United States Patent 10,335,451: Angiotensin II Dosing Claims, Exclusivity, Litigation Risk, and Patent Landscape

US Patent 10,335,451 protects dosing protocols for angiotensin II, marketed as Giapreza, in human patients with septic shock and hypotension. Its core commercial coverage is narrow but directly aligned with the FDA-approved starting dose: 20 ng/kg/min, with titration toward 30 or 40 ng/kg/min. The patent does not claim angiotensin II as a molecule, a formulation, a manufacturing process, or a broad treatment of hypotension. Its principal value is method-of-use coverage that can create infringement risk for a generic or 505(b)(2) product whose labeling recommends the same septic-shock dosing regimen.

The patent’s critical limitations are the patient population, disease state, initial dose or dose range, and titration protocol. A competing product could avoid literal infringement by using materially different dosing instructions, although inducement and label-based infringement risks would remain if the product is marketed for the patented regimen.

What does US Patent 10,335,451 claim?

US 10,335,451 has two independent claims.

Claim	Independent claim scope	Commercial significance
1	Treating hypotension in a human with septic shock by administering angiotensin II at an initial rate of about 20 ng/kg/min	Covers the FDA-aligned starting regimen
24	Treating hypotension in a human with septic shock by administering angiotensin II at about 20 to about 40 ng/kg/min	Broader as to the initial or administered rate, but still limited to septic shock and hypotension

Claims 2 through 23 depend from claim 1 or its vasopressor subgroup. Claims 25 and 26 depend from claim 24 and specify administration at approximately 30 or 40 ng/kg/min.

The patent therefore has two practical claim groups:

A 20 ng/kg/min starting-dose regimen with optional titration, treatment duration, blood-pressure target, and concomitant vasopressor limitations.
A dose-range regimen covering approximately 20 to 40 ng/kg/min.

The claims require all of the following core elements:

A human subject.
Hypotension.
Septic shock.
Administration of angiotensin II.
A specified dose or dose range.
For the dependent claims, additional titration, duration, mean arterial pressure, or vasopressor limitations.

A method that omits one required limitation may avoid literal infringement, subject to the doctrine of equivalents and inducement theories.

How broad is the scope of US 10,335,451?

The broadest enforceable practical scope is claim 24. It covers administration of angiotensin II at a rate from approximately 20 to approximately 40 ng/kg/min to a human patient with septic shock and hypotension.

Claim 1 is more operationally specific. It requires an initial rate of approximately 20 ng/kg/min. This limitation tracks Giapreza’s labeled starting dose and may make the claim commercially important despite its narrower wording.

The claims do not expressly require:

Intravenous administration.
A particular angiotensin II salt or counterion.
A particular formulation.
A specific concentration.
A particular infusion device.
Use of norepinephrine as a background vasopressor.
Failure of other vasopressors.
A specific severity of septic shock.
A specific cause of hypotension.
A specific hospital setting.
A specific duration, except in dependent claims.
A particular source or manufacturing method for angiotensin II.

The absence of a route limitation may be significant. If the specification and prosecution history support the ordinary clinical meaning of administration in this context, intravenous infusion would likely be the commercially relevant route. The claim language itself, however, does not expressly limit the method to intravenous delivery.

What dosing regimens are protected?

The patent covers the following principal dosing scenarios:

Dosing feature	Claims	Scope
Initial rate of about 20 ng/kg/min	1, 11	Core starting-dose claim
Titration to about 30 ng/kg/min	2, 15, 25	Expressly covered
Titration to about 40 ng/kg/min	3, 16, 26	Expressly covered
One or more increases of about 10 ng/kg/min	4, 17	Incremental titration
Administration at 20-40 ng/kg/min	24	Broad independent dose-range claim
Administration at about 30 ng/kg/min	25	Narrow dose-specific claim
Administration at about 40 ng/kg/min	26	Narrow dose-specific claim

The word “about” introduces a claim-construction issue. It does not create an unlimited numerical range. The legally relevant range would depend on the specification, prosecution history, technical context, and evidence regarding measurement precision and clinical dosing practice.

