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`Argentum Pharmaceuticals LLC, v. Cipla, Ltd.
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`Robert P. Schleimer
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` UNITED STATES PATENT AND TRADEMARK OFFICE
` _________________
`
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` _________________
`
`
` ARGENTUM PHARMACEUTICALS LLC
` Petitioner
` v.
` CIPLA LTD.
` Patent Owner
` _________________
` Case IPR2017-0087
` Patent 8,168,620
` _________________
` DEPOSITION OF ROBERT P. SCHLEIMER, Ph.D.
` March 30, 2018
` Chicago, Illinois
`______________________________________________
` DIGITAL EVIDENCE GROUP
` 1730 M Street, NW, Suite 812
` Washington, D.C. 20036
` (202) 232-0646
`
`www.DigitalEvidenceGroup.com
`
`Digital Evidence Group C'rt 2018
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`202-232-0646
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`CIP2179
`Argentum Pharmaceuticals v. Cipla Ltd.
`IPR2017-00807
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`3/30/2018
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`Argentum Pharmaceuticals LLC, v. Cipla, Ltd.
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`Robert P. Schleimer
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`Page 2
` The deposition of ROBERT P. SCHLEIMER, Ph.D.,
`called by the Patent Owner for examination, taken
`before Cynthia J. Conforti, CSR, RPR, CRR, at Foley
`& Lardner LLP, 321 North Clark Street, Suite 2800,
`Chicago, Illinois, commencing at the hour of
`9:08 a.m. on the 30th day of March, A.D., 2018.
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`A P P E A R A N C E S:
`ON BEHALF OF THE PETITIONER:
` FOLEY & LARDNER LLP
` 321 North Clark Street
` Suite 2800
` Chicago, Illinois 60654-5313
` 312.832.4500
` BY: MICHAEL R. HOUSTON, ESQ.
` mhouston@foley.com
`
`ON BEHALF OF THE PATENT HOLDER:
` STERNE, KESSLER, GOLDSTEIN & FOX PLLC
` 1100 New York Avenue, NW
` Washington, DC 20005
` 202.772.8979
` BY: JOSHUA I. MILLER, ESQ.
` jmiller@sternekessler.com
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` INDEX
`TESTIMONY OF ROBERT P. SCHLEIMER, Ph.D. PAGE
`Examination by Mr. Miller 6
`Examination by Mr. Houston 110
`
` DEPOSITION EXHIBITS
`NUMBER DESCRIPTION PAGE
`Exhibit 1001 U.S. Patent 8,168,620 B2 29
` (15 pages)
`Exhibit 1003 Declaration of Schleimer 102
` (60 pages)
`Exhibit 1011 European Patent Application 33
` EP 0 780 127 A1
` (9 pages)
` Exhibit 1144 Second
` Declaration of Schleimer
` (71 pages)
`Exhibit 1012 International Application 33
` WO 09/48839
` (13 pages)
`Exhibit 1031 Juniper article 75
` (9 pages)
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` DEPOSITION EXHIBITS (Continued)
`NUMBER DESCRIPTION PAGE
`Exhibit 1035 Drouin article 21
` (10 pages)
`Exhibit 1038 Brooks article 59
` (7 pages)
`Exhibit 1041 Galant article 12
`Exhibit 1045 Ratner article 94
` (8 pages)
`Exhibit 1055 Dr. Accetta Patient Record 8
` (1 page)
`Exhibit 1148 Han article 107
` (6 pages)
`Exhibit 1160 "Clinical Therapeutics" 107
` (12 pages)
`CIP2041 Howarth article 62
` PTX0337-00001 - 6
`CIP2042 Nielsen article 62
` PTX0338-00001 - 17
`CIP2147 Second Declaration of 46
` Carr
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` (Witness sworn.)
` ROBERT P. SCHLEIMER, Ph.D.,
`having been duly sworn, was examined and testified
`as follows:
` DIRECT EXAMINATION
`BY MR. MILLER:
` Q. All right, Dr. Schleimer. How are you
`doing this morning?
