Case 1:14-cv-01515-SLR-SRF Document 83 Filed 12/04/15 Page 1 of 114 PageID #: 3587
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`ICEUTICA PTY LTD and
`IROKO PHARMACEUTICALS, LLC,
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`
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`C.A. No. 14-1515-SLR-SRF
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`)))))))))))
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`
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`
`
`Plaintiffs,
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`v.
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`
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`Defendants.
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`
`LUPIN LIMITED and LUPIN
`PHARMACEUTICALS, INC.,
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`
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`
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`
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`
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`DECLARATION OF DR. MANSOOR M. AMIJI, PH.D., RPH IN SUPPORT
`OF DEFENDANTS’ ANSWERING CLAIM CONSTRUCTION BRIEF
`
`
`
`I, Mansoor M. Amiji, do hereby declare as follows:
`
`1.
`
`I submit this declaration in support of Defendants Lupin Limited and Lupin
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`Pharmaceuticals, Inc. (collectively, “Lupin”) Answering Claim Construction Brief. I have
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`personal knowledge of the matters set forth in this declaration, and if I am called upon to testify,
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`I could and would testify competently thereto.
`
`I. INTRODUCTION AND QUALIFICATIONS
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`2.
`
`I am currently the Bouvé College Distinguished Professor and Chair of the
`
`Department of Pharmaceutical Sciences in the School of Pharmacy at Northeastern University. I
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`have been Chair of that department since 2006 and have been a full-time faculty member in that
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`department since 1993. I am also a registered pharmacist in the Commonwealth of
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`Massachusetts.
`
`3.
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`In addition, I am currently an Affiliate Faculty Member in the Department of
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`Chemical Engineering and the Department of Biomedical Engineering at Northeastern
`
`1
`
`ICEUTICA 2002
`Lupin v. iCeutica
`IPR2016-00399
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`

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`Case 1:14-cv-01515-SLR-SRF Document 83 Filed 12/04/15 Page 2 of 114 PageID #: 3588
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`University. I am also currently a Distinguished Adjunct Professor in the Faculty of Pharmacy at
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`King Abdulaziz University in Jeddah, Saudi Arabia.
`
`4.
`
`I earned my B.S. in Pharmacy (magna cum laude) at Northeastern University in
`
`June 1988 and my Ph.D. in Pharmaceutics from Purdue University in July 1992. Prior to
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`beginning my professorship at Northeastern University in 1993, I served as a Senior Research
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`Scientist at Columbia Research Laboratories, in Madison, Wisconsin.
`
`5.
`
`I have been fortunate enough to receive a number of distinctions for my work in
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`pharmaceutical chemistry, including: the “Nano Science and Technology Institute (NSTI)
`
`Fellowship Award for Outstanding Contributions towards the Advancement, in Nanotechnology,
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`Microtechnology, and Biotechnology” in 2006; the “Meritorious Manuscript Award” from the
`
`American Association of Pharmaceutical Scientists (AAPS) in 2007; and the “Tsuneji Nagai
`
`Award from the Controlled Release Society in 2012.
`
`6.
`
`I am also a member of various professional societies, including the American
`
`Association of Pharmaceutical Scientists (Fellow), Controlled Release Society (Fellow),
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`American Association of College of Pharmacy, and the Phi Lambda Sigma, Pharmacy
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`Leadership Society (Honorary Member).
`
`7.
`
`I have served as an editor of seven textbooks related to pharmaceutical chemistry.
`
`I have authored, or co-authored, over 180 peer-reviewed articles and roughly 40 book chapters,
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`including numerous publications related the use of nanotechnology in drug delivery.
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`8.
`
`Currently, the primary focus of my laboratory research is on the development of
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`biocompatible materials from natural and synthetic polymers, target-specific drug and gene
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`delivery systems for cancer and infectious diseases, and nanotechnology applications for medical
`
`diagnosis, imaging, and therapy.
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`9.
`
`My curriculum vitae is included as Appendix I. In the last four years I testified in
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`the following cases: 1:10-CV-00329 (D. Del.), 11-CV-840 (N. D. Cal.), 2011-CV-12226 (D.
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`Ma.), 11-CV-02038 (S.D.N.Y.), 12-CV-05615 (S.D.N.Y.), 13-CV-00139 (S. D. Cal.), 13-CV-
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`1674 (D. Del.), 14-CV-0422 (D. Del.), 1:13-6502 (D.N.J.), and 1:14-3653(D.N.J.).
