UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
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`LUPIN LIMITED
`AND LUPIN PHARMACEUTICALS. INC.,
`Petitioners
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`v.
`iCEUTICA PTY LTD.
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`Patent Owner
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`Case No. TBD
`U.S. Patent No. 9,017,721
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`DECLARATION OF MANSOOR M. AMIJI, PH.D., RPH
`IN SUPPORT OF PETITION FOR INTER PARTES
`REVIEW OF U.S. PATENT NO. 9,017,721
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`LUPIN EX. 1002
`Lupin v. iCeutica
`US Patent No. 9,017,721
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`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
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`LUPIN LIMITED
`AND LUPIN PHARMACEUTICALS. INC.,
`Petitioners
`
`v.
`iCEUTICA PTY LTD.
`
`Patent Owner
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`Case No. TBD
`U.S. Patent No. 9,017,721
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`DECLARATION OF MANSOOR M. AMIJI, PH.D., RPH
`IN SUPPORT OF PETITION FOR INTER PARTES
`REVIEW OF U.S. PATENT NO. 9,017,721
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`
`
`LUPIN EX. 1002
`Lupin v. iCeutica
`US Patent No. 9,017,721
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`
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
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`1.
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`I, Dr. Mansoor M. Amiji, have been retained by Knobbe, Martens,
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`Olson & Bear, LLP, counsel for Lupin Limited and Lupin Pharmaceuticals, Inc.
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`(“Lupin” or “Petitioners”). I understand that Lupin is submitting a petition for
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`Inter Partes Review of U.S. Pat. 9,017,721 (“the ’721 patent”) and requests that
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`the U.S. Patent and Trademark Office cancel Claims 1-24 of the ’721 patent as
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`unpatentable. The following discussion and analyses address the bases for Lupin’s
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`petition.
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`I.
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`QUALIFICATIONS AND COMPENSATION
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`A. Qualifications
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`2.
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`I am currently the Bouvé College Distinguished Professor and Chair
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`of the Department of Pharmaceutical Sciences in the School of Pharmacy at
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`Northeastern University. I have been Chair of that department since 2006 and
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`have been a full-time faculty member in that department since 1993. I am also a
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`registered pharmacist in the Commonwealth of Massachusetts.
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`3.
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`In addition, I am currently an Affiliate Faculty Member in the
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`Department of Chemical Engineering and the Department of Biomedical
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`Engineering at Northeastern University. I am also currently a Distinguished
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`Adjunct Professor in the Faculty of Pharmacy at King Abdulaziz University in
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`Jeddah, Saudi Arabia.
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
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`4.
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`I earned my B.S. in Pharmacy (magna cum laude) at Northeastern
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`University in June 1988 and my Ph.D. in Pharmaceutics from Purdue University in
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`July 1992. Prior to beginning my professorship at Northeastern University in
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`1993, I served as a Senior Research Scientist at Columbia Research Laboratories,
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`in Madison, Wisconsin.
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`5.
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`I have been fortunate enough to receive a number of distinctions for
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`my work in pharmaceutical chemistry, including: the “Nano Science and
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`Technology Institute (NSTI) Fellowship Award for Outstanding Contributions
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`towards
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`the Advancement,
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`in Nanotechnology, Microtechnology,
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`and
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`Biotechnology” in 2006; the “Meritorious Manuscript Award” from the American
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`Association of Pharmaceutical Scientists (AAPS) in 2007; and the “Tsuneji Nagai
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`Award from the Controlled Release Society in 2012.
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`6.
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`I am also a member of various professional societies, including the
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`American Association of Pharmaceutical Scientists (Fellow), Controlled Release
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`Society (Fellow), American Association of College of Pharmacy, and the Phi
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`Lambda Sigma, Pharmacy Leadership Society (Honorary Member).
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`7.
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`I have served as an editor of seven
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`textbooks related
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`to
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`pharmaceutical chemistry. I have authored, or co-authored, over 180 peer-reviewed
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
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`articles and roughly 40 book chapters, including numerous publications related the
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`use of nanotechnology in drug delivery.
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`8.
