IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`DR. REDDY’S LABORATORIES, LTD. AND
`DR. REDDY’S LABORATORIES, INC.,
`Petitioners,
`
`v.
`
`INDIVIOR UK LIMITED,
`Patent Owner.
`
`Case No. IPR2016-01113
`Patent No. 8,475,832
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`DC: 6136622-5
`
`
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`EXHIBIT LIST
`
`Exhibit
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`Description
`Redline comparison of Teva IPR2016-00280 Petition and Dr.
`Reddy’s IPR2016-01113 Petition
`Redline comparison of Teva IPR2016-00280 Declaration of Dr.
`Das and Dr. Reddy’s IPR2016-01113 Declaration of Dr. Celik
`Dr. Reddy’s to acquire product portfolio from TEVA for US
`Market, Press Release, Dr. Reddy’s Laboratories Ltd., June 11,
`2016
`Email from Dr. Reddy’s counsel summarizing meet and confer
`teleconference conducted July 6, 2016
`Teva/Allergan Divestiture Products Table, Docket No. C-4589
`(F.T.C. July 27, 2016)
`FTC Requires Teva to Divest Over 75 Generic Drugs to Settle
`Competition Concerns Related to its Acquisition of Allergan’s
`Generic Business, Press Release, Federal Trade Commission (July
`27, 2016), https://www.ftc.gov/news-events/press-
`releases/2016/07/ftc-requires-teva-divest-over-75-generic-drugs-
`rival-firms-settle
`PTAB Telephonic Conference Transcript, IPR2016-01111,
`IPR2016-01112, IPR2016-01113 (August 1, 2016)
`Carl O’Donnell, Teva Pharm finalizing asset sales to clear
`Allergan deal - source, Reuters (May 5, 2016),
`http://www.reuters.com/article/allergan-ma-teva-pharm-ind-
`assets-idUSL2N1820VD
`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)
`
`i
`
`

`
`
`
`Exhibit
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`
`
`Case No. IPR2016-01113
`
`Description
`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 (2001)
`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)
`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)
`
`ii
`
`

`
`
`
`Exhibit
`2025
`
`
`
`Case No. IPR2016-01113
`
`Description
`Ulrike Werner, In Situ Gelling Nasal Inserts for Prolonged Drug
`Delivery (Dissertation, Free University Berlin 2003)
`
`
`iii
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`TABLE OF CONTENTS
`
`I.
`
`Introduction ................................................................................................... 1
`
`II. Development Of The Inventions And The ’832 Patent ............................. 5
`
`A.
`
`The ’832 Patent Solved a Problem with Existing Suboxone®
`Tablets by Creating a Mucoadhesive Orally-Disintegrating Film ....... 5
`
`B. When the ’832 Patent Was Filed in 2009, Oral Transmucosal
`Delivery Films Were Considered A Pioneering Technology
`That Was Not Well Defined ................................................................. 7
`
`C.
`
`The Inventors of the ’832 Patent Surprisingly Discovered That
`Buprenorphine Absorption Does Not Follow Well-Established
`pH Partition Theory .............................................................................. 9
`
`1. Weinberg (1988) ...................................................................... 12
`
`2. Mendelson (1997) .................................................................... 13
`
`3.
`
`4.
`
`5.
`
`Hao (2003) ............................................................................... 14
`
`Robertson (2005)...................................................................... 16
`
`Batheja (2007) .......................................................................... 16
`
`III. Claim Construction Under “Broadest Reasonable Interpretation” ...... 17
`
`IV. Petitioners Fail To Show A Reasonable Likelihood That Any
`Challenged Claim Of The ’832 Patent Is Unpatentable ......................... 18
`
`A.
`
`Petitioners Fail To Disclose Any Reference That Teaches A
`Buffer To Provide A Local pH Of About 3.0 To About 3.5. ............. 18
`
`1.
`
`2.
`
`Exhibits 1008 and 1009 Do Not Teach or Suggest The
`Buffer and Local pH Limitations. ............................................ 19
`
`Petitioners’ Remaining Arguments Do Not Remedy the
`Fatal Deficiencies of Exhibits 1008 and 1009 ......................... 21
`
`a)
`
`b)
`
`pH Tests of Suboxone® Tablets .................................... 22
`
`Published Buffer Tables ................................................ 22
`
`iv
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`c)
`
`d)
`
`The pH in Cassidy ......................................................... 23
`
`The pH in Birch ............................................................. 25
`
`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 ............................. 26
`
`Ground I: Petitioners Fail to Show That Claims 1–2, 4–7, and
`9–10 are Unpatentable Over LabTec, Yang, Exhibits 1008 and
`1009, and Birch .................................................................................. 32
`
`1.
