DCT

2:22-cv-01754

La Jolla Pharmaceutical Co v. Gland Pharma Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:22-cv-01754, D.N.J., 03/29/2022
  • Venue Allegations: Venue is alleged to be proper based on personal jurisdiction over the defendants. Fosun Pharma USA Inc. is alleged to maintain its principal place of business in Princeton, New Jersey, and Gland Pharma Limited and Shanghai Fosun Pharmaceutical are foreign corporations subject to jurisdiction in any district where personal jurisdiction exists.
  • Core Dispute: Plaintiffs allege that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA, seeking to market a generic version of Giapreza®, constitutes an act of infringement of ten U.S. patents covering methods of using angiotensin II to treat hypotension.
  • Technical Context: The patents relate to methods of using angiotensin II, a naturally occurring peptide that increases blood pressure, to treat patients with septic or other forms of distributive shock, a life-threatening condition characterized by dangerously low blood pressure.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of a Paragraph IV Notice Letter on February 15, 2022, in which Defendant Gland Pharma stated its belief that the patents-in-suit are invalid or would not be infringed by its proposed generic product.

Case Timeline

Date Event
2009-12-16 Priority Date for ’856 and ’863 Patents
2013-12-18 Priority Date for ’745, ’995, ’124, ’983, ’451, ’247, and ’943 Patents
2015-12-29 U.S. Patent No. 9,220,745 Issues
2017-02-21 U.S. Patent No. 9,572,856 Issues
2017-12-21 FDA approves Giapreza® (angiotensin II)
2018-01-16 U.S. Patent No. 9,867,863 Issues
2018-01-12 Priority Date for ’662 Patent
2018-07-24 U.S. Patent No. 10,028,995 Issues
2019-07-02 U.S. Patent No. 10,335,451 Issues
2019-12-03 U.S. Patent No. 10,493,124 Issues
2019-12-10 U.S. Patent No. 10,500,247 Issues
2020-02-04 U.S. Patent No. 10,548,943 Issues
2021-08-24 U.S. Patent No. 11,096,983 Issues
2022-01-11 U.S. Patent No. 11,219,662 Issues
2022-02-14 Defendants send Paragraph IV Notice Letter
2022-03-29 Complaint Filed

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

U.S. Patent No. 11,219,662 - “Method for Treating Hypotension in a Patient that Has Received an ACE Inhibitor by Administering Angiotensin II”

  • Patent Identification: U.S. Patent No. 11219662 (“the ’662 Patent”), titled “Method for Treating Hypotension in a Patient that Has Received an ACE Inhibitor by Administering Angiotensin II,” issued January 11, 2022 (Compl. ¶1, 83).

The Invention Explained

  • Problem Addressed: The patent addresses the specific clinical scenario of treating hypotension in patients who have also received an Angiotensin-Converting Enzyme (ACE) inhibitor, a common class of blood pressure medication (’662 Patent, Abstract). The presence of an ACE inhibitor can complicate treatment by altering the body's natural blood pressure regulation systems.
  • The Patented Solution: The invention is a method of treating hypotension in this specific patient population by administering angiotensin II (’662 Patent, Abstract; col. 2:5-24). Angiotensin II acts downstream of the step blocked by ACE inhibitors, providing a direct mechanism to raise blood pressure in these patients.
  • Technical Importance: The method provides a targeted therapy for patients whose response to other vasopressors might be unpredictable due to concomitant ACE inhibitor therapy.

Key Claims at a Glance

  • The complaint alleges infringement of one or more claims of the ’662 Patent without specifying which claims are asserted (Compl. ¶96). Independent claim 1 is representative.
  • Key elements of independent claim 1 include:
    • A method of treating hypotension in a human patient that has received an ACE inhibitor within a preceding period of time of up to seven days.
    • Administering to the patient a composition comprising angiotensin II.
    • The angiotensin II is administered at an initial rate of 5 ng/kg/min or less.
    • Titrating the rate up or down.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 9,220,745 - “Angiotensin II Alone or in Combination for the Treatment of Hypotension”

  • Patent Identification: U.S. Patent No. 9220745 (“the ’745 Patent”), titled “Angiotensin II Alone or in Combination for the Treatment of Hypotension,” issued December 29, 2015 (Compl. ¶1, 64).

