ROBERT GETTLEMAN, District Judge
This court has conducted a bench trial on plaintiff GlaxoSmithKline Beecham Corp.'s claims against defendant Apotex, Inc. for a declaration of infringement of patent nos. 4S62181 and 4,820,833, and on Apotex's counterclaims of invalidity. In accordance with Fed.R.Civ.P. 52(a), the court enters the following findings of fact and conclusions of law.
This order contains both findings of fact ("Findings") and conclusions of law ("Conclusions"). To the extent that any Findings may be deemed conclusions of law, they shall also be considered Conclusions. To the extent that any Conclusions may be deemed findings of fact, they shall also be considered Findings. See Miller v. Fenton, 474 U.S. 104, 113-14 (1985).
PARTIES' STIPULATION OF UNCONTESTED FACTS
Additional findings of the court are indicated in bold lettering. To the extent not contained herein, the court adopts the parties' Revised Stipulation of Uncontested Facts filed on February 28, 2003.
1. This is an action for patent infringement. The Court has subject matter jurisdiction under 28 U.S.C. § 1331 and 1338(a), 2201 and 2202. The Court has personal jurisdiction over the parties. Venue in this judicial district is proper under 28 U.S.C. § 1391.
2. Plaintiff Glaxo Group Ltd. is a British corporation having a principal place of business in Brentford, United Kingdom. Plaintiff SmithKline Beecham Corp. is a Pennsylvania corporation having a place of business in Research Triangle Park, North Carolina. (Plaintiffs Glaxo Group Ltd. and SmithKline Beecham Corp. are collectively referred to as "GlaxoSmithKline"). GlaxoSmithKline is an innovator pharmaceutical company engaged in the research, development, clinical testing and regulatory approval of new drug substances and drug formulations for use in medicines.
3. Defendant Apotex Inc. ("Apotex") is a Canadian corporation having its principal place of business in Weston, Ontario. Apotex sells generic drug products which emulate Pharmaceuticals developed and marketed by innovator companies. Apotex markets and sells generic drug products throughout the United States.
4. GlaxoSmithKline is the owner by assignment of U.S. Patent No. 4,562,181 ("the `181 patent"), entitled "Amorphous Form of Cefuroxime Ester", which issued on December 31, 1985 and claims highly pure, substantially amorphous cefuroxime Axetil. The `181 patent expires on July 29, 2003.
5. GlaxoSmithKline is the owner by assignment of U.S. Patent No. 4,820,833, ("the `833 patent"), entitled "Preparation of a Highly Pure, Substantially Amorphous Form of Cefuroxime Axetil", which issued on April 11, 1989, and is directed to preparing highly pure substantially amorphous cefuroxime axetil by spray drying. The `833 patent also expires on July 29, 2003.
6. GlaxoSmithKline filed this suit for infringement of the `181 patent under 35 U.S.C. § 271(e) et seq. and the Declaratory Judgment Act on September 20, 2000. On June 25, 2001, GlaxoSmithKline filed an amended complaint adding a claim for declaratory judgment of infringement of the `833 patent.
7. On March 7, 2001 and July 20, 2001, Apotex filed its Answer and Counterclaims and Amended Answer and Counterclaims. Apotex denied infringement and asserted counterclaims for noninfringement and invalidity of both the `181 and `833 patents.
8. On June 5, 2002, the Court held a hearing on GlaxoSmithKline's motion for preliminary injunction and, on June 10, 2002, issued an order finding in GlaxoSmithKline's favor on all of the mandatory preliminary injunction factors and granting a preliminary injunction. Apotex's appeal of the preliminary injunction order has been rejected by the U.S. Court of Appeals for the Federal Circuit in an unpublished order dated April 22, 2003.
9. GlaxoSmithKline is the holder of a New Drug Application ("NDA") approved by the Food and Drug Administration ("FDA") for tablets containing, as the active ingredient or drug substance, highly pure, substantially amorphous cefuroxime axetil for use as abroad spectrum antibiotic. GlaxoSmithKline markets and sells its tablets under the tradename Ceftin®.
10. GlaxoSmithKline filed its Ceftin® NDA on July 30, 1985.
11. GlaxoSmithKline received approval for its Ceftin® NDA in December 1988. GlaxoSmithKline Ceftin® tablets were launched immediately after receiving FDA approval.
