DCT

1:25-cv-00281

Biocryst Pharma Inc v. Annora Pharma Pvt Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:25-cv-00281, D. Del., 03/10/2025
  • Venue Allegations: Venue is asserted in the District of Delaware based on Defendants Hetero USA, Inc. and Camber Pharmaceuticals, Inc. being Delaware corporations, and on the basis that Defendants Annora Pharma Private Limited and Hetero Labs Limited are foreign corporations subject to personal jurisdiction in the district through their business activities.
  • Core Dispute: Plaintiff alleges that Defendants’ submission of an Abbreviated New Drug Application (ANDA) seeking to market generic versions of Plaintiff's drug ORLADEYO® constitutes an act of infringement of three patents directed to crystalline salt forms of the active ingredient, berotralstat.
  • Technical Context: The technology relates to specific crystalline forms of a plasma kallikrein inhibitor used for the prophylactic treatment of hereditary angioedema (HAE), a rare genetic disease causing severe swelling attacks.
  • Key Procedural History: The lawsuit was initiated under the Hatch-Waxman Act following a Paragraph IV certification notice letter sent by Defendant Annora to Plaintiff BioCryst on January 24, 2025. This letter notified BioCryst of Annora's filing of ANDA No. 220116 and certified that the patents-in-suit are invalid or will not be infringed by the proposed generic products.

Case Timeline

Date Event
2018-11-02 Earliest Priority Date for ’160, ’867, and ’733 Patents
2020-05-26 ’160 Patent Issue Date
2020-12-03 FDA Approval of ORLADEYO® (NDA No. 214094)
2021-09-14 ’867 Patent Issue Date
2023-04-04 ’733 Patent Issue Date
2024-09-18 DMF for berotralstat dihydrochloride submitted by Hetero Labs
2025-01-24 Annora sends Paragraph IV Notice Letter to BioCryst
2025-03-10 Complaint Filing Date

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

U.S. Patent No. 10,662,160 - Crystalline Salts of a Plasma Kallikrein Inhibitor

The Invention Explained

  • Problem Addressed: The patent background describes plasma kallikrein's role in pathways related to inflammation and coagulation, including its relevance to hereditary angioedema (HAE). The specification notes the need to develop plasma kallikrein inhibitors that can be formulated into improved therapeutic compositions, implying a need for forms of the active compound with favorable physicochemical properties for drug development (’160 Patent, col. 3:9-23).
  • The Patented Solution: The invention is a specific crystalline salt of berotralstat (referred to as "Compound I"), which is a potent plasma kallikrein inhibitor (’160 Patent, Abstract). By creating a specific crystalline form—the bis(hydrochloride) salt—the invention aims to modulate and improve properties critical for pharmaceutical development, such as purity, stability, and solubility, thereby enabling a drug product with a consistent and predictable pharmacokinetic profile (’160 Patent, col. 4:30-47). The specific crystalline structure is characterized by data including the X-ray powder diffraction (XRPD) pattern shown in Figure 1 (’160 Patent, FIG. 1).
  • Technical Importance: Developing a stable, pure, and well-characterized crystalline form of an active pharmaceutical ingredient (API) is a critical step in creating a safe, effective, and manufacturable oral solid dosage form (’160 Patent, col. 4:30-47).

Key Claims at a Glance

  • The complaint asserts infringement of claims 1-28, with claim 1 identified as a representative claim (Compl. ¶¶73, 82).
  • Independent Claim 1 requires:
    • A crystalline salt of Compound I, having a specific chemical structure
    • wherein the salt is a bis(hydrochloride) salt
  • The complaint reserves the right to assert other claims (Compl. ¶84).

U.S. Patent No. 11,117,867 - Crystalline Salts of a Plasma Kallikrein Inhibitor

The Invention Explained

  • Problem Addressed: As with the parent ’160 Patent, the specification describes the need for improved compositions and formulations of plasma kallikrein inhibitors for treating conditions like HAE (’867 Patent, col. 3:9-23).
  • The Patented Solution: The patent claims a pharmaceutical composition containing the crystalline salt of Compound I. The invention focuses on an oral dosage form containing a specific range of the active ingredient, designed for therapeutic use (’867 Patent, Claim 1). This provides a specific drug product formulation for administering the crystalline salt to patients.
  • Technical Importance: The invention defines a specific pharmaceutical product—an oral dosage form with a defined amount of the crystalline API—which translates the discovery of the crystalline salt into a practical therapeutic application for patients with HAE (’867 Patent, col. 11:1-4).

