Free Declaration - District Court of Delaware - Delaware

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 1 of 19

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. JEFFREY A. HUBBELL 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

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 2 of 19

I, Jeffrey A. Hubbell, 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 2. I was awarded the degree of Bachelor of Science in Chemical Engineering from

Kansas State University in 1982, and the degree of Doctor of Philosophy in Chemical Engineering from Rice University in 1986. 3. Since 2004, I have been a Professor of Bioengineering and the Director of the

Institute of Bioengineering, as well as a Professor of Chemical Engineering at the Institute for Chemical Sciences and Technology, both of the École Polytechnique Fédérale de Lausanne ("EPFL") in Lausanne, Switzerland. My research at EPFL concerns mainly polymers for delivery of small molecule drugs, including delayed-release formulations; polymer and biopolymer hydrogels for delivering protein and peptide drugs in regenerative medicine, including bone, skin and muscle repair and inducing angiogenesis; polymers for delivery of gene-based drugs; polymers for antigen and danger signal delivery in vaccine formulations; and polymers for targeted and sustained delivery in local targets, such as articular cartilage and coronary artery. 4. From 1997 to 2003, I held the position of Professor of Biomedical Engineering in

the Department of Materials at Swiss Federal Institute of Technology Zurich ("ETHZ") and in the Faculty of Medicine at the University of Zurich, as well as the post of Director of the Institute for Biomedical Engineering (ETHZ and University of Zurich). There I conducted research on polymers for delivery of small molecule drugs, including delayed-release formulations; on polymer and biopolymer hydrogels for delivering protein and peptide drugs in 2

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 3 of 19

regenerative medicine, including bone, skin and nerve repair and induction of angiogenesis; and on polymers and peptides for delivery of gene-based drugs. 5. From 1995 to 1997, I was a Professor of Chemical Engineering at the California

Institute of Technology. There I conducted research on polymer and biopolymer hydrogels for delivering protein and peptide drugs in regenerative medicine; and on polymers for local drug delivery. 6. From 1986 to 1994, I taught at the University of Texas, Austin, first as an

Assistant Professor, and after 1991 as an Associate Professor of Chemical Engineering. At the University of Texas, Austin, I conducted research on mechanisms of and pharmacological interference with surface-initiated and biomaterials-initiated thrombosis; on polymers for presentation of biologically active peptides and proteins; and on polymers for local drug delivery. 7. In 1991, I founded Focal, Inc., a Cambridge, Massachusetts company that

operated in the domain of polymers for surgery and drug delivery. I served as chairman of its scientific advisory board for several years, and spent a one-year sabbatical working full-time in the company. The company became publicly traded on the NASDAQ stock exchange and was later acquired by Genzyme, Inc., also of Cambridge, Massachusetts. After the acquisition, I continued my work as a consultant for Genzyme. 8. In 2000, I founded Kuros Therapeutics, AG, a company located in Zurich,

Switzerland, now acquired by Institut Straumann, AG, of Basel, Switzerland. I served as member of the Board of Directors and as Chief Scientific Officer of Kuros Therapeutics, and continued as a consultant to Institut Straumann after Kuros Therapeutics' acquisition.

3

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 4 of 19

9.

In 2002, I founded Kuros Biosurgery, AG, in Zurich, Switzerland. I currently

serve as a Chief Scientific Advisor and a member of the Board of Directors of Kuros Biosurgery. The company is privately held and employs approximately 80 individuals. The domain of activity of the company is polymer and biopolymer hydrogels for delivering protein and peptide drugs in regenerative medicine, including bone and skin repair, and polymers for delivery of small molecules. 10. I am a Fellow at the American Institute for Medical and Biological Engineering;

President of Society for Biomaterials; member of the Executive Council of International Society for Applied Cardiovascular Biology; member of the Board of Directors of Tissue Engineering and Regenerative Medicine International Society; former Board of Directors member of Biomedical Engineering Society;. I am also a member of various other professional societies. 11. I am the author of over 230 scientific research and review articles, most of them

in the area of biomaterials for the delivery or presentation of pharmaceutical substances. I have authored several book and textbook chapters on biomaterials, tissue engineering, and drug delivery. I am a co-inventor of more than 75 patents in the area of biomaterials, mostly for the delivery or presentation of pharmaceutical substances. 12. A true and correct copy of my curriculum vitae, which includes a list of my

honors, papers that I have published, and the committees and editorial boards on which I have served, is attached to this declaration as Exhibit A. II. BASES FOR OPINION 13. In forming the opinions set forth in this declaration, I have relied upon my

education, background and experience in the field of the delivery of pharmaceutical substances. I have also reviewed U.S. Patent No. 5,681,588 ("the `588 patent") and its associated file history.

