United States Patent 10,493,124: Angiotensin II Titration Claims, Exclusivity and Patent Landscape
United States Patent No. 10,493,124 protects a clinical dosing protocol for angiotensin II in hypotensive human patients. Its core requirement is an initial infusion rate of approximately 20 ng/kg/min followed by downward titration while achieving or maintaining a mean arterial pressure of approximately 65 mmHg or higher. The patent is directed to treatment conduct, not to the angiotensin II molecule itself, a formulation, or an infusion device.
The patent is commercially relevant to Giapreza, the FDA-approved angiotensin II product marketed in the United States. The patent family is associated with La Jolla Pharmaceutical Company, now within the CSL Vifor organization. The base statutory patent term runs to approximately May 24, 2034, subject to any applicable patent-term adjustment.
What does U.S. Patent 10,493,124 protect?
The patent protects methods that combine four principal elements:
- A human patient with low blood pressure.
- Administration of angiotensin II.
- An initial dose of approximately 20 ng/kg/min.
- Downward titration to maintain or achieve a MAP of approximately 65 mmHg or higher.
Independent claim 1 is the principal treatment claim. Independent claim 16 covers achieving a target MAP of at least approximately 65 mmHg, but does not expressly repeat the broader "low blood pressure" treatment language in the same form.
| Claim group |
Core limitation |
Commercial significance |
| Claims 1-15 |
Treatment of low blood pressure using angiotensin II, initially at approximately 20 ng/kg/min, followed by downward titration |
Broadest treatment-method group |
| Claims 2-5 |
Titration to approximately 15, 10, 5 or 1.25 ng/kg/min |
Protects specified maintenance endpoints |
| Claims 6-12 |
Low blood pressure associated with shock, distributive shock, cardiogenic shock, sepsis or acute kidney injury |
Adds disease and clinical-setting limitations |
| Claims 7, 8 and 13 |
Angiotensin II corresponding to SEQ ID NO: 1, with intravenous administration in claim 8 |
Narrows the peptide and route |
| Claims 14-15 |
Titration to approximately 0.25 ng/kg/min |
Extends protection to a very low maintenance dose |
| Claims 16-30 |
Achieving MAP of at least approximately 65 mmHg after an initial 20 ng/kg/min dose and downward titration |
Separate MAP-focused claim group |
SEQ ID NO: 1 is native angiotensin II, the octapeptide Asp-Arg-Val-Tyr-Ile-His-Pro-Phe. The claims therefore reach the clinical use of the naturally occurring peptide when administered under the claimed dosing protocol.
How broad are the independent claims?
Claim 1 is broad in patient population and route of administration. It requires a human patient with low blood pressure but does not itself require shock, sepsis, acute kidney injury or intravenous administration. Those limitations appear in dependent claims.
The central limitation is the dosing sequence:
- Initial administration at approximately 20 ng/kg/min.
- Subsequent downward titration.
- A rate sufficient to achieve or maintain MAP at approximately 65 mmHg or above.
Claim 16 is similar but is framed around the goal of achieving target MAP. It requires the initial approximately 20 ng/kg/min administration and downward titration, but the claim does not expressly state that the patient must have one of the specific conditions listed in claim 6.
The use of "about" creates a fact-dependent infringement issue. A court would likely evaluate the term in light of the specification, prosecution history, pharmacologic variability and clinical dosing practice. The claims are not limited to a single exact numerical infusion rate if a clinically equivalent rate falls within the ordinary meaning of "about."
What does "titrating the rate down" require?
The claims do not appear to require one specific titration schedule or a fixed time interval between dose reductions. They require an initial rate near 20 ng/kg/min followed by a reduction in infusion rate.
The dependent claims identify specific endpoints:
- Approximately 15 ng/kg/min.
- Approximately 10 ng/kg/min.
- Approximately 5 ng/kg/min.
- Approximately 1.25 ng/kg/min.
- Approximately 0.25 ng/kg/min.
A protocol that begins at 20 ng/kg/min and reduces the infusion to any one of those levels may satisfy a corresponding dependent claim if the other claim elements are met. The claims do not require that every listed intermediate rate be used.
What diagnoses and clinical settings are covered?
Claim 6 identifies:
- Shock.
