United States Patent US 12,398,133: Scope of Claims, Claim Validity Levers, and KRAS G12C Landscape Implications
US 12,398,133 claims a tightly defined chemical crystalline “M atropisomer” form of a specific fluorinated pyridopyrimidinone (Compound 1), with explicit 19F solid-state NMR peak patterns used as the identity-defining characterization. It then extends protection to (i) pharmaceutical compositions (including 120 mg tablets) and (ii) methods of treating KRAS G12C cancers across a broad list of tumor types, with dependent claims narrowing to non-small cell lung cancer and specific indications like colorectal and pancreatic cancer.
The patent’s enforceable core is not a generic KRAS G12C inhibitor claim. It is a form-and-identity claim: crystalline form + atropisomer identity + NMR fingerprint. That design pushes the patent toward policing “same compound, same form” rather than policing “any drug with the same mechanism.”
What do the independent claims actually cover?
Claim 1: chemical definition + crystalline M-atropisomer + 19F solid-state NMR fingerprint
Claim 1 defines the subject matter as:
- A crystalline form of the M atropisomer of:
- 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one (“Compound 1”)
- And the compound is characterized by 19F solid state NMR with peaks at approximately:
This is a classic “product-by-analytical-feature” structure. Practically, the patent tries to make the identity of the claimed material depend on a quantitative/qualitative analytical readout (peak positions) rather than solely on synthetic description.
Claims 2-3: broader 19F NMR fingerprint + spinning frequency condition
- Claim 2 expands the NMR fingerprint: peaks at approximately
−49, −60, −79, −90, −109, −120, −138, −150, −168, −179 ppm
- Claim 3 adds an experimental condition:
the 19F solid state NMR is measured at 14 kHz spinning frequency
These dependent claims increase the “lock-in” strength by adding:
- more peaks to match (harder to design around), and
- the rotor speed parameter that affects peak shape/position reporting and method comparability.
Claims 4-6 and 7-9 and 10-12: composition claims with tablet format and dose amount
The patent then claims formulations that include the claimed form:
- Claim 4: pharmaceutical composition containing the compound of claim 1 + excipient
- Claim 5-6: tablet format with 120 mg of the compound
The same pattern repeats for the more precisely defined NMR embodiments:
- Claims 7-9: tablet, 120 mg, compound of claim 2
- Claims 10-12: tablet, 120 mg, compound of claim 3
So the composition claims are not merely “oral dosage forms.” They are anchored to tablet and a specific tablet payload.
Claims 13-42: KRAS G12C cancer treatment methods, broad tumor list, dependent narrowing
The patent claims methods of treating KRAS G12C cancers by administering the claimed form:
- Claim 13: method of treating KRAS G12C cancer; “therapeutically effective amount” of compound of claim 1
- The cancer is limited to a broad list that includes:
- non-small cell lung cancer, small intestine, appendix, colorectal, endometrial, pancreatic, liver, small cell lung cancer, cervical, germ cell tumor, ovarian, pancreatic neuroendocrine tumor, bladder, myelodysplastic/myeloproliferative neoplasms, head and neck, esophageal, soft tissue sarcoma, malignant mesothelioma, thyroid, skin, gastric, bile duct
- Claims 14-18 narrow the list progressively; e.g., claim 15 targets non-small cell lung cancer, claim 16 targets colorectal, claim 17 targets pancreatic, claim 18 allows a 3-tumor set.
- Claims 19-22 add an “administered to an adult” limitation.
The same structural method-of-use claims repeat for:
- Claim 23: compound of claim 2
- Claim 33: compound of claim 3
with analogous tumor lists and adult limitation claims (29-32 for claim 2; 39-42 for claim 3).
How broad is the claim scope, and where is it narrow?
Breadth by claim category
| Claim category |
Independent basis |
Practical coverage |
| Chemical product (Claims 1-3) |
crystalline form + M atropisomer + 19F solid-state NMR peak set |
Strong on “same material identity,” weaker on “similar molecules” |
| Formulation (Claims 4-12) |
compound identity from 1-3 + excipient + tablet + 120 mg |
Polices manufacturing/form factor/dose specifics |
| Method of treatment (Claims 13-42) |
KRAS G12C mutation cancers + administration of claimed compound |
Broad tumor label reach, but only for the claimed form |
Narrowness levers
The patent narrows scope in at least three ways that matter for design-around and infringement analysis:
-
Crystalline form + M atropisomer
- Even if a competitor has the same chemical skeleton, a different polymorph or different atropisomer arrangement can avoid literal “crystalline form of the M atropisomer” coverage.
-
19F solid-state NMR fingerprint
- The identity requirement in claim 1 (−109 and −120 ppm) and claim 2 (10-peak list) creates an analytical gating step.
- A competitor can target different solid-state form or different NMR characteristics (for example via amorphous content, different polymorph, or processing changes that shift measured peak positions).
-
Experimental condition (14 kHz spinning)
- Claim 3 ties the definition to a measurement parameter. This tends to increase proof specificity in infringement and can increase method comparability disputes.