` A. I am doing all right. How are you?
` Q. All right. Great. We have had a couple
`depositions in related matters, related to the '620
`patent. You testified previously in Apotex
`litigation between Meta and Cipla against Apotex,
`correct?
` A. Against Apotex?
` Q. No, I'm sorry. The case was Meta and
`Cipla versus Apotex. You testified --
` A. Yes, I testified in that case.
` Q. -- on Apotex's behalf.
` And now we're here. You're testifying on
`behalf of Argentum Pharmaceuticals?
` A. That is correct.
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` Q. And the '620 patent was involved in both
`litigations?
` A. Yes.
` Q. Okay. I want to start with Exhibit 1144,
`which is your second declaration in this IPR.
` A. Okay.
` Q. One of the things that you talk about here
`is the early and late phase, and your view is that
`those are relevant to clinical therapy, correct?
` A. Yeah, they're often relevant to clinical
`therapy. They're more relevant as a way to
`understand allergic reactions.
` Q. Okay. And so this is -- the phases are
`really the mechanism of the disease itself, part of
`the mechanism of the disease itself, and not really
`the symptom; is that right?
` A. Well, the phases are indicators of the
`underlying mechanisms, but the mechanisms are what
`drive the symptoms, so you can't unlink them.
` Q. Okay. Now, I'd like to flip to
`paragraph 54 in your declaration if we could. It's
`page 37.
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` A. Okay.
` Q. You talk about Dr. Accetta's records here,
`correct?
` A. Yes.
` Q. Now, just to be clear, Dr. Accetta was a
`physician who testified in the Apotex litigation?
` A. That's right.
` Q. And he's a physician, correct?
` A. Yes.
` Q. You are not.
` A. That's correct.
` Q. So you do not treat patients?
` A. Correct.
` Q. Okay. Let me hand you -- this is
`Exhibit 1055.
` MR. HOUSTON: And just to be clear, I think the
`original was in color, wasn't it? Or am I
`remembering that wrong?
` MR. MILLER: Yes, it is in color.
` MR. HOUSTON: I don't know that it matters,
`but...
` MR. MILLER: Fair enough.
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` MR. HOUSTON: Okay.
`BY MR. MILLER:
` Q. And this was also used in Dr. Carr's
`deposition, which is why you see the exhibit at the
`top there. This is one of the exhibits that
`Dr. Accetta testified about in trial, correct,
`Dr. Schleimer?
` A. I believe so.
` Q. And you rely on this in paragraph 54.
`This is the prescription that you're talking about?
` A. I believe that's correct.
` Q. Okay. Now, to be clear, Dr. Carr is a
`clinician. He treats patients, right?
` A. Yes.
` Q. Dr. Accetta treats patients?
` A. Yes.
` Q. You do not.
` A. Correct.
` Q. So when you say that your interpretation
`of this -- and let's back up a second.
` So you can't actually see the complete
`record that's buried under this callout, correct?
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`If you look, there's --
` A. That's correct. It covers the writing
`underneath.
` Q. Okay. Now, the underlying document there,
`the document you're referring to in 54, Dr. Carr and
`Dr. Accetta actually write these documents
`themselves, don't they?
` A. Yes --
` Q. And you don't.
` A. -- usually.
` That's correct. We've established I am not
`a physician.
` Q. Okay. And I just wanted to clarify that
`you don't actually ever write these things?
` A. Correct.
` Q. So you wouldn't know what a doctor is
`thinking when he puts down, for example, under the
`general:
` Patient's physical exam is normal.
` A. Well, I can certainly have -- I can read
`the English language. I'm very familiar with
`medicine and the practice of medicine, and in my
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`recollection Dr. Carr had made a statement in his
`declaration or maybe it was his deposition, I don't
`remember, that he wouldn't treat a normal patient
`with these drugs, and in this case Dr. Accetta said
`the patient's physical examination is normal.
` And my take of Dr. Carr's statements was
`that he was suggesting that the patient being normal
`doesn't have allergic disease, so that was what the
`issue was.