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`Currently, the primary focus of my laboratory research is on the
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`development of biocompatible materials from natural and synthetic polymers,
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`target-specific drug and gene delivery systems for cancer and infectious diseases,
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`and nanotechnology applications for medical diagnosis, imaging, and therapy.
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`9. My curriculum vitae is included as Exhibit 1003 to this Inter Partes
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`Review. In the last four years I testified in the following cases: 1:10-CV-00329 (D.
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`Del.), 11-CV-840 (N. D. Cal.), 2011-CV-12226 (D. Ma.), 11-CV-02038
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`(S.D.N.Y), 12-CV-05615 (S.D.N.Y.), 13-CV-00139 (S. D. Cal.), 13-CV-1674 (D.
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`Del.), 14-CV-0422 (D. Del.), 1:13-6502 (D.N.J.), and 1:14-3653(D.N.J.).
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`B. Compensation
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`10.
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`I am being compensated at my normal consulting rate of $870 per
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`hour. I have no personal financial interest in any of the entities involved in this
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`litigation, and my compensation does not depend in any way on my testimony, my
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`conclusions or the outcome of my analysis.
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`II. MATERIALS CONSIDERED
`
`
`11.
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`Included as Exhibit 1004 is a list of the documents that I have
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`considered in forming my opinions provided in this report.
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
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`III. SUMMARY OF OPINIONS
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`
`12.
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`It is my opinion that the challenged claims of the ’721 patent are
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`unpatentable and should be cancelled because the claimed subject matter would
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`have been obvious to a person of ordinary skill before April 2009, the earliest
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`possible priority date of the patent.
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`13. The independent claims of the ’721 patent relate to a solid oral unit
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`dose of diclofenac acid, wherein (1) the unit dose contains 18 mg (or 35 mg) of
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`diclofenac acid; and (2) the diclofenac acid has a median particle size between
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`1000 nm and 25 nm. The independent claims also include a clause stating that the
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`unit dose, when tested in vitro via a standard test method, has a dissolution rate
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`characterized as 94% (or 95%) diclofenac acid released in 75 minutes.
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`14.
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`It is my opinion that a person of ordinary skill in the art would have
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`known to reduce the particle size of diclofenac acid to improve its solubility and to
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`reduce the administered dosage amount. A person of skill in the art would have
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`been well aware that the United States Pharmacopeia discloses the dissolution test
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`conditions and would have understood that the dissolution rate is simply the result
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`of the recited dissolution test conditions and particles size. Below I provide
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`background information related to the state of the art, followed by my analysis of
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`the patentability of the claims based on the following grounds:
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
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`Ground No. Claims
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`References
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`1-24
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`1-24
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`Obvious over Meiser in view of the Novartis
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`Package Insert
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`Obvious over Meiser in view of the Novartis
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`Package
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`Insert,
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`the United
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`States
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`Pharmacopeia, and Chuasuwan
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`1-24
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`Obvious over Meiser in view of the Novartis
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`Package
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`Insert,
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`the United
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`States
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`Pharmacopeia, Chuasuwan, and Reiner
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`1
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`2
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`3
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`IV. BACKGROUND AND STATE OF THE ART
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`A. NSAIDs and Diclofenac
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`15. The challenged claims of the ’721 patent relate to diclofenac, a
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`compound that is classified as a nonsteroidal anti-inflammatory drug, or NSAID.
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`Other well-known NSAIDs include aspirin, ibuprofen, naproxen, and celecoxib.
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`Like other NSAIDs, diclofenac has long been used as an anti-inflammatory and
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`analgesic agent, or pain killer, to treat both chronic and acute pain. Reiner, Ex.
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`1010 at 1. Research has found diclofenac efficacious in treatment of conditions
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
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`such as dental pain, lower back pain, headache, influenza, and dysmenorrhea.
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`Moore, Ex. 1012 at 170-177.
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`16. The Novartis Package Insert discloses two solid dosage forms of
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`diclofenac, the sodium or potassium salt known as Voltaren or Cataflam,
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`respectively. Ex. 1006 at 1, 8. The Novartis Package Insert describes solid dosage
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`forms having 25 mg, 50 mg, and 75 mg of diclofenac. Id. at 2. Moore also
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`discloses solid dosage forms having 12.5 mg of diclofenac. Ex. 1012 at 168. Reiner
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`also discloses pharmaceutical compositions of diclofenac unit doses containing
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`12.5, 25, 37.5, 50, 75, and 100 mg of diclofenac. Ex. 1010 at 12.
