UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________
`
`BIODELIVERY SCIENCES INTERNATIONAL, INC.
`Petitioner
`
`v.
`
`RB PHARMACEUTICALS LIMITED
`Patent Owner.
`
`____________________
`
`Case IPR2014-00325
`Patent 8,475,832
`____________________
`
`DECLARATION OF PROFESSOR THOMAS P. JOHNSTON
`IN SUPPORT OF PATENT OWNER’S RESPONSE
`
`Page 1
`
`RB Ex. 2003
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________
`
`BIODELIVERY SCIENCES INTERNATIONAL, INC.
`Petitioner
`
`v.
`
`RB PHARMACEUTICALS LIMITED
`Patent Owner.
`
`____________________
`
`Case IPR2014-00325
`Patent 8,475,832
`____________________
`
`DECLARATION OF PROFESSOR THOMAS P. JOHNSTON
`IN SUPPORT OF PATENT OWNER’S RESPONSE
`
`Page 1
`
`RB Ex. 2003
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`
`
`
`I, Thomas P. Johnston, Ph.D., hereby declare as follows:
`
`I have been retained by counsel for Patent Owner RB Pharmaceuticals
`
`1.
`
`2.
`
`Limited and its licensee, Reckitt Benckiser Pharmaceuticals Inc. (“RBP”) as an
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`expert in pharmaceutical science to address topics relevant to the subject matter of
`
`this inter partes review proceeding involving certain claims U.S. Patent No
`
`8,475,832 (Ex. 1001; the “ʼ832 patent”). I am being compensated at the rate of $400
`
`per hour. My compensation is in no way dependent on the outcome of this case
`
`I.
`
`SUMMARY OF QUALIFICATIONS
`
`3.
`
`4.
`
`My curriculum vitae is Ex. 2004.
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`I am a tenured Full Professor of Pharmaceutics in the Division of
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`Pharmaceutical Sciences at the University of Missouri-Kansas City School of
`
`Pharmacy.
`
`5.
`
`I received a Bachelor of Science degree in Pharmacy and a Ph.D. in
`
`Pharmaceutics from the University of Minnesota in 1980 and 1987, respectively.
`
`6.
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`I held a joint-appointment as a Post-Doctoral Research Fellow from
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`1987-1988 in the Department of Pediatric Cardiology, the University of Michigan
`
`Medical School and the Department of Pharmaceutics, the University of Michigan
`
`College of Pharmacy.
`
`7.
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`I was an Associate Professor of Pharmaceutics in the Division of
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`Pharmaceutical Sciences at the University of Missouri-Kansas City School of
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`Pharmacy from 1995 until I obtained my current position in 2008. From 1988 to
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`1994, I was an Assistant Professor of Pharmaceutics in the Department of
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`Pharmaceutics and Pharmacodynamics at the University of Illinois College of
`
`Pharmacy.
`
`8.
`
`I have presented scientific lectures at a number of institutions as well
`
`as to the United States Food and Drug Administration. These lectures have focused
`
`on dissolution, stability, pharmacokinetics, and in vitro/in vivo correlation of
`
`pharmaceuticals.
`
`9.
`
`I was awarded the Rho Cho Pharmacy Honor Society Faculty Member
`
`of the Year award in March 2008. I was awarded Outstanding Teacher of the Year
`
`in November 2007 and 2013 at the University of Missouri-Kansas City and in May
`
`of 1994 and 1990 at the University of Illinois College of Pharmacy. In July 2002, I
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`was designated as a Master Instructor in the field of pharmaceutics by the American
`
`Association of Colleges of Pharmacy. I was also cited as an Outstanding
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`Pharmaceutical Educator at an American Association of Colleges of Pharmacy
`
`meeting in July 1994. My other scientific honors and awards are listed in my
`
`curriculum vitae, which also includes a list of my publications, presentations at
`
`scientific meetings, and professional and honorary memberships.
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`10. My research has resulted in more than 90 peer-reviewed published
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`research papers, 10 book chapters and encyclopedia contributions, and
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`approximately 100 presentations at scientific meetings to national and international
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`audiences.
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`11.
