DCT
1:17-cv-01019
Takeda Pharma USA Inc v. Granules Pharma Inc
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Takeda Pharmaceuticals U.S.A., Inc. (Delaware)
- Defendant: Granules Pharmaceuticals Inc. (Delaware)
- Plaintiff’s Counsel: Womble Carlyle Sandridge & Rice, LLP; Munger, Tolles & Olson LLP
- Case Identification: 1:17-cv-01019, D. Del., 07/25/2017
- Venue Allegations: Venue is alleged to be proper as Defendant is a corporation organized under the laws of Delaware, is registered to do business in Delaware, and regularly conducts business in the state.
- Core Dispute: Plaintiff alleges that Defendant's Abbreviated New Drug Application (ANDA) seeking approval to market a generic version of the drug Colcrys® (colchicine) constitutes an act of infringement of seventeen patents covering methods of using colchicine.
- Technical Context: The patents relate to pharmaceutical methods for safely administering colchicine, a potentially toxic drug, particularly concerning dosage adjustments when co-administered with other drugs that inhibit its metabolic pathways.
- Key Procedural History: The action arises under the Hatch-Waxman Act, triggered by Defendant’s submission of ANDA No. 210425 to the FDA. Defendant provided Plaintiff with a Paragraph IV Notice Letter asserting that the asserted patents are invalid, unenforceable, and/or would not be infringed by its proposed generic product. The complaint notes Defendant has "carved out" the patented use for treating gout from its proposed label, seeking approval only for the treatment of Familial Mediterranean Fever (FMF).
Case Timeline
| Date | Event |
|---|---|
| 2008-10-15 | Priority Date for ’731, ’298, ’004, ’758 Patents |
| 2009-01-14 | Priority Date for ’519, ’648, ’297, ’681, ’269, ’721, ’722 Patents |
| 2009-10-13 | U.S. Patent No. 7,601,758 Issued |
| 2009-11-17 | U.S. Patent No. 7,619,004 Issued |
| 2009-01-01 | FDA grants approval for Colcrys® (approximate date from complaint) |
| 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 No. 7,964,647 Issued |
| 2011-06-21 | U.S. Patent No. 7,964,648 Issued |
| 2011-07-19 | U.S. Patent No. 7,981,938 Issued |
| 2012-01-01 | American College of Rheumatology issues guidelines adopting Takeda’s regimen (approximate date from complaint) |
| 2012-01-10 | U.S. Patent No. 8,093,296 Issued |
| 2012-01-10 | U.S. Patent No. 8,093,297 Issued |
| 2012-01-10 | U.S. Patent No. 8,093,298 Issued |
| 2012-01-17 | U.S. Patent No. 8,097,655 Issued |
| 2013-04-09 | U.S. Patent No. 8,415,395 Issued |
| 2013-04-09 | U.S. Patent No. 8,415,396 Issued |
| 2013-05-14 | U.S. Patent No. 8,440,721 Issued |
| 2013-05-14 | U.S. Patent No. 8,440,722 Issued |
| 2016-07-29 | Orphan Drug exclusivity for Colcrys® expired |
| 2017-06-23 | Takeda receives Paragraph IV Notice Letter from Granules |
| 2017-07-25 | 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 danger of co-administering colchicine with other drugs that inhibit its metabolic breakdown, which can lead to increased colchicine levels, toxicity, and potentially death (Compl. ¶22; ’681 Patent, col. 5:4-10). Colchicine has a low therapeutic index, meaning the margin between an effective dose and a toxic dose is narrow, making such drug-drug interactions particularly dangerous (’758 Patent, col. 1:41-47).
- The Patented Solution: The invention provides specific methods for safely co-administering colchicine with a second drug that is a CYP3A4 or P-glycoprotein (P-gp) inhibitor. The solution involves administering a reduced dosage amount of colchicine compared to the standard dosage, thereby avoiding toxic plasma levels while maintaining therapeutic efficacy (’681 Patent, Abstract; ’681 Patent, col. 6:4-16).
- Technical Importance: The invention provided a scientifically-grounded method to manage previously unknown and dangerous drug interactions, allowing patients to be treated safely and effectively with colchicine while taking other necessary medications (Compl. ¶¶ 17, 22).
Key Claims at a Glance
- The complaint asserts infringement of at least claim 1 (Compl. ¶79).
- Claim 1 of the ’519 Patent contains the following essential elements:
- A method of using colchicine for the treatment of Familial Mediterranean Fever (FMF) in a human adult or child >12 years of age in need of treatment thereof.
- Orally administering a reduced colchicine dosage amount to the human who is concomitantly receiving administration of a second active agent that is a CYP3A4 inhibitor or a P-gp inhibitor, 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 the second active agent.
- 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.
- Wherein 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: As described for the ’519 Patent, this patent addresses the health risk presented by the enhancement of colchicine toxicity when co-administered with macrolide antibiotics, which are known to inhibit the metabolic pathways for colchicine (Compl. ¶22; ’758 Patent, col. 5:4-10).
