DCT

2:15-cv-08132

Helsinn Healthcare SA v. Qilu Pharmaceutical Co Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: Helsinn Healthcare S.A. v. Qilu Pharmaceutical Co., Ltd., 2:15-cv-08132, D.N.J., 11/17/2015
  • Venue Allegations: Venue is alleged based on Defendants' business activities, registration of a corporate agent, and acts of infringement within New Jersey, including the sending of Abbreviated New Drug Application (ANDA) notice letters into the district.
  • Core Dispute: Plaintiffs allege that Defendants’ filing of an ANDA seeking FDA approval to market generic versions of Plaintiffs’ Aloxi® intravenous solution constitutes an act of patent infringement under the Hatch-Waxman Act.
  • Technical Context: The technology concerns shelf-stable liquid pharmaceutical formulations of palonosetron, an anti-emetic used to prevent nausea and vomiting induced by cancer chemotherapy and radiotherapy.
  • Key Procedural History: The patents-in-suit are listed in the U.S. Food and Drug Administration’s "Orange Book" as covering Plaintiffs’ Aloxi® product. Defendants filed ANDA No. 20-5648, which included a "Paragraph IV certification" alleging that the asserted patents are invalid. This certification triggered the current litigation. The complaint notes extensive prior litigation by Plaintiffs to enforce this patent portfolio against other generic drug manufacturers.

Case Timeline

Date Event
2003-01-30 Earliest Priority Date for all Patents-in-Suit
2011-05-24 U.S. Patent No. 7,947,724 Issued
2014-05-20 U.S. Patent No. 8,729,094 Issued
2015-06-30 U.S. Patent No. 9,066,980 Issued
2015-10-19 Defendants Sent ANDA Notice Letters
2015-10-26 Plaintiffs Received ANDA Notice Letters
2015-11-03 U.S. Patent No. 9,173,942 Issued
2015-11-17 Complaint Filed

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 7,947,724 - Liquid Pharmaceutical Formulations of Palonosetron

  • Patent Identification: U.S. Patent No. 7,947,724, Liquid Pharmaceutical Formulations of Palonosetron, issued May 24, 2011.

The Invention Explained

  • Problem Addressed: The patent’s background section describes the difficulty in creating a liquid formulation of the potent anti-emetic drug palonosetron with sufficient shelf-life stability. An earlier formulation was described as having a shelf stability of less than the one-to-two-year period required by health authorities, necessitating improved solutions for commercial viability (’724 Patent, col. 2:1-4).
  • The Patented Solution: The invention provides a shelf-stable aqueous formulation of palonosetron by controlling a combination of factors: buffering the solution to a specific pH range (4.0 to 6.0), and including a chelating agent (like EDTA) and a tonicifying agent (like mannitol) (’724 Patent, Abstract; col. 5:1-21, 50-65). This combination is described as creating a formulation that can be stored for over 24 months at room temperature and allows for terminal sterilization, a preferred manufacturing process (’724 Patent, col. 2:58-62).
  • Technical Importance: This approach enables a ready-to-use, injectable version of a highly effective anti-emetic that does not require refrigeration or reconstitution, simplifying its use in clinical settings (’724 Patent, col. 2:58-62).

Key Claims at a Glance

  • The complaint generally asserts the patent’s claims, with Claim 1 being a representative independent claim (Compl. ¶24).
  • Claim 1 requires:
    • A pharmaceutically stable intravenous solution for reducing emesis.
    • Comprising palonosetron (or a salt) at a concentration of 0.03 mg/ml to 0.2 mg/ml.
    • The solution is buffered to a pH of 4.0 to 6.0.
    • The solution includes a sterile aqueous carrier containing a "tonicifying effective amount of mannitol" and EDTA at a concentration of 0.005 mg/ml to 1.0 mg/ml.

U.S. Patent No. 8,729,094 - Liquid Pharmaceutical Formulations of Palonosetron

  • Patent Identification: U.S. Patent No. 8,729,094, Liquid Pharmaceutical Formulations of Palonosetron, issued May 20, 2014.

The Invention Explained

  • Problem Addressed: As with the ’724 Patent, this patent addresses the need for a palonosetron formulation with increased stability and shelf life suitable for commercial pharmaceutical products (’094 Patent, col. 2:45-47).
  • The Patented Solution: This patent claims methods of using a specific, stable formulation of palonosetron to reduce the likelihood of chemotherapy-induced nausea and vomiting. The claimed method involves administering a single-use, 5 mL unit-dose solution containing specific concentrations of palonosetron hydrochloride, mannitol, EDTA, and a citrate buffer, buffered to a pH of about 5.0, before the start of cancer chemotherapy (’094 Patent, Abstract; Claim 1).
  • Technical Importance: The invention claims a specific, optimized method of administering a ready-to-use, stable palonosetron formulation, providing clinicians with a precise, pre-packaged treatment protocol for preventing a major side effect of chemotherapy (’094 Patent, col. 2:18-24).

