IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`TEVA PHARMACEUTICALS USA, INC.,
`Petitioner,
`
`v.
`
`INDIVIOR UK LIMITED
`(F/K/A RB PHARMACEUTICALS LIMITED),
`Patent Owner.
`
`Case No. IPR2016-00280
`Patent No. 8,475,832
`
`PATENT OWNER INDIVIOR UK LIMITED’S
`PRELIMINARY RESPONSE PURSUANT TO 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`
`
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`
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`DC: 5951590-21
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`

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`Docket No. 036617.0020-US01
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`Case No. IPR2016-00280
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`EXHIBIT LIST
`
`Exhibit
`2001
`
`2002
`2003
`2004
`2005
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`
`Description
`Doc. No. 7, Summons and Proof of Service dated Dec. 3, 2014, Case
`No. 1:14-cv-01451-UNA
`Original Certificate of Service for the IPR2016-00280 petition
`Amended Certificate of Service for the IPR2016-00280 petition
`FedEx Tracking Reports
`Declaration of Michael I. Chakansky
`Patent Review Processing System Frequently Asked Questions,
`http://www.uspto.gov/patents-application-process/appealing-patent-
`decisions/trials/patent-review-processing-system-prps-0
`Nandita G. Das & Sudip K. Das, Development of Mucoadhesive
`Dosage Forms of Buprenorphine for Sublingual Drug Delivery, 11
`Drug Delivery 89 (2004)
`Priya Batheja et al., Basic Biopharmaceutics of Buccal and
`Sublingual Absorption, in Enhancement in Drug Delivery 175, 182
`(Elka Touitou & Brian W. Barry eds. 2006)
`David S. Weinberg et al., Sublingual absorption of selected opioid
`analgesics, 71 Clinical Pharmacology & Therapeutics 335 (1988)
`John Mendelson et al., Bioavailability of Sublingual Buprenorphine,
`37 J. Clinical Pharmacology 31 (1997)
`Jinsong Hao & Paul W.S. Heng, Buccal Delivery Systems, 29(8)
`Drug Development & Industrial Pharmacy 821 (2003)
`S.A. Robertson, PK-PD modeling of buprenorphine in cats:
`intravenous and oral transmucosal administration, 28(5) Journal of
`Veterinary Pharmacology and Therapeutics 453 (2005)
`Yamamoto et al., Absorption of water-soluble compounds with
`different molecular weights and [Asu1.7]-eel calcitonin from various
`mucosal administration sites, 76 J. Controlled Release 363 tbl 1, 372
`(2001)
`
`i
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`Docket No. 036617.0020-US01
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`Case No. IPR2016-00280
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`Exhibit
`2014
`
`2015
`
`2016
`
`2017
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`Description
`Amir H. Shojaei, Buccal Mucosa as a Route for Systemic Drug
`Delivery: A Review, 1(1) J. Pharmacy & Pharmaceutical Sci. 15
`(1998)
`Rakesh Hooda et al., A Review on Oral Mucosal Drug Delivery
`System, 1(1) Pharma Innovation 14 (2012)
`N.V. Satheesh Madhav, Orotransmucosal Drug Delivery Systems: A
`Review, 140 J. Controlled Release 2 (2009)
`U.S. Patent No. 7,331,251
`Swatantra K.S. Kushwaha et al., Advances in Nasal Trans-Mucosal
`Drug Delivery, 1(7) J. Applied Pharmaceutical Sci. 21 (2011)
`Yeda’s Preliminary Patent Owner Response, Mylan Pharm. Inc. v.
`Yeda Research & Dev. Co. Ltd., IPR2015-00644, Paper No. 12 (May
`26, 2015)
`Javier O. Morales & Jason T. McConville, Manufacture and
`Characterization of Mucoadhesive Buccal Films, 77 Eur. J.
`Pharmaceutics and Biopharmaceutics 187 (2011)
`Thakur Smriti, Mouth Dissolving Films: A Review, 4(1) Int’l J.
