Free Claim Construction Opening Brief - 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. ) ) ) ) ) ) ) ) ) )

C.A. No. 06-774 (JJF)

PLAINTIFF RELIANT PHARMACEUTICALS, INC.'S OPENING CLAIM CONSTRUCTION BRIEF 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 Of Counsel: John M. 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

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TABLE OF CONTENTS Page NATURE AND STAGE OF THE PROCEEDINGS ......................................................................1 SUMMARY OF ARGUMENT .......................................................................................................1 ARGUMENT...................................................................................................................................2 I. II. III. LEGAL STANDARD FOR CONSTRUING CLAIMS ......................................................2 RELIANT'S RYTHMOL® SR DRUG PRODUCT ............................................................4 BACKGROUND OF THE CLAIMED INVENTION ........................................................5 A. The Field Of The Invention .....................................................................................5 1. Tablet Formulation.......................................................................................5 2. Delayed Release Tablets ..............................................................................6 B. The `588 Patent ........................................................................................................8 RELIANT'S PROPOSED CLAIM CONSTRUCTIONS ...................................................9 A. "Delayed Release Microtablet"................................................................................9 B. "Cylindrical" ..........................................................................................................11 C. "Convex Or Flat Upper Side And Lower Side".....................................................13 D. "The Tablet Contains No Release-Delaying Ancillary Substance".......................13 E. "Lubricant" ............................................................................................................16 F. "Other Conventional Ancillary Substances" .........................................................18 G. "Release Rate Is Virtually Independent Of The Pressure When Compressing The Tablets".....................................................................................19 H. "Active Ingredient Density" ..................................................................................21 I. "A Pronounced Plasma Level Plateau With A PTF<75%" ...................................22 J. "Bioavailability Does Not Depend On The Intake Of Food" ................................23 K. "Cylindrical Mold" ................................................................................................24 CONCLUSION..................................................................................................................25

IV.

V.

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TABLE OF AUTHORITIES Cases Conoco, Inc. v. Energy & Envtl. Int'l, L.C., 460 F.3d 1349 (Fed. Cir. 2006)........................................................................................... 4 Markman v. Westview Instruments, Inc., 517 U.S. 370 (1996)............................................................................................................ 4 Microsoft Corp. v. Multi-Tech Sys., Inc., 357 F.3d 1340 (Fed. Cir. 2004)........................................................................................... 3 Netword, LLC v. Centraal Corp., 242 F.3d 1347 (Fed. Cir. 2001)........................................................................................... 3 Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005)................................................................................... 2, 3, 4 Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298 (Fed. Cir. 1999)........................................................................................... 2 Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576 (Fed. Cir. 1996)............................................................................................. 3

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NATURE AND STAGE OF THE PROCEEDINGS Plaintiff Reliant Pharmaceuticals, Inc. ("Reliant") brought this suit against Par Pharmaceutical, Inc. ("Par") for infringement of U.S. Patent No. 5,681,588 ("the `588 patent") entitled "Delayed Release Microtablet of -Phenylpropiophenone Derivatives." D.I. 1, 8.

Reliant's Amended Complaint alleges, inter alia, that Par's generic propafenone extended release products described in ANDA 78-540 infringe the `588 patent. D.I. 8. Par has asserted defenses and counterclaims of non-infringement, invalidity and unenforceability of the `588 patent. D.I. 11. Fact discovery is ongoing. The parties have exchanged interrogatories and

document requests and responses. Document production is substantially complete. Pursuant to the March 28, 2007 Scheduling Order, fact discovery is to be completed by March 7, 2008. D.I. 27. However, depositions are ongoing and have been scheduled throughout March.

Accordingly, subject to the Court's approval, the parties have agreed to continue fact discovery through at least April 7, 2008. The parties exchanged lists of claim terms for construction on February 20, 2008. SUMMARY OF ARGUMENT The terms of a patent claim are properly construed according to their ordinary and customary meaning -- the meaning that one of skill in the art at the time of the invention would ascribe to them. In determining the meaning of claim terms, a court must look to the words of the claims, the specification of the patent, and the history before the U.S. Patent and Trademark Office ("Patent Office"). Reliant seeks claim constructions for 11 claim terms of the `588 patent. Reliant's proposed constructions comport with the ordinary and customary meanings that would be ascribed to the terms by one of ordinary skill in the art upon reading the patent.

