•
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Attorney Docket: 07026316
`
`Applicant:
`
`Kao et al
`
`Application Serial No.: 111680,432
`
`Filed: February 28, 2007
`
`)
`)
`)
`)
`)
`)
`)
`Title: OXYMORPHONE CONTROLLED)
`RELEASE FORMULATIONS
`)
`)
`
`Examiner:
`
`L.S. Channavajjala
`
`Group Art Unit:
`
`1615
`
`DECLARATION OF SOU-CHAN CHANG, Ph.D
`
`I, Sou-Chan Chang, hereby state as follows:
`
`•
`
`1.
`
`I am the Director of Pharmaceutics Development and Process Chemistry at Endo
`
`Pharmaceuticals, Inc., which is the owner of U.S. Application Serial No. 111680,432 (''the '432
`
`Application"). A true and correct copy of my curriculum vitae is attached as Exhibit 1.
`
`2.
`
`In my role as Director, I am responsible for the portion of new drug developmenf
`
`characterized by U.S. Food and Drug Administration (FDA) practice as Chemistry,
`
`Manufacturing and Control (CMC). In discharging this responsibility I coordinate/manage
`
`development partners, contract developers, contract testing laboratories, and contract
`
`manufacturers. I also direct research and development (R&D) activities concerning drug
`
`formulation, manufacturing processes, analytical methods and stability testing. Furthermore, I
`
`also oversee technology transfer to different facilities ofEndo and to contract partners, scale-up
`
`of processes from the laboratory through pilot plant to full manufacturing scale, validation of all
`
`aspects of CMC, and production of clinical samples. In addition I support post-market product
`
`re-formulation, line-extension, and manufacturing process improvement.
`
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`

`
`3.
`
`My experiences in the development of controlled-release pharmaceutical oral
`
`dosage forms include: Morphine Sulfate ER Tablets, (Generic alternative toMS Contin®);
`
`Oxycodone HCl ER tablets (Generic alternative to OxyContin®); Opana® ER (Oxymorphone
`
`HCl) ER tablets; and several other generic and proprietary developmental ER products. My
`
`experiences in the development of immediate-release pharmaceutical oral dosage forms include:
`
`Oxy/APAP capsules, ButalbitaVASNCodiene capsules, Etodolac tablets, Percocet tablets,
`
`Zydone tablets, Symmetrel tablets, Opana® IR tablets, and several other generic and proprietary
`
`developmental IR products.
`
`The '432 Application
`
`4.
`
`I have read and I understand the contents of the '432 Application, including the
`
`claims. Generally, the '432 Application discloses controlled-release phannaceutical
`
`compositions comprising oxymorphone, particularly oxymorphone HCl, and methods for using
`
`such compositions. Oxymorphone is a narcotic analgesic, useful in the treatment of acute and
`
`chronic pain. The '432 Application discloses,' among other things, examples of controlled-
`
`release oxymorphone formulations, release rates of the oxymorphone from such formulations,
`
`and pharmacokinetic data relating to oxymorphone and its active metabolite, 6-0H
`
`oxymorphone, including data under fasting and fed conditions. The '432 Application concludes
`
`with claims, which I understand define the invention to which the application is directed. The
`
`independent claims currently pending are as follows:
`
`A controlled release phannaceutical composition in the form of a tablet,
`1.
`comprising oxymorphone or a pharmaceutically acceptable salt thereof as the sole
`active ingredient in the tablet, and a controlled release delivery system comprising
`at least one pharmaceutical excipient, wherein upon placement of the composition
`in an in vitro dissolution test comprising USP Paddle Method at 50 rpm in 500 m1
`media having a pH of 1.2 to 6.8 at 37 oc, about 15% to about 50%, by weight, of
`
`2
`
`•
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`1433613
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`461
`
`

`
`the oxymorphone or salt thereof is released from the tablet at about 1 hour in the
`test.
`
`A controlled release pharmaceutical composition in the form of a tablet,
`20.
