I. Executive Summary and Procedural Information
- Parties & Counsel:
- Case Identification: 1:19-cv-00078, D. Del., 12/16/2019
- Venue Allegations: Venue is alleged to be proper on the basis that the Defendant is a foreign corporation not residing in any U.S. district and may therefore be sued in any judicial district.
- Core Dispute: Plaintiffs allege that Defendant’s submission of an Abbreviated New Drug Application (ANDA) seeking to market generic pirfenidone tablets constitutes an act of infringement of fifteen patents associated with Plaintiffs’ drug Esbriet®.
- Technical Context: The dispute centers on pirfenidone, the active ingredient in the drug Esbriet®, which is used to treat Idiopathic Pulmonary Fibrosis (IPF), a rare, progressive, and fatal lung disease.
- Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by Defendant’s submission of ANDA No. 212747 to the FDA. Defendant notified Plaintiffs of its filing via a Paragraph IV Certification notice letter dated December 21, 2018, and a second notice letter dated November 14, 2019, asserting that Plaintiffs' patents are invalid, unenforceable, or will not be infringed. This First Amended Complaint was filed in response to the second notice letter.
Case Timeline
| Date |
Event |
| 2008-11-10 |
Priority Date for ’729 and ’707 Patents |
| 2009-07-28 |
U.S. Patent No. 7,566,729 Issues |
| 2009-12-22 |
U.S. Patent No. 7,635,707 Issues |
| 2014-10-15 |
FDA grants first NDA approval for Esbriet® |
| 2018-12-21 |
Defendant Aizant sends First Notice Letter to Plaintiffs |
| 2019-02-01 |
Plaintiffs file original Complaint |
| 2019-11-14 |
Defendant Aizant sends Second Notice Letter to Plaintiffs |
| 2019-12-16 |
Plaintiffs file First Amended Complaint |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 7,566,729 - "Modifying Pirfenidone Treatment for Patients with Atypical Liver Function"
The Invention Explained
- Problem Addressed: The patent addresses the clinical challenge of managing patients who develop abnormal liver function as an adverse effect of pirfenidone therapy (Compl. ¶21; ’729 Patent, col. 4:46-49). Discontinuing the drug deprives the patient of its therapeutic benefit, but continuing at the full dose may pose safety risks.
- The Patented Solution: The invention provides a method to safely continue treatment. When a patient exhibits a specific level of liver function abnormality (defined as "grade 2"), the daily dose of pirfenidone is temporarily reduced. Once the patient's liver biomarkers return to normal or near-normal levels, the dosage is re-escalated to the full therapeutically effective dose (Compl. ¶21; ’729 Patent, Abstract; col. 2:33-40). This dose modification regimen allows for continued therapy while managing the adverse event.
- Technical Importance: This method provides a protocol for physicians to manage a known side effect of pirfenidone, potentially allowing more patients with Idiopathic Pulmonary Fibrosis to remain on a beneficial therapy long-term (Compl. ¶21; ’729 Patent, col. 4:6-11).
Key Claims at a Glance
- The complaint asserts independent claim 1 (Compl. ¶61).
- The essential elements of claim 1 are:
- A method of administering pirfenidone to treat a patient with idiopathic pulmonary fibrosis (IPF).
- The patient has exhibited a grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration.
- The method comprises: (a) administering pirfenidone at doses lower than 2400 mg/day for a time period, followed by...
- (b) administering pirfenidone at doses of 2400 mg/day or 2403 mg/day.
- The complaint does not explicitly reserve the right to assert other claims of the ’729 Patent, but infringement is alleged for "at least one of the claims" (Compl. ¶61).
U.S. Patent No. 7,635,707 - "Pirfenidone Treatment for Patients with Atypical Liver Function"
The Invention Explained
- Problem Addressed: Like its parent patent, the ’707 Patent addresses the management of patients who exhibit abnormal liver function while on pirfenidone therapy for IPF (Compl. ¶23; ’707 Patent, col. 4:51-54).
- The Patented Solution: This patent claims an alternative management strategy. Claim 1 describes a method where, after identifying a patient with a "grade 2" liver function abnormality, the physician continues to administer the full therapeutic dose of 2400 mg/day or 2403 mg/day (Compl. ¶23; ’707 Patent, col. 2:19-23, claim 1). This approach implies that for certain patients, dose reduction may not be necessary, allowing for uninterrupted administration of the full target dose while biomarkers are monitored.
