DCT

1:23-cv-00747

CMP Development LLC v. Hetero USA Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:23-cv-00747, D. Del., 07/10/2023
  • Venue Allegations: Plaintiff alleges venue is proper in the District of Delaware because Defendant Hetero USA, Inc. is a Delaware corporation, Defendants conduct continuous business in the state, and Defendants have previously consented to venue in the district for similar Abbreviated New Drug Application (ANDA) matters.
  • Core Dispute: Plaintiff alleges that Defendants’ filing of an ANDA to market a generic version of Plaintiff’s CaroSpir® product constitutes an act of infringement of eight patents related to aqueous formulations of the drug spironolactone.
  • Technical Context: Spironolactone, a diuretic used to treat conditions like heart failure and hypertension, has poor water solubility, making stable, ready-to-use liquid versions historically difficult to produce and necessitating pharmacy-compounded alternatives.
  • Key Procedural History: This is a Hatch-Waxman action filed under 35 U.S.C. § 271(e)(2), triggered by Defendants' submission of ANDA No. 218085 to the FDA with a "Paragraph IV certification" alleging that the patents covering the branded drug CaroSpir® are invalid, unenforceable, or would not be infringed by the proposed generic product.

Case Timeline

Date Event
2015-10-30 Earliest Priority Date for all Patents-in-Suit
2017-08-04 FDA Approval of CaroSpir®
2017-09-12 U.S. Patent No. 9,757,394 Issues
2019-12-03 U.S. Patent No. 10,493,083 Issues
2020-04-21 U.S. Patent No. 10,624,906 Issues
2020-05-26 U.S. Patent No. 10,660,907 Issues
2021-01-12 U.S. Patent No. 10,888,570 Issues
2022-07-19 U.S. Patent No. 11,389,461 Issues
2022-07-26 U.S. Patent No. 11,395,828 Issues
2022-11-08 U.S. Patent No. 11,491,166 Issues
2023-06-06 Hetero sends Notice Letter to CMP regarding ANDA filing
2023-07-10 Complaint Filed

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

No probative visual evidence provided in complaint.

U.S. Patent No. 9,757,394 - "Spironolactone Aqueous Formulations"

The Invention Explained

  • Problem Addressed: The patent describes the difficulty in creating a commercially available, aqueous-based liquid form of spironolactone due to the drug's very low water solubility (28 µg/mL) (Compl., Ex. A, '394' Patent, col. 1:21-23, 1:45-47). Consequently, physicians have had to rely on pharmacists to prepare compounded formulations from tablets, which can lead to microbial contamination, dosing errors, and unknown stability (Compl., Ex. A, '394 Patent, col. 1:47-59).
  • The Patented Solution: The invention is a stable, "ready-to-use" aqueous suspension of spironolactone that uses a specific suspending agent, xanthan gum, in combination with other excipients (Compl., Ex. A, '394 Patent, Abstract). This formulation is designed to have acceptable long-term stability and resuspension properties, ensuring uniform dosing and patient compliance while reducing the likelihood of dosing errors associated with compounded versions (Compl., Ex. A, '394 Patent, col. 4:51-59).
  • Technical Importance: This technology provided the basis for the first, and only, FDA-approved ready-to-use oral suspension of spironolactone, offering a standardized and stable alternative to pharmacy-compounded liquids for patients with difficulty swallowing (Compl. ¶¶ 31-33).

Key Claims at a Glance

The complaint alleges infringement of "one or more claims" but does not identify specific claims (Compl. ¶ 66). Independent claim 1 is representative of the patent's core invention.

  • Independent Claim 1:
    • A ready-to-use liquid formulation, comprising:
    • (a) about 0.50% w/v of spironolactone;
    • (b) from about 0.18% w/v to about 0.36% w/v of a xanthan gum;
    • (c) a pharmaceutically acceptable excipient; and
    • (d) a sufficient amount of a water vehicle;
    • wherein the formulation has a spironolactone content of 100±10% labeled content when stored for about 24-months at 25±2° C. and 40±5% relative humidity.