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`17.
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` Diclofenac, like other NSAIDs, inhibits activity of the class of
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`enzymes known as cyclooxygenase (COX). Diclofenac inhibits both the COX-1
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`and COX-2 enzymes (Moore, Ex. 1012 at 165), with preferential inhibition of the
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`COX-2 enzyme. Chuasuwan, Ex. 1009 at 1207-8. Diclofenac’s anti-inflammatory
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`and analgesic properties are known to stem from inhibiting the COX enzymes from
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`synthesizing prostaglandins and thromboxanes, which are the lipids involved in
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`regulating inflammation and pain receptor sensitivity. Ex. 1012 at 165.
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`18. Like other NSAIDs, diclofenac usage is associated with an increased
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`risk of gastrointestinal bleeding and serious cardiovascular side effects.
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`Chuasuwan , Ex. 1009 at 1208. One NSAID, rofecoxib, was withdrawn from the
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
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`market in 2004, following the VIGOR study; subsequent studies which showed
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`elevated risk of cardiovascular incidents with all NSAIDs. Moore, Ex. 1012 at 188.
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`At least one study has suggested that diclofenac may be associated with higher
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`risks of myocardial infarction. Id. The FDA recommended, on the heels of the
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`cardiovascular safety issues, that all NSAIDs remaining on the market should be
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`prescribed at the lowest effective dose for the shortest duration possible. Jenkins
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`Memo, Ex. 1024 at 15.
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`19. Diclofenac acid was first developed in the late 1960s by Ciba-Geigy
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`(now Novartis) and patented as U.S. Patent No. 3,558,690 in 1971. Ex. 1033. Its
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`chemical name is 2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid, and its
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`chemical structure is shown below:
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`
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`The presence of the carboxylic acid functional group (shown in red circle) in the
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`chemical structure indicates that diclofenac is a weak acid; it has a pKa value of
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`approximately 4.0. Ex. 1012 at 165; Ex. 1022 at 356. Diclofenac’s acidic
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
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`properties stem from the carboxylic acid (–COOH) functional group bonded to
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`diclofenac’s phenyl group.
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`20. The scientific literature classifies diclofenac in the biopharmaceutical
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`classification system (BCS) as Class II, meaning it is poorly water-soluble, but
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`highly permeable. Ex. 1009 at 1214. Thus, diclofenac’s poor water solubility
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`becomes the rate-limiting factor in its oral bioavailability.
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`21. The solubility of diclofenac acid is pH dependent, having aqueous
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`solubility which ranges from 17.8 mg/L at neutral pH, when the molecule is more
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`ionized to less than 1mg/L at acidic pH, when the molecule is un-ionized. Ex. 1022
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`at 356. To improve solubility, diclofenac is often formulated as a sodium or
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`potassium salt, thus overcoming the pH-dependent solubility issues. Ex. 1009 at
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`1208.
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`22. For diclofenac to be formulated as a salt, the H+ atom (or proton) on
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`the carboxyl group is removed (making a diclofenac an anion with the negatively
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`charged carboxylate group, –COO–), and then the molecule is ionically associated
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`with another positive ion, such as a Na+ molecule (sodium ion) or a K+ molecule
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`(potassium ion). See Novartis Package Insert, Ex. 1006, at 1. As an anion, the
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`negatively-charged diclofenac molecule is better able to dissolve in polar aqueous
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`media, such as water; however, the negatively charged diclofenac molecule is less
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
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`readily absorbed in the GI tract as compared to the neutral diclofenac acid
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`molecule, according to the pH-partition principle. See Ex. 1035 at 715-716.
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`23. The first diclofenac tablet was the sodium salt, marketed in Japan as
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`Voltaren® in 1974 for anti-inflammatory use. Ex. 1012 at 164. The potassium salt
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`tablet was introduced in the early 1980s for use as an analgesic. Id.
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`24.