- Technical Importance: This method offers physicians the flexibility to maintain maximum therapeutic dosage in patients with mild-to-moderate liver function elevations, which may be beneficial if the abnormality is determined to be transient and not indicative of severe liver injury (Compl. ¶23; ’707 Patent, col. 2:19-23).
Key Claims at a Glance
- The complaint asserts independent claim 1 (Compl. ¶70).
- The essential elements of claim 1 are:
- A method of administering pirfenidone to treat a patient with idiopathic pulmonary fibrosis (IPF).
- The patient has exhibited a grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration.
- The method comprises administering to said patient pirfenidone at doses of 2400 mg/day or 2403 mg/day.
- The complaint alleges infringement of "at least one of the claims" of the ’707 Patent (Compl. ¶70).
Multi-Patent Capsule: U.S. Patent No. 8,383,150
- Patent Identification: U.S. Patent No. 8,383,150, "Granulate Formulation of Pirfenidone and Pharmaceutically Acceptable Excipients," issued February 26, 2013 (Compl. ¶37).
- Technology Synopsis: This patent is directed to a specific pharmaceutical formulation of pirfenidone. It claims a granulate formulation containing pirfenidone and particular excipients (inactive ingredients), which is designed to provide desirable pharmacokinetic properties when administered to a patient.
- Asserted Claims: The complaint asserts independent claims 1 and 27 (Compl. ¶135).
- Accused Features: The complaint alleges that the Aizant ANDA Product itself contains the same components recited in claim 1, and that its use in accordance with its label will infringe method claim 27 (Compl. ¶136).
Multi-Patent Capsule: U.S. Patent No. 8,084,475
- Patent Identification: U.S. Patent No. 8,084,475, "Pirfenidone Therapy and Inducers of Cytochrome P450," issued December 27, 2011 (Compl. ¶33).
- Technology Synopsis: This patent addresses a drug-drug interaction. It describes methods for administering pirfenidone therapy that involve avoiding or discontinuing the use of an inducer of the CYP1A2 enzyme, which metabolizes pirfenidone. The claimed method aims to prevent reduced effectiveness of pirfenidone that can occur when a CYP1A2 inducer is co-administered.
- Asserted Claims: The complaint asserts independent claim 1 (Compl. ¶¶ 117-118).
- Accused Features: The infringement allegation is based on the instructions in the proposed label for the Aizant ANDA Product, which would allegedly cause physicians to instruct patients in a manner that practices the claimed method of avoiding certain drug interactions (Compl. ¶¶ 122-123).
(Analyst Note: The complaint asserts thirteen other patents that are not given a full analysis or capsule here for brevity, consistent with the prompt's instructions for cases with more than two asserted patents. These additional patents generally relate to other methods of administering pirfenidone, managing other side effects or drug interactions, and specific formulations.)
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is Defendant Aizant's proposed generic pirfenidone tablets in 267, 534, and 801 mg strengths, as described in ANDA No. 212747 (the "Aizant ANDA Product") (Compl. ¶¶1, 7).
Functionality and Market Context
- The Aizant ANDA Product is a generic version of Plaintiffs' Esbriet® drug, intended for treating Idiopathic Pulmonary Fibrosis (IPF) (Compl. ¶1). By filing its ANDA, Aizant has represented to the FDA that its product contains the same active ingredient, has the same dosage form and strength, and is bioequivalent to Esbriet® (Compl. ¶57). The infringement allegations for the method patents are based on the contention that the proposed FDA-approved label for Aizant's product will instruct physicians and patients to use the drug in a manner that practices the steps claimed in the patents-in-suit (Compl. ¶¶ 62, 71).
