`
`
`
` Paper No. __
`Filed: November 7, 2014
`
`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
`____________________
`
`PATENT OWNER’S RESPONSE
`
`
`
`

`

`TABLE OF CONTENTS
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`Page
`I. INTRODUCTION .......................................................................................... 1
`II. BUPRENORPHINE PHARMACOKINETICS BACKGROUND .............. 10
`III. CLAIM CONSTRUCTION .......................................................................... 17
`A. Legal Standard For Claim Construction In Inter Partes Review .................. 18
`B. Claim 15’s “Wherein” Clause Is Entitled To Patentable Weight ................ 18
`C. The ‘832 Patent Solely Concerns Oral Transmucosal Absorption ............... 20
`IV. CLAIMS 15-19 OF THE ’832 PATENT ARE NOT ANTICIPATED BY
`LABTEC 26
`A. Labtec Proposes Only Oral Films Designed To Provide GI Absorption To
`Mimic The Pharmacokinetics Of Peroral GI-Absorbed Dosages ................ 27
`B. Labtec Does Not Anticipate Because It Does Not Disclose Oral-
`Transmucosal Films As Required By The Properly Construed Claims ....... 29
`C. Labtec Does Not Anticipate Because It Only Discloses A Wish Or A Goal
`And Not The Claimed Film .......................................................................... 30
`D. Labtec Does Not Anticipate Because It Fails To Enable The Claimed
`Invention ....................................................................................................... 32
`1. Labtec Only Proposes A Film Version Of Suboxone® Tablets By
`Mistake 32
`2. Even If The Claims Are Not Limited To Oral-Transmucosal Films,
`Labtec Is Inoperable On Its Own Terms If Applied To Suboxone®
` 33
`3. Even If The Claims Are Not Limited To Oral Transmucosal Films,
`GI-Absorbed Dosages Do Not Accomplish Therapeutically
`Acceptable Effects 35
`4. It Is Not Technically Possible To Meet Claim 19 Through Peroral
`Administration Of Naloxone Under Any Reading Of The Claim 36
`V. CLAIMS 15-19 ARE NOT RENDERED OBVIOUS BY LABTEC, YANG,
`OR BIRCH 38
`A. Labtec Cannot Render Obvious Claims Requiring Oral-Transmucosal Films
`As Required By The Properly Construed Claims ......................................... 39
`B. A Person Of Skill In The Art Would Not Look To Labtec In Seeking To
`Develop A Film For Delivery Of Buprenorphine ........................................ 39
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`TABLE OF CONTENTS
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`Page
`C. Petitioner Failed To Provide Any Evidence That A Person Skilled In The
`Art Would Have Had A Reasonable Expectation Of Successfully Combining
`Labtec, Birch, And Yang To Arrive At The Claimed Invention .................. 41
`1. Yang Teaches Pharmaceutical Film Manufacturing Methods To
`Achieve Uniformity Of Active Content 41
`2. Birch Has Nothing To Do With Pharmaceutical Films 43
`3. Labtec Cannot Be Transmogrified Into Its Opposite 44
`D. Even If Labtec, Yang And Birch Were Combined, It Would Require Undue
`Experimentation To Arrive At The Claimed Invention................................ 47
`E. Secondary Considerations Support A Finding Of Nonobviousness ............ 53
`VI. CONCLUSION ............................................................................................. 57
`
`ii
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`Case IPR2014-00325
`Patent No. 8,475,832
`
`I.
`
`INTRODUCTION
`
`Patent Owner RB Pharmaceuticals Limited respectfully submits this
`
`Response to BDSI’s Petition (Paper 8) seeking inter partes review (“IPR”) of
`
`Claims 15-19 (“the challenged claims”) of U.S. Patent No. 8,475,832 (“the ‘832
`
`patent”) (Ex. 1001).1
`
` The only issue presently before the Board is whether Petitioner has carried
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`its burden of proving that the challenged claims are invalid as i) anticipated by
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`Labtec or ii) obvious over the combination of Labtec, Yang and Birch.2 Paper 17,
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`21. As shown below, the complete record demonstrates that these claims are valid,
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`and that Petitioner has failed to carry its burden of proving otherwise.