`Pharma and Bio Sciences P-899 (2013)
`Heiko Tietgen, Physicochemical Properties, in Drug Discovery and
`Evaluation: Safety and Pharmacokinetic Assays 399 (Hans Gerhard
`Vogel et al. eds., 2006)
`Ulrika Espefalt Westin, Olfactory Transfer of Analgesic Drugs After
`Nasal Administration (Dissertation, Uppsala University 2007)
`Ulrike Werner, In Situ Gelling Nasal Inserts for Prolonged Drug
`Delivery (Dissertation, Free University Berlin 2003)
`
`ii
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`Docket No. 036617.0020-US01
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`Case No. IPR2016-00280
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`TABLE OF CONTENTS
`
`I.
`
`Introduction ................................................................................................... 1
`
`II. Development Of The Inventions And The ’832 Patent ............................. 3
`
`A.
`
`The ’832 Patent Solved a Problem with Existing Suboxone®
`Tablets by Creating a Mucoadhesive Orally-Disintegrating Film ....... 3
`
`B. When the ’832 Patent Was Filed in 2009, Oral Transmucosal
`Delivery Films Were Considered Pioneering Technology That
`Was Not Well Defined ......................................................................... 5
`
`C.
`
`D.
`
`Even Petitioner’s Expert, Dr. Das, Tried and Failed to Create a
`Mucoadhesive Buprenorphine Film ..................................................... 6
`
`The Inventors of the ’832 Patent Surprisingly Discovered That
`Buprenorphine Absorption Does Not Follow Well-Established
`pH Partition Theory .............................................................................. 7
`
`1. Weinberg (1988) ...................................................................... 10
`
`2. Mendelson (1997) .................................................................... 11
`
`3.
`
`4.
`
`5.
`
`Hao (2003) ............................................................................... 12
`
`Robertson (2005)...................................................................... 13
`
`Batheja (2007) .......................................................................... 14
`
`III. Claim Construction Under “Broadest Reasonable Interpretation” ...... 15
`
`IV. Petitioner Fails To Show A Reasonable Likelihood That At Least
`One Claim Of The ’832 Patent Is Unpatentable ...................................... 17
`
`A.
`
`Petitioner Fails to Meet Its Threshold Burden to Establish That
`Exs. 1008 and 1009 Are Printed Publications .................................... 17
`
`1.
`
`2.
`
`Petitioner’s Failure to Establish That Exhibits 1008 and
`1009 Are Printed Publications Is Fatal to Every Ground
`in the Petition ........................................................................... 24
`
`Petitioner’s Remaining Arguments Do Not Remedy the
`Fatal Deficiencies of Exhibits 1008 and 1009 ......................... 27
`
`iii
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`Docket No. 036617.0020-US01
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`Case No. IPR2016-00280
`
`a)
`
`b)
`
`c)
`
`d)
`
`pH Tests of Suboxone® Tablets .................................... 28
`
`Published Buffer Tables ................................................ 29
`
`The pH in Cassidy ......................................................... 30
`
`The pH in Birch ............................................................. 31
`
`B.
`
`C.
`
`The Petition Fails to Offer Articulated Reasons Why a POSA
`Would Look to Nasal Absorption of Buprenorphine to Develop
`a Formulation for Oral Transmucosal Absorption ............................. 32
`
`Ground I: Petitioner Fails to Show That Claims 1–2, 4–7, and
`9–10 are Unpatentable Over LabTec, Yang, Exhibits 1008 and
`1009, and Birch .................................................................................. 38
`
`1.
`
`Claim 4 ..................................................................................... 41
`
`D. Ground II: Petitioner Fails to Show That Claims 3 and 11–12
`are Unpatentable Over LabTec, Yang, Exhibits 1008 and 1009,
`Birch, and the ’055 Publication .......................................................... 41
`
`E.
`
`F.
`
`1.
`
`Claim 3 ..................................................................................... 42
`
`Ground III: Petitioner Fails to Show That Claims 1–2, 4–7, and
`9–10 are Unpatentable Over Oksche, Yang, Exhibits 1008 and
`1009, and Birch .................................................................................. 43
`
`1.
