DCT
2:16-cv-04921
Horizon Pharma Inc v. Mylan Pharma Inc
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Horizon Pharma, Inc., Horizon Pharma USA, Inc., and Pozen Inc. (Delaware, Illinois, North Carolina)
- Defendant: Mylan Pharmaceuticals Inc., Mylan Laboratories Limited, and Mylan, Inc. (West Virginia, India, Pennsylvania)
- Plaintiff’s Counsel: McCARTER & ENGLISH, LLP
- Case Identification: 2:16-cv-04921, D.N.J., 08/11/2016
- Venue Allegations: Plaintiffs allege venue is proper in the District of New Jersey based on Defendants' business activities, including the sale of pharmaceutical products within the district.
- Core Dispute: Plaintiffs allege that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market generic versions of Plaintiffs' VIMOVO® product constitutes an act of patent infringement under the Hatch-Waxman Act.
- Technical Context: The technology concerns a coordinated-delivery pharmaceutical composition combining an anti-inflammatory drug (naproxen) with a stomach-acid reducing agent (esomeprazole) to treat arthritis while minimizing the risk of gastric ulcers.
- Key Procedural History: The patents-in-suit are listed in the U.S. Food and Drug Administration's "Orange Book" in connection with VIMOVO®. The litigation was triggered by Defendants' filing of a Paragraph IV certification with the FDA, asserting that their proposed generic product would not infringe the asserted patents or that the patents are invalid. The complaint identifies numerous other pending litigations filed by Plaintiffs against other generic drug manufacturers concerning the same family of patents, suggesting a concerted strategy to defend the VIMOVO® patent estate.
Case Timeline
| Date | Event |
|---|---|
| 2001-06-01 | ’695 Patent Priority Date |
| 2008-09-09 | ’698 Patent Priority Date |
| 2009-06-25 | ’621 Patent Priority Date |
| 2015-02-03 | ’621 Patent Issue Date |
| 2015-12-29 | ’698 Patent Issue Date |
| 2016-02-26 | Defendant files Paragraph IV certification for ’698 Patent |
| 2016-05-24 | ’695 Patent Issue Date |
| 2016-07-19 | Defendant files Paragraph IV certification for ’695 Patent |
| 2016-08-11 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 8,945,621
- Patent Identification: U.S. Patent No. 8,945,621, "Method for Treating a Patient at Risk for Developing an NSAID-Associated Ulcer," issued February 3, 2015.
The Invention Explained
- Problem Addressed: The patent describes the substantial risk of upper gastrointestinal ulcers and related complications for patients undergoing chronic therapy with non-steroidal anti-inflammatory drugs (NSAIDs) like naproxen ( ’621 Patent, col. 1:21-28). The risk is compounded by factors including patient age and concomitant aspirin use, and is attributed to the combination of gastric acid and the NSAID's effect on the gastrointestinal mucosa (’621 Patent, col. 1:36-48).
- The Patented Solution: The patent discloses a method of treatment using a single unit dosage form that provides a "coordinated release" of two active ingredients (’621 Patent, col. 2:1-10). It administers esomeprazole, a proton pump inhibitor, in an immediate-release formulation to quickly raise the stomach's pH. It then delivers naproxen from an enteric-coated core, which is designed to release the NSAID only after the gastric pH has been raised to a less acidic level (pH 3.5 or higher), thereby protecting the stomach lining from the NSAID's initial contact (’621 Patent, Abstract; col. 2:1-10).
- Technical Importance: This method provides a therapeutic approach that integrates pain and inflammation relief with built-in gastrointestinal protection in a single pill, potentially improving patient compliance and safety during long-term NSAID treatment (’621 Patent, col. 1:52-59).
Key Claims at a Glance
- The complaint asserts infringement of one or more claims without specifying which ones (Compl. ¶53). Independent claim 1 is representative:
- A method of reducing the incidence of NSAID-associated gastric ulcers in patients taking low dose aspirin by administering a unit dose form comprising:
- (a) 20 mg of esomeprazole in a form sufficient to raise the gastric pH to at least 3.5;
- (b) 500 mg of naproxen;
- wherein the unit dose form provides for "coordinated release," with the esomeprazole being released independent of pH;
- and wherein the naproxen release is delayed, with less than 10% released after 2 hours in a low-pH environment (0.1N HCl).
