Patent No. 8,475,832
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`Attorney Docket No. 117744-00048
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`Paper No._______
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
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`BIODELIVERY SCIENCES INTERNATIONAL, INC.
`Petitioner
`
`v.
`
`RB PHARMACEUTICALS LIMITED
`Patent Owner
`
`
`Patent 8,475,832
`
`_______________
`
`Mailed: June 20, 2014
`
`
`PETITION FOR INTER PARTES REVIEW
`UNDER 35 USC §§ 311-319 AND 37 CFR § 42.100 ET. SEQ.
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`Patent No. 8,475,832
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`Attorney Docket No. 117744-00048
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`TABLE OF CONTENTS
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`Page
`INTRODUCTION ........................................................................................... 1
`I.
`II. MANDATORY NOTICES AND CERTIFICATIONS ................................... 2
`III. SUMMARY OF THE ‘832 PATENT AND PROSECUTION ........................ 5
`A. The film formulation of ‘832 patent presented no
`particular challenge .......................................................................... 5
`B. The invention disclosed in the ‘832 patent is not
`surprising ....................................................................................... 11
`C. The ‘832 patent was allowed in a haze of confusing
`definitions and incorrect arguments ................................................ 13
`D. The alleged novelty of the challenged claims is
`contradicted by the ‘832 patent specification .................................. 15
`E. The Patent Office has finally rejected claims that are
`narrower than challenged claim 15 ................................................. 17
`IV. CONSTRUCTION OF THE CHALLENGED CLAIMS ............................... 21
`A. Construction of “film formulation.” ............................................... 22
`B. Construction of “provides an in vivo plasma profile.” .................... 26
`V. STATEMENT OF PRECISE RELIEF REQUESTED AND
`CLAIM-BY-CLAIM EXPLANATION OF GROUNDS OF
`INVALIDITY ............................................................................................... 30
`A. The only claim elements entitled to patentable weight in
`the challenged claims are found in the admitted prior art
`and additional art cited herein ......................................................... 30
`B. The wherein clause, which recites a desired result, is not
`entitled to patentable weight ........................................................... 31
`C. Even if the desired result were entitled to patentable
`weight, it is still anticipated by and obvious in view of
`the cited art ..................................................................................... 32
`Ground 1. Claims 15-19 are obvious over Euro-Celtique ............. 34
`Ground 2. Claims 15-19 are obvious over Euro-Celtique
`in view of the EMEA Study Report .............................. 44
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`Patent No. 8,475,832
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`Attorney Docket No. 117744-00048
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`Ground 3. Claims 15-19 are obvious over Euro-Celtique
`in view of the EMEA Study Report and WO
`03/030883 .................................................................... 48
`Ground 4. Claims 15-19 are obvious over Euro-Celtique
`in view of the EMEA Study Report and Yang ............... 51
`VII. CONCLUSION ............................................................................................. 55
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`Patent No. 8,475,832
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`Attorney Docket No. 117744-00048
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`Exhibit 1001:
`
`US Patent 8,475,832 (“‘832 Patent”)
`
`Exhibit List
`
`Exhibit 1002:
`
`Reckitt Benckiser Pharmaceuticals, Inc., RB Pharmaceuticals
`Limited, and MonoSol, RX, LLC., EDNC Civil Action No. 5:13-
`cv-760, Complaint filed October 29, 2013 (“Complaint”)
`
`Exhibit 1003:
`
`Reckitt 2012 Annual Report (“Annual Report”)
`
`Exhibit 1004:
`
`Declaration of Maureen Reitman, Sc.D. (“Reitman Decl.”)
`
`Exhibit 1005:
`
`Declaration of Phillip T. Lavin, Ph.D. (“Lavin Decl.”)
