Details for Patent: 9,492,442

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Which drugs does patent 9,492,442 protect, and when does it expire?

Patent 9,492,442 protects ONIVYDE and is included in one NDA.

This patent has sixty patent family members in twenty-six countries.

Summary for Patent: 9,492,442

Title:	Methods for treating pancreatic cancer using combination therapies comprising liposomal irinotecan
Abstract:	Provided are methods for treating pancreatic cancer in a patient by administering liposomal irinotecan (MM-398) alone or in combination with additional therapeutic agents. In one embodiment, the liposomal irinotecan (MM-398) is co-administered with 5-fluorouracil and leucovorin.
Inventor(s):	Eliel Bayever, Navreet Dhindsa, Jonathan Basil FITZGERALD, Peter Laivins, Victor Moyo, Clet Niyikiza, Jaeyeon Kim
Assignee:	Ipsen Biopharm Ltd
Application Number:	US14/851,111
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,492,442
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Dosage form;

US Patent 9,492,442: Claim Scope, Exclusivity, Orange Book Status, and Generic Entry Risk for Onivyde

US Patent 9,492,442 protects a specific treatment regimen for pancreatic cancer using liposomal irinotecan, leucovorin, and 5-fluorouracil. Its core limitations are a biweekly schedule, gemcitabine-pretreated pancreatic cancer, a 60-80 mg/m² liposomal irinotecan dose, defined liposome composition and size, sequential administration with leucovorin and 5-FU, and, in narrower claims, preparation and refrigerated storage of the diluted product.

The patent is a method-of-treatment patent rather than a broad composition patent. A competitor could avoid infringement by changing a required clinical or formulation parameter, although such changes could conflict with the FDA-approved Onivyde regimen or reduce commercial utility.

What drug and treatment regimen does US Patent 9,492,442 cover?

US 9,492,442 covers treatment of exocrine pancreatic cancer, including metastatic pancreatic adenocarcinoma, after progression on or failure of gemcitabine-based therapy. The protected regimen combines:

Element	Claimed limitation
Active drug	Liposomal irinotecan
Dose	60, 70, or 80 mg/m² in dependent claims; 60-80 mg/m² in broader claims
Schedule	Once every two weeks
Administration	Intravenous infusion
Infusion duration	Approximately 90 minutes in narrower claims
Combination therapy	Leucovorin plus 5-fluorouracil
Leucovorin	200 mg/m² of the l-form, or 400 mg/m² racemic leucovorin in specified claims
5-FU	2,400 mg/m², administered over 46 hours in narrower claims
Disease setting	Pancreatic cancer after gemcitabine-based therapy
Liposome structure	Phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine
Liposome size	Approximately 80-140 nm
Encapsulated drug state	Irinotecan sucrose octasulfate in a gelated or precipitated state
Dilution	Product containing 5 mg/mL liposomal irinotecan diluted into 500 mL injectable liquid
Storage	About 2-8°C for no more than 24 hours in selected claims
Administration sequence	Liposomal irinotecan before leucovorin, followed by 5-FU

The FDA-approved Onivyde regimen uses liposomal irinotecan with leucovorin and 5-FU every two weeks after gemcitabine-based therapy. The approved standard dose is 70 mg/m², reduced to 50 mg/m² for patients homozygous for UGT1A1*28 under the applicable labeling provisions.[2]

How many independent claims does US 9,492,442 have?

The patent has four principal independent method claims: claims 1, 10, 19, and 29. They overlap substantially but use different combinations of disease, formulation, dosing, sequencing, storage, and patient-selection limitations.

Independent claim	Principal scope	Commercial significance
Claim 1	Biweekly treatment with 60-80 mg/m² liposomal irinotecan plus leucovorin and 5-FU; defined liposome size and composition	Broadest regimen claim
Claim 10	Gemcitabine-pretreated patient; 200 mg/m² l-leucovorin and 2,400 mg/m² 5-FU; defined liposome formulation	Strong regimen and formulation combination
Claim 19	Pancreatic cancer after gemcitabine; 60, 70, or 80 mg/m² dose; 500 mL diluted formulation; refrigerated storage	Adds product-handling limitations
Claim 29	Metastatic pancreatic adenocarcinoma; non-homozygous UGT1A1*28 patient; 80 mg/m² dose; defined dilution and liposome structure	Narrowest but closely aligned with commercial administration

Claims 1 and 10 are the most important claims for a product used according to the FDA-approved Onivyde regimen. Claim 29 is narrower because it requires metastatic adenocarcinoma, an 80 mg/m² dose, and a patient who is not homozygous for UGT1A1*28.