The Invention Explained

  • Problem Addressed: Critically ill patients with distributive shock (e.g., from sepsis) often fail to respond to standard vasopressor treatments like catecholamines (e.g., norepinephrine) (’745 Patent, col. 1:21-24, 1:56-62). High doses of catecholamines have toxic side effects, including cardiotoxicity, creating a need for alternative or adjunctive therapies (’745 Patent, col. 2:30-38).
  • The Patented Solution: The patent describes a method of treating these patients by administering angiotensin II, which raises blood pressure through a different biological pathway (’745 Patent, col. 2:20-35). This allows physicians to reduce or "spare" the dose of catecholamines, thereby avoiding their associated toxicities while still maintaining adequate blood pressure (’745 Patent, col. 2:30-35).
  • Technical Importance: The invention provides a "catecholamine-sparing" approach that offers a therapeutic alternative for critically ill patients who are either resistant to standard vasopressors or at high risk from their side effects.

Key Claims at a Glance

  • The complaint alleges infringement of one or more claims of the ’745 Patent without specifying which claims are asserted (Compl. ¶116). Independent claims 1, 2, and 17 are representative.
  • Key elements of independent claim 1 include:
    • A method of treating a subject having high output shock and undergoing treatment with a catecholamine at a dose equivalent to at least about 0.2 mcg/kg/min of norepinephrine.
    • Administering a dose of angiotensin II effective to raise blood pressure to a Mean Arterial Pressure (MAP) of about 65 mm Hg or above.
    • The angiotensin II dose is also effective to reduce the dose of the catecholamine required to maintain that MAP to the equivalent of about 0.05-0.2 mcg/kg/min norepinephrine or less.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

Multi-Patent Capsule: U.S. Patent No. 10,028,995

  • Patent Identification: ’995 Patent, “Angiotensin II Alone or in Combination for the Treatment of Hypotension,” issued July 24, 2018 (Compl. ¶1, 66).
  • Technology Synopsis: This patent, a continuation of the ’745 patent family, refines the method of using angiotensin II to treat hypotension. It specifically addresses maintaining a target blood pressure in a patient while reducing the rate of vasopressin administration, another common vasopressor (’995 Patent, Abstract; Claim 1).
  • Asserted Claims: The complaint alleges infringement of one or more claims (Compl. ¶156). Independent claims 1 and 23 are asserted.
  • Accused Features: The accused features are the use of the Gland ANDA Product according to its proposed label, which Plaintiffs allege will instruct physicians to practice the claimed method of treatment (Compl. ¶158-160).

Multi-Patent Capsule: U.S. Patent No. 10,493,124

  • Patent Identification: ’124 Patent, “Angiotensin II Alone or in Combination for the Treatment of Hypotension,” issued December 3, 2019 (Compl. ¶1, 68).
  • Technology Synopsis: This patent, also in the ’745 patent family, claims a method for treating a human patient with low blood pressure by administering angiotensin II at an initial rate of about 20 ng/kg/min and then titrating the rate down to maintain a target blood pressure (’124 Patent, Abstract; Claim 1).
  • Asserted Claims: The complaint alleges infringement of one or more claims (Compl. ¶136). Independent claims 1, 16, and 24 are asserted.
  • Accused Features: The infringement allegation centers on the proposed label for Gland's ANDA Product, which recommends a starting dose of 20 ng/kg/min and subsequent titration, allegedly instructing infringing use (Compl. ¶63, 138-140).

Multi-Patent Capsule: U.S. Patent No. 11,096,983

  • Patent Identification: ’983 Patent, “Angiotensin II Alone or in Combination for the Treatment of Hypotension,” issued August 24, 2021 (Compl. ¶1, 70).
  • Technology Synopsis: This patent claims a method of treating a human subject with distributive shock by administering human angiotensin II in the form of a salt at an initial rate of 20 ng/kg/min and titrating down to maintain a MAP of at least 65 mmHg (’983 Patent, Claim 1). The claims further specify the formulation details, including that it is a parenteral composition with a pH of about 5.5 (’983 Patent, Claim 27).
  • Asserted Claims: The complaint alleges infringement of one or more claims (Compl. ¶176). Independent claims 1, 24, and 27 are asserted.
  • Accused Features: The Gland ANDA Product is an angiotensin II solution for injection with a pH of 5.5, and its proposed label allegedly instructs dosing that meets the claim limitations (Compl. ¶48, 63, 178-180).

