DCT

3:18-cv-04591

Takeda Pharma USA Inc v. Zydus Pharma USA Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:18-cv-04591, D.N.J., 03/28/2018
  • Venue Allegations: Plaintiff alleges venue is proper because Defendant Zydus Pharmaceuticals (USA) Inc. is incorporated and has its principal place of business in New Jersey, both defendants conduct substantial business in the district, and both have previously litigated cases in the District of New Jersey.
  • Core Dispute: Plaintiff alleges that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic version of Colcrys® (colchicine) infringes seventeen patents covering methods of using colchicine to treat gout and Familial Mediterranean Fever (FMF).
  • Technical Context: The patents relate to specific dosing regimens for colchicine, a drug with a narrow therapeutic index, designed to improve safety and efficacy, particularly when co-administered with other common medications that can inhibit its metabolism.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 211519 with a Paragraph IV certification, asserting that the listed patents for Colcrys® are invalid or would not be infringed by the proposed generic product. Plaintiff filed this complaint within the 45-day statutory window after receiving Defendants' Paragraph IV notice letter, triggering an automatic 30-month stay of FDA approval for the ANDA.

Case Timeline

Date Event
2008-10-15 Earliest Priority Date ('731 Patent family)
2009-01-14 Earliest Priority Date ('519 Patent family)
2009-01-01 FDA granted approval for Colcrys®
2009-10-13 U.S. Patent 7,601,758 Issued
2009-11-17 U.S. Patent 7,619,004 Issued
2010-10-26 U.S. Patent 7,820,681 Issued
2011-03-15 U.S. Patent 7,906,519 Issued
2011-03-29 U.S. Patent 7,915,269 Issued
2011-05-03 U.S. Patent 7,935,731 Issued
2011-06-21 U.S. Patent 7,964,647 Issued
2011-06-21 U.S. Patent 7,964,648 Issued
2011-07-19 U.S. Patent 7,981,938 Issued
2012-01-10 U.S. Patent 8,093,296 Issued
2012-01-10 U.S. Patent 8,093,297 Issued
2012-01-10 U.S. Patent 8,093,298 Issued
2012-01-17 U.S. Patent 8,097,655 Issued
2013-04-09 U.S. Patent 8,415,395 Issued
2013-04-09 U.S. Patent 8,415,396 Issued
2013-05-14 U.S. Patent 8,440,721 Issued
2013-05-14 U.S. Patent 8,440,722 Issued
2016-07-29 Colcrys® Orphan Drug exclusivity expired
2018-02-19 Takeda received Paragraph IV Notice Letter from Zydus
2018-03-28 Complaint Filing Date

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

U.S. Patent 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 states that colchicine is potentially toxic and has been associated with deaths, particularly when administered with other drugs that inhibit its metabolism via the CYP3A4 enzyme and/or P-glycoprotein (P-gp) transporter, leading to dangerously high blood levels of colchicine (Compl. ¶27, 31). The patent’s background section notes that such drug-drug interactions can result in serious morbid complications and death (’681 Patent, col. 1:47-53).
  • The Patented Solution: The invention provides specific, reduced-dose methods for administering colchicine to patients who are also taking a second drug known to be a CYP3A4 or P-gp inhibitor. This dose reduction is intended to mitigate the risk of colchicine toxicity that arises from the drug-drug interaction, thereby allowing patients to be treated safely and effectively (’681 Patent, Abstract).
  • Technical Importance: The claimed methods provided evidence-based dosing guidelines that allow for the safe co-administration of colchicine, an important therapy for gout and FMF, with other widely used drugs, addressing a known and potentially fatal interaction (Compl. ¶26, 31).

Key Claims at a Glance

  • The complaint asserts infringement of at least claim 1 of the ’519 Patent (Compl. ¶66).
  • Independent claim 1 of the ’519 Patent recites:
    • A method of using colchicine for prophylactic treatment of gout flares in a human gout patient.
    • The patient is receiving concomitant administration of ritonavir.
    • The method comprises orally administering an adjusted daily dosage amount of colchicine.
    • The adjusted daily dosage amount is 25% to 50% of an intended daily dosage amount suitable for the patient in the absence of concomitant ritonavir.
    • The intended daily dosage amount is 0.6 mg twice daily or 0.6 mg once daily.

