DCT

1:17-cv-01614

Mayne Pharma Intl Pty Ltd v. Actavis Elizabeth LLC

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-01614, D. Del., 11/09/2017
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because both defendants are incorporated or organized under the laws of Delaware.
  • Core Dispute: Plaintiff alleges that Defendants’ submission of a supplement to an Abbreviated New Drug Application (ANDA) seeking to market generic versions of Plaintiff's DORYX® MPC drug product constitutes an act of infringement of four patents related to controlled-release doxycycline formulations.
  • Technical Context: The technology concerns pharmaceutical formulations designed to control the release of doxycycline, an antibiotic, to improve its stability over its shelf life and reduce common side effects like nausea and gastric irritation.
  • Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by Defendants' submission of a supplement to ANDA No. 090134 with a Paragraph IV certification, alleging that the patents-in-suit are invalid, unenforceable, or will not be infringed by the proposed generic products. Plaintiff received a Notice Letter regarding this certification on or about September 28, 2017.

Case Timeline

Date Event
2002-04-12 ’161 Patent Priority Date
2005-05-06 FDA approves original DORYX® tablets
2005-10-25 ’161 Patent Issue Date
2014-10-08 ’652, ’057, and ’031 Patents Priority Date
2016-03-29 ’652 Patent Issue Date
2016-05-20 FDA approves DORYX® MPC tablets
2016-09-20 ’057 Patent Issue Date
2016-12-06 ’031 Patent Issue Date
2017-09-28 Defendants send Paragraph IV Notice Letter
2017-11-09 Complaint Filing Date

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

U.S. Patent No. 6,958,161 - "Modified Release Coated Drug Preparation"

  • Issued: October 25, 2005

The Invention Explained

  • Problem Addressed: The patent’s background section describes how the release profile of some modified-release pharmaceutical preparations can change significantly after storage, potentially leading to premature drug release (e.g., in the stomach) which can "detract from the utility and effectiveness of the product" (’161 Patent, col. 1:39-51).
  • The Patented Solution: The invention introduces a "stabilising coat" as a physical barrier between the core element containing the active drug and the outer modified-release coating (’161 Patent, col. 6:55-57). This intermediate layer is intended to slow the migration of moisture or solvent, thereby preventing interactions that would alter the drug release profile over the product's shelf life and ensuring post-storage performance is substantially the same as pre-storage performance (’161 Patent, col. 1:52-57; col. 2:1-12).
  • Technical Importance: Maintaining a stable and predictable drug release profile throughout a pharmaceutical's shelf life is critical for ensuring patient safety, therapeutic efficacy, and meeting regulatory requirements (’161 Patent, col. 1:22-34).

Key Claims at a Glance

  • The complaint asserts at least one claim of the '161 Patent (Compl. ¶42). The allegations appear to track the elements of independent claim 1.
  • Claim 1 Elements:
    • A modified release preparation with one or more coated core elements.
    • Each core element contains an active ingredient from a specified group of tetracyclines, including acid salts of doxycycline.
    • The core has a "modified release coating."
    • A "stabilising coat" is provided between the core element and its modified release coating.
    • This structure results in a specific functional outcome: upon in vitro dissolution testing, the amount of active ingredient released at any time on a "post-storage dissolution profile" is within 40 percentage points of the amount released at the same time on a "pre-storage dissolution profile."

U.S. Patent No. 9,295,652 - "Controlled Release Doxycycline"

  • Issued: March 29, 2016

The Invention Explained

  • Problem Addressed: The patent background states that tetracycline antibiotics like doxycycline are known to cause "an undesirable degree of gastrointestinal irritation and nausea" when released into the stomach's acidic environment (’652 Patent, col. 1:45-51).
  • The Patented Solution: The invention is a controlled-release pharmaceutical formulation of doxycycline designed to mitigate these side effects. The patent describes pellets with a polymer coating that severely restricts drug release at the low pH of the stomach but allows for release at higher pH levels found further down the gastrointestinal tract, enabling a "clinically effective plasma level to be achieved" (’652 Patent, col. 2:9-16). The claims define the invention by specific in vitro dissolution profiles at different pH levels and by specific in vivo pharmacokinetic parameters, such as the average peak plasma concentration (Cmax) observed in patients (’652 Patent, Claim 1).
  • Technical Importance: The formulation aims to improve patient tolerability and compliance by reducing stomach-related side effects, while still delivering a therapeutically effective and bioequivalent dose of the antibiotic (’652 Patent, col. 2:20-24).

Key Claims at a Glance

  • The complaint asserts at least one claim of the '652 Patent (Compl. ¶92). The allegations appear to track the elements of independent claim 1.
  • Claim 1 Elements:
    • A dosage form comprising a plurality of modified release doxycycline pellets.
    • Each pellet comprises doxycycline and a controlled release polymer composition disposed over it.
    • The dosage form contains 60, 90, or 120 mg of doxycycline.
    • The form exhibits a specific in vitro dissolution profile: it releases less than 15% of the doxycycline at pH 1.2 and less than 40% at pH 4.5 after 60 minutes.
    • The form exhibits a specific in vivo pharmacokinetic profile: for a 60 mg dose, the average peak plasma concentration (Cmax) is 80% to 125% of 625-1600 ng/ml (with similar ranges defined for 90 mg and 120 mg doses).

