DCT

1:25-cv-01537

Mirum Pharmaceuticals Inc v. Annora Pharma Pvt Ltd

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:25-cv-01537, D. Del., 12/19/2025
  • Venue Allegations: Plaintiffs allege venue is proper in Delaware because Defendant Hetero USA is incorporated in Delaware and all Defendants have purposefully availed themselves of the district by conducting business there, including marketing other generic pharmaceutical products, and have previously litigated Hatch-Waxman cases in the district without challenging jurisdiction. Plaintiffs, all Delaware corporations, further allege that the harm from the alleged infringement will be suffered in Delaware.
  • Core Dispute: Plaintiffs allege that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic version of Plaintiffs' LIVMARLI® (maralixibat) product constitutes an act of infringement of eight U.S. patents.
  • Technical Context: The technology relates to Apical Sodium-dependent Bile Acid Transporter Inhibitors (ASBTIs), a class of drugs used to treat rare pediatric cholestatic liver diseases by inhibiting the recycling of bile acids in the gastrointestinal tract.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendants' notification to Plaintiffs of their ANDA filing, which included a Paragraph IV certification asserting that the asserted patents are invalid, unenforceable, or will not be infringed by the generic product. The complaint notes that the Defendants' notice letter did not provide any statement regarding the invalidity or non-infringement of U.S. Patent No. 11,260,053.

Case Timeline

Date Event
2010-05-26 Earliest Priority Date for ’053 Patent
2011-10-28 Earliest Priority Date for ’657, ’661, '267, and ’251 Patents
2019-02-12 Earliest Priority Date for ’647, ’745, and '578 Patents
2019-12-24 ’657 Patent Issued
2022-01-25 ’661 Patent Issued
2022-01-25 ’647 Patent Issued
2022-03-01 ’053 Patent Issued
2022-07-05 ’251 Patent Issued
2022-11-15 ’745 Patent Issued
2024-03-05 ’578 Patent Issued
2025-07-08 ’267 Patent Issued
2025-11-17 Defendants' Notice Letter Dated
2025-11-18 Plaintiffs Received Notice Letter
2025-12-19 Complaint Filed

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

U.S. Patent No. 10,512,657 - "Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases"

The Invention Explained

  • Problem Addressed: The patent describes the challenge of treating pediatric cholestatic liver diseases, noting that many current therapies are invasive (e.g., liver transplantation) or costly, and that medications designed for adults are often unsuitable for children due to difficulties with swallowing, unpleasant taste, and side effects, which can lead to safety and compliance issues (’657 Patent, col. 1:19-41).
  • The Patented Solution: The invention provides methods for treating these pediatric liver diseases by administering a pediatric dosage form of an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI). This inhibitor works non-systemically in the gastrointestinal tract to block the reabsorption of bile acids, thereby decreasing their concentration in the serum and liver and alleviating the symptoms of the disease (’657 Patent, Abstract; col. 2:1-4). The focus on a "pediatric dosage form" and a "non-systemically absorbed" compound aims to address the specific therapeutic needs and challenges of treating children (’657 Patent, col. 1:40-41; col. 2:5-15).
  • Technical Importance: This approach provided a targeted, non-systemic therapeutic strategy specifically formulated for children, offering a less invasive alternative to surgery or transplantation for rare but serious liver conditions (’657 Patent, col. 1:21-26).

Key Claims at a Glance

  • The complaint asserts independent claims 1, 2, and 3 (Compl. ¶67).
  • Independent Claim 1: A method of treating or ameliorating pediatric progressive familial intrahepatic cholestasis type 2 (PFIC2) in a pediatric subject, comprising:
    • Administering an ASBTI or a pharmaceutically acceptable salt thereof to the subject.
    • Wherein the ASBTI is effective for decreasing at least 20% of serum and/or hepatic bile acid levels compared to pre-administration levels.
  • Independent Claim 2: A method of treating or ameliorating pruritus in a pediatric subject with PFIC2, comprising:
    • Administering an ASBTI or a pharmaceutically acceptable salt thereof to the subject.
    • Wherein the ASBTI is effective for decreasing at least 20% of serum and/or hepatic bile acid levels compared to pre-administration levels.
  • Independent Claim 3: A pharmaceutical composition for treating pediatric PFIC2, comprising:
    • A pediatric dosage form of an ASBTI and a pharmaceutically acceptable excipient.
    • Wherein the ASBTI is non-systemically absorbed or formulated to be non-systemically absorbed.
    • Wherein the ASBTI is effective for decreasing at least 20% of serum and/or hepatic bile acid levels compared to pre-administration levels.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 11,229,661 - "Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases"

