Foreign Drug Manufacturer's Future Commercial Activity Contributorily Infringes U.S. Patent, Federal Circuit Says

Posted on September 5, 2007 by Brian Wm. Higgins

Summary:  Foreign supplier of active pharmaceutical drug to U.S. applicant seeking FDA approval to market generic Lexapro® was enjoined along with the U.S. applicant based on supplier's commercial partnership with the U.S. applicant.  Case:  Forest Laboratories, Inc. v. Ivax Pharmaceuticals, Inc., 07civ1059 (Fed. Cir. 2007) (Schall, J., dissenting-in-part).

 

     Ivax Pharmaceuticals, Inc., submitted an Abbreviated New Drug Application (ANDA) to the FDA seeking approval to market generic tablets containing escitalopram oxalate (“EO”), the active ingredient in Lexapro®.  Forest Laboratories, Inc., which owns the patent for Lexapro®, sued Ivax under the Hatch-Waxman Act, which provides that the mere filing of an ANDA is an act of infringement.  During discovery, Forest learned that part of Ivax's ANDA submission included information provided by Mumbai-based Cipla, Ltd., Ivax's alleged EO drug supplier. Cipla was joined in the lawsuit. After the parties stipulated to infringement and the district court found the patent-at-issue not invalid nor unenforceable, it included Cipla in the injunction against Ivax.

     On appeal, the Federal Circuit agreed with the district court's decision to include Cipla:

"Here, we do not know if Cipla first approached Ivax or vice versa, but the plan to manufacture, import, market, and sell the EO products described in the ANDA was undoubtedly a cooperative venture, and Cipla was to manufacture and sell infringing EO products to Ivax for resale in the United States. Under the standards for inducement which we apply to 35 U.S.C. § 271(b), Cipla has therefore actively induced the acts of Ivax that will constitute direct infringement upon approval of the ANDA, and it was thus not inappropriate for the district court to include Cipla within the scope of the injunction."

     The Federal Circuit cited Allergan, Inc. v. Alcon Labs, Inc., 324 F.3d 1322 (Fed. Cir. 2003) for the notion that merely filing an ANDA is a constructive act of infringement, and may support a cause of action for induced infringement.

     The dissent asserted that the safe harbor provision of § 271(e)(1) exempted Cipla from being enjoined with Ivax; however, the majority disagreed with that conclusion, saying:

"Cipla is providing information, and will provide material, that Ivax will use to obtain FDA approval. Up to that point, there is indeed no infringement. And, in fact, Ivax is not currently liable for infringement, as long as it is only pursuing FDA approval, not commercially manufacturing or selling the infringing product. However, just as Ivax will be liable for, and hence is being enjoined from, the commercial exploitation of [EO] when it is approved by the FDA and during the life of the patent, so should Cipla be enjoined. They are partners. Cipla would be contributing to the infringement by Ivax, so the injunction should cover both partners. It is true that, as the dissent states, § 271(e)(2) defines Ivax's filing of its ANDA as an infringement, and Cipla did not file the ANDA; however, when the question of an injunction against commercial activity arises, Cipla is as culpable, and hence entitled to be enjoined, as Ivax."

Result:  Ivax and Cipla are enjoined from infringing the patent-in-suit. 

Comments:

  • The claims that the parties stipulated to infringing included claims directed to the drug EO, a pharmaceutical formulation containing EO as an active ingredient, and methods of making the EO

  • Links to Teva Pharmaceuticals (reportedly owns Ivax), Cipla Ltd., and Forest Laboratories

Tags: , , , , , , , , , , , , , , , , , , , ,

Federal Circuit Considers FDA Research Exemption

Posted on July 30, 2007 by Brian Wm. Higgins

In Integra Lifesciences I, Ltd. v. Merck KGaA, No. 02 Civ. 1052, 1065 (Fed. Cir. 2007) (Rader, J., dissenting), the Court of Appeals for the Federal Circuit addressed the Food & Drug Administration (FDA) pharmaceutical research exemption (i.e., "safe harbor") provision under 35 U.S.C. 271(e)(1), which states that,

"It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention . . . solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products."

