symptoms
`of seasonal allergic rhinitis.
`Q.
`And is that DTX-22?
`A.
`Yes.
`Q.
`Let's go to DDX-4.38. Were you here for Dr.
`Accetta's testimony yesterday?
`A.
`Yes.
`Q.
`And were you here for Dr. Wedner's testimony?
`A.
`Yes.
`Q.
`Do you rely on their testimony to support your
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`opinion?
`A.
`I do.
`Q.
`How so?
`A.
`Well, both of them testified that shortly after
`Astelin became available to practicing allergists, they used
`it in combination with Flonase as an effective conjunctive
`therapy.
`Q.
`And here, are you citing DTX-1 through 10?
`A.
`Yes, and there is an excerpt from one of his charts
`which was shown yesterday.
`Q.
`Let's move on to DDX-4.39.
`What is the next key prior art reference?
`I think this is a very important piece of information
`A.
`in the case because this patent application by Cramer, et al
`from the Proctor & Gamble company essentially describes the
`invention in my opinion.
`They wanted to combine a glucocorticoid or
`steroid in an internasal drug, and they listed about six
`different possible steroids, with what they called a
`leukotriene inhibiting antihistamine.
`So at that time, already by '97, it was known,
`what I said yesterday, which is that antihistamines, when
`used topically or in the nose, can exert antiinflammatory
`effects that are not found with oral versions in general.
`So Cramer wanted to take an intranasal steroid
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`Schleimer - direct
`and combine it with an intranasal antihistamine in order to
`have a drug that with those complimentary actions, one that
`worked quickly against the early phase and one that worked
`well against the late phase.
`And among the drugs, which there was a small
`number, they specifically mentioned fluticasone and
`azelastine.
`Q.
`I don't think you mentioned the date. Was this 1997?
`A.
`Yes. June 25th.
`Q.
`And the applicant is Proctor and Gamble. What type
`of company is that?
`A.
`That is a pharmaceutical company.
`Q.
`Now, in terms of -- how many steroids are listed
`here?
`I think it was six.
`A.
`And which were the most potent steroids in that list
`Q.
`as of June 2002?
`A.
`As I testified yesterday, fluticasone, with
`mometasone a little bit behind it.
`Q.
`And in terms of the antihistamines, how many are
`listed?
`They list three, but only one of them was available
`A.
`intranasally for topical administration, and that was
`azelastine.
`Q.
`So did Cramer identify a finite number of drugs for
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`co-formulation in a pharmaceutical composition for nasal
`administration?
`A.
`Yes.
`Q.
`In fact, what would have been the most obvious drug
`combination or combinations to a person of ordinary skill in
`the art reading Cramer in June of 2002?
`A.
`Well, as discussed yesterday in the deposition of
`Mr. Fuge, I agreed with what he said, which is that
`fluticasone and azelastine would be the most obvious, not
`the only but the most obvious combination because
`fluticasone has the highest potency azelastine was the most
`effective intranasal antihistamine.
`Q.
`Is Cramer DTX-12?
`A.
`Yes.
`Q.
`Let's move on to DDX-4.40. What is the next prior
`art reference?
`A.
`This is another patent which had the same general
`idea published for, submitted by Segal disclosing a
`co-formulation of azelastine and fluticasone.
`Q.
`I think you said it is a patent. Is it a patent
`application?
`A.
`It is an application, yes.
`Q.
`Is it dated November 5th, 1998?
`A.
`Yes.
`Q.
`All right. If we go to the next demonstrative, which
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`Schleimer - direct
`is DDX-4.41. Does this show portions of the Segal
`reference?
`A.
`Yeah. That is an excerpt of the application. So
`Dr. Segal was at the Warner Lambert company, and they had
`the same general idea, a little bit less specified.
`Basically, they wanted to take an antiinflammatory steroid,
`which as I explained, by far the most effective drugs for
`the treatment of this disease. And they wanted to combine
`it with a rapidly acting drug.
`In this case, they included antihistamines, but
`they included a few others as well. And they, like Cramer,
`they specifically mentioned fluticasone and azelastine as
`good candidate drugs for this combination.
`Q.
`What kind of company is Warner Lambert?
`A.
`Pharmaceutical company.
`Q.
`Okay. To be clear, is Segal disclosing a
`co-formulation of fluticasone and azelastine?
`A.
`Yes.
`Q.
`And is this DTX-21?
`A.
`Yes.
`Q.
`Let's go to the next reference on DDX-4.42.
`Can you describe this reference, please?
