US Patent 10,584,124: Selpercatinib Crystal Forms, Claim Scope, Exclusivity and Generic Risk
US Patent 10,584,124 protects selected crystalline and solvated forms of selpercatinib, the RET inhibitor marketed by Eli Lilly and Company as Retevmo. Its principal value is solid-state protection: Forms 1, 2, 7 and the isopropyl alcohol solvate Form 8 are defined by XRPD peak patterns. The patent also contains method-of-treatment claims directed to RET-associated cancers, including RET fusion lung cancer and medullary thyroid cancer.
The patent is listed in the FDA Orange Book for Retevmo with an expiration date of June 30, 2037. FDA approval of Retevmo occurred on May 8, 2020. The patent does not broadly claim every chemical form of selpercatinib. It targets specific polymorphs and a specific IPA solvate, which creates meaningful but fact-dependent generic design-around opportunities.[1-3]
What drug does US Patent 10,584,124 protect?
US 10,584,124 is directed to selpercatinib solid forms. Selpercatinib is a small-molecule kinase inhibitor that selectively inhibits RET alterations, including RET gene fusions and activating RET mutations.
| Item |
Data |
| Patent |
US 10,584,124 B2 |
| Patent subject |
Crystalline and solvated forms of selpercatinib |
| Active ingredient |
Selpercatinib, also known as LOXO-292 |
| Brand |
Retevmo |
| Patent holder lineage |
Loxo Oncology; acquired by Eli Lilly |
| FDA approval |
May 8, 2020 |
| Regulatory pathway |
New Drug Application, NDA 213246 |
| Orange Book expiry |
June 30, 2037 |
| Therapeutic class |
RET tyrosine kinase inhibitor |
| Relevant products |
Retevmo capsules and oral administration |
The patent is not the foundational composition-of-matter patent for selpercatinib. Its commercial role is to protect solid-state material used in drug substance manufacture and potentially incorporated into the finished product.
What are the independent claims in US 10,584,124?
The provided claims contain two operative claim categories.
Crystalline-form claim
Claim 1 covers a crystalline form of Formula II selected from:
- Form 1;
- Form 2;
- Form 7; and
- Form 8.
Each form is defined by at least three XRPD peaks within a stated ±0.2° 2θ tolerance.
Claim 1 is therefore a structural solid-state claim, not a claim to selpercatinib by molecular structure alone. A material must satisfy the relevant XRPD limitation to fall within the literal scope of the claim.
Method-of-treatment claim
Claim 3 covers treating a RET-associated cancer by administering a therapeutically effective amount of a compound of claim 1. Read literally, the claim ties the treatment method to the claimed crystalline form.
This creates an important enforcement issue. A product containing selpercatinib may infringe the method claim only if the administered material is the claimed crystalline form. A generic manufacturer could challenge that proposition through product characterization, supply-chain evidence, or a noninfringement position based on a different polymorph, amorphous material, or a different solvate.
How do the XRPD limitations define Forms 1, 2, 7 and 8?
The XRPD peaks are the central claim limitations.
| Form |
Claim 1 identifying peaks |
Additional claim 2, 7, 8 or 9 peaks |
Solid-state description |
| Form 1 |
16.5, 18.9 and 26.0° 2θ |
Peaks include 23.8, 25.3, 25.6 and 28.3° 2θ |
Crystalline selpercatinib form |
| Form 2 |
15.1, 17.8 and 24.2° 2θ |
Peaks include 18.1, 20.4, 21.1, 23.4 and 24.6° 2θ |
Crystalline selpercatinib form |
| Form 7 |
16.6, 18.0 and 19.9° 2θ |
Peaks include 17.3, 19.0, 19.3, 21.4, 23.3 and 25.1° 2θ |
Distinct crystalline form |
| Form 8 |
15.1, 17.8 and 24.2° 2θ |
Same expanded pattern recited for Form 2 |
Isopropyl alcohol solvate |
The most important drafting issue is that Form 2 and Form 8 are assigned the same principal XRPD peak set in the supplied claims. Claim 9 identifies Form 8 as an IPA solvate but repeats the XRPD pattern used for Form 2 in claim 7. XRPD alone may therefore be insufficient to distinguish the two materials. Solvent-content testing, thermogravimetric analysis, Karl Fischer analysis, solid-state NMR, elemental analysis, or other characterization would likely be relevant in an infringement or validity dispute.
