Free Declaration - District Court of Delaware - Delaware

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE RELIANT PHARMACEUTICALS, INC., Plaintiff, v. PAR PHARMACEUTICAL, INC., Defendant. ) ) ) ) ) ) ) ) )

Civil Action No. 06-774-JJF

DECLARATION OF DR. CHRISTOPER T. RHODES IN SUPPORT OF RELIANT PHARMACEUTICALS, INC.'S OPENING CLAIM CONSTRUCTION BRIEF

Of Counsel: John Desmarais Gerald J. Flattmann, Jr. Christine Willgoos KIRKLAND & ELLIS, LLP Citigroup Center 153 E. 53rd Street New York, NY 10022 (212) 446-4800 March 5, 2008

MORRIS, NICHOLS, ARSHT & TUNNELL LLP Jack B. Blumenfeld (#1014) Maryellen Noreika (#3208) 1201 North Market Street P.O. Box 1347 Wilmington, DE 19899-1347 (302) 658-9200 [email protected] [email protected] Attorneys for Plaintiff

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I, Christopher T. Rhodes, declare and state as follows: 1. I have been retained as an expert consultant in this case by counsel for Reliant

Pharmaceuticals, Inc. ("Reliant") in connection with the matter Reliant Pharmaceuticals, Inc. v. Par Pharmaceutical, Inc., Civil Action No. 06-774-JJF. I. BACKGROUND AND QUALIFICATIONS 2. I have been involved in the pharmaceutical sciences in academia and consultancy

for private industry, and assisting government agencies with respect to the design and evaluation of drug products, for over 30 years. I obtained my B. Pharm. (Honors) and Ph.D. in Pharmacy from the Faculty of Medicine of the University of London in 1961 and 1964, respectively. From 1964 to 1965, I was Smith Kline and French Post-Doctoral Research Associate at Purdue University, where I worked on the development of extended-release drug products. This work was patented. 3. I served as Senior Lecturer (and subsequently as Principal Lecturer) at

Portsmouth School of Pharmacy from 1965 to 1972. In the academic year of 1969 to 1970, I was Canadian Medical Research Council, Visiting Professor at the University of British Colombia. From 1972 to 1975, I was Associate Professor at The State University of New York at Buffalo. I was appointed Professor and Chair of the Department of Pharmacy at the University of Rhode Island ("URI") in 1975. From 1992 to 2007, I served as part-time Professor at URI. In July 2007, I was appointed Professor Emeritus at URI. 4. My university teaching duties included responsibility for undergraduate and

graduate courses in Biopharmaceutics, Industrial Pharmacy, and Physical Pharmacy. Also, as part of my university activities, I directed a research group comprising visiting faculty, doctoral fellows, graduate students, and technicians. I have acted as Major Professor for more than 50

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graduate students. My research activities have been focused to a considerable extent on the design, evaluation, and regulatory approval of solid oral dosage forms. 5. I am the author or co-author of about 240 scientific or professional papers. I am

also the co-editor of five books, including the first four editions of Modern Pharmaceutics and the third edition of Drug Stability. I am a Fellow of the Academy of Pharmaceutical Sciences and a Founding Fellow of the American Association of Pharmaceutical Scientists. I have acted as a reviewer for a number of journals, including the Journal of Pharmaceutical Sciences and the International Journal of Pharmaceutics. I served as Assistant Editor of the Canadian Journal of Pharmaceutical Sciences and was the founding editor of Drug Development and Industrial Pharmacy. I have given lectures and courses at locations in North America, the European Union, and Asia. I have acted as Chair for a National Institute of Health Committee for research, grant, and contract proposals. I have been accepted as a special employee, approved by the Food and Drug Administration ("FDA"), working for that agency on the evaluation of compounded drug products. Additionally, I have served on two FDA expert advisory committees (generic and compounded drugs). For 15 years, from 1985 to 2000, I served as a member of the Committee of Revision of the United States Pharmacopoeia ("USP") (Dissolution, Stability, Excipients, and Bioavailability Committees). In June 2000, I gave invited testimony to a U.S. Senate subcommittee on drug product quality. 6. My evaluation of drug products has included in vivo studies, both

pharmacokinetic and pharmacodynamic. At different times I have been involved in clinical trials of humans as a participant, principal investigator, auditor, or consultant. I have acted as an FDA-approved auditor for bioavailability studies. Also, I have consulted for pharmaceutical companies on the design and interpretation of clinical studies intended to monitor both safety and

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efficacy. My work as an expert witness has included testimony on the causation and monitoring of adverse events for drug products. Between 1992 and 2007 I held an adjunct appointment at Roger Williams Hospital, which is linked to Brown University Medical School. My expertise in examining membrane flux phenomena was recognized by my appointment, in subsequent years as Vice Chair and Chair of a Gordon Research Conference on membrane transport. 7. In addition to my university-related activities, I have provided confidential

consulting services to pharmaceutical companies and other entities in the United States, Canada, Australia, and the European Union. Also, I have consulted for government and international organizations, including the Government of Bermuda, the World Bank, the Population Council, the U.S. Internal Revenue Service, and the U.S. Army Chemical Warfare Defense Command. Among the topics for which my advice has been sought are design, evaluation, production, troubleshooting, and regulatory approval of drug products, including extended-release products. 8. I have been admitted as an expert witness on drug products by courts in the U.S.,

Canada, U.K., Australia, Korea, and Israel. 9. My curriculum vitae, attached as Exhibit A, sets forth my educational and

professional experience. Included in my curriculum vitae is a list of all publications that I have authored within the preceding 10 years. There are no additional publications since 2002. II. BASES FOR OPINION 10. In forming the opinions set forth in this declaration, I relied upon my education,

background and experience in the area of design, evaluation and production of pharmaceutical products.