`
`10.
`
`I am being compensated at my normal consulting rate of $870 per hour. I have no
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`personal financial interest in any of the entities involved in this litigation, and my compensation
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`does not depend in any way on my testimony, my conclusions or the outcome of my analysis.
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`II. MATERIALS REVIEWED
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`11.
`
`Appendix II is a list of materials I reviewed in preparation of this declaration.
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`III. BACKGROUND AND STATE OF THE ART
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`NSAIDs and Diclofenac
`
`12.
`
`The patents-in-suit relate to diclofenac, a compound that is classified as a
`
`A.
`
`
`nonsteroidal anti-inflammatory drug, or NSAID. Like other NSAIDs, diclofenac has long been
`
`used as an anti-inflammatory and analgesic agent, or pain killer. Ex. 1 (Moore at 164-165).
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`13.
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`Diclofenac, like other NSAIDs, inhibits activity of the class of enzyme known as
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`cyclooxygenase (COX). Diclofenac inhibits both the COX-1 and COX-2 enzymes (Ex. 1 (Moore
`
`at 165)), with preferential inhibition of the COX-2 enzyme. Ex. 2 (Chuasuwan at 1207-08). Its
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`anti-inflammatory and analgesic properties are hypothesized to stem from inhibiting the COX
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`enzymes in synthesizing prostaglandins and thromboxanes, which are the lipids involved in
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`regulating inflammation and pain receptor sensitivity. Ex. 1 (Moore at 165).
`
`14.
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`Like other NSAIDs, diclofenac usage is associated with an increased risk of
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`gastrointestinal bleeding and serious cardiovascular side effects. Ex. 2 (Chuasuwan at 1208).
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`Because of cardiovascular safety concerns, FDA recommended that all NSAIDs remaining on
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`the market should be prescribed at the lowest effective dose for the shortest duration possible.
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`Ex. 3 (Jenkins Memo at 15).
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`15.
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`The scientific
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`literature classifies diclofenac
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`in
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`the biopharmaceutical
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`classification system (BCS) as Class II, meaning it is poorly water-soluble, but highly permeable.
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`Ex. 2 (Chuasuwan at 1214). Thus, diclofenac’s poor water solubility becomes the rate-limiting
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`factor in its oral absorption and bioavailability.
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`16.
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`The first commercially available diclofenac tablet was the sodium salt, marketed
`
`in Japan as Voltaren® in 1974 for anti-inflammatory use. Ex. 1 (Moore at 164.) The potassium
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`salt tablet was introduced in the early 1980s for use as an analgesic. Id. iCeutica also previously
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`developed diclofenac acid formulations prior to the patents-in-suit. See Ex. 4 (Payne) and Ex. 5
`
`(Meiser) discussed in paragraphs 24-28 below.
`
`B.
`
`
`Milling Drug Particles to Improve Dissolution Rate and Oral Bioavailability
`
`17.
`
`By at least 1993, it was known that a drug with low water solubility “often shows
`
`insufficient bioavailability because of the poor solubility in gastrointestinal fluids, which
`
`compels said drug to pass through the site of absorption before it completely dissolves in the
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`fluids.” Ex. 6 (Samejima, 1:19-24).
`
`18.
`
`“An active material's bioavailability is the degree to which the active material
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`becomes available to the target tissue in the body or other medium after systemic administration
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`through, for example, oral or intravenous means.” JA22 (1:19-23)1. Bioavailability, in turn,
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`depends, to a large extent, on the drug’s ability to dissolve in the small intestine
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`19.
`
`The patents-in-suit recognize the importance of reducing particle size to improve
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`dissolution rate and bioavailability: “[i]t is known that the rate of dissolution of a particulate drug
`
`
`1 All references to the shared specification are to the ’544 patent (JA1-JA57).
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`will increase with increasing surface area. One way of increasing surface area is decreasing
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`particle size.” JA22 (1:32-34).
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`20.
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`Reducing the particle size of the drug increases the overall surface area of the
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`administered dose of the drug. Dokoumetzidis et al. observed “[a]nother factor that influences
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`the dissolution rate is the surface exposed in the solvent. This is primarily affected by the
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`particle size, meaning the smaller the particles, and, therefore, in greater number, the higher their
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`total exposed surface as compared to larger, but fewer, particles of the same total mass. The
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`effect is especially dramatic with poorly soluble compounds.” Ex. 7 (Dokoumetzidis at 5).