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Each of Reliant's proposed claim constructions is supported by the plain meaning of the terms, the specification of the `588 patent, and the prosecution history of the patent. In addition, Reliant provides declarations from pharmaceutical formulation experts, Drs. Jeffrey Hubbell and Christopher Rhodes, that confirm that Reliant's proposed constructions reflect the understanding of one of ordinary skill in the art at the time of the invention. Accordingly, Reliant requests that the Court adopt Reliant's proposed claim constructions as set forth herein. ARGUMENT I. LEGAL STANDARD FOR CONSTRUING CLAIMS The metes and bounds of a patent are defined by the claims. See Phillips v. AWH Corp., 415 F.3d 1303, 1312 (Fed. Cir. 2005) (en banc) ("It is a `bedrock principle' of patent law that `the claims of a patent define the invention to which the patentee is entitled the right to exclude'") (internal citations omitted). Thus, "[t]he starting point for any claim construction must be the claims themselves." Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305 (Fed. Cir. 1999). The legal principles governing claim construction were recently summarized and clarified by the en banc Federal Circuit in Phillips v. AWH Corp. See id. The Court explained that claim terms "are generally given their ordinary and customary meaning," which is "the meaning that the term would have to a person of ordinary skill in the art in question at the time of the invention." See id. at 1312-13 (internal quotations omitted). To determine this meaning, "the court starts the decision making process by reviewing the same resources as would that person, viz., the patent specification and the prosecution history." See id. at 1313. Thus, claim construction rests primarily on three sources of intrinsic evidence -- the claims, the specification, and the prosecution history.

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In many cases, "the claims themselves provide substantial guidance as to the meaning of particular claim terms." See id. at 1314. When the ordinary meaning of the claim terms is readily apparent, claim construction may involve "little more than the application of the widely accepted meaning of commonly understood words." Id. "In such circumstances, general purpose dictionaries may be helpful." Id. The claims "do not stand alone," however, and "must be read in view of the specification, of which they are a part." See id. at 1315 (internal quotations omitted). The specification is highly relevant to the claim construction analysis. Id. The specification will often provide "the single best guide to the meaning of a disputed term." See id.; Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996). One reason for this is that "[t]he claims are directed to the invention that is described in the specification; they do not have meaning removed from the context from which they arose." See Netword, LLC v. Centraal Corp., 242 F.3d 1347, 1352 (Fed. Cir. 2001); see also Microsoft Corp. v. Multi-Tech Sys., Inc., 357 F.3d 1340, 1347 (Fed. Cir. 2004) ("Although it is improper to read a limitation from the specification into the claims, `[c]laims must be read in view of the specification, of which they are a part'") (internal citations omitted). Moreover, a patentee may use the specification to define the patent's use of specific claim terms. See Phillips, 415 F.3d at 1316 ("[O]ur cases recognize that the specification may reveal a special definition given to a claim term by the patentee that differs from the meaning it would otherwise possess. In such cases, the inventor's lexicography governs."). Similarly, the prosecution history of the patent should be considered in defining claim terms. "Like the specification, the prosecution history provides evidence of how the PTO and the inventor understood the patent." See id. at 1317.

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In addition, expert testimony may serve an important role in claim construction proceedings, and is particularly appropriate when dealing with complex technologies or those outside of the Court's expertise. See Markman v. Westview Instruments, Inc., 517 U.S. 370, 387 (1996). The Federal Circuit recently restated the important role experts may play in claim construction: [E]xtrinsic evidence in the form of expert testimony can be useful to a court for a variety of purposes, such as to provide background on the technology . . . to explain how an invention works, to ensure that the court's understanding of the technical aspects of the patent is consistent with that of a person of ordinary skill in the art, or to establish that a particular term in the patent or prior art has a particular meaning in the pertinent field. Conoco, Inc. v. Energy & Envtl. Int'l, L.C., 460 F.3d 1349, 1362 (Fed. Cir. 2006) (citing Phillips, 415 F.3d at 1318). II. RELIANT'S RYTHMOL® SR DRUG PRODUCT Reliant markets in the United States a sustained release (delayed release) formulation of propafenone hydrochloride under the trade name Rythmol® SR. Rythmol® SR is an antiarrhythmic drug for the treatment of irregular heartbeat (arrhythmia). It is approved by the U.S. Food and Drug Administration (FDA) and indicated to prolong the time to recurrence of symptomatic atrial fibrillation in patients without structural heart damage. Ex. 1. Unlike generic versions of instant release propafenone hydrochloride, Rythmol® SR is formulated as a sustained release (delayed release) drug. Accordingly, Rythmol® SR may be administered every twelve hours. Rythmol® SR may be taken with or without food. Ex. 1. Rythmol® SR is covered by the claims of the `588 patent. Ex. 2.

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III.

BACKGROUND OF THE CLAIMED INVENTION A. The Field Of The Invention 1. Tablet Formulation

The most commonly used orally administered drug products are solid pharmaceuticals in the form of compressed tablets. Tablets consist of therapeutic drug (often referred to as active pharmaceutical ingredient or "API") and non-pharmacologically active materials called excipients.1 Rhodes Decl. at ¶ 18.2 Tablets are manufactured by compaction on a tablet press of a powder or granular mix of API and excipients. 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. Rhodes Decl. at ¶ 19. Excipients may have many functions, including to improve the processing, storage or use of the product. For example, although some APIs are inherently readily

compressible and can be easily fabricated into tablets, many drugs do not compress easily unless they are mixed with substantial amounts of excipients that function as compaction aids (fillers). This is disadvantageous because such tablets may require large amounts of filler, resulting in a large tablet that is not easy to swallow. Rhodes Decl. at ¶¶ 18, 20. Most compressed tablets also contain an excipient that functions as a lubricant, commonly magnesium stearate. Lubricants act by reducing the frictional forces between the 1 In the `588 patent, non-pharmacologically active materials are generally referred to as "ancillary substances" rather than as excipients. The terms "excipients" and "ancillary substances" are used interchangeably herein. "Rhodes Decl." as used herein refers to the Declaration of Dr. Christopher T. Rhodes In Support Of Reliant Pharmaceuticals, Inc.'s Opening Claim Construction Brief.

