DCT

1:18-cv-00464

Takeda Pharma USA Inc v. Zydus Pharma USA Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:18-cv-00464, D. Del., 03/27/2018
  • Venue Allegations: Plaintiff alleges venue is proper because Defendants conduct regular business in Delaware, intend to market the accused product in the district, and have previously litigated patent cases in the District of Delaware, thereby availing themselves of the forum.
  • Core Dispute: Plaintiff alleges that Defendants’ submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic version of the drug "Colcrys®" (colchicine) constitutes an act of infringement of seventeen patents covering methods for safely administering colchicine.
  • Technical Context: The patents relate to specific dosing regimens for colchicine, a potent but potentially toxic anti-inflammatory drug, designed to treat gout and Familial Mediterranean Fever (FMF) while minimizing adverse effects, particularly in cases of drug-drug interactions.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 211519 and a "Paragraph IV Notice Letter", received by Plaintiff on February 19, 2018, which asserted that the patents-in-suit are invalid or would not be infringed by the proposed generic product. The complaint was filed within the 45-day statutory window, triggering an automatic 30-month stay of FDA approval for the ANDA.

Case Timeline

Date Event
2008-10-15 Earliest Priority Date Asserted (’758, ’004 Patents)
2008-12-17 Priority Date Asserted (’647, ’938, ’395, ’396 Patents)
2009-01-14 Priority Date Asserted (’681 Patent)
2009-02-12 Priority Date Asserted (’519, ’731, ’298, ’648, ’297, ’269, ’296, ’655, ’721, ’722 Patents)
2009 FDA Approval for "Colcrys®"
2009-10-13 U.S. Patent No. 7,601,758 Issued
2009-11-17 U.S. Patent No. 7,619,004 Issued
2010-10-26 U.S. Patent No. 7,820,681 Issued
2011-03-15 U.S. Patent No. 7,906,519 Issued
2011-03-29 U.S. Patent No. 7,915,269 Issued
2011-05-03 U.S. Patent No. 7,935,731 Issued
2011-06-21 U.S. Patent Nos. 7,964,648 and 7,964,647 Issued
2011-07-19 U.S. Patent No. 7,981,938 Issued
2012-01-10 U.S. Patent Nos. 8,093,298, 8,093,297, and 8,093,296 Issued
2012-01-17 U.S. Patent No. 8,097,655 Issued
2013-04-09 U.S. Patent Nos. 8,415,395 and 8,415,396 Issued
2013-05-14 U.S. Patent Nos. 8,440,721 and 8,440,722 Issued
2018-02-19 Plaintiff Received Defendants' "Paragraph IV Notice Letter"
2018-03-27 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 patent addresses the significant health risk posed by colchicine, a drug with a low therapeutic index, when co-administered with other drugs that inhibit its metabolism (specifically, CYP3A4 inhibitors) or its removal from cells (P-gp inhibitors) (Compl. ¶¶27, 31; ’681 Patent, col. 5:1-17). Such interactions can lead to dangerously high levels of colchicine, resulting in severe toxicity and, in some cases, death (Compl. ¶31).
  • The Patented Solution: The invention provides specific, reduced-dose methods for administering colchicine to patients who are also taking a second active agent that inhibits CYP3A4 or P-gp. By defining a reduced dosage amount relative to a standard dose, the method claims to allow for safe concomitant use, achieving therapeutic benefit without the toxic side effects associated with elevated colchicine levels (’681 Patent, col. 6:4-21).
  • Technical Importance: The invention provided a scientifically grounded method to manage a known, life-threatening drug-drug interaction, thereby improving the safety profile for patients with conditions like Familial Mediterranean Fever (FMF) who require both colchicine and other common medications (Compl. ¶¶24, 31).

Key Claims at a Glance

  • The complaint asserts infringement of at least independent claim 1 ('519 Patent, col. 17:35-51).
  • The essential elements of claim 1 include:
    • A method of treating a patient having Familial Mediterranean Fever (FMF) with colchicine.
    • The patient is concomitantly receiving administration of a second active agent that is a P-gp inhibitor.
    • The method comprises orally administering a reduced colchicine daily dosage amount.
    • The reduced dosage is 25% to 50% of an intended daily dosage amount for FMF treatment in the absence of the P-gp inhibitor.
    • Concomitant administration occurs within 1 to 2 days of administering the colchicine.

