United States Patent 9,006,224: Everolimus Treatment of Pancreatic Neuroendocrine Tumors
U.S. Patent No. 9,006,224 protects a narrow method of using everolimus, identified in the patent as 40-O-(2-hydroxyethyl)-rapamycin, to treat advanced pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy. The independent claim requires monotherapy. Dependent claims narrow the regimen to 10 mg/day and to islet cell tumors.
The patent does not claim everolimus as a chemical compound, all everolimus formulations, or every use of everolimus in oncology. Its commercial value is concentrated in the pancreatic neuroendocrine tumor indication and in the 10-mg daily monotherapy regimen reflected in the FDA-approved Afinitor labeling.
What does U.S. Patent 9,006,224 claim?
The patent contains three relevant claims:
| Claim |
Scope |
Practical effect |
| 1 |
Treatment of advanced pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy by administering a therapeutically effective amount of everolimus as monotherapy |
Broadest claim |
| 2 |
Claim 1, where the unit dose is 10 mg/day |
Covers the labeled 10-mg daily dose |
| 3 |
Claim 1, where the tumor is an islet cell tumor |
Narrows the covered tumor type |
The patent is directed to a treatment method rather than a composition of matter. It covers conduct by a party that administers, directs, or potentially induces the claimed treatment regimen. It does not, on its face, prohibit manufacture or sale of everolimus for every indication.
What is the active ingredient covered by the patent?
The claimed active ingredient is 40-O-(2-hydroxyethyl)-rapamycin, the compound commonly known as everolimus. Everolimus is an mTOR inhibitor. Its approved oncology products include Afinitor tablets and Afinitor Disperz tablets.
The patent uses the chemical designation rather than relying solely on the brand name. A product containing the same active pharmaceutical ingredient can fall within the claim if the claimed treatment conditions are also met.
How should claim 1 be construed?
Claim 1 requires all of the following elements:
- A human subject.
- A need for treatment.
- A pancreatic neuroendocrine tumor.
- An advanced tumor.
- Prior failure of cytotoxic chemotherapy.
- Administration of a therapeutically effective amount of everolimus.
- Everolimus administered as monotherapy.
The claim uses “comprising,” which generally makes the claim open-ended as to additional steps or procedural elements. The more important limitation is “as a monotherapy.” That limitation distinguishes the claim from a regimen in which everolimus is administered with another anticancer agent as part of the treatment protocol.
“Therapeutically effective amount” is functional language. It does not impose a single numerical dose in claim 1. Claim 2 supplies the principal numerical limitation by specifying 10 mg/day.
Does claim 1 cover all pancreatic neuroendocrine tumors?
No. The claim is narrower than all pancreatic neuroendocrine tumors. It is limited to advanced tumors after failure of cytotoxic chemotherapy. The claim does not expressly cover:
- Newly diagnosed tumors before cytotoxic chemotherapy;
- Tumors treated in an adjuvant setting;
- Tumors that have not progressed or are not advanced;
- Non-pancreatic neuroendocrine tumors;
- Treatment in combination with another anticancer therapy, if the combination defeats the monotherapy limitation;
- Nonhuman treatment; or
- Uses of everolimus unrelated to pancreatic neuroendocrine tumors.
The phrase “pancreatic neuroendocrine tumors” includes tumors historically described as pancreatic islet-cell tumors. Claim 3 confirms that islet cell tumors are a claimed species.
What does claim 2 add to the patent?
Claim 2 limits claim 1 to a unit dose of 10 mg/day. This is commercially significant because the FDA-approved Afinitor regimen for progressive pancreatic neuroendocrine tumors is 10 mg orally once daily, subject to dose modification for toxicity and clinical circumstances.[2]
Claim 2 is narrower than claim 1. A treatment using 7.5 mg/day, 5 mg/day, or an intermittent dose may fall outside the literal wording of claim 2, but it could still fall within claim 1 if the dose is therapeutically effective and the remaining limitations are satisfied.
The word “unit dose” may raise an interpretation issue. The claim is directed to the amount administered per day, not necessarily to the strength of a single tablet. A 10-mg daily dose could be supplied as one 10-mg tablet or as multiple tablets whose total daily amount is 10 mg.
What does claim 3 protect?
Claim 3 covers treatment under claim 1 when the tumor is an islet cell tumor. It is a species claim within the broader pancreatic neuroendocrine tumor category.
Claim 3 does not eliminate the other limitations of claim 1. The tumor still must be advanced, the patient must have failed cytotoxic chemotherapy, and everolimus must be administered as monotherapy in a therapeutically effective amount.
What is the patent’s priority, filing, and expiration position?