`
`Exhibit 1006:
`
`First Office Action mailed August 31, 2011 (“First OA”)
`
`Exhibit 1007:
`
`Response filed February 29, 2012 (“First Response”)
`
`Exhibit 1008:
`
`Second Office Action mailed May 2, 2012 (“Second OA”)
`
`Exhibit 1009:
`
`Response to filed October 22, 2012 (“Second Response”)
`
`Exhibit 1010:
`
`Third Office Action mailed November 6, 2012 (“Third OA”)
`
`Exhibit 1011:
`
`Response to filed April 30, 2013 (“Third Response”)
`
`Exhibit 1012:
`
`Notice of Allowance mailed May 24, 2013, including the
`attached Interview Summary (“NOA”)
`
`Exhibit 1013:
`
`Suboxone® tablet label, Revised September 2006 (“Suboxone
`Tablet Label”)
`
`Exhibit 1014:
`
`Excerpt from MERRIAM-WEBSTER’S COLLEGIATE DICTIONARY,
`10TH ED., Merriam-Webster, Inc. (2000)
`
`Exhibit 1015:
`
`European Medicines Agency (EMEA) Study Report on
`Suboxone® tablets, 2006 (“EMEA Study Report”)
`
`Exhibit 1016:
`
`US Patent No. 7,357,891, published December 23, 2004 and
`issued April 15, 2008, to Yang et al. (“Yang”)
`
`
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`Patent No. 8,475,832
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`Attorney Docket No. 117744-00048
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`Exhibit 1017:
`
`International Patent Publication No. WO 2008/040534,
`published April 10, 2008, to Applicant Labtec GmbH
`(“Labtec”)
`
`Exhibit 1018:
`
`International Patent Publication No. WO 2008/025791,
`published March 6, 2008, to Applicant Euro-Celtique S.A.
`(“Euro-Celtique”)
`
`Exhibit 1019:
`
`US Patent Publication No. 2005/0085440, published April 21,
`2005, to Birch et al. (“Birch”)
`
`Exhibit 1020:
`
`Power of Attorney
`
`Exhibit 1021:
`
`Assignment from Reckitt Benckiser Healthcare (UK) Limited
`to RB Pharmaceuticals Limited
`
`Exhibit 1022:
`
`Assignment from MonoSol Rx, LLC to Reckitt Benckiser
`Healthcare (UK) Limited
`
`Exhibit 1023:
`
`US Patent No. 7,425,292, published June 12, 2003 and issued
`September 16, 2008, to Yang et al. (“‘292 patent”)
`
`Exhibit 1024: M.Voet, THE GENERIC CHALLENGE (Brown Walker Press 2d ed.
`2008)
`
`Exhibit 1025:
`
`Dismissal of Complaint, EDNC Civil Action No. 5:13-cv-760,
`May 21, 2014
`
`Exhibit 1026:
`
`US Patent Application No. 13/964,975, published on Jan. 2,
`2014 as US Patent Publication No. US2014/0005218
`
`Exhibit 1027:
`
`Office Action in US Patent Application No. 13/964,975, dated
`November 7, 2013
`
`Exhibit 1028:
`
`Amendment and Response to Office Action in US Patent
`Application No. 13/964,975, dated Jan. 2, 2014
`
`Exhibit 1029:
`
`Office Action in US Patent Application No. 13/964,975, dated
`March 7, 2014
`
`Exhibit 1030:
`
`International Patent Publication No. WO 2005/079750, “Films
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`Patent No. 8,475,832
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`for Use as Dosage Forms,” published September 1, 2005
`
`Exhibit 1031:
`
`International Patent Publication No. WO 03/030883, “Uniform
`Films for Rapid Dissolve Dosage Form Incorporating Taste-
`Masking Compositions,” published April 17, 2003
`
`Exhibit 1032:
`
`US Patent No. 4,582,835, issued April 15, 1986, to Lewis et al.
`
`Exhibit 1033:
`
`Declaration of Metin Çelik, Ph.D. (“Çelik Decl.”)
`
`Exhibit 1034:
`
`Excerpts from Ansel, H., et al., PHARMACEUTICAL DOSAGE
`FORMS AND DRUG DELIVERY SYSTEMS, 7TH ED., Lippincott
`Williams & Wilkins (1999)
`
`Exhibit 1035:
`
`Excerpt from MERRIAM-WEBSTER’S COLLEGIATE DICTIONARY,
`10TH ED., Merriam-Webster, Inc. (2000)
`
`Exhibit 1036:
`
`FDA, “Guidance for Industry: Bioavailability and
`Bioequivalence Studies for Orally Administered Drug
`Products—General Considerations,” March 2003
`
`Exhibit 1037:
`
`Print-out from www.accessdata.fda.gov, last viewed June 12,
`2014
`
`Exhibit 1038:
`
`European Patent Application Publication No. 0 069 600,
`published in 1983 (“EP 0 069 600”)
`
`Certificate of Service
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`Patent No. 8,475,832
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`Attorney Docket No. 117744-00048
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`I.