Key Claims at a Glance

  • The complaint asserts infringement of claims 1-20, with claim 1 identified as a representative claim (Compl. ¶¶73, 104).
  • Independent Claim 1 requires:
    • A pharmaceutical composition
    • comprising a crystalline salt of Compound I
    • and a pharmaceutically acceptable carrier
    • wherein the composition is an oral dosage form
    • containing about 75 mg to about 250 mg of the crystalline salt of Compound I
  • The complaint reserves the right to assert other claims (Compl. ¶106).

U.S. Patent No. 11,618,733 - Crystalline Salts of a Plasma Kallikrein Inhibitor

  • Technology Synopsis: This patent, from the same family as the ’160 and ’867 patents, is directed to methods of using the previously described pharmaceutical compositions. It specifically claims a method of treating hereditary angioedema by orally administering a pharmaceutical composition containing the bis(hydrochloride) crystalline salt of Compound I in a specific dosage range (’733 Patent, Abstract, Claim 1).
  • Asserted Claims: Claims 1-16, with claim 1 identified as representative (Compl. ¶¶73, 126).
  • Accused Features: Defendants are accused of infringement by seeking FDA approval for a generic drug product with proposed labeling that will instruct and encourage physicians and patients to use the product for the treatment of HAE, thereby performing the steps of the claimed method (Compl. ¶¶69-70, 131-132).

III. The Accused Instrumentality

Product Identification

The "Annora ANDA Products" are identified as berotralstat hydrochloride capsules for oral administration, in dosages equivalent to 110 mg and 150 mg of the base compound (Compl. ¶6). Annora Pharma Private Limited seeks to market these products through ANDA No. 220116 (Compl. ¶6).

Functionality and Market Context

The Annora ANDA Products are generic versions of BioCryst’s branded drug, ORLADEYO® (Compl. ¶66). The complaint alleges the proposed products are plasma kallikrein inhibitors indicated for the prophylaxis of HAE attacks in patients aged 12 and older (Compl. ¶69). The recommended dosages of 110 mg and 150 mg are alleged to be stated in the proposed prescribing information, which will substantially copy the label for ORLADEYO® (Compl. ¶¶68, 70). The products are intended to compete directly with ORLADEYO® upon receiving final FDA approval (Compl. ¶15).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

’160 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A crystalline salt of Compound I... The Annora ANDA Products are berotralstat hydrochloride capsules, and the complaint alleges that the active ingredient they will contain upon commercial manufacture is the crystalline salt of Compound I. ¶¶67, 84 Claim 1
...wherein the salt is a bis(hydrochloride) salt. The Annora ANDA Products are identified as "berotralstat hydrochloride capsules," and the complaint alleges they will infringe claim 1, which specifically requires the bis(hydrochloride) salt form. ¶¶67, 82 Claim 1
  • Identified Points of Contention:
    • Technical Question: A primary factual question will be whether the API in the Annora ANDA product is, in fact, the specific crystalline polymorph claimed in the ’160 Patent. The resolution will likely depend on expert analysis of the ANDA product samples and comparison to the characterization data in the patent, such as the XRPD pattern disclosed in Figure 1.
    • Scope Question: A potential dispute may arise over whether the API used by Annora, allegedly supplied by Hetero Labs (Compl. ¶¶31-32), meets the specific structural and crystalline limitations required by the claim.

’867 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical composition, comprising a crystalline salt of Compound I... The Annora ANDA Products are alleged to be pharmaceutical compositions (capsules) that contain the crystalline salt of Compound I as their active ingredient. ¶¶6, 106 Claim 1
...and a pharmaceutically acceptable carrier... As finished pharmaceutical capsules, the Annora ANDA Products are alleged to necessarily contain pharmaceutically acceptable carriers (excipients) in addition to the active ingredient. ¶¶106, 107 col. 8:51-54
...wherein the pharmaceutical composition is an oral dosage form... The Annora ANDA Products are explicitly identified as "oral" "capsules" in the ANDA submission. ¶6 Claim 1
...and the oral dosage form contains about 75 mg to about 250 mg of the crystalline salt of Compound I. The Annora ANDA Products are offered in dosages equivalent to 110 mg and 150 mg base, both of which fall within the claimed range of "about 75 mg to about 250 mg." ¶6 Claim 1
  • Identified Points of Contention:
    • Technical Question: Infringement of the ’867 Patent also hinges on the factual question of whether the Annora ANDA product actually contains the crystalline salt of Compound I, as described in Section IV for the ’160 Patent.
    • Scope Question: This raises the question of how the term "about" will be construed in the context of the dosage range. While the accused 110 mg and 150 mg dosages appear to fall literally within the claim, disputes over the scope of "about" are common in pharmaceutical patent litigation.