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`In addition to the salt formulations, diclofenac has also been
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`formulated in the free acid form. For example, U.S. Patent No. 5,256,699 (Ex.
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`1013), filed in 1992, is directed to diclofenac formulated as the free acid in a solid
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`dispersible form, for oral consumption. iCeutica also previously developed
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`diclofenac acid formulations prior to filing the application that led to the ’721
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`patent. See Payne, Ex. 1011; Meiser, Ex. 1005. As an acid, diclofenac remains un-
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`ionized, meaning that it retains the hydrogen atom (or proton) on the carboxyl
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`group and is electrostatically neutral. In the salt forms, a sodium or potassium ion
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`is required for charge neutralization.
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`B.
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`Improving Dissolution Rate and Oral Bioavailability
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`25. Bioavailability describes “either the extent to which a particular drug
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`is utilized pharmacologically or, more strictly, the fraction of dose reaching the
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`general circulations.” Dokoumetzidis, Ex. 1014 at 3. As early as the 1950s,
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`researchers understood that “following the oral administration of solid dosage
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
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`forms, if the absorption process of drug from the gastrointestinal tract is rapid, then
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`the rate of dissolution of that drug can be the step which controls its appearance in
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`the body.” Id. at 3. In other words, the dissolution rate of a rapidly absorbed drug is
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`a controlling, rate-limiting factor in the drug’s bioavailability. Thus, it was
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`understood that bioavailability can be improved by improving the dissolution rate
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`of a drug. By at least 1993, it was known that a drug with low water solubility
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`“often shows insufficient bioavailability because of the poor solubility in
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`gastrointestinal fluids, which compels said drug to pass through the site of
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`absorption before it completely dissolves in the fluids.” Samejima, Ex. 1016 at
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`1:19-24.
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`26. Samejima describes numerous methods that have been employed to
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`improve absorption of poorly or slightly water-soluble drugs in the gastrointestinal
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`tract. These methods include using water-soluble salts, using nonaqueous solvents,
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`and adsorbing drugs on to porous materials, but these methods, despite improving
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`solubility to some extent, all involve drawbacks or difficulties. Id. at 1:29-2:10.
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`Samejima overcame these limitations and reported improved dissolution of the
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`slightly water-soluble NSAID, naproxene (now known in the U.S. as naproxen,
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`and marketed as Aleve®, among other tradenames), by milling naproxene into
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`ultrafine particles having an average diameter “preferably less than 1 μm” Id. at
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
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`2:43-45; 4:14-45. Thus, it was well-known at the time of the ’721 patent’s earliest
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`priority date that the dissolution rate of a particulate drug increases with decreasing
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`particle size, and to make submicron, or nanosize, particles of NSAIDs.
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`27. The relationship between dissolution rate and particle size is described
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`by the Nernst-Brunner/Noyes-Whitney equation. This equation has the form:
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`, where A is particle surface area, D is diffusion co-efficient,
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`h is a boundary layer thickness, Cs is saturation solubility, Xd is the amount
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`dissolved, and V is the volume of fluid available for dissolution. See Kesisoglou,
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`Ex. 1015 at 632, eq. 1. All parameters in the equation, except particle surface area,
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`A, are properties of the dissolution medium, which are determined by the identity
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`of the solvent or the dissolution conditions. Thus, the only drug-related parameter
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`that an experimenter can control is A, the particle surface area. In the equation, as
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`A increases, dX/dT also increases. Thus, the Nernst-Brunner/Noyes-Whitney
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`equation makes it clear that increasing the surface area of a particle will increase
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`the dissolution rate of the substance.
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`28. The ’721 patent itself affirms the applicability of the Nernst-
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`Brunner/Noyes-Whitney relationship, stating, “[i]t is known that the rate of
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`dissolution of a particulate drug will increase with increasing surface area. One
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`IPR re U.S. Patent 9,017,721
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`way of increasing surface area is decreasing particle size.” Ex. 1001 at 1:45-47.
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`Dokoumetzidis et al. also observed “[a]nother factor that influences the dissolution
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`rate is the surface exposed in the solvent. This is primarily affected by the particle
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`size, meaning the smaller the particles, and therefore in greater number, the higher
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`their total exposed surface as compared to larger but fewer particles of the same
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`total mass. The effect is especially dramatic with poorly soluble compounds.” Ex.
