DCT
1:18-cv-00189
Takeda Pharma USA Inc v. Alkem Laboratories Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Takeda Pharmaceuticals U.S.A., Inc. (Delaware)
- Defendant: Alkem Laboratories Limited (India) and Ascend Laboratories, LLC (New Jersey)
- Plaintiff’s Counsel: Womble Bond Dickinson (US) LLP
- Case Identification: 1:18-cv-00189, D. Del., 02/01/2018
- Venue Allegations: Plaintiff alleges venue is proper based on Defendants' business activities in Delaware, including deriving substantial revenue from the state, and Defendants' prior litigation conduct within the district, which is asserted to constitute consent to jurisdiction.
- Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of the drug Colcrys® (colchicine) constitutes an act of infringement of seventeen U.S. patents covering methods of using colchicine to treat gout and Familial Mediterranean Fever (FMF).
- Technical Context: The patents relate to pharmaceutical methods, specifically dosing regimens for the drug colchicine that mitigate the risk of potentially fatal toxicity when co-administered with other common drugs that are metabolic inhibitors.
- Key Procedural History: This is a Hatch-Waxman action triggered by Defendants' filing of ANDA No. 211250 with a Paragraph IV certification, asserting that the asserted patents are invalid, unenforceable, and/or not infringed. The complaint alleges Defendants sought FDA approval only for the FMF indication, "carving out" the much larger gout indication, which Plaintiff frames as a strategy to induce widespread off-label infringement.
Case Timeline
| Date | Event |
|---|---|
| 2008-10-15 | Earliest Priority Date for Gout Patents (e.g., '004, '758 Patents) |
| 2009-01-14 | Earliest Priority Date for FMF Patents (e.g., '519, '731 Patents) |
| 2009-01-01 | FDA approves Takeda’s New Drug Application for Colcrys® (approximate date) |
| 2009-10-13 | U.S. Patent No. 7,601,758 Issues |
| 2009-11-17 | U.S. Patent No. 7,619,004 Issues |
| 2010-10-26 | U.S. Patent No. 7,820,681 Issues |
| 2011-03-15 | U.S. Patent No. 7,906,519 Issues |
| 2011-03-29 | U.S. Patent No. 7,915,269 Issues |
| 2011-05-03 | U.S. Patent No. 7,935,731 Issues |
| 2011-06-21 | U.S. Patent No. 7,964,647 Issues |
| 2011-06-21 | U.S. Patent No. 7,964,648 Issues |
| 2011-07-19 | U.S. Patent No. 7,981,938 Issues |
| 2012-01-01 | American College of Rheumatology issues guidelines adopting Takeda's low-dose regimen (approximate date) |
| 2012-01-10 | U.S. Patent No. 8,093,296 Issues |
| 2012-01-10 | U.S. Patent No. 8,093,297 Issues |
| 2012-01-10 | U.S. Patent No. 8,093,298 Issues |
| 2012-01-17 | U.S. Patent No. 8,097,655 Issues |
| 2013-04-09 | U.S. Patent No. 8,415,395 Issues |
| 2013-04-09 | U.S. Patent No. 8,415,396 Issues |
| 2013-05-14 | U.S. Patent No. 8,440,721 Issues |
| 2013-05-14 | U.S. Patent No. 8,440,722 Issues |
| 2016-07-29 | Orphan Drug exclusivity for Colcrys® expires |
| 2017-12-24 | Takeda receives Defendants' Paragraph IV Notice Letter (approximate date) |
| 2018-02-01 | Complaint for Patent Infringement Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 7,906,519 - "Methods for Concomitant Administration of Colchicine and a Second Active Agent," Issued March 15, 2011
The Invention Explained
- Problem Addressed: The complaint alleges that colchicine has a low therapeutic index, meaning the margin between an effective and a toxic dose is narrow (Compl. ¶26). Co-administration of colchicine with drugs that are inhibitors of the CYP3A4 enzyme or the P-glycoprotein (P-gp) efflux transporter can dangerously increase colchicine plasma levels, leading to toxicity and, in some cases, death (Compl. ¶30).