Multi-Patent Capsule: U.S. Patent No. 9,572,856

  • Patent Identification: ’856 Patent, “Method of Treating Low Blood Pressure,” issued February 21, 2017 (Compl. ¶1, 72).
  • Technology Synopsis: This patent claims a method of treating refractory hypotension by administering angiotensin II at a rate of 20 ng/kg/min to a patient who is already receiving another vasopressor, such as norepinephrine or vasopressin (’856 Patent, Abstract; Claim 1).
  • Asserted Claims: The complaint alleges infringement of one or more claims (Compl. ¶196). Independent claim 1 is asserted.
  • Accused Features: The proposed label for the Gland ANDA product allegedly instructs administration to patients with distributive shock, a condition that may include refractory hypotension, thereby inducing infringement (Compl. ¶62, 198-200).

Multi-Patent Capsule: U.S. Patent No. 9,867,863

  • Patent Identification: ’863 Patent, “Method of Treating Low Blood Pressure,” issued January 16, 2018 (Compl. ¶1, 74).
  • Technology Synopsis: This patent claims a method of treating refractory hypotension in a human patient by administering angiotensin II at a rate of 5 ng/kg/min to about 20 ng/kg/min while the patient is receiving another vasopressor (’863 Patent, Abstract; Claim 21).
  • Asserted Claims: The complaint alleges infringement of one or more claims (Compl. ¶216). Independent claims 1 and 21 are asserted.
  • Accused Features: The alleged infringement stems from the proposed label for the Gland ANDA Product, which allegedly instructs dosing and patient selection consistent with the claimed method (Compl. ¶62-63, 218-220).

Multi-Patent Capsule: U.S. Patent No. 10,335,451

  • Patent Identification: ’451 Patent, “Method of Treating Low Blood Pressure,” issued July 2, 2019 (Compl. ¶1, 76).
  • Technology Synopsis: This patent covers a method of treating low blood pressure in a patient suffering from septic shock by administering angiotensin II at an initial rate of 20 ng/kg/min and titrating up or down as needed (’451 Patent, Abstract; Claim 24).
  • Asserted Claims: The complaint alleges infringement of one or more claims (Compl. ¶236). Independent claims 1 and 24 are asserted.
  • Accused Features: The Gland ANDA Product is indicated for septic shock, and its proposed label allegedly instructs an initial dose and titration protocol that falls within the scope of the claims (Compl. ¶62-63, 238-240).

Multi-Patent Capsule: U.S. Patent No. 10,500,247

  • Patent Identification: ’247 Patent, “Method of Treating Low Blood Pressure,” issued December 10, 2019 (Compl. ¶1, 78).
  • Technology Synopsis: This patent claims a method of treating hypotension in a patient with septic shock, acute kidney injury, or related conditions by administering angiotensin II. The claims cover specific initial dosing rates and titration protocols (’247 Patent, Abstract; Claim 1).
  • Asserted Claims: The complaint alleges infringement of one or more claims (Compl. ¶256). Independent claims 1 and 10 are asserted.
  • Accused Features: The infringement theory is based on the proposed label for Gland's ANDA Product, which is indicated for conditions like septic shock and allegedly recommends a dosing regimen that practices the claimed method (Compl. ¶62, 258-260).