U.S. Patent No. 9,446,057 - "Controlled Release Doxycycline"

  • Issued: September 20, 2016

  • Technology Synopsis: Belonging to the same family as the ’652 Patent, this patent addresses the same technical problem of reducing nausea and irritation caused by doxycycline releasing in the stomach (’057 Patent, col. 1:45-50). The invention is a controlled-release formulation defined by a specific dissolution profile, claiming that at pH 5 the formulation provides a "clinically effective plasma level of doxycycline," and is further defined by specific in vivo Cmax and area-under-the-curve (AUC) pharmacokinetic parameters (’057 Patent, Abstract; Claim 1).

  • Asserted Claims: At least one claim is asserted (Compl. ¶135).

  • Accused Features: Defendants' ANDA Products are alleged to be modified release doxycycline pellets with a controlled release polymer composition that meets the claimed dissolution and pharmacokinetic profiles (Compl. ¶¶136-150).

U.S. Patent No. 9,511,031 - "Controlled Release Doxycycline"

  • Issued: December 6, 2016

  • Technology Synopsis: Also a member of the ’652 Patent family, this patent likewise seeks to solve the problem of stomach-related side effects from doxycycline (’031 Patent, col. 1:45-50). The invention is a controlled-release composition defined by a specific "normalized average release" profile at pH 5.0 at particular time points (15, 20, and 25 minutes). The claims further define the invention by specific in vivo pharmacokinetic parameters (Cmax and AUC) that are normalized based on the administered dose (’031 Patent, Abstract; Claim 1).

  • Asserted Claims: At least one claim is asserted (Compl. ¶177).

  • Accused Features: Defendants' ANDA Products are alleged to consist of a doxycycline composition that meets the claimed normalized average release profile and the dose-normalized pharmacokinetic parameters (Compl. ¶¶178-198).

III. The Accused Instrumentality

  • Product Identification: The accused instrumentalities are Defendants' proposed 60 mg and 120 mg generic versions of DORYX® MPC (doxycycline hyclate delayed-release tablets), as described in a supplement to ANDA No. 090134 (Compl. ¶1, ¶8).
  • Functionality and Market Context: The complaint alleges, on information and belief, that the accused "ANDA Products" are modified and controlled release pharmaceutical preparations designed for oral administration (Compl. ¶¶43, 68, 93). The formulation is alleged to consist of a plurality of coated core elements, or pellets, that are compressed to form a tablet (Compl. ¶63, ¶93). Functionally, these products are alleged to incorporate a drug core containing an acid salt of doxycycline, an intermediate "stabilising coat," and an outer "modified release coating" that controls the drug's dissolution profile (Compl. ¶¶44, 46, 69, 71). The products are intended to be generic competitors to Plaintiff's branded DORYX® MPC, an oral antibacterial drug (Compl. ¶¶1, 21).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

'161 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
each core element comprising an active ingredient selected from the group consisting of the acid salts of doxycycline... The accused ANDA Products include an active ingredient that is an acid salt of doxycycline. ¶44, ¶69 col. 11:38-41
and having a modified release coating... The accused ANDA Products include a modified release coating. ¶45, ¶70 col. 7:17-24
wherein a stabilising coat is provided between each core element and its modified release coating... The accused ANDA Products include a stabilising coat between a core element and its modified release coating. ¶46, ¶71 col. 6:55-61
so that, upon in vitro dissolution testing, the amount of active ingredient released at any time on a post-storage dissolution profile is within 40 percentage points of the amount of active ingredient released at any time on a pre-storage dissolution profile. The complaint alleges that upon in vitro testing, the amount of active ingredient released from the ANDA Products on a post-storage profile is within 40 percentage points of the amount released on a pre-storage profile. ¶47 col. 2:1-12
  • Identified Points of Contention:
    • Scope Questions: The case may present a question of whether the intermediate layer in Defendants' formulation, if one exists, meets the definition of a "stabilising coat" as that term is used in the patent.
    • Technical Questions: A central evidentiary question will be whether testing of Defendants' ANDA Products demonstrates that they meet the functional stability limitation of Claim 1. The complaint alleges this on "information and belief," suggesting the definitive evidence resides in the confidential ANDA and associated stability studies.

