DCT
1:18-cv-01564
Shionogi Inc v. Amneal Pharma LLC
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Shionogi Inc. (Delaware) and Andrx Labs, L.L.C. (Delaware)
- Defendant: Amneal Pharmaceuticals, LLC (Delaware)
- Plaintiff’s Counsel: Bayard, P.A.; Wilmer Cutler Pickering Hale and Dorr LLP
- Case Identification: 1:18-cv-01564, D. Del., 10/11/2018
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because the Defendant is a Delaware corporation and therefore resides in the district.
- Core Dispute: Plaintiffs allege that Defendant’s Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiffs' FORTAMET® tablets constitutes an act of infringement of two patents related to controlled-release metformin formulations.
- Technical Context: The technology concerns oral drug delivery systems for metformin, a primary treatment for Type 2 diabetes, designed to release the drug over an extended period to enable once-daily dosing.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendant Amneal's submission of ANDA No. 212148. Amneal sent a notice letter dated August 27, 2018, with a Paragraph IV certification asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed by its proposed generic product. The patents are listed in the FDA's "Orange Book" as covering the branded drug FORTAMET®.
Case Timeline
| Date | Event |
|---|---|
| 2000-11-03 | Priority Date for ’459 and ’866 Patents |
| 2004-09-14 | U.S. Patent No. 6,790,459 Issued |
| 2005-03-15 | U.S. Patent No. 6,866,866 Issued |
| 2018-08-27 | Date of Amneal's Paragraph IV Notice Letter |
| 2018-10-11 | 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”
The Invention Explained
- Problem Addressed: The patent describes that metformin, a widely prescribed drug for non-insulin-dependent diabetes mellitus (NIDDM), is a short-acting drug requiring frequent (e.g., twice or three times daily) dosing. This can lead to gastrointestinal side effects and challenges with patient compliance (’459 Patent, col. 1:5-14).
- The Patented Solution: The patent discloses a method of treating NIDDM by administering a controlled-release metformin dosage form once per day. The method is defined by the specific pharmacokinetic profile achieved, particularly a mean time to maximum plasma concentration (Tmax) of 5.5 to 7.5 hours after administration, preferably with an evening meal. This timing is intended to counteract the body's natural peak glucose production at night (’459 Patent, Abstract; col. 9:1-10).
- Technical Importance: This approach sought to improve both the convenience and therapeutic effectiveness of metformin therapy by enabling once-daily dosing and synchronizing peak drug levels with peak patient metabolic need (’459 Patent, col. 1:14-17).
Key Claims at a Glance
- The complaint asserts at least independent claim 1 (Compl. ¶26).
- Independent Claim 1 requires:
- A method for lowering blood glucose in NIDDM patients.
- Comprising orally administering, on a once-a-day basis, at least one oral controlled release dosage form of metformin.
- Wherein a single dose provides a mean Tmax of metformin from 5.5 to 7.5 hours after administration following dinner.
- Wherein a 2000 mg dose provides specific mean AUC and Cmax values on day 1 and day 14 of administration.
- The prayer for relief refers to "one or more claims," preserving the right to assert additional claims (Compl. ¶(a), p. 8).
U.S. Patent No. 6,866,866 - “Controlled Release Metformin Compositions”
The Invention Explained
- Problem Addressed: As with its related method patent, the ’866 Patent addresses the problems associated with the short-acting nature of conventional metformin, including the need for multi-day dosing and associated side effects (’866 Patent, col. 1:5-17).
- The Patented Solution: The patent claims the controlled-release oral dosage form itself—the composition—that is suitable for once-daily administration. The composition is defined by its performance: it must be capable of providing a mean Tmax of metformin between 5.5 and 7.5 hours after being administered following dinner (’866 Patent, Abstract; col. 3:20-32). The specification also describes a physical structure for achieving this, comprising a drug core surrounded by a membrane with at least one passageway for drug release (’866 Patent, col. 3:37-43).
- Technical Importance: By claiming the physical product, this patent provides protection for the drug formulation that enables the therapeutic method, complementing the protection of the ’459 patent (’866 Patent, col. 2:54-58).
