UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________
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`TEVA PHARMACEUTICALS USA INC.,
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`Petitioner
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`v.
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`MONOSOL RX, LLC,
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`Patent Owner
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`
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`U.S. Patent No. 8,017,150
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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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` EXHIBIT NO. 1003 Page 1 of 56
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`1. My name is Nandita Das. I have been retained by counsel for Petitioner
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`Teva Pharmaceuticals USA, Inc. (“Teva”). I understand that Teva is petitioning
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`for inter partes review of U.S. Patent No. 8,017,150 (the “’150 patent”), which is
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`owned by MonoSol RX, LLC. I further understand that Teva will request that the
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`United States Patent and Trademark Office (“USPTO”) cancel certain claims of
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`the ’150 patent as unpatentable. I submit this expert declaration, which addresses
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`and supports Teva’s petition.
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`I.
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`2.
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`Qualifications and Background
`A. Education and Experience; Prior Testimony
`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
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`promoted to Associate Professor in Spring 2012. Prior to my time at Butler
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`University, I was an Assistant Professor of Pharmaceutics at Idaho State
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`University, previous to which I taught as an Adjunct Professor at Nova
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`Southeastern University while working full time as a licensed pharmacist in the
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`state of Florida. A copy of my curriculum vitae and list of publications is
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`attached as Ex. 1047.
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`3.
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`I received a B.Pharm. in Pharmacy from Banaras Hindu University in India
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`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 University
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`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 graduate
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`scholar with SmithKline Beecham Pharmaceuticals, studying microcalorimetry
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`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, Butler
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`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 2002
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`through July 2006, I conducted a study on the use of mucadhesive buprenorphine
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`in opioid addiction therapy for the National Institute of Health’s National
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`Institute on Drug Abuse.
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`10.
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`In 2004, I published an article on the development of mucoadhesive dosage
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`forms of buprenorphine for sublingual delivery in Drug Delivery – The Journal
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`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 State
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`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
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`(2012).
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`13.
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`I have authored or co-authored over 70 articles, abstracts, papers and book
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`chapters and am a named inventor on one domestic patent. I have also appeared
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`at 6 conferences on topic areas of present interest, including mucoadhesive
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`sublingual delivery systems for buprenorphine.
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`14.
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`I am a member of various professional societies, including the American
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`Association of Pharmaceutical Scientists and the American Association of
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`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
`15. Exhibit 1048 includes a list of the materials I considered, in addition to my
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`experience, education, and training, in providing the opinions contained herein.
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`Scope of Work
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`C.
`I have been retained by Teva as a technical expert in this matter to provide
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`16.
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`various opinions regarding the ’150 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
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`any other current or past affiliation as an expert witness or consultant with Teva.
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`I do not have any current or past affiliation with MonoSol RX, LLC, or any of the
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`named inventors on the ’150 patent.
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`II.
`17.
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`Summary of Opinions
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`I understand that Teva is challenging the validity of claims 1, 4-10, and 13-
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`18 of the ’150 patent (“the Challenged Claims”).
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`18.
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`In reaching these opinions, I have reviewed the ’150 patent as well as
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`portions of the file history of the ’150 patent. I have also reviewed references and
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`articles, which I describe in greater detail below, and the materials listed in
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`Exhibit 1048 attached hereto. I have also relied upon my education, background,
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`and experience in reaching the conclusions and in forming the opinions set forth
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`herein.
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`19. To summarize, for the reasons set forth below, it is my opinion that the
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`Challenged Claims of the’150 patent are obvious in view of the prior art,
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`including art that discloses the use of hydrophilic cellulosic polymers and both
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`low and high molecular weight polyethylene oxide (“PEO”) to form uniform film
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`products containing active pharmaceutical ingredients.
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`20. For the reasons set forth below, the Challenged Claims are entitled to a
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`priority date no earlier than April 22, 2008. Alternatively, to the extent the Board
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`determines that the specification of the ’150 patent contains a sufficient written
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`description to support the claimed invention, the Challenged Claims are entitled
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`to a priority date no earlier than May 23, 2003. It is my further opinion that the
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`Challenged Claims would have been obvious to a person of ordinary skill in the
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`art as of May 23, 2003 and April 22, 2008. The Challenged Claims of the ’150
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`patent represent no more than a combination of familiar elements assembled
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`according to known methods to yield predictable results.
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`21.