Key Claims at a Glance

  • The complaint generally asserts the patent’s claims, with Claim 1 being a representative independent claim (Compl. ¶32).
  • Claim 1 requires:
    • A method for reducing the likelihood of cancer chemotherapy-induced nausea and vomiting.
    • Comprising intravenously administering a single-use, 5 mL sterile aqueous isotonic solution.
    • The solution is buffered at a pH of about 5.0±0.5 and contains about 0.05 mg/mL palonosetron hydrochloride, about 41.5 mg/mL mannitol, about 0.5 mg/mL EDTA, and a citrate buffer.
    • The formulation is stable for 24 months at room temperature.
    • Administration occurs before the start of cancer chemotherapy.

Multi-Patent Capsule: U.S. Patent No. 9,066,980 - Liquid Pharmaceutical Formulations of Palonosetron

  • Patent Identification: U.S. Patent No. 9,066,980, Liquid Pharmaceutical Formulations of Palonosetron, issued June 30, 2015.
  • Technology Synopsis: Belonging to the same patent family, the ’980 patent claims specific, single-use, unit-dose formulations of palonosetron designed for long-term stability. The invention addresses the need for a commercially viable liquid formulation by claiming an isotonic solution containing palonosetron, a tonicifying agent, and optionally a chelating agent, stable for at least 24 months at room temperature (’980 Patent, Abstract; Claim 1).
  • Asserted Claims: The complaint generally asserts the claims of the ’980 Patent (Compl. ¶40).
  • Accused Features: The accused act is Defendants' filing of ANDA No. 20-5648 seeking to market generic palonosetron intravenous solutions that are alleged to be covered by the claims of the ’980 Patent (Compl. ¶¶39, 41).

Multi-Patent Capsule: U.S. Patent No. 9,173,942 - Liquid Pharmaceutical Formulations of Palonosetron

  • Patent Identification: U.S. Patent No. 9,173,942, Liquid Pharmaceutical Formulations of Palonosetron, issued November 3, 2015.
  • Technology Synopsis: This patent, also from the same family, claims specific stable aqueous intravenous formulations of palonosetron. The claimed solution includes palonosetron hydrochloride, mannitol within a specified concentration range, and a chelating agent, with the solution having a pH between 4.0 and 6.0, addressing the technical problem of creating a long-term, room-temperature stable injectable product (’942 Patent, Abstract; Claim 1).
  • Asserted Claims: The complaint generally asserts the claims of the ’942 Patent (Compl. ¶¶49-51).
  • Accused Features: Defendants are accused of infringement by continuing to seek approval of ANDA No. 20-5648 after the ’942 patent issued. The complaint alleges that the law requires Defendants to certify against this patent and that their continued pursuit of FDA approval for their generic palonosetron solutions constitutes infringement (Compl. ¶¶47-51).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are the proposed generic 0.25 mg / 5 mL and 0.075 mg / 1.5 mL palonosetron hydrochloride intravenous solutions for which Defendants filed ANDA No. 20-5648 with the FDA (Compl. ¶13).

Functionality and Market Context

The products are intended as generic equivalents of Plaintiffs’ Aloxi® brand palonosetron hydrochloride intravenous solutions (Compl. ¶23). Their function is to prevent nausea and vomiting associated with medical treatments like chemotherapy (Compl. ¶23; ’724 Patent, col. 1:11-14). The complaint alleges that Defendants seek approval to engage in the commercial manufacture, use, and sale of these generic solutions in the United States prior to the expiration of the patents-in-suit (Compl. ¶13).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint alleges infringement under 35 U.S.C. § 271(e)(2)(A), which defines the submission of an ANDA seeking approval to market a generic drug before patent expiration as a statutory act of infringement (Compl. ¶¶25, 33, 41, 51). The complaint does not contain specific factual details or a claim chart comparing the proposed generic formulation to the patent claims. The infringement theory is predicated on the assertion that the product described in the ANDA, if approved and marketed, would meet the limitations of the asserted claims.

’724 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutically stable intravenous solution for reducing emesis... The complaint alleges Defendants seek to market an intravenous solution of palonosetron hydrochloride, a generic version of Aloxi®, which is used for reducing emesis. ¶¶13, 23 col. 1:11-14
comprising: a) from 0.03 mg/ml to 0.2 mg/ml palonosetron or a pharmaceutically acceptable salt thereof... The accused 0.25 mg / 5 mL product contains palonosetron hydrochloride at a concentration of 0.05 mg/mL, which is within the claimed range. ¶13 col. 5:40-44
...buffered at a pH of from 4.0 to 6.0 The complaint does not provide sufficient detail for analysis of this element. col. 5:8-10
and b) a pharmaceutically acceptable sterile aqueous carrier including a tonicifying effective amount of mannitol and from 0.005 mg/ml to 1.0 mg/ml EDTA. The complaint does not provide sufficient detail for analysis of this element. col. 5:50-65