U.S. Patent No. 9,220,698
- Patent Identification: U.S. Patent No. 9,220,698, "Method for Delivering a Pharmaceutical Composition to Patient in Need Thereof," issued December 29, 2015.
The Invention Explained
- Problem Addressed: The patent addresses the need for a clinically effective therapy that delivers both naproxen and esomeprazole in a manner that achieves specific, desirable pharmacodynamic (PD) and pharmacokinetic (PK) outcomes (’698 Patent, col. 1:41-48). This involves not just separating the release of the drugs, but ensuring their absorption profiles in the body produce both effective pain relief and sustained stomach acid suppression.
- The Patented Solution: The invention is a method of treatment involving twice-daily (AM and PM) administration of a unit dose form containing naproxen and esomeprazole. The claims are directed not to the composition's structure, but to the specific clinical results it "targets" and achieves (’698 Patent, col. 2:1-22). These results are defined by specific numerical ranges for the drugs' peak plasma concentration (Cmax), time to peak concentration (Tmax), and total exposure over time (Area Under the Curve, or AUC), as well as the resulting percentage of time the gastric pH remains above 4.0 (’698 Patent, cl. 1).
- Technical Importance: By claiming specific PK/PD profiles, the patent attempts to protect the precise clinical performance of the drug product, which is a key attribute demonstrated during the FDA approval process and is what a generic manufacturer must replicate to prove bioequivalence.
Key Claims at a Glance
- The complaint asserts infringement generally (Compl. ¶76). Independent claim 1 is representative:
- A method for treating arthritis by orally administering AM and PM doses of a unit dose form containing about 500 mg naproxen and esomeprazole, which "target":
- A specific pharmacokinetic profile for naproxen, including distinct mean Cmax values for the AM and PM doses (86.2 µg/mL ±20% and 76.8 µg/mL ±20%, respectively).
- A specific pharmacokinetic profile for esomeprazole, defined by mean AUC values over different time intervals for the AM and PM doses.
- A specific pharmacodynamic outcome, wherein the mean time the intragastric pH remains at or above 4.0 is at least about 60% over a 24-hour period.
Multi-Patent Capsule: U.S. Patent No. 9,345,695
- Patent Identification: U.S. Patent No. 9,345,695 ("’695 Patent"), "Pharmaceutical Compositions for the Coordinated Delivery of NSAIDs," issued May 24, 2016.
- Technology Synopsis: The ’695 patent claims the pharmaceutical composition itself, rather than a method of use. The invention is a unit dosage form comprising a core that contains an NSAID (e.g., naproxen). This core is surrounded by an enteric coating that prevents the NSAID's release until the ambient pH is 3.5 or higher. An outer layer containing an acid inhibitor (e.g., esomeprazole) is applied over the enteric-coated core, and this outer layer is formulated for immediate release regardless of pH (’695 Patent, Abstract; cl. 1).
- Asserted Claims: The complaint asserts infringement of one or more claims without further specification (Compl. ¶98).
- Accused Features: The accused feature is the physical structure of Mylan's proposed generic drug, which is alleged to be a copy of the VIMOVO® product and thus embody the claimed multilayer, coordinated-release composition (Compl. ¶83).
III. The Accused Instrumentality
- Product Identification: The accused instrumentalities are Defendants' proposed generic "naproxen and esomeprazole magnesium delayed-release tablets" in 375 mg/20 mg and 500 mg/20 mg strengths ("Mylan's ANDA Product") (Compl. ¶20).
