Shionogi Inc v. Zydus Pharma USA Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Shionogi Inc. (Delaware) and Andrx Labs, L.L.C. (Delaware)
  • Defendant: Zydus Pharmaceuticals (USA) Inc. (New Jersey)
  • Plaintiff’s Counsel: Walsh Pizzi O'Reilly Falanga LLP
• Case Identification: 3:18-cv-12898, D.N.J., 08/16/2018
• Venue Allegations: Venue is alleged to be proper in the District of New Jersey because Defendant is organized under the laws of New Jersey, resides in the district, and has committed acts of infringement there.
• Core Dispute: Plaintiffs allege that Defendant’s Abbreviated New Drug Application (ANDA) for generic extended-release metformin hydrochloride tablets constitutes an act of infringement of two patents covering the formulation and method of use for Plaintiffs’ branded drug, FORTAMET®.
• Technical Context: The dispute centers on controlled-release pharmaceutical formulations for metformin, a widely prescribed oral antihyperglycemic drug for managing Type 2 diabetes mellitus.
• Key Procedural History: This action was initiated under the Hatch-Waxman Act following a Notice Letter dated July 2, 2018, in which Defendant Zydus notified Plaintiffs that it had filed an ANDA containing a Paragraph IV certification, asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed by its proposed generic product.

Case Timeline

Date	Event
2000-11-03	Priority Date for ’459 and ’866 Patents
2004-09-14	U.S. Patent No. 6,790,459 Issues
2005-03-15	U.S. Patent No. 6,866,866 Issues
2018-07-02	Defendant sends ANDA Notice Letter to Plaintiffs
2018-08-16	Complaint Filed

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

U.S. Patent No. 6,790,459: "Methods for Treating Diabetes Via Administration of Controlled Release Metformin" (Issued Sep. 14, 2004)

The Invention Explained

• Problem Addressed: The patent describes that conventional, immediate-release metformin is a short-acting drug requiring twice or three-times daily dosing, which can lead to gastrointestinal side effects and issues with patient compliance (’459 Patent, col. 2:5-10). Furthermore, the bioavailability of immediate-release metformin is decreased when taken with food (’459 Patent, col. 2:25-35).
• The Patented Solution: The invention is a method of treating non-insulin-dependent diabetes mellitus (NIDDM) by administering a controlled-release metformin formulation on a once-a-day basis. The key feature of the method is that the formulation provides a specific pharmacokinetic profile, namely a mean time to maximum plasma concentration (Tmax) of 5.5 to 7.5 hours after administration (’459 Patent, col. 3:25-34). This delayed peak is intended to coincide with the time when the body’s natural glucose production is highest (e.g., overnight), particularly when the dose is taken with an evening meal (’459 Patent, col. 5:8-14). Figure 1 of the patent graphically contrasts this delayed peak with the faster peak of the prior art drug, Glucophage (’459 Patent, Fig. 1).
• Technical Importance: This method sought to improve patient compliance through once-daily dosing and potentially reduce side effects by avoiding sharp peaks in drug concentration, while timing the drug’s maximum effect to counteract the patient’s highest period of glucose production (’459 Patent, col. 9:1-12).

Key Claims at a Glance

• The complaint asserts at least independent claim 1 (Compl. ¶26).
• Claim 1 is a method claim with the following essential elements:
  • A method for lowering blood glucose levels in human patients needing treatment for NIDDM.
  • Comprising orally administering to human patients on a once-a-day basis at least one oral controlled release dosage form.
  • The dosage form comprises an effective dose of metformin or a pharmaceutically acceptable salt thereof.
  • Following a single dose administration after dinner, the dosage form provides a mean Tmax of metformin from 5.5 to 7.5 hours.
  • For a 2000 mg once-a-day dose, the administration provides specific mean AUC (area under the curve) and Cmax (maximum concentration) values on the first and 14th day of administration.
• The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 6,866,866: "Controlled Release Metformin Compositions" (Issued Mar. 15, 2005)

