DCT

1:16-cv-01045

Forest Laboratories LLC v. Apotex Corp

Log In

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:16-cv-01045, D. Del., 11/10/2016
  • Venue Allegations: Venue is alleged to be proper based on Defendant Apotex Corp.'s incorporation in Delaware and both Defendants' intent to sell the accused generic products in the district.
  • Core Dispute: Plaintiffs allege that Defendants’ submission of an Abbreviated New Drug Application (ANDA) to the FDA for generic versions of Plaintiffs' NAMZARIC® capsules constitutes an act of patent infringement.
  • Technical Context: The technology involves pharmaceutical compositions for treating central nervous system (CNS) disorders, such as Alzheimer's disease, using a combination of memantine and donepezil in modified-release formulations.
  • Key Procedural History: The complaint notes a prior patent infringement action filed by Forest and Adamas against Apotex in 2014, which asserted the ’009 patent in connection with a generic version of Namenda XR®. That action was dismissed by stipulation in February 2016.

Case Timeline

Date Event
2004-06-17 ’009 Patent Priority Date
2005-04-06 ’291, ’485, ’486, ’858 Patents Priority Date
2011-10-18 ’009 Patent Issued
2011-11-15 ’291 Patent Issued
2012-12-25 ’485 Patent Issued
2012-12-25 ’486 Patent Issued
2013-11-12 ’858 Patent Issued
2014-02-14 Prior complaint filed by Forest and Adamas against Apotex asserting ’009 Patent
2016-02-16 Prior litigation dismissed by stipulation
2016-09-26 Apotex submitted ANDA No. 208512 to the FDA (on or before this date)
2016-09-28 Plaintiffs received written notification of Apotex's ANDA filing
2016-11-10 Complaint Filing Date

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

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

  • Issued: October 18, 2011

The Invention Explained

  • Problem Addressed: The patent's background describes the challenges with immediate-release memantine tablets, which require twice-a-day dosing. This can lead to decreased patient compliance and a faster rate of drug absorption that may cause a greater frequency of adverse events. (’009 Patent, col. 2:65-col. 3:9).
  • The Patented Solution: The invention is a once-a-day, modified-release oral dosage form of memantine. It uses a polymeric matrix, such as hydroxypropyl methylcellulose, that swells upon contact with gastric fluid to sustain the release of the drug over an extended period, thereby enabling once-daily administration and potentially improving tolerability. (’009 Patent, Abstract; col. 3:10-23).
  • Technical Importance: By enabling a once-daily regimen, the formulation improves the likelihood of patient compliance, a critical factor for patients with cognitive impairments such as Alzheimer's disease. (’009 Patent, col. 2:65-col. 3:2).

Key Claims at a Glance

  • The complaint asserts independent Claim 1 and dependent Claims 2, 21-23. (Compl. ¶26).
  • Claim 1 requires:
    • A method for treating Alzheimer's disease
    • Comprising once daily administration of a modified release solid oral dosage form
    • Comprising 28 mg ±5% of memantine or a pharmaceutically acceptable salt thereof
    • And a pharmaceutically acceptable polymeric carrier substantially contributing to the modification of the release
    • Wherein the dosage form sustains the release of memantine from about 4 hours to about 24 hours following entry into a use environment
    • And wherein the dosage form has a single phase dissolution rate of less than about 80% after passage of about 6 hours following entry into said use environment

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

  • Issued: November 15, 2011

The Invention Explained

  • Problem Addressed: The patent background explains that existing dosage forms of N-Methyl-D-Aspartate receptor (NMDAr) antagonists often require dose escalation at the start of therapy to avoid side effects associated with the initial exposure. This complicates treatment regimens and can reduce patient compliance. (’291 Patent, col. 2:58-col. 3:10).
  • The Patented Solution: The invention provides a combination of an NMDAr antagonist (e.g., memantine) and an acetylcholinesterase inhibitor (AChel) (e.g., donepezil). The key feature is that the memantine is provided in an extended-release dosage form that reduces the rate of change in its plasma concentration over time (dC/dT), thereby avoiding the need for dose escalation and improving tolerability. (’291 Patent, Abstract; col. 3:11-col. 4:14).
  • Technical Importance: This approach allows for the administration of a therapeutically effective dose from the onset of therapy without a titration period, simplifying treatment and potentially improving patient adherence and outcomes in treating conditions like Alzheimer's disease. (’291 Patent, col. 4:30-38).

