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Pfizer, Inc. v. Mylan Laboratories

February 27, 2007

PFIZER, INC., PLAINTIFF AND COUNTERCLAIM DEFENDANT,
v.
MYLAN LABORATORIES, INC. AND MYLAN PHARMACEUTICALS, INC., DEFENDANTS AND COUNTERCLAIM PLAINTIFFS.



The opinion of the court was delivered by: Terrence F. McVerry, Judge United States District Court

FINDINGS OF FACT AND CONCLUSIONS OF LAW

TABLE OF CONTENTS

Findings of Fact ............................................................ 1

I. The Parties and General Information ................................... 1

II Pharmaceutical Salts ................................................ 6

III. Amlodipine and Amlodipine Maleate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Solubility Findings ................................................ 20

Hygroscopicity Findings ............................................ 21

Formulation Stability Findings ....................................... 22

Processability Findings ............................................. 24

IV. The Discovery of Amlodipine Besylate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

V. The '303 Patent Prosecution ......................................... 28

A. The'303 Patent Application ...................................... 28

B. Obviousness .................................................. 29

i. The Scope and Content of the Prior Art . . . . . . . . . . . . . . . . . . . . . . . . . . 29

ii. Ordinary Skill in the Art ...................................... 33

iii. The Differences Between the Claimed Invention and

The Prior Art .............................................. 35

The '909 Patent ....................................... 35

The Berge Article ...................................... 36

The Tanouchi Patent ................................... 37

The Laber Patent ...................................... 37

The Teijin Patent ...................................... 38

i.

iv. Motivation Provided by the Prior Art to Make Amlodipine

Besylate ............................................... 38

v. Reasonable Expectation of Success . . . . . . . . . . . . . . . . . . . . . . . . . . 39

vi. Unexpected Superior Formulation Properties of Amlodipine Besylate ................................................ 42

C. Inequitable Conduct - Alleged Misrepresentations and Omissions Contained in the Wells Declaration ...................................... 43

Conclusions of Law .................................................... 48

I. Controlling Authority .............................................. 48

A. Jurisdiction ................................................... 48

B. Federal Circuit Law Applies ...................................... 49

C. The Presumption of Validity ...................................... 50

II. The Validity of the '303 Patent - Obviousness . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

A. The Selection of The Besylate Salt Would Not Have Been Obvious . . . . 56

B. There Was No Reasonable Expectation of Success . . . . . . . . . . . . . . . . . 57

C. Unexpected Superior Formulation Properties of Amlodipine Besylate . .................................................. 58

D. Conclusion Regarding Obviousness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

III. Inequitable Conduct - Violation of Duty of Candor . . . . . . . . . . . . . . . . . . . . . . . 61

A. Materiality ................................................. 62

B. Intent to Deceive ............................................ 63

C. No One Associated with Pfizer Committed Inequitable Conduct During The Prosecution of the '303 Patent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

ii.

D. Conclusion Regarding Inequitable Conduct . . . . . . . . . . . . . . . . . . . . . . . 66

V. Summary of Conclusions ........................................... 67

Order of Court

iii.

Pfizer Inc. filed this lawsuit against Defendants Mylan Laboratories, Inc., and Mylan Pharmaceuticals, Inc. for infringement of United States Patent Nos. 4,572,909 (the '909 patent) and Patent No. 4,879,303 (the '303 patent).*fn1 The parties tried this case on the '303 patent before the Court without a jury from November 28, 2006, through December 6, 2006. Following the trial, the parties filed Supplemental Proposed Findings of Fact and Conclusions of Law.

Based on the testimony and evidence presented during the bench trial and the applicable law, the Court finds that Defendants Mylan Laboratories, Inc., and Mylan Pharmaceuticals, Inc., have failed to prove by clear and convincing evidence that the '303 patent is invalid as obvious under 35 U.S.C. § 102. The Court also finds that Defendants have failed to prove by clear and convincing evidence that the '303 patent is unenforceable due to inequitable conduct before the United States Patent and Trademark Office ("PTO").