`
`INTRODUCTION
`
`Challenged claims 15-19 fail to recite any features that patentably
`
`distinguish the claimed formulation from prior art formulations. The only
`
`formulation limitations recited in the challenged claims are an orally dissolving
`
`combination of two drugs, buprenorphine and naloxone. The recited orally
`
`dissolving combination of buprenorphine and naloxone has long been known. See,
`
`e.g., Ex. 1032, US Patent No. 4,582,835, at Abstract (issued in 1986 and disclosing
`
`a “sublingually effective dose of buprenorphine together with an amount of
`
`naloxone sufficient to prevent substitution in an opiate dependent subject.”).
`
`The recitation of Cmax ranges and other pharmacokinetic ranges—that are
`
`broader than the acknowledged ranges resulting from Reckitt Benckiser Group’s
`
`prior art SUBOXONE tablets—would also have been obvious to the person of
`
`ordinary skill in the art. And even if these ranges were not obvious, a formulation
`
`claim must recite the formulation that it seeks to protect—e.g., the combination of
`
`components that is novel and non-obvious over the prior art—and not desired
`
`properties that are the result of an unrecited, optional administration step.
`
`In short, the challenged claims 15-19 fail to recite even one non-obvious
`
`feature. That the recitations of these claims would have been obvious to the person
`
`of ordinary skill in the art—even those recitations not entitled to patentable
`
`weight—renders these claims invalid.
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`Patent No. 8,475,832
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`Upon institution of a review in the related and overlapping IPR2014-00325
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`proceedings, Petitioner intends to request that this proceeding be joined with the
`
`IPR2014-00325 review.
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`II. MANDATORY NOTICES AND CERTIFICATIONS
`
`NOTICE OF LEAD AND BACKUP COUNSEL
`
`Lead Counsel: Danielle L. Herritt (Reg. 43,670); Tel: 617.449.6513
`
`Backup Counsel: Kia L. Freeman (Reg. 47,577); Tel: 617.449.6549
`
`Address: McCarter & English, LLP; 265 Franklin Street; Boston, MA 02110
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`617-549-6500 (reception); 617-607-9200 (fax)
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`NOTICE OF EACH REAL PARTY-IN-INTEREST
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`
`
`The real-party-in-interest for this Petition is BioDelivery Sciences
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`International, Inc. (“Petitioner”); 801 Corporate Center Drive, Suite 210; Raleigh,
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`North Carolina 27607 USA.
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`NOTICE OF RELATED MATTERS
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`The subject of this petition is US Patent No. 8,475,832 (“the ‘832 patent”),
`
`Ex. 1001. This petition is directed to the same five claims of the same patent as the
`
`IPR2014-00325 proceedings. This petition involves the same parties as the
`
`IPR2014-00325 proceedings. The grounds in this petition are substantially based
`
`on a subset of the references cited in the IPR2014-00325 proceedings. While
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`grounds in this petition cite two references that were not cited in IPR2014-00325,
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`these two references are related to a reference cited in IPR2014-00325. Euro-
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`Celtique (Ex. 1018), a primary reference in both this petition and the IPR2014-
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`00325 petition, incorporates by reference one of the two additional references and
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`repeatedly cites the other. Upon institution of a review in the IPR2014-00325
`
`proceedings, Petitioner intends to request that this proceeding be joined with the
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`IPR2014-00325 review.
