Trials@uspto.gov
`571-272-7822
`
`
`
`
`
`
`
`Paper 16
`Date: December 2, 2016
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`
`
`DR. REDDY’S LABORATORIES, LTD. AND
`DR. REDDY’S LABORATORIES, INC.,
`Petitioner,
`
`v.
`
`INDIVIOR UK LIMITED,
`Patent Owner.
`____________
`
`Case IPR2016-01113
`Patent 8,475,832 B2
`____________
`
`
`
`Before TONI R. SCHEINER, JACQUELINE WRIGHT BONILLA, and
`ZHENYU YANG, Administrative Patent Judges.
`
`BONILLA, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`

`

`IPR2016-01113
`Patent 8,475,832 B2
`
`I.
`
`INTRODUCTION
`
`Dr. Reddy’s Laboratories, Ltd. and Dr. Reddy’s Laboratories, Inc.,
`
`(collectively “Petitioner”) filed a Petition requesting an inter partes review
`
`of claims 1–7 and 9–12 of U.S. Patent No. 8,475,832 B2 (Ex. 1001, “the
`
`’832 patent”). Paper 1 (“Pet.”). Indivior UK Limited (“Patent Owner”) filed
`
`a Preliminary Response. Paper 12 (“Prelim. Resp.”). Under 35 U.S.C.
`
`§ 314(a), an inter partes review may not be instituted unless it is determined
`
`that there is “a reasonable likelihood that the petitioner would prevail with
`
`respect to at least 1 of the claims challenged in the petition.”
`
`We determine that Petitioner has not established a reasonable
`
`likelihood that it would prevail in showing the unpatentability of any claim
`
`challenged in the Petition. Accordingly, we decline to institute an inter
`
`partes review.
`
`A. Related Proceedings
`
`The parties identify multiple lawsuits where Patent Owner has filed
`
`suit against Teva Pharmaceuticals USA, Inc. (“Teva”), and other defendants
`
`asserting infringement of the ’832 patent in several U.S. district courts. Pet.
`
`6–8; Paper 5, 1–3. Patent Owner states that Petitioner admits that “it has
`
`‘successfully completed’ the acquisition of Teva’s two Abbreviated New
`
`Drug Applications (ANDAs) for a generic version of Suboxone® Film.”
`
`Prelim. Resp. 1 n.1 (referring to Paper 10, 4). Patent Owner also states that
`
`“[b]ased on its acquisition of the Teva ANDAs, Petitioner will likely be
`
`substituted for Teva in the co-pending district court litigation.” Id.
`
`In addition, the parties identify IPR2016-00280, a case in which this
`
`panel previously issued a Decision denying an inter partes review based on
`
`a Petition filed by Teva, which challenged the same claims of the same
`
`
`
`2
`
`

`

`IPR2016-01113
`Patent 8,475,832 B2
`
`patent at issue here. Case No. IPR2016-00280, Teva Pharmaceuticals USA,
`
`Inc., v, Indivior UK Limited, Paper 23 (“Teva IPR Decision”); Pet. 8–10.
`
`We issued the Teva IPR Decision after Petitioner filed the current Petition in
`
`this case.
`
`The parties also discuss IPR2014-00998, where the panel previously
`
`denied an inter partes review based on a Petition filed by a different
`
`petitioner, challenging claims 15–19 of the same patent at issue here. Pet.
`
`8–9; Paper 7, 2; BioDelivery Scis. Int’l., Inc. v. RB Pharm. Ltd., Case No.
`
`IPR2014-00998 (PTAB Dec. 19, 2014) (Paper 12). The parties also refer to
`
`IPR2014-00325, where the panel determined in a Final Written Decision that
`
`the same petitioner as in IPR2014-00998 had established by a preponderance
`
`of the evidence that claims 15–19 of the ’832 patent were unpatentable. Pet.
`
`8–9; Paper 7, 2; BioDelivery Scis. Int’l., Inc. v. RB Pharm. Ltd., Case No.
`
`IPR2014-00325 (PTAB June 30, 2015) (Paper 43). Patent Owner indicates
`
`that the Final Written Decision “is currently on appeal to the Court of
`
`Appeals for the Federal Circuit, Docket No. 16-1044.” Paper 7 at 2–3; Pet.
`
`9. On August 8, 2016, the Federal Circuit affirmed the Final Written
`
`Decision in that case via Rule 36 judgment. RB Pharms. Ltd., v.
`
`BioDelivery Scis. Int’l., No. 2106-1044, Fed. Cir. R. 36 (Fed. Cir. 2016).
`
`B. Proposed Grounds of Unpatentability
`
`Petitioner advances four grounds of unpatentability under 35 U.S.C.
`
`§ 103(a) in relation to claims 1–7 and 9–12 of the ’832 patent, as outlined in
`
`the table below. Pet. 11–12.
`
`
`
`3
`
`