` MR. MILLER: Okay. And just for the record,
`Mr. Marghese just joined us.
` MR. MARGHESE: Good morning, Dr. Schleimer.
`BY MR. MILLER:
` Q. Okay. So we can put that aside for a
`moment.
` I've handed you -- I'm going to hand you
`in just a moment an article by Stanley Galant, or is
`it Galant? I always mix this up.
` A. Galant is the way I pronounce it, but it
`may be wrong.
` Q. You're familiar with this?
` A. I have seen it, yes.
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`Page 12
` Q. Okay. Flip in your declaration quickly to
`paragraph 7, returning to the early-late phase
`concept that we talked about a minute ago.
` A. Okay.
` Q. You see from the header this is the
`section of your declaration that discusses the early
`and late phase and how they're clinically relevant
`prior to 2002, correct?
` A. Yes.
` Q. All right. So looking at paragraph 7
`here, you dispute Dr. Carr's view that the early and
`late phase are not relevant to clinical treatment of
`patients. Is that essentially an accurate summary
`of what you wrote there?
` A. I believe that they are relevant to not
`only the understanding of allergic disease but also
`to the treatment of allergic disease.
` Q. Okay. Now, the Galant reference I just
`handed you, Exhibit 1041, you see that, and that's
`cited in paragraph 7 of your declaration?
` A. Yes.
` Q. It's page 455. Can you flip to page 455
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`for me? Take a moment.
` I assume that the reference that you're
`citing here, the portion of this article that you're
`citing in paragraph 7 is Section 3, the pathogenesis
`section?
` A. Well, that section certainly mentions the
`early and the late phase and the mediators and
`cellular responses that are involved in those two
`distinguishable phases, yes.
` Q. Okay. Now, I just want to explore this
`document a little bit because you also talked a good
`deal about the context of an article in your
`declaration. If you look at Section 2 immediately
`preceding the section you just reviewed?
` A. Reviewed. You mean Section 4?
` Q. No. Go back to Section 2, the one
`immediately preceding, Evaluation and Diagnosis, so
`evaluation and diagnosis is what a physician does
`when he has a patient, correct?
` A. Yes.
` Q. All right. Go ahead and take a look at
`that and tell me if you see the word "phase"
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`anywhere.
` A. I take it by the fact you're asking me that
`I won't find it. I skimmed it, I don't see it, but
`that doesn't mean that the symptoms or the
`manifestations of allergic disease are not mediated
`by the pathogenic events that are discussed fairly
`well in paragraph 3 or Section 3.
` Q. But the concept in section 2 is
`essentially that when you're evaluating a patient
`with allergic rhinitis you look at their history.
`You look at their symptoms. Doesn't say anything
`about phase. Is that accurate?
` A. I think it's context dependent. If a
`physician has a patient in front of them that
`reports that when they go visit a friend who has a
`cat and they start sneezing wildly, and then they go
`home and in the middle of the night they can't sleep
`because they're wheezing or they have complete
`blockage, the physician in that case will say, "Oh,
`well, that's classic early phase and late phase of
`an allergic response," so it's very case dependent.
`So I wouldn't agree with what you said. I think
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`Page 15
`that all well-trained allergists understand about
`phases and how they contribute to disease.
` Q. Okay. And that's a very helpful answer in
`terms of understanding, but I just want to be clear
`that the evaluation and diagnosis section does not
`say anything about phase.
` A. This paragraph that you directed me to does
`not say anything about phase, but that does not
`embrace the totality of evaluation and diagnosis of
`allergic disease.
` Q. Okay. Now, you mentioned Section 4.
`Title is "Treating AR in the Child," correct?
` A. I see that, yes.
` Q. All right. And that's the one after the
`section that you talked about, pathogenesis, in your
`paragraph 7?
` A. Yes.
` Q. I'll represent to you, because this is far
`too long to ask you to read, but the only place that
`the word "phase" appears in the treatment section is
`on page 456 of the article that's stamped 04. You
`see "Histamine H1 Receptor Antagonists"?
