Full opinion text
MEMORANDUM GREGORY M. SLEET, Chief Judge. I. INTRODUCTION In this consolidated patent infringement action, plaintiffs Aventis Pharma S.A. and Sanofi-Aventis U.S., LLC (collectively, “Sanofi” or “the plaintiffs”) allege that pharmaceutical products proposed by defendants Hospira, Inc. (“Hospira”) and Apotex, Inc. (“Apotex”) (collectively, “the defendants”) infringe the asserted claims of the patents-in-suit. (D.I. 1.) The court held a seven-day bench trial in this matter on October 26 through November 3, 2009. (D.I. 369-375.) Presently before the court are the parties’ post-trial proposed findings of fact and conclusions of law concerning the validity and enforceability of the patents-in-suit and whether the defendants’ proposed products infringe the patents-in-suit. (D.I. 378 & 383.) Pursuant to Fed.R.Civ.P. 52(a), and after having considered the entire record in this case and the applicable law, the court concludes that: (A) claims 2 and 10 of the '561 Patent are invalid due to indefiniteness; (B) all asserted claims of the patents-in-suit are invalid due to obviousness; (C) the asserted claims are unenforceable due to inequitable conduct; (D) the asserted claims are not invalid due to double patenting; (E) the defendants’ proposed products infringe asserted claims 2, 5, and 10 of the '561 Patent and. claim 33 of the '512 Patent; and (F) each of the parties Rule 52(c) motions are granted in part and denied in part. These findings of fact and conclusions of law are set forth in further detail below. II. FINDINGS OF FACT A. The Parties 1. Plaintiff Aventis Pharma S.A. is a French corporation with its principal place of business in Paris, France. 2. Plaintiff sanofi-aventis U.S., LLC is a Delaware corporation with its principal place of business in Bridgewater, New Jersey. 3. Aventis Pharma S.A. and sanofi-aventis U.S., LLC will be collectively referred to as “Sanofi” or “Plaintiffs.” 4. Rhone-Poulenc Rorer, SA is a predecessor in interest to Aventis Pharma SA. 5. Defendant Hospira, Inc. is a Delaware corporation with its principal place of business in Lake Forest, Illinois. Hospira and Maybe Pharma, will be collectively referred to as “Hospira”. 6. Defendant Apotex, Inc. is a Canadian company with a principal place of business in Toronto, Ontario, Canada. 7. Defendant Apotex Corp. is a Delaware corporation with a principal place of business in Florida. 8. Apotex, Inc. and Apotex Corp. will be collectively referred to as “Apotex”. 9. The Court has subject matter jurisdiction, as well as personal jurisdiction over all parties. B. Background 10. Taxanes are a group of chemotherapeutic agents which include the compounds paclitaxel and docetaxel. 11. Derived from a yew tree, i.e., taxus brevifolia, paclitaxel (also known by its commercial name “Taxol”) and docetaxel (which is also derived from a yew tree), are both hydrophobic antineoplastic agents demonstrating significant antitumor activity. 12. Docetaxel and paclitaxel work by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular function. Thus they are referred to as “anti-mitotic” drugs. 13. Taxanes interfere with cell division and thus preferentially disrupt the growth of cells, such as tumor cells, undergoing rapid cell division. C. The Patents-in-Suit 14. U.S. Application Number 07/930,392, from which U.S. Patent No. 5,714,512 B1 (the “'512 patent”) issued, was filed on August 23, 1993. The '512 patent issued on February 3, 1998 to Jean-Pierre Bastart, Thierry Depechez, and Jean-Louis Fabre. 15. U.S. Application Number 07/930,393, from which U.S. Patent No. 5,750,561 B1 (the “'561 patent”) issued, was filed on August 4, 1993. The '561 patent issued on May 12, 1998 to Jean-Pierre Bastart, Thierry Depechez, and Jean-Louis Fabre. 16. Both the '512 patent and '561 patent refer to French patent application FR 91 08527, which was filed on July 8, 1991. 17. Sanofi-aventis U.S. LLC is the current holder of approved New Drug Application (“NDA”) No. 020-449 for a docetaxel injection product, which has the proprietary name Taxotere®. 18. The FDA’s Orange Book lists the following patents associated with NDA 20-449: the '512 patent, the '561 patent, U.S. Patent No. 4,814,470 (“'470 patent”), U.S. Patent No. 5,438,072, and U.S. Patent No. 5,698,582. 19. Sanofi sells a commercial version of a docetaxel formulation called Taxotere®. Taxotere® was first commercially available in the U.S. on or about May 14, 1996. 20. The first commercial version of Taxotere® used Formulation 2. That formulation was submitted in Sanofi’s NDA 30-449. The label for this formulation stated that perfusions should be administered as soon as possible. 21. NDA 20-449 (for Taxotere®) was approved on May 14,1996. 22. In 1997, Sanofi submitted a supplemental NDA or “sNDA” to the FDA with the same reference number, 20-449. This submission referred to what Sanofi called “Formulation 3” for Taxotere®. Formulation 3 was the same as Formulation 2 except that citric acid was added to the formulation. 23. Formulation 3 for Taxotere® was approved by the FDA in 1999. Taxotere® is currently commercially sold using Formulation 3. 24. Taxotere® is sold as a two-vial product. One vial is called a concentrate and the other is called a diluents. The concentrate vial has docetaxel, along with polysorbate 80, and residual amounts of ethanol. The diluent has water and ethanol. 25. The Taxotere® concentrate includes 40 mg/ml of docetaxel dissolved in polysorbate 80. The Taxotere® diluent includes 13% ethanol and the rest is water. 26. The concentrate vial and the diluents vial are then combined to form a “premix.” The premix is a solution that can be added to an IV bag to make a perfusion. According to the Taxotere® label, the premix is stable for up to 8 hours. 27. The premix can be diluted with 0.9% sodium chloride or 5% glucose solutions to prepare a perfusion for administration to patients. The recommended docetaxel concentrations in the perfusions are between 0.3 and 0.74 mg/ml. According to the Taxotere® label, the perfusion is stable for up to 4 hours. 28. Other than Taxotere®, there is not now and has never been another clinically tested or commercially available formulation of docetaxel in the U.S. 29. There is not now and has never been a clinically tested or commercially available formulation of paclitaxel in a formulation including polysorbate 80. 30. On July 3, 1992, applicants filed two applications under the Patent Cooperation Treaty (“PCT”). The first PCT application, PCT/FR/00624 (“PCT624”), entered the national phase in the United States in the priority chain leading to issuance of the '512 patent. The second PCT application, PCT/FR/00625 (“PCT625”), entered the national phase in the United States in the priority chain leading to issuance of the '561 patent. The specifications for PCT524 and PCT625 are not identical. 31. The application for the '512 Patent was filed on December 1995 and was assigned serial number 08/568, 760 (“the '760 Application”). The '760 Application was filed as a continuation-in-part application claiming priority through U.S. Patent Application Serial No. 08/398, Oil (“'Oil Application”) back to French national application serial number 91 08527 (“FR527”). The application was originally filed with 35 claims and was assigned to a different examiner than the person that had examined and allowed the 'Oil Application. 32. On May 23, 1997, the PTO issued a Notice of Allowability of all pending claims on the '512 patent. 