12. Antibiotics are substances which either kill or inhibit the growth of bacteria. There are many classes of antibiotics; the most well known are the penicillins.
13. The antibacterial properties of penicillins are conferred by the-lactam ring in the structure of the molecule that allows it to bind to proteins in the cell wall of the bacterium. This binding by the antibiotic prevents the cell wall from budding effectively, thereby inhibiting bacterial replication.
14. Although penicillins are broad spectrum antibiotics, they are not effective against all bacteria. Also, as a result of wide use, penicillin-resistant strains of bacteria have developed. These resistant bacteria develop during infections when mutant bacteria produce-lactamases that can open the -lactam ring of the penicillin molecule — destroying its effectiveness. This -lactamase penicillin-resistance is then transmitted by the bacteria from one population to another.
15. Closely related structurally to penicillins are the cephalosporins. Like penicillins, the cephalosporins have a -lactam ring and both classes are generally referred to as -lactam antibiotics.
16. The cephalosporin molecule differs from that of the penicillin molecule in that the ring adjacent to the -lactam ring is a six-membered ring as opposed to the five-membered ring of penicillin. This six-membered ring adds rigidity to the -lactam ring and protects it from bacterial -lactamase attack.
17. In the 1970s, GlaxoSmithKline's scientists synthesized a new drug substance, cefuroxime, a broad spectrum cephalosporin antibiotic. Cefuroxime was disclosed and claimed in the patent no. 3974153.
18. Cefuroxime (the carboxylic acid) is not readily absorbed into the bloodstream from the small intestine, and cannot be administered orally because it is poorly absorbed into the bloodstream from the gastrointestinal tract and does not provide the systemic effect required for effective treatment. As a result, cefuroxime is only administered by injection.
19. Because orally administered medicines are preferred for ease of use, cost efficiency and patient compliance, GlaxoSmithKline invested in a development effort to synthesize an orally absorbable form of cefuroxime, that is, one which could pass through the wall of the small intestine into the bloodstream on oral administration. The goal was to synthesize a prodrug of cefuroxime, that is, a compound that could cross the intestinal wall to allow the cefuroxime, the portion of the molecule that imparts antibacterial activity, to be cleaved off the prodrug and enter the circulation.
20. GlaxoSmithKline synthesized many cefuroxime derivatives, including different cefuroxime esters. Among these was a class of cefuroxime esters that showed promise as orally absorbable compounds, including cefuroxime axetil in which an axetil group is attached to the cefuroxime molecule.
21. Cefuroxime axetil is absorbed through the intestinal wall, the axetil portion of the molecule is cleaved off by enzymes and cefuroxime is released to provide its antibiotic activity.
22. The discovery of the new class of cephalosporins, the cefuroxime esters, became the subject matter of U.S. Patent No. 4,267,320 ("the `320 patent" or "Gregson patent"), which issued to GlaxoSmithKline on May 12, 1981. The *320 patent, entitled "Cephalosporin Antibiotics," generally discloses many different cefuroxime esters, including the preferred ester, cefuroxime axetil. Further development was needed to achieve the necessary high bioavailability and stability in orally administrable form. The `320 patent has now expired. Glaxo's Dr. Gordon Gribble testified that the *320 patent generally discloses at least 15-20 different cefuroxime esters, including the preferred ester, cefuroxime axetil.
23. Apotex filed an Abbreviated New Drug Application ("ANDA") No. 65-069 on April 5, 2000, seeking approval to market a generic cefuroxime axetil drug product containing a co-precipitate cefuroxime axetil, sorbitol and zinc chloride.
24. 35 U.S.C. § 271(e)(2) states "[I]t shall be an act of infringement to submit —
(A) an application under section 505(j) of the Federal Food, Drug, and Cosmetic Act or described in section 505(b)(2) of such Act for a drug claimed in a patent or the use of which is claimed in a patent".
25. Apotex submitted its ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act.
26. Unlike an NDA submitted by an innovator pharmaceutical company, an ANDA submission by a generic company like Apotex does not require any independent efficacy or safety testing. The ANDA applicant must only demonstrate that its generic version is bioequivalent to the innovator medicine and otherwise relies on the data provided by the innovator.