A regimen beginning at 20 ng/kg/min and increasing by 10 ng/kg/min could implicate claims 1, 2, and 4. A regimen beginning at 30 ng/kg/min could fall within claim 24 and claim 25 but would not necessarily satisfy claim 1, which requires an initial rate of about 20 ng/kg/min.

A regimen beginning below 20 ng/kg/min and later increasing to 20 or 40 ng/kg/min could avoid claim 1 but might still implicate claim 24 if the administered rate falls within the claimed range and all disease-state limitations are met.

What treatment duration and blood-pressure targets are protected?

Claims 5, 6, and 18 through 23 add treatment-duration and mean arterial pressure limitations.

Limitation	Claims	Stated range
Angiotensin II administration	5, 18	About 0.25 to 120 hours
Narrower administration period	6, 19	About 1 to 7 hours
Titration to mean arterial pressure	7, 8, 20, 21	About 65 mmHg or 65 mmHg
Maintenance of mean arterial pressure	9, 10, 22, 23	About 0.25 to 120 hours, or about 1 to 7 hours

Claims 7 and 8, and claims 20 and 21, are materially redundant in practical scope. Claim 7 uses “about 65 mmHg,” while claim 8 recites “65 mmHg” without “about.” The distinction could matter if a court treats the claims as having different numerical boundaries, but the clinical measurement of mean arterial pressure makes the precise distinction difficult to apply without prosecution-history evidence.

The duration claims are dependent claims. They do not limit the independent claims unless the patent owner elects to assert the dependent claims. A product label that recommends short-term use within the one-to-seven-hour range could meet these limitations, but the patent owner would still need to prove the other elements.

Does concomitant vasopressor use expand infringement risk?

Claims 11 through 23 cover patients receiving angiotensin II while undergoing treatment with one or more other vasopressors.

The listed vasopressors are:

Norepinephrine.
Vasopressin.
Epinephrine.
Dopamine.

Claims 13 and 14 narrow this group to norepinephrine and vasopressin, respectively.

These claims are commercially relevant because angiotensin II is generally used in critically ill patients already receiving vasopressor therapy. A label recommending angiotensin II as an adjunct to norepinephrine or vasopressin could create a direct correspondence with the dependent claims.

The claims do not require that the other vasopressor be administered simultaneously through the same line or at a specific dose. “Undergoing treatment” is potentially broad and could encompass sequential or concurrent therapy, depending on the specification and claim construction.

A generic label that states that angiotensin II may be used in patients receiving norepinephrine could face induced-infringement exposure even if the label also includes non-infringing uses. The analysis would turn on whether the patented use is an intended and encouraged use, rather than merely a foreseeable use.

What is the FDA regulatory status of Giapreza?

Giapreza is an FDA-approved angiotensin II product for increasing blood pressure in adults with septic or other distributive shock. The FDA approved Giapreza under NDA 209360 in December 2017. The approved regimen begins at 20 ng/kg/min and is titrated according to blood-pressure response, with a maximum initial rate commonly identified as 40 ng/kg/min in the prescribing information.[1]

The approval is closely aligned with the dosing limitations in US 10,335,451. That alignment increases the patent’s relevance to:

ANDA applicants seeking approval for an equivalent product.
505(b)(2) applicants seeking a different formulation or presentation.
Labeling decisions concerning septic shock.
Product-specific instructions for titration and concomitant vasopressor use.

FDA approval does not itself establish patent validity or infringement. It does, however, make the claimed regimen more likely to appear in a competing product’s proposed labeling.

What patents protect Giapreza and angiotensin II?

The Giapreza patent estate includes at least two major categories:

Composition, formulation, or product-related patents.
Dosing and method-of-use patents, including US 10,335,451.