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tablet and the press tooling and thereby prevent the tablet from adhering to the tooling. In the absence of a lubricant, when the tablet press enters the ejection mode and delivers the finished tablets into the product delivery chute, a significant proportion of the tablets may adhere to the tooling and thus be incomplete. In an extreme case the press will simply cease operation because the force required to eject the tablets is excessive. Rhodes Decl. at ¶ 21. Another type of excipient often included in tablet formulations 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 ejection from the press or during storage or transport stress. Rhodes Decl. at ¶ 22. 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 quality assurance testing for tablets. This release is evaluated using standard United States Pharmacopia (USP) 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. Rhodes Decl. at ¶ 23. 2. Delayed Release Tablets In an

Tablets may be classified as immediate release or delayed release.

immediate release tablet there is no design element included to control or delay the rate of drug release. For such tablets, the majority of the drug dose is released quickly, for example, within 30 minutes. Delayed release tablets are designed so that 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. Rhodes Decl. at ¶ 24. 6

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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, an important part of drug therapy. Rhodes Decl. at ¶ 25. Another advantage of delayed release drug products is that the concentration of drug in the blood over time is steady. 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 high concentration of drug in the bloodstream (i.e., a peak). This concentration decreases with time as the drug is removed from the bloodstream by the liver or kidneys. As a result of this drug clearance, the concentration of drug in the bloodstream immediately before the next dose is administered may be very low (i.e., a trough). The drug peaks may be associated with an increased incidence or severity of undesirable side effects; the drug troughs may be associated with lack of therapeutic response because the blood concentrations of drug are too low. In contrast, a well-designed 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. Rhodes Decl. at ¶ 26. There are two primary means to formulate a delayed drug release, use of a matrix or coating. Rhodes Decl. at ¶ 27; Hubbell Decl. at ¶ 19. 3
3

In a matrix system, the active

"Hubbell Decl." as used herein refers to the Declaration of Dr. Jeffrey A. Hubbell In Support Of Reliant Pharmaceuticals, Inc.'s Opening Claim Construction Brief.

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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. Rhodes Decl. at ¶ 28; Hubbell Decl. at ¶ 21. 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. Rhodes Decl. at ¶ 29; Hubbell Decl. at ¶ 20. The use of coatings and matrices to delay release of active drug from tablets was well known in the art at the time of invention of the `588 patent. Indeed, these methods were at that time, and still are, the two most common methods by which to formulate a delayed release drug product. Rhodes Decl. at ¶ 30. B. The `588 Patent The `588 patent is directed to solid oral dosage forms of -phenylpropiophenone derivatives, specifically to delayed release microtablets, with a high content and density of active ingredient and a delayed release which is independent of the compressive force, with no releasedelaying ancillary substances. Ex. 3 at Col 1:9-14. Surprisingly, the inventors of the `588 patent discovered that compaction of a high content and density of -phenylpropiophenone derivatives, including propafenone hydrochloride, when formed into microtablets with particular shape and size, resulted in delayed release of the API without the addition of release-delaying coatings or matrices. Ex. 3 at Col. 2:11-22. This discovery was contrary to the prior art, which taught that non-film-coated tablets required large amounts of ancillary substances to form matrices in order to delay release of an API. Ex. 3 at Col. 1: 20-45.

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In addition, the inventors found that the delayed release microtablet of the invention has significant advantages over the prior art: the release rate of the API is virtually independent of the compaction pressure used to make the microtablets, the in vivo plasma blood level fluctuations are consistently less with the microtablets than with the film-coated bolus form of the drug, and the absence of a release-delaying matrix or coating makes for easier production, manufacture and storage of the pharmaceutical formulation. Ex. 3 at Col. 2:30-41, Cols. 2:463:33, Fig. 11. The claimed delayed release microtablet of the `588 patent embodies these surprising discoveries. IV. RELIANT'S PROPOSED CLAIM CONSTRUCTIONS A. "Delayed Release Microtablet" Reliant requests that the term "delayed release microtablet"4 be defined as "a small unit of solid medicament prepared by compaction in which the release of active ingredient after 3 hours is not more than 80% and after 24 hours is not less than 80%." This definition is consistent with the plain meaning of the word microtablet, is set forth in Claim 1, and is supported by the specification and file history of the `588 patent. In short, one of skill in the art would understand that the term "delayed release microtablet" means a small unit of medicament with the delayed release properties set forth in the claim. 4

Par proposes to construe this preamble term as two separate terms, "delayed release" and "microtablet." However, in the context of the invention, these terms are not properly separable. The inventions of the patent are directed to delayed release microtablets that have specific properties and characteristics, and accordingly, "delayed release microtablet" is properly construed as a single claim term. No "microtablet" other than a delayed release microtablet is described or claimed by the patent. As will be clear in Par's brief, Par's attempt to parse the term is merely a means to improperly import limitations into the term that are not present in the claims of the `588 patent.