U.S. Patent 7,935,731 - "METHODS FOR CONCOMITANT ADMINISTRATION OF COLCHICINE AND MACROLIDE ANTIBIOTICS," Issued May 3, 2011

The Invention Explained

  • Problem Addressed: The invention addresses the specific danger of co-administering colchicine with macrolide antibiotics, such as clarithromycin (Compl. ¶31). These antibiotics are potent inhibitors of CYP3A4 and P-gp, which are responsible for colchicine metabolism and efflux, and their co-administration can dramatically increase colchicine plasma levels and toxicity risk (’758 Patent, col. 5:1-7).
  • The Patented Solution: The patent claims methods of treating Familial Mediterranean Fever (FMF) by orally administering a "reduced colchicine dosage amount" to a patient who is also receiving a macrolide antibiotic like clarithromycin. The claims specify the maximum reduced dosage (e.g., 0.6 mg per day) relative to the normal maximum dosage (e.g., 2.4 mg per day) (’731 Patent, claim 1).
  • Technical Importance: The invention provides a specific, safer dosing protocol for patients with FMF who require treatment with both colchicine and common macrolide antibiotics, mitigating a known risk of fatal toxicity (Compl. ¶31).

Key Claims at a Glance

  • The complaint asserts infringement of at least claim 1 of the ’731 Patent (Compl. ¶72).
  • Independent claim 1 of the ’731 Patent recites:
    • A method of using colchicine for the treatment of Familial Mediterranean Fever in a human adult or child >12 years of age.
    • The method comprises orally administering a reduced colchicine dosage amount to a patient who is concomitantly receiving administration of clarithromycin.
    • The reduced dosage is compared to a daily dosage amount administered in the absence of clarithromycin.
    • The daily dosage amount in the absence of clarithromycin is a maximum of 2.4 mg per day.
    • The reduced colchicine dosage amount is a maximum of 0.6 mg per day.

Multi-Patent Capsule: U.S. Patent 8,093,298

  • Patent Identification: U.S. Patent 8,093,298 ("the '298 Patent"), "METHODS FOR CONCOMITANT ADMINISTRATION OF COLCHICINE AND MACROLIDE ANTIBIOTICS," Issued January 10, 2012 (Compl. ¶32.C).
  • Technology Synopsis: This patent, like the ’731 Patent, is directed to methods of safely administering colchicine to patients with FMF who are also taking the macrolide antibiotic clarithromycin. It claims a specific reduced dosage regimen to avoid toxicity resulting from this drug-drug interaction (Compl. ¶50).
  • Asserted Claims: At least claim 1 (Compl. ¶78).
  • Accused Features: The proposed label for Defendants' ANDA Product, which is required to be the same as the Colcrys® label, allegedly instructs medical professionals and patients to perform the claimed method of reducing the colchicine dose when co-administering with clarithromycin (Compl. ¶49-51).

Multi-Patent Capsule: U.S. Patent 7,964,648

  • Patent Identification: U.S. Patent 7,964,648 ("the '648 Patent"), "METHODS FOR CONCOMITANT ADMINISTRATION OF COLCHICINE AND A SECOND ACTIVE AGENT," Issued June 21, 2011 (Compl. ¶32.D).
  • Technology Synopsis: This patent is directed to methods of using colchicine to treat FMF or gout by administering a reduced dosage when the patient is concomitantly receiving a P-gp inhibitor, such as cyclosporine. The method aims to prevent colchicine toxicity caused by the drug interaction (Compl. ¶33, 34).
  • Asserted Claims: At least claim 1 (Compl. ¶84).
  • Accused Features: The proposed label for Defendants' ANDA Product allegedly instructs users on dose adjustments for colchicine when co-administered with P-gp inhibitors, thereby teaching the claimed method (Compl. ¶49-51).

Multi-Patent Capsule: U.S. Patent 8,093,297

  • Patent Identification: U.S. Patent 8,093,297 ("the '297 Patent"), "METHODS FOR CONCOMITANT ADMINISTRATION OF COLCHICINE AND A SECOND ACTIVE AGENT," Issued January 10, 2012 (Compl. ¶32.E).
  • Technology Synopsis: This patent claims methods for using colchicine to treat FMF or gout in patients who are also taking a strong CYP3A4 inhibitor, such as ketoconazole. It specifies a reduced colchicine dosage to avoid toxicity from the drug interaction (Compl. ¶33, 34, 36).
  • Asserted Claims: At least claim 1 (Compl. ¶90).
  • Accused Features: The proposed label for Defendants' ANDA Product allegedly includes instructions for reducing the colchicine dosage when co-administered with strong CYP3A4 inhibitors, thereby teaching the patented method (Compl. ¶49-51).

