AVENTIS PHARMA S.A. v. HOSPIRA, INC. (D.Del. 9-27-2010)

The defendants' infringement defenses fall into four categories. First, they assert that their proposed products are not "capable of being injected without anaphylactic . . . manifestations," as required by all three asserted claims of the `561 patent. Second, the defendants assert that their proposed products do not meet the "consisting essentially of" requirement for claims 2 and 10 of the `561 patent because their products contain PEG 300. Third, Apotex asserts that its proposed product is not "dissolved in" polysorbate 80 or ethanol. Lastly, both defendants assert that their proposed products are not "essentially free of ethanol," as required by asserted claim 7 of the `512 patent. For the reasons that follow, the court rejects the first three of these arguments and concludes that the defendants' products would infringe all of the asserted claims of the `561 Patent as well as claim 33 of the `512 Patent. Apotex further asserts that the plaintiffs have failed to meet their burden of showing infringement under § 271(b). The court rejects this argument as well. The court concludes that the defendants' products are not, however, "essentially free of ethanol" as required by asserted claim 7 of the '512 Patent.

The court interprets the "forms" and "is used to form" language in the `561 Patent in the manner discussed in section III.A.1, supra — i.e., that it refers to actually using the claimed stock solutions to form perfusions, and not merely to stock solutions that are capable of being used to form perfusions. Consequently, for the asserted claims of the `561 Patent, the defendants' infringement liability is premised on inducement to infringe under § 271(b) and contributory infringement under § 271(c), since their proposed stock solutions would not actually be used to form perfusions until after they are sold. Apotex asserts that the plaintiffs have failed to demonstrate inducement to infringe under § 271(b), since the plaintiffs failed to show a specific intent to induce infringement. The court disagrees.

Where the act of infringement is the filing of a B2 application, the infringement analysis is hypothetical, comparing the asserted claims against the product that is likely to be sold should the FDA approve the application. Bayer AG v. Elan Pharm. Research Corp., 212 F.3d 1241, 1248-49 (Fed. Cir. 2000). In Hatch-Waxman cases, "[s]tatements in a package insert that encourage infringing use of a drug product are alone sufficient to establish intent to encourage direct infringement" within the meaning of 35 U.S.C. § 271(b). AbraxisBioscience, Inc. v. Navinta, LLC, 640 F. Supp. 2d 553, 570-71 (D.N.J. 2009). See also 3M Co. v. Chemque, Inc., 303 F.3d 1294, 1305 (Fed. Cir. 2002) (defendant who is aware of a patent and supplies a product to a customer with instructions for use, which when followed lead to infringement, has encouraged acts constituting direct infringement). In order to establish liability for "contributory infringement" under 35 U.S.C. § 271(c), "in addition to proving an act of direct infringement, the plaintiff must show that defendant knew that the combination for which its components were especially made was both patented and infringing, and that the defendant's components have no substantial non-infringing uses." Lucent Techs., Inc. v. Gateway, Inc., 580 F.3d 1301, 1320 (Fed. Cir. 2009) (internal quotation and citation omitted).

In this case, both defendants have filed B2 applications with the FDA seeking approval to market generic docetaxel intravenous infusion products. ( See Findings of Fact ¶¶ 53, 58.) Both defendants' products are labeled for "intravenous use only," (PTX 503 at Hospira0152578; ATX 552 at API-DOC-0000042), and both will be sold accompanied by prescribing information instructing physicians and pharmacists to prepare perfusions from the defendants' products in accordance with the prescribing information. (JTX 37 at Hospira0049062; ATX 552 at API-DOC-0000025; ATX 552 at API-DOC-0000042.) The sole lawful and intended use for the defendants' products is the preparation of such perfusions for the treatment of cancer; there is no other substantial non-infringing use. ( See JTX 37 at Hospira0049158; ATX 552 at API-DOC-0000013-14. See also Tr. 1201:1-4 (discussing how a person of ordinary skill in the art "would know what the stock solution" described in the GV reference "is going to be used for").) Accordingly, if the perfusions made from the defendants' products in accordance with the accompanying prescribing information would infringe the asserted claims, then the defendants' B2 applications indirectly infringe under both inducement and contributory infringement theories. For the reasons discussed below, the court finds that they would directly infringe claims 2, 5, and 10 of the `561 Patent and claim 33 of the `512 Patent, but that they would not infringe claim 7 of the `512 Patent.

