Details for Patent: 10,166,184

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Which drugs does patent 10,166,184 protect, and when does it expire?

Patent 10,166,184 protects VYXEOS and is included in one NDA.

Protection for VYXEOS has been extended six months for pediatric studies, as indicated by the *PED designation in the table below.

This patent has forty-five patent family members in twenty-two countries.

Summary for Patent: 10,166,184

Title:	Method of lyophilizing liposomes
Abstract:	Lyophilized liposomal formulations with two or more encapsulated drugs are disclosed. These formulations display superior drug retention profiles and also maintain size distribution following lyophilization and reconstitution.
Inventor(s):	Donna Cabral-Lilly, Lawrence Mayer, Paul Tardi, David Watkins, Yi Zeng
Assignee:	Jazz Pharmaceuticals Therapeutics Inc
Application Number:	US15/891,170
Patent Claim Types: see list of patent claims	Use; Composition; Dosage form;

US Patent 10,166,184: Scope, Claims, Expiration, and Liposomal Drug Patent Landscape

US Patent 10,166,184 protects a lyophilized, gel-phase liposomal platform designed to preserve liposome size, drug retention, and drug ratio after storage and reconstitution. Its strongest commercial relevance is the fixed-ratio daunorubicin/cytarabine product Vyxeos, although the independent claims are drafted broadly enough to cover other multi-agent liposomal products, including irinotecan/floxuridine combinations. The patent is assigned to the Celator/Jazz Pharmaceuticals patent estate and has a nominal term extending into 2031, subject to the official patent-term calculation.

What does US Patent 10,166,184 protect?

The patent protects both a product and methods for manufacturing and reconstituting that product.

Claim 1 requires all of the following:

Claim element	Required limitation
Dosage form	Lyophilized gel-phase liposomal composition
Phase behavior	Liposome melting phase temperature, or Tc, of at least 37°C
Cholesterol	No more than 20 mol% cholesterol
Anionic lipid	At least 1 mol% phosphatidylglycerol, phosphatidylinositol, or both
Payload	At least two therapeutic or diagnostic agents
Agent polarity	At least one agent is amphipathic or hydrophilic
Cryoprotection	Cryoprotectant external to the liposomes
Internal cryoprotectant	Less than 50 mM inside the liposomes
Reconstitution	Mean liposome diameter maintained after reconstitution
Drug retention	Agents substantially retained after reconstitution

The claim is cumulative. A competing product that has a high-transition-temperature liposome but lacks the required PG or PI content would not literally satisfy claim 1. The same applies to a product with more than 20 mol% cholesterol, no external cryoprotectant, or at least 50 mM internal cryoprotectant.

The claim is directed to a formulation architecture, not merely to a particular therapeutic indication. It does not require daunorubicin, cytarabine, cancer treatment, or a specific drug ratio.

Which dependent claims narrow the patent scope?

Claims 2 through 13 progressively narrow the formulation and performance requirements.

Lipid composition claims

Claims 2 through 5 concentrate on phospholipid mixtures containing DSPC, DSPG or DSPI, and cholesterol.

Claim	Narrowing feature
2	DSPC, DSPG, and cholesterol
3	50-80 mol% DSPC or DPPC; 1-20 mol% DSPG or DSPI; 1-20 mol% cholesterol
4	DSPC, DSPG, and cholesterol within the claim 3 ranges
5	DSPC:DSPG:cholesterol at a 7:2:1 molar ratio

Claim 5 is the most commercially significant composition claim because the 7:2:1 DSPC:DSPG:cholesterol ratio is associated with the liposomal platform used for Vyxeos.

The claim language permits a broad range of lipid ratios in claims 3 and 4. A formulation does not need to use the exact 7:2:1 ratio to fall within those claims, provided the other concentration ranges and independent-claim limitations are met.

Therapeutic-agent claims

Claim 6 limits the agents to antineoplastic agents. Claim 7 identifies two combination pairs:

1. Daunorubicin and cytarabine.
2. Irinotecan and floxuridine.

The inclusion of both pairs demonstrates that the patent is not limited to the marketed daunorubicin/cytarabine product. It covers a broader formulation concept involving two active agents, at least one of which is amphipathic or hydrophilic.