U.S. Patent No. 10,493,083 - "Spironolactone Aqueous Compositions"

The Invention Explained

  • Problem Addressed: The patent addresses the same core problem as its parent '394 patent: the need for a stable, uniform, and easily resuspendable liquid oral formulation of spironolactone to overcome the issues associated with compounded suspensions, such as non-uniformity and patient compliance challenges due to extended shaking times (Compl., Ex. B, '083' Patent, col. 3:9-23).
  • The Patented Solution: The invention claims a more specific formulation for a ready-to-use spironolactone liquid suspension, detailing concentration ranges for multiple categories of excipients including an anti-foaming agent, preservative, dispersing agent, sweetening agent, flavoring agent, and a citrate buffer to maintain a specific pH range (Compl., Ex. B, '083 Patent, Abstract; col. 4:60-64). This refined composition is designed to ensure dosage uniformity is achieved with minimal shaking (e.g., within 5 to 10 seconds) (Compl., Ex. B, '083 Patent, col. 8:1-4).
  • Technical Importance: This patent protects a specific, optimized formulation that achieves superior resuspendability and stability, addressing practical usability concerns for patients and caregivers (Compl. ¶ 33).

Key Claims at a Glance

The complaint alleges infringement of "one or more claims" but does not identify specific claims (Compl. ¶ 73). Independent claim 1 is representative.

  • Independent Claim 1:
    • A ready-to-use liquid formulation, comprising:
    • (a) 0.50% w/v of spironolactone;
    • (b) from 0.18% w/v to 0.36% w/v of a xanthan gum;
    • (c) from 0.2% w/v to 0.6% w/v of an anti-foaming agent;
    • (d) from 0.125% w/v to 0.250% w/v of a preservative;
    • (e) from 1.8% w/v to 2.4% w/v of a dispersing agent;
    • (f) from 0.04% w/v to 0.6% w/v of a sweetening agent;
    • (g) from 0.1% w/v to 0.5% w/v of a flavoring agent;
    • (h) a sufficient amount of a citrate buffer to maintain the pH of the formulation from 4.5 to 5.5; and
    • (i) a sufficient amount of a water vehicle,
    • wherein the formulation exhibits a spironolactone content of 100±10% labeled content for about 24-months when stored at 25±2° C. and 40±5% relative humidity.

U.S. Patent No. 10,624,906 - "Spironolactone Aqueous Compositions"

  • Technology Synopsis: This patent, a continuation of the application leading to the '083 patent, claims a ready-to-use liquid formulation of spironolactone with specific excipients, including xanthan gum. The claims focus on achieving dose uniformity within about 10 seconds of shaking.
  • Asserted Claims: One or more claims (Compl. ¶ 79).
  • Accused Features: The complaint alleges the entire formulation of the Hetero ANDA Product infringes (Compl. ¶¶ 51-54).

U.S. Patent No. 10,660,907 - "Spironolactone Aqueous Compositions"

  • Technology Synopsis: This patent, also in the same family, claims methods of treating conditions such as heart failure and hypertension by administering a ready-to-use liquid spironolactone formulation. The claims are directed to methods of use for the previously claimed compositions.
  • Asserted Claims: One or more claims (Compl. ¶ 85).
  • Accused Features: The complaint alleges Hetero's product, intended for the same uses as CaroSpir®, will infringe these method claims (Compl. ¶ 59).

U.S. Patent No. 10,888,570 - "Spironolactone Aqueous Compositions"

  • Technology Synopsis: This patent continues to refine the claimed spironolactone formulation, focusing on achieving content uniformity of about 100% labeled content after about 10 seconds of shaking.
  • Asserted Claims: One or more claims (Compl. ¶ 91).
  • Accused Features: The complaint alleges the entire formulation of the Hetero ANDA Product infringes (Compl. ¶¶ 51-54).

U.S. Patent No. 11,389,461 - "Spironolactone Aqueous Compositions"

  • Technology Synopsis: This patent claims methods of treating a patient by administering a ready-to-use liquid formulation with specific compositional elements and functional characteristics, such as viscosity ranges.
  • Asserted Claims: One or more claims (Compl. ¶ 97).
  • Accused Features: The complaint alleges Hetero's product, intended for the same uses as CaroSpir®, will infringe these method claims (Compl. ¶ 59).

U.S. Patent No. 11,395,828 - "Spironolactone Aqueous Compositions"

  • Technology Synopsis: This patent claims methods of treating a patient by administering a spironolactone formulation with specific components, including xanthan gum and glycerin, and achieving a certain bioavailability profile relative to a tablet formulation.
  • Asserted Claims: One or more claims (Compl. ¶ 103).
  • Accused Features: The complaint alleges Hetero's product, which it states must be bioequivalent to CaroSpir®, will infringe these method claims (Compl. ¶ 60).

