UNITED STATES PATENT AND TRADEMARK OFFICE
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`_________________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_________________________________
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`TEVA PHARMACEUTICALS USA, INC.,
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`Petitioner
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`v.
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`RB PHARMACEUTICALS LTD.,
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`Patent Owner
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`
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`U.S. Patent No. 8,475,832
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`_______________
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`Case IPR2016: Unassigned
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`DECLARATION OF NANDITA DAS, Ph.D.
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`_________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_________________________________
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`TEVA PHARMACEUTICALS USA, INC.,
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`Petitioner
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`
`
`v.
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`RB PHARMACEUTICALS LTD.,
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`Patent Owner
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`
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`U.S. Patent No. 8,475,832
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`_______________
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`Case IPR2016: Unassigned
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`
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`DECLARATION OF NANDITA DAS, Ph.D.
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`
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`I.
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`Introduction
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`1. My name is Nandita Das. I have been retained by counsel for
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`Petitioner Teva Pharmaceuticals USA, Inc. (“Teva”). I understand that Teva
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`petitioned for inter partes review of U.S. Patent No. 8,475,832 (the “’832 patent”),
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`which is owned by RB Pharmaceuticals Ltd. (“Patent Owner”). I further
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`understand that Teva requests that the United States Patent and Trademark Office
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`(“USPTO”) cancel certain claims of the ’832 patent as unpatentable. I submit this
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`expert declaration, which addresses and supports Teva’s petition.
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`II.
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`Personal Background and Expert Qualifications
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`a. Education, Experience and Prior Testimony
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`2.
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`Currently, I am an Associate Professor of Pharmaceutics at Butler
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`University with over 15 years of experience teaching pharmaceutical sciences. I
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`have been on the faculty at Butler University since 2004 with a full-time campus-
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`based tenure-track faculty position since 2005. I was granted tenure and promoted
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`to Associate Professor in Spring 2012. Prior to my time at Butler University, I was
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`an Assistant Professor of Pharmaceutics at Idaho State University, previous to
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`which I taught as an Adjunct Professor at Nova Southeastern University while
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`working full time as a licensed pharmacist in the state of Florida. A copy of my
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`curriculum vitae and list of publications is attached as Exhibit A.
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`3.
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`I received a B.Pharm. in Pharmacy from Banaras Hindu University in
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`India in 1988, achieving first rank among my classmates.
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`4.
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`I received an M.Pharm. in Pharmaceutics from Banaras Hindu
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`University in 1990. My research focused on controlled release dosage forms.
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`5.
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`I received a Ph.D. in Pharmaceutical Sciences from the University of
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`Pittsburgh in 1995. My research focused on the kinetics of solid-state
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`microcalorimetry.
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`6.
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`From 1993-1995, I completed my doctoral research work as a
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`graduate scholar with SmithKline Beecham Pharmaceuticals, studying
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`microcalorimetry under the mentorship of Dr. Theodore D. Sokoloski, Ph.D.
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`7.
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`From 1995-1998, I worked as a commercial pharmacist, managing a
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`community pharmacy.
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`8. My business address is College of Pharmacy & Health Sciences,
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`Butler University, 4600 Sunset Avenue, Indianapolis, IN 46208-3485.
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`9.
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`Among the numerous research grants I have received, from August
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`2002 through July 2006, I conducted a study on the use of mucoadhesive
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`buprenorphine in opioid addiction therapy for the National Institute of Health’s
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`National Institute on Drug Abuse.
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`10.
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`In 2004, I published an article on the development of mucoadhesive
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`dosage forms of buprenorphine for sublingual delivery in Drug Delivery – The
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`Journal of Delivery and Targeting of Therapeutic Agents, Volume 11 (2004).
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`11.
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`I have also researched, as part of my work during my time at Idaho
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`State University, mucoadhesive properties of polymers used in sublingual drug
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`delivery.
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`12.
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`I also co-authored a paper regarding drugs used in the treatment of
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`addiction for the Indian Journal of Pharmacy Practice, Volume 5, Issue 4 (2012).
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`13.
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`I have authored or co-authored over 70 articles, abstracts, papers and
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`book chapters and am a named inventor on one domestic patent. I have also
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`appeared at six conferences on a topic areas of present interest, including
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`mucoadhesive sublingual delivery systems for buprenorphine.
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`14.