Multi-Patent Capsule: U.S. Patent No. 10,548,943

  • Patent Identification: ’943 Patent, “Method of Treating Low Blood Pressure,” issued February 4, 2020 (Compl. ¶1, 80).
  • Technology Synopsis: This patent covers a method of increasing blood pressure in a human subject with septic shock by administering angiotensin II at a rate of 20 ng/kg/min to 40 ng/kg/min (’943 Patent, Abstract; Claim 24).
  • Asserted Claims: The complaint alleges infringement of one or more claims (Compl. ¶276). Independent claims 1, 11, and 24 are asserted.
  • Accused Features: The allegation is that the proposed label for Gland's ANDA Product, which is indicated for septic shock, will instruct physicians to use a dose within the claimed range, thereby inducing infringement (Compl. ¶62-63, 278-280).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is "Gland's ANDA Product," an angiotensin II, 2.5 mg/mL solution for intravenous infusion, for which Gland Pharma Limited has filed Abbreviated New Drug Application No. 216966 with the U.S. Food and Drug Administration (FDA) (Compl. ¶11, 56).

Functionality and Market Context

  • The Gland ANDA Product is a proposed generic version of Plaintiffs' Giapreza®, a sterile, aqueous solution of synthetic human angiotensin II (Compl. ¶46, 57). According to the complaint, Gland's proposed product label states that the product "is indicated to increase blood pressure in adults with septic or other distributive shock" and "recommends starting angiotensin II injection intravenously at 20 nanograms (ng)/kg/min, and titrating by increments of up to 15 ng/kg/min as needed" (Compl. ¶62-63). The complaint includes a figure from the ATHOS-3 clinical study, which is part of the prescribing information for Giapreza®, showing that 70% of patients receiving the drug achieved the primary endpoint for blood pressure response compared to 23% of placebo subjects (Compl. ¶51). The filing of the ANDA with a Paragraph IV certification is a statutory act of infringement intended to clear a path for the commercial manufacture and sale of this generic product before the expiration of the patents-in-suit (Compl. ¶11, 94).

IV. Analysis of Infringement Allegations

’662 Patent Infringement Allegations

The complaint does not specify which claims of the ’662 Patent are asserted. The following chart is based on representative independent claim 1.

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating hypotension in a human patient that has received an angiotensin converting enzyme (ACE) inhibitor within a preceding period of time of up to seven days... The complaint alleges that Defendants' proposed product will be prescribed to patients with distributive shock, a population that may include patients who have received ACE inhibitors (Compl. ¶50, 62). ¶99-100 col. 32:60-64
...comprising: administering to the patient a composition comprising angiotensin II... Gland's ANDA Product is a 2.5 mg/mL solution of angiotensin II intended for intravenous administration (Compl. ¶56). ¶11, 56 col. 32:65-67
...wherein the angiotensin II is administered at an initial rate of 5 ng/kg/min or less, and titrating the rate up or down. The complaint alleges the product label will instruct physicians to use the product in a manner that infringes, although the complaint cites a starting dose of 20 ng/kg/min, which is higher than this element. This discrepancy suggests a potential point of contention or reliance on unpleaded infringement theories for other claims (Compl. ¶63, 99). ¶63, 99 col. 32:67-col. 33:2
  • Identified Points of Contention:
    • Scope Questions: A potential issue is whether the patient population indicated on the proposed label, "adults with septic or other distributive shock," necessarily reads on the claimed population of "a patient that has received an ACE inhibitor."
    • Technical Questions: The complaint alleges the proposed label recommends a starting dose of 20 ng/kg/min, which does not meet the "5 ng/kg/min or less" limitation of claim 1 (Compl. ¶63). This raises the question of what evidence supports infringement of this specific claim, or if infringement is alleged under different claims not analyzed here.

’745 Patent Infringement Allegations

The complaint does not specify which claims of the ’745 Patent are asserted. The following chart is based on representative independent claim 1.