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`Over the course of my career, I have 29 years of experience teaching
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`and conducting pharmaceutical research, including a specialization in the oral
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`transmucosal delivery of conventional and polypeptide drugs through the buccal
`
`mucosa.
`
`12.
`
`I have contributed five book chapters that describe the anatomy and
`
`physiology of the oral cavity as it pertains to the administration of small molecule
`
`organic drug as well as peptidic compounds. In particular, I published a book
`
`devoted to buccal drug delivery: T.P. Johnston and P.P. Bhatt, Buccal Drug
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`Delivery, Technomic Co., Lancaster, PA, pp. 1-315, 1996. Also, my most recent
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`book chapter, which will be published in late 2014, or early 2015, is entitled,
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`“Anatomy and physiology of the oral mucosa and its relevance to local and systemic
`
`oral mucosal drug delivery”, Chapter 1, In: Oral Mucosal Drug Delivery and
`
`Therapy.
`
`13.
`
`I am familiar with how pharmaceutical film dosage forms are
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`prepared/manufactured, administered, and subsequently evaluated both in vitro and
`
`in vivo, including the interpretation of pharmacokinetic data arising from said
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`testing. I am also familiar with drug absorption by the sublingual and/or buccal
`
`mucosa in the oral cavity, which includes the effects of pH modifiers, routes of drug
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`transport, potential depot effects, relevant anatomy and physiology of the oral cavity,
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`mucoadhesion of dosage forms intended for oral transmucosal drug delivery, and the
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`relevant pharmacokinetics after the drug has been absorbed and enters the
`
`bloodstream so as to produce a plasma concentration-time profile. I am also familiar
`
`with the pharmacokinetics associated with drug input by other routes of drug
`
`administration. I have evaluated numerous dosage forms for drug delivery through
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`the mucosa in the oral cavity, including various types of tablets, solutions, hydrogels
`
`and films.
`
`II. MATERIALS CONSIDERED
`
`14.
`
`In reaching the conclusions set forth below, I have relied on my close
`
`to three decades of experience in pharmaceutical studies and have specifically
`
`considered the ʼ832 patent, its file history, relevant portions of BioDelivery Sciences
`
`International, Inc.’s (“BDSI”) 1/15/2014 Petition for IPR (Paper 8; the “Petition”),
`
`the Board’s 7/29/2014 Institution Decision (Paper 17), and the other materials cited
`
`below.
`
`III. UNDERSTANDNG OF THIS PROCEEDING
`
`15.
`
`I understand that this is an inter partes review (“IPR”) proceeding
`
`conducted before the Patent Trial and Appeal Board (“Board”) of the U.S. Patent
`
`and Trademark Office (“PTO”) to determine if claims 15-19 of the ʼ832 patent (the
`
`challenged claims) should be cancelled as unpatentable. I understand that BDSI
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`5
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`Page 5
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`requested institution of this proceeding through a Petition dated January 15, 2014,
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`and that the Petition asserted that the challenged claims of the ʼ832 patent are
`
`anticipated by three references and also invalid as obvious over nine combinations of
`
`references. Pet. at 26-56. The Petition also asserted claim constructions for two
`
`claim terms. Pet. at 14-22. The Petition was accompanied by declarations by
`
`Maureen Reitman, Sc.D. and Phillip T. Lavin, Ph.D.1
`
`16.
`
`I understand that on April 30, 2014 Patent Owner submitted a
`
`Preliminary Response in opposition to BDSI’s Petition.
`
`17.
`
`I understand that the Board, in a decision on July 29, 2014 (the “Inst.
`
`Dec.”), decided to institute an IPR, but only on two of the twelve grounds proposed
`
`in the Petition. Inst. Dec. at 21. The first ground on which the IPR was instituted is
`
`that International Patent Publication No. 2008/040534 (Ex. 1017) referred to in this
`
`proceeding as Labtec allegedly anticipates the challenged claims of the ʼ832 patent.
`
`The second ground on which the IPR was instituted is that the challenged claims of
`
`1 I have not specifically addressed the Reitman and Lavin declarations here
`
`because I understand and am advised that neither declaration addressed the
`
`references (Labtec, Yang, Birch) which provide the Grounds on which the Board
`
`instituted trial in this proceeding and neither declaration was relied on i) in the
`
`Petition with respect to the Grounds on which the Board instituted, or ii) by the
`
`Board in instituting the on the Grounds that are now in issue.