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`I am a member of various professional societies, including the
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`American Association of Pharmaceutical Scientists and the American Association
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`of Colleges of Pharmacy. I am also a peer reviewer for five scientific and medical
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`journals.
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`b. Bases for Opinion and Materials Considered
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`15. Exhibit 10026 includes a list of the materials I considered, in addition
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`to my experience, education, and training, in providing the opinions contained
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`herein.
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`c. Scope of Work
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`16.
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`I have been retained by Teva as a technical expert in this matter to
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`provide various opinions regarding the ’832 patent. I receive $400 per hour for my
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`services and $500 per hour for deposition testimony. No part of my compensation
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`is dependent upon my opinions given or the outcome of this case. I do not have any
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`other current or past affiliation as an expert witness or consultant with Teva. I do
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`not have any current or past affiliation with RB Pharmaceuticals Limited, or any of
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`the named inventors on the ’832 patent.
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`III.
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`Summary of Opinions
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`17. As explained in detail in Section VIII, it is my opinion that all of the
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`challenged claims (1-7, 9-12) of the ’832 patent1 would have been obvious in light
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`of the LabTec reference, the Oksche reference, the 2002 Suboxone® Label, and
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`other prior art, which would have collectively taught and motivated a person of
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`ordinary skill in the art to make and use the same compositions and methods that
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`are claimed in the ’832 patent.
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`1 It is my understanding that claims 15-19 have been found invalid in IPR2014-
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`00325.
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`IV.
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`Priority Date of the ’832 Patent
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`18.
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`I am informed and understand that prior art is evaluated based on the
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`priority date attributed to the patent under review. Further, I understand that Patent
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`Owner claims the ’832 patent is entitled to priority date of August 7, 2009. I
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`understand that patents and printed publications published prior to August 7, 2009
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`are available as prior art to the ’832 in this proceeding.
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`V.
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`Legal Standards
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`19.
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`I understand that a preponderance of evidence must be presented to
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`render a patent claim invalid in this proceeding.
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`20.
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`I have been informed that the standard for obviousness is set out in 35
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`U.S.C. §103(a), the relevant version of which is quoted below:
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`“A patent may not be obtained though the invention is not identically
`disclosed or described as set forth in section 102 of this title, if the
`differences between the subject matter sought to be patented and the
`prior art are such that the subject matter as a whole would have been
`obvious at the time the invention was made to a person having
`ordinary skill in the art to which said subject matter pertains.
`Patentability shall not be negatived by the manner in which the
`invention was made.”
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`35 U.S.C. § 103(a).
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`21.
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`I have been informed that in order for a patent claim to be considered
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`obvious, at the time the invention was made, each and every limitation of the claim
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`must be present within the prior art, or within the prior art in combination with the
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`general knowledge held by a person of ordinary skills in the art, and that such a
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`person would have a reasonable expectation of success in combining these
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`teachings to achieve the claimed invention. I also understand that the reason to
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`select and combine features, the predictability of the results of doing so, and a
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`reasonable expectation of success of doing so may be found in the teachings of the
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`prior art themselves, in the nature of any need or problem in the field that was
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`addressed by the patent, in the knowledge of persons of ordinary skill in the art at
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`the time, as well as in common sense or the level of creativity exhibited by a
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`person of ordinary skill in the art. There need not be an express or explicit
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`suggestion to combine references. I understand the combination of familiar
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`elements according to known methods is likely to be obvious when it does no more
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`than yield predictable results.
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`22.
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`I understand that the obviousness of a claim is ultimately a legal
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`conclusion based on underlying factual inquiries. I understand that the following
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`factors are relevant to whether a claim is obvious: the scope and content of the
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`prior art, the differences between the prior art and the claims at issue, the level of
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`ordinary skill in the art, and whatever objective evidence may be present.
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`23.
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`I understand that a claim may be obvious where it is the result of
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`combining familiar elements according to known methods to achieve predictable
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`results. The claim is obvious where a person of ordinary skill in the art would have
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`been motivated to combine the teachings of the prior art and would have had a
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`reasonable expectation of success in doing so.
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`24.
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`I understand that secondary considerations of non-obviousness must
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`be considered because such factors are probative of obviousness. These factors
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`include unexpected results, commercial success, long felt but unresolved need,
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`teaching away, and failure of others.
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`25.
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`I have relied upon this understanding of the applicable legal standards
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`in reaching my opinions set forth in this declaration.
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`VI.
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`Person of Ordinary Skill in the Art
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`26.