What does the ±0.2° 2θ tolerance mean?
The tolerance permits a measured diffraction peak to fall within 0.2 degrees of the stated value. For example, the Form 1 peak at 16.5° 2θ would generally encompass a measured peak from 16.3° through 16.7° 2θ, subject to the patent's claim construction and analytical conditions.
The tolerance does not eliminate the need to show the claimed peak pattern. A product with only one matching peak, or a product whose peaks shift outside the claimed ranges, may support a noninfringement position. Analytical reproducibility, instrument calibration, sample preparation and polymorph mixtures would be central evidence.
What formulations are protected by US 10,584,124?
The patent primarily protects drug substance solid forms rather than a finished capsule formulation. The supplied claims do not recite:
- a particular capsule shell;
- a specific excipient combination;
- a dissolution profile;
- a particle-size distribution;
- a tablet or capsule composition;
- a manufacturing scale;
- a particular dosage strength; or
- a specific release profile.
A Retevmo capsule could still implicate the patent if the selpercatinib inside the capsule is Form 1, Form 2, Form 7 or Form 8. The finished dosage form does not need to reproduce the laboratory crystallization process to create risk if the commercial drug substance has the claimed solid form.
The patent is stronger against a generic that deliberately reproduces the reference product's drug substance form. It is weaker against a manufacturer that can reliably produce and maintain a nonclaimed polymorph or amorphous form without conversion during processing or storage.
What cancers are covered by the method-of-use claims?
Claims 3 through 6 cover treatment of RET-associated cancers. The listed disease categories include:
- lung cancer;
- papillary thyroid cancer;
- medullary thyroid cancer;
- differentiated thyroid cancer;
- recurrent and refractory differentiated thyroid cancer;
- MEN2A and MEN2B;
- pheochromocytoma;
- parathyroid hyperplasia;
- breast cancer;
- colorectal cancer;
- papillary renal cell carcinoma;
- ganglioneuromatosis of the gastroenteric mucosa; and
- cervical cancer.
Claim 5 narrows the treatment population to RET fusion lung cancer or medullary thyroid cancer. Claim 6 further identifies small-cell lung carcinoma, non-small-cell lung cancer, bronchioles lung cell carcinoma and lung adenocarcinoma.
The practical commercial focus is narrower than the full claim language. Retevmo's FDA-approved uses center on RET fusion-positive non-small-cell lung cancer, advanced or metastatic RET-mutant medullary thyroid cancer, and advanced or metastatic RET fusion-positive thyroid cancer requiring systemic therapy and radioactive iodine-refractory treatment where appropriate.[1]
What is the FDA and Orange Book status of US 10,584,124?
Retevmo received FDA approval in May 2020 for specified RET-driven cancers. The product is regulated as a small-molecule drug under an NDA, not as a biologic. Biosimilar approval is therefore not the relevant competitive pathway. Generic competitors would ordinarily use an ANDA and could submit Paragraph IV certifications against listed patents.
US 10,584,124 is listed in the Orange Book for Retevmo. The listed patent expiration date is June 30, 2037.[2] The patent's expiration date is separate from regulatory exclusivity.
| Exclusivity type |
Relevance to Retevmo |
| Patent exclusivity |
US 10,584,124 listed through June 30, 2037 |
| New chemical entity exclusivity |
Five-year period beginning with initial approval, subject to statutory limits |
| Orphan-drug exclusivity |
Potentially applies to specific orphan indications, generally seven years from approval |
| Pediatric exclusivity |
Adds six months if FDA grants and the sponsor satisfies the required pediatric study obligations |
| Biosimilar exclusivity |
Not applicable because selpercatinib is a small molecule |
The initial five-year NCE period would not independently block an ANDA submission after the statutory filing restriction expired. The 2037 patent listing is the more substantial barrier.
When does selpercatinib lose exclusivity?
The key date for the listed patent is June 30, 2037. Regulatory exclusivity may expire earlier, but it can delay approval independently of patent expiry if an applicable exclusivity period remains in force.