The Court now enters the following Findings of Fact and Conclusions of Law pursuant to Federal Rule of Civil Procedure 52(a):

FINDINGS OF FACT

I. The Parties and General Information

1. Plaintiff, Pfizer Inc. ("Pfizer"), is a corporation organized and existing under the laws of the State of Delaware. Pfizer has a principal place of business at 235 East 42nd Street, New York, New York. (Stip. of Uncontested Facts ("Stip. Facts"), ¶ 1.)

2. Mylan Laboratories, Inc., is a corporation organized and existing under the laws of the Commonwealth of Pennsylvania and has its principal place of business at 1500 Corporate Drive, Canonsburg, Pennsylvania. (Stip. Facts, ¶ 2.)

3. Mylan Pharmaceuticals, Inc., is a corporation organized and existing under the laws of the State of West Virginia and has its principal place of business at 781 Chestnut Ridge Road, Morgantown, West Virginia. Mylan Pharmaceuticals, Inc. is a wholly-owned subsidiary of Mylan Laboratories, Inc.*fn2 (Stip. Facts, ¶ 3.)

4. The '909 patent, entitled "2-(Secondary Aminoalkoxymethyl) Dihydropyridine Derivatives as Anti-Ischaemic and Antihypertentive Agents," was issued by the PTO on February 25, 1986. The '909 patent covers a genus of compounds, including amlodipine, the active ingredient in Norvasc®. (See '909 patent; MTX 1.)

5. Simon F. Campbell, Peter E. Cross, and John K. Stubbs, are identified in the '909 patent as the inventors. Pfizer is identified as the owner of the '909 patent. (Id.)

6. The '303 patent, entitled "Pharmaceutically Acceptable Salts," was issued by the PTO on November 7, 1989. The '303 patent covers the besylate salt of amlodipine. (Stip. Facts, ¶ 5.)

7. Dr. James I. Wells ("Dr. Wells") and Mr. Edward Davison ("Mr. Davison") are identified in the '303 patent as the inventors. (Stip. Facts, ¶ 7.) Both Dr. Wells and Mr. Davison were employees of Pfizer in its Pharmaceutical Research & Development Group ("Pharm. R&D") during the time that the tests described in the '303 patent were performed. (Stip. Facts, ¶ 28.)

8. Pfizer is identified as the owner of the '303 patent. (See '303 patent, PTX 2 and MTX 2.)

9. Mr. Keith Ruddock was the Pfizer in-house patent agent who oversaw the drafting and prosecution of the '303 patent. Mr. Ruddock was supervised by Dr. David Wood. James McManus was the Pfizer U.S. patent agent responsible for the prosecution of the '303 patent before the PTO. (See Depo. of James McManus, Pfizer v. Mylan, at 99.)

10. Typically, the Pfizer U.S. patent agents would not talk to the Pfizer U.K inventors before filing a U.S. patent application. (See Depo. of James McManus, Pfizer v. Mylan, at 24.) The U.S. patent agents would rely on the U.K patent lawyers or U.K patent agents to provide the information which needed to be submitted to the PTO. (Id. at 34.)

11. Pursuant to the provisions of 21 U.S.C. § 355a, the United States Food and Drug Administration ("FDA") granted Norvasc® a six-month period of pediatric exclusivity, which is applicable to the '303 patent. (Stip. Facts, ¶ 9.) The expiration date of the '303 patent is March 25, 2007, and the six-month period of pediatric exclusivity for the '303 patent, to the extent applicable, expires on September 25, 2007. (Stip. Facts, ¶¶ 8, 10.)

12. Pfizer filed a New Drug Application ("NDA") for Norvasc® (amlodipine besylate) tablets with the FDA on December 23, 1987. In the application, Pfizer advised the FDA that it had switched from maleate salt to besylate salt because the besylate salt had significantly better chemical stability and less sticking to processing equipment than the maleate salt. (See Stip. Fact, ¶ 14.)

13. The FDA approved Pfizer's NDA for amlodipine besylate tablets in late 1991. Thereafter, Pfizer proposed, and the FDA approved a four-year shelf life for amlodipine besylate tablets based on Pfizer's long-term stability data for the tablets. The current shelf life for Norvasc® tablets in bottles is 5 years. (Stip. Facts, Trial Transcript V, at 2.)