Key Claims at a Glance
- The complaint asserts at least independent claim 1 (Compl. ¶30).
- Independent Claim 1 requires:
- A controlled release oral dosage form for reducing serum glucose levels in NIDDM patients.
- Comprising an effective dose of metformin and a controlled-release carrier.
- Being suitable for once-a-day oral administration.
- Wherein a single dose provides a mean Tmax of metformin from 5.5 to 7.5 hours after administration following dinner.
- The prayer for relief refers to "one or more claims," preserving the right to assert additional claims (Compl. ¶(a), p. 8).
III. The Accused Instrumentality
Product Identification
The accused products are Amneal’s Metformin Hydrochloride Extended Release 500 mg and 1000 mg tablets, for which Amneal seeks FDA approval via ANDA No. 212148 (the "Amneal ANDA Products") (Compl. ¶¶ 1, 16).
Functionality and Market Context
The Amneal ANDA Products are alleged to be a generic version of Shionogi’s branded FORTAMET® tablets (Compl. ¶1). By filing its ANDA, Amneal has represented to the FDA that its proposed generic product has the same active ingredient, dosage form, strength, and method of administration as FORTAMET®, and that it is bioequivalent to FORTAMET® (Compl. ¶18). The infringement allegations rely on this representation of bioequivalence as evidence that Amneal's product will necessarily possess the pharmacokinetic characteristics claimed in the patents-in-suit (Compl. ¶¶ 26, 30).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
- ’459 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method for lowering blood glucose levels in human patients needing treatment for non-insulin-dependent diabetes mellitus (NIDDM)... | Amneal’s proposed product label will allegedly instruct medical practitioners and patients to use the Amneal ANDA Products for this purpose. | ¶24 | col. 5:15-20 |
| comprising orally administering to human patients on a once-a-day basis at least one oral controlled release dosage form... | The Amneal ANDA Products are oral controlled-release tablets intended for once-daily administration, and the proposed label will instruct such use. | ¶¶18, 24 | col. 3:25-29 |
| wherein following oral administration of a single dose, 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... | The complaint alleges that because Amneal's product must be bioequivalent to FORTAMET® to gain FDA approval, it will necessarily provide the claimed Tmax profile when administered as instructed. | ¶¶18, 26 | col. 3:29-32 |
| and the administration of the at least one metformin dosage form provides a mean AUC...and a mean Cmax...on the first day...and a mean AUC...and a mean Cmax...on the 14th day of administration, for administration of a 2000 mg once-a-day dose of metformin. | The complaint alleges that Amneal's representation of bioequivalence to FORTAMET® means its product will also meet the specific AUC and Cmax pharmacokinetic parameters recited in the claim for a 2000 mg dose. | ¶¶18, 26 | col. 21:24-30 |
Identified Points of Contention:
- Evidentiary Question: The infringement allegation is based on the legal fiction of 35 U.S.C. § 271(e)(2), where the filing of the ANDA is the act of infringement. The central factual question will be whether the data in Amneal's ANDA, once produced in discovery, actually shows that its product meets the specific Tmax, Cmax, and AUC values required by claim 1 under the specified conditions (Compl. ¶19).
- Scope Question: A potential dispute may arise over the term "following dinner." The parties may contest whether this requires administration with a substantial meal, as described in the patent's clinical studies, and whether Amneal's proposed label instructions will result in administration under conditions that fall within the claim's scope (’459 Patent, col. 16:49-53).
’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 in human patients with NIDDM... | The Amneal ANDA Products are controlled-release oral dosage forms intended for this therapeutic use. | ¶¶16, 18 | col. 2:54-58 |
| said dosage form being suitable for providing once-a-day oral administration of the metformin... | The product is formulated as an extended-release tablet designed for once-daily dosing. | ¶18 | col. 3:25-29 |
| 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. | The complaint alleges that Amneal's representation of bioequivalence to FORTAMET® serves as a representation that its product is a composition that provides this specific pharmacokinetic result. | ¶¶18, 30 | col. 4:18-24 |
- Identified Points of Contention:
- Evidentiary Question: As with the ’459 patent, the dispositive issue for infringement will be whether Amneal's product actually has the structure and formulation to produce the claimed pharmacokinetic profile. The complaint alleges this by inference (Compl. ¶30), but it must be proven with data from the ANDA.