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`It is my opinion that in the context of the ’832 patent, a person of
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`ordinary skill in the art would include a person who possesses a Master’s or Ph.D.
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`in pharmaceutical sciences, formulation chemistry, or a related filed, plus a number
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`of years of relevant experience in developing drug formulations.
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`VII.
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`The ’832 Patent
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`A.
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`The Challenged Claims of the ’832 Patent
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`27. The challenged claims of the ’832 patent are directed to a composition
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`(claims 1-7), and a method of treating narcotic dependence of a user (claims 9-12).
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`More particularly, the challenged claims recite:
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`1.
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`A film dosage composition comprising:
`a.
`A polymeric carrier matrix;
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`A therapeutically effective amount of
`b.
`buprenorphine or a pharmaceutically acceptable salt
`thereof;
`c.
`A therapeutically effective amount of naloxone or
`a pharmaceutically acceptable salt thereof; and
`d.
`A buffer in an amount to provide a local pH for
`said composition of a value sufficient to optimize
`absorption of said buprenorphine, wherein said local pH
`is from about 3 to about 3.5 in the presence of saliva.
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`The composition of claim 1, wherein said film dosage
`2.
`composition provides a bioequivalent absorption of
`buprenorphine to that of a tablet having an equivalent amount
`of buprenorphine or a pharmaceutically acceptable salt thereof.
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`The composition of claim 1, wherein said polymeric
`3.
`carrier matrix comprises at least one polymer in an amount of at
`least 25% by weight of said composition.
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`The composition of claim 1, wherein said buffer is
`4.
`present in an amount of from about 2:1 to about 1:5 by weight
`of buffer to buprenorphine.
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`The composition of claim 1, wherein said polymeric
`5.
`carrier matrix comprises at least one self-supporting film
`forming polymer.
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`The film dosage composition of claim 1, wherein said
`6.
`buprenorphine is present in an amount of from about 2 mg to
`about 16 mg per dosage.
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`The film dosage composition of claim 1, wherein said
`7.
`buffer comprises sodium citrate, citric acid, and combinations
`thereof.
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`A method of treating narcotic dependence of a user,
`9.
`comprising the steps of:
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`a.
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`providing a composition comprising:
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`a polymeric carrier matrix;
`i.
`a therapeutically effective amount of
`ii.
`buprenorphine or a pharmaceutically acceptable
`salt thereof;
`iii.
`a therapeutically effective amount of
`naloxone or a pharmaceutically acceptable salt
`thereof; and
`iv. A buffer in an amount to provide a local pH of
`about 3 to about 3.5 for said composition of a
`value sufficient to optimize absorption of said
`buprenorphine and also sufficient to inhibit
`absorption of said naloxone; and
`administering said composition to the oral cavity
`b.
`of a user.
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`10. The composition of claim 9, wherein said method
`provides a bioequivalent absorption of buprenorphine to that of
`a tablet having an equivalent amount of buprenorphine or a
`pharmaceutically acceptable salt thereof.
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`11. The method of claim 9, wherein said film dosage
`composition is administered to the user through buccal
`administration, sublingual administration, and combinations
`thereof.
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`12. The method of claim 9, wherein said film dosage
`composition remains in the oral cavity of the user for a period
`of at least 1 minute.
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`Prosecution History of the ’832 Patent
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`I have reviewed the prosecution history of the ’832 patent. The
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`B.
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`28.
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`application leading to the ’832 patent (U.S. Patent Application No. 12/537,571)
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`was filed on August 7, 2009 and lists Garry L. Myers, Samuel D. Hilbert, Bill J.
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`Boone, B. Arlie Bogue, Pradeep Sanghvi, and Madhusudan Hariharan as inventors.
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`I also understand that the ’832 patent was assigned to RB Pharmaceuticals Limited.
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`(’832 patent, Ex. 1001.) As filed, the ’571 application included 31 claims. (U.S.
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`Patent App. No. 12/537,571, Ex. 1002 at 33-36 ( the “’571 application”).) Claims
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`1, 11, 15, 17, 24, 26, and 27 were independent claims. (Id. at 33-36.) None of these
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`independent claims recited any pH ranges. (Id. at 33-36.)