14. Norvasc® is approved by the FDA for treating hypertension and chronic stable and vasospastic angina. Norvasc® was launched as a commercial product by Pfizer in the United States in November 1992. (See Stip. Facts, ¶¶ 15 and 54.)

15. Pursuant to 21 U.S.C. § 355(b)(1) and the regulations of the FDA promulgated pursuant thereto, Pfizer listed the '909 patent and the '303 patent in the FDA's publication "Approved Drug Products with Therapeutic Equivalence Evaluations" (the "Orange Book") as covering the drug substance, amlodipine besylate, in Norvasc®. (Stip. Facts, ¶ 6.)

16. On May 22, 2002, Mylan filed with the FDA an Abbreviated New Drug Application ("ANDA") No. 76-418, in which it sought approval to commercially sell 2.5 mg, 5 mg, and 10 mg dosage strength generic amlodipine besylate tablets (the "ANDA products"), before the expiration of the terms of the Pfizer '909 and '303 patents. (Stip. Facts, ¶ 4.)

17. By letter dated July 23, 2002, Mylan certified pursuant to 21 C.F.R. § 314.94(a)(12(i)A)(4) that it was seeking approval to market a generic version of Norvasc®.

18. Mylan has received final approval from the FDA of its ANDA No. 76-418, and plans to commercially sell the ANDA products in the United States, pursuant to 21 U.S.C. § 355(j)(2). (Stip. Facts, ¶ 21.)

19. On September 22, 2002, Pfizer commenced this patent infringement action against Mylan pursuant to 35 U.S.C. § 271(e)(2)(A), which makes it an act of infringement to file an ANDA for a drug claimed in a patent.

20. Pfizer seeks, inter alia, an order "permanently enjoining [Mylan]" from making, using, selling, offering to sell, or importing into the United States the Mylan Amlodipine Tablets described in ANDA No. 76-4618 until the expiration of the '909 patent term, . . . , and after the expiration of the '303 patent term . . . ."

21. The '909 patent expired on July 31, 2006. Thereafter, by Order of this Court dated October 18, 2006, the claims relating to the '909 patent were dismissed from this action for lack of subject matter jurisdiction.

22. Pfizer is asserting infringement only of claims 1, 2 and 3 of the '303 patent. Mylan does not contest infringement of these claims. However, Mylan alleges that claims 1, and 3 of the '303 patent are invalid under 35 U.S.C. § 103 as obvious and that the '303 patent is unenforceable for inequitable conduct before the PTO. (See Stip. Facts, ¶ 22.)

23. Claim 1 of the '303 patent is "[t]he besylate salt of amlodipine," which is generally known as "amlodipine besylate."

24. Claim 2 of the '303 patent is "[a] pharmaceutical composition comprising an anti-hypertensive, antiischaemic or angina-alleviating effective amount of the besylate salt of amlodipine as claimed in claim 1 together with a pharmaceutically acceptable diluent or carrier."

25. Claim 3 of the '303 patent is "[a] tablet formulation comprising antihypertensive, antiischaemic or angina-alleviating effective amount of the besylate salt of amlodipine as claimed in claim 1 in admixture with excipients."

26. If the Court holds that the '303 patent is valid and enforceable, the Mylan ANDA products, if manufactured, used, sold, or offered for sale in the United States, or imported for sale into the United States, will literally infringe claims 1, 2, and 3 of the '303 patent. (Stip. Facts, ¶ 22.)

II. Pharmaceutical Salts

27. A "base," such as amlodipine, is a compound which can become a positively charged ion. The positively charged ion of a base is called a "cation." An "acid" is a compound which can become a negatively charged ion. The negatively charged acid ion is called an "anion." (Stip. Facts, ¶ 20.)

28. A salt is the product of the reaction of a base and an acid. (Stip. Facts, ¶ 19.)

29. Acid addition salts may form as crystalline or amorphorous solids, or as liquids, such as oils. (See Testimony of James I. Wells, Trial Transcript I, at 196.)