Public patent records identify U.S. Patent No. 9,006,224 as a Novartis-related everolimus use patent directed to pancreatic neuroendocrine tumors. The patent issued on April 14, 2015.[1]
| Event |
Date or status |
| Earliest reported priority |
December 18, 2007 |
| U.S. issue date |
April 14, 2015 |
| Patent type |
Method-of-treatment patent |
| Patent holder associated with the family |
Novartis AG and related Novartis entities |
| Expected ordinary patent-term endpoint |
December 2028, subject to patent-term adjustment, disclaimers, and terminal events |
| Regulatory relevance |
Everolimus treatment of pancreatic neuroendocrine tumors |
The expected expiration date should be determined from the issued patent, continuity data, patent-term adjustment, and any terminal disclaimer. The 20-year term generally runs from the earliest effective nonprovisional filing date, not from the issue date.[3]
What is the FDA and Orange Book status of U.S. Patent 9,006,224?
Everolimus was approved by the FDA for progressive pancreatic neuroendocrine tumors of pancreatic origin in 2011 under the Afinitor brand. The approval was based principally on the RADIANT-3 study, which evaluated everolimus in patients with advanced pancreatic neuroendocrine tumors.[2]
The FDA labeling states that Afinitor is indicated for adults with progressive neuroendocrine tumors of pancreatic origin that are unresectable, locally advanced, or metastatic. The labeled dose is 10 mg once daily, with dose reductions for adverse reactions and drug interactions.[2]
For Orange Book purposes, the relevant distinction is between:
- Patents covering the active ingredient;
- Patents covering dosage forms or formulations;
- Patents covering methods of use; and
- Regulatory exclusivity.
The compound patent for everolimus is separate from the pancreatic neuroendocrine tumor method patent. The commercial barrier after compound-patent expiration therefore depends heavily on listed use patents, formulation patents, FDA labeling, and the scope of an ANDA applicant’s Paragraph IV certification.
The current Orange Book listing and patent-use-code entries control the operative regulatory position. A patent may remain relevant to litigation even when a generic applicant uses a Section viii statement to carve out a patented indication from its labeling.[4]
What formulation patents protect Afinitor and Afinitor Disperz?
U.S. Patent 9,006,224 is not a formulation patent. It does not claim:
- The tablet matrix;
- Particle size;
- Solid dispersion technology;
- Coating materials;
- Excipients;
- Oral suspension technology; or
- Manufacturing parameters for an everolimus dosage form.
Separate Novartis patent families have addressed everolimus solid oral dosage forms and dispersible tablets. Those patents can create additional barriers even when an applicant designs around a method-of-use claim.
A generic product may therefore avoid literal infringement of Patent 9,006,224 by omitting the pancreatic neuroendocrine tumor indication, while still facing formulation or process patents. Conversely, a product may avoid a formulation patent but create method-of-use exposure if its labeling instructs use in the claimed patient population.
How strong is the patent estate for pancreatic neuroendocrine tumor treatment?
The estate is strongest when the accused product or label aligns with the full clinical profile in claim 1:
- Everolimus;
- 10 mg daily;
- Monotherapy;
- Advanced pancreatic neuroendocrine tumors;
- Prior cytotoxic chemotherapy failure.
The estate is weaker where a generic applicant:
- Omits the pancreatic neuroendocrine tumor indication;
- Uses a Section viii carve-out;
- Markets only for unpatented indications;
- Avoids instructions for monotherapy;
- Supplies a formulation that does not practice a separate formulation patent; or
- Relies on physician-directed use outside the labeled population.
Literal infringement risk by scenario
| Scenario |
Likely relation to Patent 9,006,224 |
| 10 mg everolimus monotherapy for advanced pNET after chemotherapy failure |
Highest literal infringement risk |
| Everolimus for pNET before chemotherapy failure |
Claim 1 limitation not met on the stated facts |
| Everolimus combined with another anticancer agent |
Potentially outside the monotherapy limitation |
| Everolimus for renal cell carcinoma |
Outside the claimed tumor indication |
| Everolimus for breast cancer |
Outside the claimed tumor indication |
| Everolimus for non-pancreatic NET |
Outside the express tumor limitation |
| Everolimus 5 mg/day for pNET |
May avoid claim 2, but claim 1 remains relevant |
| Generic label omitting pNET |
Reduces inducement and regulatory risk |
| Physician-prescribed off-label pNET use |
May create downstream use issues despite a carve-out |
What Paragraph IV challenges and generic entry risks apply?
An ANDA applicant seeking approval for generic everolimus can certify under Paragraph IV that listed patents are invalid, unenforceable, or not infringed. The applicant must provide notice to the patent holder, which can trigger Hatch-Waxman litigation and a potential 30-month FDA approval stay.[5]
A Section viii statement is a different path. The applicant can seek approval for non-patented indications while carving out the patented pNET indication from its labeling. The commercial value of that strategy depends on whether the remaining indications support viable sales.
The principal generic-entry scenarios are:
- Full-label challenge. The applicant seeks the pNET indication and challenges the method patent.
- Skinny-label entry. The applicant omits the pNET indication and enters for non-patented uses.
- Formulation challenge. The applicant challenges tablet or dispersible-formulation patents separately.