`
`21.
`
`Different milling techniques have been developed over several decades to reduce
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`the particle size of poorly-soluble drug compounds, in order to increase the drug’s solubility and
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`bioavailability. Milling is also referred to as grinding in the patents-in-suit, as well as the
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`broader literature. Dry milling and wet milling are milling methods that have been employed to
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`reduce particle size. The distinction between wet milling and dry milling is that wet milling is
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`performed in a liquid medium, whereas dry milling “should be understood to refer to milling in
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`at least the substantial absence of liquids.” JA33 (23:24-25). Wet and dry milling each have
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`benefits and drawbacks. One drawback of wet milling is that flocculation, or the clumping
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`together of milled particles, prevents size reduction below certain levels. See, e.g., Ex. 8
`
`(Liversidge ’684 at 1:40-43).
`
`22.
`
`In 1993, Samejima addressed poor solubility and bioavailability by reducing drug
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`particle size through dry milling. Specifically, Samejima discloses dry milling naproxene (an
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`NSAID like diclofenac, which is marketed in the U.S. as Aleve) to “preferably less than 1 (cid:541)m
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`[1,000 nm]” to improve dissolution, solubility, and bioavailability. Ex. 6 (Samejima at 2:43-45,
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`4:14-45).
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`23.
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`Kesisoglou, in 2007, described that “nanosizing,” or “the reduction of the active
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`pharmaceutical ingredient (API) particle size down to the sub-micron range,” improves
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`dissolution of the drug compound. Ex. D (Kesisoglou at 632). Kesisoglou states that particle
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`size reduction had been employed in the pharmaceutical industry for decades, but “recent
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`advances in milling technology and our understanding of such colloidal systems have enabled
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`the production of API particles of 100-200 nm size in a reproducible manner. . . . These
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`nanoformulations 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 and IV) such
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`as solubility enhancers (i.e. surfactants). . . . ” Id. Furthermore, it was well-known at the time of
`
`the patents-in-suit that diclofenac exhibits poor solubility in water, and is classified as a BCS II
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`compound. See Ex. 2 (Chuasuwan, at Abstract).
`
`24.
`
`iCeutica recognized the value of nanosizing diclofenac acid to improve solubility
`
`and bioavailability as early as December 2005, the filing date of PCT Application No.
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`PCT/AU2005/001977, which later published as WO2006/069419. Ex. 4 (Payne). Payne states,
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`“[i]t is known that the rate of dissolution of a particulate drug can increase with increasing
`
`surface area, that is, decreasing particle size.” Id. at 1:25-26. Payne describes improving
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`dissolution of diclofenac acid using dry milling techniques to create nanoparticles having an
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`average size less than 200 nm. Id. at 1:25-26, 17:1-4, 26 Table 1, 42:9-43:26, Claim 36.
`
`25.
`
`Payne, in the Background Section, states that for wet milling techniques,
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`“flocculation restricts the lower particle size to limit to approximately 10 microns (10,000 nm).”
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`Id. at 2:2-4. Payne disparages wet milling further, stating that wet milling is “prone to
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`contamination, thereby leading to a bias in the pharmaceutical art against wet milling.” Id. at
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`2:4-6. In the Background Section, Payne also refers to another milling technique called, airjet
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`milling, which involves repeatedly projecting the drug particles against a target or against each
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`other at high speeds to reduce the size of the particles. Payne states that airjet milling can only
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`produce particle sizes in the range of “as low as about 1 to about 50 microns (1,000-50,000 nm).”
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`Id. at 2:6-8.
`
`26.
`
`iCeutica filed another patent application disclosing techniques for milling
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`diclofenac acid in PCT Application No. PCT/AU2007/00910, published in January 2008 as
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`WO2008/000042. Ex. 5 (Meiser). Meiser states, “[i]t is known that the rate of dissolution of a
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`particulate drug will increase with increasing surface area. One way of increasing surface area is
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`decreasing particle size.” Id. at 1. Meiser teaches improving solubility of poorly water-soluble
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`drugs, such as diclofenac, using dry milling techniques to obtain nanoparticulate diclofenac acid.