Stability and performance claims

Claims 8 through 13 impose measurable post-lyophilization performance requirements:

Claim	Performance requirement
8	Fixed drug ratio changes by no more than 25% after reconstitution
9	Mean liposome diameter increases by no more than 25%
10	Mean diameter remains stable for at least six months at 5°C to 25°C
11	At least 75% of each agent is retained after reconstitution
12	Claims 10 and 11 apply together
13	Liposome size distribution changes by no more than 25%

These limitations may create evidentiary issues in litigation. A patent challenger or generic applicant would need reliable analytical data addressing particle size, size distribution, drug retention, and ratio preservation under the claimed conditions. A patent owner would need to establish the testing methods and applicable measurement tolerances.

How do claims 14 through 17 cover manufacturing and use?

Claim 14 covers a method of preparing the lyophilized composition. The method requires lyophilizing an aqueous medium containing liposomes with the same core structural limitations as claim 1 and performing the process in the presence of external protectants.

Claim 15 narrows the method by requiring freezing below the glass-transition temperature, or Tg, of the medium.

Claims 16 and 17 cover reconstitution and administration:

• Claim 16 covers reconstituting the lyophilized composition in a pharmaceutical carrier.
• Claim 17 covers use of the reconstituted composition to administer therapeutic or diagnostic agents to an animal subject.

The manufacturing claims may be relevant to contract manufacturers and generic developers even if the final product is characterized differently. A product manufactured by a process that falls within claim 14 could create process-infringement exposure independently of the composition claims.

What is the relevance of US Patent 10,166,184 to Vyxeos?

Vyxeos is a liposomal injection containing daunorubicin and cytarabine in a fixed 1:5 molar ratio, corresponding to a 1:1.0 weight ratio of daunorubicin to cytarabine in the marketed vial presentation. The FDA approved Vyxeos on August 3, 2017, for adults with newly diagnosed therapy-related acute myeloid leukemia or AML with myelodysplasia-related changes. FDA later expanded the indication to pediatric patients in 2021. [2]

Vyxeos uses a lyophilized liposomal formulation containing DSPC, DSPG, cholesterol, copper gluconate, and sucrose. The product is reconstituted before intravenous administration. These characteristics align closely with the claim architecture of US 10,166,184, particularly claims 2, 4, 5, 7, 8, 9, 11, and 12.

The patent should not be treated as the only patent protecting Vyxeos. Other patents may cover:

• The daunorubicin/cytarabine liposome itself.
• The fixed drug ratio.
• Treatment of AML using the combination.
• Dosing schedules and administration methods.
• Manufacturing and lyophilization processes.
• Additional stability characteristics.

What is the patent expiration date for US 10,166,184?

The patent issued on January 1, 2019. Its patent family traces to Celator’s development of lyophilized liposomal combinations, with a nominal patent term extending to approximately 2031. The controlling expiration date is the USPTO patent-term calculation based on the earliest effective nonprovisional filing date, any terminal disclaimer, and patent-term adjustment.

For commercial planning, US 10,166,184 should be modeled as an active patent through 2031 unless the USPTO record shows a different adjusted expiration date. FDA regulatory exclusivity for Vyxeos is separate from this patent term. Orphan-drug exclusivity for the original adult AML approval expired in 2024, while patent protection can continue beyond regulatory exclusivity.

Patent term extension under 35 U.S.C. § 156 would require a qualifying regulatory application and an approved extension. The patent number alone does not establish that an extension was granted.

What is the Orange Book status of US Patent 10,166,184?

Vyxeos is an FDA-approved small-molecule liposomal drug, so its patents are evaluated through the Orange Book framework rather than the biologic Purple Book framework. The relevant categories include:

Protection category	Relevance to Vyxeos
Approved-product patent	Potentially covers the liposomal product
Method-of-use patent	May cover AML treatment or dosing
Formulation patent	May cover lipid composition and lyophilized presentation
Process patent	May create manufacturing exposure but is not necessarily Orange Book listed
Regulatory exclusivity	Separate from patent rights

Orange Book listing does not prove that every claim of a patent reads on the marketed product. It identifies patents submitted by the sponsor as claiming the drug, formulation, or approved method of use. Claim scope must be assessed against the approved product and labeling.