V. Key Claim Terms for Construction

  • The Term: "crystalline salt" (from ’160 Patent, Claim 1; ’867 Patent, Claim 1)

    • Context and Importance: This term is the central limitation of the composition claims. The dispute will likely turn on whether Defendants' proposed generic product contains an API that meets this limitation, as opposed to an amorphous form or a different, non-infringing crystalline polymorph. The patentability of the claims over the prior art also depends on the specific properties of this "crystalline salt."
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: A party might argue that the term should be given its plain and ordinary meaning, covering any form of the salt that exhibits a crystalline, as opposed to purely amorphous, structure.
      • Evidence for a Narrower Interpretation: The specification provides extensive characterization data defining a specific crystalline form. A party will almost certainly argue that this data limits the scope of "crystalline salt" to the specific polymorph disclosed. For example, the patent states, "In certain embodiments, the crystalline salt of Compound I has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (° 20±0.2°) of 5.28, 8.96, and 22.01" (’160 Patent, col. 5:23-28) and provides a full XRPD pattern in Figure 1. This could be used to argue that the claim is limited to a polymorph with a substantially identical XRPD pattern.

  • The Term: "about 75 mg to about 250 mg" (from ’867 Patent, Claim 1)

    • Context and Importance: This term defines the dosage strength of the claimed oral pharmaceutical composition. The accused products, with dosages of 110 mg and 150 mg, fall within this range. Practitioners may focus on this term because the scope of "about" can determine the boundary between infringement and non-infringement, particularly if manufacturing tolerances or prior art products are near the claimed endpoints.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The use of "about" suggests the inventors did not intend the endpoints to be rigid. The specification lists numerous exemplary unit dosages, including "125 mg, 150 mg, 175 mg, 200 mg, 250 mg" (’867 Patent, col. 13:43-44), which reinforces that the invention covers a range of practical dosages and not just the precise numerical endpoints.
      • Evidence for a Narrower Interpretation: While unlikely to be a central dispute given the accused dosages, a party could argue that the scope of "about" should be constrained by the data presented. The pharmacokinetic study described in the patent tested doses of 125 mg, 250 mg, and 500 mg, which could be used to frame arguments about what range is enabled and described by the specification (’867 Patent, Table 1).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement against all defendants. This allegation is based on the assertion that Defendants will market the Annora ANDA Products with proposed labeling that substantially copies the FDA-approved label for ORLADEYO® (Compl. ¶¶86, 108, 130). It is alleged that this label will actively instruct and encourage healthcare providers and patients to administer the drug in a way that directly infringes the method claims of the patents-in-suit (Compl. ¶¶87-89, 109-111, 131-133).
  • Willful Infringement: The complaint alleges that Defendants' infringement is and will be willful. The basis for this allegation is Defendants' pre-suit knowledge of the patents-in-suit, evidenced by their filing of an ANDA with a Paragraph IV certification that specifically identifies each of the asserted patents (Compl. ¶¶92, 114, 136). The complaint alleges that despite this knowledge, Defendants have continued to seek approval to market an infringing product (Compl. ¶¶92, 114, 136).

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

  • A central question will be one of API characterization: does the active pharmaceutical ingredient in the Annora ANDA product, as it will be commercially manufactured, possess the specific bis(hydrochloride) crystalline structure defined by the characterization data in the patents-in-suit, or is it a different, non-infringing form?
  • A key evidentiary issue will be one of infringement by formulation: do the accused 110 mg and 150 mg oral capsules, containing the API and necessary excipients, fall within the scope of the pharmaceutical composition claims, particularly the limitation requiring an oral dosage form containing "about 75 mg to about 250 mg" of the crystalline salt?
  • For the method patent, the case will raise a question of induced infringement: does the proposed label for the Annora ANDA product contain instructions that would lead a medical professional or patient to inevitably perform the patented method of treating hereditary angioedema, thereby establishing the requisite intent for inducement?