`
`Claim 4 ..................................................................................... 35
`
`D. Ground II: Petitioners Fail to Show That Claims 3 and 11–12
`are Unpatentable Over LabTec, Yang, Exhibits 1008 and 1009,
`Birch, and the ’055 Publication .......................................................... 35
`
`E.
`
`F.
`
`1.
`
`Claim 3 ..................................................................................... 36
`
`Ground III: Petitioners Fail to Show That Claims 1–2, 4–7, and
`9–10 are Unpatentable Over Oksche, Yang, Exhibits 1008 and
`1009, and Birch .................................................................................. 37
`
`1.
`
`Claim 4 ..................................................................................... 39
`
`Ground IV: Petitioners Fail to Show That Claims 3 and 11–12
`are Unpatentable Over Oksche, Yang, Exhibits 1008 and 1009,
`Birch, and the ’055 Publication .......................................................... 39
`
`1.
`
`Claim 3 ..................................................................................... 40
`
`V. Conclusion ................................................................................................... 40
`
`
`
`v
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`ActiveVideo Networks, Inc. v. Verizon Commc’ns, Inc.,
`694 F.3d 1312 (Fed. Cir. 2012) .......................................................................... 34
`
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268 (Fed. Cir. 2015), aff’d sub nom. Cuozzo Speed
`Techs., LLC v. Lee, 136 S. Ct. —— (2016) ........................................................ 17
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 32
`
`Medtronic, Inc. v. Nuvasive, Inc.,
`IPR2014-00487, Paper 8 (P.T.A.B. Sept. 11, 2014)............................................. 2
`
`In re Suitco Surface, Inc.,
`603 F.3d 1255 (Fed. Cir. 2010) .......................................................................... 18
`
`Teva Pharmaceuticals USA, Inc. v. Indivior UK Ltd.,
`IPR2016-00280, Paper 23 (P.T.A.B. June 10, 2016) ..................................passim
`
`Statutes
`
`35 U.S.C. § 102 .......................................................................................................... 2
`
`35 U.S.C. § 311(b) ........................................................................................... 2, 4, 22
`
`35 U.S.C. § 325(d) ..................................................................................................... 2
`
`Regulations
`
`37 C.F.R. § 42.65(a) ........................................................................................... 27, 34
`
`37 C.F.R. § 42.100(b) .............................................................................................. 17
`
`
`
`vi
`
`

`
`
`
`I.
`
`Introduction
`
`
`
`Case No. IPR2016-01113
`
`Patent Owner Indivior UK Limited (“Patent Owner”) provides the following
`
`preliminary response to the Petition filed by Petitioners Dr. Reddy’s Laboratories,
`
`Ltd. and Dr. Reddy’s Laboratories, Inc. (“Petitioners” or “Dr. Reddy’s”) 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 arguments raised in the Petition are virtually identical to those raised in
`
`the petition filed by Teva Pharmaceuticals USA, Inc. in Case IPR2016-00280.
`
`(Ex. 2001, redline comparison of petitions.) The respective accompanying expert
`
`declarations of Dr. Das (Teva) and Dr. Celik (Dr. Reddy’s) are also virtually
`
`identical. (Ex. 2002, redline comparison of expert declarations.) As the redline
`
`exhibits show, many paragraphs are taken word-for-word from the older petition
`
`
`1 As Petitioner admits, it has “successfully completed” the acquisition of Teva’s
`
`two Abbreviated New Drug Applications (ANDAs) for a generic version of
`
`Suboxone® Film. Paper No. 10, p. 2. Based on its acquisition of the Teva
`
`ANDAs, Petitioner will likely be substituted for Teva in the co-pending district
`
`court litigation. Patent Owner, therefore, reserves the right to raise privity issues if
`
`and when they become ripe for the Board’s consideration.
`
`1
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`and declaration. In the Teva IPR, the Board declined to institute inter partes
`
`review, finding that Teva failed to provide a threshold showing that two exhibits it
`
`relied upon qualified as printed publications under 35 U.S.C. §§ 102 and 311(b).