`comprising oxymorphone or pharmaceutically acceptable salt thereof as the sole
`active ingredient in the tablet and a controlled release delivery system comprising
`a hydrophilic material that forms a gel upon exposure to gastrointestinal fluid,
`wherein upon placement of the composition in an in vitro dissolution test
`comprising USP Paddle Method at 50 rpm in 500 ml media having a pH of 1.2 to
`6.8 at 37 oc, about 15% to about 50%, by weight, of the oxymorj>hone or salt
`thereof is released from the composition at about 1 hour in the test, about 45% to
`about 80%, by weight, of the oxymorphone or salt thereof is released from the
`composition at about 4 hours in the test, and at least about 80%, by weight, of the
`oxymorphone or salt thereof is released from the composition at about 1 0 hours in
`the test.
`
`5.
`
`I have been told that the Examiner has rejected these independent claims, as well
`
`as several other claims, as not being enabled because it would require undue experimentation to
`
`choose from the options given by the specification and determine a formulation that would yield
`
`the claimed limitations. As explained below, I disagree with the Examiner's conclusions.
`
`6.
`
`The '432 Application describes numerous different controlled release systems,
`
`including the osmotic pump, a number of controlled release coatings, and a variety of controlled
`
`release matrix systems. Some of these are well-known in the art and are marketed by companies
`
`as usable for a variety of diverse drugs.
`
`Enablement of the '432 Application Claims
`
`7.
`
`Based on my review of the '432 Application and my experience as one of skill in
`
`the pharmaceutical arts, the following paragraphs contain my conclusions as to why Endo's
`
`claimed invention is enabled and would be obtainable by one of ordinary skill in the art without
`
`undue experimentation given the disclosure of the '432 Application .
`
`•
`
`1433613
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`•
`
`8.
`
`The prior art controlled release systems are generally well understood in the
`
`pharmaceutical arts. Drug formulation companies market these systems as being usable for a
`
`variety of drug substances and tout their ability to conform the systems to needed specifications.
`
`9.
`
`For instance, the specification has an extensive discussion of the osmotic pump
`
`technology pioneered by Alza Corporation. This technology is old and well known. One of the
`
`first patents on this technology was issued back in 1973.
`
`10.
`
`Assuming that one already knows the dissolution profile that is needed for safe,
`
`therapeutic effect for a given drug substance, a person of skill in the art would be able to choose
`
`one of the available and known controlled release systems, incorporate the drug product into said
`
`system, and run routine tests to determine whether a given formulation obtains the dissolution
`
`profile needed. It is the determination of exactly what the dissolution profile should be for a
`
`given drug to provide safe yet therapeutic blood levels that requires inventive effort and
`
`substantial experimentation. Indeed, for a given drug there may not even be a dissolution profile
`
`that provides safe and therapeutic effect for the time period desired.
`
`11.
`
`I am told that the Examiner has asserted that "one can not expect the same release
`
`profile from all kinds of release systems". I believe that many release systems can be adjusted to
`
`achieve a wide range of release profiles, first because I have done this, and second because the
`
`assorted competing drug formulation companies are each readily able to provide a given release
`
`profile with their chosen technology without undue experimentation. Those companies will
`
`readily supply a formulation with whatever release profile is desired to a customer who requests
`
`it. Likewise, one of skill in the art would know how to use a variety of other prior art
`
`technologies and would understand how they could be altered to give the same release profile.
`
`1433613
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`463
`
`

`
`12.
`
`It would not require undue experimentation or further invention to alter the
`
`formulation of such a controlled release system to obtain the desired dissolution profile because
`
`the function of the known controlled release systems is well understood by those of skill in the
`
`art. As such, one of skill in the art would know how to alter the formulation in order to obtain
`
`the desired dissolution profile.
`
`Conclusions
`
`13.
`
`It is my opinion that it would not require undue experimentation to alter the
`
`disclosed and known controlled release systems to obtain a given dissolution profile of
`
`oxymorphone ..
`
`I4.
`
`This declaration summarizes my views regarding the above topics. It is not
`
`intended to be comprehensive. As such, I reserve the right to modify or supplement the
`
`• statements made herein .
`
`IS.
