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`·2· ·UNITED STATES PATENT AND TRADEMARK OFFICE
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`·3· ·BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`· · ·BIODELIVERY SCIENCES INTERNATIONAL, INC.
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`· · · · · · · · · · · · · · · · ·Petitioner,
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`·7· · · · · · · · · · · · ·v.
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`·8· ·RB PHARMACEUTICALS LIMITED,
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`·9· · · · · · · · · · · · · · · ·Patent Owner.
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`10· ·------------------------------------------
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`11· · · · · · · ·Case IPR2014-00325
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`12· · · · · · · · Patent 8,475,832
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`14
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`15
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`16· · · · DEPOSITION OF THOMAS P. JOHNSTON
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`17· · · · · · FRIDAY, JANUARY 23, 2015
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`18· · · · · · · · · ·8:30 a.m.
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`25· ·Reported by:· Adrienne M. Mignano, RPR
`· · · · · · · · · ·Job Number:· 265794
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`Page 1
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`·2· ·UNITED STATES PATENT AND TRADEMARK OFFICE
`· · ·------------------------------------------
`·3· ·BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`· · ·BIODELIVERY SCIENCES INTERNATIONAL, INC.
`·5
`· · · · · · · · · · · · · · · · ·Petitioner,
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`·7· · · · · · · · · · · · ·v.
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`·8· ·RB PHARMACEUTICALS LIMITED,
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`·9· · · · · · · · · · · · · · · ·Patent Owner.
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`10· ·------------------------------------------
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`11· · · · · · · ·Case IPR2014-00325
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`12· · · · · · · · Patent 8,475,832
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`14
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`15
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`16· · · · DEPOSITION OF THOMAS P. JOHNSTON
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`17· · · · · · FRIDAY, JANUARY 23, 2015
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`18· · · · · · · · · ·8:30 a.m.
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`19
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`25· ·Reported by:· Adrienne M. Mignano, RPR
`· · · · · · · · · ·Job Number:· 265794
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`Page 1
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`·1
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`·2· ·A P P E A R A N C E S:
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`·3
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`·4· ·McCARTER & ENGLISH
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`·5· ·Attorneys for Petitioner
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`·6· · · · · · ·265 Franklin Street
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`·7· · · · · · ·Boston, Massachusetts 02110
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`·8· ·BY:· · · ·KIA L. FREEMAN, ESQ.
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`·9· · · · · · ·WYLEY S. PROCTOR, ESQ.
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`10
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`11
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`12· ·TROUTMAN SANDERS
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`13· ·Attorneys for Patent Owner
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`14· · · · · · ·405 Lexington Avenue
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`15· · · · · · ·New York, New York· 10174
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`16· ·BY:· · · ·DANIEL A. LADOW, ESQ.
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`17· · · · · · ·MAGNUS ESSUNGER, ESQ.
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`18
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`19
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`20· ·ALSO PRESENT:
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`21· · · · · · ·DAVID W. FEIGAL, M.D.
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`22
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`23
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`24
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`25
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`Page 2
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`·1· · · · · · · · · ·Johnston
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`·2· ·T-H-O-M-A-S· P.· J-O-H-N-S-T-O-N, called as
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`·3· · · · · a witness, having been duly sworn
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`·4· · · · · by a Notary Public, was examined and
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`·5· · · · · testified as follows:
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`·6· ·EXAMINATION BY
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`·7· ·MS. FREEMAN:
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`·8· · · ·Q· · ·Good morning, Professor
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`·9· ·Johnston.
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`10· · · ·A· · ·Good morning.
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`11· · · ·Q· · ·Are you feeling okay today?
`
`12· · · ·A· · ·Tired.
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`13· · · ·Q· · ·Me too.
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`14· · · · · · ·Is there anything that you're
`
`15· ·aware of that may interfere with your
`
`16· ·ability to testify today?
`
`17· · · ·A· · ·Only as Mr. Ladow said I take a
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`18· ·little diuretic so I might have to run to
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`19· ·the men's room now and then, but other
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`20· ·than that, no.
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`21· · · ·Q· · ·Professor Johnston, what does
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`22· ·peroral mean?
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`23· · · ·A· · ·Peroral to me means a dosage
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`24· ·form is swallowed for subsequent
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`25· ·absorption in the gastrointestinal tract.
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`Page 3
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`·1· · · · · · · · · ·Johnston
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`·2· · · ·Q· · ·What is peroral administration?
`
`·3· · · ·A· · ·Well, in my opinion, that means
`
`·4· ·administering a drug substance that
`
`·5· ·ultimately is absorbed from the
`
`·6· ·gastrointestinal tract.
`
`·7· · · ·Q· · ·And how do you know if the drug
`
`·8· ·is absorbed in the GI tract?
`
`·9· · · ·A· · ·Well, one of those factors would
`
`10· ·be the rate at which the maximum blood
`
`11· ·concentration is attained, typically
`
`12· ·that's 90 minutes after gastrointestinal
`
`13· ·administration of a drug substance.
`
`14· · · ·Q· · ·For any drug?
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`15· · · ·A· · ·For most drugs.
`
`16· · · ·Q· · ·So you know something has been
`
`17· ·absorbed in the GI tract if you get your
`
`18· ·CMAX within 90 minutes?
