DCT

1:16-cv-00669

AstraZeneca Pharma LP v. Mylan Institutional LLC

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:16-cv-00669, D. Del., 08/05/2016
  • Venue Allegations: Venue is alleged to be proper as Defendant is a Delaware limited liability company that conducts business in the district.
  • Core Dispute: Plaintiff alleges that Defendant's Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's FASLODEX® (fulvestrant) injection product infringes four patents directed to specific long-acting pharmaceutical formulations of fulvestrant.
  • Technical Context: The technology addresses the challenge of creating a stable, long-acting injectable formulation for the anti-cancer drug fulvestrant, which is highly effective but has extremely low aqueous solubility.
  • Key Procedural History: The complaint states that this action is a "protective suit" filed to preserve Plaintiff's rights under the Hatch-Waxman Act. It was filed shortly after a nearly identical action was initiated in the District of New Jersey, suggesting Plaintiff anticipates a potential jurisdictional challenge by Defendant in that district and is securing an alternative venue. The complaint also notes several other related litigations against different generic manufacturers concerning the same patents and product.

Case Timeline

Date Event
2000-01-10 Earliest Priority Date for ’122, ’160, ’680, ’139 Patents
2004-08-10 U.S. Patent No. 6,774,122 Issues
2008-11-25 U.S. Patent No. 7,456,160 Issues
2012-12-11 U.S. Patent No. 8,329,680 Issues
2013-06-18 U.S. Patent No. 8,466,139 Issues
2016-06-27 Date of Defendant's Notice Letter regarding ANDA No. 208811
2016-07-29 AstraZeneca files related complaint in D.N.J.
2016-08-05 Complaint Filed in D. Del.

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

U.S. Patent No. 6,774,122 - “Formulation”

Issued August 10, 2004

The Invention Explained

  • Problem Addressed: The patent addresses the difficulty of formulating the anti-cancer drug fulvestrant for injection. Fulvestrant is described as a "particularly lipophilic molecule" with "extremely low" aqueous solubility, which makes it difficult to create a solution concentrated enough to be administered in a small, clinically acceptable injection volume for sustained release (’122 Patent, col. 2:50-58).
  • The Patented Solution: The invention is a pharmaceutical formulation that overcomes this solubility problem by dissolving fulvestrant in a specific combination of solvents: a ricinoleate vehicle (castor oil), at least one alcohol, and a non-aqueous ester solvent miscible in the vehicle (’122 Patent, Abstract; col. 6:46-51). The patent explains that this combination "surprisingly eases the solubilisation of fulvestrant" to a high concentration, which was not achievable with an oil-based solvent alone (’122 Patent, col. 6:49-51).
  • Technical Importance: This formulation enabled the creation of a long-acting "depot" injection of fulvestrant, allowing for a therapeutically effective dose to be administered in a single, low-volume intramuscular injection that releases the drug over several weeks (’122 Patent, col. 2:35-41).

Key Claims at a Glance

  • The complaint asserts independent claim 1 and dependent claims 2-5 and 9 (Compl. ¶32).
  • The essential elements of independent claim 1 are:
    • A method of treating a hormonal dependent disease of the breast or reproductive tract.
    • Administering by intra-muscular injection a formulation comprising fulvestrant.
    • The formulation contains a mixture of 10% w/v ethanol, 10% w/v benzyl alcohol, and 15% w/v benzyl benzoate.
    • The formulation also contains a sufficient amount of a castor oil vehicle.
    • The method results in a therapeutically significant blood plasma fulvestrant concentration of at least 2.5 ngml⁻¹ for at least 2 weeks after injection.

U.S. Patent No. 7,456,160 - “Formulation”

Issued November 25, 2008

The Invention Explained

  • Problem Addressed: As a continuation of the ’122 Patent, the ’160 Patent addresses the same technical problem of formulating the highly insoluble drug fulvestrant into a high-concentration, injectable solution for sustained release (’160 Patent, col. 2:48-56).
  • The Patented Solution: The patent claims a solution similar to that of the ’122 Patent, involving a formulation of fulvestrant in a ricinoleate vehicle, a mixture of alcohols, and a non-aqueous ester solvent. The claims of the ’160 Patent cover different and, in some cases, broader ranges of the excipients compared to the claims of the parent patent (’160 Patent, col. 6:46-51, claims 1-4).
  • Technical Importance: This patent broadened the proprietary scope around the successful formulation, protecting variations of the excipient concentrations while achieving the same goal of a long-acting, low-volume depot injection (’160 Patent, col. 2:35-41).

