DCT

1:18-cv-02032

Par Pharmaceutical Inc v. Amneal Pharma Of New York LLC

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:18-cv-02032, D. Del., 12/20/2018
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Amphastar Pharmaceuticals, Inc. is a Delaware corporation and thus resides in the district.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) for a generic vasopressin injection product constitutes an act of infringement of six patents related to stable vasopressin formulations and methods for treating hypotension.
  • Technical Context: The technology concerns ready-to-use, stable liquid formulations of vasopressin, a hormone used in critical care settings to increase blood pressure in patients with conditions like vasodilatory shock.
  • Key Procedural History: This patent infringement action was initiated under the Hatch-Waxman Act following Defendant’s submission of ANDA No. 211857 to the U.S. Food and Drug Administration (FDA). On or about November 14, 2018, Defendant sent a Paragraph IV Notice to Plaintiff, certifying its belief that the patents-in-suit are invalid and/or not infringed by its proposed generic product. The filing of this complaint within 45 days of that notice triggers a statutory 30-month stay of FDA approval for the Defendant's generic product.

Case Timeline

Date Event
2012-09-25 Original New Drug Application (NDA) for VASOSTRICT® submitted
2014-04-17 FDA approves original NDA for VASOSTRICT®
2015-01-30 Priority Date for all Patents-in-Suit
2016-03-18 FDA approves supplemental NDA for 20 units/mL formulation of VASOSTRICT®
2016-06-28 U.S. Patent No. 9,375,478 (’478 Patent) is issued
2016-12-17 FDA approves supplemental NDA for 200 units/10mL formulation of VASOSTRICT®
2017-06-27 U.S. Patent No. 9,687,526 (’526 Patent) is issued
2017-08-29 U.S. Patent No. 9,744,209 (’209 Patent) is issued
2017-08-29 U.S. Patent No. 9,744,239 (’239 Patent) is issued
2017-09-05 U.S. Patent No. 9,750,785 (’785 Patent) is issued
2018-04-10 U.S. Patent No. 9,937,223 (’223 Patent) is issued
2018-11-14 Defendant submits ANDA No. 211857 and sends Paragraph IV Notice (on or before this date)
2018-12-20 Complaint for patent infringement is filed

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

No probative visual evidence provided in complaint.

U.S. Patent No. 9,744,239 - "Vasopressin Formulations for Use in Treatment of Hypotension", issued August 29, 2017

The Invention Explained

  • Problem Addressed: The patent's background section describes that prior art formulations of vasopressin, a hormone used to treat low blood pressure, suffer from "poor long-term stability" and require either refrigeration or reconstitution from a lyophilized powder before use ('239 Patent, col. 1:24-27).
  • The Patented Solution: The invention is a method of treating hypotension by administering a specific, stable, ready-to-use liquid formulation of vasopressin. The stability is achieved through a formulation with a controlled pH range (3.5 to 4.1) and a defined composition that includes vasopressin, water, acetic acid or acetate, and optionally chlorobutanol as a preservative ('239 Patent, col. 8:34-47; Claim 1). This obviates the need for refrigeration or reconstitution, simplifying clinical administration.
  • Technical Importance: Providing a stable, ready-to-use liquid formulation of an emergency drug like vasopressin reduces the risk of preparation errors and delays in critical care settings (Compl. ¶21, ¶27).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶34).
  • Essential Elements of Claim 1:
    • A method of increasing blood pressure in a hypotensive human.
    • The method comprises (a) providing a specific pharmaceutical composition, (b) diluting it, and (c) administering it intravenously.
    • The provided composition consists of vasopressin (0.01-0.07 mg/mL), optional chlorobutanol, acetic acid/acetate, 0-2% degradation products, and water.
    • The provided composition has a pH of 3.5 to 4.1.
    • The administration step provides vasopressin at a rate of about 0.01 to 0.1 units per minute.
  • The complaint's phrasing "at least claim 1" suggests the right to assert other claims is reserved (Compl. ¶34).