`Yes. So this is an excerpt from a paper by Charlie
`A.
`Spector who is a leader in this field. And in my opinion,
`he really laid it out. He said that the optimal treatment
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`Schleimer - direct
`for patients with SAR, which is seasonal allergic rhinitis,
`can only be achieved by managing both the early phase
`response, the EPR, and the late phase response.
`And he went on to say that the most
`effective drugs for the early phase response were the H1
`antihistamines and the most effective drugs for late phase
`response were the corticosteroids.
`So he concluded by saying the ideal
`pharmacologic therapy would be a drug that contained both of
`those drugs.
`Q.
`I don't think you mentioned the date. Are we talking
`March of 1999?
`A.
`Yes.
`Q.
`Is Spector DTX-50?
`A.
`Yes.
`Q.
`If we go to DDX-4.43. Is this another snapshot from
`the Spector reference?
`A.
`It is. And it's also relevant to the proceedings
`today. You can see on the left the title of this editorial
`is The Ideal Pharmacotherapy For Allergic Rhinitis. And
`during this discussion, Dr. Spector points out that
`decongestants, although they can have some beneficial
`effects against congestion, have minimal effects against all
`the other important symptoms of allergic rhinitis. So they
`would not be a good complementary drug when combined with a
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`180
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`steroid.
`
`Chromium sodium and that family of drugs has to
`be taken for weeks; and as Dr. Wedner testified, it has to
`be taken four times a day. So it's not a practical
`solution.
`
`And the anticholinergic drugs such as
`ipratropium, although they are good at drying runny nose,
`they also doesn't address the other important symptoms of
`allergic rhinitis, like sneezing, congestion, itchiness, et
`cetera.
`So what does Dr. Spector suggests for managing both
`Q.
`the early and late phases of allergic rhinitis?
`A.
`As I said in the previous slide, it was his opinion
`that the ideal pharmacologic therapy would be a drug that
`addresses the early and the late phase response, and that
`would be an antihistamine and a steroid.
`Q.
`Let's go to the next slide, which is DDX-4.44. What
`is the next prior art reference you are relying on?
`A.
`In 2001, the guidelines, called the ARIA guidelines,
`that were discussed yesterday, which is a document of
`about 180 pages that gives recommendations to practicing
`physicians how to treat this disease, was released; and it
`is specifically recommended the combination of steroid,
`intranasal steroid and antihistamine cotherapy.
`Q.
`And we'll take a closer look in a moment. But before
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`we do so, how did allergy doctors and scientists view the
`ARIA guidelines as of June 2002?
`A.
`Well, as mentioned by Dr. Wedner, the ARIA guidelines
`and the practice parameters are documents generated by
`international leading experts, and they're found to be
`generally very useful by practicing physicians.
`Q.
`And we're referring to PTX-326; right?
`A.
`Yes.
`
`MR. KLEIN: Can we go to DDX-4.45.
`BY MR. KLEIN:
`Q.
`Can you explain what is on the screen?
`THE COURT: And for the record, the screen is
`now working happily.
`THE WITNESS: Yes.
`BY THE WITNESS:
`A.
`This is a section of the treatment or management of
`severe persistent disease.
`Where it says in that first red box, a stepwise
`approach is proposed. It is advised to use intranasal
`glucocorticosteroids as a first line treatment. In other
`words, a drug of first choice.
`And if that doesn't manage the disease to add an
`H1 antihistamine.
`Q.
`And to be clear, is azelastine an H1 antihistamine?
`A.
`Yes.
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`Schleimer - direct
`And because it is a long document, I'll identify the
`Q.
`page. It is PTX-326 at S251.
`Okay. Let's turn to your obviousness analysis.
`You offered an opinion on whether it was obvious
`as of June 2002 to combine Flonase with Astelin to treat
`allergic rhinitis.
`A.
`I do. I think it was obvious and had been for
`several years. Flonase was popular first-line therapy for
`allergic rhinitis. It was already combined with
`antihistamines routinely due to the complementary mechanisms
`that I talked about.
`Combining a fast acting drug and a slow acting
`but more effective drug together.
`The prior art encouraged the use of intranasal
`antihistamines and the most effective one of the two
`available were azelastine, and doctors such as Drs. Accetta
`and Wedner and many others combined Flonase and Astelin in
`their clinical practice with success.
`Q.
`Did you also offer an opinion as to whether it was
`obvious to a person of ordinary skill in the art as of June
`2002 to co-formulate fluticasone and azelastine?