4

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 5 of 19

14.

I understand that Reliant has alleged that Par Pharmaceutical, Inc.'s ("Par")

generic propafenone drug products described in ANDA 78-540 infringe the claims of the `588 patent. 15. I understand that the parties disagree about the meaning of some of the claim

terms used in the patent, and that the purpose of my declaration is to assist the Court in understanding and defining those claim terms. 16. I understand that the Court reads the claims of the patent from the viewpoint of

"one of ordinary skill in the art." In my opinion, that person has basic training and education, but is not an expert, in the relevant field of the invention. The `588 patent claims are directed to a focused field (controlled drug delivery), and those of skill in the art at the time of the invention would have had basic knowledge of how to modulate the release of drugs in vivo, and in particular, in a human. In my opinion, one of ordinary skill in the art of controlled drug delivery would have had at least one degree in pharmacy (B.S., M.S., or Pharm. D.) and at least two years experience related to the formulation and evaluation of pharmaceutics, including delayed release drug products. Alternatively, one skilled in the art would have had at least one degree in another discipline related to pharmacy, such as chemistry, biology, chemical engineering or bioengineering, in addition to at least four years work experience related to the formulation and evaluation of pharmaceutics, including delayed release drug products. 17. I also understand that the relevant date for defining the claim terms 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 on that date.

5

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 6 of 19

18.

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. III. RELEASE-DELAYING TECHNOLOGIES 19. Several technologies have been developed to delay the release of an active

pharmaceutical substance from a tablet. These include the use of release-delaying ancillary substances, among which are hydrophobic polymers, which may be used as release-delaying coatings or as release-delaying matrices. 20. One approach is to utilize a hydrophobic polymer to form coatings on small

particles of the active pharmaceutical substance. One method to form such a release-delaying coating is to suspend small particles of the active pharmaceutical substance within a solution or colloidal dispersion of the polymer, followed by drying. This results in a thin coating of the hydrophobic polymer on the surfaces of the particles. Upon compaction of the coated particles, perhaps with other ancillary substances such as lubricants and binders, the solid dosage form is obtained. The hydrophobic coating on the individual particles serves to slow water uptake into the coated particles and to slow dissolution of the active pharmaceutical substance. This method may utilize relatively low ratios of the hydrophobic polymer to the active pharmaceutical substance, since only a thin coating upon the particles is required. Alternatively, a coating may be applied after compaction of a tablet. 21. A second approach is to utilize a hydrophobic polymer to form a matrix in which

the active pharmaceutical substance is embedded. One method to form a release-delaying matrix is to mix a powder of the hydrophobic polymer with a powder of the active pharmaceutical substance, perhaps with other ancillary substances such as lubricants and binders, and to compact this powder into a tablet. The hydrophobic matrix serves to slow water uptake into the tabletand 6

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 7 of 19

thus, to slow dissolution. In this approach, the particle size of the hydrophobic polymer powder can be important. For example, small particles generally yield more delayed release than larger particles. Similarly, the ratio of polymer to the active pharmaceutical substance can be important, with larger ratios yielding more delayed release than smaller ratios. Ratios in excess of 25% of the tablet by mass may be necessary in order to delay release. 22. When forming tablets, polymers can also be used in ways other than as release-

delaying ancillary substances. For example, polymers can also function as binders, film-formers, and masking agents, among other functions. When used for these purposes, polymers are generally included in percentages lower than those required for use as a release-delaying matrix. IV. CLAIM DEFINITIONS A. 23. in dispute. 24. It is my opinion that one of ordinary skill in the art would understand the term "DELAYED RELEASE MICROTABLET" I understand that the meaning of the claim term "delayed release microtablet" is

"delayed release microtablet" to mean 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%. 25. The accepted meaning of the term "tablet" is a "unit form[] of solid medicaments

prepared by compaction." Ex. B, Keith Marshall and Edward M. Rudnic, Tablet Dosage Forms, in Modern Pharmaceutics 355, 355 (Gilbert S. Banker & Christopher T. Rhodes eds., 2d ed. 1990). "Micro" means "small." Therefore, a "microtablet" means a small unit of compacted solid medicament. 26. "Delayed release microtablet" is not a term that is commonly used with precision

in the art. One of skill in the art, therefore, would look to the patent to understand its meaning. 7