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`29. On August 31, 2011, the Examiner issued a non-final Office Action
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`rejecting claims 1, 4, 5, 7-10, 15, 17, and 20-24 as anticipated by the Oksche, et al.,
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`reference (US2010/0087470). (8/31/11 Office Action (’571 Application), Ex. 1002
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`at 2.) The Examiner pointed to certain embodiments in the Oksche reference that
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`disclosed all of the elements of the rejected claims. (Id. at 2-3.)
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`30.
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`In addition, the Examiner rejected claims 1-31 as obvious, noting that
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`it would have been obvious to a person of ordinary skill to modify the teachings of
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`Oksche to identify the optimal pH range “in an effort to identify formulations that
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`would provide optimal absorption of both agonist and antagonist.” (Id. at 5.)
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`Oksche disclosed “buprenorphine/naloxone formulations [that] may comprise the
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`citric acid as a pH modifier.” (Id. at 4.) And the Examiner explained that because
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`the general conditions of the claimed invention were known in the prior art,
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`identification of the optimal pH range “appears to be a matter of routine
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`experimentation.” (Id. at 5.)
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`31. The Examiner concluded that it was inconsequential that Oksche did
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`“not teach formulations [of] buprenorphine and naloxone, where the buffer is
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`present in an amount sufficient to inhibit the absorption of naloxone.” (Id. at 4.)
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`The Examiner also stated that it did not matter that Oksche did not “teach the
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`specific range of pH recited in the instant claims.” (Id. at 4.)
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`32. On February 29, 2012, Applicants responded to the Office Action and
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`amended the claims “to recite a particular local pH value and/or to recite that the
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`buffer optimizes absorption of buprenorphine while also inhibiting absorption of
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`the naloxone.” (2/29/12 Amendment and Response (’571 Application), Ex. 1002 at
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`7.) In particular, claim 1 was amended to include a “local pH” of “from about 2 to
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`about 3.5 in the presence of saliva.” (Id. at 2.) Claim 17 (which issued as
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`independent claim 9) was also amended to include a “local pH” of “about 2 to
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`about 3.5.” (Id. at 4.)
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`33.
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`In addition to amending the claims, Applicants described the
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`invention and acknowledged that the simultaneous delivery of buprenorphine and
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`naloxone was not novel; it had been previously known in the form of the
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`Suboxone® tablet. (Id. at 7.) The alleged invention was intended to provide a
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`maximum blood concentration (Cmax) that is 80 to 125% of the level provided by a
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`Suboxone® tablet at the same dosage levels of buprenorphine and naloxone. (Id. at
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`7.) In order to achieve this desired result, Applicants “discovered that the film
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`product should include a buffer that provides a specific buffer capacity to the
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`film.” (Id. at 7.)
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`34. Notably, Applicants did not inform the Examiner that the claimed film
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`used the identical buffer (citric acid and sodium citrate) as had been used in
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`Suboxone® tablets.
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`35. Applicants told the Examiner that “it was particularly surprising to
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`find that both [buprenorphine and naloxone] may be included in one film by
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`providing a buffer having a pH of from about 2 to about 3.5.” (Id. at 8.) Applicants
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`cited the “Partition Theory” as the reason for their surprise. (Id. at 7.)
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`36. The “Partition Theory” holds that when a drug is capable of being
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`ionized, only the non-ionized form of molecules can be readily absorbed through
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`mucous membranes and into the bloodstream. (Ex. 1024, Shore, et al, The Gastric
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`Secretion of Drugs: a pH Partition Hypothesis, J. Pharmacol. Exp. Ther., 119: 361-
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`9 (1957).)
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`37. Applicants also implicitly relied on the well-known fact that these
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`drugs are more ionized at pH values farther from the drug’s pKa, and less ionized
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`at pH values nearer to the drug’s pKa. (2/29/12 Amendment and Response (’571
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`Application), Ex. 1002 at 7-8.) The pKa is the pH value at which there are
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`equivalent concentrations of ionized and non-ionized species. The pKa of naloxone
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`is 7.94. (The European Medicines Agency Initial Marketing-Authorisation
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`Document, Scientific Discussion, Oct. 19, 2006 for Suboxone® sublingual tablets,
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`Ex, 1011 at 3 (“EMEA”).) The pKa of buprenorphine is 8.42. (Ex. 1001 at 11:46-
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`47.)
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`38.