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`Id. at, e.g., 6-7, 27-28. Meiser states, “as discussed in the context of the background to the
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`invention, biologically active compounds that are poorly water-soluble at physiological pH will
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`particularly benefit from being prepared in nanoparticulate form.” Id. at 27. Meiser identifies
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`diclofenac acid as one of the poorly water-soluble compounds for which the nanosizing methods
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`of Meiser are suitable. Id. at 28.
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`27. Meiser also shows that it was well known that drugs in nanoparticulate form have
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`advantages over conventional compounds by way of more rapid therapeutic action and by using
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`a lower dose to achieve the same therapeutic effect. Id. at 7.
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`28. Meiser, in its Background Section, repeats word-for-word Payne’s disparagement
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`of wet milling and airjet milling techniques to reduce particle size: “[w]et grinding may be
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`employed to reduce particle size, but flocculation restricts the lower particle size limit to
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`approximately 10 microns (10,000 nm). The wet milling process, however, is prone to
`
`contamination, thereby leading to a bias in the pharmaceutical art against wet milling.” Id. at 2.
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`Payne’s disparagement of airjet milling to reduce particle size is also repeated word-for-word:
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`“Another alternative milling technique, commercial airjet milling, has provided particles ranging
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`in average size from as low as about 1 to about 50 microns (1,000-50,000 nm).” Id.
`
`C.
`
`
`Dissolution Testing in the Prior Art
`
`29.
`
`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
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`standardized conditions of liquid-solid interface, temperature, and media composition.” Ex. 9
`
`(Handbook at 17). In essence, dissolution testing is an in vitro (“outside the body”) measure of
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`drug solubility. When a drug’s solubility is the rate-limiting step to its absorption in the
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`gastrointestinal (GI) tract (as is the case for diclofenac), dissolution testing is a useful in vitro
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`proxy for understanding a drug’s in vivo bioavailability and efficacy. Id. at 25-26, 29; Ex. 10
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`(FDA Guidance at 2-3). The FDA requires dissolution testing data to be provided in regulatory
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`filings such as new drug applications (NDAs) and abbreviated new drug applications (ANDAs).
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`Ex. 9 (Handbook at 13); Ex. 10 (FDA Guidance at 2).
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`30.
`
`Dissolution testing can be used as a first-step approximation of bioequivalence
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`between drug formulations. Dissolution testing becomes valuable in the context of comparing
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`solubility of differing drug formulations under the same test conditions. The measured
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`dissolution rate of a drug will depend on a number of variables associated with the testing
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`conditions, such as the dissolution medium, stir rate, apparatus, temperature, pH, and volume.
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`Maintaining the same conditions from test to test when comparing the dissolution rates of drug
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`formulations is important because altering the test conditions can alter the final dissolution rate.
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`31.
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`The independent claims of the patents-in-suit refer to USP Apparatus 1 (basket
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`method) for the dissolution testing of diclofenac. Example 14 of the patent specification indicates
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`that the Apparatus 1 (basket method) is performed according to section <711> of the USP.
`
`32.
`
`According to section <711> of the United States Pharmacopeia (USP), the
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`dissolution tests were developed “to determine compliance with the dissolution requirements
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`where stated in the individual monograph for dosage forms administered orally.” Ex. G (USP
`
`<711> at 267). Section <711> includes generalized information about operation of the
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`dissolution apparatus, and refers the reader to the individual drug monographs for test conditions
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`specific to each particular drug. For example, the Procedure section of <711> directs the reader
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`to the individual monograph for the apparatus, dissolution medium, volume, pH, and other test
`
`conditions. Id. at 272.
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`33.
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`Drug monographs include known information about the particular drug and about
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`specific drug formulations. Drug monographs can also include standardized test conditions for
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`dissolution testing and other common procedures for establishing bioequivalence. I understand,
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`however, that there is no USP monograph for diclofenac acid formulations.
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`34.
`
`For formulations lacking a USP monograph (and hence lacking standardized
`
`conditions by which to perform the dissolution test), the USP provides section <1092>, titled
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`“The Dissolution Procedure: Development and Validation.” Section <1092> “provides
`
`recommendations on how to develop and validate a dissolution procedure.” Ex. G (USP <1092>
`
`at 573). Section <1092> provides “default” conditions that can be used when developing a
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`dissolution test for a new formulation.
`
`35.
`
`Section <1092> provides recommended dissolution testing conditions under the
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`following headings:
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`36. Medium: Speaking generally of selecting a dissolution medium, this subsection
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`states that selection of appropriate medium is “based on discriminatory capability, ruggedness,
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`stability of the analyte in the test medium, and relevance to in vivo performance, where
`
`possible.” Id. at 574.