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` A. I see that section, yes.
` Q. So you'll see -- the easiest way to find
`it is "in vivo," there's an "in vivo" in italics.
`The sentence after that, can you read that for the
`record?
` A. The sentence after?
` Q. "In vivo, the second generation
`antihistamine"?
` A. I'm sorry, I still don't know where
`you're --
` Q. All right. Towards the bottom under the
`header 4.1.
` A. Okay.
` Q. Towards the bottom of the left column
`there's a sentence that begins: The
`second-generation antihistamine?
` A. "The second-generation antihistamine
`cetirizine," that one --
` Q. Yes.
` A. -- that sentence?
` Q. Yes, please.
` A. -- "inhibits LTC4 and D4 production in
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`nasal secretions and inhibits recruitment of
`eosinophils in the cutaneous late-phase model."
` Q. So I'll represent to you, because I've
`read this and searched a couple times, that's the
`only place that "phase" appears in the treatment.
` And I want to be clear about what that is
`talking about. Cutaneous models are actually skin
`tests, correct?
` A. Yes.
` Q. So that's not allergic rhinitis.
` A. No, but it's a way that an allergist
`determines whether a patient is allergic to what's
`called an arrow allergen, which is an inhaled
`allergen. If you have allergic responses in your
`skin, you will also have the same allergic responses
`in your nose, so for convenience, since it's very
`difficult to test the nose, allergists will test the
`skin. If you respond to birch pollen in your skin,
`then it informs the allergist that you also will
`respond to birch pollen in your nose.
` Q. Okay. But, again, if you'll accept my
`representation that the reference to "late phase" in
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`that sentence you just read is the only one, I want
`to talk about a couple of the other --
` A. Well, but hang on. You said it's the only
`one in diagnosis of disease.
` Q. This is treatment.
` A. In treatment. You said "diagnosis and
`treatment."
` And the fact is that this is not some huge
`document that describes the totality of diagnosis
`and treatment. This is a review that a couple of
`guys wrote in a second- or third-string journal and
`gave their impression of an overview of a few
`topics. So, you know, I think if you look
`throughout the documents that are under discussion
`in this case, of which there are dozens, a very
`large number of them mention the phases, and the
`phase is irrelevant not only in pathogenesis, but
`irrelevant in symptoms, manifestation of disease,
`and sometimes in diagnosis of disease.
` Q. Okay. But to be clear, this -- you've
`actually cited this article --
` A. Yes.
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` Q. -- that's in paragraph 7, correct?
` A. Yes. The reason that I cited it is because
`it has a nice little description of the differences
`between the early phase and the late phase, and
`those differences bear direct relevance to the
`actions of drugs with the antihistamines being very
`effective against the early phase, which is a
`antihistamine-driven response to great extent, and
`the steroids being very effective against the late
`phase which is mediated by infiltration of
`inflammatory cells and the subsequent release of
`mediators by those cells. So that goes straight to
`the complementarity argument. It was very well
`known before the priority date by people in the
`field that the steroids targeted that cellular
`inflammation and the release of mediators
`secondarily in the late phase, and the
`antihistamines were very good at working quickly
`against the immediate response to antigen, which is
`largely mass cells releasing histamine; so the skin
`tests that you were talking about can be blocked
`nearly completely with antihistamines. In fact, if
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`a patient has taken oral antihistamines, an
`allergist won't even bother to skin test them
`because they will have no skin test response.
` So on the other hand, you can take huge
`doses of oral steroids, and it will not inhibit that
`immediate skin test response one iota. So that's a
`perfect example of what an allergist would know,
`which is that antihistamines target the immediate
`response, including the skin test, and steroids
`inhibit the late-phase response.
` Q. Now, going back to the sentence you read
`in 4.1, that says that an antihistamine works in the
`late-phase model; is that right?