- Technical Question: Infringement of this composition claim depends on the inherent properties of the Amneal ANDA Products. A key question is whether the product, by its nature, is a "controlled release oral dosage form" that provides the claimed Tmax. This contrasts with the method claim, which requires an action by a user.
V. Key Claim Terms for Construction
The Term: "following dinner" (in independent claim 1 of both patents)
- Context and Importance: This phrase is critical as it defines the condition under which the claimed Tmax must be achieved. Infringement will depend on whether Amneal's product is shown to meet the Tmax limitation under a proper construction of this term. Practitioners may focus on this term because pharmacokinetic results can vary significantly between fed and fasting states.
- Intrinsic Evidence for a Broader Interpretation: The specification sometimes uses more general phrasing, such as "administered once-a-day, ideally with or after a meal, preferably with or after the evening meal," which might support an argument that "following dinner" is not a rigid limitation but refers generally to administration in a fed state in the evening (’459 Patent, col. 5:9-12).
- Intrinsic Evidence for a Narrower Interpretation: The claims themselves, as well as the Abstract and key clinical study descriptions, specifically use the term "dinner" or "dinnertime" (’459 Patent, Abstract; col. 21:16-18). A defendant could argue this ties the claim to the specific conditions of the patent's supporting clinical trials, requiring administration immediately after a substantial evening meal.
The Term: "mean time to maximum plasma concentration (Tmax)" (in independent claim 1 of both patents)
- Context and Importance: The specific numerical range for the Tmax is the central technical limitation of the primary independent claims. The definition of "mean" and the population used for its calculation will be crucial for comparing Amneal's ANDA data to the claim language.
- Intrinsic Evidence for Interpretation: The patent provides an explicit definition: ""mean", when preceding a pharmacokinetic value (e.g. mean Tmax) represents the arithmetic mean value of the pharmacokinetic value taken from a population of patients unless otherwise specified" (’459 Patent, col. 8:11-14). While this appears clear, a dispute could arise over what constitutes a relevant "population of patients," as the patent reports data from both healthy volunteers and NIDDM patients, which could yield different results (’459 Patent, col. 16:39-42; col. 21:3-4).
VI. Other Allegations
- Indirect Infringement: The complaint alleges that once Amneal's ANDA is approved, its commercial activities will induce and contribute to infringement of the ’459 patent. Inducement is alleged based on the proposed package insert, which will instruct patients and physicians to use the product in an infringing manner (i.e., once-daily to treat diabetes). The complaint alleges Amneal knows of the patents and intends for this infringement to occur (Compl. ¶¶ 23-24). Contributory infringement is alleged on the grounds that the Amneal ANDA Products are not suitable for substantial non-infringing use (Compl. ¶25).
- Willful Infringement: The complaint does not include a specific allegation of willful infringement or a request for enhanced damages under 35 U.S.C. § 284.
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be an evidentiary one, driven by discovery: Does the pharmacokinetic data contained within Amneal's confidential ANDA submission, when measured against the claim limitations, demonstrate that its product is "bioequivalent" in the specific manner required by the patents? The case will likely hinge on a battle of experts analyzing the ANDA data.
- A key legal question will be one of claim construction: How narrowly will the court construe the term "following dinner"? The outcome will determine the precise experimental conditions under which Amneal's product must be tested to assess infringement, potentially narrowing or broadening the scope of the patents.
- Finally, a foundational question for the litigation will be patent validity: Amneal's Paragraph IV certification asserts the patents are invalid (Compl. ¶17). The court will have to determine if Amneal can prove by clear and convincing evidence that the claims, defined by specific pharmacokinetic outcomes, were anticipated or rendered obvious by drug formulations existing before November 2000.