TBD
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`RB Ex 2053RB Ex. 2053
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`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`1
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`RB Ex 2053RB Ex. 2053
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`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`1
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`Problem Identified by ‘832 Patent
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`Solution Provided by ‘832 Patent
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`‘832 Patent, Ex. 1001 at 1:62-2:2
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`‘832 Patent, Ex. 1001 at 4:55-60
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`•FDA approved for treatment of opioid dependency in 2002 (Ex.
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`2003, ¶ 60) (POCR p. 15), ¶ ) ( p )
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`•Active ingredients are buprenorphine and naloxone
`•Buprenorphine is an opioid agonist – absorption is desired
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`l•Naloxone is an opioid antagonist – absorption is disfavored (Ex. d b d f d (
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`2003, ¶ 23) (POCR p. 22)
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`•“When taken orally, buprenorphine undergoes first-pass metabolismWhen taken orally, buprenorphine undergoes first pass metabolism
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`with N-dealkylation and glucuroconjugation in the small intestine and
`the liver. The use of SUBOXONE by the oral route is therefore
`inappropriate. SUBOXONE tablets are for sublingual administration.”
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`(E 2007 (SUBOXONE® T bl t D t Sh t)(Ex. 2007 (SUBOXONE® Tablet Data Sheet) at 2; Ex. 2003, ¶ 43) (POCR t 2 E 2003 ¶ 43) (POCR
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`p. 16)
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`•“Administration is sublingual. Physicians must advise patients that the g y p
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`sublingual route is the only effective and safe route of administration
`for this drug.” (Ex. 2030 (Subutex Summary of Product Characteristics)
`at 2; Ex. 2003, ¶ 62) (POCR p. 15) IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`Peroral Administration: Not Therapeutically Acceptable
`Poor Bioavailability First Pass Metabolic Effects (POCR p. 10 12)
`•Poor Bioavailability – First Pass Metabolic Effects (POCR p 10-12)
`•Mean absolute bioavailability is estimated to be less than 15% and, actually, close to 0% (Ex.
`2003, ¶¶ 45-46) (POCR p. 11 fn. 4)
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`•Inter-Patient Variability (POCR p. 11-13)y p
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`•“In fact, roughly 1/3 of patients who take buprenorphine by the peroral route have
`absolutely no detectable amounts of buprenorphine in the systemic circulation.” (Ex. 2003, ¶
`47 (citing Ex. 2022, 140-41))
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`I t•Intra-Patient Variability (POCR p. 13-14)P ti t V i bilit (POCR 13 14)
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`•“Therefore, the same patient may respond significantly differently from day to day
`depending on his health, what he eats, or other drugs that he takes. Therefore, a peroral
`dose of buprenorphine that maintains a patient one day can on another day lead to
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`withdrawal, significant side effects, or worse.” (Ex. 2003, ¶ 56) (POCR p. 14), g , ( , ¶ ) ( p )
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`•“For all of these reasons, as of 2009 (indeed, long before then), peroral
`administration of buprenorphine would have been regarded by the person of ordinary
`skill in the art as therapeutically inappropriate and unacceptable.” (Ex. 2003, ¶ 63)
`(POCR p. 14)
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`Johnston Dec., Ex. 2003, ¶¶ 44-59.