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`Reckitt Benckiser Pharmaceuticals, Inc. (“Reckitt”), RB Pharmaceuticals
`
`Limited (“RB”), and MonoSol, RX, LLC (“MonoSol”) asserted the ‘832 patent
`
`against Petitioner to prevent Petitioner from launching a product that would
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`compete with its SUBOXONE films in a Complaint filed October 29, 2013. See
`
`Ex. 1002, Reckitt Benckiser Pharmaceuticals, Inc., RB Pharmaceuticals Limited,
`
`and MonoSol, RX, LLC. v. BioDelivery Sciences International, Inc., EDNC Civil
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`Action No. 5:13-cv-760, Complaint. That Complaint was dismissed as premature
`
`because the FDA had not yet approved Petitioner’s product, Petitioner’s product
`
`had not yet been launched in the market, and the separate claim under 35 USC
`
`§ 271(e)(2) failed to state a valid claim. See Ex. 1025. Now that the FDA has
`
`approved Petitioner’s product, a new complaint asserting the ‘832 patent is
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`expected.
`
`By way of background, Suboxone films are films sold by Reckitt that mimic
`
`Reckitt’s predecessor Suboxone tablets. Reckitt voluntarily discontinued its
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`Suboxone tablets (a product that, until recently, enjoyed many years of FDA
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`exclusivity for sales) in order to convert its customers to Suboxone films (a product
`
`that has recently begun to enjoy FDA exclusivity for sales). See Ex. 1003, Annual
`
`Report.
`
`MonoSol is the developer and manufacturer of Suboxone films for Reckitt.
`
`Shortly after filing the application that led to the ‘832 patent, the original assignee
`
`of that application, MonoSol1, assigned the application to Reckitt Healthcare (UK)
`
`Limited (Ex. 1022), who then later assigned it to RB (Ex. 1021). For the
`
`avoidance of confusion, MonoSol, Reckitt Healthcare (UK) Limited, and RB, the
`
`successive owners of the ‘832 patent, are collectively referred to as “Applicant.”
`
`The ‘832 patent is part of a family of applications with at least one currently
`
`pending US application of which Petitioner is aware. International Application
`
`No. PCT/US10/44488, published as WO 2011/017483 on February 10, 2011,
`
`claims the benefit of the ‘832 patent. Pending US Patent Application No.
`
`13/964,975, filed on August 12, 2013, claims the benefit of the ‘832 patent—
`
`
`
`
`1 Although MonoSol was a plaintiff in the Complaint, and therefore
`
`apparently believed it had the standing required for the Complaint, Patent Owner
`
`failed to disclose whether MonoSol is a real party in interest in the IPR2014-00325
`
`proceeding.
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`Patent No. 8,475,832
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`through abandoned US Patent Application No. 13/923,749 filed on June 21, 2013.
`
`The pending ‘975 application includes claims that are notably similar to challenged
`
`claims 15-19 of the ‘832 patent.
`
`NOTICE OF SERVICE INFORMATION
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`
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`Please direct all correspondence regarding this proceeding to lead counsel at
`
`the address shown above. Petitioner consents to electronic service by email at
`
`IPR832@mccarter.com and dherritt@mccarter.com.
`
`GROUNDS FOR STANDING
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`
`
`Petitioner certifies that the patent for which review is sought is available for
`
`inter partes review and that Petitioner is not barred or estopped from requesting an
`
`inter partes review challenging the patent claims on the grounds identified in this
`
`petition.
`
`III. SUMMARY OF THE ‘832 PATENT AND PROSECUTION
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`A. The film formulation of ‘832 patent presented no particular
`challenge.
`
`In the ‘832 patent, Applicant summarizes its alleged invention as providing a
`
`film dosage that is bioequivalent to its existing Suboxone tablet:
`
`Currently,
`
`treatment of opioid dependence
`
`is aided by
`
`administration of Suboxone® [tablet], which is an orally
`
`dissolvable tablet. This tablet which provides a combination of
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`buprenorphine (an opioid agonist) and naloxone (an opioid
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`antagonist). [sic] Therefore, the present invention provides a
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`method of treating narcotic dependence by providing an orally
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`dissolvable film dosage, which provides a bioequivalent effect
`
`to Suboxone® [tablets].
`
`(‘832 patent at 4:51-58.)
`
`In other words, the alleged invention features the same oral dissolvability,
`
`same drug combination, same strength, same route of delivery, and the same or
`
`similar pharmacokinetic parameters (such as bioequivalent Cmax and AUC) as the
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`Suboxone tablet. See also id. at Examples 1-8.