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`1014 at 5.
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`29. Kesisoglou, in 2007, described that “nanosizing,” or “the reduction of
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`the active pharmaceutical ingredient (API) particle size down to the sub-micron
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`range,” improves dissolution of the drug compound. Ex. 1015 at 632. Kesisoglou
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`states that particle size reduction had been employed in the pharmaceutical
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`industry for decades, but “recent advances in milling technology and our
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`understanding of such colloidal systems have enabled the production of API
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`particles of 100-200 nm size in a reproducible manner. . . . These nanoformulations
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`offer increased dissolution rates for drug compounds and complement other
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`technologies used to enhance bioavailability of insoluble compounds (BCS Class II
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`and IV) such as solubility enhancers (i.e. surfactants). . . . ” Id. It was well-known
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`at the time the ’721 patent was filed that diclofenac exhibits poor solubility in
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`water, and is classified as a BCS II compound. See Ex. 1009 at Abstract.
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
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`30. Forming nanoparticles to improve the dissolution rate, and thereby
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`improving oral bioavailability, has been well documented for many different drugs,
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`particularly for poorly water-soluble drugs. For example, U.S. Patent Publication
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`2006/0159628 (Ex. 1017, “Liversidge ’628”) describes “the nanoparticulate
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`raloxifene hydrochloride dosage form significantly increases the bioavailability of
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`the drug.” Ex. 1017 at ¶ [0034]-[0036]. Liversidge ’628 further notes that “a
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`nanoparticulate raloxifene hydrochloride dosage form requires less drug to obtain
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`the same pharmacological effect observed with a conventional microcrystalline
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`raloxifene hydrochloride dosage form. . . . Therefore, the nanoparticulate
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`raloxifene hydrochloride dosage form has an increased bioavailability as compared
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`to the conventional microcrystalline raloxifene hydrochloride dosage form.” Id. at
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`¶ [0037].
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`31. Vogt et al. observe similar improvement in the dissolution of
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`fenofibrate, a poorly soluble drug, upon reduction of particle size. Ex. 1018
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`(“Vogt”) at 283. Vogt states, “[a]ttempts to increase the oral bioavailability of the
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`drug have therefore chiefly centered on particle size reduction.” Id. at 284. Vogt
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`concludes “cogrinding and nanosizing/spray-drying are powerful techniques for
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`the preparation of rapidly dissolving formulations of fenofibrate. Both processes
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`IPR re U.S. Patent 9,017,721
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`could potentially lead to better bioavailability of fenofibrate drug products.” Id. at
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`288.
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`32. U.S. Patent Publication 2006/0204588 (Ex. 1019, Liversidge ’588)
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`describes nanoparticulate forms of finasteride, dutasteride and
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`tamsulosin
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`hydrochloride. Ex. 1019 at ¶ [0042]. The nanoparticulate forms of these drugs have
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`advantages over conventional forms, including “(1) increased water solubility; (2)
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`increased bioavailability; (3) smaller dosage form size or volume due to enhanced
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`bioavailability; (4) lower therapeutic dosages due to enhanced bioavailability.” Id.
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`33.
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`iCeutica (owner of the ’721 patent) recognized the value of nanosizing
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`diclofenac acid to improve solubility and bioavailability as early as December
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`2005, the filing date of PCT Application No. PCT/AU2005/001977, which later
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`published as WO2006/069419 (Ex. 1011, “Payne”). Payne states, “[i]t is known
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`that the rate of dissolution of a particulate drug can increase with increasing
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`surface area, that is, decreasing particle size.” Ex. 1011 at 1:25-26. Payne describes
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`improving dissolution of diclofenac acid using milling techniques to create
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`nanoparticles having an average size less than 200 nm. Ex. 1011 at 1:25-26, 17:1-
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`4, 26 Table 1, 42:9-43:26, Claim 36.
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`34.