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11.

I have reviewed U.S. Patent No. 5,681,588 ("the `588 patent") and its associated

file history. In addition, I have consulted general purpose and pharmaceutical dictionaries, treatises and other scientific literature as set forth herein. 12. I understand that Reliant has alleged that Par Pharmaceutical, Inc.'s ("Par's")

generic propafenone drug products described in ANDA 78-540 infringe at least Claims 1-5 of the `588 patent. 13. I understand that the parties disagree about the meaning of some of the claim

terms used in the `588 patent, and that the purpose of my declaration is to assist the Court in understanding and defining those claim terms. 14. I understand that the Court reads the claims of the patent from the viewpoint of

"one of ordinary skill in the art." I understand that this person is someone with the requisite training and education, but is not an expert in the relevant field of the invention. 15. It is my belief that the person skilled in the art to whom the patent is addressed

would have a first degree in pharmacy (B.S., M.S., or Pharm. D.) and at least two years postgraduation experience working on the formulation and evaluation of compressed tablets, including delayed release products. Alternatively, the skilled artisan would have a first degree in some discipline peripheral to pharmacy, such as chemical engineering or biology. These individuals would have at least four years post-graduation experience working on the formulation and evaluation of compressed tablets, including delayed release products. Individuals without a first degree in pharmacy will have compensated for deficiency in their educational background by attendance at appropriate courses or by a program of careful study on such topics as industrial pharmacy, pharmacokinetics and drug regulatory affairs.

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16.

I understand that the relevant date for defining the claim terms of the `588 patent

is the earliest filing date of the patent specification, i.e., April 3, 1993. My opinions are directed to what one of ordinary skill in the art would have known or understood as of that date. 17. In addition to the opinions and subject matter identified in this declaration, I may

offer additional testimony or a declaration in response or rebuttal to any expert opinions offered by Par in support of its proposed claim constructions. II. BACKGROUND OF THE `588 PATENT A. 18. Formulation of Tablets In North America and Western Europe, the most commonly used orally

administered drug products are compressed tablets. Tablets consist of drug (often referred to as active pharmaceutical ingredient or "API") and non-pharmacologically active materials, normally referred to as excipients.1 Excipients function to improve the processing, storage or use of the product. In the `588 patent, excipients are described as ancillary substances. 19. Compression of the tablet formulation, which consists of either a mixture of

powders or granular material is effected on a tablet press. The compaction force applied on the tablet press squeezes out most of the air in the powder or granular mix and forces the solid particles into very close proximity to one another so that in some instances they join together. The tablet produced on a tablet press may be subsequently subjected to additional manufacturing steps, such as applying a coat. 20. Unfortunately, although some APIs are inherently readily compressible and thus

can be easily fabricated into tablets, many drugs do not compress easily into tablets unless they
1

In the `588 patent, non-pharmacologically active materials are generally referred to as "ancillary substances" rather than as excipients. In my experience, excipients is the more commonly used term. Accordingly, throughout this declaration, the terms "excipients" and "ancillary substances" are used interchangeably.

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are mixed with substantial amounts of excipients that function as compaction aids (fillers). The disadvantage of this type of excipient is that if, for example, the compaction aid to drug ratio is 5:1 then we may produce a rather large tablet that is not easy to swallow. 21. Most compressed tablets also contain a lubricant, commonly magnesium stearate.

Lubricants act by reducing the frictional forces between the tablet and the press tooling. In the absence of a lubricant, parts of the tablet may adhere to the tooling. As a result, when the tablet press enters the ejection mode and delivers the finished tablets into the product delivery chute, a significant proportion of the tablets will be incomplete. In an extreme case the press will simply cease operation because the force required to eject the tablets is excessive. 22. Another type of excipient often included in a tablet is a binder. This material

assists in maintaining the physical integrity of the tablet so that it is less likely to break up either on injection from the press or during storage and transport stress. Ex. B, Edward Rudnic & Joseph B. Schwartz, Oral Solid Dosage Forms, in Remington's Pharmaceutical Sciences 1633, 1635 (Alfonso R. Gennaro ed., 18th ed. 1990). 23. Once a tablet is ingested by the patient it is essential that the drug be released into

the lumen of the gastrointestinal tract (GI) from where it can then enter the bloodstream. The release of drug from a tablet in the conditions likely to exist within the GI tract is thus an element of the quality assurance testing for tablets. This release is evaluated using official USP2 dissolution tests. Normally, the dissolution of drug from tablets is dependent upon the amount of force used in the compression event. In general, the greater the compression force used, the harder the tablet. An increase in tablet hardness usually slows down dissolution of drug.
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USP (United States Pharmacopia) is the compendium recognized by the Congress as providing official standards for drug substance, drug products and some test methods such as those used in dissolution testing.

