DCT

2:23-cv-01150

Par Pharmaceutical Inc v. Cipla Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:23-cv-01150, D.N.J., 02/28/2023
  • Venue Allegations: Venue is alleged to be proper based on Cipla USA having a regular and established place of business in Warren, New Jersey, and Cipla Limited being a foreign corporation, making venue proper in any district with personal jurisdiction.
  • Core Dispute: Plaintiffs allege that Defendant’s proposed generic vasopressin injection product, for which it has filed an Abbreviated New Drug Application (ANDA), will infringe eight patents related to stable pharmaceutical formulations of vasopressin.
  • Technical Context: The technology concerns formulations of vasopressin, a life-saving hormone used to treat critically low blood pressure (hypotension), particularly in cases of vasodilatory shock.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Cipla's submission of ANDA No. 217987 to the U.S. Food and Drug Administration (FDA) and its subsequent Paragraph IV Notice to Plaintiffs. The notice certified that Cipla believes Plaintiffs' patents are invalid and not infringed by its proposed generic product. The complaint notes that the matter is related to a prior action filed in the same district (2:22-cv-02814) concerning infringement of the same patents by different generic versions of VASOSTRICT®.

Case Timeline

Date Event
2012-09-25 JHP Pharmaceuticals submits NDA No. 204485 for VASOSTRICT®
2014-04-17 FDA approves NDA No. 204485 for VASOSTRICT®
2015-01-30 Earliest Priority Date for all Patents-in-Suit
2018-03-20 U.S. Patent No. 9,919,026 issues
2018-03-27 U.S. Patent No. 9,925,233 issues
2018-03-27 U.S. Patent No. 9,925,234 issues
2018-05-08 U.S. Patent No. 9,962,422 issues
2018-05-15 U.S. Patent No. 9,968,649 issues
2018-05-22 U.S. Patent No. 9,974,827 issues
2018-05-29 U.S. Patent No. 9,981,006 issues
2018-07-03 U.S. Patent No. 10,010,575 issues
2021-04-21 FDA approves supplemental NDA for VASOSTRICT® Premixed Product
2023-01-27 Cipla submits ANDA No. 217987 (on or before this date)
2023-01-30 Cipla sends Paragraph IV Notice
2023-02-01 Par receives Paragraph IV Notice
2023-02-28 Complaint filed

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

U.S. Patent No. 9,919,026 - "Vasopressin Formulations For Use In Treatment of Hypotension"

The Invention Explained

  • Problem Addressed: The patent's background section notes that "Current formulations of vasopressin suffer from poor long-term stability" (’026) Patent, col. 1:21-23). This instability can lead to degradation of the active pharmaceutical ingredient, reducing efficacy and potentially creating harmful byproducts.
  • The Patented Solution: The invention provides a stable, ready-to-use pharmaceutical composition of vasopressin for intravenous administration. The stability is achieved through a specific combination of components, including a defined concentration of vasopressin, about 5% dextrose, an acetate buffer within a specific concentration range, and a tightly controlled pH range of 3.6 to 3.9 (’026 Patent, col. 173:25-174:10). This formulation is also characterized by a specific range of impurities, suggesting a particular purity profile that contributes to or results from the stability.
  • Technical Importance: A stable, premixed vasopressin formulation eliminates the need for bedside dilution, reducing the risk of contamination or calculation errors in a critical care setting where the drug is often used for emergencies like septic shock (Compl. ¶29, 35).

Key Claims at a Glance

  • The complaint asserts at least independent Claim 1 (Compl. ¶44).
  • Essential elements of Claim 1:
    • A pharmaceutical composition for intravenous administration in a unit dosage form.
    • Comprising from about 0.1 µg/mL to about 2 µg/mL of vasopressin or a pharmaceutically-acceptable salt thereof.
    • Comprising impurities present in an amount of 0.9% to 1.7%, wherein the impurities have from about 85% to about 100% sequence homology to SEQ ID NO.: 1.
    • Comprising about 5% dextrose.
    • Comprising from about 1 mM to about 10 mM acetate buffer.
    • Wherein the unit dosage form has a pH of 3.6 to 3.9.
    • Wherein the unit dosage form is suitable for administration at a concentration of from about 0.1 µg/ml to about 2 µg/ml of vasopressin or the pharmaceutically acceptable salt thereof.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 9,925,233 - "Vasopressin Formulations For Use In Treatment of Hypotension"

The Invention Explained

  • Problem Addressed: Like the '026 patent, the '233 patent addresses the problem of poor long-term stability in vasopressin formulations (’233) Patent, col. 1:21-23).
  • The Patented Solution: This patent claims a method of treating hypotension that leverages the stability of a specific vasopressin formulation. The claimed method involves two key steps: first, storing the pharmaceutical composition at a refrigerated temperature (5° C.) for at least one month, during which it exhibits no more than about 1% degradation; and second, administering this stable composition to a hypotensive human (’233 Patent, col. 171:10-33). The composition itself is defined by its vasopressin concentration, the presence of dextrose, an acetate buffer, and a specific pH range.
  • Technical Importance: This method patent protects not just the formulation, but the full lifecycle of using a highly stable, premixed product, from its extended refrigerated storage to its ultimate administration, ensuring that a potent and safe dose is delivered.