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The ordinary plain meaning of the term "microtablet" can be easily understood by virtue of its components "micro" and "tablet." "Micro" means small. Rhodes Decl. at ¶ 42; Hubbell Decl. at ¶ 25. A "tablet" is a solid medicament containing a drug substance that is prepared by compaction. Rhodes Decl. at ¶ 43, Ex. D; Hubbell Decl. at ¶ 25, Ex. B. Thus, a microtablet, pursuant to its plain, ordinary meaning, is a small unit of solid medicament prepared by compaction. Rhodes Decl. at ¶ 44; Hubbell Decl. at ¶ 25. The microtablet of the invention is a "delayed release microtablet." The delayed release characteristic is specifically defined in Claim 1 of the patent: "the release of active ingredient in the USP paddle method at 50 rpm is 80% as a maximum after 3 hours and as a minimum after 24 hours." Ex. 3 at Claim 1(d); see also Rhodes Decl. at ¶¶ 46-47; Hubbell Decl. at ¶ 26. The specification of the `588 patent sets forth a description of a "delayed release microtablet" that is consistent with Reliant's proposed claim construction and with Claim 1 of the patent. For example, the patent discloses that "the release of active ingredient after 3, preferably 5, hours is not more than 80[%] and after 24, preferably 15, hours is not less than 80%." Ex. 3 at Col. 2:55-57; see also Rhodes Decl. at ¶¶ 47-48; Hubbell Decl. at ¶ 27. Moreover, the examples and figures of the patent specification demonstrate delayed release microtablets have a release rate of active ingredient that after 3 hours is not more than 80% and after 24 hours is not less than 80%. See Ex. 3 Figs. 1-11 and Examples 1-8. The file history also supports the construction of a "delayed release microtablet" as proposed by Reliant. In particular, the patent applicants described their invention in the file history consistently with the specification and claims of the patent. For example, the applicants stated:

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Yet another surprising result achieved by the present invention is that other medicinal substances having a similar water solubility to that of propafenone hydrochloride (one of the compounds encompassed by the present formula I) are 90% released after one hour, when produced in the same type of microtablet. However, the present microtablets provide no more than 80% release after 3 hours and no less than 80% release after 24 hours. Ex. 5 at 5 (emphasis added); 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."). Moreover, as set forth in the accompanying declarations of pharmaceutical experts Dr. Hubbell and Dr. Rhodes, one of skill in the art reading the patent would understand that the delayed release microtablet of the invention is "a small unit of solid medicament prepared by compaction in which the release of active ingredient after 3 hours is not more than 80% and after 24 hours is not less than 80%." Rhodes Decl. at ¶ 50; Hubbell Decl. at ¶ 24. B. "Cylindrical" Reliant requests that the term "cylindrical" be defined as "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." This definition is consistent with the plain meaning of the word cylindrical as that term is used in Claim 1 and is supported by the specification and file history of the `588 patent. Moreover, one of ordinary skill in the art would understand from reading the patent claims and specification that the term "cylindrical" means a three-dimensional shape which includes a flat or convex surface and in which the height and diameter are, independently of one another, 1-3 mm. The patent claims and the specification are consistent with Reliant's proposed construction of the claim term "cylindrical." Claim 1 of the patent discloses a "delayed release microtablet with a convex or flat upper side and lower side ...wherein (a) the height and 11

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diameter are, independently of one another, 1-3 mm." Thus, it is plain from the claim itself that "cylindrical" must embrace and include these structural features. Rhodes at ¶¶ 58-59; Hubbell Decl. at ¶ 31. Similarly, the specification discloses that "[t]he microtablets according to the invention are cylindrical with a flat or convex upper side and lower side and with a diameter and height which are preferably approximately equal and, independently of one another, from 1 to 3, preferably 1.5 to 2.5 mm." Ex. 3 at Col. 2:42-46 (emphasis added). The specification further states that "[t]he resulting microtablets have a cylindrical shape with [a] flat or convex surface." Ex. 3 at Col. 4:19-22 (emphasis added). Hubbell Decl. at ¶ 32. The use of the claim term "cylindrical" in the file history is consistent with the patent specification. For example, during prosecution, the applicants stated that "the cylindrical delayed release microtablet of the present invention is required to have a height and diameter that are each, independently, 1-3 mm." Ex. 5 at 2. Moreover, one of skill in the art, in reading the `588 patent, would understand that the term "cylindrical" as used in the patent is defined as a three-dimensional shape having the height and diameter limitations set forth in Claim 1. Rhodes Decl. at ¶ 59; Hubbell Decl. at ¶ 30. Accordingly, one of skill in the art would use the patent claim itself as the best guide to determine what is meant by the claim term. Rhodes Decl. at ¶¶ 52, 58; Hubbell Decl. at ¶ 31. In addition, the skilled artisan would have knowledge of other pharmaceutical formulations which are comprised of non-circular "cylindrical" tablets having convex or flat surfaces. Rhodes Decl. at ¶ 57. Thus, one of skill in the art would understand the claim term "cylindrical" to mean a three-dimensional shape which includes a flat or convex surface in which the height and