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`Patent Owner’s Preliminary Response did not have the benefit of expert
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`testimony. Now, in support of this Response, Patent Owner submits the
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`accompanying declaration of Dr. Thomas Johnston, an expert in the
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`pharmaceutical sciences, that makes clear that the challenged claims are neither
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`anticipated nor rendered obvious by the Grounds in issue. In particular, Dr.
`
`Johnston provides critical information about the pharmacokinetics of the relevant
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`active ingredients, buprenorphine and naloxone, information that fully rebuts
`
`1 This Response is timely because it is filed on revised Due Date 1 set forth in the
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`Joint Notice of Stipulated Revised Due Dates (Paper 22).
`
`2 Terms defined in the Board’s Institution Decision are used herein as so defined.
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`
`
`-1-
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`Case IPR2014-00325
`Patent No. 8,475,832
`Petitioner’s invalidity theories of anticipation and obviousness.
`
`A. Lack Of Anticipation Overview
`Dr. Johnston explains why the knowledge a skilled person would have of the
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`pharmacokinetic profile of buprenorphine in combination with a proper
`
`understanding of both Labtec and the ‘832 patent refute Petitioner’s anticipation
`
`arguments. In particular, Dr. Johnston explains that it has long been known that,
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`due to extensive first-pass metabolism effects, buprenorphine has very poor
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`bioavailability if administered perorally, i.e., swallowed such that it is absorbed in
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`the gut, as opposed to in the mouth. Thus, it has also long been known that it is
`
`not therapeutically effective or acceptable to administer buprenorphine perorally
`
`due to buprenorphine’s poor bioavailabilty and the expectation that peroral
`
`administration would likely increase inter- and intra-patient variability, make
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`effective dosing less predictable and increase the risk of incurring side effects from
`
`buprenorphine, which is a potent opioid. Additionally, given the poor
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`bioavailability resulting from peroral administration, peroral dosing would require
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`significantly higher dosing as compared, for example, to sublingual administration,
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`thus providing more of the agonist to be potentially abused or diverted, as well as
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`increasing the amounts needed, and thus increasing manufacturing costs. Peroral
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`administration, therefore, would be regarded by those skilled in the art as
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`disfavored and therapeutically inappropriate, particularly given that it has long
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`2
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`Case IPR2014-00325
`Patent No. 8,475,832
`been known that buprenorphine can be safely and effectively delivered through the
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`oral mucosa, such as by sublingual transmucosal administration, thus by-passing
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`metabolism by the gut wall and the liver.
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`By its own terms, Labtec is limited to providing an orally dissolving film
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`that is meant to follow the same metabolic route and to use the same dosage
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`amounts as the brand name products listed in Labtec. All of the brand name
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`products listed in Labtec (in Table A) are meant to be absorbed in the GI tract with
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`the exception of the two buprenorphine-containing products, Subutex® sublingual
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`tablets and Suboxone® sublingual tablets. Labtec also makes clear that it is
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`limited to non-mucoadhesive dosage forms that are intended to be absorbed only
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`in the GI tract, such as the small intestine, while avoiding oral mucosal
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`absorption. This is consistent with Labtec’s stated objective of providing a film
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`dosage form that follows the same metabolic route as all of the brand products it
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`lists (except for the two buprenorphine-containing products).
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`As discussed above, Labtec is limited to dosage forms that provide
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`absorption in the GI tract, but a person of ordinary skill in the art would know that
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`peroral administration of buprenorphine is not therapeutically effective or
`
`acceptable. Further, both Subutex® and Suboxone® tablets are sublingual
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`products that are intended to deliver buprenorphine through the oral mucosa. For
`
`these reasons, the skilled person would immediately conclude that the Labtec
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`3
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`Case IPR2014-00325
`Patent No. 8,475,832
`inventors simply made a mistake when they included the buprenorphine-
`
`containing products, Subutex® and Suboxone® tablets, in Table A among
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`numerous brand name products whose actives are in fact meant to be absorbed in
`
`the gut, evidently based on the incorrect assumption that like those products,
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`Subutex® and Suboxone® tablets, too, delivered their actives in the gut.
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`The skilled person’s recognition of this mistake would be further confirmed
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`by the listing in Labtec’s Table A of pharmacokinetic data (Cmax and AUC data)
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`for Suboxone® tablets that corresponds to established dosages of that product.