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 8 of 19

Subpart (d) of Claim 1 discloses the release rate of the claimed microtablet. It states: "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. D at Col. 8:36-38. Therefore, one skilled in the art would understand the term "delayed release" to mean the release of active ingredient after 3 hours is not more than 80% and after 24 hours is not less than 80%. 27. The patent specification is consistent with this understanding. The specification

refers to microtablets of diameter and height "from 1 to 3, preferably 1.5 to 2.5 mm." Ex. D at Col. 2:45-46. Tablets of this size would be considered small by a person of ordinary skill in the art. Further, the patent specification references a method of producing microtablets, namely, "granulation, drying, mixing, tabletting," which is consistent with preparing compacted solid units of medicament. Ex. D at Col. 3:51. And finally, the specification discloses "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. D at Col. 2:54-57. 28. I have reviewed the communications between the U.S. Patent Office and the

applicants of the patent that constitute the file history of the `588 patent. There is nothing in the file history that would lead me to believe that the term "delayed release microtablet" means anything different than 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%. In fact, this definition is reiterated in the file history of the `588 patent. Ex. E at 3, 4. B. 29. "CYLINDRICAL" I understand that the claim term "cylindrical" is in dispute.

8

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 9 of 19

30.

It is my opinion that one of ordinary skill in the art would understand this term to

mean 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. 31. The claims of the patent support this definition. In fact, in the context of the

patent claims, a cylindrical delayed release microtablet is expressly described as having "convex or flat upper side and lower side." Ex. D at Col. 8:18-19. The only other description of the "cylindrical" shape is that "the height and diameter are, independently of one another, 1-3 mm." Ex. D at Col. 8:30-31. Therefore, a person of ordinary skill in the art reading the claims of the `588 patent would understand that the claimed microtablets are not necessarily strictly cylindrical, but cylinder-like, having a height and diameter, independent of one another, between 1 mm and 3 mm. 32. The patent specification is consistent with my opinion as to the meaning of the

term "cylindrical." The specification states: "The 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. D at Col. 2:42-46. And: "The resulting microtablets have a cylindrical shape with flat or convex surface [sic]." Ex. D at Col. 4:19-21. Therefore, the specification discloses microtablets with convex upper and lower surfaces that are generally cylindrical. The file history is consistent with the patent specification. C. 33. "CONVEX OR FLAT UPPER SIDE AND LOWER SIDE" I understand that the meaning of the claim term "convex or flat upper side and

lower side" is in dispute.

9

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 10 of 19

34.

It is my opinion that one of ordinary skill in the art would understand this term to

mean that each of the upper side and lower side has a surface that is without marked projections or depressions ("flat") or is curved or rounded outward ("convex"). 35. The accepted meaning of the term "flat" is "having a surface that is without

marked projections or depressions." Ex. C. The accepted meaning of the term "convex" is "having a surface that is curved or rounded outward." Ex. C. 36. The use of the term "convex or flat upper side and lower side" in the specification

and file history of the `588 patent is consistent with this definition. D. 37. "THE TABLET CONTAINS NO RELEASE-DELAYING ANCILLARY SUBSTANCE" I understand that the claim term "the tablet contains no release-delaying ancillary

substance" is in dispute. 38. It is my opinion that one of ordinary skill in the art would have understood this

term to mean that the tablet contains no excipient that forms a release-delaying coating or matrix. 39. The accepted meaning of the term "ancillary substance" is a pharmaceutical

ingredient other than the active pharmaceutical ingredient ("API"). An "ancillary substance" is generally referred to as an excipient. 40. It is my opinion that one of ordinary skill in the art would read the term "tablet" to

refer to the delayed release microtablet disclosed in Claim 1 of the `588 patent. 41. The patentees define the term "release-delaying ancillary substance" in the

specification: "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. D at Col. 1:20-25. Therefore, a person skilled in the art would have understood this term to 10

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 11 of 19

refer to a pharmaceutical ingredient acting as either a release-delaying matrix or as a releasedelaying coating. 42. 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 tablets or microtablets. In particular, one of skill in the art would have known that the generally accepted ways to delay release at the time of invention were the use of release-delaying matrices and release-delaying coatings. One of skill in the art would also have understood that many excipients, including, for example, binders, lubricants, wetting agents, fillers and adhesives, may have some small effect on the release rate of an active pharmaceutical ingredient, but that such substances were not generally considered "release-delaying" substances. 43. 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. One of skill in the art would also have understood that the delayed release of the active pharmaceutical ingredient in the claimed delayed release microtablets was caused by the shape and size of the active ingredient microtablets, the high active ingredient content, and the high active ingredient density, and would not have considered excipients such as binders and fillers to significantly impact the function of the release-delaying properties of the claimed microtablets. Ex. D at Col. 8:18-44. Notably, the invention disclosed in the claims and the specification can explicitly encompass a microtablet that includes ancillary substances such as binders, adhesives, fillers, wet granulators, etc. Ex. D at Col. 4:16-18. 44. The `588 patent file history is consistent with this definition. In the file history,

the applicants teach that "by preparing a microtablet having the required size and shape, active