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`iCeutica filed another patent application disclosing techniques for
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`milling diclofenac acid in PCT Application No. PCT/AU2007/00910, published in
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`IPR re U.S. Patent 9,017,721
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`January 2008 as WO2008/000042 (Ex. 1005, “Meiser”). Meiser states, “[i]t is
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`known that the rate of dissolution of a particulate drug will increase with
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`increasing surface area. One way of increasing surface area is decreasing particle
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`size.” Ex. 1005 at 1. Meiser teaches improving solubility of poorly water-soluble
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`drugs, such as diclofenac, using milling techniques to obtain nanoparticulate
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`diclofenac acid. Ex. 1005 at, e.g., 6-7, 27-28. Meiser states, “as discussed in the
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`context of the background to the invention, biologically active compounds that are
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`poorly water-soluble at physiological pH will particularly benefit from being
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`prepared in nanoparticulate form.” Ex. 1005 at 27. Meiser identifies diclofenac
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`acid as one of the poorly water-soluble compounds for which the nanosizing
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`methods of Meiser are suitable. Id. at 28.
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`35. Meiser discloses that particle sizes are determined by laser light
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`diffraction scattering, measured on an equivalent spherical diameter basis, and are
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`reported as “mean particle size.” Id. at 16. Meiser discloses milling methods to
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`make nanoparticles of diclofenac acid having an average size of 100-200 nm as
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`determined by scanning electron microscopy (SEM) or transmission electron
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`microscopy (TEM) analysis, and particle sizes of 160 +/- 30 nm as determined by
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`dynamic light scattering (DLS) analysis. Ex. 1005 at 1, 68-69. Meiser also
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`describes that the dry milled particles of the invention have a “narrow particle size
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`distribution of 160 +/- 30 nm” and depicts the narrow distribution in FIG. 2. Id. at
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`12, 69. This distribution is a normal, or Gaussian distribution.
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`36. Meiser also shows
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`that
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`it was well known
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`that drugs
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`in
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`nanoparticulate form have advantages over conventional compounds by way of
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`more rapid therapeutic action and by using a lower dose to achieve the same
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`therapeutic effect. Ex. 1005 at 7.
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`37. Thus, at the time of the ’721 patent, those of skill in the art knew to
`
`make nanoparticulate diclofenac acid. And it was well known that nanoparticulate
`
`diclofenac acid would improve dissolution and bioavailability of diclofenac and
`
`allow for a reduction in dose strength as compared to then-existing diclofenac
`
`products, such as Voltaren.
`
`C. Dissolution Testing Taught in the Prior Art
`
`38. According to the Handbook of Dissolution Testing, the dissolution
`
`rate can be defined as “the amount of active ingredient in a solid dosage form
`
`dissolved in unit time under standardized conditions of liquid-solid interface,
`
`temperature, and media composition.” Handbook, Ex. 1026 at 17. In essence,
`
`dissolution testing is an in vitro (“outside the body”) measure of drug solubility.
`
`When a drug’s solubility is the rate-limiting step to its absorption in the
`
`gastrointestinal (GI) tract (as is the case for diclofenac), dissolution testing is a
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
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`useful in vitro proxy for understanding a drug’s in vivo bioavailability and efficacy.
`
`Id. at 25-26, 29; Ex. 1025 at 2-3. The FDA requires dissolution testing data to be
`
`provided in regulatory filings such as new drug applications (NDAs) and
`
`abbreviated new drug applications (ANDAs). Ex. 1026 at 13; Ex. 1025 at 2.
`
`39. Dissolution testing can be used as a first-step approximation of
`
`bioequivalence between drug formulations. Dissolution testing becomes valuable
`
`in the context of comparing solubility of differing drug formulations under the
`
`same test conditions. The measured dissolution rate of a drug will depend on a
`
`number of variables associated with the testing conditions, such as the dissolution
`
`medium, stir rate, apparatus, temperature, pH, and volume. Maintaining the same
`
`conditions from test to test when comparing the dissolution rates of drug
`
`formulations is important because altering the test conditions can alter the final
`
`dissolution rate.
`
`40. The United States Pharmacopeia (USP) has standardized two common
`
`dissolution rate test apparatuses: Apparatus 1 (basket apparatus) test and the
`
`Apparatus 2 (paddle apparatus) test. Ex. 1007.