`
`I declare that all statements made herein of my own knowledge are true and that
`
`all statements made on information and belief are believed to be true; and further, that these
`
`statements are made with the knowledge that willful, false statements and the like so made are
`
`punishable by fine or imprisonment or both, under Section I 00 I of Title IS of the United States
`
`Code and that such willful false statements may jeopardize the validity of the application or any
`
`patent issued thereon.
`
`~d-4
`
`Sou-Chan Chang
`
`1433613
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`
`464
`
`

`
`465
`
`•
`
`EXHIBIT 1
`
`465
`
`

`
`•
`
`•
`
`Sou-Chan Chang
`
`31 Cutter Ct
`West Islip, NY 11795
`(631) 902-2129
`
`Professional Experiences
`
`Experienced in the following areas:
`• Due diligence- technical (CMC) review in support of mergers and acquisitions
`• Out sourcing management - audit, selection and managing of CROs and CMOs
`• Pharmaceutics development- drug substance, analytical and formulation development;
`technology transfer and scale-up; validation and commercialization
`• R&D QA and cGMP operations
`• CMC deliverables for pre-clinical, IND, NDA, ANDA, and SUPAC applications
`• Automation and system implementation and validation
`• Project/budget management
`
`Employment History
`
`Endo Pharmaceuticals Inc, Chadds Ford, PA; Westbury, NY
`2006- present:
`Director, Pharmaceutics Development and Process Chemistry
`1999-2006:
`Director, Pharmaceutics Development
`1997- 1999:
`Manager, Analytical Development
`Manager, Analytical Development (then DuPont Merck,
`1995-1997:
`Endo Laboratories, L.L.C.)
`
`•
`
`Is responsible for new drug CMC development by coordinating/managing development
`partners, contract developers, contract testing laboratories, and contract manufacturers
`• Participate in due diligence CMC review for prospective M&A opportunities of companies
`and/or new products
`• Direct R&D activities concerning formulation, manufacturing process, analytical, stability,
`technology transfer, scale-up, validation, and clinical supplies
`• Oversee laboratory operations ensuring compliance with FDA and DEA regulations.
`Respond to FDA/DEA inspection and review comments
`• Support preparation of, and review CMC section for IND, NDA, and ANDA submissions
`• Support post-market product re-formulation, line-extension, and manufacturing process
`improvement
`• Manage resource, budget and project timeline
`
`Hoechst Marion Rousse~ Inc. (now Sano.fi Aventis), Somerville, NJ
`1994- 1995: Group Leader, Product Development/Analytical Development
`1993- 1994: Team Leader/Research Associate, Quality Assurance/Analytical Development
`1990-1993: Senior Analytical Chemist, Quality Assurance/Analytical Development
`
`• Was responsible for analytical support for various phases of new drug development including
`drug substance synthesis scale-up, pre-clinical activities, clinical supplies, and process
`validation
`Interacted with multiple disciplines in project team and supervised a group of scientists on
`day-to-day laboratory operations
`
`•
`
`466
`
`

`
`•
`
`• Performed analytical method development, validation, monograph/specifications preparation,
`reference standard qualification, release and stability testing, cleaning and process validation,
`technology transfer and environmental assessment
`• Provided analytical deliverables for the CMC section of IND, NDA, and ANDA submissions
`• Responded to FDA review comments and audit observations
`
`Hoechst Celanese Corporation, Advanced Technology Group, Corpus Christi, TX
`1988- 1990: Research Chemist/Project Analyst
`
`• Supported the synthesis/process development for commodity chemicals and pharmaceutical
`intermediates
`• Was responsible for on-line sampling system design and implementation for various projects
`at pilot-scale
`• Set up a QC laboratory and supervised the operation to support the pilot operation
`
`Rice University, Department of Chemistry, Houston, TX
`1987- 1988: Postdoctoral Research Associate
`1982- 1987: Graduate Research Fellow
`
`•
`
`Research included:
`•
`Isolation and characterization of metal methylene (M=CH2) in low temperature matrices
`• Stabilization and reactions of metal micro-particles in plasma-polymerized organic films
`• Mechanistic studies of thin film diamond formation via chemical vapor deposition process
`
`National Tsing-Hua University, Department of Chemistry, Taiwan
`1980- 1982: Research Assistant
`
`Worked on the reactions of difluoro-silylene with unsaturated hydrocarbons, and the stabilization
`of silicon-carbon double bonded intermediates in transition metal complexes.