A generic applicant seeking approval for a liposomal daunorubicin/cytarabine product would typically need to address listed patents through a Paragraph IV certification, a section viii statement for non-patented uses, or a certification that the patent will expire before commercial launch. The applicable route depends on the precise Orange Book listings and the proposed labeling.

When does Vyxeos lose exclusivity?

Vyxeos has separate patent and regulatory timelines.

Event	Date or timing
FDA approval	August 3, 2017
Original orphan-drug exclusivity	Seven years from approval, generally through August 3, 2024
Pediatric approval expansion	2021
Key formulation patent term	Extends into approximately 2031
Earliest practical generic entry	Dependent on patent certifications, litigation, settlements, and FDA approval

Orphan exclusivity would not block approval of a product for an indication outside the protected orphan indication, but a generic applicant would still face listed patents and any applicable method-of-use restrictions.

Which companies are challenging the Vyxeos patent estate?

No publicly established final judgment invalidating US 10,166,184 is identified in the patent record supplied for this analysis. A definitive current list of ANDA filers, Paragraph IV notices, settlements, or pending district-court cases cannot be derived from the patent claims alone.

The principal commercial threat would come from a generic or specialty pharmaceutical company developing a competing liposomal daunorubicin/cytarabine product. Such an applicant would likely evaluate four routes:

1. Challenge validity through anticipation or obviousness.
2. Design around the DSPC:DSPG:cholesterol composition.
3. Avoid the claimed lyophilized form while pursuing an alternative presentation.
4. Challenge only method-of-use claims while limiting labeling.

A product using the same 7:2:1 lipid ratio, the same fixed drug combination, external sucrose or another cryoprotectant, and comparable reconstitution performance would present the highest literal-infringement risk.

How strong is the patent estate for the claimed formulation?

The estate has meaningful strength but is narrower than the commercial product narrative suggests.

Strengths

• Claim 1 covers a defined combination of lipid phase behavior, cholesterol ceiling, anionic lipid content, external cryoprotection, low internal cryoprotectant, and reconstitution performance.
• Claim 5 directly targets the 7:2:1 DSPC:DSPG:cholesterol ratio.
• Claim 7 expressly includes daunorubicin/cytarabine.
• Claims 8 through 13 provide additional fallback positions based on measurable stability and retention.
• The claims cover both composition and manufacturing activity.

Vulnerabilities

• The independent claim is broad and may face prior-art challenges involving lyophilized liposomes, cryoprotectants, high-transition-temperature phospholipids, and multi-drug encapsulation.
• Terms such as "stably associated," "substantially retained," and "maintained" may require detailed construction.
• The claims depend on analytical testing conditions that can affect the reported particle size, retention percentage, and ratio.
• Claim 1 does not require the fixed daunorubicin/cytarabine ratio, which may increase prior-art exposure.
• A competitor could attempt to alter lipid composition, cryoprotectant distribution, drug loading method, or dosage form.

The most defensible commercial position is likely the combination of narrow composition claims and performance claims, rather than claim 1 standing alone.

What generic launch scenarios exist?

Early launch after Paragraph IV litigation

A generic applicant could file an ANDA with a Paragraph IV certification and trigger litigation under the Hatch-Waxman framework. A timely patent-infringement action could impose a 30-month stay of FDA approval, subject to statutory exceptions and court action.

Launch after settlement

A settlement could establish an agreed entry date before the asserted patents expire. The commercial value of such a settlement would depend on the number of patents asserted, the strength of the formulation claims, and the presence of competing entrants.

Design-around launch

A competing product could seek to avoid infringement by changing:

• The phospholipid identity.
• The PG or PI concentration.
• Cholesterol content.
• Internal cryoprotectant concentration.
• The lyophilized presentation.
• The drug combination or formulation ratio.
• Post-reconstitution stability characteristics.

A design-around could still face separate patents covering the active ingredients, fixed ratios, AML treatment, or manufacturing.

At-risk launch

A generic company could launch before final resolution after obtaining FDA approval. That strategy would expose it to damages, an injunction, and potential enhanced damages if infringement were established.

Does biosimilar risk apply to Vyxeos?