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B. 24.

Delayed Release Tablets Tablets may be classified as immediate release or delayed release. In an

immediate release tablet there is no design element included to control or delay the rate of drug release. For such tablets, we might expect that an appropriate dissolution test would indicate that most of the drug was released within a short period of time, for example, 30 minutes. However, there can be considerable advantage in developing tablets for which the dissolution is deliberately delayed so the drug is released within the GI tract over a period of several hours. This prolongs the process of absorption so that blood levels of the drug can remain at therapeutic concentrations for an extended period of time. 25. Delayed release drug products offer patients a number of significant advantages.

First, the dosing frequency can be reduced. For example, a drug with an immediate release (nondelayed) formulation that has to be administered three or four times daily may only require administration once or twice a day when provided as a delayed release product. This reduction in dosing frequency is convenient to the patient and also improves patient compliance. For example, if a patient has to take a tablet at lunch time or when they are at work, they quite often forget. In fact, we have good reason to believe that in many instances therapeutic failure in drug treatment is not caused by any inadequacy of the drug but simply that the patient failed to follow the dosing instructions. 26. Another advantage of delayed release drug products is that the so-called "peaks

and troughs" in the blood concentration time curves for the drug are greatly reduced. For example, when a drug product is provided as an immediate release tablet three times a day the surge of drug rapidly released into the GI tract often results in a quite high concentration of drug in the bloodstream (i.e., a peak). This concentration decreases with time as the drug is removed from the bloodstream, most likely by renal or hepatic action. As a result of this clearance of 8

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drug, the concentration of drug in the bloodstream immediately before the next dose is administered may be very low (i.e., a trough). The peaks may be associated with an increased incidence or severity of undesirable side effects; the troughs may be associated with lack of therapeutic response because the blood concentrations of drug are too low. In contrast, a welldesigned delayed release product may exhibit relatively stable blood concentrations of drug without the occurrence of either peaks or troughs. This can result in improved efficacy and reduced toxicity. The fluctuation in blood levels can be quantified by the peak to trough fluctuation index, PTF. 27. Although much ingenuity has been shown by pharmaceutical scientists in

designing delayed release tablets that have a control of drug dissolution so that dosing frequency can be reduced, there are two general methods normally used to delay drug release, namely matrix or coating control. 28. In a matrix system, the active pharmaceutical drug is embedded in excipients

which enclose the drug and provide a structure so that dissolution can be retarded. This approach requires a substantial amount of excipients and thus can result in a tablet which is unacceptably large. 29. The control of dissolution from tablets by coatings so as to obtain delayed release

products is also common. By judicious selection of the components of the coating, it is possible to provide a barrier so that release of drug from the tablet into the lumen of the GI tract occurs at a controlled rate over the desired period of time. 30. The use of coatings and matrices to delay release of active drug from tablets were

well known in the art at the time of invention of the `588 patent. Indeed, these methods were at

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that time, and still are, the two most common methods by which to formulate a delayed release product. C. 31. The Invention Of The `588 Patent The problem which the `588 inventors address was to develop an orally

administered delayed release drug delivery system for -phenylpropiofenone derivatives, including propafenone. Ex. C at Col. 1:9-13. In order to provide an acceptable size of dosage form it was essential that the product have a high percentage of active pharmaceutical drug. To reduce the volume of the dosage form it was desirable that the density of the drug in the individual units of the dosage form should be greater than 1. Further, it was desirable that the release rate (dissolution) of drug should be virtually independent of compressive force and uniform over a lengthy period of time. In order to achieve these goals, it was also necessary to exclude the use of certain excipients, such as release-delaying film coatings or matrices, that would control the release of drug. Ex. C at Col. 2:11-26. 32. The `588 patent teaches that the above problems can be solved by making

microtablets and subsequently filling the microtablets into conventional gelatin capsules. On ingestion by the patient the microtablets are released into the lumen of the GI tract once the capsule shell has disrupted. (This normally occurs quite rapidly). As is pointed out in the patent, the use of multiple unit delayed release dosage forms (i.e. microtablets) has considerable advantages over normal size tablets. Ex. C at Col. 1:36-53. 33. Although the -phenylpropiphenone derivatives of the invention have poor

inherent compression properties, the `588 patent teaches that the compaction of the drug into a microtablet of a certain shape, size and density allows successful compression with an active ingredient content of 81 to 99.9% of drug. The claimed formulation does not contain any