The defendants argue that their product is not "capable of being injected without anaphylactic . . . manifestations" as required by the asserted claims of the `561 Patent. In support of this assertion, the defendants note that clinical data indicates that 14% of patients administered their products will, as with Taxotere, experience some of the symptoms associated with anaphylaxis. ( See D.I. 378 at 46.) As the court explained in its indefiniteness analysis, however, the term "anaphylactic manifestations" does not extend to all symptoms that are associated with anaphylaxis. Rather, the term refers to those symptoms in the narrower context of patients who are actually suffering from anaphylaxis, a Grade 4 hypersensitivity reaction. ( See section III.A.2, supra. See also Tr. 116:20-119:14.) Thus, the court rejects the defendants argument that some of the patients in question exhibit "anaphylactic manifestations" simply because they experience some of the "multiple symptoms" associated with anaphylaxis.

The defendants also argue that their drugs do not meet this limitation because "[g]iven the tens of thousands of Taxotere patients, there is certainty that Defendants' products will cause severe hypersensitivity, specifically including anaphylaxis" in at least some patients — however few in number. (D.I. 378 at 46.) In support of this argument, the defendants note that the "[d]efendants' products will still cause anaphylaxis in at least 0.6% of patients," which "works out to about 1 in 170 patients." (Id.) This argument misapprehends the court's claim construction order. The court construed the term "capable of being injected without anaphylactic or alcohol intoxication manifestations" to mean "having a reasonable expectation of being injected without causing anaphylactic or alcohol intoxication manifestations." (D.I. 347 at 3 (emphasis added).) Under the defendants' argument, a drug does not have a "reasonable expectation" of avoiding anaphylactic manifestations unless that drug never causes those manifestations. If the court were to accept this argument, the term "reasonable expectation" in its construction would be rendered virtually meaningless.

The court's construction refers not to whether the formulation will ever cause anaphylaxis, but rather whether it can be injected into an individual patient with a reasonable expectation that it will not cause anaphylaxis. The defendants do not appear to dispute the plaintiffs' assertion that anaphylaxis will occur in the defendants' products, as with Taxotere, only rarely. ( See D.I. 378 at 40-42, 46-47.) Indeed, the defendants appear to concede that with premedication, the incidence of anaphylaxis with their products will be less than 1% ( See id. at 41, 46), which is consistent with the evidence presented at trial. The court concludes that this is sufficient to constitute a reasonable expectation that the defendants' products can be injected without anaphylactic manifestations.

The defendants argue that their products do not meet the "consisting essentially of" limitation for claims 2 and 10 of the `561 Patent because the inclusion of PEG 300 alters the basic and novel properties of the invention in two ways: 1) by increasing the solutions' stability; and 2) by adding a third solvent. When a claim includes the transition phrase "consisting essentially of," adding ingredients that "materially affect the basic and novel properties of the invention" avoids infringement. E.g., AK Steel Corp. v. Sollac Ugine, 344 F.3d 1234, 1239 (Fed. Cir. 2003). Both the plaintiffs and the defendants attempt to thread a needle with respect to their arguments on the degree to which stability is a basic and novel property of the asserted claims. The defendants argue that both physical and chemical stability are basic and novel properties of the claims even though, as they themselves assert in their argument on the construction of "perfusion," stability is mentioned nowhere in the claims. The plaintiffs assert that physical stability is a basic and novel property of the claims, but that chemical stability is not. The plaintiffs also assert that a physical stability of at least eight hours is all that is required; once that threshold level of stability is met, the plaintiffs assert, it is irrelevant whether physical stability is improved further.