27. The products that Apotex intends to market are 250 mg and 500 mg cefuroxime axetil tablets, which are bioequivalent to GlaxoSmithKline's Ceftin® tablets and impart the same medical benefit as Ceftin® tablets.
28. The antibacterial component of Apotex's co-precipitate is cefuroxime axetil.
29. Apotex's ANDA states that zinc chloride acts as a stabilizer and sorbitol acts as a solubilizer.
30. The Executive Summary of Apotex's ANDA states that the sorbitol and zinc chloride components of the co-precipitate are excipients.
31. Apotex's ANDA describes the manufacturing process for its tablets. Apotex's manufacturing process starts with pure crystalline cefuroxime axetil USP containing no more than 1.5% of related compounds. The crystalline cefuroxime axetil is added, together with 9% sorbitol and 1% zinc chloride, to a solution of acetone and water. These materials are mixed at high speed for a period of time until a clear solution is obtained. The resulting solution is spray dried under nitrogen producing an amorphous co-precipitate in the form of amorphous particles. This co-precipitate consists of 90% cefuroxime axetil, 9% sorbitol and 1% zinc chloride by weight.
32. The solvents that Apotex dissolves the crystalline cefuroxime axetil, sorbitol and zinc chloride in are acetone and water. Acetone is an organic solvent that is a ketone. Acetone and water evaporate during spray drying.
33. Each particle of amorphous co-precipitate contains hundreds of thousands, if not millions of molecules of cefuroxime axetil, sorbitol and zinc chloride randomly interdispersed in the proportions of 90% cefuroxime axetil, 9% sorbitol and 1% zinc chloride.
34. The cefuroxime axetil molecules, the sorbitol molecules and the zinc chloride molecules contained in the co-precipitate are randomly dispersed throughout the co-precipitate and have no long range order.
35. Apotex collects, compacts and mills the co-precipitate to form granules. Apotex then mixes the granulated co-precipitate with pharmaceutical excipients — namely crospovidone, sodium bicarbonate and magnesium stearate — and compresses this blend of materials into a tablet core. Apotex sprays a film coating on the tablet core, producing a film coated tablet. The crospovidone and sodium bicarbonate are disintegrates, assisting in the dissolution of the tablet. The magnesium stearate acts as a lubricant.
36. The specification for Apotex's tablets in its ANDA requires that the tablets contain no more than 2% "related impurities" which are further described as "degradation products" in the specification itself.
37. FDA granted final approval of Apotex's ANDA on October 2, 2002.
38. Apotex's Dr. Sherman testified that Apotex conducted several years of research and development to arrive at the co-precipitate that is contained in Apotex's ANDA.
39. Apotex's package insert as approved by FDA identifies Apotex's drug product as follows:
Cefuroxime Axetil Tablets contains an amorphous co-precipitate of cefuroxime axetil, sorbitol, and zinc chloride. Cefuroxime axetil has the following structural formula [formula omitted]
Cefuroxime Axetil Tablets are film-coated and contain the equivalent of 250 or 500 mg of cefuroxime as cefuroxime axetil. Cefuroxime Axetil Tablets contain the inactive ingredients crospovidone, hydroxyethyl cellulose, magnesium stearate, polyethylene glycol, sodium bicarbonate, sorbitol, titanium dioxide and zinc chloride. USP Release Test Pending.
40. Solid substances can exist in crystalline or amorphous form. In a crystalline solid, the molecules are arranged in a regularly repeating, long range order, often called a lattice. In an amorphous solid, the molecules have no regular, long range order, but are randomly distributed in relation to one another. Amorphous is often described as the "absence of crystallinity."
41. The terms "crystalline" and "amorphous" have no application to a single molecule or a few molecules of a substance.
42. The crystalline form or a drug substance is more stable than its amorphous form.
43. A technique for determining whether a substance or preparation is crystalline or amorphous is X-ray powder diffraction.
44. Claim 1 of the `181 patent reads as follows:
Cefuroxime axetil in amorphous form essentially free from crystalline material, and having a purity of at least 95% aside from residual solvents.
45. Claim 2 of the `181 patent reads as follows:
The product of claim 1 which contains less than 3% m/m of impurities.
46. Claim 3 of the `181 patent reads as follows:
The product of claim 1 in the form of a mixture of R and S isomers.