`

`IPR2016-01113
`Patent 8,475,832 B2
`
` References
`
`LabTec1 in view of Yang,2 the
`Suboxone® 2002 Label,3 SBOA,4 and
`Birch5
`
`LabTec in view of Yang, the
`Suboxone® 2002 Label, SBOA, Birch,
`and the ’055 publication6
`
`Oksche7 in view of Yang, the
`Suboxone® 2002 Label, SBOA, and
`Birch
`
`Oksche in view of Yang, the
`Suboxone® 2002 Label, SBOA, Birch,
`and the ’055 publication
`
`Statutory
`Basis
`
`Challenged Claims
`
`§ 103(a)
`
`1, 2, 4–7, 9, and 10
`
`§ 103(a)
`
`3, 11, and 12
`
`§ 103(a)
`
`1, 2, 4–7, 9, and 10
`
`§ 103(a)
`
`3, 11, and 12
`
`In addition, Petitioner supports its challenges in the Petition with a
`
`Declarations by Metin Çelik, Ph.D. (Ex. 1003) and Marlene Bobka
`
`(Ex. 1023). Pet. 12, 18–19.
`
`
`1 WO 2008/040534 A2, published Apr. 10, 2008 (“LabTec”) (Ex. 1007).
`
`2 Yang et al., U.S. Patent No. 7,357,891 B2, issued Apr. 15, 2008 (“Yang”)
`(Ex. 1006).
`
`3 Suboxone® 2002 Label (Ex. 1008).
`
`4 Suboxone® Tablet Summary Basis of Approval (“SBOA”) (Ex. 1009).
`
`5 Birch et al., U.S. Pat. Appl. Publ. No. 2005/0085440 A1, published Apr.
`21, 2005 (“Birch”) (Ex. 1004).
`
`6 Yang et al., U.S. Pat. Appl. Publ. No. 2005/0037055 A1, published Feb.
`17, 2005 (“the ’055 publication”) (Ex. 1010).
`
`7 WO 2008/025791A1, published March 6, 2008 (“Oksche”) (Ex. 1005).
`
`
`
`4
`
`

`

`IPR2016-01113
`Patent 8,475,832 B2
`
`
`C. The ’832 Patent
`
`The ’832 patent relates to compositions and methods for treating
`
`narcotic dependence using an orally dissolvable film comprising
`
`buprenorphine and naloxone, wherein the film provides a bioequivalent
`
`release profile and drug absorption as compared to that of a Suboxone®
`
`tablet. Ex. 1001, 4:53–58, 2:55–62, 3:19–21. The ’832 patent defines
`
`bioequivalent as “obtaining 80% to 125% of the Cmax and AUC values for a
`
`given active in a different product.” Id. at 3:48–50. According to the ’832
`
`patent, “Cmax refers to the mean maximum plasma concentration after
`
`administration of the composition to a human subject,” and “AUC refers to
`
`the mean area under the plasma concentration-time curve value after
`
`administration of the compositions.” Id. at 3:9–14.
`
`At the time of the ’832 patent invention, Suboxone®, an orally
`
`dissolvable tablet of buprenorphine and naloxone, was on the market for
`
`treating opioid dependency. Id. at 4:51–55. Buprenorphine, an opioid
`
`agonist, provides an effect of satisfying the body’s urge for the narcotics, but
`
`not the “high” associated with misuse. Id. at 1:36–40. Naloxone, an opioid
`
`antagonist, reduces the effect of buprenorphine, and, thus, decreases the
`
`likelihood of diversion and abuse of buprenorphine. Id. at 1:46–52.
`
`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. Id. at 1:55–62. According to the ’832 patent,
`
`[t]here [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. at 1:65–2:2.
`
`
`
`5
`
`