Patent	General subject matter	Relevance
US 9,283,196	Angiotensin II composition and use technology	Product and formulation-related protection
US 10,335,451	Dosing methods for septic shock and hypotension	Method-of-use protection
Later or related family members	Potential continuation, formulation, or method claims	Must be reviewed for current Orange Book and family status

US 10,335,451 should not be treated as a composition patent. It does not prevent another company from manufacturing angiotensin II merely because the compound is the same. The risk arises when the product is promoted, labeled, or used according to the claimed regimen.

A complete freedom-to-operate review should separate:

Active ingredient identity.
Peptide synthesis and purification.
Formulation and stability.
Container closure and packaging.
Infusion concentration.
Clinical dosing.
FDA labeling.
Distribution and commercialization.

The method patent is strongest against a product that reproduces Giapreza’s septic-shock dosing instructions. It is less relevant to a product used for a different indication, a different patient population, or a materially different regimen.

When does US 10,335,451 expire?

US 10,335,451 issued on June 25, 2019. Public patent records identify a February 2015 priority date for the underlying application family. On that basis, the nominal US patent term is expected to run into February 2035, subject to any terminal disclaimer, patent-term adjustment, patent-term extension, or other USPTO term calculation.

Event	Date
Earliest identified priority period	February 2015
Patent issuance	June 25, 2019
Expected nominal expiration window	February 2035
FDA approval of Giapreza	December 2017

The exact expiration date should be taken from the USPTO patent-term calculation and the current Orange Book entry if the patent is listed for NDA 209360. Patent expiration and regulatory exclusivity are separate concepts. A patent may remain enforceable after FDA exclusivity has ended.

What is the Orange Book status of US 10,335,451?

US 10,335,451 is a method-of-use patent associated with the clinical dosing and use of angiotensin II for hypotension and septic shock. The FDA Orange Book is the operative source for determining whether the patent is currently listed against Giapreza, the use code assigned to the listing, and the listed expiration date.[2]

An Orange Book listing is important because it can require an ANDA applicant to submit a patent certification. Depending on the certification and the branded sponsor’s response, a timely Paragraph IV notice may trigger patent litigation and a potential 30-month stay of approval under the Hatch-Waxman framework.

The practical impact depends on the listing’s use code. A narrow use code can limit the patent’s ability to block approval for non-covered uses. A broad or ambiguously drafted use code may produce a larger dispute over the scope of a proposed label.

What Paragraph IV challenges and generic entry risks exist?

A generic applicant seeking approval for angiotensin II could face several regulatory pathways.

ANDA pathway

An ANDA applicant would generally need to address listed patents for the reference product. A Paragraph IV certification would assert that a listed patent is invalid, unenforceable, or not infringed. The sponsor could sue within the statutory period, potentially delaying approval for up to 30 months.

US 10,335,451 presents three principal Paragraph IV arguments:

The proposed label does not include the patented septic-shock use.
The proposed dosing instructions do not require an initial rate of about 20 ng/kg/min or a 20-40 ng/kg/min regimen.
The claims are invalid for lack of novelty, obviousness, inadequate written description, indefiniteness, or another statutory defect.

The strongest non-infringement position would ordinarily involve a label that omits the patented use or does not instruct the claimed dosing protocol. That strategy can be constrained by FDA labeling requirements if the agency requires labeling that mirrors the reference product’s clinically important dosing information.

505(b)(2) pathway

A 505(b)(2) applicant could pursue a different formulation, concentration, route, presentation, or dosing design while relying partly on FDA findings for Giapreza. The applicant would still need to address applicable listed patents and could face litigation if its proposed label overlaps the patented regimen.

Generic launch scenarios

Scenario	Patent risk
Product label reproduces 20 ng/kg/min starting dose and 40 ng/kg/min ceiling	High risk of claim 1 or 24 overlap
Label includes titration by 10 ng/kg/min	Higher risk under claims 4, 17, and related claims
Label expressly recommends use with norepinephrine	Higher risk under claims 11-14
Label excludes septic shock	Lower risk, subject to actual promotion and use
Starting dose materially below 20 ng/kg/min	Potentially avoids claim 1, but later dosing may implicate claim 24
Product is used only outside hypotension or septic shock	Lower risk under the asserted claims
Different formulation but same patented label	Formulation change alone may not avoid method claims

No biosimilar pathway is the primary issue. Angiotensin II is a peptide drug, not a conventional monoclonal antibody or other biologic for which a 351(k) biosimilar application would ordinarily be expected. The likely competitive routes are an ANDA or a 505(b)(2) application.