`
`The film formulations disclosed in the ‘832 patent are remarkably similar to
`
`those of the Suboxone tablet—which is perhaps not surprising since Applicant was
`
`starting from its own tablet. Compare e.g., Ex. 1013, Suboxone Tablet Label, at p.
`
`1, col. 1, last two paragraphs (“Each tablet also contains lactose, mannitol,
`
`cornstarch, povidone K30 [polyvinyl pyrrolidone or PVP], citric acid, sodium
`
`citrate, FD&C Yellow No. 6 color, magnesium stearate, and the tablets also
`
`contain Acesulfame K Sweetener and a lemon/lime flavor.”) with Ex. 1001, ‘832
`
`patent at 5:30-38 (“Specific examples of useful water-soluble polymers include . . .
`
`polyvinyl pyrrolidone . . . starch”); at 9:61-10:4 (“The sweeteners may be chosen
`
`from . . . mannitol . . . acesulfame-K . . . and natural intensive sweeteners”); and
`
`Example 5 at Table 5 (“FD&C yellow #6”). Even the preferred buffer system used
`
`in all the examples of the ‘832 patent (sodium citrate and citric acid) is disclosed in
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`the Suboxone Tablet Label. Compare e.g., Ex. 1013, Suboxone Tablet Label, at 1,
`
`1st column, last two paragraphs (“Each tablet also contains … citric acid, sodium
`
`citrate”) with Ex. 1001, ‘832 patent, at Examples 1 and 4-9 and claim 7.
`
`To the extent that films or methods of making films could be considered
`
`new, the ‘832 patent admits that films could be formed by any process and
`
`methods of making its allegedly inventive films were known. See Ex. 1001, ‘832
`
`patent, at 15:29-30 (“The film compositions of the present invention may be
`
`formed via any desired process.”). Indeed, suitable processes are disclosed by
`
`incorporating prior art by reference, including US Patent Nos. 7,425,292 and
`
`7,357,891. See id. at 15:30-32. The ‘891 patent incorporated into the ‘832 patent
`
`by reference, for example, describes methods of making films using the same
`
`polymers, e.g., polyvinyl pyrrolidone (PVP), and other ingredients the ‘832 patent
`
`disclosed as suitable, and which are listed in the Suboxone Tablet Label. See Ex.
`
`1016 at 14:64 (listing polyvinyl pyrrolidone as a suitable “Film Forming
`
`Polymer”).
`
`In the examples of the ‘832 patent, Applicant describes the arrival at a
`
`Suboxone tablet alternative. See Ex. 1001, ‘832 patent, at Examples 1-8. The
`
`examples purport to teach that, in order to provide a bioequivalent effect to
`
`Suboxone tablets, a pH of 3-3.5 is critical and surprising. See id. But this pH is
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`merely the pH of Suboxone tablets. Dr. Reitman has demonstrated that the pH of
`
`Suboxone tablets is about 3.5. See Ex. 1004, Reitman Decl. at ¶5.
`
`Example 1 provides a film component list that includes the same drugs at the
`
`same dosage strengths as Suboxone tablets. See Ex. 1001, ‘832 patent, at Example
`
`1, 15:55-16:32. Example 1 uses the same buffer (citric acid and sodium citrate) as
`
`that used in Suboxone tablets. Id. Example 2 verifies the pharmacokinetic
`
`parameters of the prior art Suboxone tablets. Id. at Example 2, 16:35-64. Example
`
`3 calculates the values required “to be considered bioequivalent to the Suboxone
`
`tablet” using an 80-125% rule. Id. at Example 3, 17:15-47.
`
`Example 4 tests “various film products” at pH 3.5, having the same active
`
`ratios and amounts as the Suboxone tablets (2 mg/0.5 mg and 16mg/4mg of
`
`buprenorphine/naloxone). Id. at Example 4, 17:50-18:8. In its first film absorption
`
`study, “[t]he inventive films were . . . determined to have provided a bioequivalent
`
`absorption of buprenorphine at a local pH of 3.5 as the commercially available
`
`Suboxone® tablet.” Id. at Example 4, 18:12-15. Indeed, as appears to be admitted
`
`in the foregoing sentence, and verified by Dr. Reitman, the pH of Suboxone tablets
`
`is 3.5. See Ex. 1004, Reitman Decl. at ¶5.