`

`IPR2016-01113
`Patent 8,475,832 B2
`
`
`In relation to a “self-supporting film composition,” the ’832 patent
`
`describes that “local pH of the dosage is preferably controlled to provide the
`
`desired release and/or absorption” of the drugs. Id. at 11:8–10, 44–46,
`
`11:62–12:3. As described in the patent:
`
`Buprenorphine is known to have a pKa of about 8.42, while
`naloxone has a pKa of about 7.94. According to pH partition
`theory, one would expect that saliva (which has a pH of about
`6.5) would maximize the absorption of both actives. However,
`it has been surprisingly discovered by the Applicants that by
`buffering the dosage to a particular pH level, the optimum
`levels of absorption of the agonist and antagonist may be
`achieved. Desirably, the local pH of a composition including
`an agonist and an antagonist is between about 2 to about 4, and
`most desirably is from 3 to 4. At this local pH level, the
`optimum absorption of the agonist and the antagonist is
`achieved.
`
`Id. at 11:46–57. Thus, the inventors achieved optimum absorption of both
`
`buprenorphine (agonist) and naloxone (antagonist) at a “local pH” of “about
`
`2 to about 4, and most desirably [] from 3 to 4.” Id. The ’832 patent defines
`
`“local pH” as “the pH of the region of the carrier matrix immediately
`
`surrounding the active agent as the matrix hydrates and/or dissolves, for
`
`example, in the mouth of the user.” Id. at 3:35–38.
`
`The ’832 patent describes in an example that “a film having a
`
`combination of buprenorphine and naloxone and a local pH of 6.5 did not
`
`provide a bioequivalent effect as the Suboxone® tablet for both
`
`buprenorphine and naloxone.” Id. at 19:61–67. By contrast, as stated in
`
`another example, “in vivo data indicated 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
`
`23:1–4. The ’832 patent states that this “result was surprising as it did not
`
`
`
`6
`
`

`

`IPR2016-01113
`Patent 8,475,832 B2
`
`appear to follow the pH partition theory,” and “[f]urther, at a local pH of
`
`about 3–3.5, it was seen that the absorption of naloxone was substantially
`
`bioequivalent to that of the one dose tablet.” Id. at 23:4–11.
`
`D. Claims
`
`Among the challenged claims, claims 1 and 9 are independent. Claim
`
`1 is representative, and is reproduced below.
`
`1. A film dosage composition comprising:
`
`a. A polymeric carrier matrix;
`
`b. A therapeutically effective amount of buprenorphine or a
`pharmaceutically acceptable salt thereof;
`
`c. A therapeutically effective amount of naloxone or a
`pharmaceutically acceptable salt thereof; and
`
`d. A buffer in an amount to provide a local pH for said
`composition of a value sufficient to optimize absorption of
`said buprenorphine, wherein said local pH is from about 3 to
`about 3.5 in the presence of saliva.
`
`Claims 2–7 depend from claim 1. Independent claim 9 recites a method of
`
`treating narcotic dependence of a user comprising providing a composition
`
`similar to that recited in claim 1 and administering that composition to an
`
`oral cavity. Claims 10–12 depend from claim 9.
`
`II. ANALYSIS
`
`A. Claim Construction
`
`For inter partes review, claim terms in an unexpired patent are given
`
`their broadest reasonable interpretation in light of the patent specification.
`
`37 C.F.R. § 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131,
`
`2144–46 (2016). Claim terms are given their ordinary and customary
`
`meaning, as would be understood by one of ordinary skill in the art in the
`
`context of the entire disclosure. In re Translogic Tech., Inc., 504 F.3d 1249,
`
`
`
`7
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`