- Distributive shock.
- Cardiogenic shock.
- Sepsis.
- Acute kidney injury.
These conditions are limitations of the dependent claims, not requirements for claim 1. A patient treated for hypotension outside those listed conditions may still fall within claim 1 or claim 16 if the dosing and MAP requirements are met.
The inclusion of acute kidney injury is commercially important because the ATHOS-3 clinical program evaluated angiotensin II in vasodilatory shock and reported effects on blood pressure and renal outcomes. The FDA approved Giapreza for increasing blood pressure in adults with septic or other distributive shock, in combination with volume repletion and catecholamines or other vasopressors [2, 3].
What is the relationship between Patent 10,493,124 and Giapreza?
Giapreza is synthetic human angiotensin II marketed for intravenous use. The FDA prescribing information identifies a recommended initial dose of 20 ng/kg/min, with titration based on blood pressure response and subsequent down-titration after stabilization [2].
That label structure closely tracks the core limitations of Patent 10,493,124:
| Giapreza label element |
Patent 10,493,124 element |
| Initial dose of 20 ng/kg/min |
Claims 1 and 16 |
| Titration based on blood pressure |
Claims 1 and 16 |
| Target MAP of approximately 65 mmHg or higher |
Claims 1 and 16 |
| Intravenous administration |
Claims 8 and 23 |
| Use in distributive or septic shock |
Claims 6 and 21 |
| Dose reduction after stabilization |
Claims requiring downward titration |
The patent does not claim every use of angiotensin II. It is strongest against use of the FDA-approved product under the labeled initial-dose and titration protocol. It is less directly applicable to:
- Angiotensin II used at a materially different initial dose.
- Treatment without downward titration.
- Use for a purpose unrelated to hypotension or MAP control.
- Nonhuman use.
- A formulation or manufacturing process that does not involve the claimed method of treatment.
What is the patent family and expiration date?
Patent 10,493,124 is part of a U.S. patent family directed to the use of angiotensin II for treating hypotension. The family includes earlier U.S. patent protection, including U.S. Patent No. 9,861,659, which addresses related angiotensin II treatment methods.
| Patent |
Subject matter |
Priority date |
Issue date |
Base statutory expiration |
| U.S. 9,861,659 |
Related methods of treating hypotension with angiotensin II |
May 24, 2013 |
Jan. 9, 2018 |
Approximately May 24, 2034 |
| U.S. 10,493,124 |
Initial 20 ng/kg/min dose, downward titration and MAP target |
May 24, 2013 |
Dec. 3, 2019 |
Approximately May 24, 2034 |
The common priority date is commercially significant. Patent term is generally measured from the earliest effective nonprovisional filing date for the relevant family, rather than from the grant date. The later issuance of Patent 10,493,124 therefore does not create a new 20-year term beginning in 2019.
The patent term may include patent-term adjustment based on USPTO examination delays. The FDA Orange Book expiration date should be used for regulatory exclusivity analysis, while the USPTO patent record controls the underlying patent-term calculation [1, 4].
What is the Orange Book status of Patent 10,493,124?
Giapreza is approved under NDA 209360. The FDA Orange Book identifies patents submitted by the NDA holder for the approved drug and associated methods of use. Patent 10,493,124 is relevant to the listed-method-of-use estate for Giapreza and should be evaluated together with the other Giapreza patents rather than as an isolated right [4].
An Orange Book listing does not establish that every claim is valid or infringed. It does, however, affect the ANDA pathway. A generic applicant seeking approval before the relevant listed patent expires must address the listed patent through one of the statutory certification mechanisms.
The key regulatory effects are:
- A Paragraph III certification defers approval until the listed patent expires.
- A Paragraph IV certification asserts that the patent is invalid, unenforceable or will not be infringed.
- A timely Paragraph IV notice can trigger patent litigation by the NDA holder.
- A timely suit can impose a 30-month stay of ANDA approval, subject to statutory exceptions.
The patent is a method-of-use patent. A generic applicant may attempt a section viii statement that it will omit the patented use from its labeling. That strategy depends on whether the remaining label avoids encouraging the patented dosing regimen and whether the FDA-approved indications and dosing instructions can be cleanly separated from the claimed use.