U.S. Patent No. 7,935,731 - "METHODS FOR CONCOMITANT ADMINISTRATION OF COLCHICINE AND MACROLIDE ANTIBIOTICS," Issued May 3, 2011

The Invention Explained

  • Problem Addressed: This patent addresses the same general problem of colchicine toxicity from drug-drug interactions as the ’519 Patent but focuses specifically on the interaction with macrolide antibiotics, such as clarithromycin (’731 Patent, col. 4:55-62).
  • The Patented Solution: The invention provides methods for safely co-administering colchicine with macrolide antibiotics by specifying a reduced colchicine dosage. The claimed method involves determining a standard dosage and then administering a reduced dosage (e.g., a 50% to 75% reduction) to a patient who is concurrently receiving the antibiotic, thereby preventing a toxic accumulation of colchicine (’731 Patent, col. 6:33-42).
  • Technical Importance: The method provided a specific protocol to manage a dangerous interaction between colchicine and a widely prescribed class of antibiotics, enhancing patient safety for those needing simultaneous treatment for conditions like FMF and bacterial infections (Compl. ¶59).

Key Claims at a Glance

  • The complaint asserts infringement of at least independent claim 1 ('731 Patent, col. 17:35-18:2).
  • The essential elements of claim 1 include:
    • A method of treating a patient having Familial Mediterranean Fever (FMF) with colchicine.
    • The patient is concomitantly receiving administration of a macrolide antibiotic.
    • The method comprises orally administering a reduced colchicine dosage amount.
    • The reduced dosage is a 50% to 75% reduction of a first colchicine dosage amount adapted for oral administration in the absence of the macrolide antibiotic.
    • Concomitant administration occurs within 1 to 2 days of administering the colchicine.

Multi-Patent Capsule: U.S. Patent No. 8,093,298

  • Patent Identification: U.S. Patent No. 8,093,298, "METHODS FOR CONCOMITANT ADMINISTRATION OF COLCHICINE AND MACROLIDE ANTIBIOTICS," Issued January 10, 2012 (Compl. ¶32.C).
  • Technology Synopsis: This patent, like the '731 Patent, claims methods for safely co-administering colchicine with macrolide antibiotics, specifically clarithromycin, to treat FMF in adults or children over 12. It establishes a reduced maximum daily dose of colchicine (0.6 mg/day) when given concomitantly, compared to the standard maximum dose (2.4 mg/day) when given alone (Compl. ¶50).
  • Asserted Claims: At least claim 1 (Compl. ¶78).
  • Accused Features: The proposed product label, which allegedly instructs a dose reduction for colchicine from a maximum of 2.4 mg/day to 0.6 mg/day when co-administered with clarithromycin for the treatment of FMF (Compl. ¶¶50-51).

Multi-Patent Capsule: U.S. Patent No. 7,964,647

  • Patent Identification: U.S. Patent No. 7,964,647, "COLCHICINE COMPOSITIONS AND METHODS," Issued June 21, 2011 (Compl. ¶32.J).
  • Technology Synopsis: This patent claims a specific low-dose method for treating an acute gouty arthritis attack. The method moves away from the traditional, high-dose regimen (which often caused toxicity) by specifying a lower total dose administered over a short period (Compl. ¶¶28-29).
  • Asserted Claims: At least claim 1 (Compl. ¶120).
  • Accused Features: The proposed product label, which allegedly recites the patented low-dose regimen: "administering 1.2 mg oral colchicine...at the onset of the acute gouty arthritis attack, followed by 0.6 mg oral colchicine one hour later" (Compl. ¶48).

Given the high degree of similarity and overlapping subject matter among the remaining 13 patents-in-suit, which cover variations of dosing regimens for gout, FMF, and drug-drug interactions, they are not individually summarized.

III. The Accused Instrumentality

  • Product Identification: Defendants' proposed generic 0.6 mg oral colchicine tablets, identified in Abbreviated New Drug Application (ANDA) No. 211519 ("ANDA Product") (Compl. ¶¶1, 39).
  • Functionality and Market Context: The ANDA Product is a generic equivalent of Plaintiff's "Colcrys®" drug (Compl. ¶1). The basis for infringement is not the composition of the drug itself, but the instructions for its use that will be provided on its FDA-mandated labeling (Compl. ¶51). The complaint alleges that, pursuant to FDA regulations, the ANDA Product's label will be the same as the approved label for "Colcrys®" (Compl. ¶46). This label allegedly teaches and encourages doctors and patients to use the patented methods for treating gout and FMF, including specific dose-reduction instructions for concomitant administration with other drugs (Compl. ¶¶47-50). The product is intended to compete with "Colcrys®" upon receiving FDA approval (Compl. ¶41). A dose adjustment table from the "Colcrys®" label, which the complaint alleges will be replicated for the ANDA Product, provides specific instructions for reducing colchicine dosage when co-administered with strong or moderate CYP3A4 inhibitors (Compl. p. 16, Table 1).