The research exception was intended to encourage the development of new drugs by allowing researchers to collect information for FDA submissions, such as Investigational New Drug applications, New Drug Applications, and Abbreviated New Drug Applications, without fear of liability to patent holders.

The research at issue in this case involved studies of the efficacy, mechanism of action, pharmacology, pharmacokinetics, and safety of three structurally related RGD peptides, included the following testing:

  • αvβ3 receptor binding assay (efficacy);
  • angiogenesis chick chorioallantoic membrane (CAM) assay (efficacy, mechanism of action, and pharmacokinetics);
  • angio-matrigel tests (efficacy and mechanism of action);
  • cell adhesion assay (efficacy);
  • chemotaxis assay (efficacy and mechanism of action);
  • chick embryo pharmacokinetics assay (pharmacokinetics);
  • fluorescence-activated cell sorting (FACS) analysis (mechanism of action and efficacy); and
  • rabbit pharmacokinetics assay (pharmacokinetics)

At the trial, a jury found that the research infringed Integra's patents. The district court sustained the verdict, describing the experiments as "insufficiently direct to qualify" for the FDA exemption. On appeal, a split panel of the Federal Circuit affirmed, holding that the work "was not clinical testing to supply information to the FDA, but only general biomedical research to identify new pharmaceutical compounds." At the Supreme Court, the issue on appeal was,

"[W]hether uses of patented inventions in preclinical research, the results of which are not ultimately included in a submission to the [FDA], are exempted from infringement by 35 U.S.C. 271(e)(1)."

The Supreme Court provided examples of different types of research that qualifies for the research exemption:

"At least where a drugmaker has a reasonable basis for believing that a patented compound may work, through a particular biological process, to produce a particular physiological effect, and uses the compound in research that, if successful, would be appropriate in a submission to the FDA, that use is "reasonably related" to the "development and submission of information under . . . Federal law."   * * *

"Basic scientific research on a particular compound, performed without the intent to develop a particular drug or a reasonable belief that the compound will cause the sort of physiological effect the researcher intends to induce, is surely not 'reasonably related to the development and submission of information' to the FDA."  * * *

"It does not follow from this, however, that 271(e)(1)'s exemption from infringement categorically excludes either (1) experimentation on drugs that are not ultimately the subject of an FDA submission or (2) use of patented compounds in experiments that are not ultimately submitted to the FDA."

The Supreme Court explained that the criterion of whether the experimental investigation of a patented compound is reasonably related to the development of information for submission to the FDA is established at the time of the experiment, and does not depend on the success or failure of the experimentation or actual submission of the experimental results.

Upon returning to the Federal Circuit for further consideration, the Federal Circuit concluded that all of the research work at issue was done after the initial recognition of the "particular biological process" whereby the RGD peptide blocks the cell surface receptors, and the recognition of the "particular physiological effect" of angiogenesis inhibition.

"All of the experiments charged with infringement were conducted for the purposes of determining the optimum candidate angiogenesis inhibitor and proceeding with commercial development of the selected candidate in compliance with regulatory procedures, initially using three structurally related RGD peptides."

The Federal Circuit concluded that the RGD compound experiments that were not taken to clinical trials did not become infringing when the specific drug was selected as the drug candidate for clinical trials, because studies of compounds that are not ultimately proposed for clinical trials are within the FDA exemption when there is a reasonable basis for identifying the compounds as working through a particular biological process to produce a particular physiological effect.