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diameter are, independently of one another, 1-3 mm. Rhodes Decl. at ¶ 59; Hubbell Decl. at ¶ 30. C. "Convex Or Flat Upper Side And Lower Side" Reliant requests that the claim term "convex or flat upper side and lower side" be defined as "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')." The plain, ordinary meaning of "flat" is "having a surface that is without marked projections or depressions." Ex. 4. The plain, ordinary meaning of convex is "curved or rounded outward." Ex. 4. See also Rhodes Decl. at ¶¶ 61-62; Hubbell Decl. at ¶ 35. The patent specification and file history are consistent with the ordinary meaning of the term "convex or flat upper side and lower side." See, e.g., Ex. 3 at Col. 4:20-22 ("The resulting microtablets have a cylindrical shape with [a] flat or convex surface."). See also Ex. 5 at 5 ("Applicants have shown in the present application that by preparing the microtablets of the present invention to meet the size, shape and active ingredient content requirements, one obtains a microtablet having remarkable delayed release characteristics."). Hubbell Decl. at ¶ 36. One of skill in the art would understand this claim term to have its plain and ordinary meaning, such that each of the upper side and lower side have a surface that is without marked projections or depressions (i.e. "flat") or is curved or rounded outward (i.e. "convex"). Rhodes Decl. at ¶ 64; Hubbell Decl. at ¶ 34. D. "The Tablet Contains No Release-Delaying Ancillary Substance" Reliant requests that the Court construe the claim term "the tablet contains no release-delaying ancillary substance" to mean "the tablet contains no excipient that forms a release-delaying coating or matrix." This proposed construction comports with the plain 13 Rhodes Decl. at ¶ 63;

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meaning of the claim term, the specification and file history of the `588 patent, and the understanding of one of ordinary skill in the art. The plain, ordinary meaning of the phrase "ancillary substance" to one of skill in the art is something other than the active ingredient, i.e., an excipient. Rhodes Decl. at ¶¶ 18 n.1, 66; Hubbell Decl. at ¶ 39. Claim 1 of the patent recites that the delayed release microtablet of the invention contains the active pharmaceutical ingredient, lubricants or other conventional ancillary substances, and no release-delaying ancillary substance. This is consistent with the specification, which teaches that the active pharmaceutical ingredient itself, in the claimed formulation, provides substantially all of the release-delaying characteristics of the microtablet. See Ex. 3 at Col. 1:9-14, Col. 2:34-38. See also Rhodes Decl. at ¶¶ 66-69; Hubbell Decl. at ¶ 43. The patent specification expressly distinguishes this unique property of the invention with the prior art use of release-delaying matrices and coatings: "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. 3 at Col. 1:20-24. In contrast to these prior art coatings and matrices, the patent teaches that the small size and high content and density of active ingredient of the claimed microtablets control the release rate of the active drug substance. Ex. 3 at Col. 2:11-15, Col. 4:65-67. Thus, the specification expressly distinguishes the prior art release-delaying matrices and coatings from the claimed invention. Those releasedelaying coatings and matrices are the release-delaying ancillary substances of the prior art forbidden by the claimed invention. See Ex. 3 at Col. 1:20-24. Accordingly, the claim term "the tablet contains no release-delaying ancillary substance" means that "the tablet contains no

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excipient that forms a release-delaying coating or matrix." See Rhodes Decl. at ¶ 57, 72; Hubbell Decl. at ¶¶ 41-42. This construction of "the tablet contains no release-delaying ancillary substance" is buttressed by the remaining language of Claim 1. In particular, that claim permits the microtablet to contain "0-18.9% by weight of other conventional ancillary substances." Ex. 3 at Col. 8:43-44 (emphasis added). In other words, the presence of other conventional ancillary substances is permitted as long as those substances do not make up the release-delaying matrices or coatings of the prior art. See Rhodes Decl. at ¶ 67-68; Hubbell Decl. at ¶¶ 41-43. The file history of the `588 patent is consistent with the language of the claims and the specification. For example, the applicants represented to the Patent Office that the delayed release microtablet of the invention "is required to have a height and diameter that are each, independently, 1-3 mm, must contain the active ingredient in the range from 81-99.9% of the weight of the microtablet, and have an active ingredient density that is greater than 1." Ex. 5 at 2. The applicants then made clear that these characteristics of the claimed microtablets give the active ingredient its unique release-delaying properties, which were comparable to "other delayed release formats": 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. This is especially surprising in view of the fact that the present microtablet contains no other release-delaying additives. Ex. 5 at 2-3 (emphasis added). The only "other delayed release formats" described and

distinguished from the claimed invention in the patent specification are release-delaying coatings and matrices. See Ex. 3 at Col. 1:20-24; Rhodes Decl. at ¶ 73; Hubbell Decl. at ¶ 44.