`

`IPR2016-01113
`Patent 8,475,832 B2
`
`1257 (Fed. Cir. 2007). Any special definition for a claim term must be set
`
`forth in the specification with reasonable clarity, deliberateness, and
`
`precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`
`As noted above, the ’832 patent defines “local pH” as “the pH of the
`
`region of the carrier matrix immediately surrounding the active agent as the
`
`matrix hydrates and/or dissolves, for example, in the mouth of the user.” Ex.
`
`1001, 3:35–38; Prelim. Resp. 17–18. We adopt that definition. We
`
`determine that construction of other terms is not necessary to our analysis on
`
`whether to institute. Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d
`
`795, 803 (Fed. Cir. 1999) (only claim terms in controversy need to be
`
`construed, and only to the extent necessary to resolve the controversy).
`
`B. Arguments and Evidence Regarding the Suboxone® 2002 Label
`and SBOA as “Printed Publication” Prior Art
`
`As Patent Owner contends in its Preliminary Response, arguments
`
`raised by Petitioner in the current Petition are virtually identical to those
`
`raised by Teva in IPR2016-00280 (“the Teva IPR”). Prelim. Resp. 1–2.
`
`Patent Owner provides redline comparisons of the two Petitions and
`
`corresponding Declarations (as provided by Dr. Das in the Teva IPR and Dr.
`
`Çelik in the current case) supporting this contention. Id. (citing Ex. 2001
`
`(comparing Petitions); Ex. 2002 (comparing Declarations)).
`
`One notable addition in the current Petition, however, relates to
`
`whether the Suboxone® 2002 Label (Ex. 1008) and the SBOA (Ex. 1009)
`
`qualify as prior art printed publications in accordance with 35 U.S.C. §§ 102
`
`and 311(b). Pet 17–22 (citing Ex. 1023; Ex. 2001, 30–36). As discussed in
`
`the Teva IPR Decision, the Petitioner in the prior case relied exclusively on
`
`its contention that Patent Owner stipulated in a co-pending litigation that the
`
`Suboxone® 2002 Label and SBOA were prior art to the ’832 patent. Teva
`
`
`
`8
`
`

`

`IPR2016-01113
`Patent 8,475,832 B2
`
`IPR Decision 9–11. Based the record before us at that time, we determined
`
`that Teva failed to provide a level of “threshold evidence” that would justify
`
`going forward with a trial on any ground that relied on those two documents
`
`as “printed publication” prior art. Id.
`
`In the current Petition, however, Petitioner does not rely only on
`
`alleged stipulations by Patent Owner in a related district court case. Rather,
`
`Petitioner also relies on a Declaration by Marlene Bobka (Ex. 1023), not of
`
`record in the Teva IPR. Pet. 17–22. In her Declaration, Ms. Bobka states
`
`that she is the president of FOI Services, Inc. (“FOI”), which facilitates “the
`
`flow of information under the Freedom of Information Act (‘FOIA’)” to its
`
`customers. Ex. 1023 ¶ 1. Ms. Bobka states that on October 18, 2002, FOI
`
`submitted a FOIA request to the FDA, seeking a copy of “the complete Drug
`
`Approval Package” for the New Drug Application (“NDA”) for Suboxone
`
`tablets, which FOI received from the FDA and made available to the public
`
`in December 2004. Id. ¶¶ 3–4. Ms. Bobka states that the Suboxone® 2002
`
`Label (Ex. 1008) and the SBOA (Ex. 1009), which were included in the
`
`Drug Approval Package provided by the FDA, were made available to the
`
`public for purchase from FOI by December 2004. Id. ¶¶ 5–6.
`
`For the purposes of this Decision, we will assume that Petitioner
`
`sufficiently establishes that the Suboxone® 2002 Label (Ex. 1008) and the
`
`SBOA (Ex. 1009) qualify as prior art printed publications, in the manner
`
`required by statute. In addition, although we appreciate Patent Owner’s
`
`point regarding duplicative arguments in the two cases (Prelim. Resp. 1–3),
`
`we decline to exercise our discretion under 35 U.S.C. § 325(d) to deny the
`
`Petition without further discussion on the merits, but instead deny institution
`
`for the reasons discussed below.
`
`
`
`9
`
`