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`It is my opinion that one of ordinary skill in the art would have recognized
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`that a mucosally-adhesive, water-soluble film product as claimed in the
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`Challenged Claims of the ’150 patent was already disclosed in Yang. Yang
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`disclosed various film compositions containing combinations of low molecular
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`weight PEO, higher molecular weight PEO and hydrophilic cellulosic polymers.
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`A person of ordinary skill in the art would understand from Yang’s disclosures
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`that the exact proportions of such film compositions could be readily and easily
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`modified using the teachings of the prior art to obtain a film composition with the
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`qualities described and claimed in the ’150 patent. One of ordinary skill in the art
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`would also have recognized that combining small amounts of high molecular
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`weight PEOs with low molecular weight PEOs improved the tear resistance of
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`the final film. From Yang, one of ordinary skill in the art would have further
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`recognized that films having 60% or greater amounts of low molecular weight
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`PEO in such combinations resulted in faster dissolution of the films when in
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`contact with mucous membranes.
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`22. Even before the publication of Yang, the properties of the claimed film
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`compositions were well-described in the art and were well-known to a person of
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`ordinary skill. The use of PEO in film compositions for use in delivering active
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`pharmaceutical agents was disclosed in at least Schiraldi, including the use of
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`analgesics. This reference also teaches the use of cellulosic polymers in
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`combination with PEO to produce a film with desirable structural characteristics.
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`The combination of low molecular weight PEO and high molecular weight PEO
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`in such compositions was a well-known means of further manipulating the
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`structural properties of film compositions to attain desired thickness, uniformity,
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`and tensile and shear strength. Such film compositions were routinely employed
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`by those of ordinary skill in the art. As such, it would have been obvious to those
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`of ordinary skill in the art to combine low molecular weight PEO, higher
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`molecular weight PEO, and a hydrophilic cellulosic polymer, and modify the
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`proportions of each component of the film composition to attain a film with the
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`claimed structural properties and uniformity.
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`III. Legal Standards
`23.
`I understand that a preponderance of evidence must be presented to render
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`a patent claim invalid in this proceeding.
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`24.
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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) (2006).
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`25.
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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
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`claim must be present within the prior art, or within the prior art in combination
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`with the general knowledge held by a person of ordinary skill in the art, and that
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`such a 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 in doing so may be found in the teachings of
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`the 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
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`more than yield predictable results.
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`26.
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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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`27.
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`I understand that a claim may be obvious when it is the result of combining
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`familiar elements according to known methods to achieve predictable results. The
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`claim is obvious when a person of ordinary skill in the art would have been
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`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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`28.
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`I understand that secondary considerations of non-obviousness must be
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`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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`29.
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`I have relied upon this understanding of the applicable legal standards in
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`reaching my opinions set forth in this declaration.
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`IV. Person of Ordinary Skill in the Art
`30.
`It is my opinion that in the context of the ’150 patent, a person of ordinary
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`skill in the art would include a person who possesses a Master’s degree or Ph.D.
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`in pharmaceutical sciences, chemistry, or a related filed, and a number of years of
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`experience.
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`V. The ’150 Patent
`31.
`I have read the ’150 patent, entitled “Polyethylene Oxide-based Films and
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`Drug Delivery Systems Made Therefrom.” The ’150 patent was filed on April
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`22, 2008, as U.S. Patent Application No. 12/107,389, and is a division of U.S.
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`Patent Application No. 10/856,176, which was filed on May 28, 2004 and is now
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`U.S. Patent No. 7,666,337, which is a continuation-in-part of application No.
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`PCT/US02/032575, filed on Oct. 11, 2002, and a continuation-in-part of
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`application No. PCT/US02/32594, filed on Oct. 11, 2002, and a continuation-in-
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`part of application No. PCT/US02/32542, filed on Oct. 11, 2002. The ’150
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`patent was issued on Sep. 13, 2011.
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`32.
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`I understand that Teva is challenging claims 1, 4-10, and 13-18 of the ’150
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`patent. Claims 1 and 10 are independent.
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`33.