U.S. Patent No. 9,937,223 - "Vasopressin Formulations for Use in Treatment of Hypotension", issued April 10, 2018

The Invention Explained

  • Problem Addressed: The patent addresses the need for a vasopressin formulation that remains stable not only on the shelf but also after a multi-dose container has been opened for initial use ('223 Patent, col. 1:20-27).
  • The Patented Solution: The patent claims a method of increasing blood pressure that involves using a specific vasopressin formulation from a container on at least two separate occasions, where the second use occurs at least 48 hours after the first. The claimed method highlights the formulation's stability against degradation and contamination after the vial's seal is punctured, which is a key feature for multi-dose products ('223 Patent, Abstract; Claim 1).
  • Technical Importance: A formulation stable enough for multi-day use from a single vial reduces pharmaceutical waste and costs in a hospital setting, particularly for products that may be administered intermittently (Compl. ¶24).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶42).
  • Essential Elements of Claim 1:
    • A method of increasing blood pressure in a hypotensive human.
    • The method comprises (a) providing a pharmaceutical composition in a container with a specific pH of 3.7 to 3.8.
    • The composition comprises vasopressin (0.01-0.07 mg/mL), acetate buffer, and water.
    • The method includes the steps of: (b) puncturing the container a first time and drawing a portion; (c) administering that portion; (d) puncturing the container a second time at least 48 hours after the first puncture and drawing a second portion; and (e) administering the second portion.
  • The complaint reserves the right to assert other claims by alleging infringement of "at least claim 1" ('223 Patent, ¶42).

U.S. Patent No. 9,375,478

  • Patent Identification: U.S. Patent No. 9,375,478, "Vasopressin Formulations for Use in Treatment of Hypotension", issued June 28, 2016.
  • Technology Synopsis: This patent addresses the problem of poor long-term stability in vasopressin solutions ('478 Patent, col. 1:20-24). It claims a method for increasing blood pressure by administering a formulation defined by what it "consists essentially of": vasopressin, a 10 mM acetate buffer, and water, maintained at a specific pH of 3.8 ('478 Patent, Claim 1).
  • Asserted Claims: At least Claim 1 (Compl. ¶50).
  • Accused Features: The proposed generic product's formulation and its intended administration method, which allegedly meet the specific compositional and pH requirements of the asserted claim (Compl. ¶¶28, 51).

U.S. Patent No. 9,687,526

  • Patent Identification: U.S. Patent No. 9,687,526, "Vasopressin Formulations for Use in Treatment of Hypotension", issued June 27, 2017.
  • Technology Synopsis: This patent addresses the poor long-term stability of vasopressin ('526 Patent, col. 1:16-20). The invention is a method of treatment that includes the step of storing a specific vasopressin formulation at 2-8° C. for at least four weeks, wherein the formulation exhibits less than 5% degradation during that storage period, before administration ('526 Patent, Claim 1).
  • Asserted Claims: At least Claim 1 (Compl. ¶58).
  • Accused Features: The proposed generic product's formulation, its alleged stability when stored as directed, and its subsequent intended use to treat hypotension (Compl. ¶¶28, 59).

U.S. Patent No. 9,750,785

  • Patent Identification: U.S. Patent No. 9,750,785, "Vasopressin Formulations for Use in Treatment of Hypotension", issued September 5, 2017.
  • Technology Synopsis: Unlike the other patents-in-suit, this patent claims a pharmaceutical composition itself, not a method of use. The invention is a vasopressin formulation characterized by having a specific profile of impurities—between 0.9% and 1.7% of total impurities that have a defined sequence homology to vasopressin—within a pH range of 3.7-3.9 ('785 Patent, Claim 1).
  • Asserted Claims: At least Claim 1 (Compl. ¶66).
  • Accused Features: The composition of the Proposed ANDA Product itself, which is alleged to contain the claimed concentration of vasopressin, pH, and specific impurity profile (Compl. ¶¶28, 67).

U.S. Patent No. 9,744,209

  • Patent Identification: U.S. Patent No. 9,744,209, "Vasopressin Formulations for Use in Treatment of Hypotension", issued August 29, 2017.
  • Technology Synopsis: This patent claims a method of increasing blood pressure by administering the specific composition claimed in the '785 Patent. The claimed method requires administering a unit dosage form that contains vasopressin, has a pH of 3.7-3.9, and comprises the specific impurity profile of 0.9% to 1.7% of impurities with high sequence homology to vasopressin ('209 Patent, Claim 1).
  • Asserted Claims: At least Claim 1 (Compl. ¶74).
  • Accused Features: The intended method of administering the Proposed ANDA Product, which is alleged to have the composition and impurity profile recited in the claim (Compl. ¶¶28, 75).