When does angiotensin II lose patent and regulatory exclusivity?
Patent protection for the principal U.S. angiotensin II method-of-use family runs to approximately 2034. The commercial entry date depends on the complete Orange Book listing, any patent-term adjustment, litigation, settlement terms and the scope of an ANDA label carve-out.
| Protection type |
Relevance to Giapreza |
| New drug application approval |
Giapreza was approved by FDA in December 2017 |
| Orphan-drug exclusivity |
The relevant FDA approval carried orphan-drug protection for the approved indication |
| Method-of-use patents |
Protect dosing and clinical use of angiotensin II |
| Composition patents |
The patent at issue does not claim a novel angiotensin II composition |
| Formulation patents |
Separate analysis is required; Patent 10,493,124 is not a formulation patent |
| Manufacturing patents |
Separate process claims may create additional supply-chain barriers |
| Base patent term |
Approximately May 24, 2034 for the core family |
The practical loss of exclusivity is therefore not necessarily a single date. Generic entry could be delayed by later-expiring listed patents, pediatric exclusivity, litigation settlements or regulatory barriers unrelated to Patent 10,493,124.
Are there Paragraph IV challenges or patent litigation?
Publicly documented litigation must be analyzed at the NDA and patent-family level. A Paragraph IV notice concerning one Giapreza patent can generate litigation involving several patents, while the absence of litigation against Patent 10,493,124 would not establish that the patent is immune from challenge.
The principal litigation risks are:
-
Obviousness. A challenger could argue that starting angiotensin II at 20 ng/kg/min and titrating to a blood-pressure target would have been obvious from earlier angiotensin II infusion studies, vasopressor protocols and clinical trial disclosures.
-
Written description and enablement. The claims cover multiple diagnoses, dose endpoints and clinical contexts. A challenger could test whether the specification supports the full breadth of the claimed protocol.
-
Indefiniteness. Terms such as "about," "low blood pressure" and "titrating down" could be contested if the specification and prosecution history do not provide sufficient boundaries.
-
Infringement. Generic applicants may argue that an ANDA label does not require the patented initial dose, titration sequence or MAP target, or that the use is not induced by the proposed labeling.
-
Patent-term and listing disputes. An ANDA applicant may contest whether the patent is properly listed for the approved product or whether the listed claims cover an FDA-approved method of use.
The supplied claims do not establish whether any Paragraph IV notice, district-court action, inter partes review or settlement has occurred. A definitive current litigation status cannot be derived from the claim text alone.
What formulations are protected by Patent 10,493,124?
Patent 10,493,124 is not principally a formulation patent. Its claims do not require:
- A specific buffer.
- A particular concentration.
- A stabilizer.
- A vial or container.
- A preservative system.
- A particular pH.
- A manufacturing process.
The claims can apply to a formulation containing angiotensin II if that formulation is administered under the claimed method. The formulation itself is not the protected subject matter.
This distinction matters for generic competition. A generic manufacturer may avoid a formulation patent by using a different excipient system, but it may still face the method-of-use claims if its label directs the same 20 ng/kg/min initiation and downward titration protocol.
Does the patent create biosimilar risk?
No conventional biosimilar pathway is expected for angiotensin II. Angiotensin II is a defined synthetic peptide rather than a complex biologic manufactured in living cells. A competing product would more likely proceed through an ANDA or another abbreviated pathway, depending on FDA product classification and formulation differences.
The principal competitive risks are therefore:
- An ANDA for a generic angiotensin II product.
- A 505(b)(2) application with a modified formulation, concentration or delivery presentation.
- A hospital-compounded or repackaged product, subject to applicable FDA requirements.
- A product with a label that omits the patented method of use.
The absence of biosimilar exposure does not eliminate competition risk. It shifts the analysis toward Orange Book patents, labeling, formulation equivalence and inducement.
How strong is the patent estate?
Patent 10,493,124 has meaningful commercial strength because its core dosing protocol aligns with the approved Giapreza label. A product marketed for the same indication will face a practical challenge in avoiding the initial 20 ng/kg/min dose and subsequent titration language.
Its main weaknesses are structural:
- It is a method-of-treatment patent rather than a composition patent.
