DCT

1:17-cv-01690

Takeda Pharma USA Inc v. Strides Pharma Global Pte Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-01690, D. Del., 11/21/2017
  • Venue Allegations: Defendants consented to personal jurisdiction and venue in the District of Delaware for the purposes of this litigation.
  • 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 patents covering methods of using colchicine to treat Familial Mediterranean Fever (FMF) and to treat or prevent gout flares.
  • Technical Context: The patents relate to pharmaceutical methods for safely administering colchicine, a drug with a narrow therapeutic index, particularly focusing on specific dosage adjustments required when it is co-administered with other drugs that can increase its toxicity.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiff's receipt of a Paragraph IV Notice Letter from Defendants, which asserted that the patents-in-suit were invalid, unenforceable, or would not be infringed by the proposed generic product.

Case Timeline

Date Event
2008-10-15 Earliest Priority Date (’731, ’298, ’004, ’758, ’296, ’655 Patents)
2009-01-14 Earliest Priority Date (’519, ’648, ’297, ’681, ’269, ’647, ’938, ’395, ’396, ’721, ’722 Patents)
2009-01-01 FDA Approval of Colcrys® (colchicine) (approximate date)
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
2012-01-01 American College of Rheumatology issues guidelines adopting Takeda's low-dose regimen (approximate date)
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
2016-07-29 Colcrys® Orphan Drug exclusivity expires
2017-10-18 Takeda receives Paragraph IV Notice Letter from Strides
2017-11-21 Complaint 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 describes research conducted by Plaintiff's predecessor which revealed that co-administering colchicine with other drugs can lead to dangerous side effects and toxicity, as some drugs inhibit the enzymes (like CYP3A4) and transporters (like P-gp) responsible for metabolizing and clearing colchicine from the body (Compl. ¶¶ 18, 23; '681 Patent, col. 3:25-4:65).
  • The Patented Solution: The invention provides a method for safely treating Familial Mediterranean Fever (FMF) in patients who are also taking a second drug known to be a CYP3A4 inhibitor or a P-gp inhibitor. The solution is to administer a "reduced colchicine dosage amount" to mitigate the risk of toxicity caused by the drug-drug interaction (’519 Patent, Abstract, col. 7:59-8:13).
  • Technical Importance: This patented method provided a scientifically validated dosing regimen that allowed for the safe concomitant use of colchicine with other necessary medications, addressing a known toxicity risk associated with the drug (Compl. ¶¶ 18, 23).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶ 80).
  • Claim 1 of the ’519 Patent requires:
    • A method of using colchicine for the treatment of Familial Mediterranean Fever in a human patient.
    • The patient is concomitantly receiving administration of a second active agent that is an inhibitor of CYP3A4 or an inhibitor of P-gp.
    • The method comprises orally administering a reduced colchicine dosage amount.
    • The reduced dosage amount is reduced compared to a daily dosage amount administered in the absence of the second active agent.
    • The daily dosage amount in the absence of the second active agent is a maximum of 2.4 mg per day.
    • The reduced colchicine dosage amount is a maximum of 0.6 mg per day.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

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 invention addresses a specific subset of the general problem described for the '519 Patent: the risk of colchicine toxicity when co-administered with macrolide antibiotics (such as clarithromycin or erythromycin), which are known to be strong inhibitors of colchicine metabolism (Compl. ¶ 23; '731 Patent, col. 4:1-5:4).
  • The Patented Solution: The patent claims a method for treating Familial Mediterranean Fever (FMF) in a patient who is also taking a macrolide antibiotic. The solution involves administering a reduced dosage of colchicine, specifically limited to a maximum of 0.6 mg per day, to avoid the toxic effects of the drug interaction (’731 Patent, Abstract, col. 7:26-57).
  • Technical Importance: The method provides a precise, safer dosing protocol for a common clinical scenario where patients on colchicine therapy require treatment with a frequently prescribed class of antibiotics (Compl. ¶ 23).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶ 86).
  • Claim 1 of the ’731 Patent requires:
    • A method of using colchicine for the treatment of Familial Mediterranean Fever in a human patient.
    • The patient is concomitantly receiving administration of a macrolide antibiotic.
    • The method comprises orally administering a reduced colchicine dosage amount.
    • The reduced dosage amount is reduced compared to a daily dosage amount administered in the absence of the macrolide antibiotic.
    • The daily dosage amount in the absence of the macrolide antibiotic is a maximum of 2.4 mg per day.
    • The reduced colchicine dosage amount is a maximum of 0.6 mg per day.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

