US Patent 12,060,354: Avapritinib Crystalline Form A Patent Scope and Competitive Landscape
US Patent 12,060,354 protects methods of treating gastrointestinal stromal tumor (GIST) and acute myeloid leukemia (AML) with Crystalline Form A of Compound (I), identified in the underlying patent family as avapritinib. The strongest commercial protection is directed to the combination of a specific solid-state form and therapeutic use. The patent does not broadly claim avapritinib, all avapritinib formulations, or all uses of the active ingredient.
The principal infringement question is whether a marketed product contains Crystalline Form A and is used for one of the claimed diseases. The principal validity issues are solid-form characterization, XRPD peak variability, written description, enablement, and whether the claimed therapeutic uses were adequately supported as of the relevant filing date.
What drug does US Patent 12,060,354 protect?
The patent covers avapritinib Crystalline Form A, a solid-state form of the kinase inhibitor used in AYVAKIT. FDA approved avapritinib for unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including the PDGFRA D842V mutation, and later expanded its use to advanced systemic mastocytosis indications. [1]
The claims supplied identify Compound (I) by reference rather than by reproducing its chemical structure. The disease and mutation limitations are consistent with avapritinib's clinical and regulatory profile:
| Element |
Patent scope |
| Active pharmaceutical ingredient |
Compound (I), identified in the patent family as avapritinib |
| Solid form |
Crystalline Form A |
| Primary disease |
GIST |
| Genotype limitation |
PDGFRA exon 18 mutation; dependent claim 9 specifies D842V |
| Additional disease |
AML |
| Physical characterization |
XRPD peaks and, alternatively, DSC thermal behavior |
| Administration |
Therapeutically effective amount |
| Formulation |
Not expressly limited in the supplied claims |
| Dose, route and schedule |
Not expressly limited |
| Combination therapy |
Not expressly required |
The patent is therefore a use patent tied to a defined polymorph. It is narrower than a composition-of-matter patent covering avapritinib itself.
How many independent claims does US Patent 12,060,354 have?
The supplied claims contain two independent method claims:
- Claim 1: treatment of GIST with Crystalline Form A.
- Claim 3: treatment of AML with Crystalline Form A.
Claims 2 and 9 narrow the GIST claim by mutation. Claims 4 through 8 further define the form through XRPD or DSC characteristics. Claims 10 through 14 provide parallel narrowing limitations for the AML claim.
Claim architecture
| Claims |
Disease |
Main narrowing feature |
| 1 |
GIST |
At least three of five specified XRPD peaks |
| 2 |
GIST |
PDGFRA exon 18 mutation |
| 3 |
AML |
At least three of five specified XRPD peaks |
| 4 |
GIST |
At least seven of ten XRPD peaks |
| 5 |
GIST |
At least eight of ten XRPD peaks |
| 6 |
GIST |
All ten specified XRPD peaks |
| 7 |
GIST |
Five specified XRPD peaks |
| 8 |
GIST |
DSC endotherm at 194-195°C or onset at 193°C |
| 9 |
GIST |
PDGFRA D842V mutation |
| 10 |
AML |
At least seven of ten XRPD peaks |
| 11 |
AML |
At least eight of ten XRPD peaks |
| 12 |
AML |
All ten specified XRPD peaks |
| 13 |
AML |
Five specified XRPD peaks |
| 14 |
AML |
DSC endotherm at 194-195°C or onset at 193°C |
Claims 1 and 3 are the commercially important claims because they establish the broadest disease-use coverage within the patent. The dependent claims create fallback positions if the three-peak limitations are challenged.
What is the scope of the XRPD limitations?
The broadest XRPD limitation requires at least three peaks selected from five positions:
- 11.5° ± 0.2°
- 15.4° ± 0.2°
- 16.7° ± 0.2°
- 20.0° ± 0.2°
- 21.6° ± 0.2°
This language potentially covers any combination of three, four, or all five listed peaks, provided the accused material is Crystalline Form A and is administered for the claimed treatment.
The narrower ten-peak group includes:
- 11.5° ± 0.2°
- 15.4° ± 0.2°
- 16.7° ± 0.2°
- 18.1° ± 0.2°
- 20.0° ± 0.2°
- 21.6° ± 0.2°
- 23.1° ± 0.2°
- 23.9° ± 0.2°
- 25.9° ± 0.2°
- 30.7° ± 0.2°
Claims 6 and 12 require all ten peaks. Claims 7 and 13 require five peaks. The dependent claims materially improve evidentiary certainty because an accused sample matching a larger number of diagnostic peaks is easier to distinguish from an unrelated polymorph.