`
`19· · · ·A· · ·No, maybe I should clarify.· I'm
`
`20· ·just saying that most drugs that are taken
`
`21· ·by peroral administration would reach a
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`22· ·maximum blood concentration somewhere 60
`
`23· ·to 90 minutes after swallowing it.
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`24· ·Typically the patient ingests some water
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`25· ·with that.
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`Page 4
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`·1· · · · · · · · · ·Johnston
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`·2· · · ·Q· · ·I feel like we've gotten off
`
`·3· ·track already.
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`·4· · · · · · ·My question was how do you know
`
`·5· ·if something has been absorbed in the GI
`
`·6· ·tract?
`
`·7· · · ·A· · ·Well, as I mentioned, just by
`
`·8· ·the time that that maximum blood
`
`·9· ·concentration is achieved, and also if a
`
`10· ·drug is administered orally and it is
`
`11· ·subjected to metabolism, typically you
`
`12· ·know that a drug has been administered
`
`13· ·that way if you detect the presence of
`
`14· ·metabolites of that drug.
`
`15· · · ·Q· · ·Okay.
`
`16· · · · · · ·You just said orally
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`17· ·administered.· Is that the same as
`
`18· ·perorally administered?
`
`19· · · ·A· · ·I should have been more
`
`20· ·specific.· I meant PO, peroral, and when I
`
`21· ·say that I am referring to swallowing the
`
`22· ·actual drug substance for subsequent
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`23· ·absorption typically in the -- when I
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`24· ·refer to peroral drug administration for
`
`25· ·subsequent absorption primarily in the
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`Page 5
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`·1· · · · · · · · · ·Johnston
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`·2· ·small intestine.
`
`·3· · · ·Q· · ·Would you describe an orally
`
`·4· ·dissolving tablet as a peroral dosage
`
`·5· ·form?
`
`·6· · · ·A· · ·Yes, I would.
`
`·7· · · ·Q· · ·Do you agree that suboxone
`
`·8· ·tablets are orally dissolving tablets?
`
`·9· · · ·A· · ·They are.· And I probably should
`
`10· ·have added that most ODTs, and that is the
`
`11· ·acronym that we use for orally
`
`12· ·disintegrating tablets, are for subsequent
`
`13· ·absorption after swallowing.· In other
`
`14· ·words, it is designed for peroral
`
`15· ·administration.· But there are ODTs that
`
`16· ·are designed for absorption across the
`
`17· ·oral mucosa.
`
`18· · · ·Q· · ·Okay.· I guess I missed the
`
`19· ·answer to my question.
`
`20· · · · · · ·Is a suboxone tablet a peroral
`
`21· ·dosage form?
`
`22· · · ·A· · ·A suboxone tablet is not really
`
`23· ·technically classified as a peroral dosage
`
`24· ·form or PO.
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`25· · · ·Q· · ·What do you mean "technically
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`Page 6
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`·1· · · · · · · · · ·Johnston
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`·2· ·classified"?
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`·3· · · ·A· · ·Well, then let me reword that.
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`·4· ·The suboxone tablet would not be
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`·5· ·considered a dosage form that was
`
`·6· ·administered PO, or peroral.
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`·7· · · ·Q· · ·Why not?
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`·8· · · ·A· · ·Because the intention, the
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`·9· ·intent of suboxone tablets is to have the
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`10· ·active absorbed across the oral mucosa in
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`11· ·the oral cavity.
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`12· · · ·Q· · ·I guess I'm a little confused.
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`13· ·Are you saying that suboxone tablets have
`
`14· ·an intent?
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`15· · · · · · ·MR. LADOW:· Objection to the
`
`16· · · ·form of the question.
`
`17· · · ·A· · ·No, I'm not saying that a tablet
`
`18· ·has an intent.· I'm just saying that the
`
`19· ·suboxone tablet is designed for absorption
`
`20· ·of the active across the oral mucosa found
`
`21· ·in the oral cavity.
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`22· · · ·Q· · ·What is peroral delivery?
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`23· · · ·A· · ·Well, my opinion is that peroral
`
`24· ·delivery is the administration of a drug
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`25· ·substance for subsequent absorption in the
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`Page 7
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`·1· · · · · · · · · ·Johnston
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`·2· ·gastrointestinal tract.
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`·3· · · ·Q· · ·And what is a peroral dosage
`
`·4· ·form?
`
`·5· · · ·A· · ·Well, a peroral dosage form,
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`·6· ·classic examples would be a compressed
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`·7· ·tablet or a capsule that people ingest for
`
`·8· ·subsequent absorption in the
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`·9· ·gastrointestinal tract.
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`10· · · ·Q· · ·What does peroral GI absorption
`
`11· ·mean?
`
`12· · · ·A· · ·To me if you would use those two
`
`13· ·words in combination, that the drug
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`14· ·contained in a conventional dosage form, a
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`15· ·tablet or capsule that we're all familiar
`
`16· ·with, is absorbed in the gastrointestinal
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`17· ·tract.
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`18· · · ·Q· · ·What does the peroral add to GI
`
`19· ·absorption in that phrase GI peroral
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`20· ·absorption?
`
`21· · · ·A· · ·Well, I guess to me it just adds
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`22· ·the fact that it entered through the oral
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`23· ·cavity.· It had passed through the oral
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`24· ·cavity for subsequent absorption in the
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`25· ·gastrointestinal tract.