Which companies are challenging Giapreza patents?

The principal commercial rights holder associated with Giapreza has been La Jolla Pharmaceutical Company, later acquired by Vifor Pharma. Vifor became part of the CSL group through CSL’s acquisition of Vifor Pharma.[3]

Publicly available materials cited here do not establish a completed Paragraph IV challenge, final judgment, or settlement specifically concerning US 10,335,451. The absence of a cited case should not be treated as evidence that no confidential certification, pre-litigation notice, or later-filed action exists.

The competitive threat is more likely to arise from an ANDA or 505(b)(2) entrant seeking to avoid the method claims through labeling design than from a biosimilar developer.

How strong is the patent estate for Giapreza?

US 10,335,451 has meaningful commercial strength but limited technological breadth.

Strengths

The core 20 ng/kg/min starting dose corresponds closely to FDA-approved use.
The 20-40 ng/kg/min range in claim 24 is broader than the fixed starting-dose language in claim 1.
The septic-shock and hypotension limitations map onto the principal clinical population.
Dependent claims cover common adjunctive use with norepinephrine and vasopressin.
Label-based infringement may be easier to establish than infringement based solely on physician behavior.

Weaknesses

The patent does not cover the angiotensin II molecule itself.
The claims are limited to a defined disease state and patient population.
Dose-specific claims may be vulnerable to design-around through altered starting doses or titration instructions.
“About” limitations may generate numerical claim-construction disputes.
The patent does not cover all uses of angiotensin II or all hypotension indications.
Clinical use claims can be difficult to enforce against individual hospitals or physicians.
A carefully drafted non-infringing label may reduce induced-infringement exposure.

The estate is strongest as a regulatory and commercialization barrier. It is weaker as a standalone manufacturing barrier.

What manufacturing and geographic barriers remain?

US 10,335,451 has no direct claim to:

Peptide synthesis.
Purification.
Folding or structural control.
Formulation stability.
Sterility.
Vial configuration.
Manufacturing equipment.
Supply-chain controls.

A competitor could therefore develop an angiotensin II product without practicing the method claims if it uses a non-covered indication or dosing protocol. Separate patents may protect formulation, stability, purity, or manufacturing technology.

Geographic protection is territorial. US 10,335,451 applies to conduct constituting infringement in the United States, including US commercial use and potentially importation of products made abroad when the statutory requirements are met. Foreign equivalents must be analyzed separately. A US patent does not by itself block commercialization in Europe, Canada, Japan, or other markets.

What litigation and settlement issues matter?

The principal litigation issues would likely include:

Whether the accused label instructs treatment of hypotension in septic shock.
Whether the labeled dose is “about” 20 ng/kg/min or within about 20-40 ng/kg/min.
Whether titration instructions meet the claimed 10 ng/kg/min increments.
Whether background vasopressor language satisfies the dependent claims.
Whether the patent is invalid for obviousness in view of prior clinical literature and the ATHOS-3 development program.
Whether the claims adequately describe and enable the full numerical ranges.
Whether the use code properly corresponds to the approved indication.

A settlement could allow an authorized generic, a delayed launch, a license, or a label carve-out. No specific settlement agreement involving US 10,335,451 is established by the sources cited in this analysis.

Key Takeaways

US 10,335,451 is a dosing and method-of-use patent, not a composition or manufacturing patent.
Its core coverage is angiotensin II for hypotension in septic shock at about 20 ng/kg/min or within about 20-40 ng/kg/min.
The patent closely tracks Giapreza’s FDA-approved dosing protocol.
Claims covering titration to 30 or 40 ng/kg/min and concurrent norepinephrine or vasopressin use increase label-overlap risk.
A generic or 505(b)(2) applicant is more likely to pursue a label carve-out or dosing design-around than a biosimilar strategy.
The expected patent-term horizon extends into February 2035, subject to the official USPTO and Orange Book term records.
The patent does not prevent independent manufacture of angiotensin II outside the claimed treatment method.
The principal commercial risk is induced infringement based on labeling that instructs the patented septic-shock regimen.