No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
7,566,729 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) |
Alleged Infringing Functionality |
Complaint Citation |
Patent Citation |
| A method of administering pirfenidone to treat a patient with idiopathic pulmonary fibrosis (IPF), said patient having exhibited a grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration, |
The proposed product label for the Aizant ANDA Product allegedly instructs physicians on managing patients with IPF, including those who develop liver function abnormalities during treatment. |
¶¶ 61, 62, 66 |
col. 2:9-17 |
| comprising (a) administering to said patient pirfenidone at doses lower than 2400 mg/day for a time period, |
The proposed label allegedly instructs physicians to reduce the dose of pirfenidone for patients who exhibit the specified level of liver function abnormality. |
¶¶ 62, 66, 67 |
col. 2:36-40 |
| followed by (b) administering to said patient pirfenidone at doses of 2400 mg/day or 2403 mg/day. |
The proposed label allegedly instructs physicians to re-escalate the dose back to the full therapeutic dose after the liver function abnormality has resolved. |
¶¶ 62, 66, 67 |
col. 2:39-40 |
7,635,707 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) |
Alleged Infringing Functionality |
Complaint Citation |
Patent Citation |
| A method of administering pirfenidone to treat a patient with idiopathic pulmonary fibrosis (IPF), said patient having exhibited a grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration, |
The proposed product label for the Aizant ANDA Product allegedly instructs physicians on managing patients with IPF, including those who develop liver function abnormalities during treatment. |
¶¶ 70, 71, 75 |
col. 2:9-17 |
| comprising (a) administering to said patient pirfenidone at doses of 2400 mg/day or 2403 mg/day. |
The proposed label allegedly provides instructions for physicians to continue administering the full therapeutic dose of pirfenidone even after a patient exhibits the specified level of liver function abnormality. |
¶¶ 71, 75, 76 |
col. 2:19-23 |
- Identified Points of Contention:
- Scope Questions: A central dispute will be whether the language in Aizant's proposed product label instructs, encourages, or suggests the specific, multi-step dosing regimens claimed in the ’729 and ’707 Patents. The question for the court is one of inducement: does the label's language make it inevitable that some physicians, in following the label, will directly infringe the claims?
- Technical Questions: An evidentiary question will be whether the clinical scenarios described in the accused product label for which dose modification is recommended correspond to the definition of a "grade 2 abnormality" as defined in the patents-in-suit. The analysis will depend on the precise wording of the proposed label, which is not included in the complaint.
V. Key Claim Terms for Construction
- The Term: "grade 2 abnormality in one or more biomarkers of liver function"
- Context and Importance: This term defines the clinical trigger for the patented methods. The scope of this term is critical because infringement of the method claims depends on whether the instructions in Aizant's proposed label direct a course of action for patients meeting this specific clinical definition.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claim language "one or more biomarkers" could be argued to encompass a wide range of clinical indicators of liver function.
- Evidence for a Narrower Interpretation: The specification provides a detailed and specific definition, stating that "Grade 2 liver function abnormalities" include elevations in certain enzymes (ALT, AST, ALP, or GGT) that are ">2.5-5 x ULN" (upper limit of normal) or elevations in bilirubin that are ">1.5-3 x ULN" (’729 Patent, col. 8:1-6; Table 1). A defendant may argue that this specific disclosure limits the claim scope to only those defined biomarker levels.
VI. Other Allegations
- Indirect Infringement: The complaint's core theory is indirect infringement. It alleges that Aizant will induce infringement by providing a product with a label that instructs physicians and patients to perform the patented methods (Compl. ¶¶ 66-67). It also alleges contributory infringement, stating the Aizant ANDA Product is especially adapted for an infringing use and is not a staple article of commerce with substantial non-infringing uses (Compl. ¶¶ 64-65).
- Willful Infringement: The complaint alleges that Aizant's infringement was undertaken with knowledge of the Asserted Patents and without a good-faith belief of non-infringement, thereby constituting an "exceptional case" (Compl. ¶199). This allegation is based on Aizant having sent Paragraph IV notice letters concerning the patents-in-suit.
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of label-induced infringement: Does the precise language of the Defendant’s proposed product label instruct, suggest, or encourage physicians to perform the specific dose-adjustment methods of the asserted patents upon the occurrence of the clinically defined "grade 2 abnormality"? The outcome will likely depend on whether the label makes practicing the patented methods an inevitability for at least some patients.
- A key question for the multiple patents will be one of validity and obviousness: Given the large number of patents covering various dosing regimens, formulations, and drug interactions for a single active ingredient, the court may closely scrutinize whether each patented invention represents a non-obvious advance over the state of the art and prior patents in the same family.
- For the formulation patent ('150 Patent), a central evidentiary question will be one of compositional identity: Does the Defendant's proposed generic product contain the specific "granulate formulation" of pirfenidone and excipients as recited in the asserted claims, or is there a material difference in its composition?