`
`Claim 4 ..................................................................................... 45
`
`Ground IV: Petitioner Fails to Show That Claims 3 and 11–12
`are Unpatentable Over Oksche, Yang, Exhibits 1008 and 1009,
`Birch, and the ’055 Publication .......................................................... 45
`
`1.
`
`Claim 3 ..................................................................................... 46
`
`V. Conclusion ................................................................................................... 46
`
`
`
`iv
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`Docket No. 036617.0020-US01
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`Case No. IPR2016-00280
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`A.R.M., Inc. v. Cottingham Agencies Ltd,
`IPR2014-00671, Paper 10 (PTAB Oct. 3, 2014) .......................................... 18, 22
`
`Actavis, Inc. v. Research Corp. Techs., Inc.,
`IPR2014-01126, Paper No. 22 (PTAB Jan. 9, 2015) ......................................... 18
`
`ActiveVideo Networks, Inc. v. Verizon Commc’ns, Inc.,
`694 F.3d 1312 (Fed. Cir. 2012) .......................................................................... 40
`
`Apple Inc. v. DSS Tech. Mgmt., Inc.,
`IPR2015-00369, Paper 9 (PTAB June 25, 2015) ............................................... 20
`
`Apple Inc. v. DSS Tech. Mgmt., Inc.,
`IPR2015-00369, Paper 14 (PTAB Aug. 12, 2015) ............................................. 19
`
`Cisco Systems, Inc. v. Constellation Techs., LLC,
`IPR2014-01085, Paper 11 (PTAB Jan. 9, 2015) ................................................ 22
`
`Coalition for Affordable Drugs (ADROCA) LLC v. Acorda
`Therapeutics, Inc.,
`IPR2015-00817, Paper 12 (PTAB Aug. 24, 2015) ............................................. 18
`
`Coalition for Affordable Drugs III LLC v. Jazz Pharm., Inc.,
`IPR2015-01018, Paper 17 (PTAB Oct. 15, 2015) .............................................. 26
`
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268 (Fed. Cir. 2015) .......................................................................... 15
`
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) .......................................................................... 18
`
`Gold Seal Importers v. Westerman-Rosenberg, Inc.,
`133 F.2d 192 (2d Cir. 1943) ............................................................................... 23
`
`In re Hall,
`781 F.2d 897 (Fed. Cir. 1986) ............................................................................ 18
`
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`Case No. IPR2016-00280
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`Hewlett-Packard Co. v. U.S. Philips Corp., et al.,
`IPR2015-01505, Paper 16 (PTAB Jan. 19, 2016) .................................. 19, 22, 23
`
`Higgins v. Mississippi,
`217 F.3d 951 (7th Cir. 2000) .............................................................................. 23
`
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ............................................................................ 38
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 38
`
`In re Lister,
`583 F.3d 1307 (Fed. Cir. 2009) .......................................................................... 18
`
`Mylan Pharm. Inc. v. Yeda Research & Dev. Co. Ltd.,
`IPR2015-00644, Paper No. 14 (PTAB Aug. 25, 2015) ................................ 23, 24
`
`Matter of Raiford,
`695 F.2d 521 (11th Cir. 1983) ............................................................................ 23
`
`In re Suitco Surface, Inc.,
`603 F.3d 1255 (Fed. Cir. 2010) .......................................................................... 16
`
`In re Wyer,
`655 F.2d 221 (CCPA 1981) .......................................................................... 19, 24
`
`Statutes
`
`35 U.S.C. § 102(a) ................................................................................................... 21
`
`35 U.S.C. § 102(b) ............................................................................................. 18, 21
`
`35 U.S.C. § 102(f) .................................................................................................... 21
`
`35 U.S.C. § 102(g) ................................................................................................... 21
`
`35 U.S.C. § 311(b) ............................................................................................passim
`
`35 U.S.C. § 314(a) ................................................................................................... 21
`
`35 U.S.C. § 315(b) ..................................................................................................... 1
`
`35 U.S.C. § 316(e) ................................................................................................... 18
`
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`Regulations
`
`37 C.F.R. § 42.63 ..................................................................................................... 20
`
`37 C.F.R. § 42.65(a) ..................................................................................... 28, 33, 40
`
`37 C.F.R. § 42.65(b) ................................................................................................ 28
`
`37 C.F.R. § 42.100(b) .............................................................................................. 15
`
`Other Authorities
`
`77 Fed. Reg. 48756 (Aug. 14, 2012)........................................................................ 20
`
`
`
`vii
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`Docket No. 036617.0020-US01
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`Case No. IPR2016-00280
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`I.