1. '512 Patent Specification 33. According to the '512 patent, the pri- or art formulation of paclitaxel caused “manifestations of alcohol poisoning during treatment.” According to the '512 patent, “the present invention provides compositions that make it possible either to reduce the ethanol concentrations greatly, or to eliminate Cremophor and ethanol completely from the perfusions.” 34. The specification of the '512 patent beings with the following introductory paragraph: The present invention relates to compositions and especially pharmaceutical dosage forms containing therapeutic agents having antitumor and antileukemic activity. It relates more especially to compositions suitable for injection containing taxane derivatives, such as, in particular, taxol or one of its analogues or derivatives of the formula (1) [ILLUSTRATION SHOWN] in which R1 and R2 each represent a hydrogen atom or one of R1 and R2 represents a hydrogen atom and the other represents a hydroxyl, acyloxy, or acylcarbonylocy radical, or R2 represents a hydrogen atom and R1 forms a single bond together with the methyl carbon atom situated in the alpha position, so they can form together a cyclopropane ring, one of R3 and R4 represents a hydrogen atom and the other represents a hydroxyl radical, or R3 and R4 taken together form a oxo radical, R5 and R6 taken together form a oxo radical, R7 represents an alkoxy, alkenyloxy, cycloakyloxy or phenyl radical and Ar represents an aryl radical or preferably a phenyl radical optionally substituted by one or several atoms or radicals identical or different and selected from halogen, alkyl, alkoxy, dialkylamoni, acylamino, alkylcarbonylamino or trifluoromethyl, or a 5 membered heterocyclic radical with one or more identical or different heteroatoms chosen from nitrogen, oxygen or sulfur, it being understood that alkyl radical are straight chain or branched chain and contain 1 to 8 carbon atoms and the alkenyl radicals contain 2 to 8 carbon atoms and provided that when R2 is a hydrogen atom and R1 is a hydroxyl radical, R3 and R4 cannot be simultaneously an oxo radical when R6 is a hydrogen atom, R5 is a dydroxy, aceyloxyradical, R7 is a t.butoxy or a phenyl radical and Anticipatory repudiation is a phenyl radical. ['512 Patent, Col. 1, lines 7-52]. The specification further discloses that known taxane derivatives encompassed by the general forums (I) [above] include two compounds which are known by the name of Taxol and the name Taxotere. 35. The specification describes one of the problems to be solved by the alleged subject invention in the following terms: “Unfortunately, these products possess such low solubility in water that it has been necessary to prepare formulations for injection containing surfactant and ethanol.” ['512 Patent, Col. 2, lines 8-10]. 36. The specification compares the alleged subject invention to a prior art composition of Rowinsky that solubilized Taxol in a mixture of ethanol and Cremophor EL. The specification describes Cremophor EL as follows: ... polyethoxylated castor oil, also known as glycerol polyethyleneglycol ricinoleate, as marketed, e.g., under the name Cremophor, preferably CREMO-PHOR® EL ... CREMOPHOR® EL is a non-ionic solubulizer and emulsifier that can be obtained by reacting ethylene oxide with castor oil in a molar ration of 35-40 mol ethylene oxide to 1 mol glyceride and is commercially available from BASF and has been assigned CAS Registry Number 61791-12-6. The main component of CREMO-PHOR® EL is glycerolpolyethyleneglycol ricinoleate, which together with fatty acid esters of polyethylene glycol, represents the hydrophobic part of the product. The smaller, hydrophilic part consists of polyethylene glycols and ethoxylated glycerol. ['512 Patent, Col. 2, line 58-Col. 3, line 4]. 37. The specification describes a preferred method of making a “stock solution” in the following terms: The stock solution may be prepared by dissolving the active principle in ethanol, which is the best biocompatible solvent for the taxane derivatives, and then gradually adding the surfactant. Solutions containing 10 to 100 mg/ml of active principle in a mixture containing approximately 50% of surfactant can be prepared in this manner. The ethanol is then completely, or almost completely, eliminated. To prepare, according to the present invention, the solution having a low ethanol content, the taxane derivative is dissolved in ethanol, and the surfactant, which enables micelles to be formed in [sic] containing the taxane derivative encapsulated in the surfactant after dilution in an aqueous medium, is then added. The ethanol contained in this solution is then removed at least partially by evaporation under vacuum or by any other suitable means. ['512 Patent, Col. 3, lines 5-19]. 38. The specification describes an alternative means for making a stock solution composition with a low ethanol content: According to a second method of preparing the stock solution, the taxane derivative is dissolved directly in the surfactant. According to a preferred method, a solution of surfactant containing, in particular, 1 to 2% of ethanol is prepared, and the taxane derivative is added continuously to this solution with stirring, e.g. using a helical grinder or a centrifugal disintegrator. The presence of a small amount of ethanol provides several advantages: the medium possesses a lower viscosity, and the wetting of the powder and the final filtration of the solution are improved. ['512 Patent, Col. 3, lines 20 29]. 39. The specification includes a “Comparative Example According To The Prior Art” which states, at column 4, as follows: Taxol (0.180 g) is dissolved in ethanol (15 ml). The mixture is made to volume with Cremophor to obtain a solution (30 ml) which contains taxol (6 mg/ml). This solution is diluted in a 5% glucose perfusion solution in a proportion of 1 mg/ml; the perfusion solution in a proportion of 1 mg/ml; the perfusion solution contains 87.7 ml/, of Cremophor and 87.7 ml/1 of ethanol. The perfusion solution is stable for more than 21 hours. ['512 Patent, Col. 4, lines 21-28]. 2. '561 Patent Specification 40. Neither the '512 patent or the '561 patent discloses PEG 300 or citric acid. 41. As with the specification for the '512 patent, the '561 specification begins by stating that it relates to taxane derivatives, including taxol and taxotere. [Col. 1, lines 6 30]. 42. The specification states that it is desirable to be able to inject sufficient doses of active principle: “to this end, clinicians would like to inject concentrations of active principle of between approximately 0.3 and 1 mg/ml in the perfusion fluid.” ['561 Patent, Col. 1, lines 56-59]. 43. The specification identifies two problems in the prior art that needed to be overcome: Now, it is desirable to be able to inject sufficient doses of active principle; to this end, clinicians would like to inject concentrations of active principle of between approximately 0.3 and 1 mg/ml in the perfusion fluid; above these doses, anaphylactic shock phenomena which are difficult to control, due in the main to the Cremophor, are seen (see the publication by Rowinsky, page 1250, second column, last paragraph), This publication also discloses that, to obtain such concentrations (between 0.3 and 1 mg/ml), it is necessary to inject solutions containing, as well as the active principle, concentrations of each of the following compounds, ethanol and most especially Cremophor, of approximately 8 g per 100 mil of solution. Since the treatment often requires the administration of high doses of active principle, and since the concentration of the active principle in the solution is relatively low, the injection of a large volume has the effect of causing, in addition to anaphylactic manifestations, manifestations of alcohol intoxication during the treatment. It has been discovered that, by the use of the pharmaceutical dosage forms of the present invention, it is possible to avoid the use of Cremophor and greatly to reduce the ethanol concentrations used. ['561 Patent, Col. 1, line 56-Col. 2, line 11]. 