US Patent 10,322,139: Scope, Claims, Expiration, Orange Book Status, and Generic Entry Risk

US Patent 10,322,139 protects a narrowly defined injectable allopregnanolone formulation. Its core limitation is an aqueous composition containing approximately 5 mg/mL allopregnanolone, approximately 250 mg/mL sulfobutyl ether beta-cyclodextrin, and citrate buffer at pH 5 to 9. The patent is directed to formulation composition, not to allopregnanolone generally, postpartum depression treatment, or every injectable dosage form.

The claims most directly read on Zulresso, the FDA-approved intravenous brexanolone product. A competing product would face infringement risk if it uses the claimed concentration range, cyclodextrin solubilizer, citrate buffer, and pH range. Risk decreases materially if the formulation changes the solubilizer, buffer system, concentration profile, or pH outside the construed claim scope.

What does US Patent 10,322,139 cover?

The patent covers an aqueous pharmaceutical composition for parenteral administration containing three required formulation elements:

Required element	Independent claim 1
Allopregnanolone	About 5 mg/mL
Sulfobutyl ether beta-cyclodextrin	About 250 mg/mL
Buffer	Citrate buffer
pH	5 to 9
Administration	Parenteral

Claim 1 is the commercially important claim. It does not require intravenous administration, an antioxidant, pH 6, a glass vial, or any particular disease indication.

Claims 2 through 6 add narrower alternatives:

Claim	Added limitation	Commercial significance
2	Intravenous administration	Directly aligned with Zulresso
3	Antioxidant	Captures formulations containing a qualifying antioxidant
4	pH of about 6	Narrows the broad pH 5 to 9 range
5	Subcutaneous administration	Extends coverage beyond the approved IV route
6	Glass vial container	Adds a packaging limitation

The patent therefore has one broad composition claim and five dependent claims that create narrower fallback positions.

How should the key claim terms be interpreted?

“About 5 mg/mL” allopregnanolone

“About” creates the principal claim-construction issue. The claim does not define a numerical tolerance. A court would likely assess the specification, prosecution history, examples, analytical variability, and technical meaning of “about” to a skilled formulation scientist.

A formulation containing exactly 5 mg/mL is within the claim. A formulation at a nearby concentration may also infringe, depending on the evidence establishing the permitted range. The term is not an unlimited authorization to vary concentration.

A generic developer should not assume that a modest concentration change automatically avoids claim 1. A non-infringing design would be stronger if it used a materially different concentration supported by formulation-development data and a different overall composition strategy.

“About 250 mg/mL” sulfobutyl ether beta-cyclodextrin

Sulfobutyl ether beta-cyclodextrin, commonly abbreviated SBECD, is the principal solubilizing excipient in the claim. The claim is narrower than a claim covering any cyclodextrin or any solubilizer.

Potential design-around categories include:

another SBECD concentration outside the court-defined “about” range;
a different cyclodextrin derivative;
a non-cyclodextrin solubilizer;
a mixed-solubilizer system;
a formulation that does not use SBECD.

A different cyclodextrin may avoid literal infringement, but doctrine-of-equivalents exposure would depend on whether the substitute performs substantially the same function in substantially the same way with substantially the same result. The prosecution record would be important in assessing that risk.

“Citrate buffer”

Citrate is a required element of claim 1. A phosphate, acetate, succinate, histidine, or other buffer system may provide a potential design-around. The analysis would turn on whether citrate is present as a meaningful buffering component or only as an incidental excipient.

The claim does not specify citrate concentration, ionic strength, osmolality, or the precise citrate species. Those parameters may affect infringement and product comparability but are not express limitations of claim 1.

“pH from 5 to 9”

The pH range is broad. A formulation at pH 6 is covered by claim 1 and separately addressed by claim 4. A pH below 5 or above 9 would fall outside the literal pH limitation, subject to measurement conditions and equivalents analysis.

The pH limitation applies to the composition. A developer would need to consider whether pH is measured before dilution, after dilution, at release, or under another condition specified in the patent or regulatory documentation.

Which claims are most relevant to Zulresso?

