DCT

1:19-cv-00549

Mayne Pharma Intl Pty Ltd v. Prinston Pharmaceutical Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:19-cv-00549, D. Del., 03/21/2019
  • Venue Allegations: Venue is alleged to be proper as Defendants Prinston and Solco are organized under the laws of Delaware, and Zhejiang Huahai may be sued in any judicial district where it is subject to personal jurisdiction.
  • Core Dispute: Plaintiff alleges that Defendants' submission of an Abbreviated New Drug Application supplement to the FDA seeking to market a generic version of Plaintiff's DORYX® MPC product constitutes an act of infringement of three patents related to controlled-release doxycycline formulations.
  • Technical Context: The technology concerns oral pharmaceutical formulations of the antibiotic doxycycline, designed to control the drug's release profile to minimize gastrointestinal side effects while maintaining clinical efficacy.
  • Key Procedural History: The action was initiated under the Hatch-Waxman Act following Defendants' February 7, 2019 Notice Letter, which contained a Paragraph IV certification. The complaint alleges that Defendants' detailed statement in the Notice Letter did not contest infringement of the asserted patents. The filing of the complaint within 45 days of receiving the notice triggers a 30-month statutory stay of FDA approval for the accused generic product.

Case Timeline

Date Event
2005-05-06 FDA first approves NDA for DORYX® tablets (75 mg, 100 mg)
2014-10-08 Earliest Priority Date for ’652, ’057, and ’031 Patents
2016-03-29 U.S. Patent No. 9,295,652 issues
2016-05-20 FDA approves NDA supplement for DORYX® MPC tablets (60 mg, 120 mg)
2016-09-20 U.S. Patent No. 9,446,057 issues
2016-12-06 U.S. Patent No. 9,511,031 issues
2019-02-07 Defendants send Paragraph IV Notice Letter to Plaintiff
2019-03-21 Complaint for Patent Infringement filed

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

No probative visual evidence provided in complaint.

U.S. Patent No. 9,295,652 - "Controlled Release Doxycycline," issued March 29, 2016

The Invention Explained

  • Problem Addressed: The patent describes that tetracycline antibiotics like doxycycline, when formulated for immediate release, can cause significant gastrointestinal irritation and nausea because the drug is released into the acidic environment of the stomach ( Compl. ¶25; ’652 Patent, col. 1:42-57). Previous attempts at delayed or extended-release formulations are described as suffering from inadequate dissolution profiles that fail to deliver an effective dose of the antibiotic ( Compl. ¶25; ’652 Patent, col. 1:58-63).
  • The Patented Solution: The invention is a pharmaceutical formulation of doxycycline that controls the drug's release based on pH. The formulation uses pellets coated with a polymer composition that significantly limits drug release at the low pH of the stomach (e.g., pH 1.2) but allows for effective release at the higher pH levels found in the small intestine (e.g., pH 5.0), where the drug can be absorbed (’652 Patent, col. 2:8-16). This is designed to achieve a clinically effective plasma level while reducing stomach-related side effects (’652 Patent, col. 2:20-24). The manufacturing process for these pellets is detailed in the specification, for example in the flowchart of Figure 6 (’652 Patent, Fig. 6).
  • Technical Importance: This controlled-release technology aims to improve patient tolerability and compliance for a widely used antibiotic by mitigating its most common side effects (’652 Patent, col. 2:20-24).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶47).
  • The essential elements of independent claim 1 include:
    • A dosage form comprising a plurality of modified release doxycycline pellets, each comprising doxycycline and a controlled release polymer composition disposed over the doxycycline.
    • The dosage form comprises 60, 90, or 120 mg of doxycycline.
    • A specific in vitro dissolution profile, wherein the form 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, under USP <711> conditions.
    • Specific in vivo pharmacokinetic (PK) parameters, wherein after a single dose under fasting conditions, the average peak plasma concentration (Cmax) is within a specified range (e.g., 80% to 125% of 1250-3200 ng/ml for the 120 mg dose).
  • The complaint does not explicitly reserve the right to assert dependent claims, but the infringement count refers to "one or more claims" (Compl. ¶71).

