Details for Patent: 8,992,970

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Summary for Patent: 8,992,970

Title:	Liposomes useful for drug delivery
Abstract:	The present invention provides liposome compositions containing substituted ammonium and/or polyanion, and optionally with a desired therapeutic or imaging entity. The present invention also provides methods of making the liposome compositions provided by the present invention.
Inventor(s):	Keelung Hong, Daryl C. Drummond, Dmitri Kirpotin
Assignee:	Ipsen Biopharm Ltd
Application Number:	US14/175,365
Patent Claim Types: see list of patent claims	Composition; Formulation; Compound; Dosage form;

US Patent 8,992,970: Scope, Claims, Expiration and Liposomal Irinotecan Patent Landscape

US Patent 8,992,970 protects a specific liposomal irinotecan platform rather than ordinary irinotecan hydrochloride. The core combination is irinotecan and sucrose octasulfate encapsulated in liposomes made from DSPC, cholesterol and PEGylated DSPE. The patent also covers selected substituted ammonium counterions, defined lipid ratios, high irinotecan loading, near-stoichiometric drug-to-sucrose octasulfate ratios and parenteral formulations.

The patent is closely associated with the liposomal irinotecan product ONIVYDE, marketed by Ipsen after its acquisition of Merrimack Pharmaceuticals’ oncology assets. The ordinary 20-year patent term runs into late September 2027 based on the priority chain publicly associated with the patent family. FDA orphan-drug exclusivity for ONIVYDE expired in October 2022, leaving patent rights and regulatory requirements as the principal barriers to competing products.

What does US Patent 8,992,970 protect?

The independent claim protects a composition with five essential technical elements:

1. An aqueous liposomal composition.
2. A liposomal membrane containing:
   • 1,2-distearoyl-sn-phosphatidylcholine, or DSPC;
   • cholesterol; and
   • a PEGylated phosphatidylethanolamine, identified in the claims as PEG-DSPE.
3. Irinotecan encapsulated within the liposome.
4. Sucrose octasulfate encapsulated with irinotecan.
5. Irinotecan concentration inside the liposome exceeding its concentration in the surrounding aqueous medium.

Claim 1 has two alternatives. The first requires irinotecan and sucrose octasulfate. The second adds a substituted ammonium compound. Claims 2 through 5 narrow the second alternative by defining the ammonium compound and identifying specific counterions.

The patent therefore does not broadly claim every liposomal irinotecan formulation. A competing product would need to be assessed against the complete combination of membrane composition, encapsulated materials, concentration gradient and dependent-claim limitations.

Core claim elements

Claim feature	Scope
Drug	Irinotecan
Encapsulated co-agent	Sucrose octasulfate
Lipid 1	DSPC
Lipid 2	Cholesterol
Lipid 3	PEG-DSPE, with PEG-2000 expressly claimed in claim 7
Physical structure	Liposome with an interior aqueous space
Concentration limitation	Internal irinotecan concentration exceeds external concentration
Formulation	Aqueous composition; parenteral formulation in claim 8
Loading limitation	Irinotecan-to-total-lipid molar ratio of at least 1.0 in claim 9
Stoichiometry	Near or at stoichiometric equivalence between irinotecan and sucrose octasulfate
Buffer limitation	HEPES and sodium chloride in claim 13
Process-related limitation	Partial or substantial removal of external irinotecan in claim 14

How broad is claim 1 of US 8,992,970?

Claim 1 is composition-based and potentially broad within its defined formulation class. It does not require a particular cancer indication, dose, administration schedule, particle size, release profile or manufacturing process.

The claim reaches formulations containing the specified lipid classes even if the commercial formulation uses additional excipients, provided those additional components do not remove the required claim elements. The claim also does not expressly require the exact 59.8:39.9:0.3 molar lipid ratio later recited in claim 6.

The principal limitations are structural and compositional:

• The membrane must include DSPC, cholesterol and PEG-DSPE.
• Irinotecan and sucrose octasulfate must be inside the liposome.
• Irinotecan must be more concentrated inside the liposome than outside.
• The formulation must be a liposomal composition in an aqueous medium.

A product using hydrogenated soy phosphatidylcholine instead of DSPC, a different PEG-lipid, or a different internal trapping agent could avoid literal infringement of claim 1, subject to a doctrine-of-equivalents analysis. A formulation containing irinotecan outside the liposome but not inside would not satisfy the claim.

What do claims 2 through 5 add?

Claims 2 through 5 cover formulations using substituted ammonium compounds during or in connection with the encapsulation system.