`
`Introduction
`
`Patent Owner Indivior UK Limited (“Patent Owner”) provides the following
`
`preliminary response to the Petition filed by Petitioner Teva Pharmaceuticals USA,
`
`Inc. (“Petitioner”) requesting inter partes review of claims 1–7 and 9–12 of U.S.
`
`Patent No. 8,475,832 (the “’832 Patent”). For at least the reasons set forth below,
`
`Patent Owner requests that the Board deny inter partes review as to all grounds of
`
`the Petition.1
`
`The Petition’s omissions are fundamental and fatal. Section 311(b) of the
`
`Patent Code expressly limits inter partes review proceedings to patents and printed
`
`publications. The Petition offers no evidence whatsoever that the documents
`
`submitted as Exhibits 1008 and 1009 − which are necessary components of each
`
`asserted ground of unpatentability − are printed publications. Petitioner has failed
`
`
`1 As authorized by the Board’s Order dated February 18, 2016 (Paper No. 8),
`
`Patent Owner filed a Motion to Change the December 3, 2015 Filing Date to
`
`December 4, 2015 on February 29, 2016 (Paper No. 10). Petitioner filed an
`
`opposition to the motion on March 10, 2016 (Paper No. 12). Should Patent
`
`Owner’s Motion be granted, there is no dispute that the Petition is time-barred
`
`under 35 U.S.C. § 315(b) (see Paper No. 8, p. 2), and should be denied in its
`
`entirety for that reason as well.
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`1
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`to carry its burden of showing that those documents were publicly disseminated or
`
`otherwise publicly accessible. Exhibits 1008 and 1009 are thus not available as a
`
`basis for instituting an inter partes review, and for this reason alone each ground of
`
`the Petition fails.
`
`Other omissions compound this failure. Nowhere does the Petition discuss
`
`pH Partition Theory − the standard theory of absorption described by the ’832
`
`Patent against which the inventors’ results were “surprising.” See Ex. 1001,
`
`11:48–53, 23:1–7. Decades of scientific literature leading up to the priority date
`
`uniformly confirmed that, according to the well-established pH Partition Theory, a
`
`weakly basic compound like buprenorphine would have poor permeation through
`
`oral mucosa and poor absorption in a low pH (i.e., acidic) environment. See infra
`
`Section II.D. A person of ordinary skill in the art (“POSA”) at the priority date
`
`would not have expected that a formulation designed to provide just such a low-pH
`
`environment would work. Yet in the face of extensive scientific literature and a
`
`POSA’s consequent expectations, the inventors of the ’832 Patent made the
`
`surprising discovery that absorption across the oral mucosa of the buprenorphine in
`
`the claimed buprenorphine and naloxone formulations could be optimized even at
`
`the low pH range of 3 to 3.5.
`
`The Petition overlooks the surprising and unexpected nature of this
`
`discovery.
`
` Instead,
`
`the Petition focuses
`
`its obviousness challenges on
`
`2
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`unsubstantiated similarities between the claimed buprenorphine and naloxone film
`
`formulations and Suboxone® tablets. Beyond failing to substantiate its assertions,
`
`the Petitioner repeats a crucial and fatal error: it again ignores that inter partes
`
`review proceedings are limited to challenges based on patents and printed
`
`publications. See 35 U.S.C. § 311(b). Suboxone® tablets are neither a patent nor
`
`a printed publication, leaving Petitioner’s arguments without cognizable support.