- The Patented Solution: The patent discloses methods for safely administering colchicine to a patient who is also being treated with a macrolide antibiotic. The solution is a specific, reduced colchicine dosing regimen that achieves therapeutically effective plasma levels without the significant toxicity associated with standard doses under these conditions (’758 Patent, col. 6:4-16). The patent describes that this method allows for concomitant administration "without undue hazard" despite prior warnings against such a combination (’758 Patent, col. 6:12-16).
- Technical Importance: The invention established specific, safer dosing protocols that enabled the concurrent use of colchicine and common macrolide antibiotics, mitigating a known risk of severe or fatal toxicity (Compl. ¶22).
Key Claims at a Glance
- The complaint asserts infringement of at least claim 1 (Compl. ¶85).
- Claim 1 of the ’731 Patent contains the following essential elements:
- A method of using colchicine for the treatment of Familial Mediterranean Fever (FMF) in a human adult or child >12 years of age in need of treatment thereof.
- Orally administering a reduced colchicine dosage amount to the human 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.
- Wherein 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: U.S. Patent No. 8,093,298, "METHODS FOR CONCOMITANT ADMINISTRATION OF COLCHICINE AND MACROLIDE ANTIBIOTICS," issued January 10, 2012 (Compl. ¶23.C).
Technology Synopsis: This patent addresses the risk of colchicine toxicity when co-administered with macrolide antibiotics like clarithromycin. It provides a method of use involving a specific reduced dosage of colchicine to ensure safety and efficacy during such concomitant treatment (Compl. ¶45).
Asserted Claims: At least claim 1 is asserted (Compl. ¶91).
Accused Features: The proposed label for Granules's ANDA Product is alleged to instruct the claimed method of use for treating FMF, including the specific dose adjustments for concomitant administration with clarithromycin (Compl. ¶¶ 45-46).
Analyst Note: The complaint asserts 14 additional patents. These patents are generally titled "METHODS FOR CONCOMITANT ADMINISTRATION OF COLCHICINE AND A SECOND ACTIVE AGENT," "METHODS FOR CONCOMITANT ADMINISTRATION OF COLCHICINE AND MACROLIDE ANTIBIOTICS," or "COLCHICINE COMPOSITIONS AND METHODS." The infringement allegations for these patents follow the same pattern as those detailed for the lead patents, focusing on either direct instructions for FMF treatment or anticipated off-label use for gout treatment, based on the proposed ANDA product and its label (Compl. ¶¶ 95-168).
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is Defendant Granules's proposed generic 0.6 mg oral colchicine tablet, for which it seeks FDA approval via ANDA No. 210425 (Compl. ¶¶ 1, 36).
Functionality and Market Context
The complaint alleges that the act of infringement is the filing of the ANDA itself, which seeks approval to market the generic product for uses claimed in the patents-in-suit (Compl. ¶¶ 79, 85). The infringement analysis centers on the proposed product label for the Granules ANDA Product, which, under FDA regulations, must be the same as the label for the reference listed drug, Colcrys® (Compl. ¶43). The complaint alleges this label explicitly instructs medical professionals and patients to administer the drug using the patented methods, including specific dose reductions when co-administered with certain other drugs known to be CYP3A4 and P-gp inhibitors (Compl. ¶¶ 44, 47). The complaint reproduces a dose adjustment table from the Colcrys® label, which provides recommendations for treating FMF when co-administered with strong or moderate CYP3A4 inhibitors (Compl. p. 16, Table 1).
The complaint alleges that although Granules has "carved out" the indication for gout, the market for the approved FMF indication is exceptionally small compared to the gout market (99.77% of prescriptions are for gout) (Compl. ¶30). It is alleged that Granules intends to manufacture its product in quantities that "far exceed the available market for the treatment of FMF" and that the product will inevitably be prescribed and dispensed off-label for the treatment of gout, thereby infringing the "Gout Patents" (Compl. ¶¶ 31, 53, 65).