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`Independent claim 1 recites:
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`A mucosally-adhesive water-soluble film product comprising: an
`analgesic opiate pharmaceutical active; and at least one water-soluble
`polymer component consisting of polyethylene oxide in combination
`with a hydrophilic cellulosic polymer; wherein: the water-soluble
`polymer component comprises greater than 75% polyethylene oxide
`and up to 25% hydrophilic cellulosic polymer; the polyethylene
`oxide comprises one or more low molecular weight polyethylene
`oxides and one or more higher molecular weight polyethylene oxides,
`the molecular weight of the low molecular weight polyethylene oxide
`being in the range of 100,000 to 300,000 and the molecular weight of
`the higher molecular weight polyethylene oxide being in the range of
`600,000 to 900,000; and the polyethylene oxide of low molecular
`weight comprises about 60% or more in the polymer component.
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`34.
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`Independent claim 10 recites:
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`A mucosally-adhesive water-soluble film product comprising: an
`analgesic opiate pharmaceutical active; and at least one water-soluble
`polymer component consisting of polyethylene oxide in combination
`with a hydrophilic cellulosic polymer; wherein: the water-soluble
`polymer component comprises the hydrophilic cellulosic polymer in a
`ratio of up to about 4:1 with the polyethylene oxide; the polyethylene
`oxide comprises one or more low molecular weight polyethylene
`oxides and one or more higher molecular weight polyethylene oxides,
`the molecular weight of the low molecular weight polyethylene oxide
`being in the range of 100,000 to 300,000 and the molecular weight of
`the higher molecular weight polyethylene oxide being in the range of
`600,000 to 900,000; and the polyethylene oxide of low molecular
`weight comprises about 60% or more in the polymer component.
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`35. Dependent claims 4-9 and 13-18 of the ’150 patent relate to the addition to
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`the formulation of other pharmaceutical actives, sweeteners, flavors, and buffers.
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`36.
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`I understand that the claim terms in the ’150 patent are presumed to take on
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`their ordinary and customary meaning based on the broadest reasonable
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`construction in light of the specification of the patent in which it appears. I have
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`been informed by counsel that Patent Owner has alleged in a co-pending
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`litigation that claims 1 and 10 do not require a hydrophilic cellulosic polymer
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`component.1 For the term:
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`least one watersoluble polymer component consisting of
`at
`polyethylene oxide in combination with a hydrophilic cellulosic
`polymer; wherein the water-soluble polymer component comprises
`greater than 75% polyethylene oxide and up to 25% hydrophilic
`cellulosic polymer,
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`(Ex. 1001, ’150 Patent at claim 1), Patent Owner proposed the following as a
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`construction:
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`at
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`least one water-soluble polymer component consisting of
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`polyethylene oxide and optionally hydrophilic cellulosic polymer,
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`wherein the polyethylene oxide is in an amount of greater than 75% of
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`the polymer component and there may be up to 25% hydrophilic
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`cellulosic polymer in the polymer component.
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`1 See Ex. 1009, Joint Claim Construction Chart, Reckitt Benckiser Pharmaceuticals
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`Inc. v. Teva Pharmaceuticals USA, Inc., CA No. 14-1451-RGA (November 17,
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`2015), D.I. 91, at 4-5.
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`(Ex. 1009, Joint Claim Construction Chart at 4-5) (emphasis added).)
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`37. Similarly, for the term:
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`at least one water soluble polymer component consisting of
`polyethylene oxide in combination with a hydrophilic cellulosic
`polymer; wherein: the water-soluble polymer component comprises
`the hydrophilic cellulosic polymer in a ratio of up to about 4:1
`with the polyethylene oxide
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`(Ex. 1001, ’150 Patent at claim 10). Patent Owner proposed the following
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`construction:
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`at least one water-soluble polymer component consisting of
`polyethylene oxide and optionally hydrophilic cellulosic polymer,
`wherein the ratio of hydrophilic cellulosic polymer to polyethylene
`may be up to about 4:1.
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`(Ex. 1009, Joint Claim Construction Chart at 5 (emphasis added))
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`38.
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`I have applied the ordinary and customary meaning of all claim terms,
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`unless otherwise provided.
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`B. Relevant Prosecution History of the ’150 Patent
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`39. Generally, as described above, the film formulations of the Challenged
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`Claims include a polymer component that has three requirements: (a) a
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`combination of PEO and HPC2; (b) a combination of PEOs having low and high
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`2 As stated earlier, it is my understanding that Patent Owner has proposed in a
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`separate proceeding that independent claims 1 and 10 should be construed as not
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`average molecular weight3; and (c) a specific percentage of low molecular weight
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`PEO. Although the ’150 patent claims priority to several applications dating as
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`far back as 2001, as explained below, these three requirements were not actually
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`disclosed in Patent Owner’s applications until much later.