Key Claims at a Glance

  • The complaint asserts at least independent Claim 1 (Compl. ¶59).
  • Essential elements of Claim 1:
    • A method of increasing blood pressure in a human in need thereof.
    • The method comprises: (a) storing at 5° C. for at least about one month a pharmaceutical composition comprising specified amounts of vasopressin, dextrose, and acetate buffer at a pH of 3.6 to 3.9.
    • The composition exhibits no more than about 1% degradation of vasopressin after the storage period.
    • And (b) administering the composition to a hypotensive human at a specified rate.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 9,962,422 - "Vasopressin Formulations For Use In Treatment of Hypotension"

  • Patent Identification: U.S. Patent No. 9962422, "Vasopressin Formulations For Use In Treatment of Hypotension," issued May 8, 2018 (Compl. ¶22).
  • Technology Synopsis: This patent claims a method of increasing blood pressure by providing and administering a vasopressin formulation. The formulation is defined by its components (vasopressin, dextrose, acetate buffer), pH, and a "plurality of peptides in an amount of about 1.5% to about 12.9%," representing a different way to characterize the impurity/degradation profile (’422) Patent, col. 175:53-176:2).
  • Asserted Claims: At least Claim 1 (Compl. ¶73).
  • Accused Features: Cipla's proposed generic product and its intended method of use, which allegedly meet the compositional and administrative requirements of the claim (Compl. ¶74).

U.S. Patent No. 9,968,649 - "Vasopressin Formulations For Use In Treatment of Hypotension"

  • Patent Identification: U.S. Patent No. 9968649, "Vasopressin Formulations For Use In Treatment of Hypotension," issued May 15, 2018 (Compl. ¶23).
  • Technology Synopsis: This patent claims a method for increasing blood pressure by providing and administering a vasopressin formulation. This formulation is characterized by a specific pH, an impurity range of 0.9%-1.7% with high sequence homology to vasopressin (SEQ ID NO.: 1), and the presence of dextrose and an acetate buffer (’649) Patent, col. 171:59-172:13).
  • Asserted Claims: At least Claim 1 (Compl. ¶87).
  • Accused Features: Cipla's proposed generic product and its intended method of use are alleged to satisfy the recited elements of the claim (Compl. ¶88).

U.S. Patent No. 9,974,827 - "Vasopressin Formulations For Use In Treatment of Hypotension"

  • Patent Identification: U.S. Patent No. 9974827, "Vasopressin Formulations For Use In Treatment of Hypotension," issued May 22, 2018 (Compl. ¶24).
  • Technology Synopsis: This patent claims a method of increasing blood pressure involving providing a specific vasopressin composition, storing it at 2-8° C. for at least 24 hours, and then administering it. The composition is defined by its vasopressin, dextrose, acetate buffer, and pH content (’827) Patent, col. 173:25-174:10).
  • Asserted Claims: At least Claim 1 (Compl. ¶101).
  • Accused Features: Cipla's proposed generic product and its intended method of manufacture, storage, and use are alleged to meet the claim's requirements (Compl. ¶102).

U.S. Patent No. 9,981,006 - "Vasopressin Formulations For Use In Treatment of Hypotension"

  • Patent Identification: U.S. Patent No. 9981006, "Vasopressin Formulations For Use In Treatment of Hypotension," issued May 29, 2018 (Compl. ¶25).
  • Technology Synopsis: This patent claims a method of increasing blood pressure by administering a vasopressin formulation containing a specific peptide impurity, SEQ ID NO.: 2. The claim also requires a specific ratio of vasopressin to SEQ ID NO.: 2, along with other formulation components like dextrose and an acetate buffer (’006) Patent, col. 171:58-172:19).
  • Asserted Claims: At least Claim 1 (Compl. ¶115).
  • Accused Features: Cipla's proposed generic product is alleged to contain the formulation recited in the claim and to be used in a manner that infringes the method (Compl. ¶116).

