US Patent 10,137,124: Scope, Claims, Exclusivity, and RET-Inhibitor Patent Landscape
US Patent 10,137,124 is a Loxo Oncology patent covering methods of treating RET-dysregulated cancers with a broad class of pyrazolo[1,5-a]pyridine-3-carbonitrile compounds. The patent expressly includes selpercatinib, marketed by Eli Lilly as Retevmo. Its strongest commercial relevance is the method-of-treatment coverage for RET fusion-positive and RET-mutant cancers, while its broadest legal exposure arises from the genus claim in claim 1.
The patent has an earliest priority date of February 3, 2015 and an expected ordinary patent expiration in February 2036, subject to any patent-term adjustment, terminal disclaimer, or other recorded term modification. FDA regulatory exclusivity for Retevmo is separate from the patent term and does not extend to February 2036.
What drug does US Patent 10,137,124 protect?
The patent protects methods using a chemical genus that includes selpercatinib and related RET inhibitors. The patent is associated with Loxo Oncology, the developer of selpercatinib. Eli Lilly acquired Loxo in 2019 and commercializes Retevmo in the United States.
Selpercatinib is the compound recited in claim 11:
6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile.
The patent also covers related analogs that vary the following structural elements:
| Structural element |
Scope in claim 1 |
| Core heteroaryl system |
A pyrazolo[1,5-a]pyridine-type nitrile system with up to two ring nitrogens |
| A substituent |
Cyano, or CN |
| B substituent |
Alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heteroarylalkyl, or heterocyclic alkyl |
| Ring D |
Saturated nitrogen-containing cyclic or bridged diamine systems |
| E substituent |
Arylalkyl, heteroarylalkyl, or heteroaryl carbonyl groups |
| Therapeutic target |
RET gene, RET protein, or RET expression, activity, or level |
| Disease scope |
RET-dysregulated cancers, including RET fusion and RET-mutant cancers |
The composition is not claimed in isolation in the claims supplied. The principal claims are method claims requiring administration to a patient with a specified RET-related cancer condition.
How broad is claim 1 of US 10,137,124?
Claim 1 is a broad genus method claim. It combines:
- A functional disease limitation, requiring cancer exhibiting dysregulation of RET.
- A large chemical Markush genus.
- Administration of a therapeutically effective amount.
- A requirement that the compound be Formula I, or a pharmaceutically acceptable salt or solvate.
The structural genus is broad because each of the B, Ring D, and E variables includes multiple independent chemical alternatives. Ring D alone covers saturated four- to seven-membered heterocycles with two nitrogen atoms and seven- to nine-membered bridged systems that may contain oxygen.
The claim reaches compounds containing:
- Piperazine-type Ring D structures.
- 3,6-Diazabicyclo[3.1.1]heptane structures.
- Morpholine-related side-chain substituents.
- Pyridyl, pyrazinyl, and other heteroaryl groups.
- Alkoxy, hydroxyalkoxy, aminoalkoxy, and heteroarylalkoxy substituents.
The breadth creates substantial potential coverage, but it also creates validity pressure. A challenger would likely examine whether the specification adequately supports the full structural genus and whether the disclosure enables the full range of claimed compounds and RET-related cancer uses.
What limitations materially narrow claim 1?
The most important limitations are:
- The compound must have the claimed Formula I architecture.
- A must be cyano.
- No more than two of X1 through X4 may be nitrogen.
- Ring D must contain two ring nitrogen atoms.
- E must be one of the specified aryl, heteroaryl, or heteroaryl carbonyl groups.
- The patient’s cancer must involve RET dysregulation.
- Administration must be therapeutically effective.
The claim does not require:
- A specific dose.
- A particular route of administration.
- A particular treatment line.
- A particular cancer stage.
- A specific RET biomarker assay.
- Combination therapy.
- A particular formulation or dosage form.
Which claims specifically cover selpercatinib?
Claims 9 and 11 are the principal selpercatinib claims.
Claim 9 lists ten specific compounds, including selpercatinib. Claim 11 separately claims the selpercatinib chemical entity as a method of treating a RET-dysregulated cancer.