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`Page 8
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`·1· · · · · · · · · ·Johnston
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`·2· · · ·Q· · ·So let me try to understand.
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`·3· ·Let me make sure I've got this right.
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`·4· · · · · · ·Did you say that an orally
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`·5· ·dissolving tablet is a peroral dosage
`
`·6· ·form?
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`·7· · · · · · ·MR. LADOW:· Objection.
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`·8· · · ·Misstates his testimony.
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`·9· · · · · · ·MS. FREEMAN:· I'm not stating
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`10· · · ·his testimony.· I'm asking him if that
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`11· · · ·was his testimony.
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`12· · · ·A· · ·Can I ask you --
`
`13· · · ·Q· · ·Let me start over.
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`14· · · · · · ·Is an orally dissolving tablet a
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`15· ·peroral dosage form?
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`16· · · · · · ·MR. LADOW:· Asked and answered.
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`17· · · ·Objection.
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`18· · · ·A· · ·Well, I believe I did answer
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`19· ·that.· The ODT could be dissolved so that
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`20· ·the drug substance would be swallowed as
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`21· ·it is mixed with saliva and then
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`22· ·subsequently absorbed from the
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`23· ·gastrointestinal tractor.
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`24· · · · · · ·In some cases, an ODT is meant
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`25· ·to dissolve in the oral cavity with the
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`Page 9
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`·1· · · · · · · · · ·Johnston
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`·2· ·active being absorbed across the oral
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`·3· ·mucosa or mucosae, plural, of the oral
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`·4· ·cavity itself.
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`·5· · · ·Q· · ·Okay.
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`·6· · · · · · ·What does the orally dissolving
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`·7· ·part of an orally dissolving tablet mean?
`
`·8· · · · · · ·Let me ask that question in a
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`·9· ·more clear way.
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`10· · · · · · ·In the phrase orally dissolving
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`11· ·tablet, what does orally dissolving mean?
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`12· · · ·A· · ·Well, to me that means that it
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`13· ·is dissolving in the oral cavity.
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`14· · · ·Q· · ·Okay.
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`15· · · · · · ·So do orally dissolving tablets
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`16· ·normally dissolve in the oral cavity?
`
`17· · · ·A· · ·Well, in my opinion, that's
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`18· ·where most of them are designed to be
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`19· ·dissolved.· Sometimes an ODT is also
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`20· ·called an orally disintegrating tablet,
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`21· ·and I use those terms interchangeably.· It
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`22· ·is dissolving and disintegrating in the
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`23· ·oral cavity.
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`24· · · ·Q· · ·Okay.
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`25· · · · · · ·So if an orally dissolving
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`Page 10
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`·1· · · · · · · · · ·Johnston
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`·2· ·tablet dissolves in the oral cavity, what
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`·3· ·is swallowed?
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`·4· · · ·A· · ·Well, that is a good question
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`·5· ·and typically that is mixed with saliva
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`·6· ·that is naturally found in the oral
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`·7· ·cavity, and that drug solution, if you
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`·8· ·will, the active that's been released and
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`·9· ·mixed with the saliva is then subsequently
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`10· ·swallowed for gastrointestinal absorption.
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`11· · · · · · ·Now, there are ODTs where the
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`12· ·active mixes and dissolves in the saliva
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`13· ·and that is intended to be absorbed across
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`14· ·the mucosae of the oral cavity.
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`15· · · ·Q· · ·Okay.
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`16· · · · · · ·Is the orally dissolving tablet
`
`17· ·itself usually swallowed?
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`18· · · ·A· · ·Well --
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`19· · · ·Q· · ·So let me ask that better.
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`20· · · · · · ·Is the orally dissolving tablet
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`21· ·swallowed in tablet form?
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`22· · · · · · ·MR. LADOW:· Objection to the
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`23· · · ·form of the question.
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`24· · · · · · ·MS. FREEMAN:· What is your
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`25· · · ·objection, John?
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`Page 11
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`·1· · · · · · · · · ·Johnston
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`·2· · · · · · ·MR. LADOW:· I'm objecting to the
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`·3· · · ·form of the question.
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`·4· · · · · · ·MS. FREEMAN:· I'm asking you to
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`·5· · · ·clarify so I can rephrase the
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`·6· · · ·question.
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`·7· · · · · · ·MR. LADOW:· The way you formed
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`·8· · · ·the question, it sounded to me like is
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`·9· · · ·a tablet a tablet type question, which
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`10· · · ·didn't make sense to me.
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`11· · · · · · ·MS. FREEMAN:· Okay.· Let me
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`12· · · ·repeat my question.
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`13· · · ·Q· · ·Is an orally dissolving tablet
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`14· ·swallowed in tablet form?
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`15· · · · · · ·MR. LADOW:· Objection to form.
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`16· · · ·A· · ·Well, in general in ODT, those
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`17· ·were developed for people, patients that
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`18· ·sometimes had difficulty swallowing an
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`19· ·entire tablet.
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`20· · · · · · ·So normally an ODT disintegrates
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`21· ·and dissolves in the oral cavity.· So to
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`22· ·answer your question, typically the ODT is
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`23· ·not swallowed whole.· Hence, the name
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`24· ·orally disintegrating tablet.· I know that
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`25· ·seems confusing because if it had
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`Page 12
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`·1· · · · · · · · · ·Johnston
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`·2· ·perorally disintegrating tablet, it would
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`·3· ·be a different story.· But anyway, to
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`·4· ·answer your question, typically it is not
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`·5· ·swallowed whole.