- The Patented Solution: The invention provides methods for safely administering colchicine to treat Familial Mediterranean Fever (FMF) in patients who are also taking a second drug that inhibits CYP3A4 and/or P-gp (Compl. ¶¶50, 52). As exemplified by the similar U.S. Patent No. 8,093,298, the method involves administering a "reduced colchicine dosage amount" (e.g., a maximum of 0.6 mg per day) compared to the standard daily dosage (a maximum of 2.4 mg per day) when a patient is concomitantly receiving a drug like clarithromycin (Compl. ¶53).
- Technical Importance: The claimed methods created a safe dosing protocol for patients with FMF who required colchicine therapy but also needed to take other commonly prescribed drugs, such as certain antibiotics, that would otherwise pose a significant risk of a fatal drug interaction (Compl. ¶¶25-26, 30).
Key Claims at a Glance
- The complaint asserts infringement of at least claim 1 of the '519 Patent (Compl. ¶87). The complaint does not quote this claim, but quotes the analogous claim 1 from the related '298 Patent (Compl. ¶53), the essential elements of which include:
- A method of using colchicine for treating FMF in a human.
- Orally administering a reduced colchicine dosage amount.
- The administration is to a human who is concomitantly receiving a CYP3A4/P-gp inhibitor (e.g., clarithromycin).
- The reduced dosage amount is defined relative to a higher daily dosage amount used in the absence of the inhibitor (e.g., max 0.6 mg/day vs. max 2.4 mg/day).
- The complaint reserves the right to assert infringement of other claims (Compl. ¶¶98, 104).
U.S. Patent No. 7,601,758 - "Methods for Concomitant Administration of Colchicine and Macrolide Antibiotics in the Treatment of Gout Flares," Issued October 13, 2009
The Invention Explained
- Problem Addressed: The patent's background describes the danger associated with co-administering colchicine, a drug with a low therapeutic index, with macrolide antibiotics (such as clarithromycin) which are potent inhibitors of the CYP3A4 enzyme and the P-gp transporter, leading to increased and potentially toxic colchicine levels (’758 Patent, col. 1:11-3:61).
- The Patented Solution: The invention provides a specific, reduced-dose method for safely treating acute gout flares with colchicine in patients who are also taking a macrolide antibiotic (’758 Patent, Abstract; col. 6:4-16). The method involves determining the standard dose, calculating a "two thirds reduction," and administering that reduced single dose, after which administration is not repeated for at least three days (’758 Patent, col. 18:8-12).
- Technical Importance: This research established a clinically tested low-dose regimen that was as effective as traditional high-dose regimens for gout flares but without the severe adverse effects, which became the standard of care (Compl. ¶¶28-29).
Key Claims at a Glance
- The complaint asserts infringement of at least claim 10 of the '758 Patent (Compl. ¶125). Claim 10 is dependent on claim 1. Claim 1, the independent claim, recites:
- A method of using colchicine to treat a gout flare in a human patient who is receiving concomitant administration of clarithromycin or erythromycin.
- Determining a first colchicine dosage amount adapted for oral administration...in the absence of concomitant administration.
- Determining a second colchicine dosage amount that is about a two thirds reduction of the first dosage amount.
- Orally administering the second colchicine dosage amount to the patient.
- Not repeating colchicine administration for at least three days.
- The complaint reserves the right to assert infringement of additional claims (Compl. ¶125).
Multi-Patent Capsule: U.S. Patent No. 7,964,648
- Patent Identification: U.S. Patent No. 7,964,648, "Methods for Concomitant Administration of Colchicine and a Second Active Agent," Issued June 21, 2011 (Compl. ¶31.D).
- Technology Synopsis: This patent, identified by the complaint as being both an "FMF Patent" and a "Gout Patent," covers methods of safely administering colchicine concurrently with a second drug that poses an interaction risk (Compl. ¶33). The claims cover treatment of both FMF and gout flares, bridging the two asserted patent categories.
- Asserted Claims: At least claim 1 is asserted for both FMF and gout indications (Compl. ¶¶104, 107).
- Accused Features: Defendants' ANDA product and its proposed labeling are alleged to induce infringement for the on-label FMF indication, and the product itself is alleged to be contributorily infringing and intended for off-label induced infringement for the gout indication (Compl. ¶¶50-60, 106-107).
III. The Accused Instrumentality
Product Identification
The Accused Instrumentality is Defendants' Abbreviated New Drug Application ("ANDA") No. 211250 for a generic version of Colcrys® (colchicine, USP) 0.6 mg oral tablets (the "ANDA Product") (Compl. ¶¶1, 44, 74).