`
`Teva Pharmaceuticals USA, Inc. v. Indivior UK Ltd., IPR2016-00280, Paper 23 at
`
`9–11 (P.T.A.B. June 10, 2016) [hereinafter “Teva Denial”]. All four grounds of
`
`invalidity relied on the two documents. Id. at 8. The Board then made a series of
`
`important factual findings that demonstrate Teva’s failure to establish a reasonable
`
`likelihood of success in invalidating any challenged claim. Many of those same
`
`factual findings apply equally to this case and, thus, also demonstrate that the
`
`present Petition likewise fails to establish a reasonable likelihood of success in
`
`invalidating any challenged claim.
`
`The Board has discretion to deny institution when “the same or substantially
`
`the same prior art or arguments previously were presented to the Office.” 35
`
`U.S.C. § 325(d); Medtronic, Inc. v. Nuvasive, Inc., IPR2014-00487, Paper 8 at 5–7
`
`(P.T.A.B. Sept. 11, 2014) (informative). Because the instant Petition contains all
`
`of the same failings as the Teva Petition (see Ex. 2001), the Board should exercise
`
`its discretion and deny institution on the basis of duplicative argument. Even if the
`
`Board chooses not to exercise its discretion under § 325(d) to deny the Petition, the
`
`2
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`Petition nevertheless should be denied for the same substantive reasons set forth in
`
`the Teva Denial.2
`
`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.C. 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 about 3 to about 3.5.
`
`
`2 Because Dr. Reddy’s petition copies large portions of Teva’s petition, this
`
`preliminary response will resemble Patent Owner’s preliminary response from the
`
`Teva proceeding.
`
`3
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`The Petition overlooks the surprising and unexpected nature of this
`
`discovery.
`
` Instead,
`
`the Petition focuses
`
`its obviousness challenges on
`
`unsubstantiated similarities between the claimed buprenorphine and naloxone film
`
`formulations and Suboxone® tablets. Beyond failing to substantiate its assertions,
`
`the Petition 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); Teva Denial at 13 n.8. Suboxone® tablets
`
`are neither a patent nor a printed publication, leaving Petitioners’ arguments
`
`without cognizable support.
`
`As discussed in greater detail below, the Board identified the following
`
`critical failings of the Teva Petition, each of which persists in Dr. Reddy’s Petition.
`
`• First, the Board agreed with Patent Owner that the Teva petition and
`
`declaration provided insufficient evidence to conclude that the pH of
`
`the Birch intranasal buprenorphine formulations “teaches or suggests
`
`a buffer providing a specific ‘local pH . . . in the presence of saliva’ as
`
`it pertains to a film composition comprising both buprenorphine and
`
`another drug, naloxone, as required in the challenged claims.” Teva
`
`Denial at 14.
`
`• Second, the Board noted that neither the petition nor the declaration
`
`adequately explained why, based on LabTec or Oksche
`
`in
`
`4
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`combination with Yang, “an ordinary artisan would have wanted to
`
`try to make a film that produced a local pH of 3 to 3.5 in saliva in the
`
`first place.” Id. at 15, 18.
`
`• Third, the Board discounted the teachings of Cassidy, finding that the
`
`petition did not adequately explain “how solubility of buprenorphine
`
`relates to absorption of the drug when administered in a film or how
`
`teachings in Cassidy relate to a film comprising buprenorphine,
`
`naloxone, and a buffer producing a local pH.” Id. at 15 n.9.
`
`• Fourth, the Board found that “LabTec does not suggest preparing a
`
`film that lowers a local pH to 3–3.5 in the saliva for the purpose of
`
`increasing absorption of . . . buprenorphine” because LabTec actually
`
`taught that lowering pH would reduce absorption of basic active
`
`ingredients like buprenorphine. Id. at 16.
`
`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
`
`5
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`naloxone (an opioid antagonist).” Id. at 4:53–55; Teva Denial at 4–5. “The tablet
`
`form, however, still has the potential for abuse because it can be removed easily
`
`from the mouth for later extraction and injection of buprenorphine.” Teva Denial
`
`at 5 (citing Ex. 1001, 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 mouth, rendering it difficult to
`
`remove once placed in the mouth, thereby making abuse of the agonist difficult.”
`
`Id. (quoting Ex. 1001, 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; Teva Denial at 5–6. 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.C; Teva Denial at 6.
`
`6
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`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.
`
`B. When the ’832 Patent Was Filed in 2009, Oral Transmucosal
`Delivery Films Were Considered A 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.
`
`2021, 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 with regard to bioavailability for a drug delivered across oral mucosa.
