DCT

1:17-cv-00673

Forest Laboratories LLC v. Macleods Pharma Ltd

Log In

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-00673, D. Del., 06/02/2017
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware based on Defendant Macleods Pharma USA, Inc. being a Delaware corporation and Defendant Macleods Pharmaceuticals, Ltd. having systematic and continuous contacts with the district, including through prior litigation.
  • Core Dispute: Plaintiffs allege that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA for generic versions of NAMZARIC® constitutes an act of infringement of five patents related to modified-release formulations of memantine and its combination with donepezil for treating CNS-related conditions.
  • Technical Context: The technology concerns pharmaceutical formulations for treating central nervous system disorders such as Alzheimer's disease, focusing on modified-release mechanisms to improve patient compliance and reduce side effects compared to immediate-release drugs.
  • Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of a Paragraph IV notice letter from Defendants, which asserted that the patents-in-suit are invalid and/or would not be infringed by the commercial manufacture, use, or sale of Defendants' proposed generic products.

Case Timeline

Date Event
2004-06-17 Earliest Priority Date for ’009 Patent
2005-04-06 Earliest Priority Date for ’291, ’485, ’486, ’858 Patents
2011-10-18 U.S. Patent No. 8,039,009 Issues
2011-11-15 U.S. Patent No. 8,058,291 Issues
2012-12-25 U.S. Patent No. 8,338,485 Issues
2012-12-25 U.S. Patent No. 8,338,486 Issues
2013-11-12 U.S. Patent No. 8,580,858 Issues
2017-04-19 Alleged date on or before which Defendants submitted ANDA No. 208672
2017-06-02 Complaint Filed

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

U.S. Patent No. 8,039,009 - “Modified Release Formulations Of Memantine Oral Dosage Forms”

The Invention Explained

  • Problem Addressed: The patent describes that the then-current dosing regimen for memantine required twice-a-day administration of immediate-release tablets, which could lead to decreased patient compliance and a faster rate of drug absorption, potentially increasing the frequency of adverse events (’009 Patent, col. 2:65-3:5).
  • The Patented Solution: The invention is a once-a-day, solid oral dosage form of memantine that provides a modified, sustained release of the drug over an extended period. This is achieved by incorporating memantine into a polymeric matrix, such as hydroxypropyl methylcellulose, which swells in gastric fluid and controls the rate at which the drug diffuses out of the tablet, thereby smoothing the drug's absorption profile (’009 Patent, Abstract; col. 3:10-24; col. 6:50-57).
  • Technical Importance: This technology provided a method to simplify the dosing schedule for a key Alzheimer's drug, which could improve patient adherence and mitigate side effects associated with the sharp peaks in plasma concentration seen with immediate-release formulations.

Key Claims at a Glance

  • The complaint asserts independent claims 1 and 21 (Compl. ¶24).
  • Essential elements of independent claim 1 include:
    • A method for treating Alzheimer's disease.
    • Comprising once-daily administration of a modified release solid oral dosage form.
    • The dosage form comprises 28 mg ±5% of memantine (or a salt) and a polymeric carrier.
    • The dosage form sustains the release of memantine for about 4 to 24 hours.
    • The dosage form has a "single phase dissolution rate of less than about 80% after passage of about 6 hours" after entering a use environment.
  • The complaint reserves the right to assert additional claims (Compl. ¶25).

U.S. Patent No. 8,058,291 - “Methods And Compositions For The Treatment Of CNS-Related Conditions”

The Invention Explained

  • Problem Addressed: The patent explains that combining therapeutics for CNS disorders, such as an NMDAr antagonist (like memantine) and an acetylcholinesterase inhibitor (AChel, like donepezil), is challenging. Standard immediate-release versions often require frequent administration and a dose-escalation period at the start of therapy to manage side effects, which complicates treatment and can reduce patient compliance (’291 Patent, col. 1:50-2:67).
  • The Patented Solution: The invention provides a combination therapy where at least one of the drugs, typically the NMDAr antagonist, is delivered in an extended-release formulation. This formulation is specifically designed to slow the rate of increase in the drug's plasma concentration (dC/dT) compared to an immediate-release version. This "gentler" absorption profile is intended to allow for the administration of a therapeutically effective dose from the outset of treatment, avoiding the need for dose titration and improving tolerability (’291 Patent, Abstract; col. 4:9-31).
  • Technical Importance: This invention provided a pharmacokinetic-based approach to creating a more tolerable and convenient combination drug product for Alzheimer's disease, potentially enabling patients to benefit from two distinct mechanisms of action with a simplified, once-daily regimen.