- Functionality and Market Context: The complaint alleges that Mylan's ANDA Product is a generic version of Plaintiffs' VIMOVO® Delayed-Release Tablets (Compl. ¶20). As a generic, the product is designed to be bioequivalent to VIMOVO®, meaning it is intended to provide the same clinical effect and safety profile. The infringement alleged is the "artificial" act of filing ANDA No. 204920 with the FDA to seek approval for this generic product, an act that creates a justiciable controversy under 35 U.S.C. § 271(e)(2) (Compl. ¶¶22, 38).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
8,945,621 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of reducing the incidence of NSAID-associated gastric ulcers... comprising administering... a pharmaceutical composition... | The proposed product label for Mylan's ANDA Product will instruct physicians and patients to administer the drug for its approved indications, which include decreasing the risk of NSAID-associated ulcers. | ¶¶10, 39 | col. 1:12-19 |
| (a) 20 mg of esomeprazole... in a form and route sufficient to raise the gastric pH... to at least 3.5... | Mylan's ANDA Product is formulated to contain 20 mg of esomeprazole magnesium in an immediate-release form designed to be bioequivalent to VIMOVO®, thereby raising gastric pH. | ¶20 | col. 2:58-59 |
| (b) 500 mg of naproxen... | Mylan's ANDA Product is formulated to contain a therapeutically effective amount of naproxen, including a 500 mg dosage strength. | ¶20 | col. 2:62-63 |
| wherein said unit dose form provides for coordinated release... wherein at least a portion of said esomeprazole... is released independent of the pH... | The product is alleged to be a structural and functional copy of VIMOVO®, which has an immediate-release esomeprazole component. | ¶20 | col. 2:1-5 |
| wherein the unit dosage form releases less than 10% of the naproxen... after 2 hours when tested using the USP Paddle Method in 1000 ml of 0.1N HCl... | The product is alleged to contain naproxen in an enteric-coated or delayed-release form that restricts its release in acidic conditions, consistent with the formulation of VIMOVO®. | ¶20 | col. 3:28-34 |
- Identified Points of Contention:
- Scope Questions: The claims are for a method of treatment. Infringement will depend on whether the product label for Mylan's ANDA Product will instruct or encourage users to perform the claimed method. A central question may be whether Mylan's proposed label will include the indication for "decrease the risk of developing stomach ulcers" as the VIMOVO® label does (Compl. ¶10).
- Technical Questions: The analysis will depend on the specifications and bioequivalence data within Mylan's confidential ANDA filing. A key question is whether Mylan's formulation exhibits the specific dissolution profiles required by the claims for both the esomeprazole and naproxen components.
9,220,698 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method for treating osteoarthritis, rheumatoid arthritis... comprising orally administering AM and PM unit dose forms... | The proposed product label for Mylan's ANDA Product will instruct for twice-daily dosing for approved indications such as osteoarthritis. | ¶¶10, 62 | col. 16:28-34 |
| wherein the naproxen is about 500 mg... and esomeprazole... is released... at a pH of from about 0 or greater... | Mylan's ANDA Product is a generic copy of the 500 mg VIMOVO® tablet, which contains naproxen in a delayed-release core and esomeprazole in an immediate-release outer layer. | ¶¶20, 62 | col. 16:50-65 |
| a) a pk profile for naproxen where the mean Cmax is 86.2 µg/mL (±20%) for the AM dose and 76.8 µg/mL (±20%) for the PM dose... | As a bioequivalent product, Mylan's ANDA Product is expected to achieve the same pharmacokinetic (PK) profile for naproxen as the branded drug. | ¶¶20, 60 | col. 42:8-9 |
| b) a pk profile for esomeprazole where the mean... AUC0-10,am is 1216 hr*ng/mL (±20%)... and AUC0-14,pm is 919 hr*ng/mL (±20%)... | As a bioequivalent product, Mylan's ANDA Product is expected to achieve the same PK profile for esomeprazole as the branded drug. | ¶¶20, 60 | col. 36:5-13 |
| c) the total mean area under the plasma concentration for esomeprazole... (AUC0-24) is about 2134 hr*ng/mL (±20%)... | As a bioequivalent product, Mylan's ANDA Product is expected to achieve the same total daily esomeprazole exposure as the branded drug. | ¶¶20, 60 | col. 36:5-13 |
| and the AM and PM unit dose forms further target a mean % time at which intragastric pH remains at about 4.0 or greater... is at least about 60%. | The bioequivalence of Mylan's ANDA Product is expected to result in the same pharmacodynamic (PD) effect on gastric pH as the branded drug. | ¶¶20, 60 | col. 30:45-53 |
- Identified Points of Contention:
- Scope Questions: A question for the court may be the meaning of the term "target." Does it require that the accused product achieve these PK/PD results in every instance, or that it is merely designed and formulated in a way that is statistically likely to achieve them in a patient population?
