DCT

1:19-cv-00883

Hikma Pharma USA Inc v. Micro Labs Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:19-cv-00883, D. Del., 05/10/2019
  • Venue Allegations: Plaintiff alleges venue is proper as Defendants, through counsel, consented to venue in the District of Delaware for the purposes of this action.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's Mitigare® (colchicine) product infringes five patents related to methods of safely co-administering colchicine with certain other drugs.
  • Technical Context: The patents address a known safety issue with the gout medication colchicine, which can become toxic if its metabolic clearance is inhibited by other co-administered drugs.
  • Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Defendant’s submission of ANDA No. 212880 and notification to Plaintiff via a Paragraph IV certification letter that Defendant believes the patents-in-suit are invalid, unenforceable, and/or will not be infringed.

Case Timeline

Date Event
2013-08-20 Priority Date for ’607, ’036, ’029, ’613, and ’108 Patents
2015-01-06 U.S. Patent No. 8,927,607 Issues
2016-07-26 U.S. Patent No. 9,399,036 Issues
2017-01-31 U.S. Patent No. 9,555,029 Issues
2017-06-13 U.S. Patent No. 9,675,613 Issues
2017-10-17 U.S. Patent No. 9,789,108 Issues
2019-03-27 Plaintiff receives Defendant's ANDA Notice Letter
2019-05-07 Defendant consents to personal jurisdiction and venue
2019-05-10 Complaint Filed

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

U.S. Patent No. 8,927,607 - Methods of colchicine administration

The Invention Explained

  • Problem Addressed: Colchicine, a drug used to treat gout, has a narrow margin of safety and can become toxic if its concentration in the blood increases (Compl. ¶22). This can occur when it is co-administered with other drugs that inhibit either of two key biological pathways responsible for its clearance: the metabolic enzyme CYP3A4 or the cellular efflux pump P-glycoprotein (P-gp) (’607 Patent, col. 2:6-38). The prior medical consensus was that colchicine dosage should be reduced when co-administered with a drug known to inhibit either pathway to avoid toxicity (’607 Patent, col. 2:45-53).
  • The Patented Solution: The inventor discovered that certain drugs that inhibit only one of these two pathways—but not both—can be safely co-administered with colchicine at its standard therapeutic dose without requiring a dose reduction (Compl. ¶23). The patent describes a method that enables non-toxic co-administration of colchicine with specific single-pathway inhibitors (e.g., voriconazole, fluconazole, cimetidine) at their ordinary levels, thereby maintaining therapeutic efficacy for both drugs (’607 Patent, Abstract; col. 3:26-33).
  • Technical Importance: This discovery provided a method for patients requiring both colchicine and a single-pathway inhibitor drug to continue effective treatment without risking colchicine toxicity or suffering reduced efficacy from a lowered colchicine dose (Compl. ¶23).

Key Claims at a Glance

The complaint asserts "one or more claims" of the ’607 Patent (Compl. ¶37). Independent claim 1 is representative:

  • A method of treating a patient for an inflammatory disorder selected from chronic gout, familial Mediterranean fever or Behçet's disease, with colchicine
  • while concomitantly administering a second drug that is an inhibitor of the cytochrome P450 3A4 isoenzyme (CYP3A4) but is not an inhibitor of P-glycoprotein 1 (P-gp),
  • wherein the second drug is voriconazole, fluconazole or cimetidine,
  • the method comprising administering a fixed maintenance dose of colchicine from about 0.6 to about 1.2 mg/day for a plurality of days,
  • and after commencing administration of the second drug, continuing to administer the fixed maintenance dose of colchicine without dose reduction.

U.S. Patent No. 9,399,036 - Methods of colchicine administration

The Invention Explained

  • Problem Addressed: As a continuation of the application leading to the ’607 Patent, the ’036 patent addresses the identical technical problem: the risk of colchicine toxicity when co-administered with drugs that inhibit its metabolic or clearance pathways, and the prior art's solution of dose reduction which could compromise efficacy (’036 Patent, col. 2:5-52).
  • The Patented Solution: The patent claims methods of administering colchicine with specific drugs that are single-pathway inhibitors (inhibiting CYP3A4 but not P-gp), allowing the colchicine to be given at its normal maintenance dose "without dose reduction" (’036 Patent, col. 4:18-21; Abstract).
  • Technical Importance: The method allows for the continued safe and effective use of colchicine in patients who also require treatment with specific drugs that were previously thought to necessitate a potentially sub-therapeutic reduction in colchicine dosage (Compl. ¶23).