IV. Analysis of Infringement Allegations
U.S. Patent No. 7,906,519 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 (FMF) in a human adult or child >12 years of age in need of treatment thereof | The Granules ANDA Product is a 0.6 mg colchicine tablet for which Granules seeks approval to treat FMF. The proposed label will instruct this use. | ¶¶36, 42, 46 | col. 7:16-21 |
| said method comprising: orally administering a reduced colchicine dosage amount to the human... who is concomitantly receiving administration of a second active agent that is a CYP3A4 inhibitor or a P-gp inhibitor | The proposed label, mirroring the Colcrys® label, allegedly instructs dose adjustments when colchicine is co-administered with drugs known to inhibit CYP3A4 and/or P-gp. | ¶¶44, 47, 48 | col. 8:1-12 |
| wherein the reduced colchicine dosage amount is reduced compared to a daily dosage amount to be administered in the absence of the second active agent | The proposed label's dosing table for FMF allegedly instructs a reduction from a standard maximum daily dose to a lower maximum daily dose when co-administered with CYP3A4 inhibitors. | ¶¶44, 45; p. 16, Table 1 | col. 6:35-38 |
| 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 proposed label allegedly specifies that the "Original Intended Dosage" for FMF is a maximum daily dose of 1.2-2.4 mg. | ¶45; p. 16, Table 1 | col. 8:44-46 |
| and wherein the reduced colchicine dosage amount is a maximum of 0.6 mg per day. | The proposed label allegedly instructs that when co-administered with a strong CYP3A4 inhibitor, the "Adjusted Dose" for FMF is a "Maximum daily dose of 0.6 mg". | ¶45; p. 16, Table 1 | col. 8:47-49 |
Identified Points of Contention
- Scope Questions: The primary legal dispute centers on indirect infringement. For the FMF patents, the central question may be whether the instructions on Granules's proposed label will actively encourage or instruct practitioners and patients to perform all steps of the claimed method, thereby establishing the requisite intent for induced infringement. For the patents directed to treating gout (the "Gout Patents"), a key question will be whether Takeda can prove inducement or contributory infringement for an indication that Granules has expressly "carved out" of its label, based on allegations of economic incentives and established medical and pharmaceutical practices.
- Technical Questions: The complaint's infringement theory relies on the ANDA label being the same as the Colcrys® label. A potential technical question is whether the specific drugs listed as examples in the label (e.g., clarithromycin, ketoconazole) provide sufficient basis to find infringement of claims that may recite broader functional categories (e.g., "a second active agent that is a CYP3A4 inhibitor or a P-gp inhibitor").
V. Key Claim Terms for Construction
- The Term: "concomitantly receiving administration"
- Context and Importance: The timing relationship between the administration of colchicine and the second active agent is a crucial element of the claimed method. The definition of "concomitantly" will determine the window of time during which the dosage reductions are required, which is central to the infringement analysis. Practitioners may focus on this term because the defendant could argue for a very narrow, simultaneous-only interpretation, whereas the patent's safety objective may require a much broader window to account for lingering metabolic inhibition.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The '681 Patent specification states that "concomitant" refers to administration "either simultaneously or within a time period during which the effects of the first administered drug are still operative," noting that for CYP3A4 inhibitors like clarithromycin, this period can be "as much as about one to two weeks" (’681 Patent, col. 11:41-52).
- Evidence for a Narrower Interpretation: While the specification provides a broad definition, a defendant may point to specific claim language, such as "within 1 to 2 days of oral administration of colchicine" in claim 1 of the ’519 Patent, to argue that for that particular claim, the scope is explicitly limited to that narrower timeframe.
VI. Other Allegations
Indirect Infringement
- The complaint's allegations are based entirely on theories of indirect infringement under 35 U.S.C. § 271(b) and (c), as the direct infringers would be the physicians and patients who follow the instructions on the proposed label.
- Induced Infringement: The complaint alleges inducement of the FMF patents based on the explicit instructions for dose reduction that will be on the ANDA product's label (Compl. ¶¶ 47-48). It alleges inducement of the Gout patents based on Granules's knowledge that its generic product, despite the label's carve-out, will be prescribed and substituted for Colcrys® for the treatment of gout, which constitutes the overwhelming majority of the market (Compl. ¶¶ 56, 70-72).
- Contributory Infringement: The complaint alleges contributory infringement of the Gout patents, asserting that the ANDA Product is not a "staple article of commerce suitable for substantial non-infringing use" because the on-label FMF market is insubstantial compared to the anticipated off-label use for gout (Compl. ¶¶ 73-74, 99).
Willful Infringement
- The complaint alleges that Granules was aware of the patents-in-suit prior to filing the lawsuit, based on their listing in the FDA's Orange Book and on Granules's own Paragraph IV certification letter identifying the patents (Compl. ¶¶ 27, 37, 75). It further alleges Granules "had no basis" for submitting its ANDA and Paragraph IV certification, which may form the basis for an allegation of willful infringement and a request for enhanced damages (Compl. ¶76).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of "induced infringement for a carved-out use": Can Takeda establish that Granules possessed the specific intent to induce infringement of the Gout Patents, an indication it explicitly carved out of its label, by presenting evidence of market size disparities, known physician prescribing habits, and economic incentives for off-label substitution?
- A key evidentiary question will be one of "substantial non-infringing use": Can the on-label use for treating FMF, which the complaint alleges accounts for less than 1% of the total market, be deemed a "substantial" non-infringing use, or will the court find that the ANDA product's only substantial use is the infringing off-label treatment of gout, thereby supporting a claim for contributory infringement?
- A central question of "claim scope and labeling" will be: Do the specific instructions and examples provided in the proposed ANDA label, which are dictated by the reference drug's label, meet every limitation of the asserted method claims, and does that labeling actively instruct or encourage the performance of the patented methods?