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`C.
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`Priority Date Of The ’150 Patent
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`40.
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`I understand that prior art is evaluated based on the priority date afforded
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`to the patent under review. I understand that Patent Owner has asserted in a
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`separate litigation a priority date of on or after May 28, 2003 for the ’150 patent.
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`(See, e.g., Ex. 1013, Reckitt Benckiser v. Watson, CA No. 13-cv-01674-RGA,
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`D.I. 347, at 6.)
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`41.
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`I understand that a patent is entitled to the priority date of an earlier filed
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`application if (1) the written description of the earlier filed application discloses
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`requiring a hydrophilic cellulosic polymer (“HPC”). The claims are obvious, in my
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`opinion, whether or not HPC is construed as a limitation of the claim.
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`3 It should be understood that whenever I am refer to polymer molecular weight in
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`this declaration, I am referring to average molecular weight. Sometimes in this
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`declaration, I will explicitly say “average molecular weight” and at other times, to
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`improve readability, I will simply say “molecular weight.” Unless expressly stated
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`otherwise, I mean the phrases “average molecular weight” and “molecular weight”
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`to mean the same thing in the context of polymers.
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`the invention claimed in the later filed application sufficient to satisfy the
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`requirements of § 112; (2) the applications have at least one common inventor;
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`(3) the later application is filed before the issuance or abandonment of the earlier
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`filed application; and (4) the later application contains a reference to the earlier
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`filed application. I understand that a description that merely renders the invention
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`obvious does not satisfy the written description requirement, and support in the
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`written description must be based on what actually is disclosed and not an
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`obvious variant of what is disclosed. I further understand that if the later filed
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`application claims priority through a hereditary chain of applications, each
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`application in the chain must satisfy § 112.
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`42.
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`I understand that the burden resides with the proponent of invalidity to
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`demonstrate that the patentee is not entitled to the benefit of the earlier filing
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`date.
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`43.
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`It is my opinion that the ’150 patent is not entitled to a priority date any
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`earlier than April 22, 2008. The first disclosure of a film in which the polymer
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`component as a whole was made up of low molecular weight PEO appeared in
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`the claims of the application that would become the ’150 patent, filed on April
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`22, 2008. Although Table 22 of the ’150 patent describes films containing HPC
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`and PEO, none of those compositions describes a film that satisfies the claimed
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`ratio.
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`44.
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`It is my understanding that the earliest application to which the ’150 patent
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`claims priority is U.S. Provisional Application No. 60/328,868 (“the ’868
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`application”), which was filed on October 12, 2001. That provisional application,
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`however, does not disclose a mucosally-adhesisve water-soluble film product
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`comprising a water-soluble polymer component consisting of PEO in
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`combination with HPC, as required by the Challenged Claims. Instead, the ’868
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`application discloses film formulations containing propylene glycol (“PEG”).4
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`Not only does the ’868 application lack any disclosure of PEO itself, there is no
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`disclosure of a film containing (a) a combination of PEO and HPC; (b) a
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`combination of PEOs having low and high average molecular weight; and (c) a
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`specific percentage of low molecular weight PEO.
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`45.
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`It is my understanding that the ’150 patent claims priority to other
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`applications filed before May 8, 2003, but none of them describe PEO as a
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`component of a film formulation. Certainly, none of those applications describe
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`(a) a combination of PEO and HPC; (b) a combination of PEOs having low and
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`high average molecular weight; and (c) a specific percentage of low molecular
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`weight PEO. (See, e.g., U.S. Provisional Appl. No. 60/386,937 (filed June 27,
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`4Despite its reference to PEG, a skilled artisan at the time the application was filed
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`would still understand that the molecular weights disclosed to be average
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`molecular weights.
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`2002); PCT/US02/32542 (filed October 11, 2002); PCT/US02/32575 (filed
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`October 11, 2002); PCT/US02/32594 (filed October 11, 2002); U.S. Prov. App.
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`No. 60/443,741 (filed January 30, 2003); U.S. App. No. 10/074,272 (filed
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`February 14, 2002); U.S. Provisional Appl. No. 60/371,940 (filed April 11,
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`2002); U.S. Provisional App. No. 60/414,276.)
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`46.
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`It is my understanding that the first application in the priority chain of the
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`’150 patent that discloses both PEO and HPC is U.S. Provisional Application No.