The complaint asserts 12 additional patents. Their analysis follows the patterns established above, covering various combinations of conditions (gout, FMF, acute gout flares) and interacting drugs (macrolide antibiotics, CYP3A4 inhibitors, P-gp inhibitors). The core infringement theory for each is that the Defendants' proposed drug label will instruct users to practice the claimed methods.

III. The Accused Instrumentality

  • Product Identification: Defendants' Abbreviated New Drug Application ("ANDA") Product, which is a proposed generic version of Colcrys® (colchicine, USP) 0.6 mg oral tablets, as identified in ANDA No. 211519 (Compl. ¶1, 39).
  • Functionality and Market Context: The ANDA Product is intended to be a generic substitute for Takeda's Colcrys® product (Compl. ¶1). Under federal law, the labeling for the ANDA product is required to be the same as the labeling for the reference listed drug, Colcrys® (Compl. ¶46). The complaint alleges that this label teaches and encourages specific methods of using colchicine, including a low-dose regimen for treating acute gout flares and dose-reduction regimens for patients concomitantly taking other drugs that inhibit colchicine metabolism (Compl. ¶45, 47-50). Colcrys® and its authorized generic are described as the only FDA-approved single-active-ingredient oral colchicine products for the treatment and prevention of gout flares and FMF (Compl. ¶23, 24).

IV. Analysis of Infringement Allegations

'519 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of using colchicine for prophylactic treatment of gout flares in a human gout patient... The proposed product is for, among other things, the prophylaxis of gout flares (Compl. ¶53). The proposed label will allegedly instruct this use. ¶53 col. 6:3-4
...who is receiving concomitant administration of ritonavir... The proposed label will allegedly instruct on dose adjustments for patients taking colchicine who are also taking ritonavir, a strong CYP3A4 inhibitor (Compl. ¶49, 50). ¶49 col. 6:5-6
...comprising orally administering an adjusted daily dosage amount of colchicine to the patient, wherein the adjusted daily dosage amount of colchicine is 25% to 50% of an intended daily dosage amount... The Colcrys® label, which the ANDA Product's label will allegedly mirror, provides a dose adjustment table. This table shows that for prophylaxis of gout flares, the original intended dose of 0.6 mg twice a day (1.2 mg/day) is reduced to 0.3 mg once a day (a 75% reduction), and an original dose of 0.6 mg once a day is reduced to 0.3 mg every other day (a 75% reduction). These reductions fall within the claimed 50-75% reduction range (equivalent to a dose of 25-50% of the original). ¶49-50 col. 6:7-12
...wherein the intended daily dosage amount of colchicine is a daily dosage amount suitable for the patient if the patient were not receiving concomitant ritonavir, wherein the intended daily dosage amount is 0.6 mg twice daily or 0.6 mg once daily. The dose adjustment table in the Colcrys® label shows "Original Intended Dosage" for prophylaxis of gout flares as "0.6 mg twice a day" and "0.6 mg once a day" (Compl. p. 16, Table 1). This is the visual evidence that supports the "intended daily dosage amount" limitation. ¶49, p. 16 col. 6:13-17

'731 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of using colchicine for the treatment of Familial Mediterranean Fever in a human adult or child >12 years of age... The proposed product is for, among other things, the treatment of FMF (Compl. ¶53). The proposed label will allegedly instruct this use. ¶53 col. 16:21-23
...orally administering a reduced colchicine dosage amount to the human adult or child...who is concomitantly receiving administration of clarithromycin... The proposed label will allegedly instruct on dose adjustments for patients taking colchicine who are also taking clarithromycin, a strong CYP3A4 inhibitor (Compl. ¶49, 50). ¶49-50 col. 16:24-28
...wherein the reduced colchicine dosage amount is reduced compared to a daily dosage amount to be administered in the absence of concomitant clarithromycin... The Colcrys® label's dose adjustment table provides for a reduction in the colchicine dose when co-administered with clarithromycin for the treatment of FMF (Compl. p. 16, Table 1). ¶50 col. 16:29-32
...wherein the daily dosage amount to be administered in the absence of concomitant clarithromycin is a maximum of 2.4 mg per day... The Colcrys® label's table indicates that the "Original Intended Dosage" for FMF is a "Maximum daily dose of 1.2-2.4 mg" (Compl. p. 16, Table 1). ¶50 col. 16:33-36
...and wherein the reduced colchicine dosage amount is a maximum of 0.6 mg per day. The Colcrys® label's table indicates that the "Adjusted Dose" for FMF when taken with clarithromycin is a "Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)" (Compl. p. 16, Table 1). ¶50 col. 16:37-39