`
`Rather, a POSA would have understood that the 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
`
`7
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`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. 2010, 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
`
`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.
`
`2022, Thakur Smriti, Mouth Dissolving Films: A Review, 4(1) Int’l J. Pharma and
`
`Bio Sciences P-899, P-900, P-907 (2013).
`
`The failed efforts of Teva’s expert, Dr. Das, confirm just how hard it is to
`
`convert a buprenorphine tablet to a mucoadhesive film dosage form. Exhibit 2009,
`
`which Petitioners omit to cite (and which Teva also omitted 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. 2009, 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
`
`8
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`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 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 absent from
`
`the Petition and the Celik declaration (Ex. 1003).
`
`C. 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
`
`9
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`about 3–3.5.” Id. at 23:1–5. Every challenged claim reflects this surprising result
`
`− optimal absorption of buprenorphine and naloxone 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.
`
`The documents cited by Petitioners do not teach or even suggest this
`
`surprising result. Indeed, Petitioners’ 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 27 (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). Thus, the Board, in the Teva
`
`IPR, found that “Labtec does not suggest preparing a film that lowers a local pH to
`
`3–3.5 in the saliva for the purpose of increasing absorption of an active ingredient
`
`such as buprenorphine.” Teva Denial at 16.
`
`10
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`Petitioners have
`
`thus omitted reference
`
`to LabTec’s
`
`teaching
`
`that
`
`exemplifies pH Partition Theory. See Ex. 1024, Shore, et al., The Gastric
`
`Secretion of Drugs: a pH Partition Hypothesis, J. Pharmacol. Exp. Ther., 119: 361-
`
`9 (1957). This widely-known and well-understood theory would have led a POSA
`
`to expect that the non-ionized form of a drug should preferentially diffuse across
`
`the membrane of the oral mucosa and subsequently get absorbed into the
`
`bloodstream. Buprenorphine is a weak base that has an ionization constant (pKa)
`
`of 8.42 (Ex. 1001, 11:46–47), meaning that at a pH of 8.42, buprenorphine exists
`
`in equal amounts of its ionized and non-ionized forms. See Ex. 2023, Heiko
`
`Tietgen, Physicochemical Properties, in Drug Discovery and Evaluation: Safety
`
`and Pharmacokinetic Assays 399, 403 (Hans Gerhard Vogel et al. eds., 2006)
`
`(“The pKa . . . . is a parameter which indicates the ionization state at a given pH
`
`and describes the acidity of a compound . . . . In practice the pKa is the pH where
`
`50% of the compound is ionized.”).
`
`As LabTec explains, as the pH of the environment decreases below the pKa
`
`of a drug that is a weak base like buprenorphine (i.e., the environment becomes
`
`more acidic), a smaller proportion of the drug will exist in its non-ionized form and
`
`less of the drug is expected to permeate across the membrane and be absorbed. See
`
`Ex. 1007, p. 15. Conversely, as pH increases above the pKa of a drug like
`
`buprenorphine (i.e., becomes more basic), a greater fraction of the drug exists in
`
`11
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`the non-ionized form and more drug is expected to be absorbed across the
`
`membrane. According to pH Partition Theory, in an environment having the
`
`highly acidic pH of 3.5, very little buprenorphine would exist in its non-ionized
`
`form, leading a POSA to expect very little buprenorphine to permeate across oral
`
`mucosa and be absorbed.3
`
`What LabTec taught in 2008 exemplifies decades of understanding about
`
`absorption of basic active ingredients across oral mucosa. As of 2009, when the
`
`inventors applied for the ’832 Patent, it had long been established in the field that
`
`the absorption of buprenorphine across the oral mucosa would follow pH Partition
`
`Theory. As explained further below, this is demonstrated by an unbroken chain of
`
`references that consistently teach that expectation.
`
`1. Weinberg (1988)
`In 1988, Weinberg taught that the oral transmucosal absorption of
`
`buprenorphine follows pH Partition Theory. See Ex. 2011, David S. Weinberg et
`
`
`3 This expectation is confirmed by the absorption of naloxone, which has a similar
`
`pKa to buprenorphine but does follow partition theory. See Ex. 1001, 23:15–55
`
`(showing that naloxone absorption improved with increasing pH). Petitioners have
`
`provided no persuasive reason why a POSA would have expected buprenorphine to
`
`be absorbed differently.