`
`The Petition should be denied.
`
`II. Development Of The Inventions And The ’832 Patent
`A. The ’832 Patent Solved a Problem with Existing Suboxone®
`Tablets by Creating a Mucoadhesive Orally-Disintegrating Film
`
`The ’832 Patent significantly reduced the “potential for abuse” (Ex. 1001,
`
`1:55–56), a fundamental problem with existing Suboxone® tablets. Suboxone®
`
`tablets were used to treat “individuals who suffer from narcotic dependence,” id. at
`
`1:31–32, by providing “a combination of buprenorphine (an opioid agonist) and
`
`naloxone (an opioid antagonist).” Id. at 4:53–55. However, in “some instances,
`
`the patient who has been provided the drug may store the tablet in his mouth
`
`without swallowing the tablet, then later extract the agonist from the tablet and
`
`inject the drug into an individual’s body.” Id. at 1:56–59. Thus, there was a “need
`
`for an orally dissolvable film dosage form that provides the desired absorption
`
`levels of the agonist and antagonist, while providing an adhesive effect in the
`
`3
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`mouth, rendering it difficult to remove once placed in the mouth, thereby making
`
`abuse of the agonist difficult.” Id. at 1:65-2:2.
`
`The inventors of the ’832 Patent sought to address this potential for abuse by
`
`changing the dosage form from a tablet to a film that would adhere to the mucosal
`
`membranes in the mouth. But this change required surmounting any number of
`
`challenges. The inventors ultimately discovered that buprenorphine absorption can
`
`be optimized by administering an orally dissolvable film composition containing
`
`buprenorphine and naloxone buffered to a low local pH of about 3 to about 3.5.
`
`Ex. 1001, 11:48–55. As described further below, this discovery was surprising
`
`because
`
`it contradicted
`
`the widely and
`
`long-held understanding
`
`in
`
`the
`
`pharmaceutical arts, reflected in the literature, that the absorption of buprenorphine
`
`across the oral mucosa would require a much higher pH level, as predicted by well-
`
`established pH Partition Theory. Id. at 23:1–7; see also infra Section II.D.
`
`In addition to ameliorating the abuse problem, the film formulation
`
`presented other advantages. First, the film dissolved in less than five minutes, so
`
`that patients would not need to hold it in their mouths for an uncomfortably long
`
`period of time. Id. at 6:65–7:3. Second, the film could incorporate various
`
`sweeteners to mask the unpleasant taste of buprenorphine. Id. at 9:61–10:6.
`
`4
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`B. When the ’832 Patent Was Filed in 2009, Oral Transmucosal
`Delivery Films Were Considered Pioneering Technology That
`Was Not Well Defined
`
`Even by 2011, two years after the priority date, “only a handful of
`
`[mucoadhesive buccal films] ha[d] reached the market, and … only two products
`
`for oral mucosal drug delivery ha[d] been successfully commercialized.” Ex.
`
`2020, Javier O. Morales & Jason T. McConville, Manufacture and
`
`Characterization of Mucoadhesive Buccal Films, 77 Eur. J. Pharmaceutics and
`
`Biopharmaceutics 187, 189
`
`(2011).
`
` Pharmaceutical
`
`industry
`
`literature
`
`demonstrates the error of the Petition’s assertion that a POSA would have focused
`
`on pH to improve bioavailability for a drug delivered across oral mucosa. Rather,
`
`a POSA would have understood that improving bioavailability of a drug through
`
`an oral transmucosal delivery route would depend on numerous factors because, as
`
`explained in a foundational reference, “lipid solubility, degree of ionization, pKa of
`
`the drug, pH of the drug solution, presence of saliva and the membrane
`
`characteristics, molecular weight and size of the drug, various physicochemical
`
`properties of the formulation, and the presence or absence of permeation
`
`enhancers, all affect the absorption and the permeation of drugs through the oral
`
`mucosa.” Ex. 2008, Priya Batheja et al., Basic Biopharmaceutics of Buccal and
`
`Sublingual Absorption, in Enhancement in Drug Delivery 175, 182 (Elka Touitou
`
`& Brian W. Barry eds. 2006). Thus, in 2013 − nearly four years after the filing of
`
`5
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`the ’832 Patent − “[f]ast-dissolving buccal film drug delivery systems” were
`
`considered the “newest frontier in drug delivery technology,” “not well defined in
`
`the literature,” and “a revolutionary and an innovative drug delivery system.” Ex.