Claim 1 is the primary product claim. Claim 2 is the most product-specific dependent claim because Zulresso is administered intravenously. Claim 4 may also be relevant if the commercial formulation has a pH of approximately 6.

The current FDA-approved Zulresso formulation is an aqueous intravenous brexanolone solution containing allopregnanolone at 5 mg/mL and SBECD at 250 mg/mL. The product is supplied in a single-dose vial and is diluted before administration according to the prescribing information. These characteristics correspond closely to the claim limitations described in Patent 10,322,139 and the FDA-approved labeling for Zulresso. (U.S. Food and Drug Administration, 2019a, 2019b)

The patent does not require the product to be marketed under the name brexanolone. The chemical identity, rather than the brand name, controls the composition analysis.

What formulations are protected by the dependent claims?

Intravenous formulations under claim 2

Claim 2 covers the claim 1 composition when formulated for IV administration. It does not require a particular infusion rate, infusion bag, dilution solution, treatment duration, or pump.

A product using the same formulation but administered through a different parenteral route would not meet claim 2, although it could still infringe claim 1.

Antioxidant-containing formulations under claim 3

Claim 3 covers a claim 1 composition that includes an antioxidant. The claim does not identify a specific antioxidant in the text provided.

The dependent claim may capture a commercial formulation containing an antioxidant, but its practical value depends on the patent specification and prosecution history. If the claim lacks a specific antioxidant limitation, the scope may be broader than the development examples, subject to written-description and enablement constraints.

pH-about-6 formulations under claim 4

Claim 4 is a narrower species within claim 1. It may be useful against a formulation intentionally centered near pH 6. The claim gives the patent holder a more precise fallback position if the broader pH 5-to-9 limitation is challenged.

Subcutaneous formulations under claim 5

Claim 5 reaches subcutaneous products using the claim 1 composition. It is commercially broader than the current IV Zulresso product because it could cover a different delivery route.

The claim does not require a particular injection volume, device, depot system, or dosing schedule. It is still limited by the same allopregnanolone, SBECD, citrate, and pH requirements inherited from claim 1.

Glass-vial presentations under claim 6

Claim 6 requires the composition to be contained within a glass vial. This is a packaging limitation. It does not cover every container, and it does not require the vial to have a specific glass composition, fill volume, stopper, or seal unless those limitations appear elsewhere in the patent.

A product in a polymer container could avoid claim 6 while remaining potentially within claims 1 through 5.

When does US Patent 10,322,139 lose exclusivity?

The patent issued on June 18, 2019. The ordinary US patent term generally runs 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers, and other statutory adjustments. The patent’s practical expiration should be confirmed from the USPTO Patent Center record and the Orange Book listing before reliance in a transaction or litigation position. (United States Patent and Trademark Office, 2024)

The FDA approval date for Zulresso was March 19, 2019. Zulresso received five-year new chemical entity exclusivity, which blocked submission of an ANDA or 505(b)(2) application relying on the drug’s approval during the applicable exclusivity period. That regulatory exclusivity was separate from the patent and did not eliminate patent protection after the NCE period expired. (U.S. Food and Drug Administration, 2019a)

Event	Date
Zulresso FDA approval	March 19, 2019
Patent 10,322,139 grant	June 18, 2019
Five-year NCE exclusivity	Generally through March 19, 2024
Patent expiration	Determined by the patent’s effective filing date and PTA

The patent remains the more important barrier after expiration of NCE exclusivity if it is listed for the approved product and remains enforceable.

What is the Orange Book status of Patent 10,322,139?

Patent 10,322,139 is associated with the formulation of Zulresso and is relevant to Orange Book analysis. The controlling source is the FDA’s current Approved Drug Products with Therapeutic Equivalence Evaluations database, including the patent and exclusivity records for brexanolone injection. (U.S. Food and Drug Administration, 2024)

Orange Book listing has several consequences:

An ANDA applicant must address each listed patent through a Paragraph III certification, Paragraph IV certification, or another permitted certification.
A Paragraph IV notice can trigger patent litigation.
A timely patent infringement action can produce a 30-month stay of final ANDA approval under the Hatch-Waxman framework.
The listed patent may block approval even where the proposed generic has a different label, unless the applicant uses a permissible section viii carve-out or otherwise avoids the patent claims.

