throbber
157
`
`CIVIL ACTION
`
`NO. 14-1453-LPS
`
`::
`
`::
`
`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
`:
`:
`:
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`
`1
`
`CIP2019
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

`APPEARANCES: (Continued)
`
`158
`
`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.)
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`2
`
`2
`
`

`

`159
`
`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`3
`
`3
`
`

`

`160
`
`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`4
`
`4
`
`

`

`161
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`5
`
`5
`
`

`

`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`6
`
`6
`
`

`

`163
`
`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`7
`
`7
`
`

`

`164
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`8
`
`8
`
`

`

`165
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`9
`
`9
`
`

`

`166
`
`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?
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`10
`
`10
`
`

`

`Schleimer - direct
`
`167
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`11
`
`11
`
`

`

`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`12
`
`12
`
`

`

`169
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`13
`
`13
`
`

`

`170
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`14
`
`14
`
`

`

`171
`
`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`15
`
`15
`
`

`

`172
`
`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`16
`
`16
`
`

`

`173
`
`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`17
`
`17
`
`

`

`174
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`18
`
`18
`
`

`

`Schleimer - direct
`
`175
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`19
`
`19
`
`

`

`176
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`20
`
`20
`
`

`

`177
`
`Schleimer - direct
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`21
`
`21
`
`

`

`178
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`22
`
`22
`
`

`

`179
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`23
`
`23
`
`

`

`Schleimer - direct
`
`180
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`24
`
`24
`
`

`

`181
`
`Schleimer - direct
`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`25
`
`25
`
`

`

`182
`
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`26
`
`26
`
`

`

`Schleimer - direct
`
`183
`
`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`27
`
`27
`
`

`

`184
`
`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?
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`28
`
`28
`
`

`

`185
`
`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?
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`29
`
`29
`
`

`

`Schleimer - direct
`
`186
`
`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?
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`30
`
`30
`
`

`

`187
`
`Schleimer - direct
`No. Astemizole was withdrawn from development.
`A.
`And do these two

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket