DCT
1:17-cv-01469
Takeda Pharma USA Inc v. Macleods Pharma Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Takeda Pharmaceuticals U.S.A., Inc. (Delaware)
- Defendant: Macleods Pharmaceuticals Ltd. (India) and Macleods Pharma USA, Inc. (Delaware)
- Plaintiff’s Counsel: Womble Carlyle Sandridge & Rice, LLP
- Case Identification: 1:17-cv-01469, D. Del., 10/17/2017
- Venue Allegations: Plaintiff alleges venue is proper in the District of Delaware because Defendant Macleods Pharma USA, Inc. is a Delaware corporation and, upon information and belief, both Defendants conduct regular business in the district.
- Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's Colcrys® (colchicine) product constitutes an act of infringement of seventeen U.S. patents covering methods of using colchicine.
- Technical Context: The patents relate to methods for safely administering colchicine, a drug used for treating inflammatory conditions like gout and Familial Mediterranean Fever (FMF), particularly concerning dosage adjustments to avoid toxicity when co-administered with other drugs.
- Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by Defendants' submission of ANDA No. 210633 with a Paragraph IV certification. Defendants seek FDA approval to market their generic colchicine product for the treatment of FMF, having "carved out" the patented indications for gout treatment from their proposed label. Plaintiff contends this carve-out is legally insufficient to avoid infringement, alleging the generic product will inevitably be prescribed and dispensed for the much larger off-label gout market, thereby inducing and contributing to infringement of its patents.
Case Timeline
| Date | Event |
|---|---|
| 2008-10-15 | Earliest Priority Date for ’758, ’004, ’731, ’298, ’296, and ’655 Patents |
| 2009-02-10 | Earliest Priority Date for ’647 and ’938 Patents |
| 2009-02-12 | Earliest Priority Date for ’681, ’519, ’269, ’648, and ’297 Patents |
| 2009-02-17 | Earliest Priority Date for ’721 and ’722 Patents |
| 2009-04-14 | Earliest Priority Date for ’395 and ’396 Patents |
| 2009-01-01 | FDA granted approval for Colcrys® (colchicine) tablets (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 |
| 2012-01-01 | American College of Rheumatology issued guidelines for gout management (approximate date) |
| 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 |
| 2016-07-29 | Colcrys® Orphan Drug exclusivity expired |
| 2017-09-07 | Macleods sent Paragraph IV Notice Letter to Takeda |
| 2017-10-17 | 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 patent addresses the health risk presented by drug-drug interactions that enhance colchicine toxicity, which can occur when colchicine is co-administered with other drugs that inhibit certain metabolic pathways (Compl. ¶25; ’681 Patent, col. 2:37-44). Colchicine has a narrow therapeutic index, meaning the margin between an effective dose and a toxic dose is small, making unexpected increases in colchicine levels dangerous (’681 Patent, col. 1:40-43).
- The Patented Solution: The invention provides methods for safely administering colchicine to a patient who is also taking a second drug that inhibits the CYP3A4 enzyme and/or the P-gp transporter, two key pathways for colchicine metabolism and clearance (’681 Patent, col. 5:1-12). The solution involves administering a specific, reduced dosage of colchicine compared to the standard dose to prevent toxic accumulation while maintaining therapeutic effect (’681 Patent, col. 6:50-65).
- Technical Importance: These methods provide specific, clinically tested dosage adjustments that allow patients to continue necessary colchicine therapy while also being treated with other essential medications, reducing the risk of severe or fatal toxicity (Compl. ¶¶25-26, 30).
Key Claims at a Glance
- The complaint asserts infringement of at least Claim 1 (Compl. ¶87).
- Claim 1 is a method for treating Familial Mediterranean Fever (FMF) in a human, comprising the elements of:
- Orally administering a reduced colchicine dosage amount;
- To a human in need of treatment for FMF who is concomitantly receiving a second active agent that is an inhibitor of CYP3A4 or P-gp;
- Wherein the reduced colchicine dosage amount is a 25% to 50% reduction of a first colchicine daily dosage amount suitable for daily oral administration in the absence of the second active agent; and
- Wherein the first colchicine daily dosage amount is 1.2 mg to 2.4 mg per day for an adult, 0.9 mg to 1.8 mg per day for a child 6-12 years, or 0.3 mg to 1.8 mg per day for a child 4-6 years.
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: The patent identifies a specific and dangerous interaction between colchicine and macrolide antibiotics (e.g., clarithromycin), which are known to inhibit the CYP3A4 enzyme and P-gp transporter responsible for colchicine metabolism (’731 Patent, col. 6:29-37). Co-administration without dose adjustment can lead to "increased exposure to colchicine," resulting in clinical symptoms of toxicity (Compl. ¶¶25-26; ’731 Patent, col. 6:32-37).
- The Patented Solution: The invention discloses a method for safely co-administering colchicine with clarithromycin by defining a specific "reduced colchicine dosage amount" (’731 Patent, col. 18:8-18). The method requires reducing the standard daily dose of colchicine for FMF (a maximum of 2.4 mg/day) to a maximum of 0.6 mg/day when clarithromycin is administered concomitantly (’731 Patent, col. 18:8-18).
- Technical Importance: This invention provided a specific, evidence-based dosing protocol that allows for the necessary concurrent use of a common antibiotic and colchicine, mitigating the risk of potentially fatal drug interactions that were previously observed in patients (Compl. ¶30).
Key Claims at a Glance
- The complaint asserts infringement of at least Claim 1 (Compl. ¶93).
- Claim 1 is a method of using colchicine for the treatment of FMF in a human adult or child >12 years of age, comprising the elements of:
- Orally administering a reduced colchicine dosage amount;
- To a human adult or child >12 years of age in need of treatment for FMF who is concomitantly receiving administration of clarithromycin within 1 to 2 days of oral administration of colchicine;
- Wherein the reduced colchicine dosage amount is reduced compared to a daily dosage amount to be administered in the absence of concomitant clarithromycin;
- Wherein the daily dosage amount to be administered 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.
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 same technical problem as the ’731 Patent: the dangerous interaction between colchicine and macrolide antibiotics. The claimed solution is a specific method for treating FMF in adults or children over 12 by orally administering a reduced dose of colchicine (max 0.6 mg/day) when a patient is concomitantly receiving clarithromycin, compared to a standard dose (max 2.4 mg/day) when not receiving clarithromycin.
- Asserted Claims: At least Claim 1 (Compl. ¶99).
- Accused Features: The complaint alleges that Defendants' proposed product label for their ANDA Product will instruct medical professionals and patients to administer colchicine in a manner that directly infringes the claimed method (Compl. ¶¶53-56, 100).
(Analyst Note: The complaint asserts seventeen patents in total. Capsule summaries for the remaining fourteen patents are omitted for conciseness but would follow the same format, addressing methods of using colchicine for FMF and gout, including specific dosing regimens and interactions with other active agents such as ketoconazole, ritonavir, and verapamil, as alleged in Counts IV through XVII of the complaint.)
III. The Accused Instrumentality
Product Identification
- Defendants' ANDA Product, a generic version of Colcrys® containing 0.6 mg of colchicine in an oral tablet form, for which Defendants seek FDA approval under ANDA No. 210633 (Compl. ¶¶1, 44).
Functionality and Market Context
- The accused instrumentality is the filing of the ANDA itself, which is a statutory act of infringement under 35 U.S.C. § 271(e)(2) (Compl. ¶¶87, 93). The future commercial product is intended to be a bioequivalent generic substitute for Takeda's Colcrys® (Compl. ¶74).
- Defendants are seeking FDA approval solely for the treatment of FMF and have "carved out" the gout indication from their proposed label (Compl. ¶77). However, the complaint alleges that the FMF market is less than 1% of the total colchicine prescription market, which is dominated by treatment for gout (Compl. ¶38). Plaintiff alleges that Defendants intend to manufacture and sell quantities of their ANDA product that "far exceed the market for treatment of FMF" and that the product will be prescribed and dispensed for the much larger off-label gout market (Compl. ¶¶73, 78).
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 the treatment of Familial Mediterranean Fever in a human adult...or child | Defendants' ANDA seeks approval to market their generic colchicine product for the treatment of FMF. | ¶87 | col. 20:30-31 |
| said method comprising: orally administering a reduced colchicine dosage amount to the human...in need of treatment for Familial Mediterranean Fever who is concomitantly receiving administration of a second active agent that is an inhibitor of CYP3A4 or P-gp | The proposed label for Defendants' ANDA Product, on information and belief, will instruct physicians and patients to reduce the colchicine dose when co-administered with CYP3A4 or P-gp inhibitors for the treatment of FMF. | ¶¶52, 54-56 | col. 20:32-38 |
| wherein the reduced colchicine dosage amount is a 25% to 50% reduction of a first colchicine daily dosage amount suitable for daily oral administration in the absence of...the second active agent | The complaint alleges that the dose adjustments on Defendants' proposed label will correspond to the reductions claimed in the patent. The Colcrys® label, reproduced in part in the complaint, provides a table of specific dose adjustments for FMF patients. | ¶¶52-53 | col. 20:39-44 |
'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 | Defendants' ANDA seeks approval to market their generic colchicine product for the treatment of FMF. | ¶93 | col. 18:8-10 |
| said method comprising: orally administering a reduced colchicine dosage amount...who is concomitantly receiving administration of clarithromycin | The complaint provides a dose adjustment table from the Colcrys® label showing specific instructions for FMF patients taking clarithromycin. The complaint alleges Defendants' label will contain the same instructions. This table is presented as probative visual evidence of the claimed method. (Compl. p. 17). | ¶¶52-54 | col. 18:11-15 |
| 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 instructs adjusting the dose from a maximum of 2.4 mg/day to a maximum of 0.6 mg/day when co-administered with clarithromycin, a strong CYP3A4 inhibitor. | ¶53 | col. 18:1-3 |
| wherein the daily dosage amount...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 specific dosage amounts recited in the Colcrys® label and allegedly recited in Defendants' proposed label are alleged to match the claimed dosage amounts. | ¶53 | col. 18:4-7 |
Identified Points of Contention
- Scope Questions: The primary dispute for the "Gout Patents" will revolve around Defendants' "skinny label" strategy. This raises the question of whether Takeda can meet the legal standard for proving induced or contributory infringement for the carved-out gout indications, especially given Defendants' formal disavowal of any intent to market for gout (Compl. ¶¶77, 81). The complaint argues that the FMF market is economically insubstantial compared to the gout market, suggesting the FMF-only label may be a pretext to access the larger off-label market (Compl. ¶¶38-39, 82).
- Technical Questions: For the "FMF Patents" (including the ’519 and ’731 Patents), the analysis will likely focus on a direct comparison between the claim limitations and the instructions for use in Defendants' proposed product labeling. A key question will be whether the specific dose reduction instructions on the label meet every limitation of the asserted method claims, including definitions of "reduced," "concomitant administration," and the specified dosage amounts.
V. Key Claim Terms for Construction
The Term: "a reduced colchicine dosage amount" (’519 Patent, Claim 1; ’731 Patent, Claim 1)
Context and Importance
- The definition of this term is central to infringement, as it requires a comparison between the dosage administered with a second drug and a "first" or "daily" dosage amount administered without that drug. The parties may dispute how this baseline dosage amount is determined and whether the reduction specified on the accused label meets the claimed percentage or comparative reduction.
Intrinsic Evidence for Interpretation
- Evidence for a Broader Interpretation: The claims define the reduction relative to a "suitable" or "usual intended dose," which could be interpreted broadly to mean the standard of care or the dose a physician would typically prescribe, not just a single fixed number (’519 Patent, col. 20:41-44; ’731 Patent, col. 18:1-3).
- Evidence for a Narrower Interpretation: The specification and claims provide specific numerical examples, such as reducing a maximum dose of 2.4 mg/day to 0.6 mg/day (’731 Patent, Claim 1). Defendants may argue that the term should be limited to the specific dose ranges and reduction percentages explicitly recited in the patent.
The Term: "concomitantly receiving administration" (’519 Patent, Claim 1; ’731 Patent, Claim 1)
Context and Importance
- This term dictates the temporal relationship required between the administration of colchicine and the second active agent. The ’731 Patent specifies this as "within 1 to 2 days," but the ’519 Patent does not. Practitioners may focus on this term because the metabolic-inhibiting effects of some drugs can last long after the drug is no longer being taken, raising questions about how long the "concomitant" period extends.
Intrinsic Evidence for Interpretation
- Evidence for a Broader Interpretation: The patents explain that drug-inhibiting effects can be long-lasting, suggesting "concomitant" could be interpreted functionally to cover any period where the second drug's metabolic inhibition is still active, even if the patient is no longer taking it (’681 Patent, col. 12:40-51).
- Evidence for a Narrower Interpretation: The plain language suggests simultaneous or near-simultaneous administration. The specificity of "within 1 to 2 days" in the ’731 Patent could be used to argue that a narrower, more explicit timeframe should be applied even to claims where it is not explicitly recited.
VI. Other Allegations
Indirect Infringement
- The complaint's primary theory of infringement is indirect. For the FMF patents, it alleges active inducement under § 271(b), asserting that Defendants' proposed label will instruct users to perform the patented methods (Compl. ¶¶55, 88, 94). For the Gout patents, the complaint alleges both induced infringement and contributory infringement under § 271(c), arguing that Defendants know their product is especially adapted for use in infringing the gout treatment methods and that the FMF indication is not a substantial non-infringing use (Compl. ¶¶74, 82, 107).
Willful Infringement
- The complaint does not use the term "willful" but does allege facts that may support such a claim post-suit. It alleges that Macleods had knowledge of all the patents-in-suit and had "no basis for submitting ANDA No. 210633 or a Paragraph IV Certification," which it claims renders the case "exceptional" under 35 U.S.C. § 285 (Compl. ¶¶83-84).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be one of indirect infringement doctrine: Can Takeda successfully argue that Defendants' "skinny label," which formally carves out the patented gout indications, is nonetheless a tool for inducing widespread, off-label infringement in the much larger gout market? This will likely turn on evidence of Defendants' intent and the economic realities of the FMF versus gout markets.
- A key question of statutory interpretation will be the scope of the § 271(e)(2) act of infringement. Does the artificial act of infringement created by an ANDA filing allow for a finding of infringement on carved-out indications based on allegations of future, foreseeable off-label use, or is the inquiry limited to the uses for which the applicant is actively seeking approval?
- A secondary issue will be one of claim construction: For the directly-accused FMF patents, the dispute may focus on whether the specific instructions on Defendants' proposed label will meet every limitation of the asserted method claims, particularly the definitions of "reduced dosage amount" and the baseline against which that reduction is measured.