Comments:

  • The dissent stated that the FDA exemption covers activities that develop information that will ultimately be submitted to the FDA, not patented processes and tools beyond the scope of the "patented compounds" that the Supreme Court placed within the statutory exemption (two of the patents-at-suit were related to "research tools")

  • See related post here

  • This case raises evidentiary questions related to documenting the circumstances surrounding a researcher's initial recognition of a drug's "particular biological process" and a "particular physiological effect"
Tags: , , , , , , , , , , , , , ,

Federal Circuit Considers Pharmaceutical Research Exception, Finds No Case or Controversy

Posted on July 24, 2007 by Brian Wm. Higgins

In Benitec Australia, Ltd. v. Nucleonics, Inc., the Federal Circuit affirmed a district court’s judgment dismissing Nucleonic’s declaratory judgment counterclaims against Benitec for lack of subject matter jurisdiction after the district court granted Benitec’s motion to dismiss its infringement claims without prejudice. In reaching its decision, the Federal Circuit evaluated the standard for declaratory judgment at two time periods: (1) at the time the declaratory judgment counterclaims were initially filed, and (2) at a later time after intervening events had affected the parties’ relationship.

With regard to the first time period, the Federal Circuit noted that at the time Nucleonics filed its counterclaims for declarations of invalidity and unenforceability, Benitec’s patent infringement claims were pending. Thus, because Nucleonics had been charged with infringement of Benitec’s U.S. Patent No. 6,573,099 (which is directed to RNA-based disease therapy), there existed a case or controversy adequate to support jurisdiction at that time.

With regard to the second time period, the Federal Circuit noted that it had previously rejected the argument that subsequent events cannot divest a trial court of jurisdiction. In this case, the district court and Federal Circuit considered a number of intervening events, including:  (1) Benitec had withdrawn its infringement claims, (2) Benitec had given Nucleonics a covenant not to sue, and (3) Nucleonics was not close to filing a New Drug Application (NDA) for its RNA drug products. 

Considering point (3), the Federal Circuit commented that the Supreme Court’s Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005) “read[] expansively the pharmaceutical research exception of § 271(e)(1)”: 

“It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention…solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.” 35 U.S.C. § 271(e)(1).

In view of the Supreme Court’s decision in MedImmune, Inc. v. Genentech, Inc., 127 S. Ct. 764 (2007) (which was decided after oral arguments in this case), the Federal Circuit stated that a party seeking to base jurisdiction on the Declaratory Judgment Act bears the burden of proving that the facts alleged, "‘under all the circumstances, show that there is a substantial controversy, between the parties having adverse legal interests, of sufficient immediacy and reality to warrant the issuance of a declaratory judgment.'"  Applying that standard to the case at hand, there was no case or controversy adequate to support declaratory judgment, because:

“The parties have now both taken the position that Nucleonics’s present activities related to the human medical application of RNAi are, in light of § 271 and the Supreme Court’s decision in Merck, not infringing and cannot become infringing until after Nucleonics files a new drug application (“NDA”) with the U.S. Food and Drug Administration (“FDA”). Nucleonics does not even anticipate filing an NDA before ‘at least 2010-2012, if ever.’ Therefore, Nucleonics’s activities of developing and submitting information to the FDA related to human application of RNAi does not present a case or controversy of sufficient immediacy and reality to warrant declaratory judgment jurisdiction over the enforceability of the ’099 patent. The fact that Nucleonics may file an NDA in a few years does not provide the immediacy and reality required for a declaratory judgment.”

Comments: 

  • This case should have considerable interest to the many Maryland pharmaceutical companies that are involved in developing new drugs and that anticipate filing NDAs in the future, as well as to patent holders seeking a dialog with those companies about licensing and infringement issues. 


  • Other recent cases in which the Federal Circuit has considered the application of the standards set forth in MedImmune for determining declaratory judgment jurisdiction: Teva Pharmaceuticals USA, Inc. v. Novartis Pharmaceuticals Corp., 482 F.3d 1330 (Fed. Cir. 2007), and Sandisk Corp. v. STMicroelectronics NV, 480 F.3d 1372 (Fed. Cir. 2007).


  • Cite to slip opinion:  Benitec Australia, Ltd. v. Nucleonics, Inc., No. 06 Civ 1122 (Fed. Cir. July 20, 2007) (Dyk, J., dissenting)


  • Others commenting on this case:  Patently-O and 271 Blog
Tags: , , , , , , , , ,