`
`12
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`al., Sublingual absorption of selected opioid analgesics, 71 Clinical Pharmacology
`
`& Therapeutics 335 (1988). Weinberg studied the sublingual absorption of weak-
`
`base opioids (including buprenorphine and methadone), and explained that these
`
`opioids “at physiologic pHs, can exist in two forms: ionized or unionized. The
`
`unionized form is favored by a basic microenvironment.” Id. at 340. Weinberg
`
`further explained that “an alkaline pH microenvironment that favors the unionized
`
`fraction of opioids increased sublingual drug absorption.” Id. at 335 (emphasis
`
`added).4
`
`Weinberg has repeatedly been cited by others skilled in the art to lead to the
`
`expectation that buprenorphine follows pH Partition Theory, i.e., that decreasing
`
`the pH of the environment would lead to decreased permeation and absorption of
`
`buprenorphine.
`
`2. Mendelson (1997)
`In 1997, Mendelson confirmed Weinberg’s finding that the absorption of
`
`buprenorphine should follow pH Partition Theory. See Ex. 2012, John Mendelson
`
`
`4 Weinberg further reported that the absorption of methadone, another weak-
`
`base opioid that has a pKa of approximately 9.0, more than doubled when pH was
`
`increased from 6.5 to 8.5. Id. at 340.
`
`
`
`13
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`et al., Bioavailability of Sublingual Buprenorphine, 37 J. Clinical Pharmacology
`
`31, 36 (1997). Mendelson used saliva recovery after sublingual buprenorphine
`
`administration to estimate the upper limits of sublingual bioavailability. Id. Thus,
`
`the lower the percentage of buprenorphine recovered from saliva, the higher the
`
`absorption, and bioavailability, of buprenorphine. See id. Mendelson explained
`
`that increasing saliva pH was positively correlated with sublingual bioavailability
`
`of buprenorphine. See id. Mendelson attributed this correlation to pH Partition
`
`Theory: “Saliva pH may alter the absorption of buprenorphine (a weak base with a
`
`pKa of 8.24) by dictating the degree of its ionization, as has been observed for
`
`other narcotic and nonnarcotic basic drugs.” Id. (citations omitted). And
`
`Mendelson cited Weinberg for this discovery about buprenorphine. See id. at 36 &
`
`n.6. Mendelson concluded that “[e]nsuring a more basic saliva pH during
`
`sublingual administration might thus be a strategy worthy of investigation to
`
`increase the extent, and potentially to decrease the variability, of absorption.” Id.
`
`at 36 (emphasis added).
`
`3. Hao (2003)
`Hao further confirmed that oral transmucosal absorption of weakly basic
`
`drugs should follow pH Partition Theory. He also explained why, at least for
`
`weakly basic drugs, pH Partition Theory predicts that highly soluble drugs are not
`
`expected to be highly absorbed. Hao studied the absorption of lidocaine, which is
`
`14
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`a weakly basic drug and has a pKa of 7.9, which is close to the pKa of
`
`buprenorphine. See Ex. 2013, Jinsong Hao & Paul W.S. Heng, Buccal Delivery
`
`Systems, 29(8) Drug Development & Industrial Pharmacy 821, 823 (2003). Hao
`
`explained that the “permeability of ionizable drugs across buccal mucosa follows
`
`the pH-partitioning theory characteristic of passive diffusion.” Id. More
`
`specifically, Hao reported that “[i]ncreasing nonionized fraction of ionizable drugs
`
`could favor drug penetration.” Id.
`
`Hao further explained that, for weakly basic drugs, there is an important
`
`distinction between solubility and absorption. See id. While a reduction in pH
`
`may cause an increase in solubility of a drug, it may also decrease absorption of
`
`that drug because, according to pH Partition Theory, ionized drugs do not permeate
`
`well, if at all, across the oral mucosa. See id. Hao observed this exact result for
`
`lidocaine, which is a weakly basic drug with a pKa value close to buprenorphine.
`
`See id. Hao observed that a “decrease in dissolution pH increased the ionic
`
`fraction of the drug and thus its apparent solubility, but decreased its permeability
`
`through buccal mucosa.” Id. (emphasis added). Therefore, a POSA reading Hao
`
`would understand that for weakly basic drugs like buprenorphine, even though a
`
`reduction in pH of the environment may cause an increase in solubility, pH
`
`Partition Theory would still lead a POSA to expect that a reduction in pH would
`
`15
`
`

`
`
`
`
`
`Case No. IPR2016-01113
`
`decrease absorption because permeabili