U.S. Patent No. 11,491,166 - "Spironolactone Aqueous Compositions"

  • Technology Synopsis: This patent claims a ready-to-use liquid formulation with specified ingredients and a functional requirement that a uniform content of spironolactone is achieved within about 10 seconds of shaking.
  • Asserted Claims: One or more claims (Compl. ¶ 109).
  • Accused Features: The complaint alleges the entire formulation of the Hetero ANDA Product infringes (Compl. ¶¶ 51-54).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is the proposed generic spironolactone oral suspension, 25 mg/5 mL, described in Defendants' ANDA No. 218085 ("Hetero ANDA Product") (Compl. ¶¶ 2-3, 49).

Functionality and Market Context

  • The complaint alleges that the Hetero ANDA Product is a "ready-to-use oral suspension" that will have the same active ingredient, route of administration, dosage form, and strength as CMP's CaroSpir® product (Compl. ¶¶ 48, 56). Upon approval, it is alleged to be bioequivalent to CaroSpir® and will be approved for the same uses, including treatment of heart failure and hypertension (Compl. ¶¶ 59-60). The product is intended to be a lower-cost, generic competitor to CaroSpir® (Compl. ¶ 3). The complaint identifies the alleged inactive ingredients as: sorbic acid, potassium sorbate, citric acid anhydrous, sodium citrate dihydrate, simethicone emulsion, saccharin sodium, xanthan gum, Magnasweet 110, glycerin, banana flavor, and purified water (Compl. ¶ 52).

IV. Analysis of Infringement Allegations

9,757,394 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A ready-to-use liquid formulation... The Hetero ANDA Product is alleged to be a "ready-to-use oral suspension with spironolactone as the active ingredient." ¶56 col. 4:51-52
...comprising: (a) about 0.50% w/v of spironolactone; The Hetero ANDA Product allegedly has the same strength as CaroSpir®, which is 25 mg/5 mL (equivalent to 0.5% w/v). ¶49 col. 5:1-3
(b) from about 0.18% w/v to about 0.36% w/v of a xanthan gum; The Hetero ANDA Product allegedly contains xanthan gum as an inactive ingredient. ¶52 col. 5:4-10
(c) a pharmaceutically acceptable excipient; The Hetero ANDA Product allegedly contains multiple inactive ingredients, including glycerin, sorbic acid, potassium sorbate, and others. ¶52 col. 4:61-62
wherein the formulation has a spironolactone content of 100±10% labeled content when stored for about 24-months... The complaint does not provide specific allegations or evidence that the Hetero ANDA Product meets this functional stability limitation. N/A col. 7:1-14

10,493,083 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A ready-to-use liquid formulation, comprising: (a) 0.50% w/v of spironolactone; The Hetero ANDA Product allegedly has a strength of 25 mg/5 mL (0.5% w/v). ¶49 col. 5:1-3
(b) from 0.18% w/v to 0.36% w/v of a xanthan gum; The Hetero ANDA Product allegedly contains xanthan gum. ¶52 col. 5:4-10
(c) from 0.2% w/v to 0.6% w/v of an anti-foaming agent; The Hetero ANDA Product allegedly contains simethicone emulsion. ¶52 col. 5:11-18
(d) from 0.125% w/v to 0.250% w/v of a preservative; The Hetero ANDA Product allegedly contains sorbic acid and potassium sorbate. ¶52 col. 5:20-33
(e) from 1.8% w/v to 2.4% w/v of a dispersing agent; The Hetero ANDA Product allegedly contains glycerin. ¶52 col. 5:48-52
(f) from 0.04% w/v to 0.6% w/v of a sweetening agent; The Hetero ANDA Product allegedly contains saccharin sodium and Magnasweet 110. ¶52 col. 5:60-65
(g) from 0.1% w/v to 0.5% w/v of a flavoring agent; The Hetero ANDA Product allegedly contains banana flavor. ¶52 col. 6:11-18
(h) a sufficient amount of a citrate buffer to maintain the pH of the formulation from 4.5 to 5.5; The Hetero ANDA Product allegedly contains citric acid anhydrous and sodium citrate dihydrate. ¶52 col. 6:19-24
wherein the formulation exhibits a spironolactone content of 100±10% labeled content for about 24-months... The complaint does not provide specific allegations or evidence that the Hetero ANDA Product meets this functional stability limitation. N/A col. 8:36-42
  • Identified Points of Contention:
    • Scope Questions: A central question for the '394 Patent will be whether the general allegation that the Hetero ANDA Product contains "xanthan gum" and other "pharmaceutically acceptable excipients" is sufficient for infringement, given the complaint does not specify their concentrations (Compl. ¶ 52).
    • Technical Questions: For the more specific '083 Patent, the analysis will depend on whether the concentrations of the accused ingredients fall within the claimed ranges. The complaint does not provide sufficient detail for analysis of the concentration ranges of the inactive ingredients in the Hetero ANDA Product. A further point of contention may arise from the complaint's allegation that if any of the listed inactive ingredients is absent, it is replaced by a "substantially similar" one, which raises the possibility of an infringement dispute under the doctrine of equivalents (Compl. ¶ 53).
    • Functional Limitations: Both representative claims contain a "wherein" clause reciting a specific long-term stability profile. A key legal and evidentiary question will be whether infringement of this functional limitation can be established based on the accused product's composition alone, or if Plaintiff must provide evidence that the Hetero ANDA Product actually exhibits the claimed stability over a 24-month period.