Key Claims at a Glance

The complaint asserts "one or more claims" of the ’036 Patent (Compl. ¶46). Independent claim 1 is representative:

  • A method of administering colchicine to a patient while concomitantly administering a second drug that is an inhibitor of CYP3A4 but is not an inhibitor of P-gp,
  • wherein the second drug is voriconazole, fluconazole or cimetidine,
  • the method comprising administering a therapeutic fixed maintenance dose of colchicine in an amount from about 0.6 to about 1.2 mg/day,
  • and after commencing administration of the second drug, administering the colchicine dose concomitantly with the second drug without dose reduction.

U.S. Patent No. 9,555,029 - Methods of colchicine administration

  • Technology Synopsis: This patent is from the same family and addresses the same technical problem of drug-drug interactions with colchicine. It claims methods for safely co-administering colchicine without dose reduction, but focuses on a second drug, propafenone, which is an inhibitor of the P-gp pathway but not the CYP3A4 pathway (’029 Patent, Abstract; col. 4:8-21). This is the converse of the scenario claimed in the ’607 and ’036 patents.
  • Asserted Claims: One or more claims of the ’029 patent are asserted (Compl. ¶55).
  • Accused Features: The proposed use of Defendant's generic colchicine product, per its labeling, is alleged to infringe by instructing co-administration with propafenone without a dose reduction (Compl. ¶¶33-34, 55).

U.S. Patent No. 9,675,613 - Methods of colchicine administration

  • Technology Synopsis: This patent is also from the same family. It claims methods for administering colchicine with propafenone (a P-gp-only inhibitor) without reducing the colchicine dose, similar to the ’029 patent (’613 Patent, Abstract; col. 12:4-18).
  • Asserted Claims: One or more claims of the ’613 patent are asserted (Compl. ¶64).
  • Accused Features: The proposed instructions for use of Defendant's generic colchicine product are alleged to infringe by directing co-administration with propafenone without a dose adjustment (Compl. ¶¶33-34, 64).

U.S. Patent No. 9,789,108 - Methods of colchicine administration

  • Technology Synopsis: This patent is also from the same family and claims methods of co-administering colchicine with propafenone (a P-gp-only inhibitor) without dose reduction, addressing the same technical problem and solution as the ’029 and ’613 patents (’108 Patent, Abstract; col. 12:1-15).
  • Asserted Claims: One or more claims of the ’108 patent are asserted (Compl. ¶73).
  • Accused Features: The infringement allegation is based on the instructions for use in the proposed labeling for Defendant's generic colchicine, which allegedly direct co-administration with propafenone without a dose reduction (Compl. ¶¶33-34, 73).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is "Micro Labs' ANDA Product," a proposed generic version of Hikma's Mitigare® (colchicine) 0.6 mg capsule, for which Defendant has filed ANDA No. 212880 with the FDA (Compl. ¶¶11, 28).

Functionality and Market Context

  • The infringement alleged in the complaint is not based on the composition of the drug product itself, but on its proposed method of use as will be described in its prescribing information, or "label" (Compl. ¶37). The complaint alleges that Defendant’s filing of its ANDA is an act of infringement under 35 U.S.C. § 271(e)(2) because the proposed label will instruct and encourage healthcare providers and patients to use the generic colchicine in a manner that practices the patented methods (Compl. ¶¶33, 38). Specifically, the complaint notes that the prescribing information for the branded Mitigare® product encourages using full colchicine doses when co-administered with drugs like voriconazole and fluconazole, and alleges Defendant's product will be used in the same way (Compl. ¶26).
  • No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not include the Defendant's proposed product label or a formal claim chart. The infringement theory is based on the allegation that the instructions in the proposed label for the ANDA Product will direct users to practice the patented methods.

U.S. Patent No. 8,927,607 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating a patient for an inflammatory disorder wherein the inflammatory disorder is chronic gout... with colchicine while concomitantly administering a second drug that is an inhibitor of...CYP3A4 but is not an inhibitor of P-gp, wherein the second drug is voriconazole, fluconazole or cimetidine... The proposed label for the ANDA Product will instruct healthcare providers and patients to treat chronic gout by co-administering the 0.6 mg colchicine capsule with voriconazole, fluconazole, or cimetidine. ¶¶33, 37 col. 2:12-14; col. 10:54-67
...administering to the patient the fixed maintenance dose of colchicine of step (a) without dose reduction. The proposed label will instruct users that the standard dose of colchicine can be administered with these specified drugs "without a need for dose adjustment." ¶¶26, 33, 37 col. 4:1-4; col. 10:61-64