44. The specification teaches that use of the pharmaceutical dosage of the invention made it possible to avoid the use of Cremophor and “greatly reduce” the ethanol concentrations used. ['561 Patent, Col. 2, lines 8-11]. The specification teaches the preparation of a “stock solution” in the following manner: For this purpose, a stock solution is prepared, containing the active principle of formula I in a solvent mixture composed of ethanol, which is the best bio-compatible solvent for active principles of this class, and a polysorbate surfactant, e.g. as marketed, in particular, under the name “Tween”. The stock solution is prepared by dissolving the active principle in ethanol and then gradually adding the surfactant. Solutions containing 10 to 100 mg/ml of active principle in a mixture containing approximately 50% of surfactant can be prepared in this manner. ['561 Patent, Col. 2, lines 12-22], 45. Polysorbate (or “Tween”) is the only surfactant that is identified for use in the alleged, invention claimed in the '561 Patent. 46. The specification includes the following “comparative example according to the prior art”: Taxol (0.180 g) is dissolved in ethanol (15 ml). The mixture is made to volume •with Cremophor to obtain a solution (30 ml) which contains taxol (6 mg/ml). This solution is diluted in the same perfusion solution as above to five [sic] a final concentration of 1 mg/ml; the perfusion solution contains 87.7 ml/1 of Cremophor and 87.7 ml/1 of ethanol. ['561 Patent, 3, lines 7-15]. 3. The Asserted Claims 47. Plaintiffs are asserting claims 7 and 33 of the '512 patent against both Hospira and Apotex in this case. 48. Plaintiffs are asserting claims 2, 5, and 10 of the '561 patent against both Hospira and Apotex in this case. 4. '512 patent, Claim 7 49. Claim 1 of the '512 patent, upon which asserted Claim 7 depends, reads (including alterations made by a Certificate of Correction indicated by brackets): “A composition comprising a compound of: (I) [ILLUSTRATION SHOWN] in which Ar is unsubstituted phenyl, R7 is phenyl or [tert-butoxy], R6 is hydrogen, R5 is aceyloxy or hydroxyl, R3 and R4 taken together form an oxo radical, Rx is hydroxyl and R2 is hydrogen, said composition being dissolved in a surfactant selected from polysorbate, polyoxyethylated vegetable oil, and polyoxyethylated castor oil, said composition being essentially free or free of ethanol. 50. Claim 6, upon which asserted Claim 7 depends, reads (including alterations made by a Certificate of Correction indicated by brackets): The composition of claim 1 wherein R5 is hydroxyl and R7 is [tertbutoxy]. 51. Claim 7 reads: The composition of claim 6, wherein said surfactant is polysorbate. 52. The '470 patent’s “Composition Example” discloses a docetaxel formulation with a concentration of 2 mg/mL docetaxel, 5% by volume ethanol and 5% by volume Emulphor (a surfactant). ['470 Patent, Col. 10, lines 5-11]. 53. Apotex’s infusion prepared from Apotex’s proposed product in accordance with the proposed prescribing information set forth in Apotex’s NDA, at a docetaxel concentration of 0.3 mg/mL, would contain approximately 1.8 ml/L of ethanol, or 0.18% v/v of ethanol. 54. Apotex’s infusion prepared from Apotex’s proposed product in accordance with the proposed prescribing information set forth in Apotex’s NDA, at a docetaxel concentration of 0.74 mg/mL, would contain approximately 4.5 ml/L of ethanol, or 0.45% v/v of ethanol. 5. '512 patent, Claim 33 55. Claim 24 of the '512 patent, upon which asserted Claim 33 depends, reads (including alterations made by a Certificate of Correction indicated by brackets): A stock solution comprising a compound of the formula (I) [ILLUSTRATION] in which Ar is unsubstituted phenyl, R7 is phenyl or [tert-butoxy], R6 is hydrogen, R6 is aceyloxy or hydroxyl, R3 and R4 taken together form an oxo radical, Rj is hydroxyl and R2 is hydrogen, said compound being dissolved in a surfactant selected from polysorbate, polyoxyethylated vegetable oil, and polyoxyethylated castor oil, wherein said stock solution contains from 10 to 200 mg/mL of said compound of formula (I). 56. Claim 32, upon which asserted Claim 33 depends, reads (including alterations made by a Certificate of Correction indicated by brackets): the stock solution of claim 24, wherein R5 is hydroxyl and R7 is [tert-butoxy]. 57. Claim 33 reads: The stock solution of claim 32, wherein said surfactant is polysorbate. 58. Apotex’s premix contains docetaxel, 59. Apotex’s premix contains polysorbate. 60. Apotex’s premix, when prepared according to Apotex’s prescribing information it submitted to the FDA, contains 10 mg/mL of docetaxel. 6. '561 patent, Claim 2 61. Claim 1 of the '561 patent, upon, which asserted Claim 2 depends, reads (including alterations made by a Certificate of Correction indicated by brackets): A composition consisting essentially of a compound of formula (I) [ILLUSTRATION] in which R represents a hydrogen atom or an acetyl radical and Rj represents a tert-bytoxyearbonylamino or benzoylamino radical, dissolved in a mixture of ethanol and a polysorbate whereby said composition is used to form an injectable solution which contains up to about 1 mg/ml of the compound of formula I, said injectable solution being capable of being injected without anaphylactic or alcohol intoxication manifestations being associated therewith. 62. Claim 2 reads: A composition according to claim 1, wherein, in the compound of formula (I), R represents a hydrogen atom and Rj represents a tert-bytoxycarbonylamino radical. 63. Plaintiffs assert that Hospira’s proposed product would infringe Claim 2. 64. Plaintiffs assert that Apotex’s premix, when prepared according to Apotex’s proposed prescribing information, would infringe Claim 2. 7. '561 patent, Claim 5 65. Claim 5 of the '561 patent reads as follows: “A perfusion, which contains approximately 1 mg/ml or less of compound of formula as defined in claim 1 and which contains less than 35 ml/1 of ethanol and less than 35 ml/1 of polysorbate, wherein said perfusion is' capable of being injected without anaphylactic or alcohol intoxication manifestations being associated therewith.” 66. Plaintiffs assert that Apotex’s infusion prepared from Apotex’s proposed product according to Apotex’s proposed prescribing information would infringe Claim 5. 8. '561 patent, Claim 10 67. Claim 8 of the '561 patent, upon which asserted Claim 10 depends, reads: “A therapeutic composition consisting essentially of a taxane derivative dissolved in a mixture of ethanol and a polysorbate, whereby said therapeutic composition forms or is used to form an injectable solution which contains up to about 1 mg/ml of the compound of formula as defined in claim 1, said injectable solution being capable of being injected without anaphylactic or alcohol intoxication manifestations being associated herewith.” 