Key Claims at a Glance

  • The complaint asserts independent Claim 3 and numerous dependent claims. (Compl. ¶26).
  • Claim 3 requires:
    • A method of treating a CNS-related condition
    • Comprising orally administering once a day to a human subject
    • 5-40 mg of memantine (or a salt) provided in an extended release dosage form
    • Wherein the extended release form provides a change in plasma concentration over time (dC/dT) that is less than about 50% of the dC/dT of the same quantity of an immediate release form of memantine
    • And a therapeutically effective amount of donepezil (or a salt)

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

  • Patent Identification: U.S. Patent No. 8,338,485, issued December 25, 2012. (Compl. ¶17).
  • Technology Synopsis: This patent, related to the ’291 patent, claims pharmaceutical compositions comprising an extended-release formulation of memantine and an immediate-release formulation of donepezil. The claims focus on specific dosages and pharmacokinetic profiles, such as the rate of change in plasma concentration (dC/dT) of memantine upon administration. (’485 Patent, Abstract).
  • Asserted Claims: Claims 1, 3, 9, and 11. (Compl. ¶26).
  • Accused Features: The complaint alleges that Defendants' proposed generic products, containing extended-release memantine and donepezil, meet the limitations of the asserted claims. (Compl. ¶23, 27).

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

  • Patent Identification: U.S. Patent No. 8,338,486, issued December 25, 2012. (Compl. ¶18).
  • Technology Synopsis: This patent claims methods of treating neurological conditions like Alzheimer's disease by administering the compositions covered in the '485 patent family. It specifies a once-daily administration of a composition containing extended-release memantine and immediate-release donepezil that results in a particular pharmacokinetic profile for memantine. (’486 Patent, Abstract).
  • Asserted Claims: Claims 1, 3, 7, and 9. (Compl. ¶26).
  • Accused Features: The complaint alleges that the use of Defendants' proposed generic products, as will be directed by their product labeling, will infringe these method claims. (Compl. ¶27, 30).

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

  • Patent Identification: U.S. Patent No. 8,580,858, issued November 12, 2013. (Compl. ¶19).
  • Technology Synopsis: This patent claims pharmaceutical compositions for once-daily oral administration that comprise extended-release memantine and immediate-release donepezil. The claims further define the composition by the resulting pharmacokinetic profile, specifying a particular ratio of maximum to mean plasma concentration (Cmax/Cmean) for memantine over a defined period after administration. (’858 Patent, Abstract).
  • Asserted Claims: Claims 1, 2, 4, and 10. (Compl. ¶26).
  • Accused Features: The complaint alleges that Defendants' proposed generic drug products possess the composition and will produce the pharmacokinetic profiles recited in the asserted claims. (Compl. ¶23, 27).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are the generic drug products for which Apotex submitted Abbreviated New Drug Application (ANDA) No. 208512 to the U.S. Food and Drug Administration. (Compl. ¶23).

Functionality and Market Context

  • The ANDA seeks approval for the commercial manufacture, use, and sale of generic capsule products containing either 28 milligrams of extended-release memantine hydrochloride and 10 milligrams of donepezil hydrochloride, or 14 milligrams of extended-release memantine hydrochloride and 10 milligrams of donepezil hydrochloride. (Compl. ¶23).
  • The complaint alleges these products are generic versions of Plaintiffs' NAMZARIC® brand capsules, and Apotex seeks approval to market them prior to the expiration of the patents-in-suit. (Compl. ¶20, 23).
  • The filing of the ANDA itself, with a certification under 21 U.S.C. § 355(j)(2)(A)(vii)(IV), constitutes the statutory act of infringement alleged in the complaint. (Compl. ¶26).
  • No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide a detailed claim chart. The infringement allegations are based on the statutory act of filing an ANDA for a generic version of a branded drug (NAMZARIC®) that is listed in the FDA's Orange Book as being covered by the patents-in-suit. (Compl. ¶20, 23, 27).

’009 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for treating Alzheimer's disease comprising once daily administration of a modified release solid oral dosage form... The proposed generic product is intended for once-daily administration to treat Alzheimer's disease, as it is a generic equivalent of NAMZARIC®. ¶23, 27 col. 21:8-10
comprising 28 mg ±5% of memantine or a pharmaceutically acceptable salt thereof... Apotex’s ANDA describes a capsule product containing 28 milligrams of extended-release memantine hydrochloride. ¶23 col. 21:11-12
and a pharmaceutically acceptable polymeric carrier substantially contributing to the modification of the release of the memantine... The complaint alleges Apotex’s product is an extended-release formulation of memantine, which implies the use of a carrier to modify the release profile. ¶23 col. 21:13-16
wherein said dosage form has a single phase dissolution rate of less than about 80% after passage of about 6 hours following said entry into said use environment. The complaint alleges that Apotex's product, by virtue of being a generic copy of NAMZARIC®, will exhibit the claimed dissolution profile. ¶27 col. 21:17-21