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`Buprenorphine: Oral Transmucosal Absorption
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`“T•“Transmucosal oral delivery is superior to peroral delivery because l l d li i i t l d li b
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`buprenorphine delivered oral transmucosally would be absorbed mainly
`via the tissues in the oral cavity and cleared by the lingual blood vessels,
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`which are not part of the hepatic portal system. Therefore, oral p p p y ,
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`transmucosal delivery avoids the significant first-pass metabolism of
`buprenorphine.” (Ex. 2003, ¶ 61) (POCR p. 15)
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`•“While peroral administration of buprenorphine has long been recognized• While peroral administration of buprenorphine has long been recognized
`as inappropriate, it has long been known the oral transmucosal absorption
`is a safe and effective route for delivering buprenorphine to treat opioid
`dependent outpatients.” (Ex. 2003, ¶ 60) (POCR p. 14-15)
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`•“[S]ublingual administration would be expected to produce results that
`are . . . far more consistent among patients in the target population than
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`peroral administration would be able to produce.” (Ex. 2003, ¶ 48, fn 4)peroral administration would be able to produce. (Ex. 2003, ¶ 48, fn 4)
`Johnston Dec., Ex. 2003, ¶¶ 44-59
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`•Because of the pharmacokinetics of buprenorphine, a POSA
`y
`p
`y
`would know OTA is the only therapeutically effective and
`acceptable form of oral administration (POCR p. 20-21)
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`•Only OTA is contemplated by the ‘832 patent (POCR p. 20)
`•Oral transmucosal absorption: “Sublingual and Buccal Film
`Compositions” (POCR p. 21)
`•Local pH (POCR p. 23-24)
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`Bi•Bioequivalence with Suboxone Tablets (POCR p. 24-25)i l ith S b T bl t (POCR 24 25)
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`
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`•Pharmacokinetic data in specification (repeated in claims)
`resulted from OTA (POCR p. 25-26)
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`Johnston Dec., Ex. 2003, ¶¶ 65-72
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`7
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`The Disclosed Films Provide OTA
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`‘832 Patent, Ex. 1001 at Title.
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`(POCR p. 21)(POCR p. 21)
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`‘832 Patent, Ex. 1001 at 11:10-16.832 Patent, Ex. 1001 at 11:10 16.
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`(POCR p. 22)
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`‘832 Patent Ex 1001 at 6:39-59832 Patent, Ex. 1001 at 6:39-59.
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`(POCR p. 23)
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`Johnston Dec., Ex. 2003, ¶¶ 66-68
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`Local pH Is Only Relevant in the Context of OTA
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`‘832 Patent, Ex. 1001 at 11:10-16.
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`‘832 Patent, Ex. 1001 at 11:57-61.
`‘832 Patent, Ex. 1001 at 23:8-11.
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`•“The concept of “local pH” as used in the context of the ʼ832 patent would be understood by oneThe concept of local pH as used in the context of the 832 patent would be understood by one
`of ordinary skill in the art as solely concerning a region in the mouth (where the matrix is
`dissolving) and not to any region in the gut . . . that the concept of local pH as used in the context
`of the patent has no relevance to perorally administered actives, because they would encounter a
`much larger and stronger volume of acids and bases in the stomach and intestines and whatever
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`i dlilimited quantity of buffer was intended for use in the mouth would be rendered ineffective in the i f b ff i d d f i h h ld b d d i ff i i h
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`stomach and intestines.” (Ex. 2003, ¶ 69)
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`PK Values in the ‘832 Patent Indicate OTAPK Values in the 832 Patent Indicate OTA
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`•“The person of ordinary skill in the art would appreciate that all of the pharmacokinetic data
`and ranges in the specification relating to Suboxone® sublingual tablets, including Tables 2
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`and 3, result or would be expected to result from oral transmucosal absorption, the known , p p ,
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`route employed by that commercial product.” (Ex. 2003, ¶ 71)
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`•“Similarly, the person of ordinary skill would understand that all of the pharmacokinetic data
`provided about the test film formulations resulted from oral transmucosal absorption.” (Ex.