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`6
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`Page 6
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`
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`the ʼ832 patent are obvious over Labtec in view of U.S. Patent No. 7,357,891 to
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`Yang et al., (Ex. 1016; “Yang”) and U.S. Patent Publication No. 2005/0085440 to
`
`Birch et al., (Ex. 1019; “Birch”).
`
`18.
`
`I understand that the Board has not made any determination that the
`
`challenged claims are in fact anticipated or obvious; the Board has only determined
`
`that, on the record then before it, BDSI’s Petition satisfied the threshold standard for
`
`instituting this proceeding, by showing a “reasonable likelihood that Petitioner
`
`would prevail in establishing the unpatentability” of the challenged claims based on
`
`its assertion of anticipation by Labtec and obviousness over the combination of
`
`Labtec, Yang, and Birch. Inst. Dec. 21. (Conversely, I also understand that the
`
`Board has not made any decision as to whether the ʼ832 patent is valid over the other
`
`ten alleged invalidity Grounds proposed by BDSI in the Petition; I understand only
`
`that the Board declined to institute an IPR on those Grounds, deeming them
`
`redundant in light of the Ground presented by Labtec, Yang, and Birch.)
`
`19.
`
`In view of the limited Grounds on which the Board instituted my
`
`Declaration is correspondingly limited to addressing relevant background
`
`pharmacological information about the two actives referred to in the challenged
`
`claims, buprenorphine and naloxone, a related issue of claim construction,
`
`anticipation based on Labtec, and obviousness over Labtec in view of Yang and
`
`Birch.
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`7
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`Page 7
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`20.
`
`I understand that the Board’s decision also provided constructions of
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`the two claim terms BDSI raised in its Petition. I agree that the Board’s construction
`
`is consistent with how one of ordinary skill in the art in 2009 would understand the
`
`claim terms in dispute. Specifically, I agree with the Board’s rejection of
`
`Petitioner’s proposed claim constructions for the terms “film formulation” and
`
`“provides an in vivo plasma profile” and adoption of the constructions proposed by
`
`Patent Owner. Paper 17, 7-12. In particular, I understand the Board construed the
`
`term “‘film formulation’ as encompassing film dosage, film composition, or film,
`
`but not a formulation that is not in the form of a film.” Id. at 11. The Board also
`
`agreed with Patent Owner that the term “provides an in vivo plasma profile” does
`
`not need to be construed beyond its ordinary meaning. Id. at 12.
`
`IV. LEGAL PRINCIPLES APPLIED AND LEVEL OF SKILL
`
`21.
`
`I am advised that in an inter partes review, as stated in the Institution
`
`Decision, the Board interprets claim terms according to their broadest reasonable
`
`construction in light of the specification of the patent in which they appear. The
`
`terms also are given their ordinary and customary meaning as would be understood
`
`by one of ordinary skill in the art in the context of the disclosure. Paper 17, 7.
`
`22.
`
`For purposes of claim construction, I understand that the ʼ832 patent
`
`must be read from the perspective of a person of ordinary skill in the relevant art at
`
`the time the invention was made, which here is approximately 2009—the earliest
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`8
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`Page 8
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`
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`filing date listed on the face of the patent is August 7, 2009. I understand the person
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`of ordinary skill in the art is a hypothetical person who is presumed to know the
`
`relevant art at the time of the invention.
`
`23.
`
`The subject to which the ʼ832 patent is directed is an oral
`
`transmucosal film dosage that is substantially bioequivalent to Suboxone® tablets, a
`
`drug product containing two actives, buprenorphine and naloxone, used to treat
`
`opioid dependence. The challenged claims specifically recite either Cmax or AUC
`
`ranges relating to in vivo bioavailability of those actives. Therefore, the person(s) of
`
`ordinary skill to whom the patent is directed would need to have a good
`
`understanding of at least: i) orally dissolving pharmaceutical films; ii) the
`
`pharmacokinetics of buprenorphine and naloxone; iii) the therapeutic objectives of
`
`treatment with Suboxone® tablets; and iv) how to interpret in vivo bioavailability
`
`data.