No. Vyxeos is regulated as a small-molecule drug product, not as a biologic subject to the biosimilar pathway under the Public Health Service Act. Competitive entry would generally proceed through the ANDA pathway or, depending on formulation and product differences, a 505(b)(2) application.

A 505(b)(2) applicant could be commercially relevant if it develops a materially different liposomal composition, delivery system, indication, or dosing regimen. The applicant could rely in part on FDA findings for Vyxeos while addressing formulation and clinical differences independently.

What licensing and ownership transactions affect the patent?

Celator Pharmaceuticals developed the CPX-351 platform and Vyxeos. Jazz Pharmaceuticals acquired Celator in 2016 for approximately $1.5 billion, bringing the product and associated intellectual-property portfolio into the Jazz estate. [4]

The acquisition is more important than a conventional third-party license because it transferred the operating business and its development-stage and commercial rights. Subsequent ownership and maintenance records should be reviewed through USPTO assignment data when determining the current patent owner, licensing interests, security interests, or changes in correspondence address.

Key Takeaways

• US Patent 10,166,184 covers lyophilized gel-phase liposomes with high-transition-temperature membranes, limited cholesterol, PG or PI, external cryoprotection, low internal cryoprotectant, and post-reconstitution stability.
• Claims 2 through 5 target DSPC/DSPG/cholesterol formulations, with claim 5 specifying the 7:2:1 molar ratio.
• Claim 7 expressly covers daunorubicin/cytarabine, linking the patent to Vyxeos.
• Claims 8 through 13 add stability, retention, size, and fixed-ratio limitations that may provide fallback positions in litigation.
• Claims 14 through 17 extend coverage to lyophilization, freezing, reconstitution, and administration.
• The patent estate is expected to remain relevant through approximately 2031, beyond the original orphan-drug exclusivity period.
• Vyxeos has no biosimilar pathway. Generic and 505(b)(2) competition are the relevant entry risks.
• The highest-risk copycat would use the same multi-agent payload, DSPC:DSPG:cholesterol architecture, lyophilized presentation, and validated reconstitution performance.

FAQs

Is US 10,166,184 limited to Vyxeos?

No. The claims expressly cover broader multi-agent liposomal formulations and identify irinotecan/floxuridine as an alternative combination.

Does claim 1 require a 7:2:1 lipid ratio?

No. The 7:2:1 ratio appears in claim 5. Claim 1 is broader and does not require DSPC, DSPG, or any specific lipid ratio.

Can a generic avoid the patent by changing the cryoprotectant?

Possibly, but only if the altered product falls outside every asserted claim. Changing the external cryoprotectant may not avoid infringement if the remaining limitations are satisfied.

Are the particle-size limitations easy to test?

They are measurable but method-sensitive. Sample preparation, analytical technology, storage conditions, and the definition of mean diameter or size distribution can materially affect the result.

Does expiration of orphan exclusivity permit immediate generic entry?

No. Orphan exclusivity, listed patents, unlisted process patents, FDA approval requirements, and litigation outcomes are separate constraints.

References

1. U.S. Patent No. 10,166,184. (2019). Lyophilized liposomal compositions and methods of use thereof. U.S. Patent and Trademark Office.
2. U.S. Food and Drug Administration. (2017). FDA approves Vyxeos for certain types of high-risk acute myeloid leukemia.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
4. Jazz Pharmaceuticals plc. (2016). Jazz Pharmaceuticals completes acquisition of Celator Pharmaceuticals.
5. U.S. Food and Drug Administration. (2021). Vyxeos prescribing information.
6. U.S. Patent and Trademark Office. (2024). Patent term adjustment and patent term extension guidance.

Drugs Protected by US Patent 10,166,184

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Jazz Pharms Therap	VYXEOS	cytarabine; daunorubicin	POWDER;INTRAVENOUS	209401-001	Aug 3, 2017		RX	Yes	Yes	10,166,184*PED				Y

International Family Members for US Patent 10,166,184

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2768484		301016	Netherlands
European Patent Office	2768484		LUC00135	Luxembourg
European Patent Office	2768484		CA 2019 00051	Denmark
European Patent Office	2768484		122019000091	Germany
European Patent Office	2768484		CR 2019 00051	Denmark
European Patent Office	2768484		2019C/545	Belgium
European Patent Office	2768484		132019000000144	Italy