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating a subject having high output shock and undergoing treatment with a catecholamine at a dose equivalent to at least about 0.2 mcg/kg/min of norepinephrine... The proposed label for Gland's ANDA product is for "septic or other distributive shock," which the complaint equates with high output shock. The complaint notes that patients in the pivotal ATHOS-3 study were receiving other vasopressors, including norepinephrine, prior to administration (Compl. ¶51, 62). ¶51, 62, 119 col. 10:29-34
...comprising administering a dose of angiotensin II which is effective to raise the blood pressure of the subject to a mean arterial pressure (MAP) of about 65 mm Hg or above... The complaint alleges Gland's proposed product is indicated to "increase blood pressure" and that its label will substantially copy the FDA-approved label for Giapreza®, which is approved for this purpose (Compl. ¶62, 118). ¶62, 118 col. 10:31-35
...and which is effective to reduce the dose of the catecholamine required to maintain a MAP...to the equivalent of about 0.05-0.2 mcg/kg/min norepinephrine or less. The complaint does not provide specific allegations on the reduction of catecholamine doses but relies on the assertion that the proposed label will induce physicians to perform the claimed methods, which include this step (Compl. ¶119-120). ¶119, 120 col. 10:35-39
  • Identified Points of Contention:
    • Scope Questions: A central question may be the construction of "high output shock" and whether the clinical realities of treating "septic or other distributive shock" as instructed by the label will necessarily meet the patent's definition.
    • Evidentiary Questions: The complaint's theory relies on inducement. A key question for the court will be whether the instructions on the proposed generic label, on their face, would necessarily lead a physician to perform every step of the claimed method, including the specific catecholamine reduction recited in the claim.

V. Key Claim Terms for Construction

  • The Term: "a patient that has received an ACE inhibitor" (’662 Patent, Claim 1)

  • Context and Importance: The definition of this term is critical because it defines the specific patient population covered by the patent. Practitioners may focus on this term because the timing of the ACE inhibitor administration relative to the angiotensin II treatment could be a key point of dispute regarding both infringement and patentability.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The claim language "within a preceding period of time of up to seven days" provides a wide window, suggesting the method applies even if the ACE inhibitor is not actively present in the patient's system (’662 Patent, col. 32:62-64).
    • Evidence for a Narrower Interpretation: The specification discusses the physiological interaction between ACE inhibitors and angiotensin II, which might be used to argue that the claim should be limited to situations where the ACE inhibitor is still biologically active and affecting the patient's response to treatment (’662 Patent, col. 2:5-24).

  • The Term: "high output shock" (’745 Patent, Claim 1)

  • Context and Importance: This term defines the medical condition to be treated and is central to the infringement analysis. The defendant may argue that its product's indication for "septic or other distributive shock" is broader than, and does not necessarily meet, the specific definition of "high output shock" as understood in the patent.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The patent specification uses "high output shock" and "distributive shock" interchangeably, suggesting they are synonymous (’745 Patent, col. 1:22).
    • Evidence for a Narrower Interpretation: The specification references a specific clinical definition for high output shock, defined as a "cardiovascular Sequential Organ Function Assessment (SOFA) score of greater than or equal to 3 or 4 as well as a cardiac index of >2.4 liters/min/BSA 1.73 m²" (’745 Patent, col. 8:50-54). A defendant may argue the claim should be limited to patients meeting these specific clinical parameters.

VI. Other Allegations

  • Indirect Infringement: The complaint's core theory is one of induced infringement. It alleges that Defendants, by seeking FDA approval for their ANDA Product with a label that substantially copies the label for Giapreza®, will knowingly encourage and instruct physicians and other medical professionals to use the product in a manner that directly infringes the method claims of the patents-in-suit (Compl. ¶86, 99, 101, 119).
  • Willful Infringement: The complaint alleges that Defendants have acted with full knowledge of the patents-in-suit. This allegation is based on Defendants' filing of an ANDA that included a Paragraph IV certification specifically referencing each of the asserted patents, which Plaintiffs contend demonstrates actual knowledge (Compl. ¶104, 124, 144).

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

  • A central issue will be one of claim construction: can the term "high output shock," which is given a specific clinical definition in the patent specification, be construed to broadly cover all patients with "septic or other distributive shock" as indicated on the defendant's proposed label? The outcome of this question will significantly impact the scope of infringement.
  • A key evidentiary question will be one of inducement: does the language of the proposed generic label, on its face, provide sufficient instruction to inevitably lead physicians to perform every step of the patented methods, particularly the specific dosing, titration, and catecholamine-reduction steps required by various claims?
  • A third question concerns the timing and context of treatment: for patents like the ’662 Patent, what evidence will be required to show that a physician, following the proposed label, would be induced to administer angiotensin II to a patient specifically because they had "received an ACE inhibitor," as opposed to administering it for other clinical reasons unrelated to the claimed method?