47. Claim 4 of the `181 patent reads as follows:
The product of claim 3 wherein the mole ratio of R to S isomers is from 3:2 to 2:3.
48. Claim 5 of the `181 patent reads as follows:
The product of claim 3 wherein the mole ratio of R to S isomers is from 0.9:1 to 1.1:1.
49. Claim 6 of the `181 patent reads as follows:
The product of claim 1 in the form of hollow microspheres.
50. Claim 7 of the `181 patent reads as follows:
A method of combating bacterial infections of the human or animal body which comprises administering to the said body orally or rectally an effective amount of a highly pure substantially amorphous form of cefuroxime axetil as claimed in claim 1.
51. Claim 8 of the `181 patent reads as follows:
An antibacterial pharmaceutical composition containing an antibacterially effective amount of cefuroxime axetil according to claim 1 in admixture with one or more pharmaceutical carriers or excipients.
52. Claim 9 of the `181 patent reads as follows:
The antibacterial pharmaceutical composition of claim 8 wherein the cefuroxime axetil is present in the form of a mixture of R and S isomers.
53. Claim 10 of the `181 patent reads as follows:
The antibacterial pharmaceutical composition of claim 8 wherein the mole ratio of R to S isomers is from 3:2 to 2:3.
54. Claim 11 of the `181 patent reads as follows:
The antibacterial pharmaceutical composition of claim 8 wherein the mole ratio of R to S isomers is from 0.9:1 to 1.1:1.
55. Claim 12 of the `181 patent reads as follows:
The antibacterial pharmaceutical composition of claim 8 wherein the cefuroxime axetil is in the form of hollow microspheres.
56. Claim 13 of the `181 patent reads as follows:
The antibacterial pharmaceutical composition of claim 8 adapted for oral administration.
57. Claim 14 of the `181 patent reads as follows:
The antibacterial pharmaceutical composition of claim 13 in dosage unit form containing from 50 to 500 mg of cefuroxime axetil.
58. Claim 1 of the `833 patent reads as follows:
A process for preparing a highly pure, substantially amorphous form of cefuroxime axetil which comprises preparing a highly pure solution of cefuroxime axetil and spray drying said solution to recover highly pure, substantially amorphous cefuroxime axetil.
59. Claim 2 of the `833 patent reads as follows:
The process of claim 1 wherein the solution contains an organic solvent selected from the group consisting of ketones, alcohols, acetonitrile, tetrahydrofuran, dioxan, esters, chlorinated solvents, homogenous mixtures of at least two of the aforesaid solvents, homogenous mixtures of at least one of the aforesaid solvents and water.
60. Claim 3 of the `833 patent reads as follows:
The process of claim 1 wherein the concentration of cefuroxime axetil in the solution prior to recovery is at least 1% m/m.
61. Claim 4 of the `833 patent reads as follows:
The process of claim 1 wherein the concentration of cefuroxime axetil in the solution prior to recovery is at least 10% m/m.
62. Claim S of the `833 patent reads as follows:
The process of claim 1 wherein the spray drying is effected in the presence of an inert gas.
63. The spray drying process described in the `833 patent starts with highly pure cefuroxime axetil in a solution containing an organic solvent. The solution is sprayed into a column through which heated gas is passing. The solvent flash-evaporates leaving the solid form of the cefuroxime axetil in a collection vessel. By this method, the highly pure cefuroxime axetil is recovered in substantially amorphous form. The `181 patent states that it is essential that the starting cefuroxime axetil material be at least as pure as the final product.
64. Today there are only a handful of commercially available solid oral drug products in which the drug substance is in amorphous form. Spectracef®, identified by Apotex's was approved in 2000 — 18 years after the `181 patent application was filed.
65. During the 15 years that Ceftin® has been marketed, GlaxoSmithKline has realized nearly $4 billion in sales, with yearly sales surpassing $300 million by 1993.
66. GlaxoSmithKline's U.S. sales for Ceftin® were close to $250 million in 2001.
67. GlaxoSmithKline projected only $50 million in sales of Ceftin® for 2002 because of the launch of Ranbaxy's generic cefuroxime axetil product.
68. During the 15 years that Ceftin ® has been marketed, it was the most prescribed oral cephalosporin antibiotic in existence.