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`2003 ¶ 71)2003, ¶ 71)
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`•“For example, Table 12, which presents pharmacokinetic data for the test films, notes
`‘lower buccalabsorption’ of naloxone provided by at least one of the formulations as
`compared to the sublingual tablet (with no mention of GI absorption of either active
`ingredient).” (Ex. 2003, ¶ 71, fn 10)
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`•“[T]he skilled person would recognize that there is no suggestion whatsoever, much less any
`teaching, in the ‘832 patent that a therapeutically acceptable film dosage form could be
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`delivered perorally or that any of the recited pharmacokinetic ranges are somehow meant todelivered perorally or that any of the recited pharmacokinetic ranges are somehow meant to
`encompass peroral administration intended for delivery of buprenorphine for absorption in
`the gut.” (Ex. 2003, ¶ 71)
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`10
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`•Labtec Is Only Directed to Non-Mucoadhesive Films for GI
`Absorption
`Absorption
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`•Labtec Has No Description of a Buprenorphine Film (With or Without
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`Naloxone) and Is Insufficient to Constitute an Anticipatory Reference ) p y
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`as to the Claims in Issue (Patent Owner Corrected Resp., Paper 25,
`30-31)
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`•Labtec Is Not Enabling (id. at 32-38)
`•Suboxone Included as a Mistake
`•Inoperable on Its Own Terms if Applied to Suboxone
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`•GI Absorption Is Not Therapeutically Acceptable•GI Absorption Is Not Therapeutically Acceptable
`•Labtec Can’t Be Used to Obtain Claim 19
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`11
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`Labtec Is Solely Directed to Films for GI Absorption
`Title Non Mucoadhesive Film Dosage Forms
`•Title – “Non-Mucoadhesive Film Dosage Forms”
`•“The term ‘non-mucoadhesive’ means that the dosage form is not designed for
`administration of the active pharmaceutical agent through the oral mucosa.” (Ex. 1017 at 9)
`(POCR pp. 27, 30, 39)
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`S mmar of the In ention•Summary of the Invention
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`•“The present invention provides film dosage forms that are formulated or administered for
`gastrointestinal absorption of the active pharmaceutical agent, and that are bioequivalent to
`and interchangeable with existing orally administered drug products. These film dosage
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`forms are non-mucoadhesive; they quickly disintegrate in the mouth when exposed to saliva; y q y g p
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`and they are absorbed predominantly through the gastrointestinal tract.” (Ex. 1017 at 4)
`(POCR p. 30)
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`•“The prompt disintegration and swallowing of the film helps to assure gastrointestinal absorption
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`of the dosage form The film is not of the conventional mucoadhesive type designed to deliverof the dosage form. The film is not of the conventional mucoadhesive type, designed to deliver
`active agent transmucosally.” (Ex. 1017 at 10)
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`•“Notably, Labtec states that if an active is used that has a tendency to be absorbed through the oral
`mucosa, the film should include a ‘means for retarding absorption of said active pharmaceutical
`ingredient through the oral mucosa.’” (Ex. 2003, ¶ 74 (quoting Ex. 1017 at 15)) (POCR p. 28-29)
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`POCR pp. 27-30, 32, 36
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`12
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`WO/2008/040534, Ex. 1017, at 9.
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`WO/2008/040534, Ex. 1017, at 3.
`POCR pp. 27-30, 32, 36
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`WO/2008/040534, Ex. 1017, at 4.
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`WO/2008/040534, Ex. 1017, at 4.
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`POCR pp. 27-30, 32, 36
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`WO/2008/040534, Ex. 1017, at 4.
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`WO/2008/040534, Ex. 1017, at 5.
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`WO/2008/040534, Ex. 1017, at 5.WO/2008/040534, Ex. 1017, at 5.
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`POCR pp. 27-30, 32, 36
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`WO/2008/040534, Ex. 1017, at 5.
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`WO/2008/040534, Ex. 1017, at 6.
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`WO/2008/040534, Ex. 1017, at 8.
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`WO/2008/040534, Ex. 1017, at 10.
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`POCR pp. 27-30, 32, 36
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`WO/2008/040534, Ex. 1017, at 10.
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`WO/2008/040534, Ex. 1017, at 11.
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`WO/2008/040534, Ex. 1017, at 11.
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`WO/2008/040534, Ex. 1017, at 11.
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`POCR pp. 27-30, 32, 36
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`WO/2008/040534, Ex. 1017, at 12.
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`WO/2008/040534, Ex. 1017, at 12.
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`POCR pp. 27-30, 32, 36
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`WO/2008/040534, Ex. 1017, at 13.
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`WO/2008/040534, Ex. 1017, at 13.
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`POCR pp. 27-30, 32, 36
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`WO/2008/040534, Ex. 1017, at 15.
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`WO/2008/040534, Ex. 1017, at 17.
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`WO/2008/040534, Ex. 1017, at 18.WO/2008/040534, Ex. 1017, at 18.
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`POCR pp. 27-30, 32, 36
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`WO/2008/040534, Ex. 1017, at 18.
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`WO/2008/040534, Ex. 1017, at 19.
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`WO/2008/040534, Ex. 1017, at 19.
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`WO/2008/040534, Ex. 1017, at 29.WO/2008/040534, Ex. 1017, at 29.
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`POCR pp. 27-30, 32, 36
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`WO/2008/040534, Ex. 1017, at 32.
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`WO/2008/040534, Ex. 1017, at 33.
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`WO/2008/040534, Ex. 1017, at 48.