`
`24.
`
`In my opinion, the person(s) of ordinary skill in the art to whom the
`
`ʼ832 patent is directed would have a good working understanding of these subjects
`
`and a Ph.D. or its equivalent in pharmaceutics or pharmaceutical science or a related
`
`field, and at least two years of experience in developing and formulating dosage
`
`forms for drugs. Alternatively, this person or persons could have had a good
`
`working understanding of these subjects and a Bachelor’s or Master’s Degree in an
`
`appropriate field and substantially more practical experience in developing and
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`9
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`Page 9
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`formulating dosage forms for drugs. I understand that to anticipate a patent claim, a
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`single prior art reference must disclose every claimed element arranged as in the
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`claim, and must enable one of ordinary skill in the art at the time to make the
`
`claimed subject matter. I also understand that the disclosure can be express or
`
`inherent in the prior art reference, but that inherent anticipation can only be
`
`established when prior art necessarily includes or produces the claimed limitations.
`
`25.
`
`I understand that a prior art reference taken by itself or combined with
`
`one or more other prior art references can render a patent claim obvious to one of
`
`ordinary skill in the art if the differences between the subject matter set forth in the
`
`patent claim and the prior art are such that the subject matter of the claim would
`
`have been obvious at the time the claimed invention was made. In analyzing
`
`obviousness, I understand that it is important to consider the scope of the claims,
`
`the level of skill in the relevant art, the scope and content of the prior art, and the
`
`differences between the prior art and the claims. I understand that so-called
`
`secondary considerations of non-obviousness, such as commercial success of the
`
`commercial product covered by the claims of the patent-in-issue, can also be
`
`considered in analyzing obviousness.
`
`26.
`
`I also understand that in assessing whether a claim is obvious one
`
`must consider whether the claimed improvement was reasonably predictable or
`
`that the person of ordinary skill would have a reasonable expectation of success in
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`making or producing the subject matter of the patent claims in dispute using not
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`more than routine experimentation, as opposed to what I understand is referred to
`
`as undue experimentation. I further understand that a person of ordinary skill is a
`
`person of ordinary creativity, but that obviousness cannot be based on the hindsight
`
`combination of components selectively culled from the prior art.
`
`27.
`
` In addition, I understand that in considering obviousness and the
`
`issues of reasonable expectation of success and routine experimentation, it is
`
`relevant to consider whether the prior art includes references that “teach away”
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`from the claimed invention or that “teach away” from using certain approaches in
`
`attempting to achieve or obtain the claimed invention, such as by discouraging the
`
`person of ordinary skill to take that approach. Also, I am informed that changing
`
`the basic principles of operation of a primary reference relied on as allegedly
`
`rendering a claimed invention obvious is indicative of a nonobvious modification.
`
`V.
`
`SUMMARY OF OPINIONS
`
`28.
`
`In my opinion, Labtec does not anticipate any of the challenged
`
`claims (i.e., 15-19) of the ʼ832 patent. My opinion in this regard, as discussed
`
`further below, rests on at least five grounds.
`
`29. First, Labtec does not anticipate Claims 15-19 of the ʼ832 patent
`
`because it would be evident to one of ordinary skill in the art that the claimed
`
`dosage form requires the film product to be an oral transmucosal film and that the
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`11
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`Page 11
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`
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`pharmacokinetic ranges recited in those claims resulted from oral transmucosal
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`absorption, while Labtec squarely involves only a peroral GI absorption dosage
`
`form.
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`30. Second, Labtec does not anticipate claims 15-19 of the ʼ832 patent
`
`because, as the skilled person would appreciate, Labtec’s inclusion of Suboxone®
`
`(and Subutex®) tablets in Table A was clearly a mistake. Labtec is directed to
`
`orally dissolving film formulations that are supposed to deliver their drug product
`
`using the same metabolic pathway and using the same dosage amounts as the
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`innovator drug and focuses on delivery of a drug for absorption in the GI tract,
`
`while attempting to avoid absorption through the oral mucosa. All of the brand
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`drug products listed in Table A in Labtec are meant to be absorbed in the GI tract,
`
`with the exception of Subutex® tablets and Suboxone® tablets both of which
`
`contain buprenorphine and are sublingual products that deliver buprenorphine
`
`through the oral mucosa.