'652 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A dosage form, comprising a plurality of modified release doxycycline pellets, wherein each doxycycline pellet comprises: doxycycline; and a controlled release polymer composition disposed over the doxycycline... The accused ANDA Products consist of a plurality of modified release doxycycline pellets that include a controlled release polymer composition disposed over the doxycycline. ¶93, ¶95 col. 8:54-57
wherein said dosage form comprises 60, 90, or 120 mg of doxycycline and releases less than about 15% of the doxycycline at pH 1.2, and less than 40% of the doxycycline at pH 4.5 after 60 minutes, measured under USP <711> conditions... The accused ANDA Products include 60 mg or 120 mg of doxycycline and allegedly meet the claimed in vitro dissolution profile at pH 1.2 and pH 4.5. ¶96, ¶97 col. 23:8-14
and wherein when the amount of doxycycline of said dosage form is 60 mg, after administration of a single dose under fasting conditions to a patient in need thereof, the average Cmax is about 80% to about 125% of about 625-1600 ng/ml... [or similar for 120 mg dose] The accused ANDA Products with 60 mg and 120 mg of doxycycline are alleged to produce an average peak plasma concentration (Cmax) that falls within the claimed pharmacokinetic ranges. ¶98, ¶99 col. 23:15-23
  • Identified Points of Contention:
    • Scope Questions: The infringement analysis will depend on whether the bioequivalence data submitted in Defendants' ANDA, which compares the generic to the branded product, also demonstrates that the generic product meets the specific, absolute pharmacokinetic ranges (e.g., "80% to 125% of 625-1600 ng/ml") recited in the claim.
    • Technical Questions: A key factual question is whether the dissolution testing and bioequivalence study results contained in the confidential ANDA confirm that the accused products meet the dual in vitro and in vivo limitations of the claim.

V. Key Claim Terms for Construction

The Term: "stabilising coat" (’161 Patent, Claim 1)

  • Context and Importance: This term defines the central structural element of the invention of the ’161 Patent. The infringement analysis will turn on whether the accused products contain a layer between the drug core and the release coating that falls within the scope of this term.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification describes the term's purpose as creating a "physical barrier" and notes it can be made of "any suitable material which makes an inert barrier" and should be "at least semi-permeable in aqueous media and may even be soluble" (’161 Patent, col. 6:55-65; col. 7:3-7). This language may support a broad, functional definition.
    • Evidence for a Narrower Interpretation: A specific embodiment describes the stabilising coat as consisting of "hydroxypropylmethyl cellulose and talc in a 2:1 mixture" (’161 Patent, col. 8:62-64). A defendant may argue this exemplary embodiment should inform a narrower construction of the term.

The Term: "average peak plasma doxycycline concentration" (’652 Patent, Claim 1)

  • Context and Importance: This pharmacokinetic parameter is a critical limitation defining the claimed invention. Whether the accused products infringe will depend on whether their performance in bioequivalence studies falls within the specific numerical ranges tied to this term. Practitioners may focus on this term because the methodology for calculating the "average" and comparing it to the claimed range could be a point of dispute.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The term "average peak plasma concentration," or Cmax, is a standard term in pharmacokinetics. Plaintiff may argue it should be given its plain and ordinary meaning as understood in the field, likely referring to the geometric mean Cmax derived from a standard bioequivalence study.
    • Evidence for a Narrower Interpretation: The patent discusses Cmax values in the context of bioequivalence with DORYX® tablets, a regulated process with specific statistical guidelines (’652 Patent, col. 10:4-12). A defendant may argue that the term must be interpreted in this specific regulatory and statistical context, potentially limiting how the "average" is calculated and compared to the claimed range.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that upon FDA approval, Defendants will induce infringement by marketing and distributing the ANDA Products with a product label and insert that will instruct healthcare professionals and end-users on how to administer the products, thereby causing direct infringement of the asserted claims (Compl. ¶¶76, 119, 161, 200).
  • Willful Infringement: The complaint alleges Defendants had "actual and constructive notice" of the patents-in-suit prior to filing the ANDA supplement (Compl. ¶¶77, 120, 162, 201). It further alleges that Defendants' conduct in certifying non-infringement, invalidity, or unenforceability was without "adequate justification" or a "reasonable basis," rendering the case "exceptional" under 35 U.S.C. § 285 (Compl. ¶¶79, 122, 164, 203).

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

  • A core issue will be one of evidentiary alignment: Do the confidential test data within Defendants' ANDA submission—including formulation details, dissolution profiles under various conditions, and human bioequivalence studies—demonstrate that the accused generic products meet the specific structural and functional limitations recited in the asserted claims of the patents-in-suit?
  • A central dispute may be one of pharmacokinetic interpretation: For the later patents (’652, ’057, ’031), does meeting the FDA's regulatory standard for bioequivalence against the DORYX® MPC product necessarily mean the accused generic product also meets the distinct, absolute pharmacokinetic ranges (Cmax and AUC) required by the patent claims, or is there a technical and legal distinction between these two standards?
  • A key question for the earliest patent (’161) will be one of functional stability: Does the accused product's formulation, when subjected to the accelerated storage conditions outlined in the patent, exhibit a post-storage dissolution profile that remains "within 40 percentage points" of its pre-storage profile, as functionally required by the claim?