V. Key Claim Terms for Construction

  • The Term: "ready-to-use liquid formulation" (present in claim 1 of both the '394 and '083 Patents)

  • Context and Importance: This term distinguishes the patented invention from prior art compounded suspensions, which are prepared by pharmacists from solid tablets just prior to dispensation. Practitioners may focus on this term because its construction defines the scope of products covered. While the complaint alleges the accused product is "ready-to-use," any evidence that it requires a step of reconstitution or special preparation before patient administration could be central to the non-infringement defense.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The specification contrasts the invention with formulations that are "compounded" in a "clinical setting" by a pharmacist, suggesting that "ready-to-use" could broadly mean any formulation that is pre-mixed by the manufacturer and does not require compounding from a solid form by the end dispenser ('083 Patent, col. 1:45-51).
    • Evidence for a Narrower Interpretation: The description of the invention as having "acceptable long-term stability and resuspension properties" could be argued to tie the definition of "ready-to-use" to a product that is not only pre-mixed but also demonstrates proven stability, excluding any product that might degrade or require extensive re-mixing after manufacturing ('083 Patent, col. 4:54-57).

  • The Term: "wherein the formulation has a spironolactone content of 100±10% labeled content when stored for about 24-months..." ('394 Patent, Claim 1)

  • Context and Importance: This functional limitation is a condition that must be met for infringement, not merely a statement of intended result. The construction of this clause will be critical because it sets a high evidentiary bar. A key dispute will be whether this limitation requires real-world testing of the accused product or if it can be satisfied by showing the accused product's composition is substantially identical to a composition proven to meet the stability requirement in the patent's examples.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Plaintiff's Interpretation: Plaintiff may argue that by copying the specific formulation of excipients, the accused product will necessarily meet the stability requirements, making separate proof unnecessary. The patent's detailed stability data (e.g., '394 Patent, Tables 9 and 10) for a specific formulation could be used to support this inference.
    • Evidence for a Defendant's Interpretation: Defendant may argue this is a clear performance-based limitation that must be proven for the accused product itself. They might point to language stating the formulation "exhibits" this property as requiring an affirmative demonstration of that property in the accused product, rather than an inference based on its composition ('083 Patent, cl. 1).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges both induced and contributory infringement for all asserted patents. The basis for inducement is the allegation that Defendants will sell the Hetero ANDA Product with prescribing information that instructs physicians and patients to use it in an infringing manner (Compl. ¶¶ 55, 66). Contributory infringement is based on the allegation that there are no substantial non-infringing uses for the product other than those claimed in the patents (Compl. ¶ 68).
  • Willful Infringement: Willfulness is alleged based on Defendants having "actual and constructive knowledge" of the patents-in-suit prior to submitting the ANDA and possessing a "specific intent to infringe" (Compl. ¶¶ 64, 67). The complaint requests a finding of an exceptional case under 35 U.S.C. § 285 to recover attorneys' fees (Compl. Prayer for Relief ¶ d).

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

  • A core issue will be one of evidentiary proof for functional claims: For the asserted claims containing limitations on long-term stability and resuspendability, will infringement be determined by comparing the composition of the Hetero ANDA Product to the patented formulation, or will the court require Plaintiff to present empirical evidence that Defendants' proposed product actually meets these specific performance metrics?
  • A second key question will be one of compositional infringement: Given that the complaint does not specify the concentrations of the inactive ingredients in the accused product, a central factual dispute will be whether those concentrations fall within the specific ranges recited in the more detailed claims of the '083 patent family and its continuations.
  • The case may also present a question of infringement by equivalence: Should discovery reveal that the Hetero ANDA Product omits a claimed excipient or uses a different one, the court will have to analyze infringement under the doctrine of equivalents, focusing on the allegation that any substituted ingredient is "substantially similar" and "performs the same function" (Compl. ¶ 53).