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

  • Patent Identification: 8,093,298, METHODS FOR CONCOMITANT ADMINISTRATION OF COLCHICINE AND MACROLIDE ANTIBIOTICS, issued January 10, 2012.
  • Technology Synopsis: This patent addresses the technical problem of colchicine toxicity when co-administered with the specific macrolide antibiotic clarithromycin. The claimed solution is a method of treating FMF by administering a reduced colchicine dosage (max 0.6 mg/day) when a patient is also taking clarithromycin (Compl. ¶¶ 45-46).
  • Asserted Claims: At least independent claim 1 (Compl. ¶ 92).
  • Accused Features: Strides's proposed product label, which allegedly recites and encourages the specific dose adjustments for colchicine when co-administered with clarithromycin for the treatment of FMF (Compl. ¶¶ 45-47).

The complaint asserts fourteen additional patents. These patents are generally directed to similar methods of adjusting colchicine dosage when co-administered with various CYP3A4 and/or P-gp inhibitors for the treatment of either FMF or gout flares. The specific infringement allegations follow the patterns established above for FMF (inducement via product label) and Gout (contributory infringement via anticipated off-label use).

III. The Accused Instrumentality

Product Identification

  • Defendants' Abbreviated New Drug Application ("ANDA") No. 209173 product, which is a generic version of Plaintiff's Colcrys® drug, formulated as 0.6 mg oral colchicine tablets (Compl. ¶¶ 1, 37).

Functionality and Market Context

  • The infringement allegations are based on the future, intended use of the ANDA Product, as will be directed by its FDA-approved label (Compl. ¶¶ 47-49). The complaint alleges that Strides's ANDA seeks approval solely for the FMF indication (Compl. ¶ 30). Under FDA regulations, the generic label for this indication is required to be the same as the label for the reference drug, Colcrys® (Compl. ¶ 44).
  • The complaint alleges that the Colcrys® label, and therefore the proposed Strides label, provides specific instructions for dose adjustments when colchicine is co-administered with drugs known to increase its toxicity (Compl. ¶ 45). The complaint includes a reproduction of a table from the Colcrys® label showing specific dose adjustments for FMF patients taking strong or moderate CYP3A4 inhibitors (Compl. p. 15).
  • Plaintiff alleges that while the ANDA Product is formally indicated only for FMF, a rare disease, the vast majority of colchicine prescriptions (over 99%) are for the treatment of gout (Compl. ¶ 31). Plaintiff alleges that Defendants intend to manufacture and market the ANDA Product in quantities that far exceed the FMF market and that, due to physician prescribing and pharmacy substitution practices, the product will be widely used off-label for gout (Compl. ¶¶ 32-36, 71-72).

IV. Analysis of Infringement Allegations

7,906,519 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 patient... Strides's ANDA product seeks approval to treat FMF, and its label will instruct physicians and patients on this use. ¶30, ¶47 col. 7:59-61
...who is concomitantly receiving administration of a second active agent, wherein the second active agent is an inhibitor of CYP3A4 or an inhibitor of P-gp. Strides's label allegedly instructs on dose adjustments when co-administered with specific CYP3A4 and P-gp inhibitors listed in a table. ¶45, ¶48 col. 8:1-4
...orally administering a reduced colchicine dosage amount... Strides's label allegedly recites and recommends specific reduced dosage amounts for colchicine when used with interacting drugs. ¶45-¶46 col. 8:5-6
...wherein the daily dosage amount to be administered in the absence of the second active agent is a maximum of 2.4 mg per day... The Colcrys® label, which Strides's label must mirror, identifies the usual intended FMF dose as a maximum of 2.4 mg per day. ¶46 col. 8:10-13
...and wherein the reduced colchicine dosage amount is a maximum of 0.6 mg per day. The dose adjustment table on the Colcrys® label instructs adjusting the dose to a maximum of 0.6 mg per day when used with strong CYP3A4 inhibitors. ¶46 col. 8:14-16

7,935,731 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 patient... Strides's ANDA product seeks approval to treat FMF, and its label will instruct physicians and patients on this use. ¶30, ¶47 col. 7:26-28
...who is concomitantly receiving administration of a macrolide antibiotic... Strides's label allegedly instructs on dose adjustments when co-administered with macrolide antibiotics such as clarithromycin. ¶45, ¶46 col. 7:29-30
...orally administering a reduced colchicine dosage amount... Strides's label allegedly recites and recommends specific reduced dosage amounts for colchicine when used with interacting drugs. ¶45-¶46 col. 7:31-32
...wherein the daily dosage amount to be administered in the absence of the macrolide antibiotic is a maximum of 2.4 mg per day... The Colcrys® label, which Strides's label must mirror, identifies the usual intended FMF dose as a maximum of 2.4 mg per day. ¶46 col. 7:36-39
...and wherein the reduced colchicine dosage amount is a maximum of 0.6 mg per day. The dose adjustment table on the Colcrys® label instructs adjusting the dose to a maximum of 0.6 mg per day when used with strong CYP3A4 inhibitors like clarithromycin. ¶46 col. 7:40-42