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The specification and file wrapper are also consistent with the understanding of those of ordinary skill in the art. One of skill in the art at the time of invention would have had knowledge of the substances commonly used to delay release of an active ingredient from a solid dosage form such as a tablet or microtablet. Rhodes Decl. at ¶ 68; Hubbell Decl. at ¶ 42. In particular, one of skill in the art would have known that the generally accepted release-delaying ancillary substances at the time of invention were release-delaying matrices and release-delaying coatings. Rhodes Decl. at ¶ 68; Hubbell Decl. at ¶ 42. In addition, one of skill in the art would have understood that many ancillary substances, including, for example, binders, lubricants, wetting agents, fillers and adhesives, might have some minimal effect on the release rate of an active pharmaceutical ingredient, but that such substances are not generally considered "releasedelaying" agents. Rhodes Decl. at ¶ 75; Hubbell Decl. at ¶ 42. Moreover, in reading the patent specification and claims, one of skill in the art would have understood 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. Rhodes Decl. at ¶¶ 70-72; Hubbell Decl. at ¶ 43. Indeed, as demonstrated in Section IV.F below, these are the "other conventional ancillary substances" expressly permitted by Claim 1. Thus, in the context of the claims, specification, and prosecution history of the `588 patent, 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. Rhodes Decl. at ¶ 76; Hubbell Decl. at ¶¶ 38, 45. E. "Lubricant" Reliant requests that the Court construe "lubricant" to mean "a pharmaceutical ingredient that reduces friction and prevents tablet adhesion, e.g., talc or magnesium stearate." 16

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This construction is supported by the plain, ordinary meaning of the word and the specification of the `588 patent.5 Lubricants are well known to serve a variety of purposes in the formulation of tablets, and talc, magnesium stearate, and calcium stearate are common examples of lubricants. For example, Remington's Pharmaceutical Sciences provides: 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 include talc, magnesium stearate, . . . stearic acid, [and] hydrogenated vegetable oils. Rhodes Decl. at ¶ 78, Ex. B; Hubbell Decl. at ¶ 48, Ex. F. The `588 patent specification is consistent with this plain and ordinary 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[,] fumarate." Ex. 3 at Col. 4:7-13. Each example in the `588 patent describes the use of a lubricant, namely magnesium stearate, to prepare the delayed release microtablets of the invention. See Ex. 3 at Cols. 5-7. Accordingly, the term "lubricant," as used in the `588 patent, means a pharmaceutical ingredient that reduces friction and prevents tablet adhesion, e.g., talc or magnesium stearate. Rhodes Decl. at ¶ 79; Hubbell Decl. at ¶ 49. 5 There is no discussion of the claim term "lubricant" set forth in the file history of the `588 patent.

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Reliant's proposed construction of "lubricant" comports with the understanding of those of skill in the art. Rhodes Decl. at ¶ 80; Hubbell Decl. at ¶ 47. F. "Other Conventional Ancillary Substances" Reliant requests that the Court construe the term "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." Reliant's proposed construction is consistent with the plain meaning of the term, the patent specification and file history, and the understanding of one of ordinary skill in the art. The plain ordinary meaning of the term "ancillary substance" as used in pharmaceutical formulation is a pharmaceutical ingredient other than the active drug product. Rhodes Decl. at ¶ 82; Hubbell Decl. at ¶ 52. Conventional ancillary substances include, for example, binders, fillers, release-delaying matrices and coatings, and adhesives. Rhodes Decl. at ¶ 83. The meaning of the claim term "other conventional ancillary substances" as used in the `588 patent is consistent with the plain and ordinary meaning of these words. This meaning can be readily determined in the context of the patent claims and specification. In particular, Claim 1 recites that the delayed release microtablet may be comprised of an active pharmaceutical ingredient, lubricants and other conventional ancillary substances, and does not contain a release-delaying ancillary substance. As set forth above in Section IV.D, "releasedelaying ancillary substance," as used in the `588 patent, means a release-delaying matrix or coating. Accordingly, the term "other conventional ancillary substances" means "commonly used pharmaceutical ingredients other than an active pharmaceutical ingredient, a lubricant, or a `release-delaying ancillary substance.'" Rhodes Decl. at ¶ 84; Hubbell Decl. at ¶ 51. 18