Key Claims at a Glance

  • The complaint asserts dependent claims 3, 7, 19, 20, 22, 37, 41, 48, 49, 50, and 53-57 (Compl. ¶24). These depend from independent claims 1 and 6.
  • Essential elements of independent claim 1 include:
    • A method of treating a CNS-related condition (e.g., Alzheimer's) by orally administering once a day a composition comprising:
    • (a) 5-40 mg of memantine (or a salt) in an extended-release dosage form.
    • This extended-release form provides a change in plasma concentration over time (dC/dT) that is less than about 50% of the dC/dT of an immediate-release form of the same quantity.
    • (b) a therapeutically effective amount of donepezil (or a salt).
  • The complaint reserves the right to assert additional claims (Compl. ¶25).

U.S. Patent No. 8,338,485 - “Compositions For The Treatment of CNS-Related Conditions”

  • Technology Synopsis: This patent, related to the ’291 Patent, claims the pharmaceutical composition itself rather than the method of treatment. It covers a solid oral dosage form containing an extended-release formulation of memantine and an immediate-release formulation of donepezil, where the memantine component is characterized by a specific pharmacokinetic profile (dC/dT) designed to improve tolerability (’485 Patent, Abstract).
  • Asserted Claims: 1, 3, 9, and 11 (Compl. ¶24).
  • Accused Features: The specific formulation of Defendants' generic capsule products containing extended-release memantine and donepezil (Compl. ¶22, 25).

U.S. Patent No. 8,338,486 - “Methods For The Treatment of CNS-Related Conditions”

  • Technology Synopsis: This patent claims a method of treating a neurological condition by administering a composition comprising extended-release memantine and immediate-release donepezil. The key limitation is that the composition must provide a specific pharmacokinetic profile for memantine (dC/dT) that is slower than that of an immediate-release formulation, which is alleged to reduce adverse effects (’486 Patent, Abstract).
  • Asserted Claims: 1, 3, 7, and 9 (Compl. ¶24).
  • Accused Features: The methods of using the Defendants' generic products, as would be instructed by the proposed product labeling for the treatment of Alzheimer's disease (Compl. ¶25, 28).

U.S. Patent No. 8,580,858 - “Compositions For the Treatment Of CNS-Related Conditions”

  • Technology Synopsis: This patent claims a solid pharmaceutical composition for oral administration containing extended-release memantine and immediate-release donepezil. The claims focus on the pharmacokinetic outcome of the formulation, requiring that it produces a specific, slower rate of change in memantine plasma concentration (dC/dT) compared to an immediate-release product (’858 Patent, Abstract).
  • Asserted Claims: 1, 2, 4, and 10 (Compl. ¶24).
  • Accused Features: The formulation of Defendants' generic capsule products, which contain extended-release memantine and donepezil (Compl. ¶22, 25).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are Defendants' proposed generic capsule products submitted to the FDA for approval under ANDA No. 208672 (Compl. ¶22).

Functionality and Market Context

  • The complaint alleges the generic products are capsule formulations containing either 28 mg of extended-release memantine hydrochloride and 10 mg of donepezil hydrochloride, or 14 mg of extended-release memantine hydrochloride and 10 mg of donepezil hydrochloride (Compl. ¶22). These formulations are generic equivalents of Plaintiffs' NAMZARIC® product, which is approved for the treatment of moderate to severe dementia of the Alzheimer's type (Compl. ¶19). The filing of the ANDA itself, seeking approval to market these generic products prior to the expiration of the patents-in-suit, constitutes the act of infringement under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶24).
  • No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide a detailed, element-by-element infringement analysis or an appended claim chart. It makes a general allegation that Defendants’ submission of ANDA No. 208672 constitutes a technical act of infringement because the proposed generic products, if approved and marketed, would meet each and every limitation of the asserted claims (Compl. ¶24-25). The central theory of infringement is that by creating a bioequivalent generic version of NAMZARIC®, the Defendants' product will necessarily practice the patented inventions covering specific modified-release formulations and pharmacokinetic profiles.