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release-delaying excipient (i.e., ancillary substance) and the dissolution of the microtablet is virtually independent of compressive force. Ex. C at Col. 2:29-30. 34. The microtablets of the invention are delayed release microtablets, that is, they

have a slow dissolution rate that is achieved without using release delaying excipients such as coatings or matrices. The dissolution of drug from the claimed microtablets is delayed such that no more than 80% of the drug is released after three hours and at least 80% is released after 24 hours. Also, the patent teaches that dissolution can be adjusted by the size of the tablet and possibly adding excipients, such as disintegrants, to speed up the dissolution. Ex. C at Col. 2:53-57. 35. In vivo studies in human subjects show that the drug product of the claimed

microtablets have a blood concentration time curve that has an extensive plateau. The absence of peaks and troughs is shown by PTF values of less than 75%. Ex. C at Fig. 11. 36. The `588 patent also discloses that the bioavailability of the drug (the rate and

extent to which the drug enters the patient's bloodstream) does not depend on the presence or absence of food. Ex. C at 3:13-19. Thus, the mode of administration is flexible with respect to meals. 37. The patent discloses that the process used for the formulation in the `588 patent is

not applicable to drugs of similar water solubility. Ex. C at Col. 2:22-26. Thus, the teachings described in the patent may be entirely specific to -phenylpropiphenone derivatives. III. CLAIM TERMS FOR CONSTRUCTION 38. Counsel for Reliant has requested that I provide my opinion on how I think a

person of skill in the art would interpret certain terms of the `588 patent claims. 39. I understand that in considering claim construction I should first examine the

intrinsic evidence in the claims, the specification and the file history. In all of the claim 11

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construction presented below, the conclusions I reach are, I believe, fully in compliance with data in the claims, specification and file history of the `588 patent. A. 40. "Delayed-release microtablet" Counsel for Reliant has asked me to inform an opinion as to how a person of

ordinary skill in the art would understand the phrase "delayed release microtablet" as it is used in claims of the `588 patent. 41. In my opinion, one of skill in the art would understand the phrase "delayed

release microtablet" to mean a small unit of solid medicament prepared by compaction methods in which the release of active ingredient after 3 hours is not more than 80% and after 24 hours is not less than 80%. 42. In my opinion, the term "microtablet" means a small tablet. The plain, ordinary

meaning of "micro" is small and the specification refers to "microtablets" having an independent diameter and height of "from 1 to 3, preferably 1.5 to 2.5 mm." Ex. C at Col. 2:45-46. Tablets of this dimension would be considered small by one of ordinary skill. 43. As set forth in a pharmaceutical treatise I edited, "tablets may be defined as unit

forms of solid medicaments prepared by compaction." See Ex. D, Keith Marshall and Edward M. Rudnic, Tablet Dosage Forms, in Modern Pharmaceutics 355, 355 (Gilbert S. Banker & Christopher T. Rhodes eds., 2d ed. 1990). 44. Thus, the ordinary meaning of "tablet" to one of ordinary skill is a small unit of

solid pharmaceutical dosage form prepared by compaction methods. 45. I have also reviewed the specification and prosecution history of the `588 patent

and it is my opinion that the patentees used the term "microtablet" consistent with its ordinary meaning. 46. The microtablets of the invention are "delayed release microtablet(s)." 12

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47.

Claim 1 makes clear that "delayed release microtablet" means a tablet that

exhibits a "release of active ingredient in the USP paddle method at 50 rpm [of] 80% as a maximum after 3 hours and as a minimum after 24 hours." 48. These same release parameters are set forth at several places in the specification.

See, e.g., Ex. C at Abstract, Col. 2:53-57. 49. Similarly, the Applicants stated during prosecution that "the present microtablets

provide no more than 80% release after 3 hours and no less than 80% release after 24 hours." Ex. E at 3. See also id. at 4 ("[T]he present invention . . . is drawn to a delayed release microtablet which is required by the claim to have no more than 80% release of the active ingredient after 3 hours and no less than 80% after 24 hours"). 50. Thus, the phrase "delayed release microtablet" means a small unit of solid

medicament prepared by compaction methods in which the release of active ingredient after 3 hours is not more than 80% and after 24 hours is not less than 80%. B. 51. "Cylindrical" I understand that the parties have asked the Court to define the claim term

"cylindrical." It is my opinion that those of ordinary skill would understand that the term "cylindrical," as used in the `588 patent, means "a three-dimensional shape which includes a flat or convex surface in which the height and diameter are, independently of one another, 1-3 mm." 52. The term "cylindrical" in Claim 1 and Claim 6 is a modifier with respect to a

description of the delayed release microtablet. The preamble of Claim 1 states: "a cylindrical delayed release microtablet with a convex or flat upper side and lower side." 53. The skilled artisan would recognize that the term "cylindrical," in the context of

the patent, is being used in an approximate, not a rigid, sense. The definition of a cylinder is "a surface or solid bounded by two parallel planes and generated by a line drawing a closed curve 13

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perpendicular to the two given planes." Ex. F. This definition requires that the upper and lower surfaces of a cylinder must be flat. Further, the patentees have specifically allowed for the upper and lower sides to be flat or convex. Thus it is apparent that the patentees were not using the term cylindrical in an exact mathematical sense. 54. The term convex means a surface that is "curved or rounded outward." Ex. F.