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`WO/2008/040534, Ex. 1017, at 48.
`POCR pp. 27-30, 32, 36
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`WO/2008/040534, Ex. 1017, at 49.
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`WO/2008/040534, Ex. 1017, at 49./ / , ,
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`WO/2008/040534, Ex. 1017, at 49.
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`WO/2008/040534, Ex. 1017, at 50.
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`WO/2008/040534, Ex. 1017, at 52.
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`WO/2008/040534, Ex. 1017, at 52.
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`POCR pp. 27-30, 32, 36
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`WO/2008/040534 Ex 1017 at 53WO/2008/040534, Ex. 1017, at 53.
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`WO/2008/040534, Ex. 1017, at 53.
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`WO/2008/040534, Ex. 1017, at 54.
`POCR pp. 27-30, 32, 36
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`Petitioner’s Reply Asserts:
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`
`
` “There is no dispute that Labtec states its “invention provides an orallyp p y
`disintegrating film comprising: (a) an active pharmaceutical agent that is
`absorbable through the oral mucosa when dissolved; and (b) means for
`retarding absorption of said active pharmaceutical ingredient through the
`oral mucosa.” Ex. 1017, 15. Thus Labtec specifically discloses OTA. Labtec
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`also discloses retarding absorption with pH adjusting agents to achievealso discloses retarding absorption with pH adjusting agents to achieve
`bioequivalence. Ex. 1017, 15-16. This is the allegedly surprising discovery
`of the ‘832 patent. Ex. 1001, 23:1-7.”
`Labtec States:
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`Paper 31, at 5
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`WO/2008/040534, Ex. 1017, at 15
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`Labtec Is Not Enabling—Suboxone® Included as a Mistake
`[W]hile Table A of Labtec lists 19 different brand name drugs of interest for use
`•“[W]hile Table A of Labtec lists 19 different brand name ‘drugs of interest’ for use
`with its disclosed methods and their respective pharmacokinetic profiles, each of
`these brand name products, with the exception of Suboxone® and Subutex®, use the
`GI tract as the ‘metabolic and bioabsorption pathway’.” (Ex. 2003, ¶ 74)
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`•“Labtec is directed to ‘a film product that mimics the pharmacokinetics of an
`innovator’s product, and that follows the same metabolic and bioabsorption pathways
`as the innovator’s product.’ That is, if an existing tablet is perorally administered and
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`uses the GI tract as a ‘metabolic and bioabsorption pathway,’ then the new filmuses the GI tract as a metabolic and bioabsorption pathway, then the new film
`should also use the GI tract.” (Ex. 2003, ¶ 79 (quoting Ex. 1017 at 2))
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`•“As a person of ordinary skill in the art would have readily recognized, the listing of
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`Suboxone® and Subutex® in Labtec’s Table A makes no sense and must clearly be aSuboxone® and Subutex® in Labtec s Table A makes no sense and must clearly be a
`mistake. Oral films intended to provide GI absorption (the only kind taught by Labtec)
`do[] not follow the same ‘metabolic and bioabsorption pathway’ as oral mucosally
`absorbed Suboxone® and Subutex® tablets.” (Ex. 2003, ¶ 81)
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`On Its Own Terms, Labtec Is Inoperable for Suboxone®
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`•“Labtec teaches oral films designed to provide GI absorption that mimic the
`pharmacokinetics of existing tablet dosage forms. In particular, Labtec requires its
`peroral dosage form to ‘contain[] the same amount of active pharmaceutical agent.’
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`Ex 1017 [11] This goal is scientifically unattainable in the case of Suboxone® ” (ExEx. 1017, [11]. This goal is scientifically unattainable in the case of Suboxone . (Ex.