Claim 2 defines a broad Markush group. The ammonium nitrogen may carry hydrogen or organic groups, subject to carbon-number limits. The claim covers aliphatic, cyclic, aromatic, heterocyclic and hydroxy-substituted structures, provided the listed structural conditions are met.

Claim 3 identifies a long list of specific compounds, including:

• triethylammonium;
• diethylammonium;
• tert-butylammonium;
• morpholinium;
• pyridinium;
• piperidinium;
• pyrrolidinium;
• tetramethylammonium;
• tetraethylammonium; and
• tetrabutylammonium.

Claim 4 narrows the formulation to triethylammonium. Claim 5 narrows it to diethylammonium.

These claims create multiple infringement positions. A product may fall outside claim 4 while remaining within claim 2 or claim 3. Conversely, a product using an ammonium compound not expressly named in claim 3 could still fall within claim 2 if it satisfies the broader structural definition.

The phrase "substituted ammonium compound" should be analyzed with attention to claim construction, including whether the claim requires the compound to remain inside the final liposome, participate in drug loading, or merely be present in the claimed composition. The claim language supplied here states that irinotecan, sucrose octasulfate and the substituted ammonium compound are entrapped inside the liposomes.

What formulation ratios are protected?

Claims 6 through 13 add commercially significant formulation limitations.

Lipid composition

Claim 6 requires approximately:

• 59.8 mol.% DSPC;
• 39.9 mol.% cholesterol; and
• 0.3 mol.% PEG-DSPE.

Claim 7 limits the PEG component to a molecular weight of about 2,000. This combination is directed to a conventional long-circulating liposome architecture, with PEG-DSPE used to reduce rapid clearance.

A formulation with materially different lipid ratios may avoid claims 6 and 7 but could still fall within claim 1. The strength of a design-around therefore depends on whether the alternative lipid composition also avoids the independent claim.

Drug-to-lipid ratio

Claim 9 requires an irinotecan-to-total-lipid molar ratio of at least 1.0. This is a high-loading limitation. A lower-loading product may avoid claim 9 but remains exposed to claim 1 unless another limitation is also absent.

Irinotecan-to-sucrose octasulfate ratio

Claims 10 and 11 require the two encapsulated components to be near, or at, stoichiometric equivalence. This limitation relates to the ion-pairing and precipitation mechanism used to load irinotecan into the liposome.

A formulation with substantially nonstoichiometric quantities may avoid these dependent claims. That does not automatically avoid claim 1, which does not require a specified ratio.

External irinotecan

Claim 14 covers formulations in which irinotecan has been partially or substantially removed from the external aqueous medium. This limitation is relevant to purification and final-product composition. It may be satisfied by a product with residual external irinotecan if the residual amount is sufficiently reduced under the applicable claim construction.

What is the patent’s relationship to ONIVYDE?

ONIVYDE is a liposomal irinotecan injection approved by FDA for use with fluorouracil and leucovorin, with or without oxaliplatin depending on the indication and labeling period. The product uses a liposomal delivery system designed to alter irinotecan disposition and maintain drug within a long-circulating formulation. FDA approved ONIVYDE in October 2015 for metastatic pancreatic adenocarcinoma after gemcitabine-based therapy. [2]

The claimed technology maps closely to the product’s formulation architecture:

Patent subject matter	Commercial relevance
Irinotecan encapsulation	Active pharmaceutical ingredient in ONIVYDE
Sucrose octasulfate	Internal trapping agent associated with liposomal loading
DSPC/cholesterol/PEG-DSPE membrane	Liposomal carrier structure
High internal irinotecan concentration	Core encapsulation feature
Parenteral aqueous formulation	Product dosage form
External-drug removal	Final formulation purification characteristic

A formulation overlap does not by itself establish infringement. Infringement requires the accused product to satisfy every limitation of an asserted claim, either literally or under the doctrine of equivalents.

When does US Patent 8,992,970 lose exclusivity?

The patent’s ordinary term is expected to end in late September 2027, based on a priority date in late September 2007 and the 20-year term applicable under 35 U.S.C. §154. The exact enforceable date depends on the patent’s term adjustment, terminal disclaimer status and any applicable patent-term extension. [1]

Exclusivity timeline

Event	Date or period
Earliest reported priority	September 2007
US patent issuance	March 31, 2015
ONIVYDE FDA approval	October 22, 2015
Orphan-drug exclusivity	Through October 22, 2022
Expected ordinary patent expiry	Late September 2027
Earliest ordinary post-expiry launch window	After expiry, subject to FDA approval and other unexpired rights

ONIVYDE did not receive new chemical entity exclusivity because irinotecan was already an approved active ingredient. Its principal FDA market exclusivity was orphan-drug exclusivity for the approved pancreatic-cancer indication. Orphan exclusivity prevents approval of the same drug for the same disease or condition in the relevant period, subject to statutory exceptions. It does not prevent all competing formulations or all uses.

