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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
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`AMNEAL PHARMACEUTICALS, LLC
`Petitioner
`v.
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`ENDO PHARMACEUTICALS INC.
`Patent Owner
`
`U.S. Patent No. 8,329,216
`_____________________
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`Inter Partes Review Case No. IPR2014-003601
`_____________________
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`THIRD DECLARATION OF VIVIAN A. GRAY
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`1 Case IPR2014-01365 has been joined with this proceeding.
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`1
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1102)
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`TABLE OF CONTENTS
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`Introduction ..................................................................................................... 2
`I.
`List of Documents I Considered in Formulating My Opinion ....................... 3
`II.
`III. The rough equivalence of the basket method at 100 rpm and the paddle
`method at 50 rpm is not limited to prednisone tablets ................................... 3
`IV. Missaghi and Fassihi (Exhibit 2034) .............................................................. 6
`V.
`Conclusion ...................................................................................................... 7
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`ii
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`2
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`I.
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1102)
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`I, Vivian A. Gray, hereby declare as follows.
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`Introduction
`I am the same Vivian Gray who submitted a declaration dated January
`1.
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`16, 2014 (“First Declaration;” AMN 1002) that was filed along with Amneal
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`Pharmaceuticals’ Petition (“Petition”) for Inter Partes Review of U.S. Patent
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`8,329,216 (“the ’216 patent”) and a declaration dated January 26, 2015 ("Second
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`Declaration;" AMN 1025) in the same proceeding. I hereby incorporate the
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`contents of my First and Second Declarations into this Third Declaration.
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`2.
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`I detailed my background and qualifications in my First Declaration
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`(See AMN 1002, Section II). As provided in my First Declaration, I am an expert
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`in the field of dissolution testing of pharmaceutical delivery systems and have been
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`since before 2001.
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`3.
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`In preparing this Declaration, I have reviewed the Declaration of Dr.
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`Dianne Burgess (“Burgess Dec.”, Ex. 2090) and considered each of the documents
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`I have cited herein, in light of general knowledge in the art. Nothing in the Burgess
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`Dec. or other materials I have reviewed changes my opinions provided in my First
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`and Second Declarations.
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`4.
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`In formulating my opinions, I have relied upon my experience,
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`education and knowledge in the relevant art. In formulating my opinions, I have
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`also considered the viewpoint of a person of ordinary skill in the art (“POSA”)
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`2
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`3
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`(i.e., a person of ordinary skill in the art). I defined a POSA at ¶13 of my First
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1102)
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`Declaration and feel that my previous definition is correct and not countered by
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`anything in the Burgess Dec.
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`II.
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`List of Documents I Considered in Formulating My Opinion
`In formulating my opinion, I have considered the documents cited in
`5.
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`my First and Second Declarations along with the following documents:
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`Exhibit or
`Paper No.
`2015
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`2090
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`Description
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`Guidance for Industry Bioavailability and Bioequivalence Studies
`for Orally Administered Drug Products — General
`Considerations; U.S. Department of Health and Human Services
`Food and Drug Administration; Center for Drug Evaluation and
`Research (CDER); March 2003; Revision 1
`Supplemental Declaration of Prof. Diane J. Burgess, Ph.D.
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`III. The rough equivalence of the basket method at 100 rpm and the paddle
`method at 50 rpm is not limited to prednisone tablets
` Dr. Burgess states in her Supplemental Declaration that:
`6.
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`The Handbook on [sic] Dissolution Testing merely states
`that the Paddle Method at 50 rpm and the Basket Method
`at 100 rpm "have proved to be roughly equivalent." It
`does not state for which pharmaceutical compositions the
`two methods have proven to be roughly equivalent or at
`what dissolution times. Grady [AMN 1080] answers that
`question: prednisone calibrator tablets at 30 minutes.
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`3
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`4
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`Ex. 2090, ¶22. I do not agree with Dr. Burgess that a POSA would find the rough
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1102)
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`equivalence of the basket method at 100 rpm and the paddle method at 50 rpm to
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`be so limited.
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`7.
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`The quote from the Handbook referred to in both my First and Second
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`Declarations states: “As specified in individual monographs – but for general
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`purposes when not otherwise specified – rates of 50 rpm for the paddle and 100
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`rpm for the basket are recommended and have proved to be roughly equivalent to
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`one another in producing dissolution.” (AMN 1008, p. 35 (emphasis added).)
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`8.
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`It is clear from the language used in this quote that the rough
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`equivalence referred to in the Handbook is derived from experience with
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`monographs. A monograph is a formal document of the United States
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`Pharmacopeial ("USP") Convention that lists information about drug products and
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`individual ingredients. (See, for example, AMN 1089.) Monographs for drug
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`products include procedures for testing the formulation and acceptance criteria.
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`Thus, a POSA would not interpret the statement in the Handbook as being limited
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`to calibrator tablets such as prednisone.