Key Claims at a Glance

  • The complaint asserts dependent claim 4 (Compl. ¶46). Claim 4 depends from independent claim 1.
  • The essential elements of independent claim 1 are:
    • A method of treating a hormonal dependent disease of the breast or reproductive tract.
    • Administering by intra-muscular injection a formulation comprising fulvestrant.
    • The formulation contains a mixture of ethanol and benzyl alcohol from 10% to 30% w/v.
    • The formulation contains benzyl benzoate from 10% to 25% w/v.
    • The formulation contains a sufficient amount of a castor oil vehicle.
    • The method results in a therapeutically significant blood plasma fulvestrant concentration of at least 2.5 ngml⁻¹ for at least 2 weeks after injection.

U.S. Patent No. 8,329,680 - “Formulation”

Issued December 11, 2012

  • Technology Synopsis: Continuing the same patent family, the ’680 Patent claims a method of treating breast cancer with a long-acting fulvestrant formulation. The invention solves the drug's poor solubility by using a specific combination of castor oil, ethanol, benzyl alcohol, and benzyl benzoate to achieve a high-concentration injectable solution that maintains a therapeutic blood plasma level for at least four weeks (’680 Patent, Abstract; col. 2:48-56).
  • Asserted Claims: The complaint asserts independent claim 1 and dependent claims 2-7 and 17 (Compl. ¶60).
  • Accused Features: The entirety of Defendant's proposed generic formulation is accused, including its composition of fulvestrant, ethanol, benzyl alcohol, benzyl benzoate, and a castor oil vehicle, and its alleged resultant pharmacokinetic profile (Compl. ¶28-29).

U.S. Patent No. 8,466,139 - “Formulation”

Issued June 18, 2013

  • Technology Synopsis: As the most recent patent-in-suit in the family, the ’139 Patent further refines the claims around the fulvestrant formulation. It protects a method of treatment using a formulation with specific percentage ranges of ethanol, benzyl alcohol, and benzyl benzoate in a castor oil vehicle, which achieves a therapeutic effect for at least two weeks (’139 Patent, Abstract; col. 2:48-56). The claims use the term "consisting essentially of," potentially limiting the presence of other unlisted active ingredients.
  • Asserted Claims: The complaint asserts claims 2, 3, 10, 12, 13, and 20, which depend from independent claims 1 and 11 (Compl. ¶74).
  • Accused Features: The specific chemical composition of Defendant's proposed product, including approximately 50 mg/ml fulvestrant, 10% w/v ethanol, 10% w/v benzyl alcohol, 15% w/v benzyl benzoate, and a castor oil vehicle, is alleged to meet the limitations of the asserted claims (Compl. ¶28).

III. The Accused Instrumentality

Product Identification

  • Defendant's "Proposed ANDA Product," a generic fulvestrant injection, 50 mg/mL, which is the subject of ANDA No. 208811 (Compl. ¶10).

Functionality and Market Context

  • The accused product is a pharmaceutical formulation alleged to contain fulvestrant, 10% w/v ethanol, 10% w/v benzyl alcohol, 15% w/v benzyl benzoate, and a castor oil vehicle (Compl. ¶28).
  • The complaint alleges that the proposed generic product is a copy of AstraZeneca's FASLODEX® product and that the ANDA relies on data demonstrating the bioequivalence of the two products (Compl. ¶10, 29). This includes allegations that the product, after injection, achieves a blood plasma fulvestrant concentration of at least 2.5 ngml⁻¹ for at least 4 weeks (Compl. ¶29).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

’122 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating a hormonal dependent benign or malignant disease of the breast or reproductive tract...by administration to a human...an intra-muscular injection of a pharmaceutical formulation Defendant’s product instructions will direct administration by intramuscular injection to treat breast cancer in humans. ¶30 col. 12:56-65
comprising fulvestrant, a mixture of 10% weight of ethanol per volume of formulation, 10% weight of benzyl alcohol per volume of formulation and 15% weight of benzyl benzoate per volume of formulation The Proposed ANDA Product is a formulation comprising fulvestrant with 10% w/v ethanol, 10% w/v benzyl alcohol, and 15% w/v benzyl benzoate. ¶28 col. 12:60-63
and a sufficient amount of a castor oil vehicle The Proposed ANDA Product contains a sufficient amount of a castor oil vehicle to achieve a concentration of about 50 mgml⁻¹ of fulvestrant. ¶28 col. 12:63-64
whereby a therapeutically significant blood plasma fulvestrant concentration of at least 2.5 ngml⁻¹ is attained for at least 2 weeks after injection. The Proposed ANDA Product is alleged to be bioequivalent to FASLODEX® and to achieve a blood plasma concentration of at least 2.5 ngml⁻¹ for at least 4 weeks after injection. ¶29 col. 12:64-66