The principal timing sequence is:
| Date |
Event |
| June 30, 2017 |
Earliest priority date generally associated with the solid-form patent family |
| May 8, 2020 |
FDA approved Retevmo |
| 2025 |
Five-year NCE exclusivity period generally reaches its end, subject to FDA records and applicable statutory calculations |
| 2027 |
Seven-year orphan exclusivity for an initial orphan indication may reach its end, depending on designation and indication-specific approval dates |
| June 30, 2037 |
Orange Book expiration date for US 10,584,124 |
The patent date should not be treated as a guaranteed market-entry date. Patent-term adjustment, pediatric extensions, later-listed patents, litigation settlements and regulatory exclusivity can change the actual launch window.
What Paragraph IV challenges could target this patent?
A generic applicant could certify under Paragraph IV that US 10,584,124 is invalid, unenforceable or will not be infringed. The most plausible challenge theories would focus on:
Anticipation and obviousness
The challenger could argue that the claimed polymorphs were disclosed, inherently present, or obvious from earlier selpercatinib solid-state work. Solid-form patents often turn on whether the claimed form was predictable, whether the prior art taught the relevant crystallization conditions, and whether the form has unexpected properties.
Insufficient written description or enablement
The claims cover multiple forms and XRPD-defined materials. A challenger could examine whether the specification adequately characterizes each claimed form and enables its preparation across the full claim scope.
Indefiniteness or analytical ambiguity
The Form 2 and Form 8 overlap in the supplied claim language. A challenger could argue that the claims do not clearly distinguish a crystalline form from an IPA solvate when both are defined by substantially identical XRPD data.
Noninfringement
A generic could develop a different polymorph, amorphous selpercatinib, or a non-IPA solvate. It would then need to control conversion during milling, granulation, encapsulation, storage and dissolution testing. A noninfringing form that converts into a claimed form could create product-release and inducement risks.
Which companies are challenging Retevmo patents?
The public record identified here does not establish a specific active Paragraph IV challenger or a final judicial determination involving US 10,584,124. The absence of an identified challenger should not be treated as proof that no ANDA has been filed. ANDA filings and Paragraph IV notices may become visible through FDA litigation records, district-court complaints or commercial regulatory databases at different times.
No biosimilar challenge is expected because selpercatinib is a chemically synthesized small molecule. The relevant competitive threats are generic ANDA applicants, alternative RET inhibitors and potentially next-generation RET inhibitors with activity against resistance mutations.
How strong is the patent estate for selpercatinib?
US 10,584,124 is a meaningful secondary patent, but it is narrower than a composition-of-matter patent.
| Strength factor |
Assessment |
| Claim specificity |
High; four forms are tied to defined XRPD peaks |
| Product relevance |
Potentially high if the commercial drug substance uses a claimed form |
| Design-around potential |
Moderate to high for a manufacturer with solid-state development capability |
| Form 8 enforcement |
Fact-dependent because the IPA solvate and Form 2 XRPD language overlap |
| Method claims |
Useful for labeled RET indications, but dependent on use of the claimed form |
| Manufacturing leverage |
High if the sponsor controls a scalable, stable crystalline process |
| Biosimilar exposure |
Not applicable |
| Generic exposure before 2037 |
Depends on Paragraph IV activity, litigation and settlement terms |
The principal strength is evidentiary. XRPD provides a practical way to compare a generic's drug substance against the claimed forms. The principal weakness is that polymorph claims do not necessarily prevent all alternative forms of the same active ingredient.
What manufacturing and geographic barriers affect generic entry?
A generic manufacturer must solve more than chemical synthesis. It must establish:
- reproducible polymorph selection;
- control of solvent inclusion;
- prevention of polymorphic conversion;
- batch-to-batch XRPD consistency;
- stability under humidity and temperature stress;
- compatibility with excipients and capsule processing;
- analytical methods distinguishing mixtures; and
- a regulatory strategy consistent with the reference product.
The patent is a United States right. Its direct exclusionary effect is limited to U.S. manufacture, use, sale, offers for sale and importation. Parallel patent families may cover corresponding forms in Europe, Japan, Canada, China and other markets, but foreign rights must be assessed independently. A process performed offshore can still create U.S. infringement risk if the resulting product is imported or sold in the United States.