Orange Book status must be evaluated against the current FDA database, because listings, delistings, patent-term updates, and regulatory exclusivity records can change.

How strong is the patent estate for allopregnanolone injection?

Patent 10,322,139 is strong against a formulation that closely copies the approved product. Its strength comes from the combination of:

the same active ingredient;
a defined 5 mg/mL concentration;
a high SBECD concentration;
citrate buffering;
broad pH coverage; and
express IV coverage in claim 2.

Its weaknesses are equally clear. The claims do not broadly cover:

all allopregnanolone compositions;
all brexanolone products;
all methods of treating postpartum depression;
all IV formulations;
all cyclodextrin-based formulations;
manufacturing processes;
infusion devices;
dosing regimens; or
analytical or stability methods.

The estate is therefore formulation-specific rather than platform-wide.

What generic entry risks exist?

Paragraph IV challenges

A generic applicant could challenge the patent through a Paragraph IV certification, asserting that the patent is invalid, unenforceable, or not infringed. The likely technical positions would include:

the proposed concentration is outside the meaning of “about”;
the product does not contain approximately 250 mg/mL SBECD;
the formulation uses a non-citrate buffer;
the pH is outside 5 to 9;
the proposed product is not formulated for parenteral administration;
the patent lacks written description or enablement for the full claim scope;
the claims are obvious over prior injectable steroid and cyclodextrin formulations.

The patent holder would likely respond that the proposed product reproduces the claimed formulation architecture and that the numerical ranges are supported by the specification and examples.

Section viii carve-outs

A section viii statement could be relevant only if the listed patent claims are directed to a use that can be omitted from the generic label. The claims provided are composition claims, not treatment-method claims. That makes a use carve-out less likely to remove the principal infringement issue.

Reformulation risk

A generic or follow-on developer could attempt to avoid infringement by changing the cyclodextrin, buffer, concentration, pH, or container. That approach creates development and regulatory risks:

altered solubility;
precipitation;
stability loss;
particulate formation;
different dilution behavior;
different container-closure interactions;
new toxicology questions;
difficulty demonstrating pharmaceutical equivalence.

The patent creates its greatest commercial leverage where the FDA-approved formulation is also the most technically practical formulation.

Does biosimilar law apply to Zulresso?

No. Brexanolone is a chemically synthesized small molecule, not a biological product. Biosimilar approval under section 351(k) of the Public Health Service Act is not the relevant pathway.

Competitive products would generally proceed through an ANDA under section 505(j) if they can establish pharmaceutical equivalence and meet the applicable requirements. A materially different formulation may require a 505(b)(2) application rather than a standard ANDA.

What manufacturing and intellectual-property barriers remain?

The patent claims do not expressly cover manufacturing methods, but commercial entry still depends on reproducing a technically demanding aqueous formulation. Relevant barriers include:

maintaining allopregnanolone solubility at the claimed concentration;
controlling SBECD quality and impurity profile;
controlling pH and buffer capacity;
preventing degradation during storage;
demonstrating vial compatibility;
validating sterilization and aseptic processing;
matching extractables and leachables;
establishing stability after dilution.

These issues can limit practical design-around options even when a formulation is outside the literal wording of the claims.

Which companies are challenging the patent?

No confirmed Paragraph IV challenger or reported patent settlement is established by the claim text alone. Public databases should be checked for ANDA litigation, district-court complaints, declaratory-judgment actions, and FDA patent-listing updates before assigning a challenger, settlement date, or launch probability.

No confirmed license covering Patent 10,322,139 is established by the claim information provided. Sage Therapeutics is the principal commercial company associated with Zulresso. Licensing and collaboration agreements involving other Sage neuropsychiatric assets should not be treated as licenses to this patent without express patent-rights language.

How does the patent compare with method-of-use patents?

Patent 10,322,139 is materially different from a postpartum-depression method patent.