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`In view of these facts, Applicants asserted that lowering the local pH
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`of the environment containing buprenorphine and naloxone would be predicted to
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`decrease absorption of both compounds. (2/29/12 Amendment and Response (’571
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`Application), Ex. 1002 at 8.) Instead, however, Applicants observed that when the
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`film included a buffer to control the pH at a range of from 2 to about 3.5,
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`buprenorphine absorption was “optimized,” while at the same time, naloxone
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`absorption was “inhibited.” (Id. at 8) Applicants then amended the claims “to
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`reflect the essence of the invention.” (Id. at 8.)
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`39. With respect to the anticipation rejections, Applicants argued that
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`Oksche did not anticipate the claims because Oksche fails to disclose the limitation
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`of a buffer capacity suitable to optimize the absorption of buprenorphine. (Id. at 9.)
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`To support their argument, Applicants explained that the “present application is
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`based upon the discovery that the delivery and absorption of buprenorphine can be
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`optimized to a desired level through administration via a film if the pH is balanced
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`appropriately.” (Id. at 9.)
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`40. To overcome the obviousness rejections, Applicants focused on the
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`Examiner’s statement that the selection of an appropriate pH range would have
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`been a matter of routine experimentation. (Id. at 10.) Notably, Applicants argued
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`that “[t]hose skilled in the art would have simply relied upon pH partition theory
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`and selected a buffering capacity that follows this theory - for example, a pH
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`commensurate with the pKa of the active.” (Id. at 9.) Further, Applicants argued
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`that “the buffer capacity suitable to optimize the absorption of buprenorphine and,
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`at the same time, to inhibit the absorption of naloxone, is not predictable.” (Id. at
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`10 (emphasis in original).) Applicants argued that “Oksche merely states that
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`buffers can be used, but includes nothing further.” (Id. at 11.) According to
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`Applicants, the “general disclosure of a buffer is not sufficient to render obvious
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`claims that require a particular buffer capacity to optimize the absorption of
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`buprenorphine and inhibit the absorption of naloxone.” (Id. at 11.)
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`41. Further distinguishing Oksche, Applicants stated that “there is no
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`reason to believe, based on the teachings of Oksche, that pH would even play any
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`role in the effectiveness of the composition.” (Id. at 11.) Applicants again
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`reiterated their argument that the alleged invention differs from what would have
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`been expected based on Partition Theory: “For example, the buffer capacity for a
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`product including both the buprenorphine and naloxone would be one that
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`minimizes the absorption of the naloxone but optimizes the absorption of the
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`buprenorphine - a concept not disclosed nor considered by Oksche.” (Id. at 12.)
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`Applicants explained how they “discovered that at a pH of about 2-3.5, the relative
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`absorptions [of buprenorphine and naloxone] can be controlled effectively.” (Id. at
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`12.)
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`42. On May 2, 2012, the Patent Office issued a Final Office Action.
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`(5/2/12 Final Office Action (’571 Application), Ex. 1002 at 1.) In particular, the
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`Examiner rejected claims 1-10, 13-14, 16-23, and 25-26 under 35 U.S.C. § 112,
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`first paragraph, for failure to comply with the written description requirement. (Id.
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`at 2.) According to the Examiner, the claims that had been amended to recite “a
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`local pH...to optimize absorption of buprenorphine, wherein said local pH is from
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`about 2 to about 3.5 in the presence of saliva” lacked corresponding support in the
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`specification. (Id. at 2-3.)
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`43. The Examiner also withdrew the rejections based on anticipation, but
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`maintained that claims 1 and 3-31 were obvious in view of Oksche. (Id. at 3.) After
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`considering Applicants’ arguments, the Examiner concluded that Oksche’s
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`disclosure of the Suboxone® tablet “provides an optimized absorption of
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`buprenorphine.” (Id. at 5.) Therefore, “it would have been obvious to the ordinary
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`skilled artisan, at the time of the instant invention, to modify their teachings so as
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`to identify the optimal range of pH/dosage in an effort to identify formulations that
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`would provide optimal absorption of both agonist and antagonist.” (Id. at 6.)
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`44.
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`In October 2012, Applicants submitted a response to the Final Office
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`Action. (10/22/12 Amendment and Response After Final Rejection (’571
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`Application, Ex. 1002.) Applicants pointed to portions of the specification that
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`allegedly supported the amended claims. (Id. at 7.) In response to the obviousness
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`rejections, Applicants argued that nothing in Oksche would direct a person of
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`ordinary skill to use the claimed pH range. (Id. at 8.) In particular, Applicants
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`argued that “the presently claimed [pH] range demonstrates unexpected and
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`significant improvements, particularly when compared to that of the prior art and
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`when compared to what one of ordinary skill in the art would have been led to
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`believe (i.e., through partition theory, as explained in the application as filed at
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`paragraph [0100]).” (Id. at 8.)
