Hikma Pharma USA Inc v. Annora Pharma Pvt Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Hikma Pharmaceuticals USA Inc. (Delaware) and Hikma International Pharmaceuticals LLC (Jordan)
  • Defendant: Annora Pharma Private Limited (India)
  • Plaintiff’s Counsel: Winston & Strawn LLP
• Case Identification: 1:23-cv-00231, D. Del., 03/02/2023
• Venue Allegations: Venue is asserted based on Defendant's business of formulating, manufacturing, and selling generic pharmaceutical drugs that it distributes in Delaware and throughout the United States.
• Core Dispute: Plaintiff alleges that Defendant's Abbreviated New Drug Application ("ANDA") to market a generic version of Plaintiff's Mitigare® (colchicine) constitutes an act of infringement of five patents related to methods of safely co-administering colchicine with other drugs.
• Technical Context: The patents address the management of drug-drug interactions for colchicine, a medication with a narrow therapeutic index, to maintain safety and efficacy when taken with other common medications.
• Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following a January 17, 2023 notification letter from Annora, in which Annora certified to the FDA that the patents-in-suit are invalid, unenforceable, or will not be infringed by its proposed generic product (a "Paragraph IV certification"). The patents-in-suit are listed in the FDA's "Orange Book" for Mitigare®.

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
2023-01-17	Date of Annora’s Notice Letter to Hikma
2023-03-02	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: The patent addresses the risk of colchicine toxicity when co-administered with other drugs. Colchicine has a narrow safety margin, and its blood concentration can increase to dangerous levels if its metabolic clearance is inhibited. Two key pathways for clearance are the enzyme CYP3A4 and the transporter P-glycoprotein (P-gp). The prevailing medical consensus was that co-administration of colchicine with a drug that inhibits either pathway required a reduction in the colchicine dose, which could compromise its therapeutic effect. (’607 Patent, col. 2:6-53).
• The Patented Solution: The patent describes the discovery that drugs that inhibit only one of these two pathways (i.e., a CYP3A4 inhibitor that does not inhibit P-gp, or vice versa) do not cause a clinically significant increase in colchicine levels. The invention is a method of treatment that allows for the co-administration of colchicine at its normal therapeutic dose with such "single-pathway inhibitors," thereby avoiding unnecessary dose reductions and maintaining efficacy without sacrificing safety. (’607 Patent, col. 3:25-41).
• Technical Importance: This approach provides a more nuanced framework for managing drug-drug interactions with colchicine, enabling patients who require multiple medications to continue effective gout therapy safely. (’607 Patent, col. 3:15-24).

Key Claims at a Glance

• The complaint asserts infringement of one or more claims, with independent claim 1 being representative.
• Essential elements of Claim 1:
  • A method of treating a patient for an inflammatory disorder (chronic gout, familial Mediterranean fever, or Behçet's disease) with colchicine.
  • The method involves concomitantly administering a second drug that is an inhibitor of CYP3A4 but not an inhibitor of P-gp.
  • The second drug is specified as voriconazole, fluconazole, or cimetidine.
  • The method comprises administering a fixed maintenance dose of colchicine (from 0.6 to 1.2 mg/day) along with the second drug "without dose reduction."
• The complaint does not explicitly reserve the right to assert dependent claims but makes a general allegation covering "one or more claims" (Compl. ¶27).

U.S. Patent No. 9,399,036 - “Methods of Colchicine Administration”

The Invention Explained

• Problem Addressed: As with the parent ’607 Patent, this patent addresses the problem of managing colchicine dosing in the presence of drugs that inhibit its metabolic pathways, specifically the risk of toxicity when co-administered with CYP3A4 or P-gp inhibitors. (’036 Patent, col. 2:8-53).
• The Patented Solution: The patent discloses methods of administering colchicine with "single inhibitors" (drugs that inhibit CYP3A4 or P-gp, but not both) at a standard fixed maintenance dose. This avoids the prior art's recommendation of reducing the colchicine dose, which could lower its effectiveness. (’036 Patent, col. 3:41-4:3).
• Technical Importance: The invention provides physicians with a safe and effective protocol for patients on chronic colchicine therapy who also need to take other common medications that were previously thought to pose a significant interaction risk. (’036 Patent, col. 3:18-28).