`

`IPR2016-01113
`Patent 8,475,832 B2
`
`
`C. Asserted Obviousness of Claims 1, 2, 4–7, 9, and 10 by LabTec,
`Yang, Suboxone® 2002 Label, SBOA, and Birch
`
`Petitioner contends that claims 1, 2, 4–7, 9, and 10 would have been
`
`obvious over LabTec in view of Yang, the Suboxone® 2002 Label, the
`
`SBOA, and Birch. Pet. 24–39. Petitioner relies on LabTec as teaching film
`
`dosage forms for delivering active agents, including buprenorphine and
`
`naloxone, where the dosage forms mimic pharmacokinetic profiles of tablet
`
`products, such as Suboxone. Id. at 24–26 (citing Ex. 1007, 1–3, 12, 20, 22).
`
`Petitioner argues that such teachings would have motivated an ordinary
`
`artisan to make a film dosage composition comprising buprenorphine and
`
`naloxone as disclosed in Table A in LabTec and recited in the challenged
`
`claims. Id. (citing Ex. 1007, 22). Petitioner also contends LabTec identifies
`
`a “need” to “replicat[e] the ‘optimum’ absorption of the Suboxone® tablet
`
`with a bioequivalent film dosage form.” Id. at 25–26 (citing Ex. 1007, 2;
`
`Ex. 1003 ¶ 115).
`
`Petitioner further contends that “Yang would have supplied the
`
`[person of ordinary skill in the art] with all the necessary knowledge needed
`
`in order to have a reasonable expectation of success regarding the
`
`manufacture of oral film products that are bioequivalent to Suboxone®
`
`tablets.” Id. at 26–27. Specifically, according to Petitioner, Yang would
`
`have taught an ordinary artisan “how to create a ‘film dosage composition’
`
`comprising a ‘polymeric carrier matrix’” (id. at 27 (citing Ex. 1003 ¶ 116)),
`
`as also recited in independent claims 1 and 9.
`
`Independent claim 1 further requires a film comprising a “buffer in an
`
`amount to provide a local pH for said composition of a value sufficient to
`
`optimize absorption of said buprenorphine, wherein said local pH is from
`
`about 3 to about 3.5 in the presence of saliva.” Ex. 1001, 23:58–67.
`
`
`
`10
`
`

`

`IPR2016-01113
`Patent 8,475,832 B2
`
`Independent claim 9 similarly requires administering to an oral cavity a
`
`composition comprising a “buffer in an amount to provide a local pH of
`
`about 3 to about 3.5 for said composition of a value sufficient to optimize
`
`absorption of said buprenorphine and also sufficient to inhibit absorption of
`
`said naloxone.” Id. at 24:25–39. Petitioner relies on LabTec as identifying
`
`an effect of pH on absorption, stating that the reference “provides the
`
`methods and materials for exploiting this pH effect to optimize absorption,”
`
`and “teaches that pH can be adjusted to decrease or increase absorption of
`
`the actives.” Pet. 27–28 (citing Ex. 1007, 15–16).
`
`Petitioner then argues that “[b]ecause LabTec discloses a film
`
`designed to mimic Suboxone® tablets,” an ordinary artisan “would have
`
`naturally looked to any publicly available information about the Suboxone®
`
`tablets for information about additional film dosage composition
`
`components, including a specific buffer system to adjust the pH.” Id. at 28.
`
`Petitioner then points to the SBOA as disclosing “several redacted pH
`
`values in a section called ‘Absorption,’” and “that those [redacted] pH
`
`values are important to the absorption (and thus the pharmacokinetic profile
`
`and efficacy) of the drug.” Id. at 28–29 (citing Ex. 1009, 28 (redacting pH
`
`values)) (emphasis added). According to Petitioner, “[f]rom this, the POSA
`
`would have concluded that the pH of the saliva as the tablets disintegrate is
`
`significant to the performance of the tablets.” Id. at 29. Petitioner also
`
`states that the SBOA teaches “that in order for buprenorphine to dissolve,
`
`the local pH of the saliva had to be below a certain value, and for naloxone
`
`to dissolve, the pH had to be above a certain value because the solubility
`
`profiles of these drugs are dependent on pH.” Id. at 29 (citing Ex. 1009, 28).
`
`Thus, according to Petitioner, this would have taught an ordinary artisan
`
`
`
`11
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`

`

`IPR2016-01113
`Patent 8,475,832 B2
`
`“that a pH range (below and above certain values) for optimal absorption
`
`had been determined and was achieved by the tablets.” Id. at 29–30 (citing
`
`Ex. 1003 ¶ 121).
`
`Petitioner also argues that the SBOA, the Suboxone® 2002 Label, and
`
`LabTec disclose the mean Cmax and AUC values for buprenorphine in the
`
`tablets. Id. at 30 (citing Ex. 1009, 29; Ex. 1008, 10; Ex. 1007, 22). In
`
`addition, Petitioner argues that “LabTec disclosed that ‘[m]ean peak
`
`naloxone levels range from 0.11 to 0.28 ng/ml in dose range of 1–4 mg.’”
`
`Id. (citing Ex. 1007, 22).
`
`Petitioner then argues that based on the SBOA, an ordinary artisan
`
`would have understood that (1) pH was important to achieving Cmax and
`
`AUC values necessary for bioequivalence, and (2) “an optimum range of pH
`
`values had been achieved by the Suboxone® tablet formulation.” Id. at 31
`
`(citing Ex. 1003 ¶ 123). Petitioner further argues that “[b]ecause Suboxone®
`
`tablets were readily available at the time, it would have been routine for a
`
`POSA to test the pH produced by the tablets in saliva and other dissolution
`
`media,” and that “[c]reating a film formulation that used the same buffers as
`
`the tablets, to produce the same pH produced by the tablets, would have
`
`been trivial.” Id. For example, according to Petitioner, upon reviewing the
`
`Suboxone® 2002 Label, an ordinary artisan would have known that the
`
`tablets “included a buffering system consisting of citric acid and sodium
`
`citrate,” which could be used “to adjust the pH of the saliva to a desired
`
`value within the range of 3.0 to 6.2,” i.e., “the range in which citric acid-
`
`based buffers operate.” Id. at 31–32 (Ex. 1003 ¶¶ 85, 87, 96, 119, 126, 129,
`
`131; Ex. 1013, 428).
`
`
`
`12
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`