69. Hampel and Hawley's Encyclopedia of Chemistry (3d ed. 1973) defines "purity" as:
A pure preparation of a chemical substance in the absolute sense is one in which all of the molecules in the preparation of the substance are molecules of the substance. No other molecules differing in any way may be present.
70. Longman's Dictionary of Scientific Usage (2d ed. 1981) defines "pure" as:
Applied to an element o[r] compound which is made up of,
a only atoms of the element;
b only ions or molecules of the compound,
e.g., a pure gold is a sample of gold which does not contain any other element;
b a sample of pure water (
i.e., chemically pure water) should contain only molecules of H20.
71. Hawley's Condensed Chemical Dictionary (11th ed. 1987) defines "purity" and "pure substance" as:
purity, chemical. A substance is said to be pure when its physical and chemical properties coincide with those previously established and recorded in the literature, and when no change in these properties occurs after application of the most selective fractionation techniques, In other words, purity exists when no impurity can be detected by any experimental procedure. There are a number of recognized standards of purity.
purification. Removal of extraneous materials (impurities) from a substance of mixture by one or more separation techniques. A pure substance is one in which no impurity can be detected by any experimental procedure.
72. Impurity is defined by the FDA Guidance for ANDAs: Impurities in Drug Substances as, "[a]ny component of the drug substance that is not the chemical entity defined as the drug substance." The FDA also defines an impurity in a drug product ( i.e., drug substance admixed with excipients) as "[a]ny component of the drug product that is not the chemical entity defined as the drug substance [ i.e. active ingredient] or an excipient in the drug product." (FDA Guidance of the Industry Q3B Impurities in New Drug Products).
73. The McGraw-Hill Dictionary of Technical and Scientific Terms (5th ed. 1994) defines excipient as "[a]ny inert substance combined with an active drug for preparing an agreeable or convenient dosage form."
74. In 1999, GlaxoSmithKline sued Ranbaxy Pharmaceuticals, Inc. ("Ranbaxy") in the District of New Jersey for infringement of the `181 patent. The district court issued an injunction against Ranbaxy preventing it from marketing generic cefuroxime axetil In an August 20, 2001, opinion, the Federal Circuit vacated the district court's injunction, determining that the court's claim construction was erroneous and that the claim limitation `"essentially free from crystalline material' means a maximum crystalline content of less than 10%."
75. Ranbaxy thereafter launched its cefuroxime axetil product, and is currently competing with GlaxoSmithKline's Ceftin®. The underlying suit remains pending in the United States District Court for the District of New Jersey.
76. In 2002, GlaxoSmithKline and its third-party distributor, Professional Detailing, Inc. ("PDI"), mutually terminated its distribution agreement with GlaxoSmithKline concerning Ceftin®.
77. On June 7, 2000, Apotex's Dr. Yuri Goldberg sent a. letter to a subcommittee of the United States Pharmacopoeia ("USP"). In this letter to USP's "USP-FDA Monograph Subcommittee" Dr. Goldberg stated:
Herein we would like to address the concerns expressed by the Committee by providing some additional information.
1. In our previous correspondence we did not mean to indicate that Apotex Cefuroxime Axetil Tablets contain a mixture of crystalline and amorphous Cefuroxime Axetil.
2. Our process of manufacturing Cefuroxime Axetil tablets converts crystalline Cefuroxime Axetil (starting material) to amorphous Cefuroxime Axetil in the form of a co-precipitate with sorbitol. This co-precipitate is further employed in the manufacturing of Apotex Cefuroxime Axetil Tablets. There is no crystalline material in our tablet product.
78. Thereafter, the USP requested that Apotex respond to certain issues concerning dissolution testing. In response, Dr. Goldberg forwarded to the UPS's dissolution and bioavailability subcommittee the complete package of correspondence between Apotex and USP, including the June 7, 2000, letter, on August 1, 2000. Apotex's Drs. Sherman and Cappuccino were listed as copy recipients on Dr. Goldberg's correspondence.
79. The active ingredient of Apotex's Cefuroxime Axetil Tablets 250 mg and 500 mg is the same as that of Glaxo Wellcome's Ceftin® Tablets 250 mg and 500 mg.