What is the Orange Book status of US 8,992,970?

Patent listing in the FDA Orange Book is legally significant for an approved drug product because a listed patent can trigger the statutory patent-certification framework for an ANDA. A Paragraph IV certification can result in notice to the patent holder and an infringement action under 35 U.S.C. §271(e)(2). A timely suit can create a 30-month stay of approval, subject to statutory exceptions and court action. [3]

US 8,992,970 is part of the patent estate associated with liposomal irinotecan. Orange Book analysis should distinguish:

• patents listed against the ONIVYDE drug product;
• patents directed to the formulation;
• method-of-use patents;
• manufacturing patents not eligible for listing; and
• patents that have expired, been delisted or remained enforceable after regulatory exclusivity ended.

The Orange Book does not establish patent validity. A listed patent may be challenged through Paragraph IV litigation, inter partes review, post-grant proceedings, district-court invalidity defenses or claim-construction disputes.

Which companies could challenge the patent?

The principal commercial challengers would be manufacturers capable of producing a complex liposomal injectable, including generic injectable companies and specialty pharmaceutical developers. The product is not comparable to a conventional small-molecule tablet or simple injectable.

Potential market participants include:

• established generic injectable manufacturers;
• companies with liposome manufacturing capacity;
• 505(b)(2) developers pursuing a modified liposomal irinotecan product;
• contract manufacturers with sterile nanoparticle or liposome capabilities; and
• oncology companies developing noninfringing irinotecan delivery systems.

A conventional irinotecan hydrochloride ANDA would not be a direct substitute for ONIVYDE and would not necessarily create an infringement dispute over this patent. The commercial product is a distinct liposomal formulation with different clinical and pharmacokinetic characteristics.

No biosimilar pathway applies. ONIVYDE is a nonbiological drug product, so the relevant regulatory routes are generally an ANDA under section 505(j) or a 505(b)(2) application under section 505(b)(2), not an abbreviated biosimilar application under the Public Health Service Act.

What generic entry risks exist?

The highest-risk entry scenario is a product that reproduces the core formulation:

• DSPC;
• cholesterol;
• PEG-DSPE;
• irinotecan;
• sucrose octasulfate;
• high internal irinotecan concentration; and
• parenteral administration.

That product would face substantial exposure under claim 1 even if it changed the ammonium salt or omitted the exact lipid ratio.

A lower-risk design-around could alter one or more central features:

Design-around approach	Potential effect
Replace DSPC with another phospholipid	May avoid the membrane limitation
Use a non-PEGylated liposome	May avoid the PEG-DSPE limitation
Use a different trapping agent	May avoid sucrose octasulfate claims
Use a non-liposomal nanoparticle	May avoid the liposome structure
Use a substantially different drug-loading mechanism	May reduce exposure to stoichiometry and ammonium claims
Use a lower irinotecan-to-lipid ratio	May avoid claim 9 only
Retain significant external irinotecan	May avoid claim 14 only
Develop conventional irinotecan injection	Not a direct formulation substitute for ONIVYDE

The most difficult design-around is likely a formulation that preserves the same pharmacological and manufacturing advantages while replacing only one narrow component. The broader independent claim makes single-feature substitutions important, but the commercial and regulatory comparability burden may limit the value of a technically noninfringing formulation.

How strong is the patent estate?

The estate is strongest against a direct copy of the claimed liposomal architecture. Its main strengths are:

• a composition claim rather than only a method-of-treatment claim;
• coverage of the principal lipid classes;
• coverage of irinotecan and sucrose octasulfate together;
• dependent claims directed to ammonium-assisted loading;
• claims covering high drug loading and stoichiometric equivalence; and
• alignment with a marketed injectable product.

Its limitations are equally important:

• the claims are tied to a specific liposomal membrane chemistry;
• the patent does not cover every irinotecan delivery system;
• dependent claims can be avoided through changes in lipid ratio, counterion or loading chemistry;
• patent validity may be tested through written-description, enablement, anticipation and obviousness challenges; and
• patent expiry is substantially earlier than the potential commercial life of the product.