’094 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for reducing the likelihood of cancer chemotherapy-induced nausea and vomiting, comprising intravenously administering to a human...a pharmaceutical...formulation The complaint alleges Defendants seek approval to market a generic version of Aloxi®, which is indicated for this use, thereby infringing the patented method. ¶¶21, 31 col. 2:18-24
...a 5 mL sterile aqueous isotonic solution buffered at a pH of about 5.0±0.5, said solution comprising: about 0.05 mg/mL palonosetron hydrochloride...about 41.5 mg/mL mannitol; about 0.5 mg/mL EDTA; and a citrate buffer The complaint does not provide sufficient detail for analysis of the specific formulation (pH, mannitol, EDTA, citrate buffer) of the accused product. col. 7:48-63
wherein said formulation is stable at 24 months when stored at room temperature The complaint does not provide sufficient detail for analysis of this element. col. 6:30-34
and wherein said intravenous administration...occurs before the start of the cancer chemotherapy. The proposed label for the generic product would instruct for administration in this manner to be therapeutically equivalent to Aloxi®. ¶31 col. 2:25-28
  • Identified Points of Contention:
    • Evidentiary Questions: A central question will be factual: what is the precise formulation of the generic product described in Defendants’ ANDA? Discovery will be required to determine if its pH, excipients (mannitol, EDTA, citrate), and their concentrations fall within the scope of the asserted claims.
    • Scope Questions: Assuming the formulation is similar to that disclosed in the patents, a key legal question will concern the validity of the claims. The dispute may focus on whether the claimed combination of a specific pH range with known excipients like mannitol and EDTA to achieve long-term stability was obvious over prior art formulations of palonosetron and other 5-HT3 antagonists.

V. Key Claim Terms for Construction

  • The Term: "pharmaceutically stable" (’724 Patent, Claim 1)

  • Context and Importance: This term is central to the invention's purported advance over the prior art. The patent links stability to a shelf life of "greater than 24 months at room temperature" and the ability to undergo "terminal sterilization" (’724 Patent, col. 2:58-62). Defendants, having certified the patent as invalid, may argue this term is indefinite or that their product is not "stable" in the way the patent requires, while Plaintiffs will argue it has a clear meaning in the art and in the context of the patent.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The term is used generally in the specification, suggesting its ordinary meaning to one of skill in the art of pharmaceutical formulation (’724 Patent, col. 3:10).
    • Evidence for a Narrower Interpretation: The specification repeatedly ties stability to specific, measurable outcomes, such as a shelf life of "greater than 24 months" and suitability for "terminal sterilization processes" (’724 Patent, col. 2:58-62; col. 6:30-46). These passages may support a construction that requires these specific properties.

  • The Term: "tonicifying effective amount of mannitol" (’724 Patent, Claim 1)

  • Context and Importance: Claim 1 specifically requires mannitol as the tonicifying agent. Practitioners may focus on this term because its definition distinguishes the invention from other potential uses of mannitol (e.g., as a sweetener at higher concentrations). The infringement analysis for the ’724 Patent will require determining if the amount of mannitol in the accused product is "tonicifying effective."

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The patent does not provide an explicit numerical range for a "tonicifying effective amount" in the claims, which may support an argument that it covers any amount that achieves isotonicity.
    • Evidence for a Narrower Interpretation: The specification distinguishes the claimed use from use as a sweetener, which occurs at "concentrations in excess of 100 mg/ml or 250 mg/ml" (’724 Patent, col. 6:11-14). Example 3 identifies an "optimum level of mannitol required for an isotonic solution" as 4.15% (41.5 mg/mL), providing a specific embodiment that could be used to argue for a narrower construction around this value (’724 Patent, col. 8:41-44).

VI. Other Allegations

  • Indirect Infringement: The complaint seeks a declaration that Defendants will infringe under 35 U.S.C. § 271(b) and (c) upon commercialization of their generic product (e.g., Compl. ¶28). The basis for these future, post-approval infringement allegations is that Defendants' product label will inevitably instruct physicians and other healthcare providers to administer the drug for the patented methods of use, thereby inducing infringement. The complaint alleges Defendants' "active and knowing participation in, contribution to, aiding, abetting, and/or inducement" through the ANDA submission process (Compl. ¶27).

VII. Analyst’s Conclusion: Key Questions for the Case

  1. A primary issue will be one of validity based on obviousness: Was it obvious to a person of ordinary skill in the art of pharmaceutical formulation to combine a specific pH range (e.g., 4.0-6.0) with a chelating agent (EDTA) and a specific tonicifying agent (mannitol) to achieve the claimed long-term, room-temperature stability for a palonosetron intravenous solution?
  2. A second core issue will be one of factual correspondence: Once the formulation of the accused generic product is revealed in discovery, does it contain every element recited in the asserted claims? Any differences in pH, excipient choice, or concentration will create a significant dispute over the literal scope of the claims and the doctrine of equivalents.
  3. A third question relates to the method of use claims: Does the proposed product label in Defendants’ ANDA instruct administration in a manner that meets all steps of the asserted method claims, such as the timing of administration relative to chemotherapy, creating liability for induced infringement?