80. There is no detectable crystalline material in Apotex's amorphous co-precipitate.
81. Dr. Barry Sherman is the chairman of Apotex. He has a Bachelor and a Masters degree in Engineering and Aeronautics and a Ph.D. in Systems Engineering.
82. Dr. Sherman decides what drugs Apotex will develop and market based on their historic sales levels, and whether he can design around the various barriers in order to bring the product to market
83. Dr. Sherman is not a patent attorney. Although he had notice of GlaxoSmithKline's patents, he did not obtain an opinion from patent counsel on noninfringement or invalidity of the `181 and `833 patents before Apotex filed its ANDA, relying instead on his own review of the patents.
84. Dr. Sherman did not review the file histories of the patents in suit before deciding to file the ANDA.
85. A patent application that Dr. Sherman wrote states, "[h]owever, when the cefuroxime axetil is used in the pure amorphous form or in the form of a co-precipitate, the zinc salt will preferably be added, in the process of making the pure amorphous cefuroxime axetil or the co-precipitate, in order to get a more intimate mixture of the zinc salt with the cefuroxime axetil."
86. The Notice of Allowance for Dr. Sherman's patent states, "[t]he following is an examiner's statement of reasons for allowance: The prior art fails to teach or suggest a solid pharmaceutical composition comprising the active agent cefuroxime axetil and zinc chloride as a stabilizer for the active agent.
ADDITIONAL FINDINGS
87. The crystalline form of a drug substance is typically preferred over the amorphous form because crystalline forms are more stable and thus provide reliable delivery and adequate shelf life.
88. Crystals are also intrinsically purer than amorphous solids because the ordered structure of the crystal tends to exclude impurities which do not conform to the crystalline structure.
89. Before the introduction of Ceftin®, all commercially available-lactam antibiotics, e.g., penicillins and cephalosporins, were in crystalline form.
90. Crystalline cefuroxime axetil did not dissolve sufficiently in gastrointestinal fluid to make an effective oral medicine. A medicine that does not dissolve adequately cannot pass via the intestinal wall membrane into the bloodstream, and is simply excreted by the individual via his/her intestinal tract without providing a medical benefit.
91. The `181 patent describes the preferred purity level of the claimed drug substance in terms of the level of impurity and identifies typical impurities.
92. Cefuroxime axetil exists as two isomers, the R and S isomers. The R and S isomers of cefuroxime axetil contain the same chemical components, but are mirror images of each other. This is unlike the isomers with different connectivity ( e.g. the E-isomer and 2 — isomers) that are considered impurities of cefuroxime axetil.
93. According to the patent, a mixture of R and S isomers of the cefuroxime axetil is preferred because the mixture has substantially improved solubility compared to a single isomer.
94. Excipients are inert additives or carriers, not the active drug substance, which are deliberately added to the active drug substance to affect its performance or manufacturability in specific ways.
95. In addition to the drug substance in highly pure substantially amorphous form, the `181 patent further describes and claims a pharmaceutical composition that is an admixture of the highly pure, substantially amorphous cefuroxime axetil "with one or more pharmaceutical carriers and/or excipients".
96. The cefuroxime axetil-containing compositions formulated with excipients may contain between 1% and 99% of the active drug substance.
97. The `181 patent also teaches that in a composition for use in tablets, capsules or granules, excipients can be formulated by spray drying the excipients along with the active drug substance.
98. On April 5, 2000, Apotex filed ANDA No. 65-069, seeking immediate approval to market its generic version of GlaxoSmithKline's Ceftin® medicine. According to its ANDA, Apotex proposes to market 250 mg and 500 mg cefuroxime axetil tablets.
99. Unlike an NDA submitted by an innovator pharmaceutical company, an ANDA submission to the FDA by a generic company like Apotex does not require any independent efficacy or safety testing. The applicant must only demonstrate that the generic version of the medicine is bioequivalent to the innovator medicine. Otherwise the ANDA applicant relies on the data provided by the innovator.
100. Apotex begins the manufacturing process by dissolving pure crystalline cefuroxime axetil ( i.e., impurities of no more than 2.0%) in a solution of acetone, water, sorbitol and zinc chloride. Acetone (a ketone) and water are solvents that evaporate during spray drying.