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`·6· · · ·Q· · ·What would perorally
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`·7· ·disintegrating tablet mean?
`
`·8· · · ·A· · ·You know, I retract that
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`·9· ·statement.· I probably should not have
`
`10· ·used that.· The only concept that I'm
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`11· ·trying to convey is, to answer your
`
`12· ·question, that an ODT would normally not
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`13· ·be swallowed whole.· There is no peroral
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`14· ·disintegrating -- forget that or strike
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`15· ·that or whatever.· It is just an ODT and
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`16· ·those are typically not swallowed whole.
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`17· · · ·Q· · ·Okay.
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`18· · · · · · ·When an orally dissolving tablet
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`19· ·dissolves in the mouth as it usually does,
`
`20· ·is the solution that's swallowed
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`21· ·considered --
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`22· · · · · · ·MS. FREEMAN:· Strike that.
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`23· · · ·Q· · ·Is it your opinion that when a
`
`24· ·person swallows a drug tablet, there is no
`
`25· ·oral mucosal absorption of the drug?
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`Page 13
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`·1· · · · · · · · · ·Johnston
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`·2· · · · · · ·MR. LADOW:· Objection to the
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`·3· · · ·form of the question.· Lacks
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`·4· · · ·foundation.
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`·5· · · · · · ·MS. FREEMAN:· Please restrict
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`·6· · · ·your objections to the ones that are
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`·7· · · ·allowed.
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`·8· · · · · · ·MR. LADOW:· I believe those are
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`·9· · · ·allowed.
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`10· · · · · · ·MS. FREEMAN:· That is
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`11· · · ·specifically not allowed under the
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`12· · · ·guidelines.· The only allowed
`
`13· · · ·objections are objection to form.
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`14· · · · · · ·MR. LADOW:· I don't think that's
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`15· · · ·true, but please continue.
`
`16· · · ·A· · ·Can I respectfully ask you to
`
`17· ·repeat the question.
`
`18· · · · · · ·MS. FREEMAN:· Can you read the
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`19· · · ·question back.
`
`20· · · · · · ·(Record read)
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`21· · · · · · ·MR. LADOW:· Same objections.
`
`22· · · ·A· · ·Well, so that's not very
`
`23· ·specific as to what type of tablet it is.
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`24· · · ·Q· · ·Does your opinion change
`
`25· ·depending on the type of drug tablet?
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`Page 14
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`
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`·1· · · · · · · · · ·Johnston
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`·2· · · ·A· · ·Oh, yes.
`
`·3· · · ·Q· · ·Okay.
`
`·4· · · · · · ·Is it your opinion that a person
`
`·5· ·swallows a conventional drug tablet, there
`
`·6· ·is no oral mucosal absorption of the drug?
`
`·7· · · ·A· · ·Generally speaking in the
`
`·8· ·pharmaceutical world or pharmaceutical
`
`·9· ·science, if you take a compressed tablet,
`
`10· ·there really isn't any absorption of the
`
`11· ·active ingredient inside the tablet from
`
`12· ·the oral mucosa or across the oral mucosa,
`
`13· ·because I suppose hypothetically there
`
`14· ·could be some sort of trace amount, but in
`
`15· ·general, most, if not all, it's designed
`
`16· ·not to be absorbed in the oral cavity, but
`
`17· ·to be swallowed whole.
`
`18· · · ·Q· · ·Okay.
`
`19· · · · · · ·Is it your opinion that when a
`
`20· ·person swallows an orally dissolving --
`
`21· ·sorry, let me start over.
`
`22· · · · · · ·Is it your opinion that when a
`
`23· ·person swallows an orally dissolving drug
`
`24· ·tablet, there is no oral mucosal
`
`25· ·absorption of the drug?
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`Page 15
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`·1· · · · · · · · · ·Johnston
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`·2· · · ·A· · ·You know, I may have heard this
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`·3· ·wrong, but I thought you said when a
`
`·4· ·person, a patient swallows an orally
`
`·5· ·dissolving tablet.
`
`·6· · · ·Q· · ·Okay.· So, I see.
`
`·7· · · ·A· · ·They wouldn't swallow an ODT.
`
`·8· · · ·Q· · ·So an orally dissolving tablet
`
`·9· ·would not be swallowed?
`
`10· · · ·A· · ·Oh, in general, no.· It is
`
`11· ·designed for its release of the active in
`
`12· ·the oral cavity for subsequent absorption
`
`13· ·as it is mixed in the gastrointestinal
`
`14· ·tract.
`
`15· · · ·Q· · ·So the drug of an orally
`
`16· ·dissolving tablet is released in the oral
`
`17· ·cavity?
`
`18· · · ·A· · ·In general, that's true, yes.
`
`19· · · ·Q· · ·And would the drug that's
`
`20· ·released from an orally dissolving tablet
`
`21· ·in the mouth be absorbed through the oral
`
`22· ·mucosa?
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`23· · · ·A· · ·Well, I believe anyway that I
`
`24· ·have answered that question and it
`
`25· ·depends.· Most ODTs are designed to
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`Page 16
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`·1· · · · · · · · · ·Johnston
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`·2· ·release their active, and then the active
`
`·3· ·saliva mixture is swallowed with
`
`·4· ·subsequent absorption in the GI tract.