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`Specifically, Labtec represents that the film dosages provided by Labtec could
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`somehow be used to achieve the same pharmacokinetic results using the
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`corresponding dosages of Suboxone® tablets. Because of the extensive first-pass
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`effect that buprenorphine undergoes when taken perorally, however, the skilled
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`person would immediately recognize that it would be impossible for Labtec’s
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`peroral dosage form to provide pharmacokinetic results equivalent to those
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`provided by sublingual Suboxone tablets® (which provides buprenorphine through
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`the oral mucosa) at the corresponding Suboxone® tablet dosages. Accordingly,
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`this confirms that Suboxone® tablets (and Subutex®) were included in the product
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`list of Table A in Labtec by mistake.3
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`3 Of course, there is no working example in Labtec of a buprenorphine and/or
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`naloxone containing film, nor any specific teachings relating to one, and the only
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`4
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`Case IPR2014-00325
`Patent No. 8,475,832
`The person of ordinary skill in the art would appreciate that not only is there
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`no teaching whatsoever in Labtec as to how to make a therapeutically acceptable
`
`oral dosage form for the delivery of buprenorphine, namely, one that is intended to
`
`allow oral mucosal absorption, but that Labtec affirmatively and definitively states
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`that its non-mucoadhesive dosage form is meant to avoid any oral mucosal
`
`absorption.
`
`One of ordinary skill in the art would also appreciate that the ‘832 patent is
`
`directed to providing a rapidly orally dissolving mucoadhesive film that delivers “a
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`pharmaceutically acceptable level” (Ex. 1001, 12:10-15) of buprenorphine through
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`the oral mucosa in order to provide “therapeutically adequate absorption” (13:11-
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`18) with the objective of producing effects that are substantially bioequivalent to
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`those produced by the commercial product Suboxone® sublingual tablets, which
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`also provide buprenorphine by absorption through the oral mucosa. The
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`specification emphasizes the inventors’ surprising discovery that inclusion of a
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`buffer that provides a certain (3-3.5) local pH in the presence of saliva at the
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`interface of the dissolving film matrix and the oral mucosa is crucial in obtaining
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`the combination of buprenorphine absorption and inhibition of naloxone absorption
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`two working examples are of brand name drugs that are meant to be absorbed, not
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`surprisingly, in the GI tract.
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`Patent No. 8,475,832
`required to produce bioavailability of those actives that is substantially
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`bioequivalent to Suboxone® tablets. The concept of “local pH” as used in the
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`context of the ‘832 patent would be understood by one of ordinary skill in the art
`
`as solely concerning a region in the mouth (where the matrix is dissolving) and not
`
`to any region in the gut; indeed, a person of ordinary skill would understand that
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`the concept of local pH as used in the context of the patent has no relevance to
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`perorally administered actives, because they would encounter a much larger and
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`stronger volume of acids and bases in the stomach and intestines and whatever
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`limited quantity of buffer was intended for use in the mouth would be rendered
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`ineffective in the stomach and intestines.
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`Finally, in addition to specifically stating that the inventive film formulation
`
`is meant to provide oral mucosal absorption, the pharmacokinetic ranges (Cmax
`
`and AUC) recited in the challenged claims are, as one of ordinary skill would
`
`appreciate, taken directly from Table 3 of the patent and represent bioequivalence
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`values calculated for Suboxone® tablets which the skilled person would
`
`understand as resulting from oral mucosal absorption. There is no teaching
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`whatsoever in the ‘832 patent of a peroral dosage form approach and the skilled
`
`person would understand that a peroral dosage form for buprenorphine would be
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`therapeutically ineffective and unacceptable in any event.
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`For these reasons and as further discussed below, the person of ordinary skill
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`Patent No. 8,475,832
`would understand that the claims refer to a film formulation that provides, and to
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`pharmacokinetic ranges that result from, oral mucosal absorption.