What formulation characteristics are protected?

The patent does not claim every irinotecan liposome. The relevant liposomes must contain the specified lipid components and, in narrower claims, must satisfy structural and encapsulation requirements.

Lipid composition

The claims identify:

1. Phosphatidylcholine;
2. Cholesterol; and
3. A PEG-derivatized phosphatidylethanolamine.

Several dependent claims require approximately one PEG molecule for every 200 phospholipid molecules. This limitation narrows the claims to a specific PEG-lipid density.

Vesicle structure

Claims 3, 8, 18, 23, 25, 27, and 29 require a unilamellar lipid bilayer vesicle. The vesicle encapsulates an aqueous space containing irinotecan in a gelated or precipitated state with irinotecan sucrose octasulfate.

This limitation is commercially important because it distinguishes the claimed product from:

• Non-liposomal irinotecan;
• Multilamellar vesicles;
• Liposomes using a different internal precipitation or gelation system;
• Liposomes lacking the claimed lipid combination;
• Formulations with materially different size distributions.

The patent recites an approximate liposome diameter of 80-140 nm. A competitor would need to assess both the literal scope of “approximately” and the potential application of the doctrine of equivalents before relying on a size outside that range.

Diluted formulation

The claims require a diluted irinotecan injection formulation containing liposomal irinotecan in 500 mL of injectable liquid. Claims 20 and 29 tie the dilution to a 5 mg/mL source composition, with the volume selected to deliver the prescribed patient dose.

Claims 24, 26, 28, and 30 identify 5% dextrose injection as the injectable liquid. The presence of this limitation makes those dependent claims easier to design around using another compatible diluent, but the resulting formulation must remain consistent with the FDA-approved product labeling and pharmaceutical compatibility requirements.

What clinical regimen is protected?

The patent covers the treatment architecture used in the NAPOLI-1 clinical program and reflected in the approved Onivyde regimen.

Dose and schedule

The broad claims cover 60-80 mg/m² administered once every two weeks. Narrower claims identify 60, 70, or 80 mg/m². Claim 29 focuses on 80 mg/m².

The commercial FDA regimen is 70 mg/m² every two weeks for patients who are not homozygous for UGT1A1*28 under the applicable label. This creates a direct overlap between the marketed regimen and claims 1, 10, and 19.

Drug sequence

The narrower claims require:

1. Liposomal irinotecan first, generally as a 90-minute infusion;
2. Leucovorin second, over approximately 30 minutes; and
3. 5-FU after leucovorin, as a 46-hour infusion.

Claim 6 also requires the agents to be administered sequentially beginning on day 1 of the two-week cycle, with the agents simultaneously present in the patient’s blood.

The sequence limitation is significant. A regimen that administers leucovorin before liposomal irinotecan, uses a materially different interval, or does not provide the claimed 46-hour 5-FU infusion may avoid literal infringement of the narrower claims. Claims 1 and 10, however, remain more consequential because they do not all require the full sequence and infusion detail found in the later dependent claims.

Patient population

The claims generally require exocrine pancreatic cancer or pancreatic cancer after gemcitabine-based therapy. Claim 29 narrows this to metastatic adenocarcinoma of the pancreas.

The gemcitabine limitation is central. A treatment for first-line pancreatic cancer without prior gemcitabine exposure would not satisfy claims requiring prior gemcitabine treatment. The FDA-approved indication is also directed to patients with metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy.[2]

How strong are the independent claims?

Claim 1

Claim 1 has the broadest practical scope. It requires the combination of:

• Exocrine pancreatic cancer;
• Biweekly intravenous treatment;
• 60-80 mg/m² liposomal irinotecan;
• A 90-minute single infusion;
• Leucovorin and 5-FU;
• Defined lipid composition;
• 80-140 nm liposomes.

Its principal vulnerability is limitation density. Although it is the broadest independent claim, a challenger can attack individual limitations involving liposome size, formulation concentration, dilution volume, infusion duration, or the “consisting of” transition.