`
`·5· · · · · · ·When I say GI, I mean
`
`·6· ·gastrointestinal.· I'm using that acronym
`
`·7· ·there.· But some ODTs are designed to
`
`·8· ·liberate their active components for
`
`·9· ·subsequent absorption across the mucosa
`
`10· ·found in the oral cavity.· I think I
`
`11· ·distinguished that previously, but I just
`
`12· ·want to make it very clear.
`
`13· · · ·Q· · ·How do you know if an orally
`
`14· ·dissolving tablet will release its drug
`
`15· ·through the oral mucosa or through the GI
`
`16· ·tract or both?
`
`17· · · · · · ·MR. LADOW:· Objection to the
`
`18· · · ·form of the question.
`
`19· · · · · · ·MS. FREEMAN:· Let me ask a
`
`20· · · ·better question.
`
`21· · · ·Q· · ·How do you know if an orally
`
`22· ·dissolving tablet will allow its drug to
`
`23· ·be absorbed through the oral mucosa?
`
`24· · · ·A· · ·Pharmaceutically, typically they
`
`25· ·are designed with certain additives that
`
`Page 17
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· ·cause for the rapid disintegration, and it
`
`·3· ·is a fancy term for breaking apart and
`
`·4· ·liberating the active substance in the
`
`·5· ·oral cavity.
`
`·6· · · · · · ·A conventional tablet,
`
`·7· ·compressed tablet is compressed under so
`
`·8· ·much pressure, it is so hard that it
`
`·9· ·doesn't disintegrate, and it is designed
`
`10· ·for gastrointestinal absorption.
`
`11· · · ·Q· · ·How do you know if an orally
`
`12· ·dissolving tablet will allow its drug to
`
`13· ·be absorbed through the oral mucosa?
`
`14· · · ·A· · ·Well, with the kind of work that
`
`15· ·I do, it's just I would know what kind of
`
`16· ·excipients or additives were in the tablet
`
`17· ·and the nature of the AP, active
`
`18· ·pharmaceutical ingredient that was
`
`19· ·contained therein.· That would give me an
`
`20· ·idea as a pharmaceutical scientist.
`
`21· · · ·Q· · ·So if I gave you the name of an
`
`22· ·orally dissolving tablet, could you tell
`
`23· ·me if it would release the active through
`
`24· ·the oral mucosa for absorption through the
`
`25· ·oral mucosa?
`
`Page 18
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· · · · · · ·MR. LADOW:· Objection to the
`
`·3· · · ·form of the question.
`
`·4· · · ·Q· · ·Let me ask a better question.
`
`·5· · · · · · ·If I gave you the name of an
`
`·6· ·orally dissolving tablet, could you tell
`
`·7· ·me if the drug contained therein would be
`
`·8· ·absorbed through the oral mucosa?
`
`·9· · · ·A· · ·Yeah, I might be able to
`
`10· ·depending on the name of that drug.
`
`11· · · ·Q· · ·You might be able to?
`
`12· · · ·A· · ·I'm reasonably sure that I would
`
`13· ·be able to.
`
`14· · · ·Q· · ·And how would you -- you would
`
`15· ·know based on the excipients and the
`
`16· ·active if it released -- if a specific
`
`17· ·orally dissolving tablet allowed its drug
`
`18· ·to be absorbed through the oral mucosa; is
`
`19· ·that correct?
`
`20· · · ·A· · ·And the fact that if the drug is
`
`21· ·formulated as an ODT, and that's in the
`
`22· ·package information, then if it is an ODT,
`
`23· ·it was designed to liberate its drug in
`
`24· ·the oral cavity for subsequent absorption
`
`25· ·across the oral mucosae.
`
`Page 19
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· · · · · · ·So to sort of cut to the chase
`
`·3· ·here, there are so many drugs that are now
`
`·4· ·being formulated as ODTs, it is almost --
`
`·5· ·it is very difficult to keep up with them
`
`·6· ·all because of this need to better dose
`
`·7· ·elderly patients that might have trouble
`
`·8· ·swallowing a conventional capsule or
`
`·9· ·tablet.
`
`10· · · ·Q· · ·Okay.
`
`11· · · · · · ·A suboxone orally dissolving
`
`12· ·tablet, does that allow its actives to be
`
`13· ·absorbed through the oral mucosa?
`
`14· · · ·A· · ·It does.
`
`15· · · ·Q· · ·And how do you know that?
`
`16· · · ·A· · ·Well, I mean, there are several
`
`17· ·reasons.· I mean, the active drug is
`
`18· ·buprenorphine, and I am a pharmaceutical
`
`19· ·scientist and I'm a licensed pharmacist,
`
`20· ·and I know from that experience that
`
`21· ·buprenorphine has always, historically,
`
`22· ·traditionally been administered across the
`
`23· ·oral mucosa and not administered perorally
`
`24· ·for subsequent absorption across the
`
`25· ·gastrointestinal tract.
`
`Page 20
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· · · ·Q· · ·So you're not basing -- is your
`
`·3· ·opinion that suboxone orally dissolving
`
`·4· ·tablets release drug through the oral
`
`·5· ·mucosa -- sorry, allow drug to be absorbed
`
`·6· ·through the oral mucosa not based on any
`
`·7· ·particular excipients in the suboxone
`
`·8· ·tablet?