The Invention Explained

• Problem Addressed: Similar to its companion patent, the ’866 Patent addresses the need for a metformin formulation that avoids the frequent dosing and gastrointestinal side effects associated with immediate-release versions (’866 Patent, col. 2:3-17).
• The Patented Solution: This patent claims the pharmaceutical composition itself, rather than the method of treatment. The invention is a controlled-release oral dosage form of metformin designed for once-a-day administration that achieves the same specific pharmacokinetic profile as described in the ’459 Patent: a mean Tmax of 5.5 to 7.5 hours after being taken with dinner (’866 Patent, Abstract; col. 3:22-35). The specification discloses an osmotic tablet structure, comprising a core with the active drug and a surrounding membrane with at least one passageway for drug release (’866 Patent, col. 9:55-col. 10:43).
• Technical Importance: The patent claims a specific drug product formulation that provides a desirable pharmacokinetic profile, enabling a more convenient and potentially better-tolerated treatment regimen for Type 2 diabetes (’866 Patent, col. 2:11-17).

Key Claims at a Glance

• The complaint asserts at least independent claim 1 (Compl. ¶30).
• Claim 1 is a composition claim with the following essential elements:
  • A controlled release oral dosage form for the reduction of serum glucose levels in human patients with NIDDM.
  • Comprising an effective dose of metformin or a pharmaceutically acceptable salt thereof and a controlled-release carrier.
  • The dosage form is suitable for providing once-a-day oral administration.
  • Following oral administration of a single dose, the dosage form provides a mean Tmax of metformin from 5.5 to 7.5 hours after administration following dinner.
• The complaint does not explicitly reserve the right to assert dependent claims.

III. The Accused Instrumentality

• Product Identification: Defendant’s Metformin Hydrochloride Extended Release 500 mg and 1000 mg tablets, for which ANDA No. 211903 was filed with the FDA (Compl. ¶1).
• Functionality and Market Context: The complaint alleges that by filing its ANDA, Defendant has represented to the FDA that its proposed generic products have the same active ingredient, method of administration, dosage form, and strength as Plaintiffs' FORTAMET® tablets (Compl. ¶18). It is further alleged that the accused products will be bioequivalent to FORTAMET® and will be marketed for the same indication: to improve glycemic control in adults with Type 2 diabetes mellitus (Compl. ¶5, ¶18).

IV. Analysis of Infringement Allegations

The infringement theory is based on Defendant's submission of ANDA No. 211903, an act of infringement under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶22, ¶29). The core of the allegation is that Defendant's product, by being bioequivalent to FORTAMET®, will necessarily exhibit the pharmacokinetic properties claimed in the patents when used as directed by its proposed label.

’459 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A method for lowering blood glucose levels... comprising orally administering to human patients on a once-a-day basis at least one oral controlled release dosage form	Defendant's proposed product is an extended-release dosage form intended for once-daily administration, and its proposed label will instruct users to take it in this manner to lower blood glucose.	¶18, ¶24, ¶26	col. 21:11-20
wherein... the dosage form provides a mean time to maximum plasma concentration (Tmax) of metformin at from 5.5 to 7.5 hours after administration following dinner	Because Defendant's product is represented as bioequivalent to FORTAMET®, Plaintiffs allege it will produce the same pharmacokinetic profile, including the claimed Tmax range, when administered as directed.	¶18, ¶26	col. 21:21-25
and the administration of the at least one metformin dosage form provides a mean AUC... and a mean Cmax... for administration of a 2000 mg once-a-day dose of metformin.	Plaintiffs allege that Defendant's product, when administered at the specified dose, will meet the claimed AUC and Cmax pharmacokinetic parameters due to its bioequivalence with FORTAMET®.	¶18, ¶26	col. 21:25-30

’866 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A controlled release oral dosage form for the reduction of serum glucose levels... comprising an effective dose of metformin... said dosage form being suitable for providing once-a-day oral administration	Defendant's product is a controlled-release oral tablet containing metformin hydrochloride, designed for once-daily use to treat Type 2 diabetes.	¶1, ¶18, ¶30	col. 21:48-57
wherein following oral administration of a single dose, the dosage form provides a mean time to maximum plasma concentration (Tmax) of the metformin from 5.5 to 7.5 hours after administration following dinner.	Based on the allegation of bioequivalence to FORTAMET®, Plaintiffs allege Defendant's product will exhibit a mean Tmax within the claimed range when taken with dinner as directed by its proposed label.	¶18, ¶30	col. 21:58-61