The “consisting of” language may exclude additional antineoplastic agents from the claimed therapy. It does not necessarily exclude routine supportive care, but an accused regimen containing another antineoplastic drug could create a noninfringement argument.

Claim 10

Claim 10 is more commercially focused. It expressly requires prior gemcitabine treatment, l-leucovorin at 200 mg/m², 5-FU at 2,400 mg/m², and the sucrose octasulfate liposomal formulation.

This claim maps closely to the approved treatment setting and is likely more useful against a follow-on product that reproduces the Onivyde formulation and regimen.

Claim 19

Claim 19 adds the 500 mL diluted formulation and refrigerated storage for no more than 24 hours. These limitations may narrow enforcement because they concern pharmacy preparation and handling rather than only the administered therapy.

The claim remains commercially relevant if the competing product labeling or standard pharmacy instructions specify the same dilution and storage conditions.

Claim 29

Claim 29 is the most detailed independent claim. It requires:

• Metastatic pancreatic adenocarcinoma;
• Progression after gemcitabine-based therapy;
• A patient not homozygous for UGT1A1*28;
• An 80 mg/m² dose;
• 5% dextrose or another claimed injectable liquid;
• 80-140 nm liposomes;
• Unilamellar vesicles;
• Irinotecan sucrose octasulfate;
• The specified lipid components;
• Preparation once every two weeks.

Its narrowness reduces its reach beyond the specific commercial regimen. Its technical detail may improve validity against a prior-art attack if the cited combination was not disclosed in a single earlier reference.

What is the patent expiration date?

The patent issued on November 15, 2016. The patent family claims priority to an August 26, 2011 filing date. On a nominal 20-year patent term measured from the earliest effective nonprovisional filing, the expected base expiration is August 26, 2031, subject to any applicable patent-term adjustment, terminal disclaimer, or regulatory patent-term extension recorded in the official patent file.[1]

The expiration date should be distinguished from FDA regulatory exclusivity. FDA approval of Onivyde occurred in October 2015. New-drug exclusivity associated with that approval was much shorter than the patent term and does not independently control generic entry after its expiration.[2][3]

Event	Date
Earliest stated family priority	August 26, 2011
FDA approval of Onivyde	October 22, 2015
US 9,492,442 issue date	November 15, 2016
Nominal base patent expiration	August 26, 2031
Practical entry analysis	Requires review of all Orange Book-listed patents, regulatory exclusivity, and any patent-term adjustment

What is the Orange Book status of US 9,492,442?

US 9,492,442 is associated with the Onivyde product and its pancreatic-cancer treatment regimen. Orange Book analysis must separate the patent’s existence from its listing status, use code, and applicability to a particular abbreviated new drug application.

For a generic applicant, the key issue is whether the applicant:

• Certifies to the listed patent under Paragraph III;
• Challenges the patent under Paragraph IV;
• Omits the patented method under a section viii statement; or
• Uses labeling that remains within the patented indication and regimen.

A section viii carve-out may be difficult if the patented treatment overlaps the principal FDA-approved indication. A Paragraph IV certification would create litigation exposure if the reference product sponsor or patent owner sues within the statutory period.

The Orange Book should be checked for the current patent listing, use code, and any later-listed continuation or related patent. The patent claims alone do not establish the complete Orange Book estate. FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations remains the controlling source for current listings.[3]

What Paragraph IV challenges and litigation risks exist?

The principal Paragraph IV risk is that a generic applicant could challenge the patent as invalid, unenforceable, or not infringed while seeking approval for liposomal irinotecan used with leucovorin and 5-FU in post-gemcitabine pancreatic cancer.

Potential invalidity arguments include:

• Obviousness based on prior clinical use of irinotecan, leucovorin, and 5-FU;
• Obviousness based on known liposomal irinotecan formulations;
• Lack of written description for the full combination of formulation, dosing, sequencing, storage, and patient genetics;
• Indefiniteness involving “approximately,” “about,” “therapeutically effective,” and “simultaneously present”;
• Anticipation by clinical protocols or product-development disclosures.

Potential infringement defenses include:

• A dose below 60 mg/m² or above 80 mg/m²;
• A schedule other than every two weeks;
• A different liposome composition;
• A liposome size outside the claimed range;
• A non-sucrose-octasulfate internal drug state;
• Different dilution volume or storage practice;
• Administration outside the post-gemcitabine population;
• A different leucovorin or 5-FU dose;
• A different order or duration of administration.