`2003, ¶ 83)
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`•“Because of the large difference in bioavailability for both actives when delivered
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`perorally and oral-transmucosally all the evidence indicate that one cannot achieveperorally and oral transmucosally, all the evidence indicate that one cannot achieve
`remotely similar (and certainly not substantially bioequivalent) pharmacokinetic values
`for buprenorphine or naloxone through use of a GI-absorbed dosage (such as
`Labtec’s proposed films) instead of an oral-transmucosal dosage (such as Suboxone®
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`tablets) using the same amount of the active ingredients in the two dosages Hencetablets) using the same amount of the active ingredients in the two dosages. Hence,
`Labtec’s stated objective cannot be reached as it pertains to mimicking the absorption
`from and producing effects bioequivalent to Suboxone® tablets with the
`corresponding dosage amounts (as listed in Labtec’s Table A).” (Ex. 2003, ¶ 85)
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`27
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`Labtec Is Not Enabling—GI Absorption Is Not Therapeutically
`Acceptable
`•“[I]t is not therapeutically acceptable to deliver buprenorphine perorally as Labtec
`requires because . . . as a result of first-pass metabolism, peroral delivery results not
`only in poor bioavailability but one of ordinary skill in the art would also reasonably
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`expect an unacceptable increase in inter- and intra-patient variability as compared toexpect an unacceptable increase in inter- and intra-patient variability as compared to
`oral mucosal delivery.” (Ex. 2003, ¶ 87)
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`•“[S]uch increased variability means that there is that much of a greater risk of
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`negative outcomes and side effects in the event of peroral administration as comparednegative outcomes and side effects in the event of peroral administration as compared
`to oral mucosal administration.” (Ex. 2003, ¶ 87)
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`•Regarding buprenorphine tablets:
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`•“Administration is sublingual Physicians must advise patients that the sublingual route is theAdministration is sublingual. Physicians must advise patients that the sublingual route is the
`only effective and safe route of administration for this drug.” (Ex. 2030 (Subutex Summary of
`Product Characteristics) at 2; Ex. 2003, ¶ 62) (POCR p. 15-16)
`•“As such, Labtec cannot anticipate a claim to what is clearly meant to be a
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`therapeutically suitable or acceptable buprenorphine containing film formulation ”therapeutically suitable or acceptable buprenorphine-containing film formulation.
`(Ex. 2003, ¶ 88) (POCR p. 36)
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`Labtec Films Cannot Meet Claim 19’s Cmax Requirement
`•“[D]ue to the first pass-effects on the bioavailability of naloxone, the literature
`indicates it is not possible to achieve the required naloxone Cmax values recited in
`independent Claim 15 (at least 41.04 pg/ml) with any of the mg dosage amounts of
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`naloxone recited in dependent Claim 19 (0.5 mg to 4 mg) through peroral p ( g g) g p
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`administration and GI absorption.” (Ex. 2003, ¶ 89) (POCR p. 37-38)
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`•“This is further demonstrated in a pharmacokinetic study in twelve patients
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`administered a 4 mg peroral solution of naloxone in which the mean plasma naloxone g p p
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`Cmax value only reaches 27.16 ± 6.29 pg/ml.” (Ex. 2003, ¶ 90 (citing Ex. 2034, Table
`4 and Fig. 5)) (POCR p. 37-38)
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`•“Similar results were obtained in subjects administered a 5 mg prolonged release j g p g
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`
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`peroral naloxone tablet.” (Ex. 2003, ¶ 91 (citing Ex. 2035, 362-64 (5 mg prolonged
`release naloxone tablet achieved a Cmax of 32.45 pg/ml with an approximated
`absolute oral bioavailability of 0.9%))) (POCR p. 37-38)
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`Labtec Films Cannot Meet Claim 19’s Cmax Requirement
`•Petitioner’s Reply asserts: “And even if Labtec’s film were swallowed, RB’s expert
`reluctantly admitted that the mean absolute bioavailability of oral naloxone is ‘one-
`third’ that of a Suboxone tablet. Ex. 1028, 45:7-20.)” (Paper 31, 12)
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`•Patent Owner’s expert testified (Ex. 1028, 45:7-20):
`
`·7 · · · Q· · · How does the mean absolute
`·8· ·bioavailability of oral naloxone compare
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`to the mean absolute bioavailability of9·9· ·to the mean absolute bioavailability of
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`10· ·naloxone from a suboxone tablet?
`11· · · ·A· · ·Okay.
