DCT
1:22-cv-00387
KAI Pharma Inc v. USV Pvt Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Amgen Inc. and KAI Pharmaceuticals, Inc. (Delaware)
- Defendant: USV Private Limited (India)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
- Case Identification: 1:22-cv-00387, D. Del., 03/25/2022
- Venue Allegations: Venue is alleged to be proper because the defendant, USV Private Limited, is a foreign corporation that may be sued in any judicial district.
- Core Dispute: Plaintiff alleges that Defendant’s proposed generic etelcalcetide drug product, for which it has filed an Abbreviated New Drug Application (ANDA) with the FDA, infringes patents related to stable liquid pharmaceutical formulations of that drug.
- Technical Context: The technology concerns pharmaceutical formulations designed to ensure the chemical stability of etelcalcetide, a peptide-based drug used to treat secondary hyperparathyroidism in patients with chronic kidney disease.
- Key Procedural History: This Hatch-Waxman litigation was initiated after Plaintiffs received a Notice Letter on February 28, 2022, in which Defendant certified under Paragraph IV that the asserted patents are invalid, unenforceable, or will not be infringed by its proposed generic product. The asserted patents are listed in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (the "Orange Book") for Plaintiffs' product, Parsabiv®.
Case Timeline
| Date | Event |
|---|---|
| 2013-06-28 | Earliest Priority Date for ’938, ’765, and ’500 Patents |
| 2017-02-07 | FDA grants approval to market Parsabiv® (etelcalcetide) |
| 2017-11-21 | U.S. Patent No. 9,820,938 issues |
| 2019-07-09 | U.S. Patent No. 10,344,765 issues |
| 2021-11-02 | U.S. Patent No. 11,162,500 issues |
| 2022-02-28 | Plaintiffs receive USV’s ANDA Notice Letter |
| 2022-03-25 | Complaint filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 9,820,938 - "Stable Liquid Formulation of AMG 416 (Etelcalcetide)"
The Invention Explained
- Problem Addressed: The patent describes that therapeutic peptides, particularly those with disulfide bonds like etelcalcetide (AMG 416), generally have poor stability in aqueous solutions and are prone to degradation through mechanisms like amide bond hydrolysis and disulfide bond instability (’938 Patent, col. 1:53-61). Consequently, such drugs are often provided in a lyophilized (freeze-dried) form, which is less convenient for administration and introduces risks of contamination or improper reconstitution (’938 Patent, col. 1:62-col. 2:4).
- The Patented Solution: The invention is a stable, ready-to-use aqueous liquid formulation of etelcalcetide. The patent discloses that stability can be achieved by maintaining the formulation within a specific acidic pH range, which balances two competing degradation pathways: C-terminal deamidation, which dominates at low pH, and homodimer formation, which dominates at higher pH (’938 Patent, col. 9:45-56). By controlling the pH, the formulation can remain stable for an extended period under typical storage conditions (’938 Patent, col. 2:5-11).
- Technical Importance: This approach provides a ready-to-use liquid formulation, which simplifies administration and reduces the potential for errors associated with reconstituting a lyophilized powder (’938 Patent, col. 2:1-4).
Key Claims at a Glance
- The complaint asserts infringement of at least independent claim 1 (Compl. ¶37).
- Claim 1 of the ’938 Patent requires:
- A pharmaceutical formulation comprising AMG 416 [etelcalcetide] in aqueous solution,
- wherein the formulation has a pH of 2.0 to 5.0.
- The complaint states that infringement of one or more claims will be alleged, which may include dependent claims (Compl. ¶38).
U.S. Patent No. 10,344,765 - "Stable Liquid Formulation of AMG 416 (Etelcalcetide)"
The Invention Explained
- Problem Addressed: The ’765 Patent addresses the same technical challenge as its parent ’938 Patent: the inherent instability of the etelcalcetide peptide in aqueous solutions (’765 Patent, col. 1:53-61).
- The Patented Solution: The solution is again a stable aqueous liquid formulation maintained within a specific pH range to minimize degradation (’765 Patent, col. 2:5-11). The claims of the ’765 Patent are specifically directed to the hydrochloride salt of etelcalcetide, which the specification describes as one form of the active ingredient (’765 Patent, col. 1:47-52).
- Technical Importance: As with the ’938 Patent, this invention provides a convenient and safer ready-to-use injectable product compared to a lyophilized alternative (’765 Patent, col. 2:1-4).
Key Claims at a Glance
- The complaint asserts infringement of at least independent claim 1 (Compl. ¶51).
- Claim 1 of the ’765 Patent requires:
- A pharmaceutical formulation comprising AMG 416 [etelcalcetide] hydrochloride in aqueous solution,
- wherein the formulation has a pH of 2.0 to 5.0.
- The complaint states that infringement of one or more claims will be alleged, which may include dependent claims (Compl. ¶52).
U.S. Patent No. 11,162,500 - "Stable Liquid Formulation of AMG 416 (Etelcalcetide)"
Technology Synopsis
Continuing the same inventive concept as the ’938 and ’765 Patents, the ’500 patent claims stable aqueous formulations of etelcalcetide. The claims of this patent add a further limitation by specifying a particular concentration range for the active ingredient in addition to the pH range (’500 Patent, Abstract; col. 28:13-19).
Asserted Claims
Independent claim 1 is asserted (Compl. ¶65).