68. Claim 10 reads: “The composition of claim 8 wherein said taxane derivative is Taxotere or an analogue or derivative thereof.” 69. Plaintiffs assert that Apotex’s premix made according to Apotex’s proposed prescribing information, would infringe Claim 10. D. Clinical Testing 70. Sanofi-aventis began enrolling patients for Phase I clinical testing on June 21, 1990. This study was called the “TAX 001” study. The TAX 001 study continued until May 13, 1992. The results from the TAX 001 study were reported in a study reported dated May 24, 1994. Testing under TAX 001 used what Sanofi referred to as “Formulation 1.” 71. Formulation 1 had a formulation of docetaxel in 50% polysorbate 80 and 50% ethanol. 72. Sanofi-aventis then began Phase II clinical testing. During Phase II testing, Sanofi-aventis used what it referred to as “Formulation 2.” 73. Formulation 2 had a formulation of docetaxel that was almost all polysorbate 80, because ethanol used during the manufacturing process has been evaporated away. E. The Accused Products 1. NDA 22-234 (Hospira’s NDA) 74. Hospira filed New Drug Application No. 22-234 with the FDA to obtain FDA approval for the commercial manufacture, use, and sale of a docetaxel injection product in the following dosage forms: 20 mg/2 ml, 80 mg/8 ml, and 160 mg/16 ml. Hospira filed its NDA No. 22-234 to obtain approval to market a generic docetaxel formulation before the expiration of certain Sanofi patents, including the '512 and '561 patents, 2. Hospira’s NDA Product 75. Hospira’s docetaxel product is a one-vial product. Hospira’s one-vial product is a stock solution that can be used to make a perfusion, without the need to make a premix. 76. Hospira’s one-vial product is suitable for “multi-dose” applications, which means that amounts can be used as needed from the vial, and then the vial can be reused. 77. The concentrations of each of the ingredients of Hospira’s proposed product found in Hospira’s infusion when the docetaxel concentration is 0.3 mg/mL are as follows: PEG 300, 18.0 mg/mL; polysorbate 80, 7.81 mg/mL; ethanol, 5.47 mg/ mL; citric acid, 0.12 mg/mL. 78. The concentrations of each of the ingredients of Hospira’s proposed product found in Hospira’s infusion when the docetaxel concentration is 0.74 mg/mL are as follows: PEG 300, 44.0 mg/mL; polysorbate 80, 19.3 mg/mL; ethanol, 13.5 mg/ mL; citric acid, 0.30 mg/mL. 3. NDA 22-312 (Apotex’s NDA) 79. Apotex filed New Drug Application 22-312 with the FDA to obtain FDA approval for the commercial manufacture, use, and sale of a docetaxel injection product in the following dosage forms: 40 mg/ ml, 20 mg/0.5 ml and 80 mg/2ml. Apotex filed its NDA No. 22-312 to obtain approval to market a generic form of Taxotere®, before the expiration of certain Sanofi patents, including the '512 and '561 patents. Apotex currently does not make, sell, offer for sale, or use in the United States, or import into the United States, any product described in NDA 22-312. 80. Apotex sent a letter dated Jun 27, 2008 to Sanofi-aventis to provide notice, pursuant to 21 U.S.C. § 355(b)(2)(B), that Apotex had filed NSA 22-312. The letter further provided notice that Apotex had filed with the FDA, pursuant to 21 U.S.C. § 355(b)(2)(A)(iv), a certification (“Paragraph IV certification”) alleging that four of the five Sanofi-aventis patents for Taxotere®, including the '512 and '561 patents, are invalid, not infringed, and/or unenforceable. 4. Apotex’s NDA Product 81. Apotex’s docetaxel injection product (hereinafter “Apotex’s proposed product”) consists of two vials — an injection concentrate and a diluent. The injection concentrate is diluted twice before being administered to a patient. The first dilution is referred to herein as a “premix.” 82. The injection concentrate vial contains 40 mg/mL of docetaxel in approximately 1088 mg/mL (q.s. to 1 mL) of PEG 300. 83. The diluents vial contains the following ingredients in the following concentrations: ethanol (90 mg/mL), polysorbate 80 (346.8 mg/mL), and water (q.s. to 1 mL). 84. The concentration of the components of Apotex’s premix, derived from a review of the concentrations of Apotex’s two vials set forth in the Apotex NDA, is as follows: docetaxel, 10 mg/mL; PEG 300, 272 mg/ mL; polysorbate 80, 260.1 mg/mL; ethanol, 52.5 mg/mL; water for injection, q.s. to 1 mL. 85. The concentrations of each of the ingredients of Apotex’s proposed product found in Apotex’s infusion when the docetaxel concentration is 0.74 mg/mL are as follows: PEG 300, 20.13 mg/mL; polysorbate 80, 19.24 mg/mL; ethanol, 3.6 mg/mL (3.89 mg/mL when 95% alcohol is used). F. Alleged Invalidity 86. Taxanes are poorly soluble in water. Docetaxel and paclitaxel are both poorly soluble in water. 87. Taxol is still commercially available today as a cancer treatment pharmaceutical product. 88. Cremophor is a surfactant. A surfactant is a surface active agent that helps to dissolve an otherwise poorly soluble compound. 89. Tween 80 is a trade name of polysorbate 80. Polysorbate 80 is a surfactant. 90. The Taxol formulation was described and. known in the prior art. One prior art publication describing the Taxol formulation was by Eric K. Rowinsky et ah, Taxol: A Novel Investigational Antimicrotubule Agent (“Rowinsky”) was published in August 1990. 91. Rowinsky reported that the Taxol stock solution has a paclitaxel active ingredient concentration of 6 mg/ml. Rowinsky reports that paclitaxel is available in 5 ml ampoules with equal parts of Cremophor (2.5 ml) and ethanol (2.5 ml). 92. Rowinsky reported that the Taxol perfusion has a paclitaxel active ingredient concentration of between 0.03 and 0.6 mg/ ml, Rowinsky reports that Taxol perfusions are stable for up to 24 hours. 93. The prior art '470 patent was issued to Rhone-Poulence Sante and subsequently assigned to Sanofí and published in March 1989. The '470 patent expired on May 14, 2010. 94. The '470 patent is titled “Taxol Derivatives, Their Preparation, and Pharmaceutical Compositions Containing Them.” The '470 patent lists Colin, Guenard, Gueritte-Voegelein, and Potier as named inventors. 95. The '470 patent disclosed copunts that are paclitaxel derivatives, including docetaxel. The '470 patent disclosed formulation for such compounds. 96. The '470 patent reported that docetaxel was tested in an in vitro test and was “found to be approximately twice as active as taxol [paclitaxel].” The '470 patent also reported that docetaxel was tested in an in vivo test and “showed an antitumour efficacy greater than that of taxol [paclitaxel] (i.e. an increased survival time, with the animals surviving long-term).” 97. The '470 patent reported that “the parenteral route, and especially the intravenous route, is the preferential route for administration.” 98. The '470 patent provided a “composition example” of a formulation made using docetaxel. In that example, a formulation of 20 mg/ml docetaxel was dissolved in a formulation containing 50% Emulphor (Cremophor) and 50% ethanol. Also in that example, this formulation is diluted 10-fold with saline. Applying this initial dilution resulted in the example stock solution having 2 mg/ml docetaxel, 5% Emulphor, and 5% ethanol. 99. The '470 patent reported that docetaxel formulations can be administered “by the intravenous (perfusion) route for an adult.” 100. Docetaxel was disclosed in the '470 patent. 