`
`With respect to the first film absorption study (Example 4), the ‘832 patent
`
`states that “[t]he values for absorption of naloxone were very close to the
`
`bioequivalent range of Suboxone®.” Ex. 1001, ‘832 patent, at 18:15-16. The ‘832
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`patent explains that the “slightly higher absorption of Naloxone was not due to the
`
`local pH but rather to the amount of buffer….” Id. at 18:17-22. Thus, Applicant
`
`identified the appropriate 3.5 pH, and used it in its film absorption study. Again,
`
`this is the pH of the prior art Suboxone tablets.
`
`Reporting results of an in vivo study in Examples 5-8, Applicant tested
`
`additional film products at a buffered pH of 3.5 (the same pH already used in
`
`Example 4, but now referred to as pH 3-3.5), side-by-side against film products at
`
`other pHs. Id. at Examples 5-8. The absorption results of Test Formulation 2 are
`
`the apparent basis for allowance of unchallenged claims in the ‘832 patent. Test
`
`Formulation 2, with a buffered pH of 3.5, is characterized in the ‘832 patent as
`
`providing a “substantially bioequivalent”2 absorption of buprenorphine and
`
`naloxone as the commercially available Suboxone tablet. Id. at 23:1-10.
`
`
`
`
`2 It is not clear what Applicant means by “substantially bioequivalent”
`
`because Test Formulation 2 does not fall within the dose-specific range of 80-
`
`125% of the pharmacokinetic values of Suboxone 8 mg buprenorphine / 2 mg
`
`naloxone tablet. See, e.g., id. at Table 11 (disclosing a Cmax value for
`
`Formulation 2 film that is 137% of the Cmax value for the Suboxone sublingual
`
`tablet); see also Ex. 1005, Lavin Decl. at ¶5 (opining on bioequivalence). The in
`
`vivo study demonstrates that none of the buffered pHs provided absorption values
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`Challenged claims 15-19 recite pharmacokinetic ranges that are broader than
`
`a standard dose-specific 80-125% bioequivalence ranges. Claims 15-19 recite
`
`ranges that encompass about 80% of the absorption of the lowest dose (2 mg)
`
`Suboxone tablet through about 125% of the absorption of the of the highest dose
`
`(16 mg) Suboxone tablet. See Ex. 1001, ‘832 patent, at Examples 2 and 3; see also
`
`Ex. 1005, Lavin Decl., at ¶6. The breadth of the ranges recited in claims 15-19
`
`makes them easy to satisfy. For example, the two films in the first film absorption
`
`study of the ‘832 patent both satisfied the broad Cmax ranges recited in claim 15.
`
`See id. at Example 4. In sum, the ‘832 patent itself demonstrates that the film
`
`formulation of claims 15-19 presented no particular challenge.
`
`In any event, both the pH and the recited pharmacokinetic ranges would
`
`have been obvious. The pH is merely the pH of Suboxone tablets. See Ex. 1004,
`
`Reitman Decl. at ¶5. And the recited pharmacokinetic ranges are those of the prior
`
`art Suboxone tablets with extensions at each end (Examples 2-3), and therefore
`
`anticipated by the prior art Suboxone tablets.
`
`
`
`in a dose-specific 80-125% bioequivalence range—as even the ‘832 patent
`
`acknowledges in Examples. See also Ex. 1005, Lavin Decl. at ¶9 (opining that
`
`Tables 7, 9, and 11 do not show bioequivalence for Test Formulations 1, 2, or 3).
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`Patent No. 8,475,832
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`B.
`
`The invention disclosed in the ‘832 patent is not surprising.
`
`Contrary to statements made in the ‘832 patent, the invention disclosed in
`
`the ‘832 patent is not surprising. Specifically, the ‘832 patent states “it has been
`
`surprisingly discovered by the Applicants that by buffering the dosage to a
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`particular pH level, the optimum levels of absorption of the agonist and antagonist
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`may be achieved.” Ex. 1001, ‘832 patent, at 11:50-53. But this statement and the
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`characterization of the results of Test Formulation 2 (pH=3-3.5) is far from
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`“surprising” (id. at 23:1-6) as revealed by the Examples themselves.