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`45. On November 6, 2012, the Examiner issued an Advisory Action
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`withdrawing the written description rejections but maintaining the obviousness
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`rejections. (11/6/12 Advisory Action (’571 Application), Ex. 1002 at 2.) First, the
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`Examiner reiterated the argument that Oksche discloses the Suboxone® tablet,
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`which provides an “optimized” absorption of buprenorphine. (Id. at 3.) Second, the
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`Examiner noted that Example 8 from the specification—on which the Applicants
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`relied to show “unexpected” results—only “tested products at a pH of from 3.0-
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`3.5.” (Id. at 3 (emphasis in original)) This was “not sufficient to provide evidence
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`of unexpected or significant benefits associated with the full scope of the claimed
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`invention, which recites a ‘local pH of about 2 to about 3.5 in the presence of
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`saliva.’” (Id. at 3-4 (emphasis in original).) Accordingly, the Examiner determined
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`that “Applicant’s showing is not commensurate in scope with the claimed
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`invention.” (Id. at 4.)
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`46. On November 15, 2012, Applicants filed a Notice of Appeal.
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`(11/15/12 Notice of Appeal (’571 Application), Ex. 1002.) Then, on April 30,
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`2013, Applicants filed a Request for Continued Examination, and amended the
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`pending claims to “recite a local pH range of about 3 to about 3.5 to provide a
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`scope that is fully and expressly supported by the experimental results.” (4/30/13
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`Amendment and Response with Request for Continued Examination (’571
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`Application), Ex. 1002 at 6.) Again, Applicants argued that they had “surprisingly
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`identified that the optimized absorption of buprenorphine and the optimized
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`limited absorption of naloxone do not follow traditional or expected absorption
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`profiles. Both compounds are conjugate organic acids with pKa’s at approximately
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`8, and yet as the pH of the film for delivering the agents decreases, one compound
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`undergoes a optimum adsorption, but the other compound surprisingly trends the
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`opposite direction and is inhibited at the same lower pH levels. This divergence
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`allows the Applicant to produce a film which delivers buprenorphine to the
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`bloodstream and passes the naloxone to the gut where it is ineffective, thus
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`providing a treatment regimen for buprenorphine.” (Id., Ex. 1002 at 6-7.)
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`Applicants argued that “Oksche is completely silent regarding adjusting pH to
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`optimize the adsorption of buprenorphine and minimize the adsorption of
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`naloxone.” (Id. at 7 (emphasis in original).)
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`47. On May 24, 2013, the Examiner issued a Notice of Allowability.
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`(5/24/13 Notice of Allowability (’571 Application), Ex. 1002.) The Examiner cited
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`the results of an interview as the basis on which the claims were allowed. (Id.) At
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`the May 20, 2013 interview, the Examiner “agreed that the prior art does not teach
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`the claimed local pH” based on Applicants’ explanation that “the prior art is silent
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`regarding the use of a buffer to provide a local pH which would achieve optimized
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`absorption of buprenorphine and naloxone.” (5/20/13 Examiner-Initiated Interview
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`Summary (’571 Application), Ex. 1002.)
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`VII. Background and Tutorial
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`A. Buprenorphine and Naloxone
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`48. Buprenorphine is a semi-synthetic compound that can be used to treat
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`certain medical conditions, including opioid dependence and chronic pain. More
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`particularly, buprenorphine is a mixed opioid receptor agonist and antagonist.
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`Because it is a partial agonist, at low doses buprenorphine produces enough agonist
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`effect to provide users with the sought-after euphoria while minimizing withdrawal
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`effects.
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`49. Drugs can be administered by several different routes to achieve a
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`therapeutic effect. But in the end, the ultimate goal is for the drug to be absorbed
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`into the bloodstream. So, for instance, a drug can be swallowed and absorbed into
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`the blood in the intestine (called “peroral” administration). Or, in another instance,
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`a drug can be absorbed through the mucous membranes of the mouth (called “oral”
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`administration).
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`50. Buprenorphine is extensively metabolized in both the gastrointestinal
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`(“GI”) tract and the liver, where it is subjected to extensive first-pass effects.