`
`·9· · · · · · ·MR. LADOW:· Objection to the
`
`10· · · ·form of the question.
`
`11· · · ·A· · ·You know, my main conclusion is
`
`12· ·that historically that is the way that
`
`13· ·buprenorphine has traditionally been
`
`14· ·dosed, or I should say that's been the
`
`15· ·typical route of administration for
`
`16· ·buprenorphine.· I mean that's the primary
`
`17· ·reason that I know that buprenorphine
`
`18· ·would be absorbed across the oral mucosa.
`
`19· · · ·Q· · ·What about naloxone in a
`
`20· ·suboxone orally dissolving tablet?
`
`21· · · · · · ·MR. LADOW:· Objection to the
`
`22· · · ·form of the question.
`
`23· · · ·A· · ·Could you be more specific?· You
`
`24· ·said what about naloxone in a suboxone.
`
`25· ·What about naloxone?
`
`Page 21
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· · · ·Q· · ·Would the naloxone in a suboxone
`
`·3· ·orally dissolving tablet be absorbed
`
`·4· ·through the oral mucosa?
`
`·5· · · ·A· · ·Well, a little bit of the
`
`·6· ·naloxone is absorbed, but the makers of
`
`·7· ·suboxone have tried to limit the
`
`·8· ·absorption of naloxone through the oral
`
`·9· ·mucosa.
`
`10· · · ·Q· · ·How have the makers of suboxone
`
`11· ·tried to limit the absorption of naloxone
`
`12· ·through the oral mucosa?
`
`13· · · ·A· · ·Well, as I understand the '832
`
`14· ·Patent which I was asked to review and
`
`15· ·express my opinions about --
`
`16· · · · · · ·THE WITNESS:· I'm sorry, can you
`
`17· · · ·read back the question.
`
`18· · · · · · ·(Record read)
`
`19· · · · · · ·MR. LADOW:· Objection to the
`
`20· · · ·form of the question.
`
`21· · · ·A· · ·So I understand that those
`
`22· ·makers used pH as a mechanism to limit the
`
`23· ·absorption of naloxone from their product.
`
`24· · · ·Q· · ·Who are the makers of suboxone
`
`25· ·products?
`
`Page 22
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· · · ·A· · ·Well, as I understand it, it's
`
`·3· ·Reckitt Benckiser, and I'm not really sure
`
`·4· ·how to spell the Benckiser part.
`
`·5· ·Sometimes go by the acronym of RBP Reckitt
`
`·6· ·Benckiser Pharmaceuticals for the tablets.
`
`·7· · · ·Q· · ·Does the pH of a tablet affect
`
`·8· ·whether the drug contained in the tablet
`
`·9· ·is absorbed through the oral mucosa?
`
`10· · · · · · ·MR. LADOW:· Objection.· Lacks
`
`11· · · ·foundation.
`
`12· · · ·A· · ·Well, it actually depends on the
`
`13· ·active drug that's incorporated in the
`
`14· ·tablet.
`
`15· · · ·Q· · ·Okay.
`
`16· · · · · · ·So would the pH of a suboxone
`
`17· ·tablet affect whether the drug contained
`
`18· ·in the tablet is absorbed in the oral
`
`19· ·mucosa?
`
`20· · · ·A· · ·You're referring to naloxone?
`
`21· · · ·Q· · ·I did not mention naloxone.
`
`22· · · ·A· · ·I think the question was would
`
`23· ·the pH affect --
`
`24· · · ·Q· · ·Would the pH of a suboxone
`
`25· ·tablet affect whether the drug contained
`
`Page 23
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· ·in the tablet is absorbed through the oral
`
`·3· ·mucosa?
`
`·4· · · · · · ·MR. LADOW:· Objection.· Lacks
`
`·5· · · ·foundation.
`
`·6· · · ·A· · ·Well, in the case of naloxone --
`
`·7· · · ·Q· · ·Excuse me, but I wasn't
`
`·8· ·referring to naloxone.
`
`·9· · · ·A· · ·Well, you're referring to the
`
`10· ·suboxone tablet which contains
`
`11· ·buprenorphine and naloxone, and I was just
`
`12· ·commenting on naloxone, that pH does
`
`13· ·influence its absorption.
`
`14· · · ·Q· · ·PH does influence the absorption
`
`15· ·of naloxone through the oral mucosa?
`
`16· · · ·A· · ·It does.
`
`17· · · ·Q· · ·And does pH influence the
`
`18· ·absorption of buprenorphine through the
`
`19· ·oral mucosa?
`
`20· · · ·A· · ·It does.
`
`21· · · ·Q· · ·Is it your opinion that the
`
`22· ·makers of suboxone orally dissolving
`
`23· ·tablet selected the pH of the tablet to
`
`24· ·control the absorption of the actives
`
`25· ·contained therein?
`
`Page 24
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· · · ·A· · ·Well, they certainly had
`
`·3· ·additives contained in their product not
`
`·4· ·necessarily to control pH.· There are
`
`·5· ·other reasons why they might have included
`
`·6· ·two additives that I'm aware of for
`
`·7· ·reasons other than pH control, and I think
`
`·8· ·that the fact that at lower pHs, there was
`
`·9· ·optimization of the buprenorphine that was
`
`10· ·absorbed and an inhibition of naloxone.