`12· · · · · · ·Well, if we use one percent
`13· ·after PO and three percent here in this
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`14· ·exhibit, one would naturally say, y y
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`15· ·one-third, but I can't commit to that as a
`16· ·scientist because those ranges for PO are
`17· ·not carved in stone.· There is a lot of
`18· ·variability.· So if you're looking for a
`19· ·quantitative one-third, I really am
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`l2020· ·reluctant to do that.d h
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`30
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`•POSA Would Not Look to Labtec to Develop a Film for Delivery of
`Buprenorphine
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`•POSA Would Have No Reasonable Expectation of Success in
`Obtaining the Claimed Invention
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`•Labtec Can’t Be Transmogrified into Its Oppositeg pp
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`•Yang Teaches Film Manufacturing to Assure Uniform Content of
`Actives; Doesn’t Mention Buprenorphine or Naloxone
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`•Combination of Labtec and Yang Would Require Undue
`Experimentation
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`P i i•Petitioner Has Not Carried Its BurdenH N C i d I B d
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`•Secondary Considerations Support Nonobviousness
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`Patent Owner Corrected Resp., Paper 25, 38-56.
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`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
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`31
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`POSA Would Not Look to Labtec to Develop a Film for Delivery of
`Buprenorphine
`Buprenorphine
`•“A person of ordinary skill seeking to design a buprenorphine dosage form would know to wholly
`avoid the peroral route of buprenorphine administration as taught by Labtec and thus would not
`have sought its teachings.” (Ex. 2003, ¶ 94) (POCR p. 40)
`
`•“Just because Labtec mentions the notion of oral films designed to provide GI absorption to mimic
`Suboxone® tablets does not mean that one of ordinary skill would look to Labtec to try to create
`such a film. In particular, the person of ordinary skill would have concluded that the Labtec
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`inventors made a mistake when they included the buprenorphine-containing products, Subutex®inventors made a mistake when they included the buprenorphine containing products, Subutex
`and Suboxone® tablets, in Table A among numerous brand name products whose actives are in
`fact meant to be absorbed in the gut. It seems obvious that Labtec incorrectly assumed that, like
`those other 17 products, Subutex® and Suboxone® tablets delivered their actives in the gut.” (Ex.
`2003, ¶ 96) (POCR p. 40)
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`•“Faced with an obviously mistaken and unintentional suggestion to pursue an avenue for
`buprenorphine delivery that was understood to be therapeutically ineffective and unacceptable, the
`person of ordinary skill would have disregarded Labtec.” (Ex. 2003, ¶ 97) (POCR p. 41)
`
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
`
`32
`
`
`
`No Reasonable Expectation of Success—Labtec Can’t Be
`Transmogrified into its Opposite
`Transmogrified into its Opposite
`•“Labtec solely addresses oral film dosage forms intended for GI absorption. In
`contrast, the challenged claims are directed to films that provide the actives via oral
`
`transmucosal absorption Even if the claims are not construed as requiring oraltransmucosal absorption. Even if the claims are not construed as requiring oral
`transmucosal absorption, the person of ordinary skill in the art at the time the ‘832
`patent was filed would regard peroral administration as ineffective and inappropriate,
`and view the oral transmucosal route as the only therapeutically acceptable oral
`
`delivery route to provide buprenorphine and naloxone at the claimed Cmax values ”delivery route to provide buprenorphine and naloxone at the claimed Cmax values.
`(Ex. 2003, ¶ 106) (POCR p. 45-46)
`
`•“In any event, it would be clear to a person of ordinary skill in the art as of 2009 that
`
`the only therapeutically acceptable way to arrive at the claimed invention would be tothe only therapeutically acceptable way to arrive at the claimed invention would be to
`completely abandon the peroral GI absorption route mandated by Labtec in favor of a
`film for oral transmucosal absorption.” (Ex. 2003, ¶ 107) (POCR p. 46)
`
`POCR p. 44
`
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
`
`33
`
`
`
`No Reasonable Expectation of Success—Yang Teaches Film
`Manufacturing Methods to Achieve Uniform Content of an Active
`Manufacturing Methods to Achieve Uniform Content of an Active
`•“Yang recognized that conventional film manufacturing processes produced
`inherently non-uniform films. [Ex. 1016] at 2:10-13.” “Accordingly, one of skill in the
`
`art understands that Yang ‘provided [] process[es] for making a film having aart understands that Yang provided [] process[es] for making a film having a
`substantially uniform distribution of components and a desired level of active
`component” in each dosage unit of the film. Id. at 4:23-35. The ‘832 patent
`incorporates Yang by reference as providing this teaching. Ex. 1001, 15:29-32.” (Ex.