`
`Academic Qualifications
`
`Ph. D. in Chemistry, Rice University, Houston, Texas, 1987
`B.S. in Chemistry, National Tsing-Hua University, Taiwan, Republic of China, 1978
`
`Professional Affiliations
`
`American Chemical Society, American Association of Pharmaceutical Scientists, Sigma Xi
`
`467
`
`

`
`•
`
`Patents
`
`1. US Patent 6,168,805, "Aqueous process for manufacturing paroxetine solid dispersions."
`2. US Patent 5,955,475, "Process for manufacturing paroxetine solid dispersions."
`3. W02007146006, "Sustained release oxycodone composition with acrylic polymer"
`4. W02007146005, "Sustained release oxycodone composition with acrylic polymer and metal
`hydroxide"
`5. W002100382, "Controlled release dosage forms using acrylic polymer, and process for
`making"
`
`Publications
`
`1. W. E. Billups, Sou-Chan Chang, Robert H. Hauge, and John L. Margrave, "Reactions of
`Atomic Manganese with CH2N2 in Solid Argon at 12K," Organometallics 1999, 18, 3551-
`3553.
`
`2. Chang, S.C., Gigantino, J. J., Radzik, D. M., and Rychtman, A. C., "The Use of Capillary
`Electrophoresis in Pharmaceutical Development", Chapter 11 in "Pharmaceutical and
`Biomedical Applications of Capillary Electrophoresis", edited by S.M. Lunte and D. M.
`Radzik, Pergamon I Elsevier, Oxford, UK, 1996
`
`3. W. E. Billups, S.C. Chang, R. H. Hauge, and J. L. Margrave, "Low Temperature Reactions
`of Atomic Cobalt with CH2N2, CH4, CH3D, CH2D2, CHD3, CD4, H2, D2, and HD" J. Am.
`Chem.Soc. 1995,117,1387.
`
`4. W. E. Billups, Sou-Chan Chang, Robert H. Hauge, and John L. Margrave, "Synthesis and
`Structure of the Unligated Carbene of Chromium," Inorg. Chern. 1993, 32, 1529.
`
`5. W. E. Billups, Sou-Chan Chang, Robert H. Hauge, and John L. Margrave, "Detection of as(cid:173)
`Complex in the Reaction of Cobalt Atoms with Methane," J. Am. Chern. Soc.1993, 115,
`2039.
`
`6. Sou-Chan Chang, Robert H. Hauge, Zakya H. Kafafi, John L. Margrave, and W. E. Billups,
`"Low-Temperature Reactions of Atomic Nickel with Diazomethane," Inorg. Chern. 1990,29,
`4373.
`
`7. Sou-Chan Chang, Robert H. Hauge, Zakya H. Kafafi, John L. Margrave, and W. E. Billups,
`"Characterization and Novel Low Temperature Reactions of FeCH2 and N2FeCH2," J. Am.
`Chern. Soc. 1988, 110,7975.
`
`8. Sou-Chan Chang, Robert H. Hauge, W. E. Billups, John L. Margrave, and Zakya H. Kafafi,
`"Low-Temperature Reactions of Methane with Photoexcited Nickel Atoms," Inorg. Chern.
`1988, 27, 205.
`
`9. Sou-Chan Chang, Robert H. Hauge, Zakya H. Kafafi, John L. Margrave, and W. E. Billups,
`"Isolation and Characterization of ZnCH2 by Fourier Transform I.R. Matrix Isolation
`Spectroscopy and Its Photolytic Rearrangement to HZnCH," Chern. Commun. 1987, 1682.
`
`468
`
`

`
`10. Sou-Chan Chang, Zakya H. Kafafi, Robert H. Hauge, John L. Margrave, and W. E. Billups,
`"The Isolation and Characterization of Copper Methylene via Matrix Isolation," Tetrahedron
`Lett. 1987, 28, 1733.