- Settlement-based entry. The parties agree to a launch date, license, or other restrictions.
- Post-expiration entry. The applicant waits for the relevant patent term to expire.
A generic label that expressly instructs 10 mg/day monotherapy for advanced pNET after chemotherapy failure creates the clearest inducement theory. A label limited to other indications materially reduces that risk, although product marketing, promotional statements, and supply-chain conduct can affect the analysis.
Which companies compete with or challenge the Afinitor patent estate?
The competitive field includes manufacturers of generic everolimus tablets and companies developing alternative treatments for pancreatic neuroendocrine tumors.
Generic competition is primarily relevant to:
- Teva Pharmaceuticals;
- Par Pharmaceutical and related entities;
- Sun Pharmaceutical Industries;
- Hikma Pharmaceuticals and West-Ward entities; and
- Other ANDA applicants seeking everolimus approval.
The exact litigation exposure depends on the applicant’s certification, proposed label, dosage form, and the patents listed at the time of filing. The mere existence of a generic everolimus approval does not establish approval for the patented pNET indication.
Alternative pNET therapies include somatostatin analogues, peptide receptor radionuclide therapy, targeted agents, and cytotoxic regimens. Those products do not directly invalidate Patent 9,006,224, but they can reduce the commercial value of the claimed indication by limiting market share and changing treatment sequencing.
What licensing and settlement issues affect the patent landscape?
Patent settlements involving generic everolimus products can determine practical launch timing even when the patent’s nominal expiration date remains later. Relevant provisions may include:
- Authorized-generic supply;
- Delayed launch;
- License rights;
- Territory limitations;
- Indication-specific entry;
- No-challenge clauses;
- Volume limits; and
- Restrictions on formulation or distribution.
A settlement does not necessarily eliminate the patent. It reallocates the risk and sets a contractual entry date. The economic result depends on whether the generic is permitted to enter with a full label, a skinny label, or an authorized-generic arrangement.
What geographic coverage does the patent provide?
U.S. Patent 9,006,224 provides rights only in the United States. Foreign counterparts require separate analysis by jurisdiction. European, Canadian, Japanese, and other national rights may have different:
- Claim scope;
- Patent-term adjustments;
- Supplementary protection certificates;
- Opposition outcomes;
- Validity rulings;
- Orange Book equivalents; and
- Generic approval procedures.
A U.S. design-around does not establish freedom to operate in Europe or other markets.
Key Takeaways
- U.S. Patent 9,006,224 is a method-of-treatment patent for everolimus in advanced pancreatic neuroendocrine tumors.
- Claim 1 requires monotherapy and prior failure of cytotoxic chemotherapy.
- Claim 2 specifically covers a 10-mg daily dose.
- Claim 3 covers islet cell tumors as a narrower species.
- The patent does not claim everolimus itself or every everolimus formulation.
- The strongest infringement case involves a 10-mg everolimus product labeled for monotherapy in post-chemotherapy advanced pNET.
- A Section viii carve-out can reduce risk by omitting the patented pNET indication.
- Formulation and manufacturing patents must be analyzed separately.
- The expected ordinary patent-term endpoint is in December 2028, subject to the issued record and any term adjustments or disclaimers.
- FDA approval of generic everolimus for other indications does not, by itself, establish authorized entry for the patented pNET use.
FAQs About U.S. Patent 9,006,224
Does Patent 9,006,224 cover Afinitor for renal cell carcinoma?
No. The stated claims are limited to pancreatic neuroendocrine tumors. Renal cell carcinoma is outside the express tumor limitation.
Can a generic company sell everolimus without infringing this patent?
Potentially. A generic company may reduce risk by omitting the patented pNET indication, using a Section viii statement, and avoiding promotional material that induces the claimed use.
Does a 5-mg everolimus tablet avoid claim 2?
It may avoid the literal 10-mg/day limitation in claim 2 if the prescribed daily dose is not 10 mg. Claim 1 must still be analyzed because it does not specify a numerical dose.
Is Patent 9,006,224 a composition-of-matter patent?
No. It is a method-of-treatment patent. It does not claim the molecular structure of everolimus as a standalone composition.
Why is the monotherapy limitation commercially important?
It narrows the claim to treatment in which everolimus is used as monotherapy. A regimen expressly combining everolimus with another anticancer agent may fall outside the literal scope, although the complete facts and infringement theory control.
References
- U.S. Patent No. 9,006,224. (2015). Treatment of pancreatic neuroendocrine tumors using 40-O-(2-hydroxyethyl)-rapamycin. United States Patent and Trademark Office.
- U.S. Food and Drug Administration. (2023). Afinitor (everolimus) prescribing information. Novartis Pharmaceuticals Corporation.
- United States Patent and Trademark Office. (2024). Patent term calculator and patent term adjustment guidance.
- U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
- U.S. Food and Drug Administration. (2024). Abbreviated new drug application submissions: Patent certification and 30-month stay provisions.