The skilled artisan would be well aware that many tablets are rounded outward on both their upper and lower sides. 55. The term flat means "having a surface that is without marked projections or

depressions." Ex. F. Thus, if a surface is flat, it can be fully defined by using only two dimensions. Again, the skilled artisan would be aware that some tablets have flat (nonprotruding, non-recessive) upper and lower surfaces. 56. Further, the skilled artisan having experience of the type of tooling normally used

in the manufacture of compressed tablets would know that tablets with convex upper and lower surfaces are common. In my experience compressed tablets with flat upper and lower surfaces are also known in the art, but are less common than those with convex surfaces. 57. It can be noted from the above dictionary definition of a cylinder that the cross

section of a cylinder does not have to be circular. Any closed surface will satisfy the definition of a cylinder. Again, the skilled artisan would be well aware that non-circular tablet press tooling is widely used. For example, the Pfizer prescription drug product Lipitor®, a tablet that is very widely used for the control of serum lipid values, has an elliptical cross section. Also, the over-the-counter Tylenol® caplets, another very large sales volume product, are manufactured on tablet presses that use tooling such that the cross section of the tablet is essentially rectangular with rounded corners. Both Lipitor® and Tylenol® have convex upper and lower surfaces.

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58.

Also, the skilled artisan, in reading the `588 patent, would understand that Claim

1 indicates that the dimensions of the delayed release microtablet can be varied independently of one another between 1 and 3 mm and that the upper and lower surfaces of the microtablets can be convex or planar. The skilled artisan would appreciate that a precise definition of the shape of the microtablet is not required in order for the reader to benefit from the teachings of the invention. 59. Thus, the skilled artisan would interpret the term "cylindrical" as it appears in

Claim 1 and Claim 6 of the invention described in the 588 patent, to mean a three-dimensional shape which includes a flat or convex surface and has dimensions (that are independently of one another) of between 1 and 3 mm. C. 60. "Convex or flat upper side and lower side" It is my opinion that those of ordinary skill would understand that the phrase

"convex or flat upper side and lower side," as it appears in Claim 1, means that each of the upper side and lower side have a surface that is without marked projections or depressions ("flat") or is curved or rounded outward ("convex"). 61. The plain, ordinary meaning of "flat" is "having a surface that is without marked

projections or depressions." Ex. F. 62. Ex. F. 63. I have reviewed the specification and the prosecution history and, in my opinion, The plain, ordinary meaning of convex is a "curved or rounded outward surface."

each is consistent with the plain, ordinary meaning of the terms "convex" and "flat." 64. Thus, one of ordinary skill in the art at the time of the invention would interpret

"convex or flat upper side and lower side" to mean that each of the upper side and lower side

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have a surface that is without marked projections or depressions ("flat") or is curved or rounded outward ("convex"). D. 65. "The tablet contains no release-delaying ancillary substance" It is my opinion that those of ordinary skill would understand that the phrase

"tablet contains no release-delaying ancillary substance," as that phrase appears in the `588 patent, means the tablet contains no excipient that forms a release delaying coating or matrix. 66. In the pharmaceutical arts, an "ancillary substance" generally refers to something

other than the active ingredient in the formulation. Thus, in the context of the patent claims, "the tablet contains no release delaying ancillary substance," it is apparent that the active pharmaceutical ingredient contributes substantially all of the release delaying properties of the delayed release microtablets of the invention. 67. According to Claim 1, the claimed tablet contains an active ingredient of the

defined formula, a lubricant, other conventional ancillary substances, and no release-delaying ancillary substance. See Ex. C at Claim 1. This composition is consistent with the specification, which, for example, provides: "In the prior art the release of active ingredient from tablets is delayed either by a release-delaying matrix in which the active ingredient is embedded, or by a release-delaying coating through which the digestive fluid diffuses in and the active ingredient diffuses out." Ex. C at Col. 1:20-24. The patent then goes on to describe several "considerable disadvantage[s]" of matrix dosage forms and coatings. Ex. C at Col. 1:25-43. 68. One of ordinary skill would understand that release delaying substances are

almost always in one of two forms for tablet dosage forms: a matrix or a coating. This was the case in 1993 and remains so today. Thus, one of ordinary skill in the art at the time of invention would have understood that the patentees were distinguishing the invention from prior art delayed release matrices and coatings. 16

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69.

The remainder of the `588 specification continues this theme. For example, the

specification indicates that the patentees prepared a "delayed release bolus film-coated tablet" containing propafenone as a comparative example and showed that it was inferior to the claimed delayed release microtablet. The specification reports: "The in vitro release from the delayed release bolus film-coated tablet [was] similar to that of the delayed release microtablets according to the invention. Nevertheless, the in vivo release is entirely different and, in fact, better according to the invention, cf. drug levels shown in FIG. 11." See Ex. C at Col. 8:11-16. 70. In addition, the wording of Claim 1, part (f) makes it clear that the patentees

allowed for the inclusion in the microtablets of excipients such as lubricants and binders. The specification states: "It is possible to employ all conventional binders or adhesives." Ex. C at Col. 3:66-67. Further, I note that Examples 1-8 in the patent all contain magnesium stearate as lubricant. Since magnesium stearate is a hydrophobic (low-water-solubility material) it will tend, to some extent, to retard dissolution from the microtablets. See Ex. G, L.V. Allen & P.E. Luner, Magnesium Stearate, in Handbook of Pharmaceutical Excipients 280, 281 (Ainley Wade & Paul J. Weller eds., 2d ed. 1994) ("Magnesium stearate is hydrophobic and may retard the dissolution of drug from a solid dosage form."). The Handbook of Pharmaceutical Excipients is an internationally recognized treatise published jointly by the American Pharmaceutical Association and the Royal Pharmaceutical Society of Great Britain. Thus, although magnesium stearate is added to the examples of the `588 patent to act as a lubricant, there will inevitably be some effect on slowing dissolution. 71. Similarly, I note that Examples 1, 2, 3, 4, 6, and 7 of the `588 patent contain

hydroxypropylmethylcellulose (HPMC). See Ex. C. The Handbook of Pharmaceutical Excipients reveals that HPMC is used both as a binder and as a matrix for extended-release