101. The '470 patent is owned by the same assignee as the patents-in-suit. 102. The '470 patent discloses the use of docetaxel as an anti-cancer remedy. 103. The following disclosure appears in Columns 9 and 10 of the '470 patent: The present invention also provides pharmaceutical compositions containing a compound of formula (I) in combination with one or more pharmaceutically acceptable, inert of physiologically active, diluents or adjuvants. These compositions may be presented in any form appropriate for the administration route envisaged. The parenteral route, and especially the intravenous route, is the preferential route for administration. The compositions according to the invention for parenteral administration may be aqueous or nonaqueous sterile solutions, suspensions or emulsions. Propylene glycol, vegetable oils, especially love oil, and injectable organic esters, e.g. ethyl oleate, may be used as the solvent or the vehicle. These compositions may also contain adjuvants, especially wetting agents, emulsifiers or dispersants. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating. They may also be in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or any other injectable sterile medium. The products of general formula (I) are more particularly used in the treatment of acute leukaemias and solid tum-ours, at daily doses which are generally between 1 and 2 mg/kg by the intravenous (perfusion) route for an adult. The following Example illustrates a composition according to the invention. COMPOSITION EXAMPLE The product of formula I obtained in Example 1 (40 mg) is dissolved in Emulphor EL 620 (1 cc) and ethanol (1 cc) and, the solution is then diluted by adding physiological saline (19 cc). This composition may be administered by introduction into an intravenous perfusion of physiological saline given over a period of 1 hour. ['470 Patent, Co. 9-10]. 104. Claim 6 of the '470 patent states as follows: “6. A pharmaceutical composition which contains a taxol derivative as claimed in claim 1 combined with one or more pharmaceutically acceptable, inert of physiologically active diluents or adjuvants.” 105. The prior art publication F. Lavelle, Experimental Properties of RP 56976, a taxol derivative, was published in 1989 by Sanofi-aventis. 106. RP 56976 was the number RhonePoulenc assigned to docetaxel. 107. Before the filing in July 1991 or FR537, at least two articles were published by Tarr et al.: Tarr, B.D. & Yalkowsky, S.H., A New Parenteral Vehicle for the Administration of Some Poorly Water Soluble Anti-Cancer Drugs, JOURNAL OF PARENTERAL SCIENCES & TECHNOLOGY, Vol. 41, No. 1, Jan-Feb 1987, pp. 31-33 (“Tarr”) and Tarr, B.D., Sambandan T.G., and Yalkowsky, S.H., A New Parenteral Emulsion for the Administration of Taxol, PHARMACEUTICAL RESEARCH, Vol. 4, No. 2, 1987, pp. 162-165. (“PR87”). 108. The prior art publication Tarr, B.D. & Yalkowsky, S.H., A New Parenteral Vehicle for the Administration of Some Poorly Water Soluble Anti-Cancer Drugs, JOURNAL OF PARENTERAL SCIENCES & TECHNOLOGY, Vol. 41, No. 1, Jan-Feb 1987, pp. 31-33 (“Tarr”) was published in February 1987. 109. The prior art patent U.S. Patent No. 4,206,221 (“'221 patent”) was issued and published in June 1980. 110. The '221 patent discloses the use of cephalomannine for treating leukemic tumors. 111. NCI Investigational Drugs, Pharmaceutical Data, U.S. Department of Health and Human Services, NIH Publication No. 81-2141, March 1981 (“NCI81”) discloses an anti-cancer therapy supplied by Bristol Laboratories of Syracuse, New York for clinical trials sponsored by the Division of Cancer Treatment, National Cancer Institute. 112. The active ingredient of the anticancer therapy discussed in NCI81 is known as Etoposide and its molecular structure is graphically depicted at page 117 of NCI81. 113. The following information appears on page 118 of NCI81: How Supplied: Injection, 100 mg, ampule, with citric acid, anhydrous 10 mgl benzyl alcohol, 150 mgl polysorbate 80, purified, 400 mgl polyethylene glycol 300, 3.25 Gm; absolute alcohol qs 5.12 Gm; The product is prepared as a solution in 5 ml ampoules. There are ten ampoules in a box. Solution Preparation: Ampule/100 mg: Etoposide, as supplied, is a non-aqueous solution. The solution in the ampule must be diluted with 20-50 volumes of 0.9% Sodium Chloride Injection, USP, before administration by slow intravenous infusion. Discard solutions that show evidence of a precipitate. [NCI81 at 118]. 114. NCI81 discloses the following at page 118: “How supplied, Injection 100 mg, ampule, with citric acid, anhydrous lOmg; benzyl alcohol 150 mg; polysorbate 80, purified 400 mgl polyethylene glycol 300, 3.25 Gm; absolute alcohol qs 5.12 Gm The product is prepared in 5 ml ampoules.” [NCI81, p. 118], 115. The publication Bissery et al., Experimental Antitumor Activity of Taxotere® (RP 56976, NSC 628503, a Taxol Analogue, Cancer Research 51, 4845-4852 (“Bissery”) was published in September 1991. 116. The Bissery paper was received by the publisher on March 21, 1991. The Bissery paper was officially accepted by the publisher on July 2, 1991. 117. Bissery reported results of testing the anti-tumor activity of docetaxel and paclitaxel for various types of cancer models. 118. Footnote 1 to Bissery states: “Presented in part at the 81st Annual Meeting of the American Association for Cancer Research, May 1990, Washington, DC.” This presentation is referred to as “AACR90.” 119. Column 2 of page 4845 of Bissery contains the following statement: Taxotere® (RP 56976, NSC 628503) was first dissolved in ethanol, then polysorbate 80 was added and the final dilution of Taxotere® was obtained with 5% glucose in water (5/5/90; v/v/v). The pH of the final solution was 5. It was injected i.v., 0.4 ml/mouse. Taxol (NSC 125973) was obtained from the National Cancer Institute (Bethesda, MD). It was prepared as described above for Taxotere®, and injected in the same volume. Reference compounds were obtained from various suppliers: cyclophosphamide (Laboratoire Lucien, Colombes, France); 5-fluorouracil (Laboratoire Roche, Neuilly sur Seine, France); doxorubicin (Laboratoire Roger Bellon, Neuilly sur Seine, France, and Mead Johnson, Evansvill, IN): cis-platinum (Laboratoire Roger Bellon). All reference compounds were prepared in 5% glucose in water, except for cix-platinum, which was prepared in 0.9% sodium chloride solution, pH 4.5. The volume of injection of all reference compounds was 0.2 ml/ mouse. [p. 4845, col. 2], 120. The prior art publication Gueritte-Voegelein, et al., Relationships between the Structure of Taxol Analogues and Their Antimitotic Activity, JOURNAL OF MEDICINAL CHEMISTRY 34, 992-998, March 1991 (the “GV reference”) was published in March 1991. 121. JMC91/GV discloses relationships between the structure of taxol analogues and their anti-mitotic activity. 122. JMC91/GV reported that: “Moreover, Taxotere (13a) showed a better solubility in excipient system (polysorbate 80/ethanol, 1:1) than the two other most active compounds taxol and [a taxol derivative].” 1:1 formulation means having 50% of each stated excipient. 123. The '470 patent discloses an “intravenous perfusion.” Col. 10, line 10. 124. The '221 patent discloses as its active ingredient cephalomannine. 125. The example given in footnote 2 of Table V of the '221 patent includes polysorbate 80 (Tween 80) and ethanol. 126. Cremophor EL can cause an anaphylactic reaction. (ReePR87; Tarr). 