`
`11· ·It was a truly innovative discovery,
`
`12· ·surprising discovery, unexpected, if you
`
`13· ·will.
`
`14· · · ·Q· · ·So you're saying that the
`
`15· ·influence of pH on the absorption of
`
`16· ·buprenorphine and naloxone from a suboxone
`
`17· ·orally dissolving tablet was unexpected?
`
`18· · · ·A· · ·What I meant to say is that
`
`19· ·unexpected as a lower pH for
`
`20· ·buprenorphine.· And the reason I say that
`
`21· ·is because since buprenorphine is
`
`22· ·considered an active that is a weak base,
`
`23· ·one would expect a higher absorption at a
`
`24· ·higher pH.
`
`25· · · ·Q· · ·Did the pH of the suboxone
`
`Page 25
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· ·orally dissolving tablet -- does the pH of
`
`·3· ·the suboxone orally dissolving tablet
`
`·4· ·affect the absorption of buprenorphine
`
`·5· ·from the tablet?
`
`·6· · · ·A· · ·Well, no.· As I understand it,
`
`·7· ·it is not -- if you were at too high of a
`
`·8· ·pH with buprenorphine, that drug is
`
`·9· ·limited by its solubility, its aqueous
`
`10· ·solubility, so there is a lot of factors
`
`11· ·that come into play here, and so I'm not
`
`12· ·sure that I answered your question.
`
`13· · · ·Q· · ·Did the pH of the suboxone
`
`14· ·orally dissolving tablet affect the
`
`15· ·absorption of naloxone from the tablet?
`
`16· · · ·A· · ·It is my opinion --
`
`17· · · · · · ·MR. LADOW:· Asked and answered.
`
`18· · · ·Objection.· Asked and answered.
`
`19· · · ·A· · ·-- that it did.
`
`20· · · ·Q· · ·What is the pH of a suboxone
`
`21· ·orally dissolving tablet?
`
`22· · · · · · ·MR. LADOW:· Objection.· Lacks
`
`23· · · ·foundation.
`
`24· · · ·A· · ·Well, I mean, in my review of
`
`25· ·materials, I have read that somebody had
`
`Page 26
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· ·actually tested that.
`
`·3· · · ·Q· · ·And do you recall what the
`
`·4· ·results of that test was?
`
`·5· · · ·A· · ·I think I -- to the best of my
`
`·6· ·recollection, I think it was a pH of 3 or
`
`·7· ·3.5.
`
`·8· · · ·Q· · ·In your opinion, would a person
`
`·9· ·of skill in the art of the '831 Patent
`
`10· ·need to have a good understanding of the
`
`11· ·pharmacokinetics of buprenorphine and
`
`12· ·naloxone?
`
`13· · · ·A· · ·Yes, I have written that in my
`
`14· ·declaration, and I do believe that they
`
`15· ·would need a good understanding of the
`
`16· ·pharmacokinetics of those two active
`
`17· ·ingredients.
`
`18· · · ·Q· · ·In your opinion, what is the
`
`19· ·approximate mean absolute oral
`
`20· ·bioavailability of naloxone?
`
`21· · · ·A· · ·Oral bioavailability as in PO,
`
`22· ·peroral.
`
`23· · · ·Q· · ·Can you not answer the question
`
`24· ·unless you use the word peroral?
`
`25· · · ·A· · ·I'm trying to clarify.
`
`Page 27
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· · · · · · ·Do you mean what is the
`
`·3· ·bioavailability of naloxone when it is
`
`·4· ·administered sublingually or by PO
`
`·5· ·administration?
`
`·6· · · ·Q· · ·Let me step back a minute.
`
`·7· · · ·A· · ·Okay.
`
`·8· · · ·Q· · ·What does mean absolute oral
`
`·9· ·bioavailability mean to you?
`
`10· · · ·A· · ·Well, the average oral
`
`11· ·bioavailability is actually calculated as
`
`12· ·a ratio mathematically of the area under a
`
`13· ·plasma concentration time curve after oral
`
`14· ·administration relative to the area under
`
`15· ·the curve, the plasma concentration time
`
`16· ·curve that is, after the same dose of the
`
`17· ·same drug to the same patient is
`
`18· ·administered intravenously.
`
`19· · · · · · ·MR. LADOW:· I'm going to ask you
`
`20· · · ·to maybe go a little slower.
`
`21· · · · · · ·THE WITNESS:· I'm sorry.
`
`22· · · ·Q· · ·Do you understand what oral
`
`23· ·administration means?
`
`24· · · ·A· · ·Well, yes, I think I answered
`
`25· ·that.· I mean, oral administration to me
`
`Page 28
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· ·means that a person takes a drug and they
`
`·3· ·swallow it, a conventional dosage form, a
`
`·4· ·compressed tablet or a capsule, for
`
`·5· ·subsequent absorption in the
`
`·6· ·gastrointestinal tract.
`
`·7· · · ·Q· · ·Does oral administration only
`
`·8· ·apply to a compressed tablet or capsule?
`
`·9· · · ·A· · ·Well, no, because I mean you
`
`10· ·could have other dosage forms like a drug
`
`11· ·solution or a drug suspension.· So no, not
`
`12· ·just tablets and capsules.· Those are the
`
`13· ·two most common.
`
`14· · · ·Q· · ·What would oral administration
`
`15· ·of a drug solution consist of?