`
`37.
`
`Section <1092> states, also under the heading Medium:
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`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 acids or buffers) such as polysorbate 80, sodium
`lauryl sulfate, and bile salts. Id. (emphasis added).
`
`
`Under the same heading, section <1092> also states that “[f]or very poorly soluble compounds,
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`aqueous solutions may contain a percentage of a surfactant (e.g., sodium lauryl sulfate,
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`polysorbate, or lauryldimethylamine oxide) that is used to enhance drug solubility.” Id.
`
`(emphasis added).
`
`38.
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`Volume: “Normally for basket and paddle apparatus, the volume of the
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`dissolution medium is 500 mL to 1000 mL, with 900 mL as the most common volume.” Id.
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`(emphasis added).
`
`39.
`
`Apparatus: “For solid oral dosage forms, Apparatus 1 and Apparatus 2 are used
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`most frequently.” Id. (emphasis added).
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`40.
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`Agitation: “For immediate-release capsule or tablet formulations, Apparatus 1
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`(baskets) at 100 rpm or Apparatus 2 (paddles) at 50 or 75 rpm are most commonly used.” Id.
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`at 575 (emphasis added).
`
`41.
`
`Time Points: “Dissolution profiles of immediate-release products typically show a
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`gradual increase reaching 85% to 100% at about 30 to 45 minutes. Thus, dissolution time
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`points in the range of 15, 20, 30, 45, and 60 minutes are usual for the most immediate-release
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`products.” Id. (emphasis added). “So-called infinity points can be useful during development
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`studies. To obtain an infinity point, the paddle or basket speed is increased at the end of the
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`run for a sustained period (typically 15 to 60 minutes), after which time an additional sample is
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`taken.” Id. (emphasis added).
`
`42.
`
`Thus, the USP teaches a typical medium for dissolution testing uses Apparatus 1
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`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
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`dissolution measurements at intervals from 15 to 60 minutes, and adding an infinity point of 15-
`
`60 additional minutes at a higher rotation speed.
`
`43.
`
`The FDA issued a publication in 1997 called “Guidance for Industry: Dissolution
`
`Testing of Immediate Release Solid Oral Dosage Forms.” Ex. 10 (FDA Guidance). The FDA
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`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
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`when a USP dissolution test is not provided. Id. at 1, 4-6.
`
`44.
`
`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 FDA Guidance also indicates that in vitro dissolution data are
`
`among the data submitted to the FDA in abbreviated new drug applications (ANDAs). Id.
`
`45.
`
`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.” Id. at A-1.
`
`Like the USP, the FDA Guidance also recommends a dissolution medium in the pH range of 1.2
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`to 6.8 and that the volume should be 500, 900, or 1000 mL. Id. It also recommends use of a
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`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
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`speed for Apparatus 1 at 50-100 rpm. Id. at A-2.
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`
`A.
`
`
`IV. THE PATENTS-IN-SUIT
`
`The Shared Specification
`
`46.
`
`I understand that the patents-in-suit claim priority to the same PCT application,
`
`and therefore share a common specification.
`
`
`
`1.
`
`47.
`
`Wet Milling and Airjet Milling are Disparaged
`
`The patents’ Background Section repeats Payne’ and Meiser’s disparagement of
`
`wet milling and airjet milling, stating that “wet grinding may be employed to reduce particle
`
`size, but flocculation restricts the lower particle size limit to 10 microns (10,000 nm).” JA22
`
`(1:44-46). The Background Section also repeats that “[t]he wet milling process, however, is
`
`prone to contamination, thereby leading to a bias in the pharmaceutical art against wet milling.”
`
`Id. (1:46-48). Also like Payne and Meiser, the patents state: “Another alternative milling
`
`technique, commercial airjet milling, has provided particles ranging in average size from as low
`
`as bout 1 to about 50 microns (1,000-50,000 nm).” Id. (1:48-51).
`
`2.
`
`48.
`
`Dry Milling is the “Present Invention”
`
`Dry milling, and the particles produced by dry milling, are repeatedly referred to
`
`as the “present invention” in the patents. For example, under FIELD OF INVENTION, the
`
`patents state: “The present invention relates to methods for producing particles of diclofenac
`
`using dry milling processes . . . .” Id. at 1:5-6. Under SUMMARY OF THE INVENTION, the
`
`patents state: [T]he present invention is directed to the unexpected finding that particles of a
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`biologically active material can be produced by dry milling processes at commercial scale.” Id.