Identified Points of Contention

  • Scope Questions: For the patents asserted based on off-label use for gout (the "Gout Patents"), a central legal question will be one of contributory infringement scope: can Defendants be held liable for contributing to the infringement of patents covering the treatment of gout, when their ANDA filing explicitly "carves out" the gout indication and seeks approval only for FMF (Compl. ¶¶ 41, 55)? The complaint's factual allegations regarding the relative market sizes for gout versus FMF and established physician prescribing practices may be intended to support the argument that the only commercially significant use of the product is the infringing one (Compl. ¶¶ 31, 66, 71).
  • Technical Questions: For the patents asserted based on the on-label FMF indication (the "FMF Patents"), the analysis will raise the question of intent for inducement: does the inclusion of dose-adjustment information on the proposed label, which is required by the FDA to mirror the brand-name label for safety, constitute sufficient evidence of Defendants' specific intent to encourage or instruct physicians and patients to perform the patented methods (Compl. ¶ 48)?

V. Key Claim Terms for Construction

  • The Term: "reduced colchicine dosage amount"
  • Context and Importance: This term is critical because infringement of all asserted claims hinges on whether the dosage specified on the accused product's label constitutes a "reduced" amount as defined by the patents. The dispute will likely focus on whether this term requires a specific quantitative reduction or if any decrease from the standard dose suffices.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The plain language of the claims often broadly recites "a reduced colchicine dosage amount... reduced compared to a daily dosage amount to be administered in the absence of" the interacting drug, which may support an argument that any reduction satisfies the limitation ('519 Patent, col. 8:5-9).
    • Evidence for a Narrower Interpretation: The claims themselves often provide specific quantitative boundaries, such as the standard dose being "a maximum of 2.4 mg per day" and the reduced dose being "a maximum of 0.6 mg per day" ('519 Patent, col. 8:10-16). Other patents in the family provide even more specific reductions, such as "about a two thirds reduction" ('758 Patent, col. 18:8-12). This language suggests the possibility that the term is not merely qualitative but is defined by the specific numerical values recited in the claims or specification.

VI. Other Allegations

  • Indirect Infringement: The complaint's theories are grounded in indirect infringement.
    • Inducement (FMF Patents): The complaint alleges inducement of infringement of the FMF Patents on the basis that Strides's product label will "explicitly instruct doctors, pharmacists, other healthcare professionals, and patients to administer Strides' ANDA Product according to methods claimed" in those patents (Compl. ¶ 48).
    • Contributory Infringement (Gout Patents): The complaint alleges that upon FDA approval, Strides will contribute to the infringement of the Gout Patents by selling its ANDA product, knowing it is "especially made or adapted for use in infringement" of those patents for treating gout flares and is "not a staple article or commodity of commerce suitable for substantial non-infringing uses" (Compl. ¶¶ 54, 67, 75, 100). The basis for this is the allegation that the FMF market is insubstantial compared to the anticipated off-label gout market (Compl. ¶¶ 74-75).
  • Willful Infringement: The complaint alleges that Strides is aware of all the Colcrys® Patents, citing their listing in the FDA's Orange Book and Strides's own Paragraph IV certification as evidence of pre-suit knowledge (Compl. ¶¶ 28, 38, 55, 76). It further asserts that Strides's actions render the case "exceptional" under 35 U.S.C. § 285 (Compl. ¶ 77).

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

  • A core issue will be one of indirect infringement liability: Can a generic manufacturer that uses a "skinny label" to carve out a patented indication (gout) be held liable for contributory infringement based on allegations that the overwhelming majority of its sales will foreseeably be for that carved-out, off-label use?
  • A second key issue will be one of inducement and regulatory compliance: Does a generic drug label that replicates safety-related dosage adjustments from the brand-name label, as required by FDA regulations, demonstrate the specific intent necessary to support a claim of induced infringement of method-of-use patents covering those exact dosage adjustments?
  • Finally, the case may present a claim construction question with significant infringement implications: Will the term "reduced colchicine dosage amount" be construed broadly to mean any reduction, or will it be limited to the specific numerical reductions and maximum dosages recited within the patent claims and specification?