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`60/473,902 (“the ’902 application”), filed on May 28, 2003. That application
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`describes multiple films containing varying amounts of PEOs having various
`
`average molecular weights, including some formulations that also combine PEO
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`with HPC. (See, e.g., Ex. 1011, ’902 application at 79.) Two of the embodiments
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`described at Table 22 of the ’902 application (DT and DU) include a polymer
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`component having: (a) a combination of PEO and HPC; and (b) a combination of
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`PEOs having low and high average molecular weight. However, there are no
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`embodiments in the ’902 application describing a polymer component that
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`includes a specific percentage of low molecular weight PEO.
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`47. The specification of the ’902 application notes that “[t]he tear resistance of
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`lower levels of PEO, however, was shown to be improved by combining small
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`amounts of higher molecular weight PEOs with the lower molecular weight
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`PEOs (e.g. Compositions DT and DU).” (Ex. 1011, ’902 application at 81.) And
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`the specification acknowledges that “[i]n those films containing combinations of
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`varying molecular weight PEOs, those with about 60% or higher of the lower
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`molecular weight PEOs (100,000 to 300,000) in the PEO combination dissolved
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`faster.” (Ex. 1011, ’902 application at 81 (emphasis added).) But, despite its
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`description of films combining PEOs of different molecular weight, the ’902
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`application does not disclose any film compositions including a polymer
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`component having a specific percentage of low molecular weight PEO, as
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`required by the claims. In other words, there is no disclosure (either generally or
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`by specific example) of a film formulation in which the polymer component, e.g.,
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`the combination of PEO and HPC, includes “the polyethylene oxide of low
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`molecular weight comprises about 60% or more in the polymer component.”
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`48. Any other application filed before April 22, 2008 and cited as an alleged
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`priority document for the ’150 patent is similarly deficient: no application filed
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`before April 22, 2008 discloses film formulations in which a PEO of low
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`molecular weight comprised 60% or more of the polymer component as a whole.
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`(See Ex. 1017, U.S. App. No. 10/856,176 (filed May 28, 2004).)
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`49.
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`It is my understanding that the application that ultimately issued as the
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`’150 patent was filed on April 22, 2008. That specification contained the same
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`disclosure as the ’902 application, describing films containing a polymer
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`component that included a combination of PEO and HPC and a combination of
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`PEOs having low and high average molecular weight, but in none of those films
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`was the low molecular weight PEO 60% of the polymer component as a whole.
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`However, Applicants prosecuted claims directed to a film composition containing
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`a polymer component reciting a specific percentage (60%) of low molecular
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`weight PEO in the polymer component as a whole. (See, e.g., Ex. 1001, ’150
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`patent claims 1 and 10.)
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`50.
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`It is my understanding that during prosecution, the Examiner rejected the
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`claims as obvious over Schiraldi (Ex. 1004), which disclosed polymers having
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`molecular weights “above 100,000 and preferably above 3,000,000.” (Ex. 1002,
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`Non-Final Rejection, April 29, 2010 at 3; Ex. 1004, Schiraldi at 4:26-27.) In
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`response, Applicants argued that Schiraldi failed to teach the claimed
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`combination of molecular weights of the ’150 patent. (Ex. 1002, Response to
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`Office Action, July 29, 2010 at 2-3.)
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`51. Further, it is my understanding that Applicants argued that the prior art did
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`not provide any motivation to select low molecular weight polymers, and did not
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`disclose the use of a particular combination of molecular weight polymers. (Ex.
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`1002, Response to Office Action, July 29, 2010 at 3.) Applicants also argued that
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`they had “discovered that the particular combination of molecular weights and
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`polymers claimed provides a suitable release profile for an opiate.” (Ex. 1002,
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`Response to Office Action, July 29, 2010 at 3.) Finally, Applicants emphasized
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`that “[t]he claims recite a particular combination of polymers, having a particular
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`molecular weight, in a particular ratio. This is not a matter of simply testing
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`different molecular weights, or simply testing different ratios.” (Ex. 1002,
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`Response to Office Action, July 29, 2010 at 4.)
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`52.
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`It is my understanding that during the prosecution history of the ’150
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`patent, the Applicants relied heavily on Examples DH-DZ in asserting the
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`claimed invention as novel and non-obvious over the prior art. (See, e.g., Ex.