`
`11. Sou-Chan Chang, Zakya H. Kafafi, Robert H. Hauge, W. E. Billups, and John L. Margrave,
`"Isolation and Characterization of Copper Methylene (CuCH2) via FTIR Matrix Isolation
`Spectroscopy," J. Am. Chern. Soc. 1987, 109,4508.
`
`12. Sou-Chan Chang, Zakya H. Kafafi, Robert H. Hauge, Kenton H. Whitmire, W. Edward
`Billups, and John L. Margrave, "Infrared Spectrum of Hexacarbonylbis(m-carbonyl)(m(cid:173)
`methylene)diiron, Fez(C0)6(m-CO)z(m-CH2), in Cryogenic Matrices," Inorg. Chern. 1986,
`25,4530.
`
`13. Sou-Chan Chang, Zakya H. Kafafi, Robert H. Hauge, W. E. Billups, and John L. Margrave,
`"Isolation and Characterization of Iron Methylene (FeCH2) via FTIR Matrix Isolation," J.
`Am. Chern. Soc. 1985,107, 1447.
`
`14. C. H. Yu, S.C. Chang, and C. S. Liu, "19F NMR Study on the Confirmation Changes of
`1,1,2,2-Tetrafluoro-1,2-disilacyclohexanes," J. Org. Chern. 1983,48, 5228.
`
`News Citation
`
`Research work reported in Scienceffechnology Concentrates, Chemical & Engineering News,
`63(11), P 17, March 18, 1985.
`
`469
`
`

`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Attorney Docket: 07026316
`
`Applicant:
`
`Kao et al
`
`Examiner:
`
`L.S. Channavajjala
`
`Group Art Unit:
`
`1615
`
`Application Serial No.: 11/680,432
`
`Filed: February 28, 2007
`
`)
`)
`)
`)
`)
`)
`)
`Title: OXYMORPHONE CONTROLLED )
`RELEASE FORMULATIONS
`)
`)
`
`DECLARATION OF SOU-CHAN CHANG, Ph.D
`
`I, Sou-Chan Chang, hereby state a~ follows:
`
`I.
`
`I am the Director of Pharmaceutics Development and Process Chemistry at Endo
`
`Pharmaceuticals, Inc., which is the owner of U.S. Application Serial No. II/680,432 ("the '432
`
`Application"). A true and correct copy of my curriculum vitae is attached as Exhibit I.
`
`2.
`
`In my role as Director, I am responsible for the portion of new drug development
`
`characterized by U.S. Food and Drug Administration (FDA) practice as Chemistry,
`
`Manufacturing and Control (CMC).
`
`In discharging this responsibility I coordinate/manage
`
`development partners, contract developers, contract
`
`testing
`
`laboratories, and contract
`
`manufacturers.
`
`I also direct research and development (R&D) activities concerning drug
`
`formulation, manufacturing processes, analytical methods and stability testing. Furthermore, I
`
`oversee technology transfer to different facilities of Endo and to contract partners, scale-up of
`
`processes from the laboratory through pilot plant to full manufacturing scale, validation of all
`
`aspects of CMC, and production of clinical samples. In addition, I support post-market product
`
`re-formulation, line-extension, and manufacturing process improvement.
`
`1438521
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`470
`
`

`
`3.
`
`My experiences in the development of controlled-release pharmaceutical oral
`
`dosage forms include: Morphine sulfate ER tablets, (Generic alternative to MSContin®);
`
`Oxycodone HCl ER tablets (Generic alternative to OxyContin®); Opana® ER (Oxymorphone
`
`HCl) ER tablets; and several other generic and proprietary developmental ER products. My
`
`experiences in the development of immediate-release pharmaceutical oral dosage forms include:
`
`oxycodone/acetominophen capsules, Butalbital/aspirin/Codiene capsules, Etodolac
`
`tablets,
`
`Percocet® tablets, Zydone® tablets, Syrnmetrel® tablets, Opana® IR tablets, and several other
`
`generic and proprietary developmental IR products.
`
`The '432 Application
`
`4.
`
`.
`I have read and I understand the contents of the '432 Application, including the
`
`.
`
`claims.