30. A finished drug product consists of an active pharmaceutical ingredient together with inactive ingredients, known as excipients, in a dosage form such as a tablet, capsule, or injectable solution. (See Testimony of Stephen W. Hoag, Trial Transcript V, at 165.)

31. A pharmaceutically acceptable salt is any salt of an active drug molecule that can be used to make a finished drug product suitable for administration of the drug to a patient.

32. Pharmaceutical salts are evaluated for use in drug products based on their physicochemical or formulation properties which include aqueous solubility, chemical stability, hygroscopicity, and processability (i.e., the ability to be manufactured into commercial dosage forms through the use of typical processing machinery).

33. The maximum amount of a compound that will dissolve at a specific temperature in a fixed amount of water, or water-based solvent, is called the aqueous solubility of the compound at that temperature. (Stip. Fact, ¶ 23.)

34. Pharmaceutical scientists, or formulators, use a rule of thumb for good solubility. Aqueous (in water or water-based solvent) solubility greater than 1 mg/ml at 37BC is good solubility. See '303 patent, Col. 2: 22-27. Drug compounds having solubilities greater than the 1 mg/ml threshold or baseline generally have good bioavailability in oral dosage form.

35. Chemical stability relates to the resistence of a drug substance to chemically breakdown. Chemical stability may be determined for the drug substance alone ("bulk stability") or for the drug substance in combination with biologically inactive compounds known as excipients ("formulation stability"). (Stip. Fact, ¶ 24.)

36. The breakdown of the drug substance is known as degradation and the products from the breakdown of the drug substance are called "degradants." (Stip. Fact, ¶ 25.)

37. Chemical stability testing is also necessary to determine the shelf-life of the product.

38. Drug manufacturers assess chemical stability of an active drug compound alone and in admixture with excipients, e.g., as the finished product.

39. Both the number and concentration of degradants in finished drug products are monitored closely as part of the drug development and approval process.

40. It is standard practice to use accelerated chemical stability testing in the pharmaceutical industry. Accelerated stability tests expose the active drug compound and finished product to high temperatures or high relative humidity in an effort to accelerate degradation that may occur over longer time periods at normal temperatures and relative humidities.

41. "Hygroscopicity," in the context of drug development, is a measure of the amount of water (moisture) that a drug compound absorbs when the drug compound is exposed to specified conditions of temperature, relative humidity, and time.

42. Hygroscopic drug compounds complicate the manufacturing process because precise measurement of the amount of active drug compound to be incorporated into a drug product is required. Absorption of moisture changes the weight of the active drug compound. Variation in the amount of the drug compound because of absorbed moisture may result in incorporating too little active drug into a drug product which will lead to variable dosing.

43. Nonhygroscopicity of a drug compound is also an important formulation property because absorbed water may promote chemical instability of a drug compound or drug product, or lead to changes in processability of the drug product.

44. "Processability" describes the ability of a formulation to be manipulated during the process of manufacturing a commercial dosage form, such as a tablet or capsule.

45. Stickiness, one aspect of processability, refers to adherence of the drug substance to the surfaces of manufacturing equipment, such as the metal surface of the punch face of a tablet press.

46. Stickiness is a problem when manufacturing a drug product because adherence of the drug substance to the surface of manufacturing equipment can interrupt production and/or cause a defective product to be made. In commercial tablet manufacturing very large quantities of tablets are produced on extremely high speed tablet presses. If a drug compound sticks to the punch faces of tablet presses while tablets are being made, the punch faces will require cleaning during tablet runs which would interrupt and slow production. Sticking to the punch face is referred to as "punch filming." Also, sticking may result in tablets having surfaces that are "picked" or pitted in appearance. (See Testimony of Stephen W. Hoag, Trial Transcript V, at 170-78.)

47. Manufacturing deficiencies, such as sticking, when observed in small experimental tablet operations will be more significant when using extremely high speed tablet presses. For that reason, pharmaceutical formulators strive to achieve "robust" tablet formulations, i.e., formulations that can be tableted without production problems in a variety of conditions.