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`In view of the foregoing, and as further discussed below, it is clear that
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`Labtec does not anticipate the challenged claims because:
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`i) Labtec’s inclusion of buprenorphine-containing brand products was
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`nothing more than a mistake and Labtec’s peroral administration route is, given
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`buprenorphine’s extensive first-pass metabolism, clearly non-enabling, indeed
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`plainly inoperable, to obtain Cmax and AUC levels equivalent to those listed for
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`Subxone® tablets at the corresponding dosage amounts listed in Labtec Table A;
`
`ii) Labtec requires peroral administration while the challenged claims, once
`
`properly construed to require a film formulation that provides, and
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`pharmacokinetic ranges that result from, oral transmucosal absorption; and
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`iii) the ‘832 patent, which is directed to a film dosage for treating opioid
`
`dependence, clearly describes and claims a dosage for therapeutic use, but Labtec’s
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`peroral administration route for buprenorphine is known not to be therapeutically
`
`effective or acceptable and is, therefore, nonenabling, for that reason as well.
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`Finally, Labtec does not anticipate Claim 19 for the additional and
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`independent reason that due to naloxone’s extensive first-pass effect, it is not
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`technically possible for a peroral dosage form of naloxone at the mg dosage
`
`amounts required in dependent Claim 19 to provide a Cmax within the range recited
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`Patent No. 8,475,832
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`in Claim 15, from which it depends.
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`B. Non-Obviousness Overview
`Dr. Johnston also explains why knowledge of the pharmacokinetic profile of
`
`buprenorphine as of the 2009 filing date of the ‘832 patent and a proper
`
`understanding of Labtec and the ‘832 patent, establishes that Petitioner cannot
`
`carry its burden of showing that the challenged claims are obvious over Labtec
`
`combined with Yang and Birch. A person skilled in the art seeking to design a
`
`buprenorphine dosage form (which is understood to only be delivered through the
`
`oral mucosa) would never have been motivated to look to Labtec in the first place.
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`Indeed, Labtec’s proposed oral film for GI absorption (the opposite of oral mucosal
`
`delivery) would have been recognized to be a complete nonstarter (as
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`therapeutically unacceptable) for the delivery of buprenorphine.
`
`With the background provided by Dr. Johnston, it is also evident that it
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`would be legally impermissible, and a person of ordinary skill in the art would
`
`have no motivation, to combine Labtec and Yang. To accomplish therapeutically
`
`acceptable buprenorphine delivery, the person of ordinary skill would be forced to
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`change the basic principles of operation of Labtec, abandoning its peroral GI
`
`absorption route in favor of its opposite, a mucoadhesive film for oral mucosal
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`absorption. Federal Circuit and Board precedent forbid transmogrifying what a
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`reference actually teaches and then trying to apply that artificial construct as a §
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`Case IPR2014-00325
`Patent No. 8,475,832
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`103 reference.
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` Finally, Dr. Johnston also shows why, in any event, the combination of
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`Labtec, Yang and Birch does not render the challenged claims obvious since
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`Petitioner has not carried its burden of showing that undue experimentation would
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`not be required to produce the subject matter of the challenged claims.
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`Specifically, even if the skilled person somehow disregarded Labtec’s insistence
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`on using the peroral route for absorption in the GI tract and decided instead to try
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`to make the opposite kind of film—a mucoadhesive film for oral mucosal
`
`absorption of the actives—she would have had no reasonable expectation of
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`success in producing a therapeutically acceptable film that meets the
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`pharmacokinetic requirements of the challenged claims without having to
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`undertake undue experimentation.
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`In designing pharmaceutical films for systemic drug delivery, as Petitioner
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`recently told the Board in another IPR, “tinkering with even one component may
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`have a significant effect on the entire system . . . the combination of ingredients
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`and desired characteristics requires a delicate balance.” Ex. 2043, IPR2014-00376,
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`Paper 22 (October 27, 2014) at 2. Here, none of Petitioner’s 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 ’832 patent. Therefore, with the three asserted
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`Patent No. 8,475,832
`references in hand, the experimentation that would have been required to get this
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`combination to work given, among other things, that oral pharmaceutical film
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`formulation technology is a relatively recent and emerging art, the multitude and
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`interrelationship of variables to be chosen and parameters to be met, the extensive
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`testing required, including through in vivo testing in humans, and the lack of any
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`buprenorphine and/or naloxone film in the prior art, would have been far beyond
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`just tinkering or small changes, and instead would have required undue
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`experimentation to arrive at the claimed films.