`
`Generally,
`
`the
`
`'432 Application discloses controlled-release pharmaceutical
`
`compositions comprising oxymorphone, particularly oxymorphone HCl, and methods for using
`
`such compositions. Oxymorphone is a narcotic analgesic, useful in the treatment of acute and
`
`chronic pain. The '432 Application discloses, among other things, examples of controlled-
`
`release oxymorphone formulations, release rates of the oxymorphone from such formulations,
`
`and pharmacokinetic data relating
`
`to oxymorphone and
`
`its active metabolite, 6-0H
`
`oxymorphone, including data under fasting and fed conditions. The '432 Application concludes
`
`with claims, which I understand define the invention to which the application is directed. The
`
`independent claims currently pending are as follows:
`
`An analgesically effective controlled release pharmaceutical composition
`1.
`with a twelve hour dosing interval in the form of a tablet, comprising
`oxymorphone or a pharmaceutically acceptable salt thereof as the sole active
`ingredient in the tablet, and a controlled release delivery system comprising at
`least one pharmaceutical excipient, wherein upon placement of the composition in
`an in vitro dissolution test comprising USP Paddle Method at 50 rpm in 500 ml
`
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`
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`
`•
`
`media having a pH of 1.2 to 6.8 at 37 °C, about 15% to about 50%, by weight, of
`the oxymorphone or salt thereof is released from the tablet at about 1 hour in the
`test..
`
`An analgesically effective controlled release pharmaceutical composition
`20.
`with a twelve hour dosing interval in the form of a tablet, comprising
`oxymorphone or pharmaceutically acceptable salt thereof as the sole active
`ingredient in the tablet and a controlled release delivery system comprising a
`hydrophilic material that forms a gel upon exposure to gastrointestinal fluid,
`wherein upon placement of the composition in an in vitro dissolution test
`comprising USP Paddle Method at 50 rpm in 500 ml media having a pH of 1.2 to
`6.8 at 37 °C, about 15% to about 50%, by weight, of the oxymorphone or salt
`thereof is released from the composition at about 1 hour in the test, about 45% to
`about 80%, by weight, of the oxymorphone or salt thereof is released from the
`composition at about 4 hours in the test, and at least about 80%, by weight, of the
`oxymorphone or salt thereof is released from the composition at about 10 hours in
`the test.
`
`The April 28, 2008 Rejections
`
`5.
`
`I have reviewed the Office Action of April 28, 2008 in the present '432
`
`Application in which the Examiner takes the position that Published PCT Application WO
`
`01/08861 by Maloney of Roxane ("Maloney") either by itself or in combination with U.S. Patent
`
`5,047,248 to Calanchi ("Calanchi") enables the preparation of an extended release formulation of
`
`oxymorphone with an appropriate release rate profile to provide plasma levels yielding safe and
`
`effective analgesia over an extended period of time.
`
`I have also reviewed both of these
`
`references.
`
`I disagree with the Examiner's position that these references inherently teach an
`
`appropriate release rate for an extended release formulation of oxymorphone for the following
`
`reasons.
`
`6.
`
`These references do not associate any release rate profile or in vitro dissolution
`
`behavior with oxymorphone. Maloney only teaches release rates appropriate for oxycodone, a
`
`drug which has dramatically different oral bioavailability, a key parameter which strongly affects
`
`appropriate release rates. Calanchi only provides teachings on the appropriate release rates for
`
`1438521
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`
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`
`drugs which bear no particular relationship to oxymorphone other than being pharmaceutically
`
`active. Both of these references do provide teachings of delivery systems which could be
`
`modified to provide a variety of release rates.
`
`7.
`
`As set out in my Declaration of7 April2008 there are available to the man skilled
`
`in the art a wide variety of delivery systems including those of Maloney and Calanchi which can
`
`be engineered to yield a desired release rate. This inevitably leads to the conclusion that none of
`
`these systems inherently teaches any particular release rate profile. They are much like an air(cid:173)
`
`conditioning system which can deliver a wide variety of temperatures but give no clue what
`
`temperature is suitable for a particular end use.
`
`8.