`
`2021, Thakur Smriti, Mouth Dissolving Films: A Review, 4(1) Int’l J. Pharma and
`
`Bio Sciences P-899, P-900, P-907 (2013).
`
`C. Even Petitioner’s Expert, Dr. Das, Tried and Failed to Create a
`Mucoadhesive Buprenorphine Film
`
`The failed efforts of Petitioner’s own expert, Dr. Das, confirm just how hard
`
`it is to convert a buprenorphine tablet to a mucoadhesive film dosage form.
`
`Exhibit 2007, which Petitioner omits to cite, describes the unsuccessful efforts of
`
`Dr. Das and her colleague in creating a sublingual film containing buprenorphine
`
`as the sole active ingredient. See Ex. 2007, Nandita G. Das & Sudip K. Das,
`
`Development of Mucoadhesive Dosage Forms of Buprenorphine for Sublingual
`
`Drug Delivery, 11 Drug Delivery 89–95 (2004). The Das authors were aware of
`
`the existence and success of Subutex® buprenorphine tablets, and attempted to
`
`create a film dosage form for delivering buprenorphine transmucosally. Id. at 90.
`
`The Das authors stated that the films they made “were not determined suitable for
`
`sublingual usage,” id. at 89, and, in fact were inferior to tablets, concluding that
`
`“mucoadhesive tablet formulations produced overall superior results compared
`
`with the mucoadhesive film formulations,” id. at 94. The Das authors also
`
`observed that “bioavailability by [sublingual delivery of buprenorphine] can be
`
`6
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`erratic because of salivary washout and involuntary swallowing.” Id. at 90. A
`
`POSA would have been aware of the Das article, and the significant challenges
`
`that confronted the inventors in developing the inventions claimed in the ’832
`
`Patent, all of which is glaringly absent from the Petition and the Das declaration
`
`(Ex. 1003).
`
`D. The Inventors of the ’832 Patent Surprisingly Discovered That
`Buprenorphine Absorption Does Not Follow Well-Established pH
`Partition Theory
`
`As explained in the ’832 Patent, “[a]ccording to pH partition theory, one
`
`would expect that saliva (which has a pH of about 6.5) would maximize the
`
`absorption of both” the agonist buprenorphine (pKa of about 8.42) and the
`
`antagonist naloxone (pKa of about 7.94). Ex. 1001, 11:46–50. However, the
`
`inventors of the ’832 Patent “surprisingly discovered … that by buffering the
`
`dosage to a particular pH level, the optimum levels of absorption of the agonist and
`
`antagonist may be achieved.” Id. at 11:50–53. The ’832 Patent reports in vivo data
`
`showing “that the absorption of buprenorphine was substantially bioequivalent to
`
`that of the one dose tablet when the film composition local pH was lowered to
`
`about 3–3.5.” Id. at 23:1–5. Every challenged claim reflects this “surprising”
`
`result − optimal absorption of buprenorphine is achieved not by maintaining pH in
`
`the 6-8 range, but rather by lowering the pH to about 3 - 3.5. See id. at 23:1–5, 64–
`
`67, 24:33–37.