Claim-construction and enforcement issues
XRPD peak positions are affected by instrument configuration, sample preparation, calibration, crystallite size, preferred orientation and humidity. The ±0.2° tolerance provides a defined measurement range, but it does not eliminate disputes concerning:
- Whether peaks are present or merely shoulders;
- Whether intensity thresholds apply;
- Whether the sample is a single polymorph or a mixture;
- Whether the accused commercial batch changes form during manufacture or storage;
- Whether the method identifies the administered material or only an intermediate;
- Whether the claimed peak pattern is sufficiently distinctive over prior art.
A generic manufacturer could attempt to avoid literal infringement by using a different polymorph, an amorphous form, a salt, a solvate, or a formulation in which the active ingredient does not retain the claimed crystalline pattern. That strategy would face potential doctrine-of-equivalents arguments, but equivalence is difficult where the patent specifically defines the invention by measurable solid-state characteristics.
What does the DSC limitation add?
Claims 8 and 14 define Form A by a DSC endothermic event with:
- A signal at 194°C to 195°C; or
- An onset temperature of 193°C.
The DSC limitation is an alternative analytical route to identifying the solid form. It can be useful where XRPD results are inconclusive, but it also creates technical attack points. DSC values can vary with heating rate, pan type, sample mass, atmosphere, instrument calibration and sample purity.
The alternative wording may raise claim-construction questions over whether the claimed range and onset temperature describe one event under different reporting conventions or two independent alternatives. A patent challenger would likely examine whether the specification provides sufficient test conditions to reproduce the claimed thermal profile.
How strong is the patent estate for avapritinib?
The avapritinib estate is likely to contain several layers of protection rather than relying solely on US 12,060,354:
| Protection layer |
Commercial purpose |
Relevance to US 12,060,354 |
| Composition of matter |
Protects avapritinib molecule |
Separate and generally broader |
| Therapeutic use |
Protects GIST, PDGFRA-mutant GIST or other diseases |
The '354 patent adds a solid-form limitation |
| Crystalline form |
Protects Form A |
Direct subject matter of the '354 patent |
| Formulation |
Protects tablets, excipients, release profiles or dosage forms |
Not present in the supplied claims |
| Manufacturing process |
Protects crystallization, purification or solid-form conversion |
May create supply-chain barriers |
| Regulatory exclusivity |
Delays approval independent of patent validity |
Controlled by FDA approval and exclusivity rules |
| Orange Book listings |
Provides notice and supports Paragraph IV litigation |
Must be assessed against current FDA records |
The '354 patent has its greatest value when the approved commercial product is manufactured and distributed as Form A. Its value is lower if the sponsor can lawfully commercialize the same active ingredient in another polymorph that retains therapeutic activity and regulatory acceptability.
What patent expiration date applies to US 12,060,354?
The patent issued on June 11, 2024. The grant date alone does not establish the enforceable expiration date. US patent term is generally measured from the earliest effective nonprovisional filing date, subject to terminal disclaimers, patent-term adjustment and any patent-term extension. [2]
The relevant commercial date must therefore be determined from:
- The patent's continuity statement;
- The earliest effective US nonprovisional filing;
- Any terminal disclaimer;
- Patent-term adjustment;
- Any patent-term extension under 35 U.S.C. § 156.
A continuation patent can expire on the same date as an earlier family patent even if it issued years later. A patent-term adjustment can move the date later, while a terminal disclaimer can tie it to another patent with an earlier expiration date.
What is the Orange Book status of US Patent 12,060,354?
AYVAKIT is an FDA-approved small-molecule drug, so the relevant competitive pathway is an ANDA, not a biosimilar application. FDA Orange Book listings determine whether a patent is formally listed against a reference product and whether an ANDA applicant must make a Paragraph IV certification. [3]
The claim text alone does not establish whether Patent 12,060,354 is currently listed in the Orange Book, whether it is listed against a particular AYVAKIT strength, or whether FDA accepted the listing as a drug-substance, drug-product, method-of-use or other patent. Those questions turn on FDA's current electronic Orange Book records and the sponsor's submitted patent information.
Even if listed, a method-of-use patent may be addressed through a section viii statement if the ANDA omits the patented indication and the remaining labeling does not encourage the patented use. A solid-form patent can present a more direct barrier if the generic's proposed drug substance or drug product contains the claimed Form A.
What Paragraph IV challenges and litigation risks exist?
A generic challenger targeting avapritinib could use several approaches:
Formulation or polymorph design-around
The applicant could develop a non-infringing polymorph, amorphous material or alternative salt. The regulatory challenge is showing equivalent pharmaceutical performance and adequate stability without using Form A.
Paragraph IV invalidity challenge
Likely grounds include:
- Anticipation by prior-art disclosures of the same polymorph;
- Obviousness based on known avapritinib forms and routine crystallization screening;
- Lack of written description for the full peak-selection alternatives;
- Lack of enablement across all claimed analytical permutations;
- Indefiniteness in the XRPD and DSC limitations;
- Ineligible or inadequately supported method-of-treatment subject matter.