  • Identified Points of Contention:
    • Scope Questions: The infringement analysis for the asserted claims will raise questions regarding the scope of terms defining specific performance characteristics. For the ’009 Patent, a central issue may be whether the dissolution profile of the Defendants' product falls within the claimed "single phase dissolution rate of less than about 80% after passage of about 6 hours." For the ’291, ’485, ’486, and ’858 Patents, a key question will be whether the term "dC/dT that is less than about 50% of the dC/dT of the same quantity of an immediate release form" can be read to cover the pharmacokinetic profile of Defendants' specific formulation. The construction of "about" will be critical in these analyses.
    • Technical Questions: A primary technical dispute will be factual: do the Defendants’ generic products, as formulated and described in their confidential ANDA, actually exhibit the specific dissolution and pharmacokinetic properties required by the claims? This will require detailed expert analysis and comparative testing of the generic product against the claimed limitations, particularly the rate of change in plasma concentration (dC/dT) and the in vitro dissolution profiles.

V. Key Claim Terms for Construction

  • The Term: "single phase dissolution rate" (’009 Patent, cl. 1)
  • Context and Importance: This term defines the controlled-release characteristic of the memantine formulation in the ’009 Patent. The patent distinguishes its invention from prior art two-phase release profiles (’009 Patent, col. 2:42-47). The infringement determination will depend on whether the release curve of the accused product is properly characterized as "single phase" and meets the numerical limitations.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification describes the invention broadly as a "modified release form" using a polymeric matrix that "substantially contributes to the modification of the release" (’009 Patent, col. 3:15-20), which may support interpreting "single phase" to encompass a variety of continuous, non-pulsatile release profiles.
    • Evidence for a Narrower Interpretation: The patent includes numerous figures depicting specific dissolution profiles from exemplary formulations (e.g., ’009 Patent, Figs. 1, 2, 8). A defendant may argue these embodiments limit the term to curves with a similar shape and characteristics, distinct from other possible sustained-release profiles.
  • The Term: "a change in plasma concentration as a function of time (dC/dT) that is less than about 50% of the dC/dT of the same quantity of an immediate release form" (’291 Patent, cl. 1)
  • Context and Importance: This pharmacokinetic limitation is the core of the invention claimed in the ’291 patent family. It quantitatively defines the "gentler" absorption profile that allegedly improves tolerability. Infringement will turn entirely on whether the accused product meets this comparative, functional limitation. Practitioners may focus on this term because it is not a structural feature but a performance characteristic that must be measured in vivo or through accepted modeling.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification's stated goal is to provide formulations that "reduce or eliminate the need to dose escalate the drug" by reducing the concentration ramp (’291 Patent, col. 4:13-17). This purpose could support a broader interpretation that captures any formulation achieving this functional goal, regardless of its specific release curve shape.
    • Evidence for a Narrower Interpretation: The patent provides modeled pharmacokinetic data, including a table with calculated dC/dT values for various formulations (’291 Patent, Fig. 8). A defendant may argue that these examples define the specific method of calculation and the context for the "less than about 50%" comparison, potentially narrowing the claim's scope to formulations that are similar to those disclosed.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that Defendants will induce infringement by doctors, pharmacists, and patients because the proposed label for the generic products will instruct them to use the product in a manner that infringes the asserted method claims (Compl. ¶25, 28). It further alleges contributory infringement, stating that the generic products are not staple articles of commerce suitable for substantial noninfringing use (Compl. ¶27).
  • Willful Infringement: The complaint alleges that Defendants were aware of the patents-in-suit prior to filing their ANDA and that their submission of § 505(j)(2)(A)(vii)(IV) allegations demonstrates specific intent to infringe (Compl. ¶28). The complaint also asserts that Defendants' actions render this an "exceptional case" under 35 U.S.C. § 285, which is the basis for seeking attorney's fees (Compl. ¶29).

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

  • A central issue will be one of functional performance: does the specific formulation of Defendants' proposed generic product, as detailed in their confidential ANDA, actually exhibit the dissolution rates and in vivo pharmacokinetic profiles (specifically, the rate of change in plasma concentration, or dC/dT) required by the asserted claims? This is a fact-intensive inquiry that will depend heavily on expert testimony and comparative bioequivalence studies.
  • A key legal question will be one of claim scope: how broadly will the court construe the functional and performance-based limitations in the claims, such as "single phase dissolution rate" and "dC/dT that is less than about 50% of the dC/dT" of an immediate-release form? The interpretation of the word "about" in these limitations will be a critical battleground that could determine the outcome of the infringement analysis.