U.S. Patent No. 10,010,575 - "Vasopressin Formulations For Use In Treatment of Hypotension"

  • Patent Identification: U.S. Patent No. 10010575, "Vasopressin Formulations For Use In Treatment of Hypotension," issued July 3, 2018 (Compl. ¶26).
  • Technology Synopsis: This patent claims a method of increasing blood pressure by administering a vasopressin formulation containing a different specific peptide impurity, SEQ ID NO.: 3. Similar to the '006 patent, it requires a specific ratio of vasopressin to this impurity, along with other formulation components (’575) Patent, col. 169:40-170:12).
  • Asserted Claims: At least Claim 1 (Compl. ¶129).
  • Accused Features: The composition and intended use of Cipla's proposed generic product are alleged to infringe (Compl. ¶130).

U.S. Patent No. 9,925,234 - "Vasopressin Formulations For Use In Treatment of Hypotension"

  • Patent Identification: U.S. Patent No. 9925234, "Vasopressin Formulations For Use In Treatment of Hypotension," issued March 27, 2018 (Compl. ¶27).
  • Technology Synopsis: This patent claims a method of increasing blood pressure by administering a vasopressin formulation defined by specific components and a low level of degradation products. The claim requires "no more than about 0-2% vasopressin degradation products," along with vasopressin, acetate buffer, dextrose, and water (’234) Patent, col. 175:20-41).
  • Asserted Claims: At least Claim 1 (Compl. ¶143).
  • Accused Features: The composition and intended use of Cipla's proposed generic product are alleged to meet the claim limitations (Compl. ¶144).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Cipla's "Proposed ANDA Product," identified as a generic "Vasopressin Injection USP, 20 units/100 mL (0.2 units/mL)" for which Cipla submitted ANDA No. 217987 to the FDA (Compl. ¶36).

Functionality and Market Context

The Proposed ANDA Product is a generic equivalent of Plaintiffs' VASOSTRICT® Premixed Product (Compl. ¶36). It is intended to be used to increase blood pressure in adults with vasodilatory shock (e.g., post-cardiotomy or sepsis) who remain hypotensive (Compl. ¶35). The complaint alleges that Cipla will market its product as a generic substitute to be administered in the same manner as VASOSTRICT® (Compl. ¶47). This context is critical in an ANDA case, as the act of filing the ANDA for a drug claimed in a patent is itself an act of infringement under 35 U.S.C. § 271(e)(2).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

U.S. Patent No. 9,919,026 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical composition for intravenous administration comprising, in a unit dosage form: The Proposed ANDA Product is alleged to be a pharmaceutical composition for intravenous administration in a unit dosage form. ¶45 col. 173:25-27
from about 0.1 µg/mL to about 2 µg/mL of vasopressin or a pharmaceutically-acceptable salt thereof; The Proposed ANDA Product is alleged to contain vasopressin within the claimed concentration range. ¶45 col. 173:28-30
impurities that are present in an amount of 0.9% to 1.7%, wherein the impurities have from about 85% to about 100% sequence homology to SEQ ID NO.: 1; The Proposed ANDA Product is alleged to contain an impurity profile that meets the claimed amount and sequence homology requirements. ¶45 col. 173:31-34
about 5% dextrose; The Proposed ANDA Product is alleged to contain about 5% dextrose. ¶45 col. 173:35
and from about 1 mM to about 10 mM acetate buffer, and wherein the unit dosage form has a pH of 3.6 to 3.9; The Proposed ANDA Product is alleged to contain an acetate buffer and have a pH within the claimed ranges. ¶45 col. 173:36-39
and wherein the unit dosage form is suitable for administration at a concentration of from about 0.1 µg/ml to about 2 µg/ml of vasopressin or the pharmaceutically acceptable salt thereof. The Proposed ANDA Product is alleged to be suitable for administration at the claimed concentration. ¶45 col. 173:40-43

U.S. Patent No. 9,925,233 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of increasing blood pressure in a human in need thereof, the method comprising: The Proposed ANDA Product's labeling is alleged to instruct physicians to perform the claimed method of increasing blood pressure. ¶60, 61 col. 171:10-11
a) storing at 5° C. for at least about one month a pharmaceutical composition... comprising... i) from about 0.1 µg/mL to about 2 µg/mL of vasopressin... ii) dextrose; and iii) from about 1 mM to about 10 mM acetate buffer, wherein the unit dosage form has a pH of 3.6 to 3.9, Cipla's proposed manufacturing and storage instructions, combined with the product's alleged composition, are asserted to meet these limitations. ¶60 col. 171:12-23
wherein the pharmaceutical composition exhibits no more than about 1% degradation... after the storage at 5° C. for about one month; The Proposed ANDA Product is alleged to possess the claimed stability profile. ¶60 col. 171:24-27
and b) administering to the human the pharmaceutical composition... wherein the administration provides to the human from about 0.01 units... to about 0.1 units... per minute; and the human is hypotensive. The Proposed ANDA Product's labeling is alleged to instruct physicians to administer the product to hypotensive patients at the claimed dosage rates. ¶60, 61 col. 171:28-33