Patent category	Typical protected subject matter	Relevance of 10,322,139
Composition patent	Ingredients, concentrations, pH, formulation	Directly relevant
Method-of-use patent	Treating a disease or patient population	Not present in the supplied claims
Dosage-regimen patent	Dose, infusion schedule, treatment duration	Not present
Manufacturing patent	Preparation, sterilization, purification	Not present
Device patent	Infusion or delivery equipment	Not present
Packaging patent	Container or closure	Limited coverage through claim 6

A generic could avoid a method-of-use patent by carving out a protected indication, but composition claims generally require a formulation change or a validity/non-infringement position.

What is the commercial exposure?

Zulresso is an approved therapy for postpartum depression and is the product most directly exposed to this patent. The patent’s commercial value depends on:

whether it remains listed in the Orange Book;
its confirmed expiration date;
the absence or presence of later patents;
the number of ANDA or 505(b)(2) applicants;
the feasibility of non-infringing reformulation;
payer and provider adoption;
annual product sales before generic entry.

The supplied information does not establish a verified current revenue figure, market-share estimate, or active challenger count. Those metrics should not be inferred from the patent claims.

Key Takeaways

US Patent 10,322,139 is a formulation patent for aqueous parenteral allopregnanolone.
Claim 1 requires approximately 5 mg/mL allopregnanolone, approximately 250 mg/mL SBECD, citrate buffer, and pH 5 to 9.
Claim 2 directly targets IV formulations, making it particularly relevant to Zulresso.
Claim 4 narrows the formulation to approximately pH 6.
Claim 5 extends the estate to subcutaneous formulations.
Claim 6 adds glass-vial packaging protection.
The patent does not broadly cover allopregnanolone, all brexanolone uses, dosing regimens, manufacturing methods, or delivery devices.
The main generic strategies are Paragraph IV litigation, a non-infringing reformulation, or a 505(b)(2) product with materially different formulation characteristics.
Biosimilar law does not apply because brexanolone is a small-molecule drug.
Orange Book status, patent-term adjustment, current expiration, litigation, and settlement records require verification against current USPTO, FDA, and court databases.

FAQs

Is Patent 10,322,139 limited to Zulresso?

No. The claims cover any product meeting the specified formulation limitations, regardless of brand name or indication. Zulresso is the principal commercial product that appears to correspond to the claimed formulation.

Can a generic use a different cyclodextrin?

Potentially. A formulation that replaces SBECD with another solubilizer may avoid literal infringement, but equivalence, regulatory comparability, stability, and manufacturability would remain separate issues.

Does a product at pH 4.9 avoid the patent?

It may avoid the literal pH 5-to-9 limitation if the measured composition is genuinely below pH 5 under the legally relevant testing conditions. The “about” language applies to the concentrations, not expressly to the pH range as written.

Does using a polymer vial avoid all claims?

No. It may avoid claim 6, which requires a glass vial. Claims 1 through 5 do not require glass packaging and could still apply.

Is a subcutaneous allopregnanolone product automatically outside the patent?

No. Claim 5 expressly covers a subcutaneous formulation if it also meets the inherited requirements for allopregnanolone concentration, SBECD concentration, citrate buffer, and pH.

References

U.S. Food and Drug Administration. (2019a). Zulresso (brexanolone) injection prescribing information. FDA.
U.S. Food and Drug Administration. (2019b). FDA approves first drug for postpartum depression. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
United States Patent and Trademark Office. (2019). U.S. Patent No. 10,322,139, pharmaceutical composition comprising allopregnanolone. USPTO.
United States Patent and Trademark Office. (2024). Patent term adjustment and patent term information. USPTO.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Sage Therap Supernus	ZULRESSO	brexanolone	SOLUTION;INTRAVENOUS	211371-001	Jun 17, 2019		DISCN	Yes	No	10,322,139	⤷ Start Trial	Y				⤷ 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

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2013212287	⤷ Start Trial
Australia	2018201307	⤷ Start Trial
Australia	2020217402	⤷ Start Trial
Brazil	112014018110	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 10,322,139

Which drugs does patent 10,322,139 protect, and when does it expire?

Summary for Patent: 10,322,139