U.S. Patent No. 9,399,036 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of administering colchicine to a patient while concomitantly administering a second drug that is an inhibitor of CYP3A4 but is not an inhibitor of P-gp, wherein the second drug is voriconazole, fluconazole or cimetidine... The proposed label for the ANDA Product will instruct users on a method of administering colchicine concomitantly with voriconazole, fluconazole, or cimetidine for the treatment of indicated conditions like gout. ¶¶46, 33 col. 2:35-41; col. 11:4-20
...administering to the patient the fixed maintenance dose of colchicine... without dose reduction. The proposed label will instruct that the normal therapeutic dose of colchicine should be used when co-administered with the specified second drugs, without any reduction. ¶¶26, 33, 46 col. 4:18-21

Identified Points of Contention

  • Factual Question: The central dispute will be factual: what are the exact contents of Micro Labs' proposed product label? The complaint's allegations are based on "information and belief," and the case will depend on whether the label's language directly instructs or encourages a method that meets every limitation of the asserted claims.
  • Scope Question: A potential point of contention may be the negative claim limitation "not an inhibitor of P-gp." The parties may dispute the proper technical and legal standard for determining that a compound is a "non-inhibitor" and whether the specified drugs (voriconazole, fluconazole, cimetidine) meet that standard.

V. Key Claim Terms for Construction

The Term: "without dose reduction"

  • Context and Importance: This term is central to the invention's departure from the prior art, which allegedly required dose reduction. The infringement allegation hinges on the Defendant's proposed label instructing administration "without dose reduction." The definition of this term will determine whether the label's instructions fall within the claim scope.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent specification repeatedly contrasts the invention with prior art that recommended reducing the colchicine dose by "about 33-75%" and administering it less frequently (’607 Patent, col. 2:55-62). This context may support an interpretation where "without dose reduction" means not engaging in the specific, significant dose-lowering practices previously recommended.
    • Evidence for a Narrower Interpretation: The claims recite a "fixed maintenance dose... in an amount of from about 0.6 to about 1.2 mg/day" (’607 Patent, Claim 1). A defendant could argue that this language itself builds in a dosing range, and that instructions to use a dose at the lower end of a standard range could be characterized as a form of "dose reduction."

The Term: "inhibitor of... CYP3A4 but is not an inhibitor of P-gp"

  • Context and Importance: This term defines the class of drugs for which co-administration is claimed. Whether the specific drugs identified in the patent (and allegedly in the Defendant's label) meet both the positive ("inhibitor of CYP3A4") and negative ("not an inhibitor of P-gp") limitations is a threshold infringement question. Practitioners may focus on this term because the negative limitation could create ambiguity.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification explicitly names voriconazole, fluconazole, and cimetidine as drugs that are CYP3A4 inhibitors but not P-gp inhibitors, suggesting these are exemplars of the claimed class (’607 Patent, col. 10:54-67). This may suggest that the term should be construed to encompass these named drugs.
    • Evidence for a Narrower Interpretation: The specification refers to FDA guidance for classifying the strength of CYP3A4 inhibitors (strong, moderate, weak) and notes the FDA also classifies drugs as P-gp inhibitors or non-inhibitors based on whether they cause a >25% increase in a substrate's AUC (’607 Patent, col. 8:51-col. 9:7). A party could argue that for a drug to be "not an inhibitor of P-gp," it must be shown to meet the corresponding objective FDA standard for a non-inhibitor.

VI. Other Allegations

Indirect Infringement

  • The complaint alleges active inducement of infringement against Micro Labs (Compl. ¶42). The factual basis for this claim is the allegation that Micro Labs, by seeking approval for and marketing its ANDA product with its proposed label, will specifically intend to encourage and instruct healthcare providers and patients to perform the steps of the patented methods (Compl. ¶¶33-34).

Willful Infringement

  • The complaint does not contain an explicit allegation of willful infringement or a request for enhanced damages under 35 U.S.C. § 284. It does allege that Micro Labs had knowledge of the patents-in-suit when it submitted its ANDA (Compl. ¶32).

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

  • A central evidentiary question will be one of instructional clarity: Does the precise language of the Defendant's proposed product label, which was not included in the complaint, contain explicit instructions or clear encouragement for physicians to co-administer generic colchicine with the specified single-pathway inhibitors without adjusting the standard dose, thereby satisfying the elements of the asserted method claims?
  • A key issue of claim construction and technical fact will be the definitional scope of a "non-inhibitor": What is the legal and scientific standard for proving a drug is "not an inhibitor of P-gp" as required by the claims, and will the parties' expert evidence establish that voriconazole, fluconazole, and cimetidine definitively meet this negative limitation?