Identified Points of Contention

  • Technical Questions: A primary factual question for all asserted patents will be whether the specific formulation detailed in Cipla's confidential ANDA actually meets the claimed compositional requirements, including pH, buffer concentration, and particularly the specific impurity profiles or degradation rates. For method claims like that of the '233 Patent, the analysis will depend on evidence that Cipla's product, when stored and used as directed by its proposed label, will meet the performance limitation (e.g., "no more than about 1% degradation").
  • Scope Questions: The interpretation of the term "about" will be central to the infringement analysis for the numerous quantitative limitations (e.g., "about 5% dextrose," "about 1% degradation"). The parties may dispute whether the specifications of the accused product fall literally within the scope of these ranges or, alternatively, are equivalent.

V. Key Claim Terms for Construction

Term for Construction: "impurities that are present in an amount of 0.9% to 1.7%, wherein the impurities have from about 85% to about 100% sequence homology to SEQ ID NO.: 1" (’026 Patent, Claim 1)

  • Context and Importance: This term defines the patented composition by a specific purity profile, which is a key feature distinguishing it from prior art formulations. Infringement will depend entirely on whether Cipla's product contains this precise impurity profile. Practitioners may focus on this term because it is a complex, multi-part limitation that may be difficult to prove is met by the accused product.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claim uses the general term "impurities," which could be argued to encompass any substance meeting the amount and homology requirements, regardless of its specific identity or method of detection.
    • Evidence for a Narrower Interpretation: The specification provides detailed examples of detecting impurities using High-Performance Liquid Chromatography (HPLC) under specific conditions (’026 Patent, col. 60:60-64:25, Example 1). A defendant may argue that the term should be limited to only those impurities detectable by the methods disclosed in the patent.

Term for Construction: "no more than about 1% degradation" (’233 Patent, Claim 1)

  • Context and Importance: This performance-based limitation defines the required stability of the formulation over a specific storage period. The case may turn on how "degradation" is measured and what margin the word "about" provides. Practitioners may focus on this term because proving that an accused product meets a negative limitation (i.e., no more than a certain amount of degradation) can present unique evidentiary challenges.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claim language itself does not specify a method for measuring degradation. A patentee could argue that any scientifically valid method showing degradation below the threshold is sufficient.
    • Evidence for a Narrower Interpretation: The specification describes stability studies where degradation and impurities were measured using HPLC (’233 Patent, Example 8, col. 69-76). A defendant could argue that "degradation" must be assessed using the analytical techniques and standards disclosed in the patent's examples.

VI. Other Allegations

Indirect Infringement

The complaint alleges that upon FDA approval, Cipla would induce and contribute to infringement by medical professionals (Compl. ¶46, ¶60). The alleged inducement is based on the product's proposed labeling, which will instruct users to administer the drug in a manner that directly infringes the asserted method claims. Contributory infringement is alleged on the basis that the product is not a staple article of commerce and has no substantial non-infringing uses (Compl. ¶46, ¶60).

Willful Infringement

Willfulness is alleged for all patents-in-suit (Compl. ¶50, ¶64, et seq.). The basis for this allegation is Cipla's knowledge of the patents, which is evidenced by its filing of a Paragraph IV certification specifically addressing the patents-in-suit.

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

  • A core issue will be one of chemical and performance equivalence: does the formulation described in Cipla's confidential ANDA possess the highly specific characteristics required by the claims, particularly the precise quantitative ranges for impurity profiles (e.g., '026 patent) and long-term degradation rates (e.g., '233 patent)? Proving these elements will likely require detailed discovery into Cipla's product and stability data.
  • A second key issue will be one of definitional scope: how broadly will the court construe the term "about" as it applies to the numerous quantitative limitations in the claims? The outcome of this construction could determine whether Cipla's product is found to infringe literally or whether Plaintiffs must rely on the more complex doctrine of equivalents.
  • Finally, for the numerous method claims, a central question will be one of induced infringement: does Cipla’s proposed product label provide sufficient instruction and encouragement for medical professionals to perform every step of the claimed methods, including the precedent storage steps that establish the required product stability before administration?