`
`The appropriate release rate for a given drug or indeed the answer to the question
`
`of whether there is any appropriate release rate for any given drug in an oral extended release
`
`formulation is controlled by how the human body processes that particular drug. This is, to a
`
`large extent, reflected in the oral bioavailability for that particular drug. Thus, the teachings of
`
`both Maloney and Calanchi with regard to the appropriate release profiles for oxycodone or
`
`theophylline or amitryptilline (sic) or methoclopramide (sic) provide very limited guidance for
`
`the design of an extended release oxymorphone formulation. The appropriate release for
`
`oxymorphone might be quite similar to or dramatically different from those taught as appropriate
`
`for these drugs.
`
`9.
`
`Indeed, the oral bioavailability of oxycodone is very different from that of
`
`oxymorphone. The oral bioavailability of oxycodone is in the vicinity of 60%, while the oral
`
`bioavailability of oxymorphone is closer to 10%. Because of the major impact of oral
`
`bioavailability on appropriate release rates and because of the stark differences in oral
`
`1438521
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`
`

`
`bioavailability between the two drugs, one skilled in the art obtains very limited guidance on
`
`appropriate release rates for extended release oxymorphone from the rates given in Maloney with
`
`regard to extended release oxycodone.
`
`10.
`
`In fact, the release rates taught by Maloney, the only reference of record in any
`
`way pertinent to oxymorphone, while evidently suitable for the oxycodone drug to which they
`
`are explicitly tied, appear to be substantially slower than the rates required for a safe and
`
`effective oral extended release oxymorphone formulation.
`
`The Maloney Reference and Dissolution Rates
`
`11.
`
`Based on my review of the '432 Application, the Maloney reference, and my
`•
`
`experience as one of skill in the pharmaceutical arts, the following paragraphs contain my
`
`conclusions as to why Endo's claimed invention is not obvious in light of the Maloney reference.
`
`12.
`
`I directed and supervised the determination of the in vitro dissolution behavior of
`
`a lot of a 20 mg oxymorphone composition which has the same formulation as the present
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`commercial Opana ER® 20 mg product, and which is very similar to the formulation of Example
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`4 of the '432 Application. Dissolution profiles for tablets in this lot were determined both by
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`USP Paddle method and USP Basket method. For the Paddle method, a speed of 50 rpm was
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`used (tests were also run at 75 rpm but because the data did not vary significantly from the 50
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`rpm data it is not reported here). For the Basket method, a speed of 100 rpm was used. Under
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`both methods, profiles were determined at pH of 1.2 (0.1 N hydrochloric acid), 4.5 (50 mM
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`phosphate buffer at pH 4.5), and 6.8 (50 mM phosphate buffer at pH 6.8). All tests were run at a
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`temperature of 37 degrees Celsius. The mean dissolution data from these tests is attached at
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`Exhibit 2.
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`13.
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`The Basket method yielded a much greater percentage dissolution at each time
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`measured. A graph of the mean dissolution profiles obtained at pH 6.8 for both the Basket and
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`Paddle tests is attached as Exhibit 3 (the results obtained at pH 4.5 did not vary significantly
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`from those at pH 6.8 and so were not separately plotted).
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`14. Maloney discloses dissolution profiles for several oxycodone formulations. Of
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`these oxycodone formulations, Formula 6 has the fastest dissolution rate. The dissolution data
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`for Formula 6 appears at page 18 ofthe Maloney reference and is reproduced in attached Exhibit
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`2.
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`15.
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`Formula 6 of Maloney was a 30 mg: oxycodone ER formulation. Its dissolution
`profile, per the Maloney reference at page 14, was determined by the USP Basket method at 1 00
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`rpm at a temperature of 3 7 degrees Celsius, with the first hour at a pH of 1.2 and the remaining
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`hours out to 12 hours at pH of7.5?
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`16.
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`In attached Exhibit 4, the dissolution profiles of the Opana® ER formulation
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`using the USP Basket method at 100 rpm at pH 1.2 and 6.8 are plotted along side the dissolution
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`profile of Maloney Formula 6 using the same method at varied pH. It is evident that even this
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`1 In Maloney the formulas for Formula 1, which has 10 mg oxycodone, and Formula 6, which has 30mg, are similar
`other than the oxycodone content but the dissolution rate for Formula 6 was a little bit higher than for Formula 1.