11

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 12 of 19

ingredient content and active ingredient density ... it is possible to provide a microtablet that has surprisingly improved delayed release characteristics compared to other delayed release formats," such as matrices or coatings. Ex. E at 2-3. 45. Therefore, it is my opinion that the term "the tablet contains no release-delaying

ancillary substance" means that the tablet contains no excipient that forms a release-delaying coating or matrix. E. 46. 47. "LUBRICANT" I understand that the Court has been asked to construe the claim term "lubricant." It is my opinion that one of ordinary skill in the art would have understood this

term to carry its plain meaning; that is, they would understand that a lubricant is a pharmaceutical ingredient that reduces friction and prevents adhesion of a tablet to tooling surfaces, e.g., talc or magnesium stearate. 48. The accepted meaning of the term "lubricant" is a pharmaceutical ingredient that

functions to "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." Ex. F, Edward Rudnic & Joseph B. Schwartz, Oral Solid Dosage Forms, in Remington's Pharmaceutical Sciences 1633, 1636-37 (Alfonso R. Gennaro ed., 18th ed. 1990). 49. The patent specification is consistent with this construction. The specification

teaches that "[a]fter 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. D at Col. 4:7-13. All of the listed 12

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 13 of 19

substances are pharmaceutical ingredients conventionally used to reduce friction and thus prevent adhesion of a tablet to tooling surfaces. F. 50. "OTHER CONVENTIONAL ANCILLARY SUBSTANCES" I understand that the parties disagree as to the meaning of the term "other

conventional ancillary substances." 51. It is my opinion that one of ordinary skill in the art would have understood this

term to carry its plain meaning; that is, one would have understood this term 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. 52. The accepted meaning of the term "conventional" is in common use. As

discussed above, the accepted meaning of the term "ancillary substance" is a pharmaceutical ingredient other than the active pharmaceutical ingredient. 53. It is my opinion, therefore, that a person skilled in the art would understand the

term "other conventional ancillary substances" to encompass commonly used pharmaceutical ingredients other than the API and other than the types of ingredients preceding this term in the claims of the `588 patent, namely lubricants or release-delaying substances such as matrices or coatings. Ex. D at Col. 8:41-44. 54. The patent specification is consistent with this meaning and further lists examples

of "other ancillary substances": "colorants, stabilizers, fillers, wetting agents, flow regulators." Ex. D at Col. 4:16-18. The listed substances are known to anyone skilled in the art to be commonly used as neither active pharmaceutical ingredients, lubricants, nor release-delaying substances.

13

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 14 of 19

G. 55.

"RELEASE RATE IS VIRTUALLY INDEPENDENT OF THE PRESSURE WHEN COMPRESSING THE TABLETS" I understand that the parties disagree as to the meaning of the claim term "release

rate is virtually independent of the pressure when compressing the tablets." 56. It is my opinion that one of ordinary skill in the art would understand this term 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. 57. The patentees explicitly define the term "release rate is virtually independent of

the pressure when compressing the tablets" in the specification. The specification states that "[i]t 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. D at Col. 2:4751. In addition, Figure 9 of the `588 patent demonstrates that the pressure when compressing the tablets does not appreciably affect dissolution rate. Ex. D at Fig. 9. 58. The `588 patent file history confirms my opinion as to the definition of this term.

The applicants stated that "the release of the active ingredient is virtually independent of the pressure used to compress the tablet ... 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..." Ex. E at 3. 59. Further, it is my opinion that one of ordinary skill in the art would understand, in

the context of the `588 patent, that the compaction pressure would refer to the ordinary range of compression used in pharmaceutical formulation. Therefore, one would understand that the