`
`31. Third, Labtec does not anticipate claims 15-19 of the ʼ832 patent
`
`because it would be evident to one of ordinary skill in the art that the Cmax and
`
`AUC values provided for buprenorphine (and naloxone) in claims 15-19 are
`
`scientifically unattainable with the dosage form as taught by Labtec using the
`
`corresponding Suboxone® tablet dosage amounts. In particular, Labtec requires its
`
`peroral dosage form to “contain[e] the same amount of active pharmaceutical
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`12
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`Page 12
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`
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`agent” as the brand name product. Ex. 1017, 12. Due to its much lower
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`bioavailability, peroral delivery of a given amount of buprenorphine or naloxone
`
`cannot possibly give close to the same or substantially bioequivalent Cmax and
`
`AUC values (80-125%) compared to oral-transmucosal delivery of the same
`
`amounts of those active ingredients.
`
`32. Fourth, Labtec does not anticipate claims 15-19 of the ʼ832 patent
`
`regardless of whether the challenged claims are read as being directed to oral
`
`mucosal absorption because the film dosage form as taught by Labtec is not
`
`therapeutically acceptable to treat opioid dependence due to buprenorphine’s
`
`extensive first-pass effects and resulting poor bioavailability and expected
`
`increased inter- and intra-patient variability.
`
`33. Finally, dependent claim 19 cannot be anticipated for the additional
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`and independent reason that, due to the first pass-effects that relate to naloxone, the
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`literature indicates that it is infeasible to achieve the required Cmax values recited in
`
`claim 15 with the mg dosage amounts of naloxone recited in claim 19.
`
`34.
`
`In my opinion, the challenged claims of the ʼ832 patent (i.e., 15-19)
`
`are not invalid as obvious over Labtec in view of Yang and Birch. My opinion in
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`this regard, as discussed further below, is based on at least the following.
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`35. First, Labtec does not render obvious claims 15-19 of the ʼ832 patent
`
`because it would be evident to one of ordinary skill in the art that the challenged
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`13
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`Page 13
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`
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`claims require the recited film to provide, and the recited pharmacokinetic ranges to
`
`result from, oral transmucosal absorption, while Labtec’s route of administration
`
`excludes oral transmucosal absorption and is limited to a peroral dosage form
`
`intended only to provide absorption in the GI-tract. Therefore, Labtec not only does
`
`not teach a film product that meets the limitations of the challenged claims but it
`
`expressly excludes film products that provide the necessary oral transmucosal route
`
`of administration required by those claims.
`
`36. Second, regardless of whether the challenged claims are read as
`
`requiring oral transmucosal absorption, the person of ordinary skill in the art at the
`
`time seeking to design an oral buprenorphine dosage form would never have been
`
`motivated to look to Labtec in the first place. Labtec’s proposed oral films, which
`
`are solely designed to provide GI absorption (the opposite of oral mucosal delivery),
`
`would have been recognized to be inappropriate, therapeutically unacceptable, for
`
`the delivery of buprenorphine. Therefore, the person of ordinary skill in the art
`
`interested in attempting to research and develop the claimed films would have
`
`disregarded Labtec as having included Suboxone® tablets in its Table A list of brand
`
`name products by mistake, recognizing that it would not be therapeutically
`
`acceptable to design a buprenorpine-containing film solely intended to provide
`
`absorption in the gut.
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`Page 14
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`37. Third, Yang provides no teaching as to how to formulate a film to
`
`ensure that it provides the desired absorption levels of the active ingredients, i.e.,
`
`there is no disclosure of how to ensure the resulting film provides a bioequivalent
`
`effect of a specific tablet. Yang especially does not provide any disclosure of how to
`
`control absorption of actives through the oral mucosa, or specifically how to obtain a
`
`desired level of buprenorphine oral mucosal absorption while achieving a certain
`
`level of inhibition of the oral mucosal absorption of naloxone—neither of which are
`
`specifically discussed in Yang. Moreover Yang does not disclose any embodiment
`
`of a film formulation containing buprenorphine and naloxone and does not even
`
`mention buprenorphine or naloxone as an active ingredient.