` A. Yes. So as I've mentioned in several of
`the documents during this case, there was the
`realization that some antihistamines, not all
`antihistamines, have some anti-inflammatory effects,
`and that includes the things mentioned here and many
`other things that are actually summarized in several
`of the documents. For example, Berger also
`summarizes them. It's less well established whether
`the various antihistamines have those profound
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`anti-inflammatory effects in vivo, but there is
`reason to believe that topical antihistamines, which
`includes azelastine and levocabastine, can exert
`some of those particularly well because they can be
`given topically to create high concentrations in the
`nose. Much of the literature that serves as the
`basis for this concept is in vitro, and in vitro a
`scientist has no limitation on the amount of drug
`they can put in, so very large amounts of drug can
`inhibit responses that are known to be important.
`But if those concentrations can't be reached in vivo
`with either oral or local administration of a drug,
`then it's only theoretical but not actual useful
`information.
` Q. Okay. Thank you, Doctor.
` Next we are going to look at -- if you
`flip back to paragraph 7, the next article that you
`cite in that string there is Exhibit 1041, which I'm
`going to hand you in just a moment.
` A. Oh, we're still with 1041?
` Q. Oh, sorry. Did I say 1041? I meant 1035.
` MR. MILLER: Mike. Ma'am.
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`BY MR. MILLER:
` Q. All right. So 1035 here, this is a Drouin
`article which you're familiar with, I assume?
` A. Yes.
` Q. And that's the article cited in
`paragraph 7, second paragraph cited in paragraph 7;
`is that right?
` A. Okay.
` Q. You cite page 341, which is the second
`page, first after the cover?
` A. Uh-huh, yes.
` Q. Now, looking at this, I'm assuming, take a
`moment to read through, but you're probably
`referring in paragraph 7 to this third paragraph,
`the nasal response to allergen?
` A. Yes. The third paragraph would be part of
`that, I believe.
` Q. Okay. Read the next paragraph. Begins
`"topical steroids" quickly for me, please.
` A. Topical steroids.
` Q. Oh, no, you don't have to read it on the
`record, sir. Just take a look at it. I'm going to
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`ask you a couple questions.
` A. Sorry.
` Q. That's okay.
` A. Okay.
` Q. So here, again, we see kind of a dichotomy
`where you talk about the phases, they are there, but
`the next paragraph is actually talking about how to
`treat patients, what symptoms they have and what
`drugs to use to treat them.
` A. Yes.
` Q. So, again, when actually talking about
`treating patients, the word "phase" did not appear
`in the paragraph, correct?
` A. It did not appear in the paragraph, but we
`know a lot about the mediators that cause the
`various symptoms.
` For instance, we know very well that
`histamine, when released quickly, causes sneezing
`and that -- for example.
` So the underlying allergic response is
`complex. It involves not only the immediate
`response of mass cells, but then many different cell
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`types come into the tissue, and they each start
`singing in a chorus, and that results in symptoms.
`And what Drouin is saying is that the congestion
`seems to be related to that later response, the
`late-phase response with all of those cells coming
`in, and steroids are very good at inhibiting that.
`The early response is like itching and sneezing
`which happen right away. The steroids don't inhibit
`those well, at least not quickly, and we know those
`to be mediated by histamine because we can
`administer a histamine to the nose of even a normal
`healthy person, and they'll start sneezing
`immediately, and we know that the antihistamines
`will block that very well.
` Q. Okay. If you'll flip to page 344. It's
`been stamped at page 5.
` A. Okay.
` Q. The table of the actual data that they
`were looking at.
` A. Yes.
` Q. Does the word "phase" appear anywhere in
`there?
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` A. It does not.
` Q. Again, they're looking at symptoms,
`correct?
` A. It might be helpful if I explain that the
`phases originally come out of experimental allergic
`reaction studies, so these are studies where someone
`with allergy, again, let's say to birch pollen, is
`brought into the clinic, and let's say outside of
`the birch pollen season, so they have no symptoms.