Functionality and Market Context
The ANDA product is a generic colchicine tablet intended as a substitute for Takeda's branded Colcrys® (Compl. ¶1). The complaint alleges that while Defendants' ANDA submission "carved out" the indication for gout and seeks approval solely for the FMF indication, this is a pretext for capturing the much larger gout market through off-label use (Compl. ¶¶37, 77). Plaintiff asserts that the U.S. market for colchicine is overwhelmingly for gout (approx. 99.77% of prescriptions), while the FMF market is a rare disease and commercially minor (approx. 0.23%) (Compl. ¶38). Plaintiff alleges that standard physician prescribing habits and pharmacy substitution laws will result in Defendants' FMF-labeled product being dispensed for gout, which is the primary indication for the reference drug Colcrys® (Compl. ¶¶40-41, 78-79).
IV. Analysis of Infringement Allegations
U.S. Patent No. 7,906,519 Infringement Allegations
| Claim Element (from analogous '298 Patent, Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of using colchicine for the treatment of Familial Mediterranean Fever... | The proposed label for Defendants' ANDA Product will instruct its use for the treatment of FMF. | ¶45 | '298 Patent, col. 18:13-16 |
| orally administering a reduced colchicine dosage amount... | The Colcrys® label, which Defendants' label must substantially replicate for the FMF indication, explicitly instructs a reduced dose for patients taking certain interacting drugs. The table on the Colcrys® label, reproduced in the complaint, specifies these reductions. | ¶¶52-54, Compl. p. 18 | '298 Patent, col. 18:17-23 |
| to the human...who is concomitantly receiving administration of clarithromycin... | The Colcrys® label table provides specific dose adjustments for co-administration with "Strong CYP3A4 Inhibitors" such as clarithromycin. | ¶¶52-53, Compl. p. 18 | '298 Patent, col. 18:21-23 |
| wherein the daily dosage amount...in the absence of concomitant clarithromycin is a maximum of 2.4 mg per day, and wherein the reduced colchicine dosage amount is a maximum of 0.6 mg per day. | The dose adjustment table from the Colcrys® label, reproduced in the complaint, explicitly teaches adjusting the maximum FMF dose from 1.2-2.4 mg daily down to a maximum of 0.6 mg daily. | ¶53, Compl. p. 18 | '298 Patent, col. 18:27-32 |
Identified Points of Contention:
- Technical Questions: For the FMF patents, the infringement allegation appears to map directly onto the instructions provided in the FDA-approved label for Colcrys®, which Defendants' generic label must substantially mirror for the FMF indication (Compl. ¶51). The primary dispute may therefore center not on infringement but on the validity of the patents, a position Defendants asserted in their Paragraph IV letter (Compl. ¶46).
U.S. Patent No. 7,601,758 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of using colchicine to treat a gout flare... | Plaintiff alleges that despite the label carve-out, Defendants' product will be prescribed and dispensed for off-label use to treat gout flares, which is the standard of care and the predominant use of the reference drug. | ¶¶63-64, 78 | '758 Patent, col. 18:13-14 |
| determining a first colchicine dosage amount...and a second...that is about a two thirds reduction... | Plaintiff alleges that physicians and pharmacists, following the standard of care established by the Colcrys® label and clinical guidelines, will be induced to instruct patients to use the reduced-dose regimens when Defendants' product is co-administered with an interacting drug. | ¶¶69, 80 | '758 Patent, col. 18:15-22 |
| orally administering the second colchicine dosage amount... | Plaintiff alleges that patients will ultimately self-administer the reduced dose of Defendants' generic product for the off-label treatment of gout flares based on instructions from induced healthcare professionals. | ¶¶69, 78-79 | '758 Patent, col. 18:23-26 |
| not repeating colchicine administration for at least three days. | Plaintiff alleges that the induced administration for gout flares will follow the patented low-dose regimen, which includes not repeating the dose for at least three days. | ¶80 | '758 Patent, col. 18:27-28 |
Identified Points of Contention:
- Scope Questions: A central question for the Gout patents is whether Defendants' filing of an ANDA with a "skinny label" that omits the gout indication can support a claim for induced infringement. The analysis will depend on evidence of Defendants' intent to encourage infringement for the carved-out use, beyond the mere act of placing a substitutable generic on the market (Compl. ¶¶73, 77-78).