`
`7
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`Case No. IPR2016-00280
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`The documents cited by Petitioner do not teach or even suggest this
`
`surprising result. Indeed, Petitioner’s lead reference, LabTec (Ex. 1007), actually
`
`teaches just the opposite − that is, lowering the pH retards absorption for a weak
`
`base like buprenorphine. As LabTec reports, “[t]he formulations can rely on
`
`various means for retarding absorption of the active ingredient through the oral
`
`mucosa, … [such as] pH adjusting agents that adjust the pH of the environment
`
`surrounding the dosage form to a pH that renders the active agent less
`
`permeable....” Pet. at 24 (quoting Ex. 1007, p. 15). The Petition omits LabTec’s
`
`teaching that retarding absorption of the active ingredient through the oral mucosa
`
`is achieved by lowering the pH of the environment: “Suitable pH adjusting agents
`
`function by ionizing the active agent to a less permeable state. . . . . [F]or a basic
`
`active ingredient, one would adjust the pH of the solution to below the pKa of the
`
`conjugate acid.” Ex. 1007, p. 15 (emphasis added).
`
`Petitioner has thus omitted reference to LabTec’s teaching that exemplifies
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`pH Partition Theory. See Ex. 1024, Shore, et al., The Gastric Secretion of Drugs: a
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`pH Partition Hypothesis, J. Pharmacol. Exp. Ther., 119: 361-9 (1957). This
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`widely-known and well-understood theory would have led a POSA to expect that
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`the non-ionized form of a drug should preferentially diffuse across the membrane
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`of the oral mucosa and subsequently get absorbed into the bloodstream.
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`Buprenorphine is a weak base that has an ionization constant (pKa) of 8.42 (Ex.
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`1001, 11:46–47), meaning that at a pH of 8.42, buprenorphine exists in equal
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`amounts of its ionized and non-ionized forms. See Ex. 2022, Heiko Tietgen,
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`Physicochemical Properties, in Drug Discovery and Evaluation: Safety and
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`Pharmacokinetic Assays 399, 403 (Hans Gerhard Vogel et al. eds., 2006) (“The
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`pKa . . . . is a parameter which indicates the ionization state at a given pH and
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`describes the acidity of a compound . . . . In practice the pKa is the pH where 50%
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`of the compound is ionized.”).
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`As LabTec explains, as the pH of the environment decreases below the pKa
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`of a drug that is a weak base like buprenorphine (i.e., the environment becomes
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`more acidic), a smaller proportion of the drug will exist in its non-ionized form and
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`less of the drug is expected to permeate across the membrane and be absorbed. See
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`Ex. 1007, p. 15. Conversely, as pH increases above the pKa of a drug like
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`buprenorphine (i.e., becomes more basic), a greater fraction of the drug exists in
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`the non-ionized form and more drug is expected to be absorbed across the
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`membrane. According to pH Partition Theory, in an environment having the
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`highly acidic pH of 3.5, very little buprenorphine would exist in its non-ionized
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`form, leading a POSA to expect very little buprenorphine to permeate across oral
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`mucosa and be absorbed.2
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`What LabTec taught in 2008 exemplifies decades of understanding about
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`absorption of basic active ingredients across oral mucosa. As of 2009, when the
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`inventors applied for the ’832 Patent, it had long been established in the field that
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`the absorption of buprenorphine across the oral mucosa would follow pH Partition
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`Theory. As explained further below, this is demonstrated by an unbroken chain of
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`references that consistently teach that expectation.
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`1. Weinberg (1988)
`In 1988, Weinberg taught that the oral transmucosal absorption of
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`buprenorphine follows pH Partition Theory. See Ex. 2009, David S. Weinberg et
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`al., Sublingual absorption of selected opioid analgesics, 71 Clinical Pharmacology
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`& Therapeutics 335 (1988). Weinberg studied the sublingual absorption of weak-
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`base opioids (including buprenorphine and methadone), and explained that these
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`opioids “at physiologic pHs, can exist in two forms: ionized or unionized. The
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`2 This expectation is confirmed by the absorption of naloxone, which has a similar
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`pKa to buprenorphine but does follow partition theory. Petitioner has provided no
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`persuasive reason why a POSA would have expected buprenorphine to be absorbed
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`differently.