`IPR2016-01113
`Patent 8,475,832 B2
`
`
`Thus, Petitioner relies on the SBOA, the Suboxone® 2002 Label, and
`
`LabTec as collectively teaching or suggesting a “buffer in an amount to
`
`provide a local pH,” as recited in claims 1 and 9. Pet. 27–32 (citing Ex.
`
`1008, 8, 10; Ex. 1009, 28, 29). Citing those references, Petitioner argues
`
`that an ordinary artisan would have known to make relevant film dosages
`
`using the same buffer of the tablets, i.e., a buffer consisting of citric acid and
`
`sodium citrate, which would have created a local pH “within the range from
`
`about 3 to about 6.” Id. at 31–32.
`
`Notably, other than indicate that an ordinary artisan would have
`
`known that “citric acid-based buffers” operate “within the range from about
`
`3 to about 6,” Petitioner does not point to where those three references,
`
`individually or in combination, teach or suggest any buffer in an amount that
`
`provides a local pH that is “about 3 to about 3.5,” as recited in challenged
`
`independent claims 1 and 9. For instance, Petitioner and its witness contend
`
`that an ordinary artisan would have known “a pH range (below and above
`
`certain values) for optimal absorption had been determined and was
`
`achieved by the tablets,” but do not point to where the SBOA, the
`
`Suboxone® 2002 Label, and/or LabTec suggest that anyone actually
`
`measured a local pH for the Suboxone tablets in an oral cavity, much less
`
`determined that local pH should be from about 3 to about 3.5, as recited in
`
`the challenged claims. Pet. 29–32 (citing Ex. 1003 ¶ 121 (discussing in vitro
`
`dissolution studies for buprenorphine and naloxone in the SBOA (Ex. 1009,
`
`28)), ¶¶ 85, 87, 94, 96, 119, 123, 125, 126, 129, 131–133; see also Ex. 1009,
`
`28 (discussing redacted pH values, without indicating that a local pH in an
`
`oral cavity was measured)). We cannot tell from this record if the Suboxone
`
`
`
`13
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`