`
`41. Claims 1 and 8 of the ’721 patent refer to USP Apparatus 1 (basket
`
`method) for the dissolution testing of diclofenac. Example 14 of the patent
`
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
`
`specification indicates that the Apparatus 1 (basket method) is performed
`
`according to section <711> of the USP.
`
`42. According to USP <711>, the dissolution tests were developed “to
`
`determine compliance with the dissolution requirements where stated in the
`
`individual monograph for dosage forms administered orally.” Id. at 277. USP
`
`<711> includes generalized information about operation of the dissolution
`
`apparatus, and refers the reader to the individual drug monographs for test
`
`conditions specific to each particular drug. For example, the Procedure section of
`
`USP <711> directs the reader to the individual monograph for the apparatus,
`
`dissolution medium, volume, pH, and other test conditions. Id. at 282.
`
`43. Drug monographs include known information about the particular
`
`drug and about specific drug formulations. Drug monographs can also include
`
`standardized test conditions for dissolution testing and other common procedures
`
`for establishing bioequivalence.
`
`44. However,
`
`there
`
`is no USP monograph for diclofenac acid
`
`formulations. The diclofenac monograph in the USP includes entries for only
`
`diclofenac potassium tablets and diclofenac sodium delayed-release tablets. Ex.
`
`1034.
`
`- 18 -
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
`
`45. For formulations lacking a USP monograph (and hence lacking
`
`standardized conditions by which to perform the dissolution test), the USP
`
`provides <1092>,
`
`titled “The Dissolution Procedure: Development and
`
`Validation.” USP <1092> “provides recommendations on how to develop and
`
`validate a dissolution procedure.” Ex. 1008 at 579. USP <1092> provides “default”
`
`conditions that can be used when developing a dissolution test for a new
`
`formulation.
`
`46. USP <1092> provides recommended dissolution testing conditions
`
`under the following headings:
`
`47. Medium: Speaking generally of selecting a dissolution medium, this
`
`subsection states that selection of appropriate medium is “based on discriminatory
`
`capability, ruggedness, stability of the analyte in the test medium, and relevance to
`
`in vivo performance, where possible.” Id. at 580.
`
`48. USP <1092> states, also under the heading Medium:
`
`Typical media for dissolution may include the following (not listed in
`
`order of preference): dilute hydrochloric acid, buffers in the
`
`physiologic pH range of 1.2 to 7.5, simulated gastric or intestinal fluid
`
`(with or without enzymes), water, and surfactants (with or without
`
`- 19 -
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
`
`acids or buffers) such as polysorbate 80, sodium lauryl sulfate, and
`
`bile salts. Id. (emphasis added).
`
`Under the same heading, USP <1092> also states that “[f]or very poorly
`
`soluble compounds, aqueous solutions may contain a percentage of a
`
`surfactant (e.g., sodium lauryl sulfate, polysorbate, or lauryldimethylamine
`
`oxide) that is used to enhance drug solubility.” Id. (emphasis added).
`
`49. Volume: “Normally for basket and paddle apparatus, the volume of
`
`the dissolution medium is 500 mL to 1000 mL, with 900 mL as the most
`
`common volume.” Id. (emphasis added).
`
`50. Apparatus: “For solid oral dosage forms, Apparatus 1 and Apparatus
`
`2 are used most frequently.” Id. at 581. (emphasis added).
`
`51. Agitation: “For immediate-release capsule or tablet formulations,
`
`Apparatus 1 (baskets) at 100 rpm or Apparatus 2 (paddles) at 50 or 75 rpm are
`
`most commonly used.” Id. (emphasis added).
`
`52. Time Points: “Dissolution profiles of immediate-release products
`
`typically show a gradual increase reaching 85% to 100% at about 30 to 45
`
`minutes. Thus, dissolution time points in the range of 15, 20, 30, 45, and 60
`
`minutes are usual for the most immediate-release products.” Id. “So-called
`
`infinity points can be useful during development studies. To obtain an infinity
`
`- 20 -
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`
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`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
`
`point, the paddle or basket speed is increased at the end of the run for a sustained
`
`period (typically 15 to 60 minutes), after which time an additional sample is
`
`taken.” Id. (emphasis added).