The relevant claim hierarchy is:
| Claim |
Function |
| 1 |
Broad Formula I treatment genus |
| 2-8 |
Structural narrowing of Ring D, E, B, and heteroaryl substitutions |
| 9 |
Closed list of ten specific compounds |
| 10 |
Specific benzylpiperazine compound |
| 11 |
Selpercatinib compound |
| 12-19 |
Additional named analogs |
| 20-26 |
Cancer types, RET fusions, and RET mutations |
| 27-29 |
Combination therapy and second RET inhibitor use |
Claim 11 is narrower than claim 1 because it identifies one exact active compound. It is also commercially stronger against a product using selpercatinib for an approved RET-related cancer indication because there is less room to dispute whether the marketed molecule falls within the claimed chemical structure.
What cancer indications are covered?
Claim 20 lists a wide range of cancers, including:
- Non-small cell lung cancer.
- Thyroid cancer.
- Medullary thyroid cancer.
- Acute lymphoblastic leukemia.
- Acute myeloid leukemia.
- Breast cancer.
- Colorectal cancer.
- Gastric cancer.
- Glioma.
- Leukemia.
- Lymphoma.
- Multiple myeloma.
- Ovarian cancer.
- Papillary renal cell carcinoma.
- Pheochromocytoma.
- Paraganglioma.
- Gastrointestinal stromal tumors.
- Multiple endocrine neoplasia type 2A and 2B.
Claims 21 through 26 focus more narrowly on leukemia, RET fusions, and RET point mutations. The listed fusion partners include KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-RET, FGFR1OP-RET, RET-PTC4, EML4-RET, and other disclosed RET rearrangements.
The mutation claims cover a large list of amino-acid substitutions, including clinically relevant RET mutations such as:
- M918T.
- C634R.
- C634Y.
- C634W.
- V804L.
- V804M.
- V804E.
- Y806C.
- G810R.
- A883F.
- G533C.
- C620R.
- C609Y.
The lists extend well beyond common clinical mutations. That breadth can improve coverage of emerging RET variants, but it also increases the need to assess written description and enablement across the full mutation set.
What are the strongest claims for Retevmo?
The practical claim strength is concentrated in three layers.
Claim 11: exact selpercatinib species
Claim 11 identifies selpercatinib by its complete chemical structure. This is the clearest claim for product-specific use of Retevmo in a RET-dysregulated cancer.
Claims 1 and 9: genus and closed compound list
Claim 1 can cover selpercatinib and structurally related compounds. Claim 9 covers a defined list of compounds, including selpercatinib and analogs that may have different pharmacological or commercial significance.
Claims 20 through 26: biomarker and cancer restrictions
These claims narrow the treatment method to specified cancers, RET fusions, or RET mutations. They are particularly relevant to approved uses involving RET fusion-positive NSCLC, RET-mutant medullary thyroid cancer, and RET fusion-positive thyroid cancer.
Does US Patent 10,137,124 cover the Retevmo formulation?
The supplied claims do not claim a tablet, capsule, excipient system, solid-state form, salt form, dissolution profile, particle size, or manufacturing process independently.
The claims recite a pharmaceutically acceptable salt or solvate, but that language does not by itself create a conventional formulation patent. It extends the method claims to administration of qualifying salts or solvates of the covered compounds.
A generic product using a different tablet formulation could still practice claim 11 if it administers selpercatinib for a covered RET-dysregulated cancer. Conversely, a formulation-only patent would create a separate infringement issue even if the underlying method claim were challenged.
What combination therapies are protected?
Claims 27 through 29 add combination-treatment coverage.
Claim 27 covers administration of an additional therapy or therapeutic agent. Claim 28 lists:
- Radiotherapy.
- Cytotoxic chemotherapy.
- Kinase-targeted therapy.
- Apoptosis modulators.
- Signal-transduction inhibitors.
- Immune-targeted therapy.
- Angiogenesis-targeted therapy.
Claim 29 specifically covers use with:
- A second RET inhibitor.
- Immunotherapy.
- A combination of those therapies.
These claims may be commercially relevant to future treatment regimens, but they are generally narrower and more fact-dependent than claim 11. Infringement would depend on the actual treatment protocol, labeling, promotional conduct, prescribing patterns, or other evidence showing use of the additional therapy.
When does US Patent 10,137,124 lose exclusivity?
The patent’s ordinary term is expected to run until approximately February 2036, based on the February 3, 2015 priority date. The exact enforceable expiration should be confirmed against the USPTO patent-term calculation and the Orange Book listing.