• Identified Points of Contention:
  • Pharmacokinetic Questions: The central dispute will likely be factual: does Defendant’s product, as formulated, actually produce a mean Tmax within the 5.5 to 7.5-hour range specified in the claims? Defendant’s Paragraph IV certification of non-infringement suggests it may contend its product has a different pharmacokinetic profile. Figure 4 of both patents, showing steady-state plasma concentration in NIDDM patients, establishes a clinical benchmark that will be important for comparing the accused product's performance (’459 Patent, Fig. 4).
  • Scope Questions: What is the proper construction of "controlled release oral dosage form"? The specifications of both patents describe a specific osmotic-pump tablet technology. A question may arise as to whether the claims are limited to this structure or if they cover any formulation that meets the pharmacokinetic limitations, regardless of the underlying release mechanism.

V. Key Claim Terms for Construction

• The Term: "mean time to maximum plasma concentration (Tmax) ... from 5.5 to 7.5 hours"

• Context and Importance: This pharmacokinetic range is the core inventive concept recited in the independent claims of both patents. The entire infringement analysis for both the method and composition claims hinges on whether the accused product falls within this specific numerical range. Practitioners may focus on this term because even a small deviation in the measured Tmax of the accused product could place it outside the literal scope of the claims.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The claims themselves define the invention by its functional pharmacokinetic result, not its structure. The language "provides a mean time" suggests any formulation achieving this result is covered.
  • Evidence for a Narrower Interpretation: The patents provide detailed clinical study data showing how Tmax was measured, including specific patient populations (healthy subjects vs. NIDDM patients) and conditions (fasted vs. fed state) (’459 Patent, col. 15:37-col. 18:50; Tables 1 & 3). A party could argue that the term must be interpreted in the specific context of these studies, potentially narrowing how Tmax for an accused product should be assessed.

• The Term: "controlled release oral dosage form"

• Context and Importance: This term defines the subject matter of the ’866 Patent’s composition claim. Its scope is critical because if it is construed narrowly to cover only the specific osmotic tablet technology disclosed in the specification, Defendant might avoid infringement if its product uses a different technology (e.g., a hydrophilic matrix system) to achieve a similar result.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The term itself is general. The claims do not recite the specific structural components (e.g., "membrane," "passageway") of the preferred embodiment, suggesting an intent to claim more broadly than the disclosed examples.
  • Evidence for a Narrower Interpretation: The detailed description focuses heavily on an osmotic tablet with a core, a semipermeable membrane, and a laser-drilled passageway (’866 Patent, col. 10:37-col. 11:43; Examples 1-3). A defendant may argue that the claims should be limited to this disclosed embodiment, as it is presented as the invention itself.

VI. Other Allegations

• Indirect Infringement: The complaint alleges both induced and contributory infringement of the ’459 Patent (Compl. ¶23-25). Inducement is based on the allegation that Defendant’s proposed package insert and instructions will actively encourage and instruct medical practitioners and patients to administer the generic drug in a manner that directly infringes the patented method (i.e., once-daily for treating NIDDM) (Compl. ¶24). Contributory infringement is alleged on the basis that the accused product is especially made for use in an infringing manner and is not a staple article suitable for substantial non-infringing use (Compl. ¶25).
• Willful Infringement: The complaint does not contain an explicit allegation of willful infringement.

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

This case appears to center on the interpretation and application of pharmacokinetic data. The primary questions for the court will likely be:

• A core issue will be one of factual bioequivalence: Does the clinical data for Defendant’s proposed generic product demonstrate a mean Tmax that falls within the precise 5.5 to 7.5-hour window required by the asserted claims, or does its formulation result in a pharmacokinetic profile that is outside the patents’ literal scope?
• A key legal question will be one of definitional scope: Is the term "controlled release oral dosage form" defined by the functional pharmacokinetic parameters claimed, or can it be narrowed to the specific osmotic-pump tablet structure detailed in the patents’ specifications, potentially creating a path for non-infringement via alternative formulation technology?