48. Pharmaceutically acceptable salts are those which are non-toxic and have no significant impurities or degradation products formed as a result of chemical breakdown of the salt, alone or in combination with excipients, over extended time periods, and which are suitable for making a dosage form that is administrable to a patient. The term "pharmaceutically acceptable salt" does not convey any information about a particular salt or its chemical structure.

III. Amlodipine and Amlodipine Maleate

49. Amlodipine is the common name for the chemical compound 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, which is a member of the class of compounds referred to as "1,4-dihydropyridines." (Stip. Fact, ¶ 16.)

50. Amlodipine is a biologically active chemical compound that has anti-hypertensive and anti-ischaemic activity in the body. (Stip. Fact, ¶ 26.) Anti-hypertensive activity means that amlodipine lowers the blood pressure of a patient. Antiischaemic activity means that amlodipine reduces angina, the pain associated with a lack of blood flow to the heart muscle.

51. Amlodipine maleate is an acid addition salt, formed from the reaction of amlodipine and maleic acid. (Stip. Fact, ¶ 27.)

52. During the 1980's, each new active moiety made at Pfizer's Sandwich, England research facility was assigned a code beginning with the prefix "UK", for the United Kingdom, followed by a five-digit number. (Stip. Fact, ¶ 29.)

53. Amlodipine was assigned compound number "UK-48,340." (Stip. Fact, ¶ 30.)

54. During the 1980's, salts made from a particular acid anion were assigned a code by Pfizer which consisted of the code for the active moiety followed by a two-digit or two-letter code used for all salts made from that acid anion. (Stip. Fact, ¶ 31.)

55. The Pfizer two-digit code for the maleate anion was "11," and amlodipine maleate was assigned code "UK-48,340-11." (Stip. Fact, ¶ 32.)

56. The two-digit Pfizer codes for the anions listed in the '303 patent are as follows: Hydrochloride anion was "01"; Acetate anion was "14"; Tosylate anion was "15"; Succinate anion was "24"; Besylate anion was "26"; Mesylate anion was "27"; Lactate anion was "50"; Salicylate anion was "AB." (Stip. Fact, ¶¶ 33-40.)

57. On or about July 14, 1982, the Pfizer Discovery Chemistry Group located at the Pfizer Central Research Laboratories in Sandwich, England, recommended that an effort be made to develop amlodipine into a commercial product. Clinical studies on amlodipine maleate were planned for 1983.

58. The finished commercial product was intended to be an 20 mg amlodipine maleate tablet. (See Deposition of Edward Davison, Pfizer v. Apotex, at 128; Deposition of Edward Davison, Pfizer v. Synthon, at 38.) Tablets are the preferred oral dosage form for several reasons, which include patient acceptance, self-administration, and tablets are the optimum economic commercial dosage form to manufacture. (Id.; See Testimony of Stephen W. Hoag, Trial Transcript V, at 179.)

59. In 1982, the Pfizer Pharm. R&D Group, also located in Sandwich, England, was responsible for developing commercial dosage forms (drug products) of pharmacologically active compounds discovered and recommended by the Pfizer Discovery Chemistry Group.

60. Neither Dr. Wells nor anyone in Pharm. R&D participated in selecting amlodipine maleate as the amlodipine salt to be developed to a commercial dosage form. The salt form was selected by the Discovery Chemistry Group. (See Testimony of James I. Wells, Trial Transcript I, at 189; see also Deposition of Edward Davison, Pfizer v. Apotex, at 5.)

61. In 1982, the head of Pharm. R&D was Mr. J.E. Jeffries. His deputy, Dr. J.R. Davidson, assigned Dr. Wells, a group development leader in Pharm. R&D, the primary responsibility to develop a commercial tablet formulation of amlodipine maleate. (See Testimony of James I. Wells, Trial Transcript I, at 192.)

62. Dr. Wells assigned Mr. Davison, a physical chemist within Pharm. R&D,*fn3 to assist him in developing the formulation properties of amlodipine maleate. Ms. Teresa Cutt, Mr. David Smith, and Ms. Sally Darling, also members of the Pharm. R&D, were also assigned to the project of developing a commercial amlodipine maleate tablet.