- Factual Questions: What evidence does the complaint provide to support the allegation that the on-label FMF use is not a "substantial non-infringing use" for the purposes of contributory infringement? The complaint offers national prescription data suggesting the FMF market is less than 0.3% of the total colchicine market, which may support the argument that the only commercially significant use is the infringing off-label use for gout (Compl. ¶38).
V. Key Claim Terms for Construction
The Term: "a method of using colchicine to treat a gout flare" ('758 Patent, claim 1)
Context and Importance
This term is critical because Defendants' product label will not mention "gout." The infringement case for the Gout patents hinges on whether Defendants can be held liable for inducing this specific, unstated use. Practitioners may focus on whether "method of using" requires active instruction by the accused infringer or can be satisfied by foreseeable off-label use that the infringer encourages through other actions.
Intrinsic Evidence for Interpretation
- Evidence for a Broader Interpretation: The patent claims a method of "using," which is ultimately performed by the end-user (the patient, at the direction of a physician). The specification focuses on the clinical application and safety benefits for the patient, suggesting the claim's scope is centered on the end user's act (’758 Patent, col. 2:41-49).
- Evidence for a Narrower Interpretation: The claims and specification are directed to methods of administering specific dosage amounts. This could support an interpretation that the "method" requires the direct involvement or instruction of a healthcare professional following a specific protocol, which Defendants' label will not provide for gout.
The Term: "concomitant administration" ('758 Patent, claim 1)
Context and Importance
The temporal relationship between the administration of colchicine and the interacting drug is a core element of the claimed safety method. Its definition will determine the window of time during which infringement can occur.
Intrinsic Evidence for Interpretation
- Evidence for a Broader Interpretation: The specification provides an explicit definition, stating that "concomitant...administration...can occur as much as about one to two weeks...after the administration of the first drug" because of the long-lasting inhibitory effects of drugs like clarithromycin (’758 Patent, col. 11:41-54). This language may support a broad temporal scope.
- Evidence for a Narrower Interpretation: A defendant might argue that the term's plain meaning implies simultaneous or near-simultaneous administration. However, the patent's explicit definitional language in the specification would present a significant hurdle to such an argument.
VI. Other Allegations
Indirect Infringement
The complaint's central theories are for indirect infringement. For the FMF patents, inducement is alleged based on the proposed product label, which will instruct users to perform the patented method (Compl. ¶¶55-56). For the Gout patents, inducement is alleged based on Defendants' knowledge of widespread off-label use combined with actions (e.g., manufacturing quantities far exceeding the FMF market) that allegedly demonstrate a specific intent to encourage infringement (Compl. ¶¶73, 78). Contributory infringement is also alleged for the Gout patents on the basis that the ANDA Product is not a staple article of commerce suitable for substantial non-infringing use (Compl. ¶¶106, 114).
Willful Infringement
The complaint alleges that Defendants are aware of all the asserted patents but have nonetheless continued to seek FDA approval for their ANDA Product (Compl. ¶¶71, 83). Knowledge of the FMF patents is established by Defendants' Paragraph IV certification against them (Compl. ¶45). Knowledge of the Gout patents is alleged based on their listing in the FDA's Orange Book (Compl. ¶62).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of intent and inducement: Can Takeda demonstrate that Alkem, despite submitting a "skinny label" that carves out the gout indication, possessed the specific intent required to induce infringement of the Gout patents? This will likely require evidence beyond the label itself, focusing on Alkem's knowledge of market realities and its business conduct.
- A key legal question will be one of substantiality: Does the on-label use for treating FMF, which the complaint alleges accounts for less than 0.3% of the relevant U.S. prescriptions, constitute a "substantial non-infringing use"? The court's interpretation of this statutory requirement will be critical to the contributory infringement claims for the Gout patents.
- For the FMF patents, where inducement allegations appear more direct, the case may turn on patent validity. While not detailed in the complaint, Defendants' Paragraph IV letter asserted invalidity, suggesting the dispute will focus on whether the claimed dosing regimens were obvious or anticipated by prior art knowledge of colchicine's metabolic pathways and drug interactions.