Solid-form patents often turn on whether the form has unexpected properties, such as improved stability, manufacturability, hygroscopicity or bioavailability. The patent's prosecution record and comparative data are more important than the issued claim language alone.
Label-based risk
The GIST claims are strongest against a generic that includes treatment of PDGFRA exon 18-mutant GIST, particularly D842V disease. The AML claims create a second use category, but the commercial significance depends on whether avapritinib has an FDA-approved AML indication or whether AML use is supported only by clinical or investigational activity.
Does the patent create biosimilar risk?
No. Avapritinib is a chemically synthesized small molecule. The relevant competitive threat is generic substitution through the ANDA pathway, not biosimilar competition under the Public Health Service Act.
The principal risk is therefore an ANDA applicant that:
- Uses Crystalline Form A and challenges the patent;
- Uses a different solid form and asserts non-infringement;
- Omits the patented indication through a section viii carve-out;
- Challenges listed patents through Paragraph IV certifications.
What manufacturing barriers does the patent create?
The patent can restrict commercial manufacture of Form A for the claimed therapeutic uses, but it does not necessarily block every route to avapritinib. Manufacturing exposure depends on whether Form A is:
- The isolated drug substance;
- Created during the final crystallization step;
- Present in the finished tablet;
- Converted into another form before formulation;
- Required for stability or bioavailability;
- Covered by separate process patents.
A freedom-to-operate analysis must test actual batch samples using XRPD and DSC. A process that begins with Form A but converts it completely to another form may present a different infringement profile from a process that produces Form A as the final API.
How does US Patent 12,060,354 compare with broader avapritinib protection?
| Issue |
'354 patent |
Composition patent |
Formulation patent |
| Protects molecule itself |
No |
Yes |
Usually no |
| Requires Crystalline Form A |
Yes |
Usually no |
May or may not |
| Covers all avapritinib forms |
No |
Often yes, subject to claim scope |
No |
| Disease-specific |
GIST and AML |
Often broader or different |
Usually dosage-form focused |
| Vulnerable to polymorph design-around |
High |
Low |
Medium |
| Key evidence |
XRPD, DSC, use records |
Chemical identity and synthesis |
Product composition and manufacturing |
| Generic risk |
Form selection and labeling |
Core API challenge |
Product equivalence and formulation |
Key Takeaways
- US Patent 12,060,354 is directed to methods of treating GIST and AML with avapritinib Crystalline Form A.
- Claims 1 and 3 are the two independent method claims.
- The broadest form limitation requires at least three of five specified XRPD peaks.
- Dependent claims require five, seven, eight or ten XRPD peaks, or a defined DSC endotherm.
- Claim 9 specifically covers PDGFRA D842V-mutant GIST.
- The patent does not, based on the supplied claims, broadly cover avapritinib as a molecule, every polymorph, every formulation or every treatment indication.
- Generic risk depends on whether the ANDA product uses Form A, whether the patented indications are included, and whether the patent is listed in the current Orange Book.
- The relevant competitive pathway is generic ANDA litigation, not biosimilar litigation.
- Patent-term analysis requires the family continuity data, terminal disclaimer status and patent-term adjustment.
FAQs
Can a generic use avapritinib without infringing US Patent 12,060,354?
Potentially. A generic may seek to use a different polymorph, amorphous form, salt or solvate, but it must establish pharmaceutical and regulatory suitability. If its API matches the claimed Form A and its labeling covers a claimed use, infringement risk increases.
Does claim 9 cover all PDGFRA-mutant GIST?
No. Claim 9 is limited to GIST characterized by the PDGFRA D842V mutation. Claim 2 is broader because it refers to an exon 18 mutation in PDGFRα.
Are the XRPD peaks sufficient to prove infringement?
They can provide strong evidence, but testing must account for instrument calibration, sample preparation, mixed forms and peak interpretation. The accused material must also satisfy the treatment and Crystalline Form A limitations.
Does the AML claim establish an FDA-approved AML indication?
No. A patent claim can cover an investigational or non-approved use. FDA approval status must be assessed separately from patent claim scope.
Can a section viii carve-out avoid this patent?
A carve-out may reduce risk for a method-of-use patent if the generic omits the patented indication and its labeling does not encourage that use. It may not resolve infringement if the patent is directed to the solid form used in the generic's drug substance or product.
References
-
U.S. Food and Drug Administration. (2024). AYVAKIT (avapritinib) prescribing information. FDA.
-
United States Patent and Trademark Office. (2024). United States Patent No. 12,060,354. U.S. Department of Commerce.
-
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.