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`9.
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`Grady recognizes that the rough equivalence between the basket
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`method at 100 rpm and paddle method at 50 rpm was known to a POSA to be
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`applicable to more than just prednisone tablets. The passage Dr. Burgess quotes
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`from Grady in ¶20 of her Supplemental Declaration states "USP Prednisone
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`4
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`5
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`Tablets were sufficiently representative of formulations at the time, that
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1102)
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`indeed others had experienced, and it is my belief that the equivalence of the
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`basket at 100 rpm to the paddle at 50 rpm was largely formed at that time." (AMN
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`1080, 8569, emphasis added.) Grady discusses of the use of prednisone calibrator
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`tablets as being sufficiently representative of other formulations and a POSA
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`would have understood from Grady that the rough equivalence of the basket
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`method at 100 rpm and the paddle method at 50 rpm was not limited to prednisone
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`calibrator tablets. Grady is consistent with the Handbook.
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`10. Also, there is nothing in Grady that alleges that the basket method at
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`100 rpm and the paddle method at 50 rpm were not roughly equivalent. Grady
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`discusses considerations in using calibrator tablets. Grady states that "[t]he present
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`calibrators definitively were adopted because of known problems from vibration.
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`They were not adopted as a check on the geometry or specifications of the
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`apparatus, temperature, or composition of dissolution media, or the deaeration of
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`dissolution media." (AMN 1080, 8568.) As discussed by Grady, calibrator tablets
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`are made for use in calibrating dissolution apparatus and are made to be sensitive
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`to issues with the apparatus, such as vibration from the motor. (AMN 1080, 8568.)
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`While Grady discusses the rough equivalence between the basket method at 100
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`rpm and the paddle method at 50 rpm, the bulk of his paper relates to the specific
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`5
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`6
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`concerns of calibrator tablets. Grady does not contradict the statements in the
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1102)
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`Handbook regarding rough equivalence.
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`IV. Missaghi and Fassihi (Exhibit 2034)
`11. Dr. Burgess's Supplemental Declaration also cites Missaghi and
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`Fassihi, International Journal of Pharmaceutics, 2005 as an alleged example of a
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`formulation where release using the basket method at 100 rpm is not roughly
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`equivalent to the paddle method at 50 rpm. (Ex. 2090, ¶¶102-108.) As discussed in
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`my Second Declaration, as Missaghi was published in 2005, it would not inform a
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`POSA’s thinking in 2001. (AMN1025, ¶34.)
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`12.
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`I discussed the f2 factor and how it can be used to compare
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`dissolution profiles in ¶20 of my Second Declaration. Dr. Burgess cites to the
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`FDA's Guidance for Industry on bioavailability and bioequivalence and concludes
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`that "Exhibit 2015 does not support the notion that an f2 between 50-100 suggests
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`that two different dissolution methods are equivalent." (Ex. 2090, ¶ 30.) But as Ex.
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`2015 is a document about bioequivalence, it discusses the use of the f2 factor for
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`bioequivalence testing. F2 is a tool for comparing profiles that is applicable in
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`comparisons beyond bioequivalence. Missaghi itself uses the f2 factor to compare
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`different dissolution methods. (Ex. 2034, p. 41, Table 4.) A POSA would have
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`understood from Missaghi that f2 can be used to compare dissolution profiles from
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`different dissolution methods because Missaghi makes this type of comparison.
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`6
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`7
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`V.
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1102)
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`Conclusion
`13. As provided in my First and Second declarations, although the
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`dissolution profile in the claims of the '216 patent was obtained using the paddle
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`method at 50 rpm and Oshlack teaches the basket method at 100 rpm, it was
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`known in the art that the paddle method at 50 rpm is roughly equivalent to the
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`basket method at 100 rpm (AMN 1008, p. 35; AMN 1002, 88.) A POSA would
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`have had a reasonable expectation of success that the controlled release
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`compositions taught by Oshlack would give an in vitro dissolution profile falling
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`within the dissolution profile ranges of the claims of the '216 patent when tested by
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`the paddle method at 50 rpm. (See, AMN 1002, ¶¶72-81.) Nothing cited or
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`discussed in the Supplemental Burgess declaration changes my opinion about this
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`reasonable expectation of a POSA.
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`7
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`Inter Partes Review of USPN 8,329,216
`Declaration of Vivian A. Gray (Exhibit 1102)
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`14.
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`I hereby declare that all statements made herein of my own
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`knowledge are true and that all statements made on information and belief are
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`believed to be true, and further that these statements were made with the
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`knowledge that willful false statements and the like so made are punishable by fine
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`or imprisonment, or both, under Section 1001 of Title 18 of the United States
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`Code.
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`Respectfully submitted,
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`Vivian A. Gray
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`Date: April 1, 2015
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`8
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