`
`38. Fourth, Birch is directed to an aqueous solution for intranasal
`
`administration of buprenorphine for analgesic purposes. Birch has nothing to do
`
`with pharmaceutical film formulations, or with buprenorphine and naloxone to treat
`
`addiction, and doesn’t even mention naloxone. Pharmacokinetic parameters, such as
`
`Cmax, AUC, and tmax would be expected to be very different for nasal administration
`
`than after administration via the oral cavity. For these reasons, the person of
`
`ordinary skill in the art would not look to Birch in the context of a pharmaceutical
`
`film to be administered in the oral cavity, including one containing buprenorphine
`
`and naloxone.
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`15
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`Page 15
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`39. Fifth, Labtec in view of Yang and Birch does not render claims 15-19
`
`of the ʼ832 patent obvious because a person of ordinary skill in the art would have
`
`no motivation to combine Labtec with Yang or Birch because it would be clear to a
`
`person of ordinary skill in the art as of 2009 that the only therapeutically acceptable
`
`way to arrive at the claimed invention would be to abandon the peroral GI
`
`absorption route mandated by Labtec in favor of the opposite approach–a film for
`
`oral mucosal absorption.
`
`40. Finally, even if the skilled person disregarded Labtec’s central
`
`teaching that relies solely on GI-absorption and excludes oral transmucosal
`
`absorption and, nevertheless tried to make a film intended to provide oral mucosal
`
`delivery, the combination of Labtec, Yang and Birch would not have rendered the
`
`challenged claims obvious because it would have taken far more than routine
`
`experimentation to achieve the claimed films. None of the references come close to
`
`suggesting, much less teaching, how to make a pharmaceutically acceptable film that
`
`provides the Cmax or AUC values for buprenorphine and naloxone recited in the
`
`challenged claims of the ʼ832 patent. The experimentation that would have been
`
`required to get this combination to work given, among other things, that oral
`
`pharmaceutical film formulation technology is a relatively recent and emerging art,
`
`the multitude and interrelationship of factors, parameters and variables to be chosen,
`
`the extensive testing required, including through in vivo testing in humans, and the
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`16
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`lack of any buprenorphine and/or naloxone film in the prior art, would have been far
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`beyond just tinkering or small changes , and instead would have required undue
`
`experimentation to arrive at the claimed films with the combination of these three
`
`references in hand.
`
`VI. BACKGROUND REGARDING BUPRENORPHINE DOSAGES AND
`PHARMACOKINETICS
`
`41. Particularly given the fact that Labtec, which is limited to a peroral
`
`delivery route, where an oral film dissolves in the mouth and is swallowed for
`
`absorption in the GI tract, has been put forward as the basis for both anticipation
`
`and obviousness arguments in regard to claims 15-19 of the ʼ832 patent, I think it
`
`is important for the Board to understand, as would a skilled person with regard to
`
`the subject matter of the ʼ832 patent, some of the important pharmaceutical and
`
`therapeutic constraints involved with administering an oral dosage formulation of
`
`buprenorphine.
`
`42. Buprenorphine is in many respects an ideal drug for the treatment for
`
`opioid dependence. It was synthesized decades ago in an attempt to develop novel
`
`analgesics with lower abuse potential and with reduced toxicity as compared with
`
`morphine. See Ex. 2005, Lewis and Readhead, “Novel analgestics and molecular
`
`rearrangements in the morphine-thebaine group. XVIII. 3- deoxy-6,14-endo-
`
`etheno-6,7,8,14-tetrahydrooripavines,” J Med Chem 13:525-7, (1970). Although
`
`buprenorphine exhibits high-affinity binding and high potency, it exhibits lower
`
`17
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`Page 17
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`
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`efficacy for pain relief and is, therefore, considered to be a mu-(µ)-opiate receptor
`
`partial agonist. Buprenorphine also exhibits a slow dissociation from opiate
`
`receptors, which results in a longer duration of action. All of these characteristics
`
`together make it a preeminent drug for the treatment of opioid dependence.