Accused Features
The accused features are the specific parameters of USV's Proposed ANDA Product, which is alleged to be an aqueous solution of etelcalcetide with a pH between 2.0 and 5.0 and a concentration between 0.5 mg/mL and 15 mg/mL (Compl. ¶65).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is "USV's Proposed ANDA Product," a generic version of Parsabiv® (etelcalcetide) for which USV seeks FDA approval via ANDA No. 216930 (Compl. ¶1).
Functionality and Market Context
- The complaint alleges, upon information and belief, that the accused product is a pharmaceutical formulation comprising the active ingredient etelcalcetide in an aqueous solution (Compl. ¶32, ¶37).
- The formulation is alleged to have a pH in the range of 2.0 to 5.0 and an etelcalcetide concentration between 0.5 mg/mL and 15 mg/mL (Compl. ¶32, ¶65). The product is intended for intravenous injection at strengths of 2.5 mg/0.5 mL, 5 mg/mL, and 10 mg/2 mL (Compl. ¶1).
- The product is intended to be marketed as a competing generic product to Plaintiffs' Parsabiv® for the treatment of secondary hyperparathyroidism in adult patients with chronic kidney disease on hemodialysis (Compl. ¶1).
- No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
U.S. Patent No. 9,820,938 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical formulation comprising AMG 416 [etelcalcetide] in aqueous solution, | USV’s Proposed ANDA Product is a pharmaceutical formulation containing etelcalcetide as the active ingredient in an aqueous solution. | ¶32, ¶37 | col. 2:12-14 |
| wherein the formulation has a pH of 2.0 to 5.0. | USV's Proposed ANDA Product is alleged to have a pH in the range of 2.0 to 5.0. | ¶32, ¶37 | col. 2:15-17 |
U.S. Patent No. 10,344,765 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical formulation comprising AMG 416 [etelcalcetide] hydrochloride in aqueous solution, | USV’s Proposed ANDA Product is a pharmaceutical formulation comprising etelcalcetide hydrochloride in an aqueous solution. | ¶51 | col. 1:47-52 |
| wherein the formulation has a pH of 2.0 to 5.0. | The formulation of the proposed product is alleged to have a pH of 2.0 to 5.0. | ¶51 | col. 2:15-17 |
Identified Points of Contention
- Evidentiary Questions: The core of the dispute will likely be evidentiary. The complaint alleges the composition of the accused product "upon information and belief." A central question for the court will be whether discovery confirms that USV's final, to-be-marketed product formulation possesses the exact chemical and physical properties required by the claims, specifically the pH range, the active ingredient concentration (for the ’500 patent), and the hydrochloride salt form (for the ’765 patent).
- Scope Questions: A potential dispute may arise over the meaning of "comprising." For example, a question could be raised as to whether additional, unlisted excipients in USV's formulation alter its fundamental character in a way that avoids infringement. Another question could be whether the pH of the accused product, as measured at different points in its lifecycle (e.g., manufacturing vs. storage vs. administration), consistently falls within the claimed range.
V. Key Claim Terms for Construction
- The Term: "AMG 416 [etelcalcetide] hydrochloride" (from ’765 Patent, claim 1)
- Context and Importance: The construction of this term is central to the infringement analysis of the ’765 Patent. Infringement of this patent depends entirely on whether the active ingredient in USV's product is specifically the hydrochloride salt form of etelcalcetide. Practitioners may focus on this term to determine if USV uses a different salt form (e.g., acetate, trifluoroacetate) or a free base, which could be a basis for a non-infringement argument.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The complaint does not provide a basis for a broad interpretation. Parties seeking one might argue that "hydrochloride" should encompass any formulation where chloride ions are associated with the peptide, even if not in a formal, crystalline salt structure.
- Evidence for a Narrower Interpretation: The specification explicitly defines and depicts the structure of "AMG-416" and then separately refers to its "hydrochloride salt" form, represented as Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂x(HCl) (’765 Patent, col. 1:35-52). This suggests that "hydrochloride" is a specific limitation referring to this particular salt, distinguishing it from other potential salt forms or the free peptide.
VI. Other Allegations
- Indirect Infringement: The complaint alleges active inducement of infringement for all three asserted patents. The basis for this allegation is that USV's proposed product labeling will instruct healthcare providers to use the product in an infringing manner (Compl. ¶34, ¶46, ¶60, ¶74).
- Willful Infringement: The complaint does not contain an explicit allegation of willful infringement. However, it does allege that USV had knowledge of the asserted patents at the time it filed its ANDA, based on the patents being listed in the FDA's Orange Book for Parsabiv® (Compl. ¶45, ¶59, ¶73).
VII. Analyst’s Conclusion: Key Questions for the Case
The complaint outlines a direct infringement theory in a specialized Hatch-Waxman context. The case will likely focus on the following key questions:
- A core issue will be one of evidentiary confirmation: Does discovery on USV's ANDA filing and manufacturing processes confirm that the proposed generic product's formulation—specifically its pH, active ingredient salt form, and concentration—will, as a factual matter, fall within the precise boundaries defined by the asserted claims?
- A second central issue, prompted by USV’s Paragraph IV certification, will be one of validity: Does the prior art teach or suggest formulating a peptide like etelcalcetide in a stable aqueous solution within the specific pH and concentration ranges claimed by the patents, potentially rendering the claims obvious?