The Invention Explained

  • Problem Addressed: The patent addresses the need for effective treatments for specific genetic subtypes of pediatric cholestatic liver disease, particularly those characterized by certain mutations in the Bile Salt Export Pump (BSEP) protein, which is critical for transporting bile acids out of liver cells (’661 Patent, col. 24:5-7).
  • The Patented Solution: The invention claims a method of treating pediatric disorders, such as PFIC2, that are specifically "characterized by having a non-truncating BSEP mutation." The solution involves administering an ASBTI to this genetically-defined patient sub-population, thereby inhibiting bile acid recycling and reducing the buildup of toxic bile acids in the liver (’661 Patent, col. 6:29-31; Claim 1).
  • Technical Importance: This patent refines the therapeutic approach by targeting a specific patient genotype, which may allow for more effective treatment in individuals with particular BSEP mutations who might otherwise respond differently to ASBTI therapy (Compl. ¶94).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶88).
  • Independent Claim 1: A method for treating or ameliorating a pediatric disorder, comprising:
    • Identifying a pediatric subject with a disorder characterized by a non-truncating BSEP mutation.
    • Wherein the disorder is selected from PFIC2, benign recurrent intrahepatic cholestasis 2 (BRIC2), or drug-induced cholestasis.
    • Administering an ASBTI or a pharmaceutically acceptable salt thereof to the subject.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 12,350,267 - "Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases"

  • Technology Synopsis: This patent relates to methods of using ASBTIs to treat pediatric cholestatic liver diseases, such as Progressive Familial Intrahepatic Cholestasis (PFIC). The claims focus on methods for treating either the disease itself or its associated symptoms, like pruritus, in a pediatric population (’267 Patent, col. 2:44-56).
  • Asserted Claims: Independent claims 1, 2, and 20 (Compl. ¶106).
  • Accused Features: The proposed labeling of Annora's ANDA Product is alleged to instruct the use of maralixibat for treating PFIC and/or pruritus in pediatric subjects, thereby infringing the claimed methods (Compl. ¶¶ 114-115).

U.S. Patent No. 11,229,647 - "Methods for treating cholestasis"

  • Technology Synopsis: This patent is directed to methods of treating cholestasis, specifically Alagille syndrome (ALGS), by administering an ASBTI. The invention specifies particular dosage ranges for the treatment (’647 Patent, Abstract).
  • Asserted Claims: Independent claims 1 and 12 (Compl. ¶127).
  • Accused Features: The proposed label for Annora's ANDA Product is alleged to instruct the use of maralixibat for treating ALGS in a pediatric subject at a dose of "about 400 µg/kg/day and/or from about 400 µg/kg/day to about 800 µg/kg/day," which falls within the claimed dosage ranges (Compl. ¶134).

U.S. Patent No. 11,376,251 - "Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases"

  • Technology Synopsis: This patent covers methods of using ASBTIs to treat pediatric cholestatic liver diseases, with a focus on treating Alagille syndrome (ALGS) or ameliorating the associated symptom of pruritus in a pediatric patient population (’251 Patent, Abstract; col. 2:44-48).
  • Asserted Claims: Independent claims 1, 14, and 19 (Compl. ¶146).
  • Accused Features: Annora's proposed product label is alleged to encourage the use of maralixibat for treating or ameliorating ALGS and associated pruritus in pediatric subjects, which is alleged to meet the limitations of the asserted claims (Compl. ¶¶ 154-155).

U.S. Patent No. 11,497,745 - "Methods for treating cholestasis"

  • Technology Synopsis: This patent claims methods for treating cholestasis, specifically Alagille syndrome (ALGS), in a subject by administering maralixibat within a specific dosage range (’745 Patent, Abstract).
  • Asserted Claims: Independent claim 1 (Compl. ¶167).
  • Accused Features: Annora's product is accused of infringement because its proposed labeling allegedly instructs the administration of maralixibat for treating ALGS in an amount of "from 360 µg/kg/day to 880 µg/kg/day," which is covered by the asserted claim (Compl. ¶174).