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`II. BUPRENORPHINE PHARMACOKINETICS BACKGROUND
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`Buprenorphine, a (mu) µ opiate receptor partial agonist, has long been
`
`known as having characteristics that make it an ideal drug for the treatment of
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`opioid dependence. Ex. 2003, Johnston Dec., ¶ 42. For example, as explained in
`
`the ‘832 patent, “[i]n order to help individuals addicted to narcotics, it is known to
`
`provide a reduced level of a drug, which provides an effect of satisfying the body’s
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`urge for the narcotic, but does not provide the ‘high’ that is provided by the misuse
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`of the narcotic.” Ex. 1001, 1:36-41.
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`One of the most important and long known pharmacokinetic facts about
`
`buprenorphine is that it undergoes extensive first-pass metabolic effects. These
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`first-pass effects are the result of both gut wall metabolism (extensive conjugation
`
`within the intestinal mucosa) and enzymatic degradation by the liver (specifically,
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`extensive hepatic oxidative metabolism by cytochrome P450 3A4/5 and 2C8
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`isoenzymes). Ex. 2003, ¶ 44. These extensive first-pass metabolic effects have
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`long been understood to result in very poor peroral bioavailability.4 Therefore, it
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`has long been known that very little of perorally administered buprenorphine enters
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`the systemic circulation, thus making the peroral route inappropriate for the
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`treatment of opioid dependence. Id. at ¶ 46.
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`Petitioner itself has repeatedly acknowledged this during the prosecution of
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`its own patents and publications relating to its own transmucosal buprenorphine
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`product. See, e.g., Ex. 2044, International Patent Publication No. WO2013096811,
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`p. 1, ln. 26-28 (“Buprenorphine is metabolized by the liver, via the CYP3A4
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`isozyme of the cytochrome P450 enzyme system, into norbuprenorphine (by N-
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`dealkylation) and other metabolites. Buprenorphine has a low oral bioavailability
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`due to very high first-pass metabolism.”); Ex. 2048, BDSI poster presentation
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`4 Thus, if buprenorphine is administered perorally, it passes through the gut
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`mucosa where it is metabolized significantly and is then delivered directly to the
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`liver via the hepatic portal circulation where it undergoes further metabolism.
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`Due to buprenorphine’s very high first-pass effect, some report that peroral
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`administration of buprenorphine results in essentially no buprenorphine reaching
`
`the systemic circulation. Other references estimate that the absolute bioavailability
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`of peroral buprenorphine is as little as 10 – 15 %. Ex. 2003, ¶ 45-46.
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`Case IPR2014-00325
`Patent No. 8,475,832
`(2010), Background (asserting their oral transmucosal buprenorphine product
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`“facilitate[s] buccal delivery of buprenorphine, which is poorly bioavailable when
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`administered orally”). Accordingly, even Petitioner’s product “facilitates buccal
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`delivery of buprenorphine” rather than using the peroral route. BDSI poster
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`presentation (2010), Background (emphasis added).
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` The person of ordinary skill in the art would also reasonably expect that the
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`extensive first-pass metabolic effects on perorally administered buprenorphine also
`
`result in a substantial increase in inter- and intra-patient variability. Such increased
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`variability would reasonably be expected to make effective dosing less predictable
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`and titration of an individual patient’s dosing more difficult, while at the same time
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`increasing the risk of significant side effects, including nausea and withdrawal, if
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`not more serious outcomes. Ex. 2003, ¶¶ 46- 47.
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`For example, in the case of buprenorphine, which is a mu (m) receptor partial
`
`agonist, there is a plateau of receptor activation with no further effect from a
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`further escalation in dose, often referred to as the “ceiling effect.” It is this partial
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`agonist activity that makes buprenorphine a safer drug with which to treat opioid
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`addiction because there is less respiratory depression, less sedation, less
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`withdrawal symptoms, lower risk of toxicity at higher doses, and a decreased risk
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`of diversion. The variability in response to drugs is extremely important, because
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`if a patient is given one drug that interferes in the metabolic pathway of another
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`Patent No. 8,475,832
`drug, it may cause toxicity of the former. For example, it has been reported that
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`midazolam and certain HIV-1 protease inhibitors, when given simultaneously with
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`buprenorphine, interfere in the metabolic pathway for the efficient metabolism of
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`buprenorphine. When this happens, it is possible to modulate the so-called
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`“ceiling effect” of the partial agonist (buprenorphine), which could potentially
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`result in drug-related morbidity or mortality due to an increase in respiratory
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`depression. Ex. 2003, ¶ 52.