’160 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
a mixture of from 10 to 30% weight of ethanol and benzyl alcohol per volume of formulation The Proposed ANDA Product contains 10% w/v ethanol and 10% w/v benzyl alcohol, for a total alcohol content of 20% w/v, which is within the claimed 10-30% range. ¶28 col. 13:9-11
and from 10 to 25% weight of benzyl benzoate per volume of formulation The Proposed ANDA Product contains 15% w/v benzyl benzoate, which is within the claimed 10-25% range. ¶28 col. 13:11-12
and a sufficient amount of a castor oil vehicle The Proposed ANDA Product contains a castor oil vehicle. ¶28 col. 13:12-13
whereby a therapeutically significant blood plasma fulvestrant concentration of at least 2.5 ngml⁻¹ is attained for at least 2 weeks after injection. The Proposed ANDA Product is alleged to achieve a blood plasma concentration of at least 2.5 ngml⁻¹ for at least 4 weeks. ¶29 col. 13:13-16

Identified Points of Contention

  • Functional Limitation: A central question will be evidentiary: can Plaintiff prove that Defendant's product, upon administration, will necessarily achieve the pharmacokinetic profile required by the method claims (e.g., "at least 2.5 ngml⁻¹ ... for at least 2 weeks")? The complaint's allegation of bioequivalence is intended to support this, but it remains a question of fact for the court (Compl. ¶29).
  • Scope Questions: The complaint alleges that the defendant's formulation contains specific percentages of excipients (10% ethanol, 10% benzyl alcohol, 15% benzyl benzoate) that appear to fall squarely within the ranges recited in the asserted claims of the patents-in-suit. The primary dispute is therefore less likely to be about a mismatch in chemical composition and more likely to be about the validity of the patents or the resulting pharmacokinetic function.

V. Key Claim Terms for Construction

  • The Term: "therapeutically significant blood plasma fulvestrant concentration" (’122 Patent, Claim 1)

    • Context and Importance: This is a functional limitation that defines the required outcome of the method. Infringement hinges not just on the formulation's composition but on its performance in the human body. Practitioners may focus on this term because the case could turn on whether Defendant's product, despite its composition, can be proven to meet this specific pharmacokinetic threshold.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The term itself is open-ended. A party might argue that "therapeutically significant" could vary by patient or clinical context, affording some flexibility.
      • Evidence for a Narrower Interpretation: The claims themselves immediately provide a more narrow, objective definition by quantifying the limitation (e.g., "of at least 2.5 ngml⁻¹ is attained for at least 2 weeks"). The specification further supports this narrow definition by explaining that achieving such levels is a key feature of the invention that enables a long-acting depot effect (’122 Patent, col. 9:1-5).

  • The Term: "a mixture of" (’122 Patent, Claim 1)

    • Context and Importance: This term precedes the list of required excipients. Its construction is important to determine if the claim requires only the listed components or if other substances could be present. The later ’139 Patent uses the more restrictive "consisting essentially of," suggesting the patentees considered this distinction important.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: "Comprising" (used in the claim preamble) and "a mixture of" generally are interpreted in patent law to be open-ended, meaning the presence of unrecited elements does not avoid infringement. A party would argue the formulation can include other components as long as it has the required ones.
      • Evidence for a Narrower Interpretation: A party could argue that the "surprising" result of the invention arises from the specific, synergistic combination of only the listed excipients in the castor oil vehicle, as described in the specification (’122 Patent, col. 6:49-51). They might argue that adding other components could disrupt this synergy, implying a narrower scope was intended.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that Defendant will induce infringement by providing product labeling and instructions that will direct physicians and patients to administer the Proposed ANDA Product in a manner that infringes the asserted method claims (Compl. ¶30, 34). It is also alleged that there are no FDA-approved, non-infringing uses for the product (Compl. ¶30).
  • Willful Infringement: Willfulness is alleged based on Defendant's knowledge of the patents-in-suit at the time it filed its ANDA with a Paragraph IV certification, which asserts that the patents are invalid, unenforceable, or will not be infringed (Compl. ¶27, 39, 53).

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

  • A central issue will be one of evidentiary proof: The complaint alleges that the accused product’s chemical composition directly reads on the patent claims. The key question for the court will be whether AstraZeneca can prove that this composition, when administered as directed, will necessarily and consistently produce the pharmacokinetic outcomes (e.g., blood plasma levels over time) required by the functional limitations of the method claims.
  • An underlying and likely dispositive question, although not detailed in the complaint, will be one of patent validity. The core of the defense in this Hatch-Waxman litigation will likely be an assertion that the claimed formulations were obvious to a person of ordinary skill in the art, given the known solubility problems of fulvestrant and the common use of the claimed excipients in other pharmaceutical formulations.
  • A foundational legal question is whether Mylan’s submission of an ANDA for a product bioequivalent to FASLODEX®, with labeling that copies the approved method of use, is sufficient to establish infringement of the asserted method claims under 35 U.S.C. § 271(e)(2) before any commercial sale or actual use occurs.