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The patent specification provides non-limiting examples of "other conventional ancillary substances," including colorants, stabilizers, fillers, wetting agents, and flow regulators. Ex. 3 at Col. 4:16-18. Such substances would be known to anyone skilled in the art to be commonly used as neither active pharmaceutical ingredients, lubricants, nor release-delaying substances. Rhodes Decl. at ¶ 85; Hubbell Decl. at ¶ 54. Accordingly, one of skill in the art would understand the claim term "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." Rhodes Decl. at ¶ 86; Hubbell Decl. at ¶ 51. G. "Release Rate Is Virtually Independent Of The Pressure When Compressing The Tablets" Reliant requests that the Court construe the claim term "release rate is virtually independent of the pressure when compressing the tablets" to mean 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." Reliant's proposed construction comports with the ordinary meaning of the words of the term, i.e., that the release rate does not depend to any significant extent on the compaction pressure. Rhodes Decl. at ¶ 88; Hubbell Decl. at ¶ 56. The specification of the `588 patent provides a clear definition of the phrase. It discloses: "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." Ex. 3 at Col. 2:47-51. See also Rhodes Decl. at ¶ 89; Hubbell Decl. at ¶ 57. The specification likewise

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makes clear that the phrase refers to tablet pressures that are within the ordinary range of compression used in the formulation of pharmaceutical tablets. For example, the tablet pressures included in Figure 9 are within the ordinary range of compression for making pharmaceutical tablets. Rhodes Decl. at ¶ 90; Hubbell Decl. at ¶ 57. Moreover, the patent discloses the problem of the prior art that fluctuation of compressive forces when tabletting results in varying release rates of the active ingredient from the final dosage form. Ex. 3 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. 3 at Col. 2:11-16; Rhodes Decl. at ¶ 90. The prosecution history reiterates the meaning of the claim term and makes clear that the claimed microtablets do not have a wide range of release rates depending on the compressive force used: 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 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.... 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. 5 at 3. See also Rhodes Decl. at ¶ 91; Hubbell Decl. at ¶ 58. In sum, one of skill in the art would understand the claim term "release rate is virtually independent of the pressure when compressing the tablets" to mean that "within the ordinary range of compression used in the formulation of pharmaceutical tablets, the effect of the

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pressure when compressing the tablets on the release rate of the active pharmaceutical ingredient can be neglected for practical purposes." Rhodes Decl. at ¶ 92; Hubbell Decl. at ¶ 56. H. "Active Ingredient Density" Reliant requests that the Court construe "active ingredient density" to refer to the density of the active ingredient in the delayed release microtablet. This definition comports with the ordinary meaning of the term, as well as its use in the context of the patent claims, specification and file history. Moreover, one of skill in the art reading the `588 patent would understand that the term "active ingredient density" refers to the active ingredient density of the microtablet. The ordinary meaning of the claim term "active ingredient density" is simply the density of the active ingredient. Rhodes Decl. at ¶ 94. In the context of the `588 patent claims, the phrase "active ingredient density" refers specifically to the active ingredient density of the microtablet. For example, Claim 1 recites: "A cylindrical delayed release microtablet . . . wherein . . . (c) the active ingredient density is greater than 1." Thus, the context of the claim makes clear that "active ingredient density" refers to a characteristic of the delayed release microtablet of the invention. Rhodes Decl. at ¶ 95; Hubbell Decl. at ¶ 62. The specification further demonstrates that "active ingredient density" is an attribute of the microtablet. For example, the specification provides: "The present invention relates to cylindrical microtablets of -phenylpropiophenone derivatives with a high content and density of active ingredient." Ex. 3 at Col. 1:9-12, see also Col. 2:11-16 ("It is an object of the present invention ... to develop propafenone and diprafenone tablets with a small size, high content and density of active ingredient."). Thus, the `588 specification makes clear that "active ingredient density" refers to delayed release microtablets with a particular density of active ingredient. Rhodes Decl. at ¶ 96; Hubbell Decl. at ¶ 63. 21

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The prosecution history also demonstrates that "active ingredient density" is an attribute of the delayed release microtablets. For example, the applicants represented that "the cylindrical delayed release microtablet of the present invention is required to ... have an active ingredient density that is greater than 1." Ex. 5 at 2, see also 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 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."). Rhodes Decl. at ¶ 97; Hubbell Decl. at ¶ 64. Consistent with the ordinary meaning and the claims, specification and file history of the `588 patent, one of ordinary skill in the art would understand that "active ingredient density" refers to active ingredient density of the microtablet. Rhodes Decl. at ¶ 98; Hubbell Decl. at ¶ 61. I. "A Pronounced Plasma Level Plateau With A PTF<75%" Reliant requests that the Court construe "a pronounced plasma level plateau with a PTF<75%" to mean "a plasma level plateau with a peak to trough fluctuation of less than 75%,
C max - C min

where peak to trough fluctuation is defined as PTF (%) =

AUC t

× 100 ." This construction

is supported by the plain, ordinary meaning of the term and the specification. The plain, ordinary meaning of the term "PTF" is peak to trough fluctuation.
C max - C min Hubbell Decl. at ¶ 68. PTF is defined by the formula PTF (%) = AUC × 100 . Rhodes t