III. The Accused Instrumentality

Product Identification

  • Defendant Amphastar's proposed generic "Vasopressin Injection USP, 20 units/1 mL vials," for which it submitted Abbreviated New Drug Application (ANDA) No. 211857 to the FDA (Compl. ¶28).

Functionality and Market Context

  • The Proposed ANDA Product is a solution for intravenous infusion containing vasopressin as the active ingredient. It is intended to be a generic equivalent to Plaintiff's VASOSTRICT® product and is indicated to increase blood pressure in adults with vasodilatory shock (Compl. ¶27, ¶28). The complaint alleges that VASOSTRICT® has achieved "tremendous commercial success," with annual sales of $400 million in 2017, positioning the accused product to enter a significant market (Compl. ¶27).

IV. Analysis of Infringement Allegations

'239 Patent 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... wherein the human is hypotensive. The Proposed ANDA Product is intended for administration to hypotensive humans to increase blood pressure, as instructed by its proposed product label. ¶35 col. 4:2-6
a) providing a pharmaceutical composition for intravenous administration consisting of...i) from about 0.01mg/mL to about 0.07 mg/mL of vasopressin... The Proposed ANDA Product is a pharmaceutical composition containing 20 units/mL (approximately 0.04 mg/mL) of vasopressin. ¶28, ¶34 col. 2:30-32
ii) optionally chlorobutanol; iii) acetic acid, acetate, or a combination thereof... v) water; The complaint does not specify the excipients in the Proposed ANDA Product but alleges its administration as intended would infringe. ¶35 col. 7:59-65
wherein: the unit dosage form has a pH of 3.5 to 4.1; The Proposed ANDA Product allegedly has a pH within the claimed range, consistent with the formulation of the reference listed drug. ¶34, ¶35 col. 22:25-27
b) diluting the unit dosage form in a diluent... c) administering the diluted unit dosage form to the human by intravenous administration... The proposed product label allegedly instructs medical personnel to dilute the product and administer it intravenously. ¶35 col. 22:46-50
the administration provides to the human from about 0.01 units of vasopressin... to about 0.1 units of vasopressin... per minute; The proposed product label allegedly instructs administration at a dosage rate falling within the claimed range. ¶35 col. 22:61-64
  • Identified Points of Contention:
    • Scope Questions: Claim 1(a) uses the transitional phrase "consisting of," which is highly restrictive. A central question may be whether Amphastar's formulation contains any unlisted ingredients (e.g., buffers, stabilizers) that materially alter the basic and novel properties of the claimed composition, thereby placing it outside the claim's scope.
    • Technical Questions: The infringement allegation relies on the content of Amphastar's proposed product label, which is not included in the complaint. An evidentiary question will be whether the label's instructions for dilution, pH, and administration rate will, in fact, direct users to perform steps that fall within all limitations of Claim 1.

'223 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
a) providing a pharmaceutical composition for intravenous administration comprising... i) vasopressin... ii) acetate buffer; and iii) water; wherein the pharmaceutical composition has a pH from about 3.7 to about 3.8; The Proposed ANDA Product is a pharmaceutical composition allegedly containing vasopressin, an acetate buffer, and water, with a pH in the claimed range. ¶28, ¶42 col. 22:25-27
b) puncturing a dispensing region of the container a first time and drawing... a portion... c) intravenously administering the portion... The proposed label allegedly instructs users to puncture the vial and administer a first dose to a hypotensive patient. ¶43 col. 22:35-36
d) puncturing the dispensing region of the container a second time... wherein: the second time... occurs at least 48 hours after the first time... The proposed label allegedly instructs or permits the vial to be punctured a second time for an additional dose at an interval of 48 hours or more after the first use. ¶43 col. 22:35-36
e) intravenously administering the second portion of the pharmaceutical composition to the human... The proposed label allegedly instructs administration of the second portion at a dosage rate within the claimed range. ¶43 col. 22:61-64
  • Identified Points of Contention:
    • Scope Questions: A key issue will be whether Amphastar's proposed label for a multi-dose vial will contain instructions or information that induces the specific act of puncturing the same vial a second time at least 48 hours later. The complaint alleges this will happen if the product is "administered as intended" (Compl. ¶43), but proof of inducement requires evidence of intent to encourage the infringing acts.
    • Technical Questions: The analysis will depend on the precise wording of the approved VASOSTRICT® label regarding multi-dose use and whether Amphastar's label must mirror that language. The specification for the branded drug states vials are to be discarded 48 hours after first puncture, language which may form the basis of Par's inducement theory ('223 Patent, col. 22:35-36).