The court is not persuaded by either party's arguments, and concludes that neither physical nor chemical stability is a basic and novel property of the claims. As discussed above ( See section III.B.1), the court rejects the plaintiffs' attempt to shoehorn a stability limitation into the claims. Certainly, such a limitation cannot be read into claims 2 and 10, since those claims do not include the term "perfusion," which the plaintiffs cite as the basis for a stability limitation. The claims require only that the docetaxel be "dissolved" in polysorbate 80 and (in the case of the `561 Patent) ethanol. Once this dissolution occurs, the claims require nothing in terms of the composition's stability. Thus, stability is not required in the claims, and certainly is not discussed in the patents as a novel characteristic of the alleged invention. The court concludes from the evidence presented at trial that neither physical nor chemical stability is a basic or novel property of the claims. Consequently, the enhanced stability of the defendants' products is irrelevant to the infringement analysis.

The defendants also argue that their proposed products' use of a three-solvent system alters the basic and novel properties of the invention. During the prosecution of the `561 Patent, the applicants distinguished the Tarr reference in a Request for Consideration by stating:

Present claim 1, as written, "consists essentially of" a two-solvent system. For Tarr to render the present claims obvious, the addition of the solvent pluronic L64 would have to not "materially affect the basic and novel characteristics of the claimed composition." However, pluronic L64 constitutes 60% of the solvent system, a considerable percentage.

(JTX 59 at JA1426.) The plaintiffs argue, however, that the defendants' reliance on this statement is misplaced, stating that the "[a]pplicants distinguished the invention from Tarr because it, like both accused products, uses polysorbate as the sole surfactant." (D.I. 383 at 46.) The plaintiffs cite the examiner's statement in allowing the claims that " carriers having similar characteristics as pluronic L64 are excluded from the claims." ( See JTX 4 at SA13141 (emphasis added).)

The court agrees with the plaintiffs that the prosecution history does not support excluding all three-solvent systems from the claims, but only those systems where the third solvent (i.e., besides polysorbate 80 and ethanol) is a surfactant. In other words, the court concludes that the use of polysorbate 80 as the sole surfactant is a basic and novel property of the invention, but that the presence of only two solvents is not. Since the defendants do not contend that PEG 300 acts as a surfactant in their products — only that it acts as an additional solvent — the court concludes that its presence does not alter the basic or novel properties of the invention.

Apotex contends that because its product used PEG 300 to "liquefy" docetaxel before polysorbate 80, it cannot meet the limitation requiring the docetaxel to be "dissolved in" either polysorbate 80 (in both asserted claims of the `512 Patent) or a mixture of polysorbate 80 and ethanol (in claims 2 and 10 of the `561 Patent). The examples and embodiments set forth in the '512 patent, however, teach that a composition according to the invention can be created by first

"dissolving" the docetaxel in ethanol, and only then adding the surfactant to the mixture. E.g., '512 Patent at 4:33-34 (Examples 1-7: "Taxotere (32 g) is dissolved in absolute ethanol (340 ml) and Polysorbate 80 (830 g) is then added"). The specification of the `561 Patent similarly states that the docetaxel is dissolved in ethanol prior to the incorporation of polysorbate 80. E.g., '561 Patent at 2:18-19. Thus, Apotex's reading of "dissolved" would run contrary to the specifications of the patents-in-suit and would exclude nearly all of the preferred embodiments. See, e.g., Anchor Wall Sys., Inc. v. Rockwood Retaining Walls, Inc., 340 F.3d 1298, 1308 (Fed. Cir. 2003) ("it is axiomatic that a claim construction that excludes a preferred embodiment . . . `is rarely, if ever correct and would require highly persuasive evidentiary support.'"). Consequently, the fact that Apotex uses PEG 300 to initially dissolve the docetaxel does not take their product outside the scope of the asserted claims.