U.S. Patent No. 11,918,578 - "Methods for treating cholestasis"

  • Technology Synopsis: The patent claims a method for treating cholestatic pruritus in a subject with Alagille syndrome (ALGS). The method requires administering maralixibat within a specific dosage range and in a particular liquid pharmaceutical composition concentration (’578 Patent, Abstract).
  • Asserted Claims: Independent claim 1 (Compl. ¶186).
  • Accused Features: The proposed label for Annora's ANDA Product, an oral solution, is alleged to instruct administration for treating cholestatic pruritus in ALGS subjects at a dosage of "from about 400 µg/kg/day to about 800 µg/kg/day," which allegedly infringes the claimed dosage and formulation type (Compl. ¶194).

U.S. Patent No. 11,260,053 - "Bile acid recycling inhibitors and satiogens for treatment of diabetes, obesity, and inflammatory gastrointestinal conditions"

  • Technology Synopsis: This patent is directed to a method of using an ASBTI to achieve a physiological effect rather than treating a specific disease. The claimed method involves increasing the concentration of bile acids and salts in the distal gastrointestinal tract by delivering a therapeutically effective amount of an ASBTI to that region (’053 Patent, Abstract).
  • Asserted Claims: Independent claim 1 (Compl. ¶206).
  • Accused Features: The LIVMARLI® label explains that maralixibat decreases the reabsorption of bile acids from the terminal ileum. The complaint alleges that this action necessarily increases the concentration of bile acids in the distal gastrointestinal tract, and that Annora's proposed label will instruct this infringing use (Compl. ¶¶ 208, 211).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is "Annora's ANDA Product," a generic version of Maralixibat Chloride Solution, Oral, in concentrations of Eq. 9.5 mg Base/mL and 19 mg Base/mL, for which Defendant Annora has submitted ANDA No. 220780 to the FDA (Compl. ¶2).

Functionality and Market Context

  • The product is an oral solution containing maralixibat, an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) (Compl. ¶75). The complaint alleges that the proposed product label is "substantially identical" to the label for the reference listed drug, LIVMARLI®, and will direct its use for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) or progressive familial intrahepatic cholestasis (PFIC) (Compl. ¶71). The mechanism of action involves decreasing the reabsorption of bile acids from the terminal ileum (Compl. ¶208).
  • The product is intended as a lower-cost generic alternative to the branded LIVMARLI® drug and seeks FDA approval to enter the U.S. market prior to the expiration of the Asserted Patents, which are listed in the FDA's Orange Book for LIVMARLI® (Compl. ¶¶ 1, 5, 41).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

U.S. Patent No. 10,512,657 - Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for treating or ameliorating pediatric progressive familial intrahepatic cholestasis type 2 (PFIC2) in a pediatric subject The proposed labeling for Annora's ANDA Product allegedly instructs and encourages its use by healthcare professionals for treating pediatric PFIC2. ¶75 col. 6:27-29
comprising administering to the pediatric subject an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof, Annora's ANDA Product is an oral solution of maralixibat, which is alleged to be an ASBTI. ¶¶2, 75 col. 2:49-53
wherein the ASBTI is effective for decreasing at least 20% of serum and/or hepatic bile acid levels in the pediatric subject as compared to bile acid levels prior to administration of the ASBTI. The proposed label is allegedly substantially identical to the LIVMARLI® label, which directs a use that results in the claimed decrease in bile acid levels. ¶¶71, 75 col. 3:20-24

U.S. Patent No. 11,229,661 - Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for treating or ameliorating a pediatric disorder characterized by having a non-truncating BSEP mutation in a pediatric subject, The proposed labeling for Annora's ANDA Product allegedly instructs its use for treating pediatric PFIC2, a disorder described in the patent as being associated with BSEP mutations. ¶94 col. 24:5-7
wherein the pediatric disorder is selected from the group consisting of progressive familial intrahepatic cholestasis 2 (PFIC2), benign recurrent intrahepatic cholestasis 2 (BRIC2), and drug induced cholestasis, The proposed labeling for Annora's ANDA Product allegedly instructs its use for treating pediatric PFIC2. ¶94 col. 6:29-31
comprising administering to the pediatric subject an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Annora's ANDA Product contains maralixibat, which is alleged to be an ASBTI. ¶94 col. 28:1-5

Identified Points of Contention

  • Scope Questions: A central question for the '661 Patent may be whether the proposed generic label, by indicating treatment for the broad category of PFIC2, induces infringement of a claim limited to the specific sub-population of patients having a "non-truncating BSEP mutation." The analysis may explore whether treating PFIC2 according to the label necessarily or inevitably results in treatment of this claimed patient group.
  • Technical Questions: For the '657 Patent, a potential point of contention could be the evidence supporting the "effective for decreasing at least 20%" limitation. The dispute may turn on the clinical data and pharmacological properties of Annora's specific formulation as described in its ANDA, and how that compares to the data supporting the branded product's label and the patent's teachings.