U.S. Patent No. 9,446,057 - "Controlled Release Doxycycline," issued September 20, 2016

The Invention Explained

  • Problem Addressed: The ’057 Patent, part of the same family as the ’652 Patent, addresses the identical problem of stomach irritation and nausea caused by conventional doxycycline formulations (’057 Patent, col. 1:42-57).
  • The Patented Solution: The solution is again a controlled-release formulation that limits release in the stomach's acid but enables it in the higher pH of the intestine. This patent focuses on claiming the formulation by its ability to achieve a "clinically effective plasma level" by maintaining specific release levels at pH 5 (’057 Patent, col. 2:14-20, Abstract). The detailed description provides specific pharmacokinetic values that correspond to this clinical effectiveness (’057 Patent, col. 6:40-65).
  • Technical Importance: As with the ’652 Patent, the invention seeks to enhance the utility of doxycycline by improving its side-effect profile and, consequently, patient compliance (’057 Patent, col. 2:20-24).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶88).
  • The essential elements of independent claim 1 include:
    • A dosage form comprising a plurality of modified release doxycycline pellets, containing doxycycline and a controlled release polymer composition.
    • The dosage form comprises 60, 90, or 120 mg of doxycycline.
    • A functional limitation requiring that the dosage form "maintains doxycycline release levels measured under USP <711> conditions at pH 5 that provide a clinically effective plasma level of doxycycline."
  • The complaint does not explicitly reserve the right to assert dependent claims but refers to infringement of "one or more claims" (Compl. ¶110).

Multi-Patent Capsule: U.S. Patent No. 9,511,031 - "Controlled Release Doxycycline," issued December 6, 2016

  • Technology Synopsis: The ’031 Patent is also from the same patent family and addresses the same technical problem of gastrointestinal side effects from doxycycline (’031 Patent, col. 1:42-57). It discloses and claims a controlled-release formulation that limits drug release in the stomach but provides effective release in the intestines, thereby improving drug tolerability while maintaining therapeutic benefit (’031 Patent, Abstract).
  • Asserted Claims: The complaint asserts at least independent claim 1 (Compl. ¶127).
  • Accused Features: The complaint alleges that Defendants' 120 mg ANDA Product is a doxycycline dosage form combined with a controlled-release composition that infringes by exhibiting specific "normalized average release" profiles at pH 5.0 and particular pharmacokinetic parameters (Cmax and AUC) that fall within the scope of the claims (Compl. ¶¶128-132, 145-146).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is "Defendants' ANDA Product," a proposed generic version of Mayne's DORYX® MPC (doxycycline hyclate delayed-release tablets) at a 120 mg dosage strength (Compl. ¶1, ¶31).

Functionality and Market Context

  • The accused product is an oral tablet designed for delayed release of the antibiotic doxycycline, intended to treat conditions such as severe acne (Compl. ¶25, ¶68). The complaint alleges the product consists of a plurality of "modified release doxycycline pellets" which include a "controlled release polymer composition disposed over doxycycline" (Compl. ¶¶48-50). The infringement alleged is statutory, arising from the Defendants' submission of a Prior Approval Supplement to an Abbreviated New Drug Application (ANDA) to the FDA, which is an act of infringement under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶1, ¶47).
  • The product is intended to be a direct market competitor to Plaintiff's branded DORYX® MPC product, and Defendants seek FDA approval to launch it prior to the expiration of the patents-in-suit (Compl. ¶1).

IV. Analysis of Infringement Allegations

9,295,652 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 Defendants' ANDA Product is alleged to consist of a plurality of modified release doxycycline pellets that include doxycycline and a controlled release polymer composition disposed over the doxycycline (Compl. ¶48-50). ¶48-50 col. 10:1-3
wherein said dosage form comprises ... 120 mg of doxycycline The Defendants' ANDA Product is alleged to include 120 mg of doxycycline (Compl. ¶51). ¶51 col. 15:52
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 Defendants' ANDA Product is alleged to release less than 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 (Compl. ¶52). ¶52 col. 14:27-34
and wherein when the amount of doxycycline of said dosage form is 120 mg, after administration of a single dose under fasting conditions to a patient in need thereof, the average peak plasma doxycycline concentration is 80% to 125% of 1250-3200 ng/ml. For the Defendants' ANDA Product, after administration of a single dose under fasting conditions to a patient, the average peak plasma doxycycline concentration is alleged to be 80% to 125% of 1250-3200 ng/ml (Compl. ¶53). ¶53 col. 6:58-60

Identified Points of Contention

  • Evidentiary Question: The primary dispute will likely concern the factual evidence contained within the Defendants' confidential ANDA filing. The key question is whether the data for the accused 120 mg product demonstrates that it meets the specific numerical ranges for both the in vitro dissolution profile and the in vivo pharmacokinetic (Cmax) parameters as claimed.
  • Scope Question: The complaint's allegation that Defendants' Paragraph IV Notice Letter did not contest infringement (Compl. ¶38, ¶74) suggests Defendants' primary defense may be invalidity. If infringement is contested, a question may arise regarding the interpretation of "about" as applied to the numerical release and concentration limits.

9,446,057 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 Defendants' ANDA Product is alleged to consist of a plurality of modified release doxycycline pellets that include doxycycline and a controlled release polymer composition (Compl. ¶89-91). ¶89-91 col. 15:42-45
wherein said dosage form comprises ... 120 mg of doxycycline The Defendants' ANDA Product is alleged to include 120 mg of doxycycline (Compl. ¶92). ¶92 col. 15:52
and maintains doxycycline release levels measured under USP <711> conditions at pH 5 that provide a clinically effective plasma level of doxycycline. The Defendants' ANDA Product is alleged to maintain doxycycline release levels at pH 5 that provide a clinically effective plasma level, supported by further allegations of specific release percentages and PK data (Compl. ¶93-96). ¶93-96 col. 2:14-16

Identified Points of Contention

  • Scope Question: A central issue for the ’057 Patent will be the construction of the functional limitation "provide a clinically effective plasma level of doxycycline." The patentee will argue this term is defined by the extensive pharmacokinetic data in the specification, while the defendant may argue the term is indefinite under 35 U.S.C. § 112.
  • Technical Question: Assuming the term is not indefinite, the factual question remains whether the specific release profile of the accused product at pH 5, as documented in the ANDA, is one that provides the "clinically effective plasma level" defined by the patent. This will likely involve competing expert analyses of the underlying formulation data.

V. Key Claim Terms for Construction

The Term: "controlled release polymer composition" (’652 Patent, claim 1; ’057 Patent, claim 1)

Context and Importance

This term defines the core technological component responsible for the claimed dissolution profile. Its construction will determine what specific coating formulations are covered by the patents.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: The specification provides a broad list of suitable materials, including various classes of enteric polymers, water-soluble polymers, and plasticizers, suggesting the term is not limited to a single combination (e.g., ’652 Patent, col. 9:1-38; col. 13:3-15).
  • Evidence for a Narrower Interpretation: The specification provides specific exemplary formulations, such as the blend of hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose (HPMC) detailed in Table 1 (’652 Patent, col. 19:54-63). A defendant might argue that the invention is limited to these specific disclosed embodiments.

The Term: "clinically effective plasma level" (’057 Patent, claim 1)

Context and Importance

This is a functional limitation at the heart of Claim 1 of the ’057 Patent. The entire infringement analysis for this claim turns on whether the accused product achieves this result. Practitioners may focus on this term as a potential indefiniteness challenge.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: The patentee may argue the term is a general descriptor for achieving the therapeutic goal of the antibiotic, a concept well understood by a person of ordinary skill in the art.
  • Evidence for a Narrower Interpretation: The patent itself appears to define what constitutes a "clinically effective" level by providing specific pharmacokinetic (Cmax and AUC) ranges for various dosage strengths in the specification and in dependent claims (e.g., ’057 Patent, claim 2; col. 6:40-65). The patentee will likely argue these values provide the necessary objective boundaries for the term, while a defendant may argue the claim itself must recite those boundaries.

VI. Other Allegations

Indirect Infringement

The complaint alleges induced infringement, stating that upon FDA approval, Defendants will market and distribute the ANDA product with a product label and insert that will include instructions for its administration. These instructions would allegedly cause healthcare professionals and patients to directly infringe the claims (Compl. ¶72, ¶111, ¶148).

Willful Infringement

The complaint alleges that Defendants had actual and constructive notice of the patents-in-suit prior to filing their ANDA Supplement (Compl. ¶73, ¶112, ¶149). It further alleges that Defendants' Paragraph IV certification lacked an adequate justification and that their failure to contest infringement in the required detailed statement renders the case "exceptional" under 35 U.S.C. § 285, warranting an award of attorneys' fees (Compl. ¶75, ¶114, ¶151).

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

  • A central issue will be one of validity: Given the complaint's allegation that Defendants did not contest infringement in their Paragraph IV notice, the case may hinge entirely on whether Defendants can prove by clear and convincing evidence that the asserted claims are invalid, for instance as obvious over prior art controlled-release antibiotic formulations.
  • A key evidentiary question will be one of factual proof: Should infringement be contested, the dispute will turn on a technical, data-driven analysis of Defendants' confidential ANDA submission. The question for the court will be whether that data demonstrates that the accused product's in vitro dissolution and in vivo pharmacokinetic performance meet the specific numerical limitations recited in the patent claims.
  • An underlying legal question will be one of claim scope: The viability of certain claims, particularly in the ’057 Patent, may depend on the construction of the functional term "clinically effective plasma level." The court will need to determine if the specification provides sufficient description to lend objective, definite meaning to this term, or if it renders the claim indefinite.