`
`2003 ¶ 99)2003, ¶ 99)
`
`•“Yang provides no discussion on how to formulate a film to ensure that it provides
`the desired absorption levels of the active ingredients . . . does not provide any
`
`disclosure of how to control absorption of actives through the oral mucosa ordisclosure of how to control absorption of actives through the oral mucosa, or
`specifically how to obtain a desired level of buprenorphine oral mucosal absorption
`while achieving a certain level of inhibition of the oral mucosal absorption of
`naloxone—neither of which are specifically discussed in Yang. Moreover, like Labtec,
`
`Yang does not disclose any embodiment of a film formulation containingYang does not disclose any embodiment of a film formulation containing
`buprenorphine [and] naloxone and does not even mention buprenorphine or naloxone
`as an active ingredient.” (Ex. 2003, ¶ 101)
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
`
`34
`
`
`
`No Reasonable Expectation of Success—Combination of Labtec and
`Yang Would Require Undue Experimentation
`Yang Would Require Undue Experimentation
`•“Suboxone® film was the first sublingual pharmaceutical film approved by the FDA (in
`2010).” (Ex. 2003, ¶ 109)
`
`•Film design is difficult especially the films claimed in the ‘832 patentFilm design is difficult, especially the films claimed in the 832 patent
`•“It undoubtedly took extensive research and development to . . . produce the claimed films,
`i.e., to successfully control the absorption of both buprenorphine (well absorbed) and
`naloxone (absorption largely inhibited) as required . . . .” (Ex. 2003, ¶ 110)
`•“The oral transmucosal absorption of a drug substance is affected by among other things a
`fine balance of [a number of factors]. Adjustment of any of these numerous parameters can
`affect the others . . . Thus, a substantial number of formulation decisions involving a wide
`range of variables would have to be made and evaluated and adjusted through both extensive
`in vitrotesting as well as in vivotesting in, human subjects to determine the pharmacokinetic
`
`results achieved.” (Ex. 2003, ¶ 114)results achieved. (Ex. 2003, ¶ 114)
`•Petitioner’s position, as patent owner in IPR2014-00376, re: pharmaceutical film
`formulation
`•“[T]inkering with even one component may have a significant effect on the entire system . . .
`the combination of ingredients and desired characteristics requires a delicate balance.” (Ex.
`2043 at 2)
`•“[E]ven small changes to the formulation may have drastic effects on the entire device.” (Ex.
`2043 at 35)
`
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
`
`35
`
`
`
`No Reasonable Expectation of Success—Combination of Labtec and
`Yang Would Require Undue Experimentation
`Yang Would Require Undue Experimentation
`•“Labtec—providing an obviously mistaken suggestion to pursue a
`bioequivalent film that mimics Suboxone® tablets through a therapeutically
`
`ineffective and unacceptable approach (peroral delivery and GI absorption)—ineffective and unacceptable approach (peroral delivery and GI absorption)—
`the opposite of the oral transmucosal route employed in Suboxone® tablets
`and in the challenged claims. Ex. 2003, ¶ 111.” (POCR p. 50)
`•“Yang—providing a vitally important disclosure for acceptable
`pharmaceutical films (a method to achieve active ingredient uniformity) but
`adding nothing to Labtec in terms of controlling absorption of any active
`and nothing specific about films with buprenorphine and/or naloxone. Id.”
`
`(POCR p 50-51)(POCR p. 50 51)
`“Birch—directed to an aqueous solution for administration of analgesic
`doses of buprenorphine alone intranasally, and teaching nothing about how
`to achieve a certain bioavailability of buprenorphine and/or naloxone in an
`
`ll diorally dissolvable film. Id.” (POCR p. 51)l bl fil Id” (POCR 51)
`
`
`
`
`POCR p. 48-53
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
`
`36
`
`
`
`No Reasonable Expectation of Success—Combination of Labtec and
`Yang Would Require Undue Experimentation
`Yang Would Require Undue Experimentation
`•“In my opinion, this development project, initiated with simply the
`wish for an oral transmucosal film that provides the claimed
`pharmacokinetic profiles of both buprenorphine and naloxone, and
`with no specific teaching in Labtec, Yang, or Birch about a
`buprenorphine and/or naloxone-containing film, would require
`
`ffefforts far beyond those that could reasonably be described as t f b d th th t ld bl b d ib d
`
`
`
`
`
`
`
`
`routine experimentation.” (Ex. 2003, ¶ 115)
`
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
`
`37
`
`
`
`Secondary Considerations—Claims 15-19 Cover Suboxone®
`Sublingual Films
`Sublingual Films
`•“Suboxone ® Sublingual film is an orally dissolvable, oral transmucosal film
`formulation comprising buprenorphine and naloxone as required by claims 15-19.”