The final issue with respect to infringement is whether the defendants' products are "essentially free of ethanol," a limitation that appears in only one of the five asserted claims. In its claim construction order, the court explicitly rejected the plaintiffs' proposed claim construction and adopted a version of Hospira's construction. For a stock solution, the court construed "essentially free of ethanol" to mean "no more than 5% ethanol by volume." (D.I. 347 at 2.) For a perfusion, Hospira initially proposed that the court construe the term to mean "made from a stock solution having no more than 5% ethanol by volume." At the Markman hearing, Hospira's counsel clarified that this proposed construction was not meant to introduce a method step, as one could imply from the words "made from," but rather to reflect that "the perfusion has the same amount of ethanol as the corresponding stock solution." ( See D.I. 140 at 49-50.) The court's ultimate construction of the term, "the same amount of ethanol as a stock solution with no more than 5% ethanol by volume," reflects this understanding of the term.

There is no dispute that a perfusion, as that term relates to both of the patents-in-suit, is formed by diluting a stock solution with an aqueous perfusion fluid. The language of the `561 Patent makes this clear in the claims themselves by stating that the stock solution "forms" or "is used to form" an injectable solution — i.e., a perfusion. The plaintiffs do not contend that the '512 Patent contemplates a different definition of perfusions, nor could they since both the abstract and the specification of the `512 Patent itself demonstrate that the perfusions described therein are formed from stock solutions containing the recited ingredients. Since the relevant perfusion fluids are ethanol free, each perfusion covered by claim 7 has, at most, the same amount of ethanol as the stock solution from which it was prepared. To define what qualifies as "too much" ethanol for this purpose, the `512 patent specifies a percentage of ethanol in the stock solution. ( See Tr. 885:12-887:4; JTX 1, `512 patent, at 3:28-30.) Once the stock solution is prepared, what amount of ethanol is "too much" does not change when that stock solution is diluted in the perfusion fluid. In short, the `512 Patent defines the maximum allowable amount of ethanol by the percentage of ethanol in the stock solution (5%, as the court adopted in its claim construction order); if there is too much ethanol in the stock solution, the same amount must be too much in the corresponding perfusion. (Tr. 875:1-876:24.)

Hospira's stock solution has 23% ethanol, which means it is not "essentially free of ethanol." Hospira's perfusion would have, by definition, the same amount of ethanol as the stock solution from which it was prepared. Consequently, the perfusion is not essentially free of ethanol and does not infringe claim 7. Similarly, Apotex's premix has 6.3% ethanol. Assuming that Apotex's premix is a stock solution as Sanofi contends, this stock solution contains greater than 5% ethanol and thus is not "essentially free of ethanol." Consequently, a perfusion made from the premix and thus containing the same amount of ethanol also is not "essentially free of ethanol." As Dr. Myrdal explained, this reading of the claims is consistent with the stated purpose of the ethanol limitation, which is to avoid alcohol intoxication manifestations. (Tr. 888:16-889:21; JTX 1, `512 patent, at 3:9-30.)

The plaintiffs urge the court to adopt a formula where the cutoff for "essentially free" with respect to an accused product would be based on a comparison with a stock solution that appears nowhere in the `512 Patent, but rather is derived from an example in the prior art `470 Patent. Specifically, the plaintiffs seized upon an example stock solution from the `470 Patent that the defendants' experts used in their invalidity analysis, trumpeted that stock solution as one that the parties "agreed" was essentially free of ethanol, and used that stock solution to "define the maximum level at which a stock solution (and therefore, a perfusion with the same amount of ethanol) could be essentially free of ethanol." ( See D.I. 383 at 48-49.) This argument is unavailing. As with their arguments concerning the proposed construction of "perfusion," the plaintiffs overlook the fact that purported "agreements" between the parties are not binding on the court. In this case, the court certainly would not use an example of a stock solution in a prior art patent to define the maximum allowable concentration of ethanol in a perfusion under the '512 Patent. After all, if the `470 patent example happened to recite a different concentration — or if the defendants' experts had chosen a different example to use in their invalidity analysis — the plaintiffs' definition of "essentially free" would change. The definition of a claim term cannot be subject to the changing winds of which prior art examples the parties' experts choose to use.