V. Key Claim Terms for Construction

  • The Term: "consisting of" ('239 Patent, Claim 1)

    • Context and Importance: This term, used to introduce the list of ingredients in the pharmaceutical composition, is a closed-ended transitional phrase. Its construction is critical because if Amphastar's generic product contains any additional, unlisted ingredient that materially affects the invention's properties (e.g., stability), it would not infringe this claim.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: A party might argue that only additional ingredients that undermine the formulation's stability are excluded. The specification's primary focus is on achieving a stable, ready-to-use formulation, suggesting that inert additives might not be material ('239 Patent, col. 1:24-27).
      • Evidence for a Narrower Interpretation: The choice of "consisting of" over the more common "comprising" is a strong indication that the inventor intended to exclude other ingredients. The patent repeatedly emphasizes a simple formulation as the solution to prior art stability problems, which could support a narrow construction that excludes nearly all unlisted substances ('239 Patent, Abstract).

  • The Term: "puncturing the dispensing region of the container a second time... at least 48 hours after the first time" ('223 Patent, Claim 1)

    • Context and Importance: This method step is central to the '223 Patent's contribution over prior art, as it relates to the stability of a multi-dose vial after its seal has been compromised. The dispute will likely focus on what actions by Amphastar constitute inducement of this specific multi-day use pattern.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The patent specification describes the use of the formulation in multi-dose vials, and the claim language describes a straightforward sequence of events consistent with such use ('223 Patent, col. 22:28-36). A party could argue that providing a multi-dose vial with instructions for multiple uses inherently encourages this behavior.
      • Evidence for a Narrower Interpretation: The claim's specificity—requiring a second puncture at least 48 hours later—is precise. A party could argue that inducement requires more than merely supplying a multi-dose vial; it would require specific instructions on the label that encourage this specific timing, such as a statement about the product's stability for 48 hours after first puncture ('223 Patent, col. 22:35-36).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges active inducement of infringement for all asserted patents. The factual basis for this allegation is that Amphastar's proposed product label and other conduct will actively and intentionally instruct and encourage medical personnel to dilute and administer the Proposed ANDA Product in a manner that practices the steps of the claimed methods (Compl. ¶35, ¶43, ¶51, ¶59, ¶67, ¶75).
  • Willful Infringement: The complaint alleges that Amphastar's infringement is willful for all asserted patents. This allegation is based on "information and belief" that Amphastar was aware of the patents-in-suit prior to the lawsuit—knowledge confirmed by its service of a Paragraph IV notice—and is aware that the commercial manufacture, use, and sale of its proposed product will lead to infringement (Compl. ¶37, ¶45, ¶53, ¶61, ¶69, ¶77).

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

  • A core issue will be one of compositional scope: can Par prove that Amphastar's proposed generic formulation "consists of" or "consists essentially of" the narrow set of ingredients recited in certain claims (e.g., '239 and '478 patents), or will the presence of any additional excipients in the generic product allow Amphastar to design around these claims?
  • A second key issue will be one of induced infringement: what specific instructions will Amphastar's proposed product label contain? The case may turn on whether these instructions are found to actively encourage clinicians to perform all the claimed method steps, particularly the multi-day use from a single vial required by the '223 patent.
  • A central evidentiary question will be one of product-by-process: for patents claiming a specific impurity profile ('785 and '209 patents), can Par establish that Amphastar's manufacturing process, as detailed in its ANDA, will necessarily and inherently result in a final product that meets the claimed limitations for impurity type and concentration?