`
`16· · · ·A· · ·Well, very simply, a drug is
`
`17· ·dissolved in some sort of vehicle and
`
`18· ·administered as a solution.· Again, it
`
`19· ·gets around having to swallow perhaps a
`
`20· ·large dosage form like a capsule or a
`
`21· ·tablet.
`
`22· · · ·Q· · ·So an oral administration --
`
`23· ·okay, I guess -- what is the oral
`
`24· ·administration of a drug solution?
`
`25· · · ·A· · ·Well, to me that's just a drug
`
`Page 29
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· ·that's been dissolved in some liquid,
`
`·3· ·usually aqueous based, and then the
`
`·4· ·patient takes a certain amount, teaspoon
`
`·5· ·or two teaspoons of that drug solution and
`
`·6· ·swallows that for drug absorption in the
`
`·7· ·gastrointestinal tract.
`
`·8· · · ·Q· · ·Can a film dosage form be orally
`
`·9· ·administered?
`
`10· · · ·A· · ·You know, in my opinion, I'm not
`
`11· ·aware of any films that are actually
`
`12· ·swallowed.· That is to say we call -- just
`
`13· ·as we call orally disintegrating tablets
`
`14· ·ODTs, we typically call films ODF or
`
`15· ·orally dissolvable film.· And I really, in
`
`16· ·my opinion, I can't think of any films
`
`17· ·that are actually swallowed for subsequent
`
`18· ·absorption in the gastrointestinal tract.
`
`19· · · ·Q· · ·So is it your opinion that
`
`20· ·orally dissolving films are not orally
`
`21· ·administered?
`
`22· · · ·A· · ·Well, I tend to be a little more
`
`23· ·specific here, that typically an ODF is
`
`24· ·meant to deliver its active ingredients
`
`25· ·through the oral mucosa, or as with the
`
`Page 30
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· ·ODT, the ODF sometimes is designed to
`
`·3· ·liberate its contents in the oral cavity
`
`·4· ·to be mixed with saliva and then to be
`
`·5· ·swallowed and subsequently absorbed in the
`
`·6· ·gastrointestinal tract.· Very similar,
`
`·7· ·analogous to the ODT.
`
`·8· · · ·Q· · ·So if a reference referred to
`
`·9· ·the oral administration of a drug film,
`
`10· ·what would you understand that to mean?
`
`11· · · · · · ·MR. LADOW:· Objection.
`
`12· · · ·Incomplete hypothetical.
`
`13· · · · · · ·THE WITNESS:· May I request that
`
`14· · · ·you read the question back.
`
`15· · · · · · ·(Record read)
`
`16· · · ·A· · ·Well, first of all, I guess
`
`17· ·because of my training, I wouldn't say the
`
`18· ·oral administration of a film.· It would
`
`19· ·be the oral administration of a drug via
`
`20· ·film.· And some companies would design
`
`21· ·that film, as I said, to deliver their
`
`22· ·contents and to be purposely,
`
`23· ·intentionally swallowed for subsequent
`
`24· ·absorption by the gastrointestinal tract,
`
`25· ·but there are films obviously that are
`
`Page 31
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· ·intended to liberate their actives in the
`
`·3· ·oral cavity for subsequent absorption of
`
`·4· ·the actives across the oral mucosa.
`
`·5· · · ·Q· · ·Is there a difference in your
`
`·6· ·opinion between drug administration and
`
`·7· ·drug absorption?
`
`·8· · · ·A· · ·Well, as a pharmaceutical
`
`·9· ·scientist, I think of drug absorption as
`
`10· ·drug molecules diffusing across the
`
`11· ·biological membrane.· I think a drug
`
`12· ·administration just means the act of
`
`13· ·administering a drug in a dosage form to a
`
`14· ·patient.
`
`15· · · ·Q· · ·Okay.
`
`16· · · · · · ·I would just like to ask about
`
`17· ·oral administration, and without any
`
`18· ·reference to absorption, what would your
`
`19· ·understanding be of oral administration of
`
`20· ·a drug film?
`
`21· · · · · · ·MR. LADOW:· Objection to form.
`
`22· · · ·But also asked and answered.· I really
`
`23· · · ·think you have asked the same thing
`
`24· · · ·almost 20 times.
`
`25· · · ·A· · ·And maybe I could -- I do
`
`Page 32
`
`
`
`·1· · · · · · · · · ·Johnston
`
`·2· ·believe I have answered.· Maybe I can be
`
`·3· ·more specific this time.
`
`·4· · · · · · ·My understanding of that would
`
`·5· ·be that the oral administration of the
`
`·6· ·drug through film could be one of two
`
`·7· ·ways.· One to liberate the drug, to be
`
`·8· ·swallowed for subsequent GI absorption, or
`
`·9· ·it could liberate its active compounds for
`
`10· ·absorption across the oral mucosa in the
`
`11· ·oral cavity.
`
`12· · · ·Q· · ·Did you say that you're a
`
`13· ·licensed pharmacist?
`
`14· · · ·A· · ·I am.
`
`15· · · ·Q· · ·If a patient came to you with a
`
`16· ·prescription for a drug film and the
`
`17· ·prescription said oral administration and
`
`18· ·the patient asked you to explain how to
`
`19· ·take the drug film, what would you tell
`
`20· ·the patient?
`
`21· · · ·A· · ·Well
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