`
`43.
`
`It was well understood by one of ordinary skill in the art as of 2009,
`
`indeed, it had been known for years, that it is not therapeutically acceptable to
`
`administer buprenorphine perorally due to its poor peroral bioavailability as a result
`
`of an extensive first-pass metabolism effect. See e.g., Ex. 2006, Stoller et al.,
`
`“Effects of buprenorphine/naloxone in opioid-dependent humans,”
`
`Psychopharmacology 154:230-242, 230 (2001) (“Stoller”). Thus, as has been stated
`
`with respect to buprenorphine in the context of information concerning Suboxone ®
`
`tablets:
`
`When taken orally, buprenorphine undergoes first-pass metabolism
`with N-dealkylation and glucuroconjugation in the small intestine and
`the liver. The use of SUBOXONE by the oral route is therefore
`inappropriate. SUBOXONE tablets are for sublingual administration.
`
`
`Ex. 2007, SUBOXONE® Tablet Data Sheet, 2006 at 2: See also, Ex. 2008, U.S.
`
`patent No. 4,464,378, 2:6-9 (“Virtually all of the members of the groups of
`
`morphine analogues [which includes buprenorphine] discussed supra are well-
`
`18
`
`Page 18
`
`
`
`absorbed by injection, but are rarely used orally because of inefficient and variable
`
`absorption by that route.”).2
`
`2 See also, Stoller, Ex. 2006, 230; Ex. 2009, Brewster et al., “The systemic
`
`bioavailability of buprenorphine by various routs of administration,” J. Pharm.
`
`Pharmacol. 33:500-506, 504-5 (1981) (“Brewster”); Ex. 2010, Bullingham et al.,
`
`“Sublingual buprenorphine used postoperatively: ten hour plasma drug
`
`concentration analysis,” Br. J. Clin. Pharmac. 13:665-673, 665 (1982)
`
`(“Bullingham 1982”); Ex. 2011, Kuhlman et al., “Human pharmacokinetics of
`
`intravenous, sublingual, and buccal buprenorphine,” Journal of Analytical
`
`Toxicology 20:369-378, 369 (1996); Ex. 2012, Mendelson et al., “Bioavailability
`
`of sublingual buprenorphine,” J. Clin. Pharmacol. 37:31-37, 31 (1997)
`
`(“Mendelson 1997”); Ex. 2013, Robinson, “Buprenorphine: An analgesic with an
`
`expanding role in the treatment of opioid addiction,” CNS Drug Reviews 8:377-
`
`390, 381 (2002); Ex. 2014, Chiang and Hawks “Pharmacokinetics of the
`
`combination tablet of buprenorphine and naloxone,” Drug and Alcohol
`
`Dependence 70:S39-S47, S40 (2003) (“Chiang”); Ex. 2015, Harris et al,
`
`“Pharmacokinetics and subjective effects of sublingual buprenorphine alone or in
`
`combination with naloxone,” Clin. Pharmacokinet. 76:329-340, 330 (2004); Ex.
`
`2016, Elkader and Sproule “Buprenorphine Clinical pharmacokinetics in the
`
`treatment of opioid dependence,” Clin. Pharmacokinet. 44:661-680, 663 (2005)
`
`19
`
`Page 19
`
`
`
`44.
`
`In particular, as with other phenolic opioids, buprenorphine is
`
`metabolized in the gastrointestinal track via extensive conjugation within the
`
`intestinal mucosa. See Ex. 2018, Rance and Shillingford “The metabolism of
`
`phenolic opiates by rat intestine,” Xenobiotica 7:529-536, 534 (1977) (“Rance”);
`
`and Brewster, Ex. 2009, 502-203. Furthermore, buprenorphine undergoes
`
`extensive hepatic oxidative metabolism by cytochrome P450 3A4/5 and 2C8
`
`isoenzymes. See Ex. 2019, Iribarne et al., “Involvement of cytochrome P450 3A4
`
`in n-dealkylation of buprenorphine in human liver microsomes,” Life Sci. 60:1953-
`
`64 (1997) (“Iribarne”); Ex. 2020, Chang et al., “Novel metabolites of
`
`buprenorphine detected in human liver microsomes and human urine,” Drug
`
`Metab. and Disp. 34:440-448, 446 (2006) (“Chang”). In fact, animal studies have
`
`estimated that the first-pass clearance of buprenorphine during passage across the
`
`gut mucosa is roughly 80 %. See Brewster, Ex. 2009, 502-504. Moreover, even
`
`without taking the first-pass clearance via the gut mucosa into consideration,
`
`hepatic first-pass clearance is estimated to be in the order of 50 %. Id. at 502-503.