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tablets, as well as for other uses such as a delayed release film coating. Ex. G, R.J. Harwood & J.L. Johnson, Hydroxypropyl Methylcellulose, in Handbook of Pharmaceutical Excipients 229, 230. In the examples given in the `588 patent, HPMC is functioning as a binder rather than a tablet matrix. However, even as a binder it is probable that in performing its adhesive function to provide structural integrity to the microtablet, it will inevitably, to some extent at least, retard dissolution. 72. Thus, it is clear that the patent distinguishes excipients (ancillary substances),

such as lubricants and binders, from release-delaying substances such as coatings and matrices. In my opinion, the term "no release-delaying ancillary substance" means that the delayed release microtablets of the invention contain only excipients that serve some primary purpose other than to retard dissolution. 73. The prosecution history of the `588 patent is consistent with the specification in

distinguishing delayed-release excipients in the form of matrices and coatings from other ancillary substances. For example, during prosecution, the patent applicants stated: "Applicants have found that by preparing a microtablet having the required size and shape, active ingredient content and active ingredient density, containing the -phenylpropiophenone derivative of formula I as its active ingredient, it is possible to provide a microtablet that has surprisingly improved delayed release characteristics compared to other delayed release formats." Ex. E at 23. Thus, the prosecution history teaches that size and shape of the microtablet along with active ingredient content and density provide the delayed release characteristics observed for the microtablet, without the addition of matrices or coatings. 74. Thus, the specification and prosecution history make clear that the microtablets

are different than the other delayed release formats, namely matrices and coatings. One of skill

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in the art at the time of the invention would appreciate this distinction since the generally accepted release delaying ancillary substances used in tablets at the time of the invention were matrices and coatings. 75. At the time of the invention, one of skill in the art would also appreciate that

many ancillary substances, including, for example, binders, lubricants, wetting agents, fillers and adhesives, might have some affect on the release rate of an active pharmaceutical ingredient, but that such substances are not generally considered "release-delaying" agents. In reading the patent specification and claims, one of skill in the art would understand that the delayed release microtablets of the invention could encompass a microtablet that included ancillary substances such as binders, adhesives, fillers, wet granulators, etc., as long as no release delaying coatings or matrices were employed. 76. Thus, one of skill in the art would have understood the term "the tablet contains

no release delaying ancillary substance" to mean that the tablet contains no excipient that forms a release delaying coating or matrix. E. 77. "Lubricant" In my opinion, one of ordinary skill would understand the term "lubricant" to

mean a pharmaceutical ingredient that reduces friction and thus prevents adhesion of a tablet to tooling surfaces, e.g., talc or magnesium stearate. 78. Lubricants serve a variety of purposes in preparing pharmaceutical tablets. Talc,

magnesium stearate, and calcium stearate are commonly used lubricants in tablet formulation. According to Remington's Pharmaceutical Sciences: Lubricants have a number of functions in tablet manufacture. They prevent adhesion of the tablet material to the surface of the dies and punches, reduce interparticle friction, facilitate the ejection of the tablets from the die cavity, and may improve the rate of flow of the tablet granulation. Commonly used lubricants 19

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include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, and polyethylene glycol (PEG). Ex. B, Edward Rudnic & Joseph B. Schwartz, Oral Solid Dosage Forms, in Remington's Pharmaceutical Sciences 1633, 1636 -37 (Alfonso R. Gennaro ed., 18th ed. 1990). 79. The specification of the `588 patent is consistent with the plain meaning of

lubricant. The specification provides: "After the granules have been dried to the defined water content, 0.1-5, preferably 0.3-2, % by weight of a lubricant for the tabletting are mixed in homogenously. It is likewise possible to use for this purpose all conventional substances such as talc, magnesium stearate, calcium stearate, stearic acid, calcium behenate, glycerin palmitostearate, sodium acetate, polyethylene glycol, sodium stearate [sic] fumarate." Ex. C at Col. 4:7-13. 80. Thus, one of ordinary skill would understand that the term "lubricant" as it is

used in the claims of the `588 patent means a pharmaceutical ingredient that reduces friction and prevents tablet adhesion, e.g., talc or magnesium stearate. F. 81. "Other conventional ancillary substances" In my opinion, one of ordinary skill would understand "other conventional

ancillary substances," which appears in Claims 1 and 6, means commonly used pharmaceutical ingredients other than an active pharmaceutical ingredient, a lubricant, or a release delaying ancillary substance as defined above, e.g., binders, adhesives, colorants, stabilizers, fillers, wetting agents, and flow regulators. 82. For the reasons stated in Paragraph 66 above, one of skill in the art would

understand that "ancillary substance" refers to a substance in the tablet other than the active ingredient.