The plaintiffs note that under the court's interpretation of "essentially free," one perfusion with a particular amount of ethanol might be "essentially free" while a different perfusion with the same amount of ethanol is not "essentially free." (Tr. 883:24-885:3; Tr. 712:15-24.) That is true, depending on whether the corresponding stock solution is "essentially free." (Tr. 884:16-886:5.) However anomalous that result, it is dictated by the fact that the `512 Patent, and thus the court's claim construction, defines "essentially free" by the percentage of ethanol in the stock solution. ( See, e.g., Tr. 886:21-887:4.) If that percentage is below 5%, the maximum concentration supported by the specification and file history of the patents-in-suit, then the stock solution is essentially free of ethanol. By extension, any perfusion formed from such a stock solution would be essentially free of ethanol, since the perfusion would contain no more ethanol than was in the stock solution. Since both of the defendants' proposed stock solutions are essentially free of ethanol, their perfusions are as well. Consequently, the defendants' proposed products do not infringe claim 7 of the `512 Patent.

The plaintiffs filed a motion for judgment on partial findings pursuant to Rule 52(c) of the Federal Rules of Civil Procedure. In it, they contend that they proved infringement of claim 5 of the `561 Patent and claim 33 of the `512 Patent, and that the defendants failed to prove inequitable conduct. For the reasons stated in section III.F, the court agrees with the plaintiffs that they met their burden on proving infringement for claim 5 of the `561 Patent and claim 33 of the `512 Patent. For the reasons stated in III.E, however, the court concludes that the defendants easily met their burden of proving inequitable conduct. The court will therefore grant in part and deny in part the plaintiffs' Rule 52(c) motion.

Each of the defendants also filed a Rule 52(c) motion. Hospira's motion urges the court to conclude that their proposed product does not infringe because it does not meet the "consisting essentially of" (claims 2 and 10), "without anaphylactic manifestations" (claims 2, 5, and 10), and "essentially free of ethanol" (claim 7) limitations in the asserted claims. Apotex urges non-infringement on the same three grounds, and also asserts that their product does not meet the "dissolved" limitation (all claims except claim 5) and that the plaintiffs have not shown inducement to infringe. For the reasons stated in section III.F, the court rejects the defendants' arguments with respect to inducement to infringe and the "consisting essentially of," "without anaphylactic manifestations," and "dissolved" limitations. The court agrees, however, that their products are not "essentially free of ethanol." Consequently, the court will grant in part and deny in part each of their Rule 52(c) motions.

For the reasons stated above, 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. An appropriate order will follow.

At Wilmington, this 27^th day of September, 2010, IT IS HEREBY ORDERED THAT: 1. The asserted claims of the patents-in-suit are invalid due to obviousness. 2. Asserted claims 2 and 10 of the `561 Patent are invalid due to indefiniteness. 3. The asserted claims of the patents-in-suit are unenforceable due to inequitable conduct. 4. Hospira's Rule 52(c) motion (D.I. 362) is GRANTED IN PART AND DENIED IN PART. 5. Apotex's Rule 52(c) motion (D.I. 363) is GRANTED IN PART AND DENIED IN PART. 6. The plaintiffs' Rule 52(c) motion (D.I. 364) is GRANTED IN PART AND DENIED IN PART. 7. The defendants' motion for leave to file a reply and objections to new exhibits (D.I. 385) are DENIED AS MOOT. 8. The Clerk of Court is directed to enter judgment in favor of the defendants and against the plaintiffs.