`And then birch pollen is put into their nose to give
`them an allergic response, very similar to what
`happens if they go outside when the birch trees are
`pollenating during the season. And what happens in
`that setting, and this has been known for almost a
`century, and everyone knows it who studies allergy,
`what happens is they have an immediate response or
`an early-phase response, and that involves all the
`things that we've discussed like itching and
`sneezing, some runny nose, and then after 4 to
`8 hours, 10 hours and maybe lasting for a day or
`two, there's a late response, which may include a
`second wave of sneezing but also congestion and
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`other things. So that's how -- and then further
`studies have shown what I said before and what
`Galant says which is that inflammatory cells come
`into the tissue and drive that late phase.
` So in the clinical setting, in clinical
`trials, it depends on the nature of the trial. If
`it's a trial that's using normal seasonal exposure
`to allergens, and the seasonal exposure lasts for
`weeks or months, as is true with these, then the
`phases -- the phases are not coming to play in that
`situation.
` If, on the other hand, there are many
`studies, none in this case where antigen challenge
`is administered and you can study the action of
`drugs, in those cases the phases are very much in
`play, and in our first meeting in this case we
`talked a little bit about antigen challenges but not
`in the second declaration.
` So this is a study where they looked at
`symptoms over a week or so, collecting data
`critically on Day 3 and Day 7, which is the early,
`early part of the treatment response, where I
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`maintain that these two drugs were known to be
`highly complementary, but it's not an
`antigen-challenge study, so there's no need to
`mention the phases. That doesn't mean that the
`components of the phases are not driving these
`symptoms. Allergists will know that they are.
` Q. You can put that off to the side, Doctor.
` A. Sure. I'm sure we'll get back to it.
` Q. At some point we probably will.
` I've asked you this before, but just for
`the sake of this deposition, you're not a
`formulator?
` A. That is not my job, correct. I am not a
`formulator, professional formulator. I've done it
`on occasion, but that's not my job.
` Q. You say you've done it on occasion. Can
`you give me a couple examples?
` A. Well, we did some studies with a drug
`decades ago that we administered to people, a simple
`formulation.
` Q. What's the simple formulation?
` A. It was just saline that was adjusted for
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`pH.
` Q. So you're not involved in the selection of
`excipients or, for example, particle size or
`anything like that?
` A. That's correct. I may not -- I have a
`minimal working knowledge of it. I understand many
`of the concepts and certainly in the court case
`heard Maureen Donovan, who is world class, discuss
`the issues not only in this case but generally in
`formulation for intranasal drugs.
` Q. If you'll flip to paragraph 5. It's the
`second page of declaration, second declaration,
`there's Footnote 1 down there. You see that?
` A. Yes, I see that.
` Q. Now, here you're responding to Dr. Carr
`mentioned in his declaration that you had not said
`anything about Claims 4 and 42 through 44.
` A. Yes.
` Q. And this is your response to his statement
`there, correct?
` A. Yes.
` Q. Now, I wanted to explore this a little
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`bit. The last sentence there, you say:
` To be clear, I consider the combination of
`azelastine and fluticasone in a formation suitable
`for nasal administration to be obvious for Claims 4
`and 42 through 44 for the same reasons as all the
`claims discussed herein.
` The "herein," are you referring to this
`declaration or is it both -- what do you mean with
`"herein"?
` A. This declaration.
` Q. Just this declaration? Does this
`declaration -- let me simplify this a little bit.
`I'll hand you the '620 patent first. That's
`Exhibit 1001, '620 patent. That's what this case is
`about, correct?
` A. Yes, I have certainly seen it.
` Q. If you flip back, you know where the
`claims are at the rear of the document. Claim 4 is
`in Column 11. It's page 13 as it's been stamped.
` A. Yes.
` Q. See Claim 4? The pharmaceutical
`formulation of Claim 1, wherein the said formulation
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`has a particle size of less than 10 micrometers,
`correct?
` A. Yes.
` Q. Now, you just said that you have not
`been -- you don't have any experience or expertise
`in selecting particle size, correct?
` A. Well, as I said, I'm aware of issues that
`particle size influences. These issues vary
`depending on the context, for instance, with inhaled
`drugs versus