`
`53. Thus, the USP teaches a typical medium for dissolution testing uses
`
`Apparatus 1 with 900 mL of medium, buffered to physiological pH range and
`
`including a surfactant, such as sodium lauryl sulfate. The USP also teaches
`
`using Apparatus 1 at 100 rpm and taking dissolution measurements at intervals
`
`from 15 to 60 minutes, and adding an infinity point of 15-60 additional minutes at
`
`a higher rotation speed.
`
`54. The FDA issued a publication in 1997 called “Guidance for Industry:
`
`Dissolution Testing of Immediate Release Solid Oral Dosage Forms.” (Ex. 1025,
`
`“FDA Guidance”). The FDA Guidance was developed to provide, “general
`
`recommendations for dissolution testing” and to explain how to set a dissolution
`
`specification for drug products seeking FDA approval, including when a USP
`
`dissolution test is not provided. Ex. 1025 at 1, 4-6.
`
`55. The FDA Guidance indicates that new drug applications (NDAs)
`
`submitted to the FDA must contain in vitro dissolution data that, along with
`
`bioavailability data and chemistry, manufacturing, and controls (CMC) data, are
`
`used to characterize the quality and performance of the drug product. Id. at 2. The
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`- 21 -
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`
`
`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
`
`FDA Guidance also indicates that in vitro dissolution data are among the data
`
`submitted to the FDA in abbreviated new drug applications (ANDAs). Id.
`
`56. Appendix A to the FDA Guidance provides dissolution testing
`
`conditions, which closely track the testing conditions provided by the USP. The
`
`FDA Guidance states that USP Apparatus 1 and Apparatus 2 “should be used
`
`unless shown to be unsatisfactory.” Ex. 1025 at A-1. Like the USP, the FDA
`
`Guidance also recommends a dissolution medium in the pH range of 1.2 to 6.8 and
`
`that the volume should be 500, 900, or 1000 mL. Id. It also recommends use of a
`
`surfactant such as sodium lauryl sulfate for sparingly water-soluble drug products.
`
`Id. The FDA Guidance, like the USP, sets the dissolution medium temperature at
`
`37 ºC and suggests a stir speed for Apparatus 1 at 50-100 rpm. Id. at A-2.
`
`V. THE ’721 PATENT
`
`
`A. The Specification of the ’721 Patent
`
`57. The ’721 patent is directed to methods of producing particles of
`
`diclofenac acid using dry milling processes, and compositions containing dry
`
`milled diclofenac acid nanoparticles. Ex. 1001, at 1:18-19; 2:66-3:4; 3:56-59;
`
`24:26-29; 47:12-53:5 (Examples 1-12); Figs. 1A-12A.
`
`58.
`
`In the Background section, the ’721 patent acknowledges that
`
`diclofenac was known to treat pain. Id. at 3:7-8. The Background section also
`
`- 22 -
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`
`
`Lupin v. iCeutica Pty Ltd
`IPR re U.S. Patent 9,017,721
`
`acknowledges that diclofenac was known to be poorly soluble in water at
`
`physiological pH, which was known to cause slow dissolution and poor absorption
`
`in the body. Id. at 1:28-38; 3:10-11. The Background section also acknowledges
`
`that dissolution rate affects the bioavailability of a drug or active material. Id. at
`
`1:36-37. The ’721 patent further admits that “[i]t is known that the rate of
`
`dissolution of a particulate drug will increase with increasing surface area. One
`
`way of increasing surface area is decreasing particle size.” Id. at 1:45-47.
`
`
`
`1. Meiser and Payne in the ’721 Patent Specification
`
`59. The ’721 patent purports to solve drug formulation issues that were
`
`previously addressed in Payne (Ex. 1011) and Meiser (Ex. 1005) (both of which
`
`are assigned to Patent Owner of the ’721 patent, iCeutica). Large portions of the
`
`Background section in the ’721 patent are copied nearly verbatim from Payne and
`
`Meiser. The first 11 paragraphs of the ’721 patent are found almost word-for-word
`
`in the Background section of Meiser.
`
`60. For example, both Payne and Meiser state that “[
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