Key Claims at a Glance

• The complaint asserts infringement of one or more claims, with independent claim 1 being representative.
• Essential elements of Claim 1:
  • A method of administering colchicine to a patient.
  • The method involves concomitantly administering a second drug that inhibits CYP3A4 but not P-gp.
  • The second drug is specified as voriconazole, fluconazole, or cimetidine.
  • The method comprises administering a fixed maintenance dose of colchicine (from about 0.6 to about 1.2 mg/day) with the second drug "without dose reduction."
• The complaint does not explicitly reserve the right to assert dependent claims but makes a general allegation covering "one or more claims" (Compl. ¶36).

U.S. Patent No. 9,555,029 - “Methods of Colchicine Administration”

• Technology Synopsis: This patent is directed to the other aspect of the core invention: safely co-administering colchicine without dose reduction with a drug that inhibits P-gp but is not an inhibitor of CYP3A4. The patent specifically claims this method where the second drug is propafenone. (’029 Patent, Abstract; Claim 1).
• Asserted Claims: One or more claims (Compl. ¶45).
• Accused Features: The intended use of Annora’s generic colchicine product as directed by its proposed labeling, which allegedly will not contain a contraindication or dose-reduction warning for co-administration with P-gp-only inhibitors. (Compl. ¶45).

U.S. Patent No. 9,675,613 - “Methods of Colchicine Administration”

• Technology Synopsis: This patent claims a method for preventing gout flares by administering colchicine with a second drug that is a single-pathway CYP3A4 inhibitor. The claim structure is similar to the ’607 Patent but is specifically directed to the prophylactic use case. (’613 Patent, Claim 1).
• Asserted Claims: One or more claims (Compl. ¶54).
• Accused Features: The intended use of Annora’s generic colchicine for the prophylaxis of gout, as will be described in its product labeling, which allegedly infringes the claimed method. (Compl. ¶18, ¶54).

U.S. Patent No. 9,789,108 - “Methods of Colchicine Administration”

• Technology Synopsis: This patent claims a method of administering colchicine with voriconazole (a strong CYP3A4-only inhibitor) that results in a specific pharmacokinetic (PK) profile. The claims are defined by the resulting concentration of colchicine in the patient's blood over time, rather than by the administration steps alone. (’108 Patent, Abstract; Claim 1).
• Asserted Claims: One or more claims (Compl. ¶63).
• Accused Features: The intended use of Annora’s generic colchicine product, which, when co-administered with voriconazole as directed by labeling, will allegedly result in the claimed PK profile. (Compl. ¶63).

III. The Accused Instrumentality

Product Identification

Annora's ANDA Product, a generic colchicine 0.6 mg capsule intended for marketing in the United States upon FDA approval (Compl. ¶20).

Functionality and Market Context

The product is a generic equivalent to Hikma's Mitigare®, which is indicated for the prophylaxis of gout (Compl. ¶18, ¶20). Under the Hatch-Waxman Act, the act of infringement is Annora's filing of its ANDA (No. 217620) seeking approval to market this generic product for a use that is allegedly covered by the patents-in-suit before their expiration (Compl. ¶28). The infringement theory is based on the intended use of the product, which will be dictated by its FDA-approved labeling.

IV. Analysis of Infringement Allegations

The complaint does not provide specific claim charts or detailed infringement contentions. The analysis below is based on the patents' claims and the description of the accused ANDA product. The infringement theory is necessarily one of indirect infringement, wherein Annora's proposed product labeling will induce physicians and patients to use the generic drug in a manner that infringes the asserted method claims.

No probative visual evidence provided in complaint.

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...	Annora's ANDA product is a generic version of Mitigare®, which is indicated for the prophylaxis of gout, a chronic inflammatory disorder. Annora seeks approval for this use.	¶18; ¶20	col. 1:12-16
...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...	Annora's proposed product label will allegedly instruct or permit the use of its colchicine product by patients who may also be taking CYP3A4-only inhibitors like those listed.	¶27; ¶28	col. 3:37-41
...administering to the patient a therapeutically effective fixed maintenance dose of colchicine in an amount of from about 0.6 to about 1.2 mg/day...	Annora's ANDA product is a 0.6 mg capsule. The standard dose for gout prophylaxis is 0.6 mg once or twice daily, which falls within the claimed range.	¶18; ¶20	col. 3:42-45
...administering to the patient the fixed maintenance dose of colchicine of step (a) without dose reduction.	The infringement theory alleges that Annora's label will not require a dose reduction when its product is co-administered with the specified single-pathway inhibitors, thereby instructing an infringing use.	¶27; ¶31	col. 4:1-4

Identified Points of Contention

• Scope Questions: The dispute may center on whether Annora’s proposed product label actively induces infringement. A key question is whether silence on the need for a dose reduction with single-pathway inhibitors is sufficient to meet the legal standard for inducement, or if an explicit instruction is required.
• Technical Questions: Does Annora's proposed label contain any information regarding co-administration with CYP3A4 or P-gp inhibitors? The complaint does not specify the contents of the label, which will be a central piece of evidence.