The estate’s practical value depends on the full family, including continuation claims, method-of-use claims, manufacturing claims and any other listed patents. US 8,992,970 should not be evaluated in isolation when assessing launch timing.

What patent litigation affects liposomal irinotecan?

The relevant litigation risk is likely to arise from an ANDA or 505(b)(2) filing directed to a liposomal irinotecan product. The likely disputes would concern:

1. Whether the proposed formulation contains DSPC, cholesterol and PEG-DSPE.
2. Whether sucrose octasulfate is entrapped inside the liposome.
3. Whether irinotecan is present at a higher internal than external concentration.
4. Whether an ammonium compound is entrapped.
5. Whether the lipid and drug ratios satisfy the dependent claims.
6. Whether the claims are anticipated or obvious over prior liposomal irinotecan technology.
7. Whether the patent’s written description supports the full breadth of the ammonium Markush group.
8. Whether the applicant’s formulation is sufficiently different to avoid literal infringement.

A settlement could permit a licensed or authorized generic launch before patent expiry. No settlement terms should be inferred from FDA approval status alone. Settlement analysis requires the actual litigation docket, notice letters, consent orders and any confidential or public license arrangements.

What licensing deals affect the patent landscape?

Merrimack developed ONIVYDE and transferred commercial rights to Ipsen in 2017. The transaction gave Ipsen global rights to ONIVYDE and related assets. [4] Licensing and acquisition agreements may allocate prosecution, enforcement, royalties, manufacturing rights and settlement authority, but the existence of a commercial transfer does not itself establish that every patent in the estate was assigned or licensed on identical terms.

The relevant commercial rights should be separated into:

• patent ownership;
• regulatory application ownership;
• product commercialization rights;
• manufacturing rights;
• territorial rights; and
• rights to enforce against generic applicants.

Key Takeaways

• US 8,992,970 is a formulation patent directed to liposomal irinotecan.
• Claim 1 requires DSPC, cholesterol, PEG-DSPE, irinotecan, sucrose octasulfate and an internal irinotecan concentration greater than the external concentration.
• Claims 2 through 5 cover substituted ammonium compounds, including triethylammonium and diethylammonium.
• Claims 6 through 14 add commercially relevant limitations for lipid ratios, PEG molecular weight, loading, stoichiometry, buffering and external-drug removal.
• The ordinary patent term is expected to run into late September 2027.
• FDA orphan exclusivity expired in October 2022.
• Biosimilar regulation does not apply; potential challengers would use an ANDA or 505(b)(2) pathway.
• The strongest infringement risk is a direct copy of the ONIVYDE-type liposomal architecture.
• A meaningful freedom-to-operate opinion requires review of the complete patent family, Orange Book listings, prosecution history and any later continuation patents.

FAQs

Can a conventional irinotecan injection infringe US 8,992,970?

Generally, no. The claims require irinotecan to be entrapped inside liposomes with a specified membrane composition and, in claim 1, sucrose octasulfate. A conventional non-liposomal irinotecan injection would not satisfy those structural limitations.

Does changing the ammonium counterion avoid the patent?

Not necessarily. Claims 2 and 3 cover broad classes of substituted ammonium compounds and named species. Changing triethylammonium to another covered compound may leave the product within the patent.

Is sucrose octasulfate required in every claim?

Yes, for the claims supplied. It is an express component of claim 1 and remains required by the dependent claims.

Can a 505(b)(2) application avoid the patent automatically?

No. The regulatory pathway does not determine patent infringement. A 505(b)(2) applicant must evaluate listed patents and may need a patent certification, a carve-out, a license or a litigation strategy.

Does expiration of orphan exclusivity permit immediate generic launch?

No. Orphan exclusivity ended in 2022, but unexpired patents, FDA approval requirements, patent certifications and possible litigation can continue to delay or restrict launch.

References

1. United States Patent and Trademark Office. (2015). United States Patent No. 8,992,970, Liposomal formulations of irinotecan.
2. U.S. Food and Drug Administration. (2024). ONIVYDE (irinotecan liposome injection) prescribing information.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
4. Ipsen. (2017). Ipsen completes acquisition of Merrimack Pharmaceuticals’ oncology assets.
5. 35 U.S.C. §§ 154, 271(e), 282 (2024).

Drugs Protected by US Patent 8,992,970

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 8,992,970

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1746976		300885	Netherlands
European Patent Office	1746976		122017000042	Germany
European Patent Office	1746976		CA 2017 00030	Denmark