127. The Dictionnaire Vidal: 65th Edition (“Vidal”) was published in 1989. The Vidal lists various commercially available drugs, including anti-cancer drugs for parenteral administration. 128. The Vidal disclosed prior art formulations for etoposide and teniposide. 129. The Vidal reported that teniposide was available under the brand name Vehem. The Vidal reported that the Vehem formulation includes Cremophor. The Vidal reported a warning for Vehem that Cremophor is likely to lead to anaphylactogenic reactions and that it is important to have oxygen readily available in the case of such a severe reaction. 130. Etoposide and teniposide are anticancer drugs. 131. Thierry Dupechez was named on correspondence also describing the prior art etoposide and teniposide prior art formulations. SA00879661-62. 132. The Vidal reference discloses the teniposide prior art drug formulation, which used Cremophor, and discloses that the Cremophor ingredient used in teniposide caused anaphylaxis. 133. The Vidal reference discloses the etoposide prior art drug formulation for an anti-cancer drug and that polysorbate 80 was used as a surfactant. 134. The prior art publication R.T. Dorr et al., Development of a Parenteral Formulation for the Anti-Tumor Agent Acronycine, (1988) (“Dorr”) was published in 1988. 135. Dorr reported testing using the Vepesid formulation, which it referred to as the “VP-16” formulation. Dorr reported using the Vepesid formulation with the drug acroncyine. Acronycine is a poorly water-soluble anti-cancer compound. 136. Dorr disclosed Emulphor as a surfactant that had been used in parenteral formulations with acronycine. 137. Dorr reported that: “Since the co-solvent system used in the present study is identical with that used in the commercial formulation of etoposide (VP-16 of Vepesid), substantial toxicology information on the vehicle is already reported.” 138. Dorr reported that: “In clinical etoposide studies however, this solvent has not produced excessive local venous toxicities nor general hypersensitivity reactions [18].” 139. Dorr reported that: “This benign toxicity profile is not found with polyoxyethylated castor oil-based solvents such as those used in the parenteral formulations of the anticancer drug teniposide and the immunosuppressant cyclsporin. Both Cremophor and Emulphor contain this castor oil-derived product and both diluents increase lipid deposition in organs, cause skin flushing and edema, and can alter circulating platelet levels.” 140. The specification of the '561 Patent states that: “The anaphylactic shock phenomena which were observed with the solutions of the prior art are not observed with these solutions.” ('561 Patent, column 2, lines 48-51). 141. Finnegan, Henderson, Farabow, Farrett & Dunner, LLP (“Finnegan”) began prosecuting the application which resulted in the '512 Patent on behalf of the applicants on December 7,1995. 142. Finnegan began prosecuting the application which resulted in the '561 Patent on behalf of the applicants on April 12, 1995. 143. Polysorbate 80 had been used in at least one intravenous pharmaceutical formulation before 1991. G. Secondary Considerations 144. Taxotere®, Plaintiffs’ commercial product, is sold in two vials, as Taxotere® (docetaxel) Injection Concentrate in strengths of 80 mg/ 2 mL of docetaxel and 20 mg/0.5 mL of docetaxel in solution with polysorbate 80. The Injection Concentrate accompanied by a diluent. The diluent vial contains 14% ethanol in water. 145. A medical professional dilutes the Taxotere® (docetaxel) Injection Concentrate twice prior to administration according to the prescribing information directions. First, the Taxotere® (docetaxel) Injection Concentrate is diluted with the diluent to prepare a “premix.” This premix is then diluted with either a 0.9% sodium chloride solution of 5% glucose solution, resulting in a perfusion for administration to patients. 146. Apotex states in its NDA that polysorbate 80 keeps the docetaxel in solution without any precipitation both in the initial diluted solution of its proposed docetaxel injection product and the final dilution solution of its proposed docetaxel infusion produce. 147. The Taxotere® formulations used by Sanofi-aventis in its Phase 1 clinical trials were one-vial formulations. 148. Hospira has stated in its NDA that “Hospira’s Docetaxel Injection was developed by Hospira as a generic equivalent of Taxotere®.” 149. Hospira has stated in its NDA that: “The concentration of Polysorbate 80 is the same for both Hospira’s Docetaxel Injection and Taxotere® when diluted into infusion solutions. However, it is theoretically possible that the additional excipients in Hospira’s Docetaxel Injection may lead to altered biological properties relative to Taxotere®. Comparative studies of the two formulations, which are listed in Table 2, have been sponsored by Hospira to examine the comparability of the extent of release of docetaxel from micelles, the extent of binding to plasma proteins, and pharmacokinetic properties in a Beagle dog study. The results of these studies demonstrated that Hospira’s Docetaxel Injection is comparable to Taxotere® with respect to the extent of release of docetaxel from micelles, the extent of binding to plasma proteins, and pharmacokinetics in dogs.” 150. Hospira has stated in its NDA that: “Although the proposed formulation is different from Taxotere® with respect to additional PEG 300 and citric acid, and higher levels of dehydrated alcohol, the PS 80 which is critical to micelle formation and stability (le Garrae et al., 2004), is present at the same concentration in both the proposed Docetaxel Injection and the Taxotere® premix (and therefore in the infusion solutions) ... the additional excipients present in docetaxel injection do not appear to affect the physicochemical properties of micellar structure relative to Taxotere®.” 151. The proposed labeling for Hospira’s Docetaxel Injection Product indicates that Hospira’s infusion is chemically and physically stable for up to four hours the same time that is indicated on Taxotere®’s package insert. H. Inequitable Conduct Allegations 152. During prosecution of the '512 patent, patentees did not amend pending claims 24-35 to add the “essentially free of free of ethanol” limitation. 153. Patentees represented to the Patent Office that it used “Tarr’s three-solvent system.” Patentees reported tests using only the combination of 60% pluronic L64, 30% ethanol, and 10% polysorbate 80. 154. The named inventor Fabre knew of the TAX 001 study. The named inventor Fabre knew the results of the TAX 001 study. 155. The Vidal reference, the etoposide prior art product formulation, and the teniposide prior art formulation were not disclosed to the Patent Office during prosecution of either the '512 or '561 patents. 156. The named inventors Fabre and Dupechez were aware of the Vidal reference before and during prosecution of the '512 and '561. patents. The named inventors Fabre and Dupechez were aware of the etoposide and teniposide prior art formulations before and during prosecution of the '512 and '561 patents. 