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`In terms of inter-individual pharmacokinetic variability, a genetic
`
`polymorphism of a metabolic enzyme resulting in a patient that hypermetabolizes
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`buprenorphine could cause that patient to receive inadequate levels of
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`buprenorphine. That unfortunate patient could start to experience opioid
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`withdrawal, thereby making the perorally administered dose ineffective.
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`Likewise, a genetic polymorphism resulting in an enzyme deficiency with
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`decreased buprenorphine clearance could result in a normally therapeutic dose
`
`causing side effects or potentially worse. Thus, a peroral dose that is effective in
`
`one patient population could lead to withdrawal in another, and a peroral dose that
`
`is therapeutic to one may cause significant side effects or potentially have even
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`more serious consequences to another. Ex. 2003, ¶ 55.
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`One of ordinary skill in the art would also regard the possibility of intra-
`
`individual variability of the metabolism of buprenorphine as making peroral dosing
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`an inappropriate route of administration. In terms of intra-individual variability,
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`gut mucosal and liver enzyme activity can be modified by drugs such as
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`phenobarbital or acetaminophen, food substances such as acetic acid or cruciferous
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`vegetables, charcoal cooked food, and pollutants, just to name a few. Therefore,
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`the same patient may respond significantly differently from day to day depending
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`on his health, what he eats, or other drugs that he takes. Therefore, a peroral dose
`
`of buprenorphine that maintains a patient one day may on another day lead to
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`withdrawal, significant side effects, or potentially worse. Ex. 2003, ¶ 56.
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`Beyond the bioavailability and expected variability problems described
`
`above, a person of ordinary skill in the art would be deterred from using the peroral
`
`route for administering therapeutic amounts of buprenorphine since, given the
`
`availability of the sublingual route of delivery, peroral dosing would require
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`significantly more buprenorphine making the dosage form that much more of a
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`target for abuse and diversion, contrary to the applicable therapeutic and public
`
`policy objectives. Ex. 2003, ¶¶ 57-58.
`
`For all of these reasons, as of 2009 (indeed, long before then), peroral
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`administration of buprenorphine would have been regarded by the person of
`
`ordinary skill in the art as therapeutically inappropriate and ineffective. Ex. 2003,
`
`¶ 63.
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`Further, the long-time recognition that peroral administration of
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`buprenorphine is therapeutically inappropriate would be heightened for the person
`
`of ordinary skill in the art by the fact that it has also long been known that oral
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`transmucosal absorption is a safe and effective route for delivering buprenorphine
`
`to treat opioid dependent outpatients. Transmucosal oral delivery is superior to
`
`peroral delivery because buprenorphine delivered oral transmucosally is absorbed
`
`mainly via the tissues in the oral cavity and cleared by the lingual blood vessels,
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`which are not part of the hepatic portal system. Therefore, oral transmucosal
`
`delivery avoids the significant first-pass metabolism buprenorphine undergoes
`
`when administered perorally for GI absorption. Ex. 2003, ¶ 61.
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`Indeed, as one of ordinary skill would know, Suboxone® sublingual tablets
`
`deliver buprenorphine primarily through the oral mucosa. Ex. 2003, ¶ 66.
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`Suboxone® tablets were first approved by the FDA in 2002 and introduced to the
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`U.S. market in 2003. RBP’s Suboxone® sublingual film (the commercial
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`embodiment of the ‘832 patent), which was approved in 2010, also delivers
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`buprenorphine through the oral mucosa.
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` Not surprisingly, prior to 2009, some of the prescribing information relating
`
`to sublingual buprenorphine tablets stated that:
`
`Administration is sublingual. Physicians must advise patients that the
`sublingual route is the only effective and safe route of administration
`for this drug.
`
`
`See Ex. 2____: Summary of Product Characteristics for Subutex 0.4 mg, 2 mg,
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`and 8 mg Sublingual tablets at
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`http://www.medicines.ie/medicine/1658/SPC/Subutex+0.4mg%2c+2mg+and+8mg
`
`+Sublingual+Tablets/ downloaded on Nov. 2, 2014.5 Similarly, years before 2009,
`
`it was publicly 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 (emphasis added); Ex.
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`2003, ¶ 62.