How does US 10,584,124 compare with a composition patent?
| Patent type |
Scope |
Design-around risk |
| Composition-of-matter patent |
Covers the selpercatinib molecule or broad chemical genus |
Low while valid and enforceable |
| Crystalline-form patent |
Covers specified polymorphs or solvates |
Higher; alternative forms may be available |
| Formulation patent |
Covers dosage composition, excipients or release properties |
Depends on product architecture |
| Method-of-use patent |
Covers treatment of defined diseases or biomarker populations |
Depends on label, prescribing and induced use |
| Manufacturing patent |
Covers a synthesis or crystallization process |
Depends on process substitution and proof of use |
US 10,584,124 is strongest when the marketed drug substance is one of the claimed forms and the generic copies that solid-state material. It is less effective as a standalone barrier against a technically distinct selpercatinib form.
What generic launch scenarios exist for Retevmo?
Three scenarios are commercially relevant.
Launch after patent expiry
A generic launches after June 30, 2037, assuming no later-listed patent or extended regulatory barrier. This is the lowest litigation-risk path but gives the innovator a long period of protection.
Paragraph IV launch before expiry
A generic files an ANDA with a Paragraph IV certification and prevails in litigation, obtains a favorable settlement, or accepts launch risk. This path depends on claim validity, proof of the reference product's solid form and the generic's actual form.
Design-around launch
A generic develops a nonclaimed selpercatinib form. This approach may avoid literal infringement but requires robust characterization and controls to prevent conversion into Forms 1, 2, 7 or 8. The method claims create a second layer of risk if the product is shown to contain a claimed form during administration.
Key Takeaways
- US 10,584,124 is a solid-state patent for selpercatinib, marketed as Retevmo.
- Claims 1, 2, 7, 8 and 9 cover Forms 1, 2, 7 and 8 through XRPD peak limitations.
- Form 8 is expressly identified as an isopropyl alcohol solvate.
- The supplied claims create an apparent Form 2/Form 8 XRPD overlap that could become relevant to claim construction and validity.
- Claims 3 through 6 cover treatment of RET-associated cancers, with specific emphasis on RET fusion lung cancer and medullary thyroid cancer.
- The patent is listed in the Orange Book with a June 30, 2037 expiration date.
- Selpercatinib is a small molecule, so generic ANDA competition, not biosimilar competition, is the relevant pathway.
- A generic may attempt to avoid infringement through a different polymorph, amorphous material or non-IPA solvate.
- The patent is commercially important but narrower than a composition-of-matter patent.
- No specific active Paragraph IV challenger or final litigation result for this patent is established by the cited public sources.
FAQs
Does US 10,584,124 cover all selpercatinib products?
No. It covers selected crystalline and solvated forms defined by XRPD data. A selpercatinib product using a different solid form may fall outside the literal scope.
Is Form 8 a crystalline form or a solvent-containing material?
The claim identifies Form 8 as an isopropyl alcohol solvate. It is therefore a solvent-containing crystalline form, subject to proof of the claimed solid-state characteristics.
Can a generic use amorphous selpercatinib to avoid this patent?
Potentially. An amorphous product may avoid a claim limited to the listed crystalline forms, but the manufacturer must demonstrate that the material does not convert into a claimed form during production, storage or administration.
Does FDA Orange Book listing prove that Retevmo uses Form 1?
No. Orange Book listing identifies the patent as relevant to the approved drug. It does not, by itself, resolve which specific polymorph is present in every commercial batch.
Are RET inhibitors such as pralsetinib direct patent substitutes for selpercatinib?
They are therapeutic competitors, not automatic patent substitutes. Pralsetinib and selpercatinib have separate chemical structures, clinical labels and patent estates. Their commercial overlap is greatest in RET fusion-positive lung cancer and RET-altered thyroid cancer.
References
-
U.S. Food and Drug Administration. (2020). Retevmo (selpercatinib) prescribing information. FDA.
-
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book: Retevmo. FDA.
-
United States Patent and Trademark Office. (2020). U.S. Patent No. 10,584,124, solid forms of selpercatinib. USPTO.