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`First, contrary to the characterization of the results of Example 8 as
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`“surprising” (id. at 23:4), the results were consistent with the results of a prior
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`example of administering films having the same pH, i.e., Example 4.3
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`Second, even the briefest examination of the data reported in Examples 6-8
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`reveals that the data was very likely obtained at the same time from the same in
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`
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`3 Indeed—from a side-by-side comparison of Test Formulation 2 of Example
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`5 and the “8/2” formulation of Example 1—it is clear that at least one of the very
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`first formulations of Example 1 also had a pH of about 3.5 because the two
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`compared formulations appear to be identical (except that Example 5 uses generic
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`descriptors for some of the specific component names). The pH is reported to be
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`3-3.5 in Example 5.
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`vivo study. Specifically, all three examples use the same Suboxone sublingual
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`data. The Tmax, Cmax, AUClast, AUCinf and T1/2 values for Suboxone tablets—
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`including the mean, standard deviation (SD) and CV%—for every single parameter
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`are identical. It is impossible that these are separate studies because these numbers
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`could never be exactly the same for three different studies. See Ex. 1005, Lavin
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`Decl. at ¶7 (“[I]t is statistically impossible for new experiments to have been
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`conducted and yield identical results for Suboxone® tablets three times in three
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`different comparisons. Contrary to the related description, the buprenorphine and
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`naloxone absorption of all three Test Formulations could have been determined in
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`a single in vivo study and the three Examples retrospectively constructed.”).
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`Third, there is nothing surprising or even novel about a formulation of the
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`recited actives with a pH of 3.5, because this is the pH of the prior art Suboxone
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`tablets. See Ex. 1004, Reitman Decl. at ¶5. The pH of the prior art Suboxone
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`tablets can be readily determined. Applicant appears to have been in a particularly
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`unique position to know the pH the Suboxone tablet, at least because it had
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`quantities of the tablets that it used as a control, and because it had manufactured
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`and sold the Suboxone tablets for many years.
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`In short, there is nothing surprising about copying the pH of a tablet one is
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`attempting to copy in film dosage form.
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`C. The ‘832 patent was allowed in a haze of confusing definitions and
`incorrect arguments.
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`Throughout prosecution, the examiner rejected challenged claims 15-19 as if
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`they recited the pH range recited in claims 1-14. See Ex. 1006, First OA, at ¶12
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`(“Furthermore, the cited reference does not teach the specific range of pH recited
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`in the instant claims [all pending claims including issued claims 15-19]”); Ex.
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`1008, Second OA, at ¶14 (referring to the “pH recited in the instant claims”); and
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`Ex. 1010, Third OA, at ¶6 (“Applicants traversed the instant rejection on the
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`grounds that [Euro-Celtique] does not disclose the pH range recited in the instant
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`claims [claims that include issued claims 15-19] . . . .”).
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`The Applicant repeatedly argued during prosecution that the pH range was
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`surprising because it “minimizes the absorption of the naloxone but optimizes the
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`absorption of the buprenorphine”—suggesting that the absorption of naloxone was
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`being decreased and the absorption of buprenorphine was being increased by
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`lowering the pH. See Ex. 1011, Third Response, at 6:6-9; Ex. 1009, Second
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`Response, at 10:10-14. But, in fact, the relevant definitions and examples reveal
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`that there is nothing surprising because the Applicant was seeking to inhibit the
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`absorption of both naloxone and buprenorphine to copy Suboxone tablets.