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`at 3:44-47. Under the heading “Commercial Scale,” the patents continue: “The present invention
`
`is directed to the unexpected finding that particles of a biologically active material can be
`
`produced by dry milling processes as described herein at commercial scale” resulting in “a more
`
`efficient and cost effective process.” Id. at 24:28-35. Under the heading “Specific,” the patents
`
`state:
`
`In one embodiment, the present invention is directed to a method for producing a
`composition, comprising the steps of: dry milling a solid biologically active
`material and a millable grinding matrix in a mill comprising a plurality of milling
`bodies, for a time period sufficient to produce particles of the biologically active
`material dispersed in an at least partially milled grinding material.” Id. at 23:53-59
`(emphasis added).
`
`Under the heading “Dry Milling,” the patents state:
`
`In the dry milling process of the present invention, the biologically active
`material and grinding matrix, in the form of crystals, powders, or the like, are
`combined in suitable proportions with the plurality of milling bodies in a milling
`chamber that is mechanically agitated (i.e. with or without stirring) for a
`predetermined period of time at a predetermined intensity of agitation. Id. at
`31:39-45 (emphasis added).
`
`Under the heading “Dry Milling,” the patents additionally state:
`
`In a preferred form of the invention, the dry milling is performed in a ball mill.
`Throughout the remainder of the specification reference will be made to dry milling
`being carried out by way of a ball mill. Examples of this type of mill are attritor mills,
`nutating mills, tower mills, planetary mills, vibratory mills and gravity-dependent-type
`ball mills. It will be appreciated that dry milling in accordance with the method of the
`invention may also be achieved by any suitable means other than ball milling. For
`example, dry milling may also be achieved using jet mills, rod mills, roller mills or
`crusher mills. Id. at 32:11-22 (emphasis added).
`
`49.
`
`Beyond these cited examples, there are other instances in the specification of the
`
`patents referring to dry milling and dry milled diclofenac acid as the “present invention.”
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`3.
`
`50.
`
`The Examples and Experiments in the Specification Involve Dry Milling
`
`The patents include 16 examples. Of these, Examples 1-12 relate to processing of
`
`various drug compounds to produce nanoparticle formulations. All 12 of these examples use dry
`
`milling technology to process the drug compounds and all 12 result in dry milled nanoparticles
`
`of the drug compounds. See JA44-47 (46:55-52:55).
`
`51.
`
`In Examples 1-12, 305 different experiments were performed. These experiments
`
`are tabulated in Figures 1A, 1B, 1C, 1D, 1E, 1F, 1G, 2A, 3A, 4A, 5A, 6A, 6B, 6C, 7A, 8A, 9A,
`
`9B, 10A, 11A, and 12A. All 305 experiments involve dry milling of various active drug
`
`compounds, either alone or along with surfactants and/or grinding matrices.
`
`
`
`4.
`
`52.
`
`Dissolution Testing in Example 14 of the Specification
`
`The specification describes a single example of dissolution testing of diclofenac
`
`acid. Example 14 describes testing the dissolution rate of the “nanoformulations of the
`
`invention” against a “commercial reference” product. JA48 (54:11-67). One 18 mg capsule of
`
`diclofenac acid (sample W from Example 9) and one 35 mg capsules of diclofenac acid (a
`
`combination of samples X and Y from Example 9) were tested for dissolution rate and compared
`
`against the dissolution rate of the commercial reference product, a 50 mg tablet of Voltarol (a
`
`diclofenac dispersible tablet). Milling and preparation of samples W, X, and Y are described in
`
`Examples 9, 13a, and 13b. JA47-48 (52:57–67; 53:30–37; 54:17-21).
`
`53.
`
`Figures 9a and 9b show the active ingredients and excipients for various dry
`
`milling processes conducted as part of Example 9. Figure 9b shows samples W, X, and Y, and
`
`lists the pharmaceutical excipients used during dry milling of diclofenac, and lists the diclofenac
`
`particle size after dry milling:
`
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`

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`Case 1:14-cv-01515-SLR-SRF Document 83 Filed 12/04/15 Page 15 of 114 PageID #: 3601
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`
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`Here, Figure 9b, shows that samples W, X, and Y each contain 150 g of diclofenac acid milled
`
`with 840 g of lactose monohydrate and 10 g of SDS (sodium dodecyl sulfate, also known as,
`
`sodium lauryl sulfate). Thus, the dry milled composition consists of 15% diclofenac acid, 1%
`
`sodium lauryl sulfate, and 84% lactose monohydrate.