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83.

"Conventional" in the pharmaceutical arts means common or accepted. Thus,

conventional ancillary substances include excipients such as binders, fillers, release-delaying matrices and coatings, and adhesives. 84. The meaning of "other conventional ancillary substances" is determined by its

context within the claims and specification of the `588 patent. Claim 1, for example, states that the delayed release microtablets comprise (a) an active ingredient, (b) a lubricant, (c) other conventional ancillary substances and (d) no release delaying ancillary substance. Thus, "other conventional ancillary substances" in the context of the claim means something other than the active ingredient, lubricant, or "release delaying ancillary substance." 85. The patent specification provides several examples of "other conventional

ancillary substances," such as binders, colorants, stabilizers, fillers, wetting agents, and flow regulators. See Ex. C at Cols. 3:66-4:3, 4:16-18. These materials are known to those skilled in the art to be used as neither active pharmaceutical ingredients, lubricants, nor release-delaying substances. 86. Thus, one of skill in the art would understand "other conventional ancillary

substances" to mean commonly used pharmaceutical ingredients other than an active pharmaceutical ingredient, a lubricant, or a release delaying ancillary substance as defined above, e.g., binders, adhesives, colorants, stabilizers, fillers, wetting agents, and flow regulators. G. 87. "Release rate is virtually independent of the pressure when compressing the tablets" In my opinion, one of ordinary skill in the art would understand that "release rate

is virtually independent of the pressure when compressing the tablets," as that term is used in the `588 patent, means that within the ordinary range of compression used in the formulation of 21

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pharmaceutical tablets, the effect of the pressure when compressing the tablets on the release rate of the active pharmaceutical ingredient can be neglected for practical purposes. 88. The plain, ordinary meaning of the term "release rate is virtually independent of

the pressure when compressing the tablets" means that the release rate of the active ingredient does not depend to any significant extent on the compaction pressure. 89. The specification of the `588 patent similarly provides: "It was furthermore not

predictable that the release of active ingredient is, in contrast to usual experience, virtually independent of the pressure when compressing the tablets....`Virtually independent' means that the effect can be neglected for practical purposes." See Ex. C at Col. 2:47-51. 90. The specification also shows that the phrase is referring to tablet pressures that are

within the ordinary range of compression used in the formulation of pharmaceutical tablets. See, e.g., Ex. C at Fig. 9. The patent discloses the problem, present in the prior art, that fluctuation of compressive forces when tabletting resulted in varying release rates of the active ingredient from the final dosage form. Ex. C at Col. 2:64-3:8 Accordingly, one of the objects of the invention was to "overcome the disadvantages of the prior art, i.e. to develop propafenone and diprafenone tablets with . . . release of active ingredient which is independent of the compressive force and uniform over a lengthy period." Ex. C at Col. 2:11-16. 91. The prosecution history reinforces this meaning of "release rate is virtually

independent of the pressure when compressing the tablets" and makes clear that the claimed microtablets are advantageous in that they do not have a wide fluctuation in release times depending on the amount of compression used. During prosecution, the patent applicants stated: A further surprising result achieved with the present microtablet formulation is that the release of the active ingredient is virtually independent of the pressure used to compress the tablet and independent of the pH. These results are unexpected in view of the 22

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fact that it is generally accepted that increases in the compressive force used in tablet production provides a slowing of the release of active ingredient (see specification at page 2 beginning at line 14). A common problem with this feature is that fluctuations in the compressive force in a single machine can result in tablets being produced that have a wide range of delay release times. Ex. E at 3. 92. Thus, one of ordinary skill in the art would understand that "release rate is

virtually independent of the pressure when compressing the tablets" means that within the ordinary range of compression used in the formulation of pharmaceutical tablets, the effect of the pressure when compressing the tablets on the release rate of the active pharmaceutical ingredient can be neglected for practical purposes. H. 93. "Active ingredient density" In my opinion, one of ordinary skill in the art would understand that "active

ingredient density," as that term is used in the `588 patent claims, means the density of the active ingredient in the delayed release microtablet. 94. ingredient. 95. In the `588 patent, the context of Claim 1 makes clear that the phrase "active The ordinary, meaning of "active ingredient density" is the density of the active

ingredient density" refers specifically to the active ingredient density of the microtablets. Indeed, Claim 1 reads: "A cylindrical delayed release microtablet . . . wherein . . . (c) the active ingredient density is greater than 1." Thus, the context of Claim 1 shows that "active ingredient density" is a characteristic of the delayed release microtablet. 96. A review of the specification also shows that "active ingredient density" is

referring to a characteristic of the microtablet. The specification provides: "It is an object of the present invention ... to develop propafenone and diprafenone tablets with a small size, high 23