Identified Points of Contention:

  • Scope Questions: A potential point of contention may be whether the dosage adjustments provided in the product label are merely recommendations or constitute active instructions sufficient for inducement. The analysis could question whether the label language requires a user to practice the claimed method or merely informs them of an option or risk.
  • Technical Questions: A central question will be whether the specific numerical dosage values and reductions stated in the proposed label meet the limitations recited in the claims. For example, for the ’519 Patent, the dispute may focus on whether the 75% dose reduction shown on the label for prophylaxis falls within the claimed range of a "25% to 50%" adjusted dose (which is mathematically equivalent to a 50-75% reduction).

V. Key Claim Terms for Construction

  • The Term: "reduced colchicine dosage amount" (from the '731 Patent and others).

    • Context and Importance: This term is central to the drug-drug interaction patents. The infringement allegation rests on the assertion that Defendants' product label instructs the administration of a "reduced" dose as claimed. Its construction will determine whether the specific dose adjustments on the label (e.g., from 2.4 mg/day to 0.6 mg/day) fall within the claim scope.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification describes the general principle of dose reduction to avoid toxicity from drug interactions, which could support a view that any significant, medically advised dose decrease qualifies as "reduced" (’758 Patent, col. 6:3-17).
      • Evidence for a Narrower Interpretation: The claims themselves often provide specific numerical context, such as defining the reduced amount as a maximum of 0.6 mg/day compared to a normal maximum of 2.4 mg/day (’731 Patent, claim 1). This language may support a construction limited to specific quantitative reductions.

  • The Term: "administering...1.2 mg oral colchicine...followed by 0.6 mg oral colchicine one hour later" (from the '647 Patent and others).

    • Context and Importance: This term defines the low-dose regimen for acute gout flares. The infringement allegation depends on the accused label teaching this exact two-step dosing sequence. Practitioners may focus on whether this precise timing and dosage must be instructed to find infringement.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The complaint notes that this regimen was discovered in the AGREE trial to be a safer, effective alternative to traditional high-dose regimens, suggesting the core invention is the move to a lower total dose, not just this specific sequence (Compl. ¶28-29).
      • Evidence for a Narrower Interpretation: The claim language is highly specific as to the initial dose (1.2 mg), the follow-up dose (0.6 mg), and the timing ("one hour later"). This specificity suggests that the claim should be narrowly construed to cover only this exact regimen, which is what the Colcrys® label explicitly states (Compl. ¶48).

VI. Other Allegations

  • Indirect Infringement: The complaint's theory for post-approval infringement is centered on induced infringement under 35 U.S.C. § 271(b) (Compl. ¶67, 73, 79). The allegations state that Defendants, by marketing and selling their ANDA Product with its FDA-mandated label, will intentionally encourage and instruct doctors, pharmacists, and patients to perform the patented methods of use, with knowledge of the patents and that such acts constitute infringement (Compl. ¶52, 54, 56).
  • Willful Infringement: The complaint does not contain a formal count for willful infringement. However, it alleges that Defendants are "aware of all of the Colcrys® Patents" (Compl. ¶62) and that their Paragraph IV certification is "without adequate basis," rendering the case "exceptional" under 35 U.S.C. § 285, for which it seeks attorneys' fees (Compl. ¶63; Prayer for Relief ¶F). This knowledge is based on the statutory requirement for an ANDA filer to certify to all patents listed in the FDA's Orange Book for the reference drug.

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

  • A core issue will be one of claim construction: can the claimed methods, which recite specific dosages and reductions (e.g., "a maximum of 0.6 mg per day"), be construed to read on the instructions in the accused product's label, or will Defendants be able to argue a mismatch between the claim language and the label's recommendations?
  • A key legal question will be one of inducement: does the language of the accused product's label, which is required by law to be the same as the innovator's label, constitute active "instruction" and "encouragement" sufficient to establish the specific intent required for induced infringement, or can it be framed as merely providing objective medical information?
  • An overarching issue, central to any ANDA litigation, will be patent validity: although not detailed in the complaint, Defendants have asserted invalidity in their Paragraph IV notice letter (Compl. ¶42), raising the question of whether the claimed dosing regimens were obvious or anticipated in light of prior art knowledge regarding colchicine's toxicity and metabolism.