The principal dates are:
| Event |
Date |
| Earliest claimed priority |
February 3, 2015 |
| Patent issuance |
November 27, 2018 |
| Retevmo FDA approval |
May 8, 2020 |
| Five-year new chemical entity exclusivity |
May 8, 2025 |
| Expected ordinary patent expiration |
Approximately February 2036 |
| Potential pediatric or patent-term adjustment |
Must be assessed from FDA and USPTO records |
FDA exclusivity and patent exclusivity operate independently. The end of five-year NCE exclusivity does not authorize a generic launch if an unexpired patent remains listed and enforceable.
Retevmo also received orphan-drug designations for certain RET-driven cancers. Orphan exclusivity is indication-specific and does not replace or extend the patent term for all uses of selpercatinib.
What is the Orange Book status of US Patent 10,137,124?
US Patent 10,137,124 is associated with Retevmo’s FDA-listed patent estate and is relevant to the product’s Orange Book protection. The patent’s importance is that it links the marketed active ingredient to methods of treating RET-driven cancers.
For a generic applicant, the principal regulatory pathway would be an ANDA with a Paragraph IV certification against any listed patent that the applicant believes is invalid, unenforceable, or not infringed. A Paragraph IV certification would create potential litigation under the Hatch-Waxman Act.
A patent listed for a method of use may be addressed through a section viii statement if the generic labeling omits the patented indication. That strategy would be more difficult where the proposed label retains RET-driven cancer indications that practice claims 11, 20, or 22-26.
Which companies compete with Retevmo?
The principal commercial and clinical comparator has been pralsetinib, marketed as Gavreto.
| Drug |
Active ingredient |
Developer or commercial sponsor |
RET profile |
Competitive position |
| Retevmo |
Selpercatinib |
Eli Lilly, following acquisition of Loxo Oncology |
Highly selective RET inhibitor |
Broad approved RET cancer use |
| Gavreto |
Pralsetinib |
Blueprint Medicines and Roche |
Highly selective RET inhibitor |
Direct RET inhibitor competitor |
| Caprelsa |
Vandetanib |
Sanofi |
Multikinase inhibitor with RET activity |
Older medullary thyroid cancer option |
| Cometriq |
Cabozantinib |
Exelixis |
Multikinase inhibitor with RET activity |
Later-line thyroid cancer competition |
| Broad kinase inhibitors |
Various |
Multiple companies |
Variable RET activity |
Less selective and less directly competitive |
Roche discontinued U.S. commercial distribution of Gavreto, but the product’s regulatory and patent position must be distinguished from its commercial availability. Retevmo therefore has a stronger current commercial position in the U.S. selective-RET segment.
Which companies are challenging Retevmo patents?
The supplied record does not identify a Paragraph IV challenger, ANDA filer, district-court complaint, or settlement involving US Patent 10,137,124. No specific challenger should be treated as established solely from the claim text.
The most likely generic challenge would target:
- Claim construction of the Formula I genus.
- Written description and enablement for the broad Markush structure.
- Obviousness based on known RET inhibitors and disclosed analogs.
- Whether the proposed generic label induces practice of the claimed RET indications.
- Whether a section viii carve-out can omit all protected uses.
- The scope of the listed cancer and mutation limitations.
A product-specific claim such as claim 11 is generally harder to avoid through a chemical modification because it identifies selpercatinib itself. A generic launching the same active ingredient would more likely contest validity, enforceability, or the reach of the treatment limitations than argue that the molecule falls outside the claim.
How strong is the patent estate for selpercatinib?
The estate is strongest where four elements align:
- The product is selpercatinib.
- The patient has RET fusion-positive or RET-mutant disease.
- The use corresponds to an approved or commercially promoted indication.
- The patent remains listed and unexpired.
The estate is weaker in several peripheral situations:
- Use of a structurally different RET inhibitor.
- Treatment of a cancer without documented RET dysregulation.
- A generic label that removes all patented indications.
- A formulation or manufacturing dispute not covered by the method claims.
- Off-label use without evidence of induced infringement.
- A challenge to the broad genus based on lack of written description or enablement.
The patent does not provide absolute exclusivity over every RET inhibitor. It protects specified chemical structures and methods using them. Competing RET inhibitors such as pralsetinib, vandetanib, and cabozantinib do not automatically infringe merely because they inhibit RET.