101. Sorbitol is an excipient that is added to foster the dissolution of the cefuroxime axetil in solution. Zinc chloride is an excipient that helps stabilize the cefuroxime axetil and prevents the formation of impurities.
102. Using nitrogen, Apotex then spray dries the solution with an APV Spray Dryer to yield a spray dried mixture of cefuroxime axetil, sorbitol and zinc chloride. Apotex refers to this spray dried mixture as "cefuroxime axetil co-precipitate 90% A.S. Spray Dried". The "90%" refers to the fact that the initial solution contains 90% cefuroxime axetil and 10% excipients — 1% zinc chloride and 9% sorbitol.
103. The spray drying process converts the crystalline cefuroxime and axetil to amorphous cefuroxime axetil. The spray dried material is collected, compacted and milled to form granules.
104. Additional excipients crospovidone, sodium bicarbonate and magnesium stearate, are added to the granules, which are further compacted and milled to form the tablet core. Both crospovidone and sodium bicarbonate are disintegrants, assisting in the dissolution of the tablet. The magnesium stearate is a lubricant. A film coating is sprayed on the tablet core to give a film coated tablet. The specifications for the tablets require that they contain less than 2% impurities aside from residual solvents.
105. With full knowledge of the GlaxoSmithKline patents in suit, Dr. Sherman designed a process for formulating cefuroxime axetil tablets. Instead of mixing the drug substance (cefuroxime axetil) with excipients after spray drying, as disclosed in the preferred embodiment of the `181 patent, Apotex mixes the active ingredient cefuroxime axetil with two excipients first, spray dries that mixture, and then combines the mixture with the remaining excipients.
106. Dr. Sherman's process consists of nothing more than the timing of the addition of the excipients during manufacture. Tablets made according to this process are the subject of Apotex's ANDA No. 65-069.
CONCLUSIONS OF LAW
107. Declaratory jurisdiction exists where a company seeking to manufacture a generic version of a patented medicine has, by virtue of its ANDA filing, made meaningful preparation to market an infringing product before the expiration of the patentholder's exclusive rights.Glaxo. Inc. v. Novopharm. Ltd., 110 F.3d 1562, 1570 (Fed. Cir. 1997);Glaxo, Inc. v. Apotex USA, Inc., 1997 U.S. Dist. LEXIS 7620 at *9 (N.D. III. May 18, 1997), vacated and remanded on other grounds, 153 F.3d 1366 (Fed. Cir. 1998); 35 U.S.C. § 271(a).
108. This court has declaratory judgment jurisdiction over this case because an actual controversy exists between the parties. 28 U.S.C. § 2201 and 2202. Glaxo Group Ltd. v. Apotex, Inc., 130 F. Supp.2d 1006 (2001).
109. The importation and sale in the United States of a product or composition manufactured by an infringing process before the relevant patent expires is an act of infringement. 35 U.S.C. § 271 (g); Biotec Biologische Naturverpackungen GmbH v. Biocorp, Inc., 249 F.3d 1341, 1352 (Fed. Cir. 2001); Ajinomoto Co., Inc, v. Archer-Daniels Midland Co., 228 F.3d 1338, 1348 (Fed. Cir. 2001).
110. Determining whether an accused device infringes a patent requires a two-step analysis. First, the claims of the patent must be construed to determine the proper scope. Second, a determination must be made as to whether the properly construed claims read on the accused device.Interactive Gift Express Inc. v. Compuserve, Inc., 231 F.3d 859, 864-65 (Fed. Cir. 2000). The first step, claim construction, is a question of law for the court. Vivid Technologies. Inc. v. American Science Eng'g, Inc., 200 F.3d 795, 804 (Fed. Cir. 1999). Only those terms in controversy need be construed, and only to the extent necessary to resolve the controversy. Id. To construe the claim, the court first examines the intrinsic evidence, consisting of the patent claims, specification and, if in evidence, the prosecution history. Id., If the intrinsic evidence alone is insufficient, extrinsic evidence, such as expert testimony, inventor testimony, dictionaries, technical treatises, articles and prior art not cited, may be examined, Id Intrinsic evidence is preferred because it encompasses the materials in the public record. Therefore, if the intrinsic evidence alone resolves any ambiguity, it is improper to rely on extrinsic evidence. Id.