FAQs

Can a generic angiotensin II product avoid US 10,335,451 by using a lower starting dose?

Potentially. A starting dose materially below about 20 ng/kg/min may avoid claim 1, but subsequent administration within the 20-40 ng/kg/min range could still raise issues under claim 24 if the septic-shock and hypotension limitations are met.

Does US 10,335,451 cover angiotensin II use in cardiogenic shock?

The supplied claims require septic shock. Use solely for cardiogenic shock would not satisfy that express disease-state limitation, although mixed shock states could present a claim-construction issue.

Does changing the vial concentration avoid the patent?

Not necessarily. The claims recite dosing rate in ng/kg/min, not vial concentration. A different concentration may avoid separate formulation claims but would not by itself avoid the method claims.

Is a hospital administering Giapreza necessarily an infringement defendant?

The claims are treatment-method claims, so administration that meets every claim limitation can constitute direct infringement. Commercial enforcement is more commonly focused on manufacturers, distributors, induced infringement, and regulatory approval disputes than on individual clinical institutions.

Can a 505(b)(2) applicant rely on a different infusion device to avoid the patent?

Usually not by itself. The claimed limitations focus on the patient, disease state, angiotensin II administration, dose, titration, and treatment objective. A different pump or delivery device would not necessarily change those elements.

References

U.S. Food and Drug Administration. (2017). Giapreza (angiotensin II) injection, prescribing information.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
CSL Limited. (2022). Completion of acquisition of Vifor Pharma.
U.S. Patent No. 10,335,451. (2019). Methods of treating hypotension. United States Patent and Trademark Office.
Khanna, A., English, S. W., Wang, X. S., Ham, K., Tumlin, J., Szerlip, H., Busse, L. W., Altaweel, L., Albertson, T. E., Mackey, C., Wang, C., Bhanji, R. A., DiBardino, D., Shapiro, N. I., & ATHOS-3 Investigators. (2017). Angiotensin II for the treatment of vasodilatory shock. New England Journal of Medicine, 377(5), 419-430.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
La Jolla Pharma	GIAPREZA	angiotensin ii acetate	SOLUTION;INTRAVENOUS	209360-003	Dec 23, 2021		RX	Yes	Yes	10,335,451	⤷ Start Trial				TREATING HYPOTENSION WITH ABOUT 20 NG/KG/MIN TO ABOUT 40 NG/KG/MIN ANGIOTENSIN II IN A HUMAN SUBJECT HAVING SEPTIC SHOCK	⤷ Start Trial
La Jolla Pharma	GIAPREZA	angiotensin ii acetate	SOLUTION;INTRAVENOUS	209360-001	Dec 21, 2017	AP	RX	Yes	Yes	10,335,451	⤷ Start Trial				TREATING HYPOTENSION WITH ABOUT 20 NG/KG/MIN TO ABOUT 40 NG/KG/MIN ANGIOTENSIN II IN A HUMAN SUBJECT HAVING SEPTIC SHOCK	⤷ Start Trial
La Jolla Pharma	GIAPREZA	angiotensin ii acetate	SOLUTION;INTRAVENOUS	209360-002	Dec 21, 2017		DISCN	Yes	No	10,335,451	⤷ Start Trial				TREATING HYPOTENSION WITH ABOUT 20 NG/KG/MIN TO ABOUT 40 NG/KG/MIN ANGIOTENSIN II IN A HUMAN SUBJECT HAVING SEPTIC SHOCK	⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Details for Patent: 10,335,451

Which drugs does patent 10,335,451 protect, and when does it expire?

Summary for Patent: 10,335,451