`Thus, the dissolution appears to be slightly faster as the amount of oxycodone is increased. Therefore it is
`scientifically reasonable to assume that the dissolution behavior for a 20 mg formulation would lie between that of
`the 10 mg formulation of Formula 1 and the 30 mg formulation of Formula 3 and thus be a bit slower than that of
`Formula 3. Therefore, had a comparison offormulations of identical strength been available it should have shown
`an even greater difference between the teachings of Maloney and the dissolution behavior of formulations made
`according to the teaching of the present application ..
`2 Maloney indicates at the end of the paragraph bridging pages II and I2 that between a pH of 1.2 and 7.5 the
`dissolution rates are pH independent for its formulations, and thus the dissolution rates should be comparable to the
`Opana® ER data at 6.8 pH. On the other hand, as the dissolution of the Opana® ER formulation is insensitive to pH
`at values between 4.5 and 6.8 making it reasonable to project that it is insensitive to pH in the range between 6.8 and
`7.5. In fact, the system used in Opana® ER (Penwest's TIMERX®) is considered to be insensitive to pH at such pH
`levels.
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`fastest of the Maloney formulations has a substantially slower dissolution profile than the
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`Opana® ER commercial formulation.
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`17.
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`If one compares Maloney at 1 hour (during which the test was conducted in a pH
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`1.2 medium) to the profile of the Opana® ER 20 mg formulation in the pH 1.2 medium, the
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`Maloney formulation has a dissolution of 24.3% as compared to the 42% dissolution of the
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`Opana® ER formulation.
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`18. When comparing Maloney at the other data points after 1 hour to the Opana ER®
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`formulation in a pH 6.8 medium, once again the dissolution profile of the fastest Maloney
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`_formulation is substantially slower than that of the Op~a® ER formulation. This is true in spite
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`of the fact that Maloney used a pH of 1.2 for the first hour instead of the mid range pH
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`conditions of the Opana® ER 6.8 pH profile. As is clear from the graph in Exhibit 4, testing the
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`Opana® ER formulation at a pH of 1.2 resulted in faster dissolution. Thus it is scientifically
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`reasonable to presume that if the Opana® ER formula had been tested in the staged pH
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`procedure of Maloney the dissolution curve would lie between that of the curve for pH 1.2 and
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`that for pH 6.8 thus showing a greater difference in dissolution behavior.3
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`19.
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`Although there is no generally established or accepted correlation between
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`dissolution results obtained from testing using the USP Basket test and those obtained from the
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`USP Paddle Test, in general, the Basket test is the more aggressive and tends to give faster
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`dissolution rates, as was the case with the Opana® ER formulation discussed above. In this
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`3 In comparing the two dissolution curves one should note that the Maloney curve is based on a first hour dissolution
`at pH 1, followed by an increase to 7.5, while the Opana® ER curve uses a constant pH value of 6.8 for the entire
`curve. Based on the Opana® ER data at pH 1.2 it is clear that the very acidic pH results in a higher dissolution rate
`for the Opana® ER formulation. Thus it is expected that were Opana® ER to be tested in the same conditions as
`Maloney (i.e. first hour in acidic conditions) the Opana® ER dissolution rate would be higher than the pH 6.8 curve
`due to the one hour "head start" in the acidic conditions.
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`regard, attached hereto are several literature articles4 (Exhibits 5, 6 and 7) reporting on the results
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`obtained on the same formulation tested by both techniques and showing faster dissolution for
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`the Basket technique. In some cases, modifying a Paddle technique by adding "sinkers" can
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`increase the observed dissolution rate bringing it closer to that observed with the Basket
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`technique on the same formulation. However, the dissolution technique reported on and featured
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`in the claims of the present '432 Patent Application utilized a Paddle technique without
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`"sinkers."
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`Conclusions
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`20.
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`~
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`In part due to the differences in oral bioavailability, a person of skill in the art
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`.
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`could not safely conclude that oxymorphone would have a release profile which would yield a
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`safe