`
`(Ex 2003 ¶ 117 (citing Ex 2038 p 1 col 1 lines 5-7 and 29-31))(Ex. 2003, ¶ 117 (citing Ex. 2038, p. 1, col. 1, lines 5 7 and 29 31))
`
`•Suboxone is marketed at buprenorphine/naloxone dosage levels of 2/0.5, 4/1, 8/2,
`and 12/3, each of which fall within the ranges recited in claims 18 and 19, i.e., 2-16
`
`mg of buprenorphine and 0 5-4 mg of naloxone respectively (Ex 2003 ¶ 117 (citingmg of buprenorphine and 0.5 4 mg of naloxone, respectively. (Ex. 2003, ¶ 117 (citing
`Ex. 2038, p. 1, col. 1, lines 33-35))
`
`•The Cmax and AUC levels for both buprenorphine and naloxone in the 2/0.5, 4/1,
`
`8/2 and 12/3 dosages fall within the ranges recited in claims 15-17 (Ex 2003 ¶8/2, and 12/3 dosages fall within the ranges recited in claims 15 17. (Ex. 2003, ¶
`118 (citing Ex. 2040, 56-59, 58))
`
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
`
`38
`
`
`
`Secondary Considerations—Commercial Success and Praise by Others
`•Suboxone® films dominate the market
`•Petitioner’s SEC 10K statement - “The total market for buprenorphine containing products
`for opioid dependence exceeded $1.7 billion in 2013.” (Ex. 2045 at 17) (POCR p.55)
`•Petitioner’s Press Release – “Suboxone is the market leader” with “2013 sales of Suboxone
`sublingual film increas[ing] to more than $1.3 billion.” (Ex. 2046 at 1-2) (POCR p.55)
`
`•Petitioner VP•Petitioner VP – [T]he vast majority of the market for buprenorphine/naloxone products is “[T]he vast majority of the market for buprenorphine/naloxone products is
`
`dominated by films or film formulations Suboxone film in particular[] . . . with 80% of
`prescriptions now being for film.” (Ex. 2047 at 15) (POCR p.55)
`•Petitioner acknowledges that the emergence of generic tablets had limited impact on Suboxone®
`film’s sales
`•Petitioner VP – “We’ve shifted [our forecast] a bit in favor of branded products based on a
`more limited use of generics than we might have originally projected.” (Ex. 2047 at 15) (POCR
`p.55)
`•Petitioner’s SEC 10K Statement – “[T]he impact of generic buprenorphine/naloxone tablets
`
`on Suboxone® film sales has been limited to date ” (Ex 2045 at 17) (POCR p 55-56)on Suboxone film sales has been limited to date. (Ex. 2045 at 17) (POCR p. 55 56)
`•Doctors and patients prefer films to tablets
`•Petitioner’s CEO – “I think the other thing is [the Patent Owner] did an outstanding job of . . .
`convinc[ing] physicians that [Suboxone® films are] just better overall than tablets.” (Ex. 2048
`at 4) (POCR p.56)
`
`
`
`
`
`
`
`
`P i i•Petitioner’s SEC 10K Statement – “The actions taken by [Patent Owner] as well as patient ’ SEC 10K S “Th i k b [P O ] ll i
`
`
`preference for a film formulation of Suboxone® resulted in significant conversion of the
`Suboxone® market to branded film formulation.” (Ex. 2045 at 17) (POCR p.56)
`Patent Owner Corrected Resp., Paper 25, 53-57.
`IPR2014-00325 – Patent Owner’s Oral Hearing Presentation
`
`39
`
`
`
`Secondary Considerations—Nexus to Claims
`•‘832 patent is listed in the Orange Book as covering Suboxone® film. (Ex.
`2050) (POCR p.56)
`
`•Suboxone® film was the first buprenorphine
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