`
`As a consequence, if buprenorphine is administered perorally, it passes through the
`
`
`(Elkader); Ex. 2017, Welsh and Valadez-Meltzer “Buprenorphine: a (relatively)
`
`new treatment for opioid dependence,” Psychiatry (Edgmont) 2:29-39, 32 (2005)
`
`(“Welsh”).
`
`20
`
`Page 20
`
`
`
`gut mucosa where it is metabolized significantly and is then delivered directly to
`
`the liver via the hepatic portal circulation where it undergoes further metabolism.
`
`45. Due to buprenorphine’s very high first-pass effect, some report that
`
`peroral administration of buprenorphine results in essentially no buprenorphine
`
`reaching the systemic circulation. Specifically, it is reported that the extraction
`
`efficiency (i.e., EE) would be close to 1 because the clearance of buprenorphine is
`
`very close to the expected blood flow to the liver. See Ex. 2021, Bullingham et al.,
`
`“Buprenorphine kinetics” Clin. Pharmacol. 28:667-672, 670-671 (1980)
`
`(“Bullingham 1980”). One of ordinary skill understands that absolute
`
`bioavailability (i.e., F) can be calculated as F = 1 – EE, which would lead to an
`
`absolute peroral bioavailability of close to 0.
`
`46. Other references estimate that the absolute bioavailability of peroral
`
`buprenorphine is as little as 10 – 15 %. See Bullingham 1982, Ex. 2010, 670 (a
`
`mean peroral bioavailability of 15% or less); Welsh, Ex. 2017, 32 (a mean peroral
`
`bioavailability of 10%). Thus, because of the extensive conjugation of
`
`buprenorphine within the intestinal mucosa and high extraction efficiency for
`
`buprenorphine by the liver very little of perorally administered buprenorphine
`
`enters the systemic circulation, thus making the peroral route inappropriate for the
`
`treatment of opioid dependence.
`
`21
`
`Page 21
`
`
`
`47. Even if it were feasible to overcome buprenorphine’s discernible first-
`
`pass metabolic effect by giving large peroral doses, such an approach would not be
`
`therapeutically acceptable due to efficacy concerns arising out of the increased
`
`inter- and intra-patient variability that one of ordinary skill would reasonable
`
`expect, particularly with opioid dependent patients.3 In fact, roughly 1/3 of
`
`patients who take buprenorphine by the peroral route have absolutely no detectable
`
`amounts of buprenorphine in the systemic circulation. See Exh. 2022, McQuay and
`
`Moore “Buprenorphine Kinetics in Humans,” In: Buprenorphine: Combatting
`
`Drug Abuse With A Unique Opioid Cowan, Lewis (Eds.) (1995) pp. 137-147, 140-
`
`41, Table II (showing that, when a group of 6 patients were given a peroral dose of
`
`0.4 mg buprenorphine, 2 had no detectable Cmax values).
`
`
`3 Buprenorphine is a potent opioid which can cause serious side effects, including
`
`withdrawal and nausea, as well as more serious consequences.
`
`
`
`22
`
`Page 22
`
`
`
`48. On the other hand, when administered by the oral transmucosal route,
`
`the person of ordinary skill would expect the results to be far more consistent
`
`among all patients in the target population. For example, Mendelson et al. reported
`
`mean value of about 30% bioavailability by the sublingual route, with a tight range
`
`of variation between patients of only 28% to 36%. Mendelson 1997, Ex. 2012,
`
`35.4
`
`49.
`
`In contrast with oral mucosal absorption, a person of ordinary skill in
`
`the art at the time would expect that administe
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