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`1002, Response to Office Action, July 29, 2010 at 3 (“The Applicant has
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`discovered that the particular combination of molecular weights and polymers
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`claimed provides a suitable release profile for an opiate, and still provides a
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`suitable dosage form. (See, for example, Examples DH-DZ).”) These purported
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`embodiments were critical to the patentee’s arguments that resulted in allowance,
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`thus the ’150 patent cannot claim priority prior to the date of their disclosure—
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`May 8, 2003.
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`53. For the reasons described above, it is my opinion that the Challenged
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`Claims of the ’150 patent are entitled to a priority date of April 22, 2008.
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`However, even if the ’150 patent is entitled to an earlier priority date of May 28,
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`2003, it is still my opinion that the Challenged Claims are invalid.
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`VI. Background and Technology Tutorial
`A. Mucosally-Adhesive Drug Delivery Systems
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`54. Since at least the 1980s, drug formulators have developed mucosally-
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`adhesive systems for transmucosal drug delivery. (See, e.g., Ex. 1018, Anders R.
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`& Merkle, H.P., Evaluation of Laminated Muco-Adhesive Patches for Buccal
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`Drug Delivery, 49 Int’l J. Pharmaceutics 231 (1989) (“Anders”).) In particular,
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`formulators recognized the benefits of delivery directly to the oral mucosa as a
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`way to ensure rapid drug delivery and avoid the hepatic first-pass effect. (Ex.
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`1018, Anders at 231.) By contrast, transmucosal delivery allows the drug to be
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`directly absorbed into circulation via the blood vessels of the submucosa (Ex.
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`1019, Patel et al., Advances in Oral Transmucosal Drug Delivery, 153 J.
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`Controlled Release 106, 107, Fig. 2 (2011).)
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`55.
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`In the 1980s and 1990s, formulators developed film formulations that
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`likewise contained a mucoadhesive layer, but lacked a backing. (See, e.g., Ex.
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`1004, Schiraldi); Ex. 1020, U.S. Patent No. 5,948,430 (“Zerbe”); Ex. 1021, WO
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`00/42992 (“Chen”); Ex. 1022, Guo & Zerbe, Water-Soluble Film for Oral
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`Administration, 13th International Symposium on Controlled Release of
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`Bioactive Materials, 227-28 (1997) (“Guo”).) With or without a backing, the
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`general premise behind these formulations was the same—mucoadhesive
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`matrices were used to deliver drugs or other agents via transmucosal absorption.
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`56. These formulators knew and employed several basic principles in ensuring
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`these drug delivery systems were suitable for their intended use. For example, as
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`with any drug formulation, it was important that the drug was homogenously and
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`uniformly dispersed throughout the mucoadhesive matrix. (See, e.g., Ex. 1023,
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`EP 0090560 at 4:15 (“Mitra”); Ex. 1024, U.S. Patent No. 4,849,246 (“Schmidt”)
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`at 1:63-69; Ex. 1021, Chen at 17:6-13; Ex. 1026, Le Person, et al., Near Infrared
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`Drying of Pharmaceutical Thin Films: Experimental Analysis of Internal Mass
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`Transport, 37 Chemical Engineering & Processing 257, 257 (1998)
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`(“LePerson”).) Uniform distribution of an active throughout the matrix is
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`important to ensure that the final dosage form satisfies the regulatory
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`requirements. (See, e.g., Ex. 1024, Schmidt at 1:63-68.)
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`57. The degree of mucoadhesion was also known to be an important
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`characteristic of transmucosal drug delivery systems—mucoadhesion is
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`necessary to ensure that the drug remains in contact with the mucosa for a
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`sufficient time to ensure delivery across the membrane. (Ex. 1027, DeGrande,
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`Specialized Oral Mucosal Drug Delivery Systems at 287.) It was known that
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`polymers, such as polyethylene oxides, could be used to achieve mucoadhesion,
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`and characteristics of the polymer such as molecular weight affected the degree
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`of mucoadhesion. (See, e.g., Ex. 1028, Apicella et al., Poly(ethylene oxide)
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`(PEO) and Different Molecular Weight PEO Blends Monolithic Devices for Drug
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`Release, 14(2) Biomaterials 83, 84 (1993) (“Apicella”); Ex. 1029, Merkle et al. at
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`133.)
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`58. Additionally, it was recognized in the 1980s and 1990s that characteristics
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`such as solubility and rate of dissolution were important factors that affected drug
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`release and absorption. (See, e.g., Ex. 1027,