- Technical Questions: The central dispute will likely involve a direct comparison of the pharmacokinetic data submitted in Mylan's ANDA with the specific numerical ranges recited in the claims. The question will be whether Mylan's own data proves it falls within the claimed PK/PD windows.
V. Key Claim Terms for Construction
The Term: "coordinated release" (’621 Patent, cl. 1)
Context and Importance: This term is the central feature of the method claimed in the ’621 Patent. Its definition will determine whether a simple sequential release of two drugs is sufficient, or if a more specific, functionally interdependent mechanism is required, thereby shaping the scope of infringement.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claim language itself describes the coordination simply as one component (esomeprazole) being released independent of pH while the other (naproxen) is not released until the pH is 3.5 or higher. This suggests any formulation achieving this sequence meets the definition.
- Evidence for a Narrower Interpretation: The specification describes a specific embodiment of a multilayer tablet with an enteric coat over the naproxen core and an immediate-release layer of esomeprazole on the outside (’621 Patent, col. 3:4-13). A defendant may argue that "coordinated release" should be limited to this specific structural arrangement.
The Term: "target" (’698 Patent, cl. 1)
Context and Importance: The entirety of Claim 1 of the ’698 Patent depends on this term, which links the act of administration to a set of specific PK/PD outcomes. Whether this term implies intent, design, or actual achievement of the subsequent numerical limitations will be critical to the infringement analysis. Practitioners may focus on this term because it sits at the intersection of the product's physical properties and its clinical performance.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The ordinary meaning of "target" suggests an aim or goal. Plaintiffs may argue the claim covers any drug formulated with the intent or design to achieve the specified PK/PD profile, which a generic copy of VIMOVO® inherently would have.
- Evidence for a Narrower Interpretation: A defendant could argue that "target" requires consistent achievement of the claimed PK/PD values in practice. The specification's extensive discussion of clinical trial data showing the achievement of these values may be cited to suggest the term is tied to the actual, measured clinical performance of the drug (’698 Patent, Tables 4, 6, 11).
VI. Other Allegations
- Indirect Infringement: The complaint alleges inducement and contributory infringement under 35 U.S.C. §§ 271(b) and (c) in its declaratory judgment counts (e.g., Compl. ¶45). The factual basis alleged is that Mylan's ANDA Product is a material part of the invention, is "especially made or especially adapted for use in an infringement" of the patented methods, and is not a staple article of commerce suitable for substantial noninfringing use (Compl. ¶¶39, 44). The complaint further alleges that Defendants are aware that their product, if approved, will be used in an infringing manner (Compl. ¶39).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of evidentiary proof from the ANDA: Will the confidential bioequivalence data Mylan submitted to the FDA demonstrate that its proposed generic product meets the specific, numerically-defined pharmacokinetic and pharmacodynamic limitations of the asserted claims in the ’698 patent? The case may turn on a direct comparison of Mylan's clinical data against the patent's claimed performance windows.
- A key question will be one of induced infringement: For the asserted method claims, Plaintiffs will need to show that the proposed product label for Mylan's generic drug will inevitably instruct or encourage medical professionals and patients to use the drug in a manner that performs every step of the claimed methods.
- A final question will be one of structural identity: For the composition claims of the ’695 Patent, the analysis will focus on whether Mylan's proposed product contains the same physical structure as that claimed—specifically, an NSAID core, a pH-sensitive enteric coating, and an immediate-release outer layer containing an acid inhibitor.