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`unionized form is favored by a basic microenvironment.” Id. at 340. Weinberg
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`further explained that “an alkaline pH microenvironment that favors the unionized
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`fraction of opioids increased sublingual drug absorption.” Id. at 335 (emphasis
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`added).3
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`Weinberg has repeatedly been cited by others skilled in the art to lead to the
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`expectation that buprenorphine follows pH Partition Theory, i.e., that decreasing
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`the pH of the environment would lead to decreased permeation and absorption of
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`buprenorphine.
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`2. Mendelson (1997)
`In 1997, Mendelson confirmed Weinberg’s finding that the absorption of
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`buprenorphine should follow pH Partition Theory. See Ex. 2010, John Mendelson
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`et al., Bioavailability of Sublingual Buprenorphine, 37 J. Clinical Pharmacology
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`31, 36 (1997). Mendelson used saliva recovery after sublingual buprenorphine
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`administration to estimate the upper limits of sublingual bioavailability. Id. Thus,
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`the lower the percentage of buprenorphine recovered from saliva, the higher the
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`3 Weinberg further reported that the absorption of methadone, another weak-
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`base opioid that has a pKa of approximately 9.0, more than doubled when pH was
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`increased from 6.5 to 8.5. Id. at 340.
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`absorption, and bioavailability, of buprenorphine. See id. Mendelson explained
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`that increasing saliva pH was positively correlated with sublingual bioavailability
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`of buprenorphine. See id. Mendelson attributed this correlation to pH Partition
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`Theory: “Saliva pH may alter the absorption of buprenorphine (a weak base with a
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`pKa of 8.24) by dictating the degree of its ionization, as has been observed for
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`other narcotic and nonnarcotic basic drugs.” Id. (citations omitted). And
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`Mendelson cited Weinberg for this discovery about buprenorphine. See id. at 36 &
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`n.6. Mendelson concluded that “[e]nsuring a more basic saliva pH during
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`sublingual administration might thus be a strategy worthy of investigation to
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`increase the extent, and potentially to decrease the variability, of absorption.” Id.
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`at 36 (emphasis added).
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`3. Hao (2003)
`Hao further confirmed that oral transmucosal absorption of weakly basic
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`drugs should follow pH Partition Theory. He also explained why, at least for
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`weakly basic drugs, pH Partition Theory predicts that highly soluble drugs are not
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`expected to be highly absorbed. Hao studied the absorption of lidocaine, which is
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`a weakly basic drug and has a pKa of 7.9, which is close to the pKa of
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`buprenorphine. See Ex. 2011, Jinsong Hao & Paul W.S. Heng, Buccal Delivery
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`Systems, 29(8) Drug Development & Industrial Pharmacy 821, 823 (2003). Hao
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`explained that the “permeability of ionizable drugs across buccal mucosa follows
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`the pH-partitioning theory characteristic of passive diffusion.” Id. More
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`specifically, Hao reported that “[i]ncreasing nonionized fraction of ionizable drugs
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`could favor drug penetration.” Id.
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`Hao further explained that, for weakly basic drugs, there is an important
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`distinction between solubility and absorption. See id. While a reduction in pH
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`may cause an increase in solubility of a drug, it may also decrease absorption of
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`that drug because, according to pH Partition Theory, ionized drugs do not permeate
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`well, if at all, across the oral mucosa. See id. Hao observed this exact result for
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`lidocaine, which is a weakly basic drug with a pKa value close to buprenorphine.
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`See id. Hao observed that a “decrease in dissolution pH increased the ionic
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`fraction of the drug and thus its apparent solubility, but decreased its permeability
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`through buccal mucosa.” Id. (emphasis added). Therefore, a POSA reading Hao
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`would understand that for weakly basic drugs like buprenorphine, even though a
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`reduction in pH of the environment may cause an increase in solubility, pH
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`Partition Theory would still lead a POSA to expect that a reduction in pH would
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`decrease absorption because permeability of the ionized drug across the oral
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`mucosa would be impeded. See id.
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`Robertson (2005)
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`4.
`In 2005, Robertson reported that the oral transmucosal absorption of
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`buprenorphine would follow pH Partition Theory. See Ex. 2012, S.A. R