`A.
`I do. I think co-formulation was logical, as was
`discussed yesterday.
`It is more convenient to use one bottle than two
`bottles for patients with severe enough disease that they
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`183
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`need both drugs.
`And as I mentioned, with the experience with
`Advair, convenient therapies improved patient compliance.
`Two pharmaceutical companies had already
`independently disclosed this specific co-formulation in
`patent applications; that is Cramer and Segal.
`And the successful co-formulation of fluticasone
`with a rapid acting complementary drug in asthma was
`extraordinarily successful by that time.
`Q.
`So would a skilled artisan in 2002 have been
`motivated to co-formulate fluticasone and azelastine in an
`intranasal formulation?
`A.
`Yes.
`Q.
`And would a skilled artisan in 2002 have a reasonable
`expectation that such a co-formulation would successfully
`treat seasonal allergic rhinitis?
`A.
`Yes.
`Q.
`And you are citing DTX-21, 22, 33, 68 and 77; right?
`A.
`Yes.
`Q.
`Go to the next slide. We're on DDX-4.49 now. How
`much fluticasone and azelastine would a skilled artisan use
`in a co-formulated product?
`A.
`Well, initial inclination would be just to use the
`amounts per spray that were already available in the
`approved products.
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`Schleimer - direct
`So what would that look like as a dosing regimen for
`Q.
`fluticasone?
`A.
`Well, if you look on the left in green, fluticasone
`was available at 50 micrograms per spray, and two regimens
`that could be used are two sprays per nostril once a
`day, or one spray per nostril twice a day, and either of
`those regimens would produce 200 micrograms per day, daily
`dose.
`Are these consistent with the FDA approved indication
`Q.
`for Flonase?
`A.
`Yes.
`Q.
`And what could the dosing for azelastine in a
`co-formulated product look like?
`A.
`Well, Astelin contains 137 micrograms per spray of
`azelastine, and you could use the same two regimens, two
`sprays per nostril once a day or one spray per nostril twice
`a day, and that would yield 548 micrograms as the daily
`dose.
`And is that an approved dosing regimen for
`Q.
`azelastine?
`A.
`Yes. It's approved in the U.K. and other European
`countries, but it's half of a dose that's approved in the
`U.S.
`And so what would the co-formulated product look like
`Q.
`in terms of a regimen?
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`Schleimer - direct
`Well, with these two regimens, I think a skilled
`A.
`artisan would clearly prefer the one on the bottom right,
`which is one spray per nostril twice a day for the reason
`that azelastine only works for about a half a day.
`Q.
`And are you referring to DTX-22 and 33 and PTX-326
`for this slide?
`A.
`Yes.
`Q.
`Let's go to the next slide. Do you understand that
`Meda is arguing that certain clinical testing in the prior
`art teaches away or otherwise discourages co-formulating
`fluticasone in azelastine?
`A.
`Yes.
`Q.
`And do you agree or disagree?
`A.
`I disagree.
`Q.
`And does this slide list some of the prior art
`clinical studies that have been cited by the parties in this
`case?
`Yes.
`A.
`And have you specifically identified which of these
`Q.
`studies that Meda is relying on?
`A.
`Yes. The ones that are shown with an asterisk.
`Q.
`Okay. How many?
`A.
`Four out of the seven.
`Q.
`And did you list these clinical studies in
`chronological order?
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`Yes.
`A.
`So how many of the seven clinical studies on this
`Q.
`slide found at least some advantage to combining a steroid
`with an antihistamine?
`A.
`Five out of the seven.
`Q.
`Now, let's take a look at the first two, Juniper 1989
`and Benincasa 1994. Did those two studies find an advantage
`in combining a steroid and an antihistamine?
`A.
`No. However, in the Juniper study, they found a
`strong trend for superiority in both eye symptoms and
`sneezing that was not statistically significant.
`In the Benincasa study, it was a large study,
`but regrettably, it didn't have a placebo group or an
`antihistamine alone group. And another issue with that
`study is they only collected data after three weeks or
`eight weeks of treatment. And as I've explained, the period
`of time when you would expect to see the real advantage of
`the combination is early on before the steroid is fully
`effective when the antihistamine is making a big, a bigger
`contribution proportionately.
`Q.
`Now, the Juniper 1989 study used an oral
`antihistamine called astemizole; is that right?
`A.
`Yes.
`Q.
`All right. Was that drug available on the market in
`June of 2002?
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`No. Astemizole was withdrawn from development.
`A.
`And do these two