Decl. at ¶ 100. 22

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The specification provides this same definition of PTF and notes that a pronounced blood level plateau was evidenced by the PTF: 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... Cmax - Cmin

PTF (%) =

AUC

× 100

t for the AUC...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%.
See Ex. 3 at 2:60-3:13 (citations omitted), Fig. 11. See also Rhodes Decl. at ¶ 101; Hubbell Decl. at ¶ 69. Accordingly, one of skill in the art would understand the phrase "a pronounced plasma level plateau with a PTF<75%" to mean a plasma level plateau with a peak to trough fluctuation of less than 75%, where PTF is defined by the formula set forth in the specification. Rhodes Decl. at ¶ 102; Hubbell Decl. at ¶ 67. J. "Bioavailability Does Not Depend On The Intake Of Food" Reliant requests that the Court construe the claim term "bioavailability does not depend on the intake of food" to mean "bioavailability of the active pharmaceutical ingredient is unaffected by food intake for practical purposes." Reliant's proposed construction comports with the plain meaning of the claim term. In addition, the specification of the `588 patent states that "the bioavailability of this form [i.e., the delayed release microtablet of the invention] is unaffected by food intake in contrast to the bolus delayed release form. The AUC found for the bolus delayed release form is 50%

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higher when fasting." See Ex. 3 at Col. 3:17-21. See also Hubbell Decl. at ¶ 72. In addition, Table 1 of the patent notes that upon repeated administration of the microtablets of Example 1, the AUC and t75% was not different in the fasting and non-fasting states and the peak to trough fluctuations (PTF) were 52% in the fasting state and 56% in the non-fasting state. See Ex. 3 at Table 1; Rhodes Decl. at ¶ 104. Thus, one of skill in the art would understand this claim term to mean that the bioavailability of the active pharmaceutical ingredient is unaffected by food intake for practical purposes. Rhodes Decl. at ¶ 105; Hubbell Decl. at ¶ 71. K. "Cylindrical Mold" Reliant requests that the Court construe the claim term "cylindrical mold" to mean "die and punch in which a formulation is formed into a `cylindrical' shape." This proposed construction comports with the plain meaning of the claim term, the specification of the `588 patent, and the understanding of one of skill in the art.6 The meaning of the term "cylindrical" within the claim term "cylindrical mold" is consistent with the construction of that term set forth in Section IV.B above, i.e. a threedimensional shape which includes a flat or convex surface in which the height and diameter are, independently of one another, 1-3 mm. The ordinary plain meaning of the term "mold" to one of skill in the art is part of the tooling for production of solid dosage form of drugs, i.e., a punch and die in which a formulation is shaped. Rhodes Decl. at ¶ 108; Hubbell Decl. at ¶ 75. The specification of the patent is consistent with this ordinary meaning. For example, the patent discloses a non-limiting example of tooling for making the delayed release 6 There is no discussion of the term "cylindrical mold" contained in the file history of the `588 patent.

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microtablets of the invention comprising "a suitable tabletting machine equipped with multiple microtablet punches." Ex. 3 at Col. 4:19-20. See also Rhodes Decl. at ¶ 109; Hubbell Decl. at ¶ 76. Consistent with the plain meaning of the term and the patent specification, one of ordinary skill in the art would have understood the term "cylindrical mold," as used in the `588 patent, to mean "die and punch in which a formulation is formed into a `cylindrical' shape." Rhodes Decl. at ¶ 110; Hubbell Decl. at ¶ 74. V. CONCLUSION For all of the foregoing reasons, Reliant requests that the claim terms of the `588 patent be construed as follows: (1) Delayed release microtablet: a small unit of solid medicament prepared

by compaction in which the release of active ingredient after 3 hours is not more than 80% and after 24 hours is not less than 80%; (2) Cylindrical: 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; (3) Convex or flat upper side and lower side: 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"); (4) The tablet contains no release-delaying ancillary substance: the tablet

contains no excipient that forms a release-delaying coating or matrix; (5) Lubricant: a pharmaceutical ingredient that reduces friction and prevents

tablet adhesion, e.g., talc or magnesium stearate;

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(6)

Other conventional ancillary substances: 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; (7) Release rate is virtually independent of the pressure when compressing the

tablets: 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; (8) Active ingredient density: the density of the active ingredient in the

delayed release microtablet; (9) A pronounced plasma level plateau with a PTF<75%: a plasma level

plateau with a peak to trough fluctuation of less than 75%, where peak to trough fluctuation is
C max - C min

defined as PTF (%) =

AUC t

× 100 ;

(10)

Bioavailability does not depend on the intake of food: bioavailability of

the active pharmaceutical ingredient is unaffected by food intake for practical purposes; and (11) Cylindrical mold: die and punch in which a formulation is formed into a

"cylindrical" shape (as defined above).

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MORRIS, NICHOLS, ARSHT & TUNNELL LLP

/s/ Jack B. Blumenfeld
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

Of Counsel: John M. 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
1762995.1

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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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