V. Key Claim Terms for Construction

  • The Term: "pediatric subject" (’657 Patent, Claim 1)

  • Context and Importance: Several asserted patents are directed to methods of treating a "pediatric subject" or "pediatric" diseases. The definition of this term is critical for determining the scope of the method claims. Practitioners may focus on this term because if the accused product's label includes indications for patient populations outside the patent's definition of "pediatric," it could support a non-infringement argument.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The claims themselves use the general term "pediatric subject" without an explicit age limitation, which may support an argument that it should be given its ordinary meaning in the field of medicine.
    • Evidence for a Narrower Interpretation: The specification provides explicit age ranges, stating a pediatric patient can be "a new born, a pre-term new born, an infant, a toddler, a pre-schooler, a school-age child... or a teenager under the age of eighteen" (’657 Patent, col. 6:58-65). This language may be used to argue for a construction that limits the term to individuals under 18 years of age.

  • The Term: "non-systemically absorbed" (’657 Patent, Claim 3)

  • Context and Importance: This term in claim 3 of the '657 patent defines a key property of the claimed ASBTI. Its construction is important because it distinguishes the claimed invention from systemic drugs that are absorbed into the bloodstream. A dispute may arise over the degree of absorption that qualifies as "non-systemic."

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The term could be construed functionally to mean that the compound's primary therapeutic effect occurs within the gastrointestinal tract, regardless of minor systemic absorption. The patent states the use of non-systemic compounds "reduces or inhibits recycling of bile acid salts in the gastrointestinal tract" (’657 Patent, col. 4:44-47).
    • Evidence for a Narrower Interpretation: The specification provides quantitative thresholds, stating that in some embodiments, "less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the ASBTI is systemically absorbed" (’657 Patent, col. 5:58-65). This may support a narrower construction requiring absorption below a specific numerical limit.

VI. Other Allegations

  • Indirect Infringement: The complaint is premised on a theory of induced infringement under 35 U.S.C. § 271(e)(2)(A), which defines an ANDA filing as a stylized act of infringement. Plaintiffs allege that Defendants will induce infringement under § 271(b) by healthcare professionals and patients because the proposed product labeling for Annora's ANDA Product "instructs and encourages" the use of the product in a manner that practices the claimed methods (Compl. ¶¶ 75, 80, 94).
  • Willful Infringement: The complaint alleges that Defendants had "actual and constructive knowledge" of the asserted patents prior to submitting their ANDA, at least because the patents are listed in the FDA's Orange Book for LIVMARLI® (Compl. ¶¶ 83, 101). It further alleges that Defendants have acted "without a reasonable basis for believing" they would not be liable for infringement, which forms the basis for a claim of willfulness and a request for a declaration that the case is "exceptional" under 35 U.S.C. § 285 (Compl. ¶¶ 84, 102; Prayer for Relief ¶G).

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

  • A core issue will be one of infringement by labeling: will the instructions and indications on Annora’s proposed generic label be found to actively encourage or instruct physicians and patients to perform all the steps of the asserted method claims? This will require a detailed comparison between the language of the proposed label and the specific limitations of each asserted claim, including the patient population, the disease treated, and any claimed dosage ranges.
  • A key question of claim scope will be central to several patents, particularly the '661 patent: can a generic drug label that indicates a broad disease category (e.g., PFIC2) be found to induce infringement of a patent claim directed to treating a narrow, genetically-defined sub-population (e.g., patients with a "non-truncating BSEP mutation")?
  • An underlying issue will be one of validity: while not the focus of the complaint, the case will likely involve Defendants’ counterclaims that the eight asserted patents are invalid. The viability of these patents, which cover different aspects of the same core therapy—from general methods to specific patient groups and dosages—will be a critical battleground, potentially involving challenges based on obviousness, written description, and enablement.