`
`Accordingly, as of 2009, one of ordinary skill in the art would view the
`
`peroral administration of buprenorphine for the treatment of opioid dependence as
`
`therapeutically ineffective and inappropriate.6 Ex. 2003, ¶¶ 63.
`
`
`5 The website reports that the Summary of Product Characteristics was last updated
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`04/16/2013; however, the document revision history as provided on pages 9-11
`
`indicates that the quote relied upon was present at least as late as 2005.
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`6 See, e.g., the statement in the Handbook of Methadone Prescribing and
`
`Buprenorphine Therapy that the oral GI route should be avoided because of the
`
`“pharmacokinetic problems of oral and parenteral opioids which include poor GI
`
`absorption, first pass metabolism, and low bioavailability. Ex. 2___ at __.
`
`16
`
`

`

`Case IPR2014-00325
`Patent No. 8,475,832
`
`III. CLAIM CONSTRUCTION
`
`The Board properly rejected Petitioner’s proposed claim constructions for
`
`the terms “film formulation” and “provides an in vivo plasma profile” and adopted
`
`the constructions proposed by Patent Owner. Paper 17, 7-12. Specifically, the
`
`Board adopted the following constructions for these terms:
`
`Term
`film formulation
`
`provides an in vivo
`plasma profile
`
`
`
`
`
`Board’s Construction
`“‘[F]ilm formulation’encompasses film dosage, film
`composition, or film, but not a formulation that is not in
`the form of a film.” Paper 17, 11 (emphasis added).
`There is “no need to construe the term ‘provides an in
`vivo plasma profile’ beyond its ordinary meaning.”
`Paper 17, 12 (emphasis added).
`
`At this stage, there are two claim construction issues for the Board to
`
`address. The first is an issue raised in the Petition that was not addressed, at least
`
`not explicitly, in the Institution Decision, namely, whether the “wherein” clause in
`
`Claim 15 should be given patentable weight—as explained below, it should.
`
`Second, Patent Owner respectfully submits, as indicated above, that the challenged
`
`claims should be construed to require a film formulation that provides, and
`
`pharmacokinetic ranges that result from, oral transmucosal absorption.
`
`
`
`
`17
`
`

`

`Case IPR2014-00325
`Patent No. 8,475,832
`A. Legal Standard For Claim Construction In Inter Partes Review
`
`While claim terms are given their broadest reasonable interpretation in this
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`proceeding pursuant to 37 C.F.R. §42.100(b), terms must still be construed as they
`
`would be understood by a person of ordinary skill in the art in light of the language
`
`of the claims and the specification. In re Translogic Tech., Inc., 504 F.3d 1249,
`
`1257 (Fed. Cir. 2007). A claim’s construction is not “reasonable” if it does not
`
`comport with how a person of ordinary skill would understand the term in light of
`
`the claim language and specification. In re Cortright, 165 F.3d 1353, 1358 (Fed.
`
`Cir. 1999) (“Although the PTO must give claims their broadest reasonable
`
`interpretation, this interpretation must be consistent with the one that those skilled
`
`in the art would reach.”) (reversing Board construction in light of narrower
`
`understanding of claim term by one of ordinary skill in view of patent disclosure).
`
`B.
`
` Claim 15’s “Wherein” Clause Is Entitled To Patentable Weight
`
`Petitioner contends that the “wherein clause” contained in Claim 15 recites
`
`merely a desired result and is “not entitled to patentable weight.” Paper 2 at 23-26.
`
`The bulk of Petitioner’s argument consists, not of relevant law, but rather the text
`
`of Claim 15 and an out of context block quote from an Office Action Response.
`
`Id. at 23. Petitioner relies only on the Markman decision to support its extreme
`
`position (id. at 24), which would require the Board to effectively read out a
`
`significant and properly claimed limitation.
`
`18
`
`

`

`Case IPR2014-00325
`Patent No. 8,475,832
`The language Petitioner quotes from the seminal Markman decision (which,
`
`of course, held that claim construction is a legal question for a district court judge
`
`to determine) merely provides introductory information on the bounds of proper
`
`claim scope. See id. at 373. Markman makes no reference to the “patentable
`
`weight” attributable to the claim elements following a wherein clause. There are
`
`numerous cases that do address such clauses, but P