- Angiotensin II itself is an old endogenous peptide.
- The core dosing concept may be vulnerable to obviousness arguments based on clinical literature.
- "About" and "titrating down" may create claim-construction disputes.
- An ANDA applicant may seek a section viii label carve-out.
- Alternative dosing regimens may avoid literal infringement.
The estate is stronger when the accused product label expressly recommends 20 ng/kg/min as the starting dose, blood-pressure-directed titration and later dose reduction. It is weaker when the competing product uses a different starting dose, omits a MAP target or leaves titration entirely to physician judgment without encouraging the claimed sequence.
What generic launch scenarios exist?
Scenario 1: Full-label generic launch
A full-label ANDA applicant would likely need to address the Orange Book patents with Paragraph III or Paragraph IV certifications. A Paragraph IV filing could lead to a 30-month stay if the NDA holder files a timely infringement action.
Scenario 2: Skinny-label launch
A generic applicant could attempt to remove the patented use from its labeling. This approach is more difficult if the remaining label still contains the 20 ng/kg/min starting dose and blood-pressure-directed titration instructions.
Scenario 3: Alternative dosing protocol
A competitor could use a different initial rate or a protocol that does not require downward titration. That may reduce literal infringement risk but could create clinical, regulatory and commercial disadvantages if the alternative protocol is inconsistent with the established Giapreza label.
Scenario 4: 505(b)(2) product
A modified concentration, container, formulation or delivery presentation could enter through a 505(b)(2) application. The applicant would still need to address applicable listed patents and could face method-of-use claims if the proposed labeling adopts the patented regimen.
Key Takeaways
- Patent 10,493,124 protects a method of administering angiotensin II beginning at approximately 20 ng/kg/min and titrating downward while achieving or maintaining MAP of approximately 65 mmHg or higher.
- The patent covers clinical use, not the basic angiotensin II molecule or a specific formulation.
- Dependent claims add specific dose endpoints from approximately 15 ng/kg/min down to 0.25 ng/kg/min.
- Claims cover low blood pressure broadly and separately identify shock, distributive shock, cardiogenic shock, sepsis and acute kidney injury.
- The patent is closely aligned with the FDA-approved Giapreza dosing protocol.
- The core family has a base statutory expiration of approximately May 24, 2034.
- Generic risk is centered on ANDA Paragraph IV challenges, section viii label carve-outs, obviousness and inducement disputes.
- Biosimilar risk is limited because angiotensin II is a synthetic peptide rather than a conventional biologic.
- Formulation and manufacturing barriers must be analyzed separately from this method-of-use patent.
- The commercial strength of the patent is highest when a competing label expressly reproduces the Giapreza initiation and down-titration regimen.
FAQs
Does Patent 10,493,124 cover all angiotensin II products?
No. It covers specified methods of administering angiotensin II. A product used under a materially different dosing protocol may fall outside the claims, although other patents or regulatory protections may apply.
Is intravenous administration required in every claim?
No. Intravenous administration is expressly required in dependent claims 8 and 23. It is not a limitation of the broadest independent claims.
Does the patent require treatment of septic shock?
No. Sepsis and shock appear in dependent claims. The broader claims address human patients with low blood pressure or patients requiring a MAP of at least approximately 65 mmHg.
Can a generic omit the patented angiotensin II use from its label?
Potentially, through a section viii strategy, but the success of that approach depends on the final label and whether it still encourages the claimed 20 ng/kg/min initiation and downward titration regimen.
Is Patent 10,493,124 a composition-of-matter patent?
No. It is a method-of-treatment patent. It does not claim a new angiotensin II molecule, a novel peptide sequence or a specific finished formulation.
References
- United States Patent and Trademark Office. (2019). U.S. Patent No. 10,493,124, Methods of treating hypotension with angiotensin II.
- U.S. Food and Drug Administration. (2017). Giapreza (angiotensin II) prescribing information.
- Khanna, A., English, S. W., Wang, X. S., Ham, K., Tumlin, J., Szerlip, H., Busse, L. W., Altaweel, L., Albertson, T. E., Mackey, C., et al. (2017). Angiotensin II for the treatment of vasodilatory shock. New England Journal of Medicine, 377(5), 419-430.
- U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