157. The GV reference was not disclosed to the Patent Office during the prosecution of the applications that led to the patents-in-suit. III. DISCUSSION AND CONCLUSIONS OF LAW The court has subject matter jurisdiction over this matter pursuant to 28 U.S.C. §§ 1331, 1338, and 2201. Venue is proper in this court under 28 U.S.C. §§ 1391 and 1400(b). After having considered the entire record in this case, the substantial evidence in the record, the parties’ post-trial submissions, and the applicable law, the court concludes that: (A) claims 2 and 10 of the '561 Patent are invalid due to indefiniteness; (B) all asserted claims of the patents-in-suit are invalid due to obviousness; (C) the asserted claims are unenforceable due to inequitable conduct; (D) the asserted claims are not invalid due to double patenting; (E) the defendants’ proposed products infringe asserted claims 2, 5, and 10 of the '561 Patent and claim 33 of the '512 Patent; and (F) each of the parties Rule 52(c) motions are granted in part and denied in part. The court’s reasoning follows. A. Indefiniteness The defendants assert that several claims of the patents-in-suit are invalid due to indefiniteness. A patent claim satisfies the definiteness requirement of 35 U.S.C. § 112 if a person of ordinary skill in the art would understand the bounds of the claim when read in light of the specification. Section 112, paragraph 2, requires that the claims of a patent, “particularly point[ ] out and distinctly claim[ ] the subject matter which the applicant regards as his invention.” 35 U.S.C. § 112 (2000). “A claim is considered indefinite if it does not reasonably apprise those skilled in the art of its scope.” Microprocessor Enhancement Corp. v. Texas Instruments Inc., 520 F.3d 1367, 1374 (Fed.Cir.2008) (quoting IPXL Holdings, L.L.C. v. Amazon. com, Inc., 430 F.3d 1377, 1383-84 (Fed.Cir.2005)). 1. Claims 2 and 10 of the '561 Patent — “formed or is used to form” The defendants first assert that claims 2 and 10 of the '561 Patent are indefinite because they impermissibly mix two categories of patentable subject matter. Specifically, the defendants assert that claims 2 and 10, both of which are composition claims, impermissibly include a process limitation: “whereby said composition is used to form” for claim 2, and “whereby said therapeutic composition forms or is used to form” for claim 10. Compare '561 Patent at 3:55-56 with id. at 4:20-21 (emphasis added). The court agrees, and concludes that claims 2 and 10 are invalid due to indefiniteness. The Federal Circuit has addressed the issue of mixing different types of patentable subject matter in two fairly recent cases. In 2004, the Federal Circuit held in IPXL Holdings, L.L.C. v. Amazon.com, Inc. that when a claim impermissibly mixes two or more classes of patentable subject matter, the claim is indefinite. 430 F.3d 1377, 1383-84 (Fed.Cir.2005). The IPXL Holdings court struck down a claim reciting “a system of claim 2[including an “input means”] wherein ... the user uses the input means to either change the predicted transaction information or accept the displayed transaction type and transaction parameters.” Id. at 1384 (emphasis added). The court held that the claim was indefinite because the claim recited both an apparatus (the “system”) and a method for using that system (“the user uses the input means ... ”). The court concluded: [I]t is unclear whether infringement of claim 25 occurs when one creates a system that allows the user to change the predicted transaction information or accept the displayed transaction, or whether infringement occurs when the user actually uses the input means to change transaction information or uses the input means to accept a displayed transaction. Because claim 25 recites both a system and the method for using that system, it does not apprise a person of ordinary skill in the art of its scope, and it is invalid under section 112, paragraph 2. Id. at 1384. In 2008, however, the Federal Circuit clarified the scope of the IPXL Holdings opinion in Microprocessor Enhancement Corp. v. Texas Instruments Inc., and held that the inclusion of functional language in apparatus claims does necessarily render such claims indefinite: [T]he use of functional language in a claim may “fail ‘to provide a clear-cut indication of the scope of subject matter embraced by the claim’ and thus can be indefinite.” Claim 7 of the '593 patent, however, is clearly limited to a pipelined processor possessing the recited structure and capable of performing the recited functions, and is thus not indefinite under IPXL Holdings. 520 F.3d 1367, 1375 (Fed.Cir.2008) (emphasis in original). Thus, after the Microprocessor Enhancement Corp. decision, an apparatus claim may state that the apparatus is capable of performing particular functions. It cannot, however, include functional limitations that create ambiguity as to when the mixed subject matter claim has been infringed, as was the case in IPXL Holdings. Claims 2 and 10 of the '561 Patent are composition claims, since the claims specify that they cover “a composition” (claim 2) and “a therapeutic composition” (claim 8). The dispute is over whether the words “is used to form” or “forms or is used to form” constitute an impermissible process limitation or step. The plaintiffs assert that the disputed phrases simply define the claimed compositions and state the intended use of those compositions: Claims 2 and 10 merely define the two types of compositions discussed throughout the patent and claimed as the inventions covered by the '561 patent — stock solutions and perfusions. A composition that is used to form an injectable solution is a stock solution- — -a term the Court construed to mean a concentrated solution. A composition that forms an injectable solution is a perfusion. (D.I. 383 at 47 (emphasis in original).) Based on the evidence presented at trial, the court rejects the plaintiffs’ argument and concludes that the asserted claims are indefinite. The disputed claims suffer from precisely the lack of clarity that drove the Federal Circuit’s decision in IPXL Holdings — i.e., it is not clear when the mixed subject matter claim would be infringed. Unlike the claims that were upheld in Microprocessor Enhancement Corp., the disputed claim language in this case does not merely provide the context in which the claimed composition is intended to be used. On the contrary, by its own terms, the claimed stock solution actually forms an injectable solution or actually is used to form an injectable solution. Had the patentees wished to state that the composition was merely “capable of’ being formed into a perfusion, they could easily have said so explicitly. Indeed, the disputed claims describe the inherent properties and intended subsequent use of the resulting “injectable solution” in precisely these terms, stating that the injectable solution must be “capable of being injected without anaphylactic or alcohol intoxication manifestations ....” ('561 Patent 3:57-59.) The court concludes that the inventors did not intend for “forms or is used to form” to have the same meaning as “capable of’ appearing in the same claim. Consequently, the court concludes that the disputed phrase, which appears in claims that purport to cover only a “composition,” serves as a process limitation in each of the claims in which it appears. These claims fall squarely within the category of indefinite claims discussed in IPXL Holdings, even as that holding was limited by Microprocessor Enhancement Corp. As the court in IPXL Holdings stated, when “two separate statutory classes of invention” are impermissibly mixed, “a manufacturer or seller of the claimed apparatus would not know from the claim whether it might also be liable for