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`(Cassidy, et al., Controlled buccal delivery of buprenorphine, J. of Controlled
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`Release, 25:21-29 (1993), Ex. 1012 at 21 (“Cassidy”).) Accordingly, a person of
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`ordinary skill would understand that buprenorphine has limited bioavailability
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`when administered perorally (by swallowing). (Id. at 21.) The preferred routes of
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`administration for buprenorphine are intravenous, intramuscular and sublingual.
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`(Id. at 21.) In addition, other transmucosal routes in addition to sublingual
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`administration, such as buccal administration, may be utilized to administer
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`buprenorphine. (Id.) Each of these routes bypasses GI metabolism, thereby
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`minimizing first-pass effects.
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`51. First discovered in 1966 by Reckitt & Colman in the U.K,
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`buprenorphine has been used since 1978 as an analgesic, in the treatment of both
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`acute and chronic pain. (Campbell, et al., The history of the development of
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`buprenorphine as an addiction therapeutic, Ann. N.Y. Acad. Sc. (Issue: Addiction
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`Reviews), 1248:124-139 (2012), Ex. 1016 at 131 (“Campbell”).)
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`52.
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`Initially, buprenorphine was administered via intravenous or
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`intramuscular injections. In the early 1980s, sublingual administration of
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`buprenorphine was reported to be effective to treat pain. (Bullingham, et al.,
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`Sublingual buprenorphine used postoperatively: clinical observations and
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`preliminary pharmacokinetic analysis, Br. J. Clin. Pharmacol., 12:117-22 (1981),
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`Ex. 1017 at 121 (“Bullingham”). Since that time, sublingual administration has
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`become the preferred non-injectable route for buprenorphine. (U.S. Patent App.
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`No. US 2010/0087470, Ex. 1018 at [0015].) The sublingual uptake of
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`buprenorphine is rapid, with near complete uptake occurring within 2 to 4 minutes
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`when it is administered as a solution. (Chiang, et al., Pharmacokinetics of the
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`combination tablet of buprenorphine and naloxone, Drug and Alcohol Dependence,
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`70:S39-S47 (2003), Ex. 1015 at S40 (“Chiang”).
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`53.
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`In 2002, two forms of sublingual buprenorphine were approved in the
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`U.S. for the treatment of opioid dependence: Subutex®, which contained only
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`buprenorphine, and Suboxone®, which combined buprenorphine with naloxone.
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`54. Naloxone is a well-known opioid antagonist and lacks any agonist
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`properties. (EMEA, Ex. 1011 at 1.) Naloxone can reverse or prevent the effects of
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`opioid agonists, such as buprenorphine.
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`55.
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`In 1984, Reckitt & Colman filed a patent application directed to a
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`method of treating pain. In this method, a composition containing a therapeutically
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`effective dose of buprenorphine, together with an amount of naloxone sufficient to
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`prevent the composition from being misused by opioid-dependent subjects, is
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`administered to patients. (U.S. Patent No. 4,582,835, Ex. 1019 at Abstract; 2:34-38
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`(the “’835 patent”). The patent disclosed sublingual and parenteral administration
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`of the composition. (Id. at Abstract; 1:13-15.)
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`B.
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`Suboxone® Sublingual Tablet
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`56. Reckitt Benckiser developed a sublingual tablet containing
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`buprenorphine and naloxone, which was approved by the FDA on October 8, 2002.
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`(Center for Drug Evaluation and Research, Approval Package for App. No. 22-
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`410/S006/S007 (approval date 8/10/12), Ex. 1020 (“Film Approval Package”).)
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`This tablet sold under the trade name Suboxone® and was indicated for the
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`maintenance treatment of opioid dependence. (Suboxone®2002 Label from NDA
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`20-732/NDA 20-733, Ex. 1008 at 26 (“Suboxone® 2002 Label”).)
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`57. Naloxone was included in the formulation “to stop people from
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`injecting (‘shooting-up’) SUBOXONE tablets.” (Suboxone® 2002 Label, Ex. 1008
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`at 26.) The Label explained that “[b]ecause it contains naloxone, SUBOXONE is
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`highly likely to produce marked and intense withdrawal symptoms if misused
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`parenterally by individuals dependent on opioid agonists such as heroin, morphine,
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`or methadone.” (Id. at 15.)
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`TEVA EXHIBIT 1003
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`58.
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`It was well-understood by those skilled in the art that the
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`buprenorphine component of the Suboxone® sublingual tablet
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