What manufacturing and geographic barriers remain?
US Patent 10,137,124 is a U.S. right. It does not directly block manufacture, sale, or use outside the United States. Parallel foreign patent families may cover the same compounds or uses in Europe, Japan, China, Canada, and other markets, but national prosecution outcomes and expiration dates can differ.
Manufacturing risk can arise from:
- Production of selpercatinib or a covered analog for U.S. sale.
- Importation into the United States.
- Use of the active ingredient in clinical trials.
- Supply of the compound to a party that practices the claimed method.
- Manufacture of a salt or solvate covered by the method claim.
The patent does not, based on the supplied claims, independently claim a synthetic route or process. Separate process, intermediate, solid-state, salt, formulation, and manufacturing patents would determine whether a non-infringing route is available.
What revenue exposure does the patent create?
Retevmo’s revenue exposure is concentrated in RET-driven cancers, particularly:
- RET fusion-positive NSCLC.
- RET-mutant medullary thyroid cancer.
- RET fusion-positive thyroid cancer.
- Potential future RET-driven indications and combination regimens.
A generic launch before approximately 2036 would threaten both price and volume if the entrant could retain RET-related indications in its label. The commercial impact would be greater for a full-label generic than for a carve-out product limited to non-patented uses.
The patent’s commercial value is therefore tied less to the full cancer list in claim 20 than to the approved, biomarker-defined uses in which selpercatinib is prescribed and reimbursed.
Key Takeaways
- US Patent 10,137,124 is a Loxo Oncology method patent covering a broad RET-inhibitor chemical genus.
- Selpercatinib is expressly covered, most directly by claim 11 and also by claims 1 and 9.
- The patent covers treatment of RET fusion-positive and RET-mutant cancers, including lung and thyroid cancers.
- Claims 27-29 extend protection to combination treatment with chemotherapy, immunotherapy, radiotherapy, and other RET inhibitors.
- The patent does not, from the supplied claims, independently claim a tablet formulation or synthetic manufacturing process.
- The expected ordinary expiration is approximately February 2036, subject to the USPTO-recorded patent term.
- FDA NCE exclusivity ended in May 2025, but patent protection can continue for approximately another decade.
- A generic challenge would likely focus on validity, claim scope, induced infringement, and indication carve-outs.
- The principal direct competitor has been pralsetinib, while vandetanib and cabozantinib are less selective alternatives.
- Commercial risk is highest for a full-label selpercatinib generic targeting approved RET-driven indications.
FAQs
Does US Patent 10,137,124 claim selpercatinib itself?
No. The supplied claims principally claim methods of treating RET-dysregulated cancer using selpercatinib and related compounds. Claim 11 identifies selpercatinib as the specific compound used in the claimed method.
Can a generic launch selpercatinib before 2036?
Only if the relevant patent barriers are invalidated, found unenforceable, not infringed, expired, or otherwise avoided. FDA approval after the end of NCE exclusivity does not eliminate an unexpired patent obstacle.
Does a RET mutation have to be listed in claims 25 or 26?
For the specific mutation-dependent claims, the mutation must fall within the listed amino-acid positions or substitutions. The broader claims may cover RET dysregulation without requiring one of those exact mutations, depending on the claim and accused use.
Does the patent cover pralsetinib?
Not automatically. Pralsetinib is a different active compound. The patent could matter only if a specific pralsetinib use or product falls within the structural and method limitations, which cannot be assumed from RET activity alone.
Are antibody or biosimilar issues relevant to this patent?
No conventional biosimilar pathway applies because selpercatinib is a small molecule. The relevant competitive pathway is an ANDA generic challenge, not a biologics license application or biosimilar application.
References
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U.S. Patent No. 10,137,124. (2018). Pyrazolopyridine compounds as RET inhibitors. United States Patent and Trademark Office.
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U.S. Food and Drug Administration. (2020). FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA.
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U.S. Food and Drug Administration. (2024). Retevmo (selpercatinib) prescribing information. Eli Lilly and Company.
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U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.
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Eli Lilly and Company. (2019). Lilly completes acquisition of Loxo Oncology. Lilly investor materials.
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U.S. Food and Drug Administration. (2020). FDA approves pralsetinib for metastatic RET fusion-positive non-small cell lung cancer. FDA.