The commercial risk is greater where the generic label directly describes the approved Onivyde regimen. Label language, prescribing instructions, pharmacy preparation directions, and product composition can all support a direct-infringement or induced-infringement theory.

No settlement terms, court judgment, or active Paragraph IV case can be established from the claim text alone. A current litigation determination requires the Federal Court docket, FDA Paragraph IV notice information where available, and the latest Orange Book records.

How does US 9,492,442 compare with composition and formulation patents?

US 9,492,442 is narrower in one respect and broader in another.

It is narrower than a composition patent because it requires treatment of a specified cancer using a specified clinical regimen. A competitor that develops the same liposome for another cancer or another dosing schedule may not infringe the method claims.

It can be broader than a pure formulation patent in enforcement against a clinically used product because it captures the combination of product, dosing, patient population, and administration sequence. A competitor may have a different manufacturing process but still practice the claimed method if the final product and treatment regimen satisfy every limitation.

The related Onivyde patent landscape includes at least three layers:

Patent layer	Typical protected subject matter	Main competitive effect
Composition	Liposomal irinotecan structure and encapsulation	Blocks substitute versions using the same core product architecture
Manufacturing	Lipid assembly, drug loading, purification, or scale-up	Raises process-development and freedom-to-operate risk
Method of treatment	Post-gemcitabine pancreatic cancer regimen	Blocks commercial use of the product in the approved indication

A generic applicant must clear all three layers. Avoiding US 9,492,442 does not establish freedom to market if a composition or manufacturing patent remains enforceable.

What generic launch scenarios exist?

Scenario 1: Paragraph IV challenge

A generic applicant files an ANDA with a Paragraph IV certification against US 9,492,442 and any related listed patents. The patent owner may sue within the statutory period, potentially triggering a 30-month stay of approval under the Hatch-Waxman framework.[4]

Scenario 2: Paragraph III certification

The applicant accepts the patent and seeks approval only after patent expiration. This reduces litigation risk but delays launch to the effective expiration date of the complete patent estate.

Scenario 3: Section viii carve-out

The applicant removes the patented pancreatic-cancer method from its labeling. This strategy is difficult if the carved-out indication is the principal commercial use of the drug or if the remaining label still encourages the patented regimen.

Scenario 4: Product redesign

A competitor could pursue a formulation outside the claimed liposome architecture, use another internal loading mechanism, alter particle size, or develop a non-liposomal irinotecan product. Such a program may avoid this patent but would face separate regulatory, clinical, manufacturing, and patent risks.

What are the manufacturing and geographic barriers?

US 9,492,442 is a US patent. It does not directly control manufacture, sale, or use outside the United States. International freedom to operate requires country-by-country review of corresponding national patents, pending applications, supplementary protection certificates, and local regulatory exclusivity.

Manufacturing risk remains material because the claimed product has several technically specific attributes:

• Controlled vesicle size;
• Unilamellar morphology;
• PEG-lipid incorporation;
• Stable irinotecan sucrose octasulfate precipitation or gelation;
• Drug loading and retention;
• Sterile manufacturing;
• Dilution stability;
• Refrigerated storage;
• Reproducible 5 mg/mL source-product concentration.

A biosimilar pathway is not applicable in the ordinary sense because Onivyde is a small-molecule liposomal drug, not a biologic. A follow-on applicant would generally pursue an ANDA if it can demonstrate pharmaceutical equivalence and bioequivalence, or an appropriate 505(b)(2) pathway if it relies on a different formulation, dosage, or clinical bridge.[2][5]

What revenue exposure does the patent create?

The highest revenue exposure is tied to the post-gemcitabine metastatic pancreatic cancer market because the patent claims track the principal approved use of Onivyde.

Exposure is reduced by:

• The narrow disease requirement;
• The specific dosing range;
• Formulation limitations;
• Potential label carve-outs;
• The possibility of noninfringing clinical protocols;
• The need to prove each claim element.

Exposure is increased by:

• The close match between the claims and the FDA label;
• The use of a standardized 70 mg/m² every-two-week regimen;
• The defined leucovorin and 5-FU doses;
• The commercial use of the claimed liposomal platform;
• Pharmacy instructions that may replicate the claimed dilution and storage steps.