14

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 15 of 19

effect of the pressure when compressing the tablets on the release rate of the active pharmaceutical ingredient can be neglected while operating within this range of compression. H. 60. "ACTIVE INGREDIENT DENSITY" I understand that the Court has been asked to construe the claim term "active

ingredient density." 61. It is my opinion that one of ordinary skill in the art would understand this term to

mean the density of the active ingredient in the delayed release microtablet. 62. A person of ordinary skill in the art would construe the term "active ingredient

density" in the context of the patent claim in which it appears, i.e., Claim 1 of the `588 patent. Claim 1 discloses the characteristics of a microtablet, namely, size (Claim 1(a)), active ingredient content (Claim 1(b)), release rate (Claim 1(d, e)), and composition (Claim 1(f)). Ex. D at Col. 8:30-44. Thus, the context of the claim makes clear that "active ingredient density" refers to the active ingredient density in the claimed delayed release microtablet. 63. The patent specification uses the term "active ingredient density" to refer to

microtablets with a particular density of active ingredient. For example, the specification states: "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...." Ex. D at Col 2:11-13. See also Ex. D at Col. 4:65-67 ("The microtablets of the examples always had a diameter and height each of 2 mm, and the density of active ingredient was always more than one"). 64. The `588 patent file history is also consistent with this definition. In the file

history, the applicants repeatedly refer to the active ingredient density of the microtablet. See, e.g., Ex. E at 2 ("the cylindrical delayed release microtablet of the present invention is required to ... have an active ingredient density that is greater than 1"); see also Ex. E at 2-3 ("by preparing a microtablet having the required size and shape, active ingredient content and active 15

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 16 of 19

ingredient density ... it is possible to provide a microtablet that has surprisingly improved delayed release characteristics compared to other delayed release formats"). 65. Therefore, one of ordinary skill in the art would understand the term "active

ingredient density" to mean the density of the active ingredient in the delayed release microtablet. I. 66. "A PRONOUNCED PLASMA LEVEL PLATEAU WITH A PTF<75%" I understand that the Court has been asked to construe the claim term "a

pronounced plasma level plateau with a PTF<75%." 67. It is my opinion that one of ordinary skill in the art would have understood this

term to mean a plasma level plateau with a peak to trough fluctuation of less than 75%, where
C max - C min

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

AUC t

× 100 .

68. 69.

The accepted meaning of the term "PTF" is peak to trough fluctuation. The patentees define this term in the specification:

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, Ecomed-Verlagsgesellschaft 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.

16

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 17 of 19

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 %. The microtablets accordingly increase therapeutic safety because excessive peaks of plasma levels and the side effects caused thereby do not occur, the plasma level does not fall below the minimum effective level. Ex. D at Cols. 2:60-3:17. J. 70. "BIOAVAILABILITY DOES NOT DEPEND ON THE INTAKE OF FOOD" I understand that the claim term "bioavailability does not depend on the intake of

food" is in dispute. 71. It is my opinion that one of ordinary skill in the art would understand this term to

carry its plain meaning; that is, one would have understood this term to mean that the bioavailability of the active pharmaceutical ingredient is unaffected by food intake for practical purposes in patients. 72. This plain meaning of the term is supported by the patent specification: "the

bioavailability of this form [the delayed release microtablets] is unaffected by food intake..." Ex. D at Col. 3:18-20. K. 73. 74. "CYLINDRICAL MOLD" I understand that the meaning of the claim term "cylindrical mold" is in dispute. It is my opinion that one of ordinary skill in the art would understand this term to

mean a die and punch in which a formulation is formed into a "cylindrical" shape as defined in Section B above. 75. My opinion as to the accepted meaning of the term "cylindrical" set forth in the

section above is equally applicable here. One of ordinary skill in the art would understand the term "mold" to mean a part of tooling for production of solid dosage form of drugs, i.e., a punch and die in which a substance is shaped.

17

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 18 of 19

Case 1:06-cv-00774-JJF

Document 196

Filed 03/05/2008

Page 19 of 19

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)

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 1 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 2 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 3 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 4 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 5 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 6 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 7 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 8 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 9 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 10 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 11 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 12 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 13 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 14 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 15 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 16 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 17 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 18 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 19 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 20 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 21 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 22 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 23 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 24 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 25 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 26 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 27 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 28 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 29 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 30 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 31 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 32 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 33 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 34 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 35 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 36 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 37 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 38 of 39

Case 1:06-cv-00774-JJF

Document 196-2

Filed 03/05/2008

Page 39 of 39

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 1 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 2 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 3 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 4 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 5 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 6 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 7 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 8 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 9 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 10 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 11 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 12 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 13 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 14 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 15 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 16 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 17 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 18 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 19 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 20 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 21 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 22 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 23 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 24 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 25 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 26 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 27 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 28 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 29 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 30 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 31 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 32 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 33 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 34 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 35 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 36 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 37 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 38 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 39 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 40 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 41 of 42

Case 1:06-cv-00774-JJF

Document 196-3

Filed 03/05/2008

Page 42 of 42