IV. Analysis of Infringement Allegations

The complaint alleges that by seeking FDA approval for its ANDA Product with a label that instructs users to perform the patented methods, Defendants will induce infringement of the patents-in-suit under 35 U.S.C. § 271(b) (Compl. ¶¶52, 56). The submission of the ANDA itself is alleged to be a technical act of infringement under 35 U.S.C. § 271(e)(2)(A) (e.g., Compl. ¶66).

  • 8,093,298 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 label will instruct use of the ANDA product for the treatment of FMF. ¶53 col. 16:1-3
orally administering a reduced colchicine dosage amount...who is concomitantly receiving administration of clarithromycin... The proposed label provides a dose adjustment table instructing a reduced colchicine dosage for patients concomitantly receiving strong CYP3A4 inhibitors, including clarithromycin. ¶50 col. 16:4-9
wherein the reduced colchicine dosage amount is reduced compared to a daily dosage amount to be administered in the absence of concomitant clarithromycin, The label’s dose adjustment table instructs a reduction from the usual intended dose. ¶50 col. 16:18-20
wherein the daily dosage amount to be administered in the absence of concomitant clarithromycin is a maximum of 2.4 mg per day, The label states that the usual intended dose of colchicine for FMF is a maximum of 2.4 mg per day. ¶50 col. 16:21-24
and wherein the reduced colchicine dosage amount is a maximum of 0.6 mg per day. The label teaches that when co-administered with a strong CYP3A4 inhibitor like clarithromycin, the colchicine dose should be adjusted to a maximum of 0.6 mg per day. ¶50 col. 16:25-27

Note: The complaint provides a detailed infringement narrative for the ’298 Patent (Compl. ¶50), which serves as a representative example for the broader group of Drug-Drug Interaction patents.

  • Identified Points of Contention:
    • Scope Questions: A potential issue for the court may be whether the instructions on the accused label meet the legal standard for inducement. The question could be framed as: Do the label’s recommendations for dose adjustments when a patient is taking an interacting drug rise to the level of actively encouraging the performance of all steps of the claimed methods, or does the label merely inform physicians of a potential interaction?
    • Technical Questions: Since infringement is based on the product label, the primary technical disputes will likely relate to claim validity rather than direct infringement. However, a question may arise as to whether the patient populations and specific conditions described on the label perfectly align with the limitations of the asserted claims (e.g., specific age groups, definitions of "acute gout flare," or what constitutes a baseline "daily dosage amount").

V. Other Allegations

  • Indirect Infringement: The core of the case is induced infringement. The complaint alleges that Defendants, by creating and marketing a product with a specific label, will have the specific intent to encourage direct infringement by doctors, pharmacists, and patients who follow the label's instructions for dosing and dose adjustments (Compl. ¶¶52, 54, 56).
  • Willful Infringement: The complaint alleges that Defendants are aware of all the patents-in-suit and that their Paragraph IV certification asserting non-infringement or invalidity is "without adequate basis" (Compl. ¶¶62-63). This allegation forms the basis for declaring the case "exceptional" under 35 U.S.C. § 285, which could entitle the plaintiff to attorneys' fees.

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

As is typical in ANDA litigation where the generic product's label is intended to mirror the brand-name label, the central questions for the court will likely revolve around patent validity rather than infringement.

  • A core issue will be one of obviousness: Were the claimed methods for dose-adjustment of colchicine—an old drug with a well-known toxicity profile—obvious to a person of ordinary skill in the art at the time of the invention? The analysis will likely focus on whether the prior art contained sufficient motivation to combine known principles of drug metabolism (e.g., the role of CYP3A4 inhibitors) with the known risks of colchicine to arrive at the specific reduced-dose regimens claimed in the patents.
  • A second key question will be one of inducement: Assuming the patents are valid, does the language of the proposed product label demonstrate the requisite specific intent to encourage infringement? The court will need to determine whether the label's instructions go beyond merely informing of a risk and actively teach and encourage the combined administration of colchicine with interacting drugs in the patented manner.