`
`54.
`
`Example 14 describes performing dissolution testing on the diclofenac acid
`
`capsules according to USP section <711> and under the following test conditions:
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`Apparatus I (basket) method;
`
`Stir speed of 100 rpm;
`
`Dissolution media of 0.05% sodium lauryl sulfate and citric acid solution buffered
`
`to 5.75 pH;
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`Volume of 900 mL;
`
`Temperature of 37°C; and
`
`Measurement intervals of 15, 30, 45, and 60 minutes, and an additional
`
`measurement at “infinity,” which is 15 additional minutes at a higher rotation speed. Id.
`
`at 54:22-30.
`
`55.
`
`The test conditions used in Example 14 (and listed in the independent claims as
`
`part of the “wherein . . . when tested” clause) are drawn directly from the USP and the FDA
`
`Guidance. See ¶¶ 34-45.
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`Case 1:14-cv-01515-SLR-SRF Document 83 Filed 12/04/15 Page 16 of 114 PageID #: 3602
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`56.
`
`The results of the dissolution testing are shown in Table 14a of the patents:
`
`
`
`57.
`
`Here, Table 14a indicates that the 18 mg dosage registered 91% dissolved in 15
`
`minutes and 94% dissolved in 30 minutes, and no additional dissolution therafter. The 35 mg
`
`dosage registered 82% dissolved in 15 minutes and 95% dissolved in 30 minutes, and no
`
`additional dissolution thereafter.
`
`
`
`5.
`
`58.
`
`Measuring Particle Size
`
`The patents-in-suit describe two well-known methods of analyzing particle size:
`
`first, photon correlation spectroscopy (PCS), also known as DLS, and second, laser diffraction.
`
`Id at 21:38-42. In the patents-in-suit, particle size measurements are taken using a PCS
`
`instrument. For measurements made using PCS, the term “number average particle size” is used
`
`and is explicitly defined in the patents-in-suit as “the average particle diameter as determined on
`
`a number basis.” Id. at 21:64-67. The patents-in-suit also state that for measurements taken
`
`using laser diffraction, the term “median particle size” is used, and is explicitly defined as “the
`
`median particle diameter as determined on an equivalent spherical particle volume basis.” Id. at
`
`22:1-5. The median particle diameter is, in turn, defined as “the particle size that divides the
`
`population in half such that 50% of the population is greater than or less than this size.” Id. at
`
`- 16 -
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`

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`Case 1:14-cv-01515-SLR-SRF Document 83 Filed 12/04/15 Page 17 of 114 PageID #: 3603
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`22:5-8. The claims recite “median particle size,” which term the specification correlates with
`
`laser diffraction instruments.
`
`B.
`
`
`The Claims of the Patents-in-Suit
`
`59.
`
`The independent claims of the ’540 and ’721 patents are directed to a “[solid oral]
`
`unit dose of a pharmaceutical composition” containing diclofenac acid. The independent claims
`
`of the ’387 patent are directed to “a method for treating pain comprising administering a solid
`
`oral unit does of a pharmaceutical composition” containing diclofenac acid.
`
`60.
`
`I consider the independent claims of all three patents to include three elements
`
`that provide limitation to the claims:
`
`(1) the pharmaceutical composition: “a [solid oral] unit dose of a pharmaceutical
`
`composition containing [x] mg of diclofenac acid”;
`
`(2) the dosage amount: [x] is either 18 mg or 35 mg of diclofenac acid; and
`
`(3) the particle size: “wherein the diclofenac acid has a median particle size, on a volume
`
`average basis, of less than 1000 nm and greater than 25 nm.”
`
`I note that Claims 1 and 6 of the ’544 patent also recite sodium lauryl sulfate and lactose
`
`monohydrate as part of the pharmaceutical composition. I further note that Claims 1 and 6 of the
`
`’544 patent also recite “a solid oral unit dose,” whereas the ’387 and ’721 patents recite a “unit
`
`dose.”
`
`61.
`
` The independent claims of the patents also include an additional clause related to
`
`diss