`IPR2016-01113
`Patent 8,475,832 B2
`
`tablets discussed in those three references produced a local pH in an oral
`
`cavity from about 3 to about 3.5.
`
`In relation to the specific local pH range recited in claims 1 and 9,
`
`therefore, Petitioner necessarily relies on Birch as motivating an ordinary
`
`artisan “to target a value between about 3 to about 3.5, since Birch taught
`
`that transmucosal absorption of buprenorphine was optimal within that
`
`range.” Id. at 32–33 (citing Ex. 1004, Figs. 1 and 3, Examples 3 (pH 3.4), 5
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`(pH 3.4), 8 (clinical study); Ex. 1003 ¶¶ 105, 127–128, 131–135). Petitioner
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`also argues an ordinary artisan “would not have expected that the claimed
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`pH would cause problematic transmucosal absorption of [naloxone] because
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`the prior art disclosed that such absorption was not seen with Suboxone®
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`tablets or the citric acid buffer system used therein.” Id. at 33. Petitioner
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`relies on the Suboxone® 2002 Label as teaching the citric acid buffer system
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`in this regard. Id. at 31.
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`As noted by Patent Owner, Petitioner relies on Birch where it provides
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`information about the pharmacokinetic profiles of buprenorphine
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`formulations administered intranasally, i.e., Birch teaches that a pH range of
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`3.4 can be used for nasal absorption, not oral transmucosal absorption
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`relevant to a film dosage or other dosage administered to the oral cavity.
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`Prelim. Resp. 26–27; Pet. 32–33. All figures and examples in Birch cited in
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`the Petition, and by Petitioner’s expert, Dr. Çelik, relate to formulations
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`administered intranasally. Ex. 1004, Figs. 1–4, ¶¶ 38–39, Examples 1–5,
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`¶¶ 139–154, Example 8, ¶¶ 206–211, claim 1 (directed to a “solution
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`suitable for intranasal administration”); Ex. 1003 ¶¶ 105, 127–128, 131–135.
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`Petitioner does not indicate sufficiently if or where Birch discusses oral
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`transmucosal absorption, or how pH information in relation to nasal
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`absorption might be relevant to oral transmucosal absorption or local pH in
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`saliva as generated by a buffer in a film. Id. at 32–33 (citing Ex. 1004; Ex.
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`1003 ¶¶ 105, 127–128, 131–135).
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`Thus, Petitioner does not explain adequately how Birch’s pH
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`information in relation to buprenorphine formulations (lacking naloxone)
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`administered intranasally teaches or suggests a buffer providing a specific
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`“local pH” in the oral cavity, as it pertains to a composition comprising both
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`buprenorphine and another drug, naloxone, as required in the challenged
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`claims.
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`At most, Petitioner cites a paragraph in Dr. Çelik’s Declaration that
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`states, without itself citing evidence in support, that the “anatomy of the oral
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`and nasal mucosa is quite similar, thus, one of ordinary skill would expect
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`that the same principle of drug delivery will apply to both tissues.” Ex. 1003
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`¶ 105; Pet. 32–33. We agree with Patent Owner that this conclusory
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`statement by Dr. Çelik, without more, is insufficient to make the leap
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`Petitioner asks us to make. Prelim. Resp. 26–27; 33–34; 37 C.F.R.
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`§ 42.65(a) (stating that “[e]xpert testimony that does not disclose the
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`underlying facts or data on which the opinion is based is entitled to little or
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`no weight”). Moreover, Patent Owner points us to evidence in Birch itself
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`indicating that buprenorphine pharmacokinetics (e.g., Cmax and
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`bioavailability) differ when administered to oral versus nasal mucosa.
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`Prelim. Resp. 27; Ex. 1004, 16, Table 11.
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`Petitioner also argues that “[e]ven without these explicit teachings,”
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`an ordinary artisan would have “had (i) the ability to prepare buffered films;
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`(ii) a starting point for testing; (iii) the published target Cmax and AUC
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`values, and (iv) knowledge of the pH dependence of the transmucosal
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`absorption of buprenorphine and naloxone.” Pet. 33. Petitioner further
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`contends that “it would have been nothing more than routine
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`experimentation” to identify “the claimed pH range of 3 to 3.5 as optimal”
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`upon testing a “number of films that produced a range of pH values in the
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`saliva.” Id. at 33 (citing Ex. 1003 ¶¶ 133–134, 140–142).
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`Neither Petitioner nor Dr. Çelik explains adequately, however, why an
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`ordinary artisan would have wanted to try to make a film that produced a
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`local pH of 3 to 3.5 in saliva in the first place, based on teachings in LabTec,
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`the Suboxone® 2002 Label, or the SBOA regarding the Suboxone tablet
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`and/or Yang’s teachings regarding general methods for making films. See,
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`e.g., Ex. 1003 ¶¶ 112, 125, 132–135, 140–143 (asserting that arriving at a