63. At the time that Dr. Wells and Mr. Davison were given this assignment, neither scientist expected that formulating a commercial dosage form of amlodipine maleate would present any problem in terms of stability or processability. It did not occur to Dr. Wells that the amlodipine and the amlodipine maleic acid would react and produce a degradation problem. (See Testimony of James I. Wells, Trial Transcript I, at 197.)

64. Dr. Wells and Mr. Davison worked closely with the Pfizer Process Research & Development Group ("Process R&D") and the Analytical Chemistry Department.

65. Dr. Wells decided that amlodipine maleate tablets should be manufactured using the direct compression process. (Id. at 194.)

66. "Direct compression" is a method of tablet making which is desirable for manufacturing purposes on a commercial scale because it has fewer processing steps, reduces the potential for hydrolytic breakdown, and is more cost effective than other tablet manufacturing processes. (See Testimony of Stephen W. Hoag, Trial Transcript V, at 179.) Water or other liquid excipients are not used in the direct compression process. (Id. at 179-81).

67. In the mid-1980's, as today, "direct compression" tablet manufacturing was the method of choice when the active drug compound in the finished drug product is less than about twenty-five per cent (25%) of the total tablet weight or when hydrolytic instability of the active drug compound is a concern. (Id.

68. Amlodipine maleate was stable in bulk form (i.e., before being mixed with excipients and processed into a useable dosage form.) However, when Dr. Wells and Mr. Davison began trying to formulate a direct compression amlodipine maleate tablet, they discovered two significant and interrelated problems: (i) the sticking of the amlodipine maleate salt to the metal punch face of the tablet making press and (ii) the chemical instability of the amlodipine maleate salt.

69. The sticking problem became exacerbated when tablets were made on a high speed commercial production press. (See Testimony of James I. Wells, Trial Transcript I, at 216.)

70. Toward the end of 1983, Pfizer's Analytical Chemistry Department "diagnosed" that the instability of the amlodipine maleate was caused by the Michael Addition Reaction ("MAR"), which was generating two percent (2%) of a new degradant compound identified as UK-57,269 in the maleate formulations. (Id. at 164, 216; see also Testimony of Robin V. Platt, Trial Transcript V, at 4; see also Deposition of Edward Davison, Pfizer v. Apotex, at 37.) Two percent (2%) of the MAR compound was not acceptable to Dr. Wells for a commercial product. (See Testimony of James I. Wells, Trial Transcript I, at 223). Dr. Robin Platt ("Dr. Platt"), a member of Pfizer's Analytical Chemistry Department, was assigned the responsibility for testing the stability of amlodipine maleate in tablet and capsule formulations. He discovered that in the capsule formulation, the degradation of amlodipine maleate was dominated by one main degradation product, UK-57,269. (See Testimony of Robin V. Platt, Trial Transcript V, at 24.)

71. Dr. Platt also discovered that in the amlodipine maleate tablet formulation the pattern of degradation was more complex in that degradation products included not only the formation of UK-57,269, but at least another ten unknown degradation products were also produced. (Id.; see PTX 120 at P0177100-102.)

72. Initially, Dr. Wells speculated that the ten unknown degradation products may be derivatives of UK-57,269 (see PTX 123 at P0187936-7); however, it was ultimately determined that those unknown degradants in the amlodipine maleate tablet formulations were not by-products of the degradant UK-57,269. (PTX 284 at P0190403-4; Trial Tr. December 4, 2006 at 42: 1-17.)

73. The development of the MAR in the capsule and tablet formulations of amlodipine maleate was not expected. (Trial Tr. December 4, 2006 at 33:6-11). It could not have been predicted from the structures of the amlodipine and maleic acid molecules. The Pfizer Discovery chemists, who were skilled synthetic organic chemists, knew about the MAR generally, i.e., as an abstract reaction such as oxidation. Nevertheless, they designated the amlodipine maleate salt as the development candidate. Had the Pfizer Discovery chemists expected that ...


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