’291 Patent Infringement Allegations

Claim Element (from Independent Claim 3) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating a CNS-related condition comprising orally administering once a day to a human subject in need thereof: (a) 5-40 mg memantine... The proposed label for Apotex's product will allegedly instruct physicians and patients to administer the drug once daily for CNS-related conditions like Alzheimer's dementia. The product contains 14 mg or 28 mg of memantine. ¶23, 27, 30 col. 30:52-56
provided in an extended release dosage form, wherein said extended release memantine...provides 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... The complaint alleges that Apotex's extended-release memantine formulation, as a generic equivalent of NAMZARIC®, will produce the claimed pharmacokinetic profile upon administration. ¶23, 27 col. 30:57-63
and (b) a therapeutically effective amount of donepezil or a pharmaceutically acceptable salt thereof... Apotex’s ANDA product contains 10 milligrams of donepezil hydrochloride. ¶23 col. 30:64-65

Identified Points of Contention

  • Scope Questions: A central point of contention in ANDA litigation is often patent validity, which Apotex has raised in its Paragraph IV certification. (Compl. ¶24). From an infringement perspective, a question may be whether the specific formulation and resulting pharmacokinetic profile of Apotex's product can be proven to fall outside the scope of the claims, despite its bioequivalence to the branded drug.
  • Technical Questions: The primary technical questions will relate to the evidence. For example: "What evidence will be presented from Apotex’s ANDA filing to demonstrate that its proposed product exhibits a 'single phase dissolution rate' as required by Claim 1 of the ’009 patent?" A further question is: "What data will show that Apotex's product, upon administration, produces a memantine dC/dT that is 'less than about 50%' of an immediate-release form, as required by Claim 3 of the ’291 patent?"

V. Key Claim Terms for Construction

  • The Term: "a single phase dissolution rate" (’009 Patent, Claim 1)

    • Context and Importance: This term defines the release characteristic of the memantine formulation. Its construction is critical because infringement depends on whether the dissolution profile of the accused product fits this description. Practitioners may focus on this term because Apotex could argue its formulation exhibits a release profile that is not "single phase," perhaps pointing to minor inflections in the dissolution curve or arguing for a multi-phasic interpretation.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification describes the overall goal as providing "sustained release of the active ingredient over an extended period of time," suggesting the exact shape of the curve is less important than the overall durational effect. (’009 Patent, col. 2:50-54).
      • Evidence for a Narrower Interpretation: The figures in the patent, such as FIG. 1 and FIG. 4, depict smooth, continuous dissolution curves without distinct phases or inflection points, which may support a narrower construction limited to such profiles. (’009 Patent, FIG. 1, 4).

  • The Term: "change in plasma concentration as a function of time (dC/dT)" (’291 Patent, Claim 3)

    • Context and Importance: This pharmacokinetic parameter is central to the claims of the '291 patent and its relatives, as it quantifies the "extended release" nature of the formulation in vivo. The dispute will likely focus on the precise methodology for measuring dC/dT and comparing it to the benchmark immediate-release formulation.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification broadly discusses the goal of altering dC/dT "to reduce or eliminate the need to dose escalate the drug," suggesting any formulation achieving this clinical outcome could be covered. (’291 Patent, col. 4:10-14).
      • Evidence for a Narrower Interpretation: The patent provides specific, albeit simulated, graphical representations of plasma concentration curves and a data table summarizing pharmacokinetic properties, including dC/dT. These could be used to argue that the term requires measurement and comparison under the specific conditions exemplified in the patent. (’291 Patent, FIG. 1B, 7, 8).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that Defendants will induce infringement of the method claims by doctors, pharmacists, and patients. This allegation is based on the proposed package insert and label for the generic products, which will allegedly instruct users to administer the drug in a manner that practices the claimed methods. (Compl. ¶27, 30). The complaint also alleges contributory infringement. (Compl. ¶26, 29).
  • Willful Infringement: The complaint alleges that Apotex was aware of the patents-in-suit prior to filing its ANDA. (Compl. ¶30). This allegation is supported by Apotex’s required Paragraph IV certification, which necessarily acknowledges the existence of the patents. The complaint also asserts that the case is "exceptional" under 35 U.S.C. § 285, seeking enhanced damages and attorneys' fees. (Compl. ¶32; Prayer for Relief F).

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

  • A central issue, as indicated by Apotex’s Paragraph IV notice, will be one of patent validity: can Apotex prove by clear and convincing evidence that the asserted claims, which cover specific extended-release formulations and pharmacokinetic profiles, are invalid as obvious or anticipated by the prior art?
  • A key evidentiary question will be one of pharmacokinetic proof: assuming the claims are valid, what evidence will emerge from Apotex’s ANDA and subsequent discovery to determine whether its proposed generic product's in vitro dissolution and in vivo plasma concentration profiles (specifically the dC/dT) fall within the numerical limitations recited in the asserted claims?
  • A third question concerns the impact of prior litigation: how, if at all, will the history of the 2014-2016 litigation involving the ’009 patent, and its stipulated dismissal, influence the legal and factual arguments in the current dispute over the same patent and its family members?