The patent is therefore more commercially significant than a narrow method patent directed to an uncommon dosing variation. It overlaps the central branded treatment pattern, even though it does not independently protect every use of irinotecan or every liposomal irinotecan product.

Key Takeaways

• US 9,492,442 is a method-of-treatment patent for liposomal irinotecan plus leucovorin and 5-FU in pancreatic cancer after gemcitabine therapy.
• Claims 1, 10, 19, and 29 are the principal independent claims.
• The most important limitations are the 60-80 mg/m² dose, biweekly schedule, 80-140 nm liposomes, specified lipid composition, irinotecan sucrose octasulfate encapsulation, and defined chemotherapy sequence.
• The commercial 70 mg/m² Onivyde regimen substantially overlaps the core claims.
• The nominal base patent expiration is August 26, 2031, subject to official patent-term adjustments and related rights.
• The patent is not the entire Onivyde patent estate. Composition, manufacturing, continuation, and related method patents must be cleared separately.
• Paragraph IV risk is material because the claims align closely with the approved post-gemcitabine indication.
• A biosimilar pathway is generally not the relevant framework; an ANDA or 505(b)(2) pathway is more likely.
• The strongest design-around opportunities involve formulation architecture, patient population, dose, administration sequence, dilution, and storage limitations.
• Patent validity and infringement cannot be assessed from claim language alone; prosecution history, prior art, Orange Book records, and litigation dockets control the final position.

Frequently Asked Questions

Does US 9,492,442 cover all uses of irinotecan?

No. It covers specified methods using liposomal irinotecan in combination with leucovorin and 5-FU for defined pancreatic-cancer populations and dosing regimens.

Does a 70 mg/m² Onivyde regimen fall within the patent claims?

Yes. The independent claims recite 60-80 mg/m², and dependent claims expressly identify 70 mg/m².

Can a generic avoid the patent by changing the diluent?

Possibly for claims that expressly require 5% dextrose, but changing the diluent does not avoid claims that require only an injectable liquid or that rely on other formulation limitations.

Is a liposomal irinotecan product a biosimilar?

No. Liposomal irinotecan is generally handled as a complex small-molecule drug product rather than a biologic subject to the biosimilar pathway.

Does patent expiration automatically permit generic launch?

No. Launch also depends on other Orange Book-listed patents, regulatory exclusivity, patent-term adjustments, litigation outcomes, and the generic product’s final label and formulation.

References

1. United States Patent and Trademark Office. (2016). United States Patent No. 9,492,442: Methods of treating pancreatic cancer.
2. U.S. Food and Drug Administration. (2024). ONIVYDE (irinotecan liposome injection) prescribing information. Ipsen Biopharmaceuticals, Inc.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
4. U.S. Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, 21 U.S.C. § 355(j).
5. U.S. Food and Drug Administration. (2024). Applications covered by section 505(b)(2).

Drugs Protected by US Patent 9,492,442

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Ipsen	ONIVYDE	irinotecan hydrochloride	INJECTABLE, LIPOSOMAL;INTRAVENOUS	207793-001	Oct 22, 2015		RX	Yes	Yes	9,492,442					TREATMENT OF EXOCRINE PANCREATIC CANCER THAT HAS PROGRESSED ON GEMCITABINE-BASED THERAPY, IN COMBINATION WITH 5-FLUOROURACIL AND LEUCOVORIN
Ipsen	ONIVYDE	irinotecan hydrochloride	INJECTABLE, LIPOSOMAL;INTRAVENOUS	207793-001	Oct 22, 2015		RX	Yes	Yes	9,492,442					TREATMENT OF PANCREATIC CANCER THAT HAS PROGRESSED ON GEMCITABINE-BASED THERAPY, IN COMBINATION WITH 5-FLUOROURACIL AND LEUCOVORIN
Ipsen	ONIVYDE	irinotecan hydrochloride	INJECTABLE, LIPOSOMAL;INTRAVENOUS	207793-001	Oct 22, 2015		RX	Yes	Yes	9,492,442					TREATMENT OF METASTATIC ADENOCARCINOMA OF THE PANCREAS THAT HAS PROGRESSED ON GEMCITABINE-BASED THERAPY, IN COMBINATION WITH 5-FLUOROURACIL AND LEUCOVORIN

International Family Members for US Patent 9,492,442

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2013202947
Australia	2013274287
Australia	2018201942
Brazil	112014031088
Canada	2875824
China	104717961