contributory infringement because a buyer or user of the apparatus later performs the claimed method of using the apparatus.” IPXL Holdings, 430 F.3d at 1384 (citing Lyell, 17 U.S.P.Q.2d at 1550). That is precisely the case with claims 2 and 10. Dr. Myrdal’s testimony aptly illustrates the ambiguity as to whether additional steps beyond the creation of a suitable stock solution are necessary in order to infringe the disputed claims, and whether particular acts constitute infringement. A manufacturer who creates only a stock solution (seemingly covered by claims 2 and 10) could not know when he would be liable for infringement if the stock solution is only used to form an injectable solution (also seemingly covered by claims 2 and 10) at a later time and in a different place. Certainly, the performance of additional affirmative process steps is necessary in order for the injectable solution to be formed. In the case of both defendants’ products, the prescribing information indicates that the perfusion is only stable for four hours and thus must be administered to a patient within that time, meaning that this step is not performed until well after the defendant-manufacturers sell the stock solution. (See JTX 37 at Hospira0049062; ATX 552 at API-DOC-0000042.) Moreover, it is quite possible that the stock solution will be discarded before it is ever “used to form an injectable solution.” In such a case, it is not clear whether infringement ever occurred. (See Tr. 894:1-895:18.) The court is persuaded that other competitors and persons of ordinary skill in the art reading the disputed claims would likewise be unable to make “an accurate determination of the ‘metes and bounds’ of protection” provided. See Ex parte Lyell, 17 U.S.P.Q.2d 1548, 1550-51 (1990). The defendants’ proposed products aptly illustrate this ambiguity. Apotex’s product is sold in two separate vials, one containing docetaxel dissolved in PEG 300 (the “docetaxel vial”), and the other containing polysorbate 80, ethanol, and water (the “diluent vial”). According to the prescribing information, the docetaxel vial is to be diluted twice before it is administered to a patient: first by mixing it with the diluent vial (forming a “premix”), and then again by mixing the premix with a perfusion fluid (e.g., saline or dextrose solution) before it is infused into a patient. (See PTX 701 at 11.) It is only after the premix is formed that a “composition” exists containing docetaxel, polysorbate 80, and ethanol, as required by claims 2 and 10. Then, it is only when that “premix” is mixed with perfusion fluid that “an injectable solution which contains up to about 1 mg/ml” of docetaxel is formed. Hospira’s product, on the other hand, is sold in a single vial that can be used to make a perfusion without the need to make a premix. Like Apotex’s premix, however, Hospira’s product must be diluted with perfusion fluid presumably at a later time and in a different place, given the prescribing information before there is an injectable solution meeting the requirements of the claims. A person of ordinary skill in the art reading the patents-in-suit could not be sure at what point during these processes the infringement is complete. The natural reading of the claim language is that the infringement is only complete when the product actually “forms or is used to form” the perfusion. On the other hand, if one takes the view that the claims are analogous to those upheld in Microprocessor Enhancement Corp., then the infringement is complete when the Hospira stock solution is prepared (prior to sale) or when Apotex’s vials are combined to form the premix (presumably after sale), since those are stock solutions capable of being used to form an “injectable solution” as recited in the claims. As mentioned above, each of those steps is likely to be performed by different individuals at different times in different places. Neither the claims nor the specification provide guidance as to when direct infringement is complete. For these reasons, the court concludes that the defendants have established by clear and convincing evidence that claims 2 and 10 of the '561 Patent are indefinite. Those claims are therefore invalid under § 112 ¶ 2. 2. Claims 2, 5, and 10 of the '561 Patent — “anaphylactic manifestations” The court is not persuaded by the defendants’ remaining indefiniteness arguments. The defendants assert that the term “anaphylactic manifestations” is indefinite. The court disagrees, and finds that this term can be construed to have a definite meaning that would be readily understood by a person of ordinary skill in the art. Specifically, the court agrees with the plaintiffs that a person of ordinary skill in the art would readily interpret “anaphylactic manifestations” in the context of the patents-in-suit as a reference to the Grade 4 hypersensitivity reaction known as anaphylaxis and the symptoms associated therewith — particularly shock. (See Tr. 117:22-119:14 (discussing the various grades of hypersensitivity reactions under the NCI’s Common Toxicity Criteria, under which grade 4 is anaphylactic shock).) The term does not. extend to all symptoms (e.g., hives and bronchospasms) that are (or can be) associated with anaphylaxis, regardless of whether the patient is actually suffering from anaphylaxis itself. Rather, the term refers to those symptoms when — and only when — the patient is actually suffering from anaphylaxis. In other words, the '561 Patent requires that the formulation be capable of being injected without causing anaphylaxis and, by extension, the symptoms associated with anaphylaxis. With this reasonable construction, the term “anaphylactic manifestations” is not indefinite. B. Anticipation “[Ijnvalidity by anticipation requires that the four corners of a single[ ] prior art document describe every element of the claimed invention, either expressly or inherently.” Advanced Display Sys., Inc. v. Kent State Univ., 212 F.3d 1272, 1282 (Fed.Cir.2000). The standards for inherent disclosure were recently discussed by the Federal Circuit in Verizon Services Corp. v. Cox Fibernet Virginia, Inc., 602 F.3d 1325 (Fed.Cir.2010): “[A] prior art reference may anticipate without disclosing a feature of the claimed invention if that missing characteristic is necessarily present, or inherent, in the single anticipating reference,” However, a patent claim “cannot be anticipated by a prior art reference if the allegedly anticipatory disclosures cited as prior art are not enabled.” “The standard for what constitutes proper enablement of a prior art reference for purposes of anticipation under section 102, however, differs from the enablement standard under section 112.” It is well-settled that utility or efficacy need not be demonstrated for a reference to serve as anticipatory prior art under section 102. Id. at 1337 (internal citations omitted). Whether a prior art reference anticipates a patent claim is a question of fact. Advanced Display Sys., 212 F.3d at 1281. 1. Safety, Efficacy, Stability, and the Construction of “Perfusion” The court was not asked to construe “perfusion” at the claim construction phase, since the parties indicated in their joint claim chart that they had agreed to a construction of this term. The parties’ proposed construction of perfusion was “a solution suitable for infusion into patients including at least active pharmaceutical ingredient and an aqueous infusion fluid such as