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 the cytochrome P450 3A4 isoenzyme (CYP3A4) but is not an inhibitor of P-glycoprotein 1 (P-gp)...	Annora's proposed label will allegedly instruct or permit the use of its colchicine product by patients who may also be taking single-pathway CYP3A4 inhibitors.	¶36; ¶37	col. 3:52-57
...wherein the second drug is voriconazole, fluconazole or cimetidine...	The specific drugs listed are commonly prescribed, and the infringement theory is that Annora's label will not warn against co-administration without a dose reduction.	¶36; ¶40	col. 3:55-57
...wherein the method comprises: (a) administering to the patient a therapeutically effective fixed maintenance dose of colchicine in an amount of from about 0.6 to about 1.2 mg/day...	Annora's product is a 0.6 mg capsule, consistent with the standard maintenance dose for gout prophylaxis.	¶18; ¶20	col. 3:58-61
...(c) concomitantly with step (b), administering to the patient the fixed maintenance dose of colchicine of step (a) without dose reduction.	As with the ’607 Patent, the core allegation is that Annora’s proposed label will lead to the administration of its product without the dose reduction that was standard in the prior art.	¶36; ¶40	col. 4:1-4

Identified Points of Contention

• Scope Questions: This patent is similar to the '607 patent. A potential point of contention could be the subtle difference in claim language ("method of administering" vs. "method of treating"), though the core infringement theory remains the same and hinges on the instructions in the proposed label.
• Technical Questions: What evidence will be presented to show that Annora specifically contemplated and intended for its product to be used in the infringing manner? The act of filing the ANDA to copy the branded drug's label is the primary evidence alleged.

V. Key Claim Terms for Construction

The complaint does not provide sufficient detail for a full analysis, but based on the patent specifications, certain terms are central to the dispute.

• The Term: "without dose reduction" (appears in Claim 1 of ’607 and ’036 patents)
• Context and Importance: This phrase captures the point of departure from the prior art, which recommended significant dose reductions. The entire infringement allegation rests on the premise that Annora's label will induce administration of the standard 0.6 mg dose even with concomitant use of a single-pathway inhibitor. Annora may argue that its label does not instruct this or that the term is indefinite.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The specification repeatedly contrasts the invention with prior art recommendations for dose reductions of "about 33-75%" (’607 Patent, col. 2:57-59). This suggests "without dose reduction" means continuing the "fixed maintenance dose" and not making the substantial reductions previously advised.
  • Evidence for a Narrower Interpretation: The claim language links the phrase directly to "the fixed maintenance dose of colchicine of step (a)" (’607 Patent, col. 4:2-4). This could support a narrow reading that any deviation from the pre-established maintenance dose, for any reason, would fall outside the claim scope.

VI. Other Allegations

• Indirect Infringement: The complaint's theory is centered on induced infringement under 35 U.S.C. § 271(b). It alleges Annora intends to and will actively induce infringement when its ANDA is approved, and that these actions will occur "immediately and imminently upon approval" (Compl. ¶¶31, 40). The basis for inducement is the allegation that Annora's proposed product labeling will instruct medical professionals and patients to use the generic colchicine in a manner that directly infringes the method claims.
• Willful Infringement: The complaint does not contain an explicit count for willful infringement or a request for enhanced damages. However, it alleges that Annora had knowledge of the patents-in-suit when it submitted its ANDA and that it sent a Paragraph IV certification letter asserting non-infringement or invalidity, establishing pre-suit knowledge (Compl. ¶22, ¶24). The complaint requests a declaration that the case is "exceptional" for the purpose of awarding attorney's fees (Compl. p. 14, ¶g).

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

This Hatch-Waxman action will likely focus on two central issues for the court's determination:

• A core issue will be one of inducement: Does the specific language of Annora's proposed product label—or its potential silence on the matter—provide sufficient instruction or encouragement to physicians and patients to co-administer generic colchicine with single-pathway inhibitors "without dose reduction," thereby meeting the legal standard for inducing infringement?
• A second, and likely primary, issue will be one of validity: As signaled by Annora's Paragraph IV certification, the patentability of the claimed methods will be challenged. The key question for the court will be whether the methods, which are based on the discovery of a specific pharmacological interaction, are non-obvious and represent patent-eligible subject matter, or if they are merely observations of a natural phenomenon that would have been obvious to a person of ordinary skill in the art.