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content and density of active ingredient." See Ex. C at Col. 2:11-16, see also Col. 1:9-12 ("The present invention relates to cylindrical microtablets of -phenylpropiophenone derivatives with a high content and density of active ingredient."). 97. The file history of the `588 patent further supports that "active ingredient density"

is a characteristic of the delayed release microtablet. For example, during prosecution, the applicants stated that "the cylindrical delayed release microtablet of the present invention is required to ... have an active ingredient density that is greater than 1." Ex. E at 2. See also id. at 2-3 ("Applicants have found that by preparing a microtablet having the required size and shape, active ingredient content and active ingredient density, containing the -phenylpropiophenone derivative...it is possible to provide a microtablet that has surprisingly improved delayed release characteristics compared to other delayed release formats."). 98. Thus, one of skill in the art would understand that "active ingredient density"

means the density of the active ingredient in the delayed release microtablet. I. 99. "A pronounced plasma level plateau with a PTF<75%" In my opinion, the phrase "a pronounced plasma level plateau with a PTF<75%,"

as it appears in Claim 2, means "a plasma level plateau with a peak to trough fluctuation of less
C max - C min PTF (%) = AUC t × 100

than 75%, where peak to trough fluctuation is defined as 100.

."

"PTF," or peak to trough fluctuation, is a commonly known pharmacokinetic

parameter. As known to those of skill in the art, PTF is defined by the formula
C max - C min PTF (%) = AUC t × 100 .

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101.

The `588 specification provides this same calculation for PTF and indicates that,

in a pharmacokinetic study using the delayed release microtablets of the invention, the patentees observed a pronounced blood level plateau in patients as evidenced by the PTF. The specification provides: Despite the short half-life, a pronounced blood level plateau develops (FIG. 11). The fluctuations in the blood level are considerably less with the microtablets. This is evident from the t75% (period in the dosage interval during which the plasma levels are at least 75% of the maximum level), which is 8 to 9 hours with the microtablets according to the invention compared with 5 to 6 hours with the bolus delayed release form, and from the PTF (peak to trough fluctuation; cf. H. P. Koch and W. A. Ritschel, Synopsis der Biopharmazie und Pharmakokinetik, EcomedVerlagsgesellschaft mbH, Landsberg und Munchen, 1986)
C max - C min PTF (%) = AUC t × 100

for the AUC, cf. J. K. Aronson et al., Europ. J. of Clinical Pharmacology 35 (1988), 1-7. which has a value for the microtablets which is only about half that for the bolus forms, in particular less than 75, preferably less than 60%. Ex. C at Cols. 2:60-3:13. 102. Thus, one of ordinary skill would understand the phrase "a pronounced plasma

level with a PTF<75%" to mean a plasma level plateau with a peak to trough fluctuation of less than 75%, where peak to trough fluctuation is calculated using the formula set forth in the specification. J. 103. "Bioavailability does not depend on the intake of food" In my opinion, the term "bioavailability does not depend on the intake of food,"

which appears in Claim 2 of the `588 patent, means to one of ordinary skill in the art that

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bioavailability of the active pharmaceutical ingredient is unaffected by food intake for practical purposes. 104. The specification of the `588 patent discusses the advantages of the claimed

microtablets and states that "the bioavailability of this form [i.e., the delayed release microtablet] is unaffected by food intake, in contrast to the bolus delayed release form." Ex. C at Col. 3:1719. The specification continues that "the AUC found for the bolus delayed release form is 50% higher when fasting." Id. at Col. 3:20-21. Additionally, Table 1 reports the results of a study using repeated administration of the delayed release microtablets of Example 1 and a bolus delayed release form. As shown in that table, upon repeated administration of the microtablets, the AUC and t75% were not different in the fasting and non-fasting states and the peak to trough fluctuations were 52% in the fasting state and 56% in the non-fasting state. See Ex. C at Table 1. 105. Thus, in my opinion, one of ordinary skill would understand "bioavailability does

not depend on the intake of food" to mean that the bioavailability of the active pharmaceutical ingredient is unaffected by food intake for practical purposes. K. 106. "Cylindrical mold" In my opinion, the phrase "cylindrical mold" as that term appears in Claim 6 of

the `588 patent means a die and punch in which a formulation is formed into a "cylindrical" shape. 107. 108. I have previously commented on the term "cylindrical." See Section III.B above. The ordinary meaning of mold to one of ordinary skill means something that is

part of tooling for the production of solid dosage forms containing pharmaceuticals, in other words, a punch and die in which a substance is shaped.

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CERTIFICATE OF SERVICE I hereby certify that on March 5, 2008 I electronically filed the foregoing with the Clerk of the Court using CM/ECF, which will send notification of such filing to: Josy W. Ingersoll, Esquire YOUNG, CONAWAY, STARGATT & TAYLOR I further certify that I caused to be served copies of the foregoing document on March 5, 2008 upon the following in the manner indicated: Josy W. Ingersoll, Esquire YOUNG, CONAWAY, STARGATT & TAYLOR The Brandywine Building 1000 West Street, 17th Floor Wilmington, DE 19801 John G. Taylor, Esquire James K. Stronski, Esquire FROMMER LAWRENCE & HAUG LLP 745 Fifth Avenue New York, NY 10151 VIA ELECTRONIC MAIL and HAND DELIVERY

VIA ELECTRONIC MAIL

/s/ Jack B. Blumenfeld
Jack B. Blumenfeld (#1014)

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