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`Applicant appears to have been confused by its own confusing definitions
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`and arguments. Applicant bases its “surprising” result on the premise that “[b]oth
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`compounds are conjugate organic acids with pKa’s at approximately 8, and yet as
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`Patent No. 8,475,832
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`the pH of the film for delivering the agents decreases, one compound undergoes a
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`optimum absorption, but the other compound surprisingly trends in the opposite
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`direction and is inhibited at the same lower pH levels.” Ex. 1011, Third Response,
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`at 7:2-6. Contrary to the Applicant’s suggestion, Examples 7 and 8 show that, as
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`the buffered pH is lowered from 5-5.5 to 3-3.5, both compounds trend in the same
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`direction and to a remarkably similar degree. See Ex. 1001, ‘832 patent, at 20:1-
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`23:11. In particular, the Cmax of buprenorphine decreases from 3.47 to 2.68
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`ng/mL (i.e., a reduction to 77% of the previous value) and the Cmax of naloxone
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`decreases from 173 to 130 pg/mL (i.e., a reduction to 75% of the previous value).
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`Id. The compounds’ absorption did not “surprisingly” trend in the opposite
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`direction, but rather both trended in the same direction. Indeed, the facts in the
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`‘832 patent specification demonstrate that the compound trending from 5-5.5 to 3-
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`3.5 is consistent in both direction and degree.
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`This line of argument—clearly incorrect, even according to the Applicant’s
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`own specification—seems to have confused and ultimately convinced the
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`examiner:
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`Applicants explained that the prior art is silent regarding the use
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`of a buffer to provide a local pH which would achieve
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`optimized absorption of buprenorphine and naloxone. The
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`examiner agreed that the prior art does not teach the claimed
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`local pH.
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`(Ex. 1012, NOA, at 7.)
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`In short, the ‘832 patent was allowed in a haze of confusion and incorrect
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`arguments. Had the Office understood the full picture—not only that Applicant’s
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`arguments were incorrect, but also that the prior art is not silent with respect to the
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`use of buffers and pH to provide adjust absorption of the actives, such as
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`buprenorphine—these claims would not have been allowed.
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`D. The alleged novelty of the challenged claims is contradicted by the
`‘832 patent specification.
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`It is not known why claims 15-19 were allowed, as they do not recite the pH
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`range that the Office relied upon in allowing the claims. But see Ex. 1007, First
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`Response, at 7 (Applicant misleadingly stating “the claims have been amended to
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`recite a particular local pH value and/or to recite that the buffer optimizes
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`absorption of buprenorphine while also inhibiting absorption of the naloxone”—
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`when the claim that issued as claim 15 included no such limitations). At the very
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`end of prosecution, despite having previously responded to rejections of the claims,
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`Applicant explicitly took the position that challenged claims 15-19 were never
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`examined: “These claims have not been addressed in any of the art rejections,
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`except by number. Thus, the limitations of these claims have never been addressed
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`by the Examiner.” Ex. 1011, Third Response, at 11:1-10.
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`Patent No. 8,475,832
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`Applicant then proceeds to identify its own reason why the claims were
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`allegedly patentable: that they recited a Cmax range for naloxone. Specifically,
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`Applicant argued that “while [Euro-Celtique] does discuss the Cmax for
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`buprenorphine, it is completely silent as to the Cmax for naloxone.” Id. at 11:9-10.
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`But Euro-Celtique very clearly discloses that the absorption parameters of
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`Suboxone tablets (which include both buprenorphine and naloxone) are known and
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`expected in its inventive preparations. See Ex. 1018, Euro-Celtique, at 21:8-12.
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`The absorption parameters of Suboxone tablets, of course, explicitly anticipate a
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`range that is 80-125% of its absorption parameters. Applicant, once again, appears
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`to have been confused or have forgotten the basis of its claimed range.
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`As explained in the ‘832 patent, the Cmax and AUC ranges recited in the
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`challenged claims are by design 80-125% of the ranges of Suboxone tablets (and
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`therefore anticipated by the Suboxone tablets). See Ex. 1001, ‘832 patent, at 17:2-
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`40 (Example 3). Whether Euro-Celtique states the actual 80-125% ranges is
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`irrelevant. The recited ranges are still anticipated by those of the Suboxone tablets
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`they were calculated to encompass.
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`In short, the recited Cmax range—relied upon by Applicant during
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`prosecution as allegedly providing novelty—is, by design, anticipated by the prior
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`art Suboxone tablets and art disclosing films with absorption equivalent to the prior
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`art Suboxone tablets. There are no other recitations that could possibly confer
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`Patent N