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`pH of 3–3.5 would have been “routine experimentation,” and “there would
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`not have been anything surprising” about identifying a pH of 3–3.5, without
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`disclosing underlying facts or data in support, other than to refer to Cmax and
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`AUC values for buprenorphine); Pet. 33–34.8
`
`
`8 In a footnote, Petitioner asserts that an ordinary artisan “would have
`known that the solubility of both drugs had to be considered, because a drug
`must be dissolved before it can absorbed into the body.” Pet. 30 n.12 (citing
`Ex. 1009, 28). Petitioner and Dr. Çelik rely on Cassidy as teaching that
`“solubility of buprenorphine increases as pH decreases,” and that
`buprenorphine is more soluble at or below a pH of 4.2 than at any pH above
`4.2. Id.; Ex. 1003 ¶¶ 75, 102, 104 (citing Cassidy, Controlled Buccal
`Delivery of Buprenorphine, 25 J. CONTROLLED RELEASE 24, 27–28, Fig. 1
`(1993) (Ex. 1012)). Petitioner does not explain adequately, however, 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.
`In addition, consistent with Patent Owner’s position (Prelim. Resp. 23–25),
`Cassidy discusses a delivery system using a non-woven or hydrogel disk, not
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`Moreover, as Patent Owner points out, LabTec teaches that
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`“formulations can rely on various means for retarding absorption of the
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`active ingredient through the oral mucosa,” including by using “pH
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`adjusting agents that adjust the pH of the environment surrounding the
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`dosage form to a pH that renders the active agent less permeable.” Prelim.
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`Resp. 10 (quoting Ex. 1007, 15). In this context, LabTec states that
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`“[s]uitable pH adjusting agents function by ionizing the active agent to a less
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`permeable state,” and “[f]or a basic active ingredient, one would adjust the
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`pH of the solution to below the pKa of the conjugate acid.” Id.; Prelim.
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`Resp. 2, 14–17 (discussing the effect of pH on buprenorphine, a “weakly
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`basic compound”). In view of such teachings, Patent Owner persuades us
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`that LabTec does not suggest preparing a film that lowers a local pH to 3–
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`3.5 in the saliva for the purpose of increasing absorption of an active
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`ingredient such as buprenorphine.
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`Upon consideration of information presented in the Petition and the
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`Preliminary Response, we are not persuaded that Petitioner has
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`demonstrated that there is a reasonable likelihood that it would prevail in
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`showing that challenged claims 1, 2, 4–7, 9, and 10 of the ’832 patent are
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`unpatentable over LabTec in view of Yang, the Suboxone® 2002 Label,
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`SBOA, and Birch.
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`D. Other Obviousness Grounds Relying on the Suboxone® 2002
`Label, SBOA, and Birch
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`The other three grounds raised in the Petition also rely on the
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`Suboxone® 2002 Label, SBOA, and Birch in essentially the same way as
`
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`a film, where the disk comprises a solution of buprenorphine (without
`naloxone) at a pH of 4, not a pH 3–3.5. Ex. 1012, 21, 23, 25–26, Fig. 4.
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`discussed above. Pet. 39–50. Grounds 2 and 4 discuss the ’055 publication
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`as it relates to certain limitations in challenged dependent claims, without
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`indicating that the publication provides any teachings or suggestion in
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`relation to a buffer providing a local pH of about 3–3.5, as recited in
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`independent claims 1 and 9. Pet. 39–40, 49–50.
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`In grounds 3 and 4, Petitioner relies on Oksche (Ex. 1005) for
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`disclosures similar to those in LabTec, i.e., an oral film comprising
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`buprenorphine and naloxone that is “just as effective as,” i.e., bioequivalent
`
`to, Suboxone tablets. Pet. 40–50. Petitioner also points to where Oksche
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`discloses “the target Cmax and AUC0–48 values for buprenorphine.” Id. at 44–
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`45 (citing Ex. 1005, 9). Petitioner again relies on the SBOA, the
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`Suboxone® 2002 Label, and Birch in relation to a buffer providing a local
`
`pH from about 3–3.5. Id. at 43–45. More specifically, Petitioner again
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`necessarily relies on Birch as motivating an ordinary artisan to “employ” a
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`local pH between about 3 to about 3.5, as required in the challenged claims.
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`Pet. 44.
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`As discussed above, on the record before us, Petitioner does not
`
`persuade us that an ordinary artisan would have understood that that the pH
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`information in Birch regarding a nasal formulation comprising
`
`buprenorphine would be applicable to an oral composition comprising
`
`buprenorphine and another drug, naloxone, as well as a buffer providing a
`
`local pH in the mouth.
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`Beyond that, Petitioner refers to the Cmax and AUC0–48 values for
`
`buprenorphine as disclosed in Oksche when asserting it “would have been
`
`nothing more than routine experimentation for a [person of ordinary skill in
`
`the art] to arrive at the claimed pH of 3 to 3.5.” Id. at 44–45 (citing Ex.
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`1003 ¶¶ 133, 141–142). Once again, neither Petitioner nor Dr. Çelik
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`explains adequately why an ordinary artisan would have wanted to try to
`
`make a composition that produced a local pH of 3 to 3.5 in the mouth i