What is “Compound 1” in claim-terms, and why the atropisomer language matters?
In claim language, “Compound 1” is not just a structural name. It is:
- a particular fluorinated pyridopyrimidinone substitution pattern,
- with a defined stereochemical element:
- “M atropisomer” (axial chirality class),
- “(2S)-2-methyl-… piperazinyl” and other stereochemical descriptors appear within the named structure.
In patent enforcement, axial chirality definitions often matter because a company can sometimes obtain the same molecular formula with a different atropisomer ratio, or isolate only one atropisomer. Claim 1’s wording requires the crystalline form of the M atropisomer, not merely “contains an M-atropisomer component.”
How do the composition claims change infringement risk?
Tablet format + 120 mg
The composition claims lock to:
- tablet dosage form, and
- 120 mg of the compound (for each of the claim family variants tied to claim 1, 2, or 3)
This affects infringement risk in two ways:
-
If a competitor markets a different unit strength (for example 60 mg or 200 mg) they may not fall within the literal scope of claims that require “the tablet comprises 120 mg.”
-
If a competitor uses tablets but the formulation contains a different polymorph (or non-claimed solid-state form), the analytical definition can still avoid literal coverage.
Excipients are not limiting
All composition claims use “pharmaceutically acceptable excipient,” which is broad. The limiting features remain:
- the claimed compound identity, and
- the tablet + 120 mg.
What is the method-of-use scope across KRAS G12C cancers?
The method claims are large and deliberate. Claim 13’s tumor list is extensive and then narrowed via dependent claims (14-18). It repeats for claims 23 and 33 for each compound identity variant.
Tumor list coverage pattern
Across claims 13/23/33, the tumor list includes (non-exhaustive list as written in the claim text you provided):
- Non-small cell lung cancer (NSCLC)
- Small cell lung cancer
- Colorectal cancer
- Pancreatic cancer
- Endometrial cancer
- Liver cancer
- Bladder cancer
- Cervical cancer
- Gastric cancer
- Bile duct cancer
- Skin cancer
- Head and neck cancer
- Esophageal cancer
- Ovarian cancer
- Soft tissue sarcoma
- Malignant mesothelioma
- Thyroid cancer
- Germ cell tumor
- Myelodysplastic/myeloproliferative neoplasms
- Pancreatic neuroendocrine tumor
- Appendix cancer
- Small intestine cancer
Then dependent claims focus on a subset:
- NSCLC (claim 15 / claim 25 / claim 35)
- Colorectal (claim 16 / claim 26 / claim 36)
- Pancreatic (claim 17 / claim 27 / claim 37)
- and combinations like NSCLC + colorectal + pancreatic (claim 18 / claim 28 / claim 38)
Adult limitation
Dependent claims add:
- “administered to an adult” (claims 19-22, 29-32, 39-42)
This restricts coverage from pediatric-only indications or pediatric trial designs that do not include adults.
Patent landscape: how this claim strategy fits US KRAS G12C technology blocks
Where US 12,398,133 likely positions in the broader landscape
Even without the full bibliographic record, the claim drafting shows it is not targeting the generic KRAS G12C mechanism. It targets:
- a specific inhibitor scaffold (as named),
- a specific solid-state form (crystalline M atropisomer),
- and an analytical fingerprint (19F solid-state NMR peaks).
In the US patent landscape for KRAS G12C, this is a common “second layer” strategy:
- primary composition-of-matter patents cover the active pharmaceutical ingredient broadly (often by structure and/or stereochemistry),
- later patents cover polymorphs, salts, hydrates, and stereochemically enriched forms,
- formulation patents then tie to dosage forms and strengths,
- method patents tie use to KRAS G12C and to cancer types.
High-probability freedom-to-operate (FTO) fault line
The practical FTO question shifts from “Does the competitor inhibit KRAS G12C?” to:
- Is the competitor using the same crystalline form and same M atropisomer?
- Does the competitor’s isolated API pass the same 19F solid-state NMR peak criteria?
- Are their marketed tablets exactly 120 mg?
- Are method claims triggered by the patient population and indication?
- for adult-only dosing, coverage is narrower if dosing is only in pediatrics (but the claims include adults, and the tumor list is broad)
This makes US 12,398,133 most sensitive to analytical comparability and solid-state characterization during manufacturing.
Claim-utility map for enforcement and licensing
What evidence typically wins under these claims
Given the claim language, enforcement tends to hinge on:
- Solid-state form qualification showing “crystalline form”
- Atropisomer confirmation showing “M atropisomer”
- 19F solid-state NMR peak reporting at defined conditions
- Tablet strength confirmation showing “120 mg”
- Indication confirmation showing KRAS G12C status and cancer type, and adult administration
Which claims are strongest for commercial blocking
- Claim 2 and Claim 3 are stronger identity anchors than claim 1 because they expand the NMR fingerprint and add a spinning frequency condition.
- Tablet 120 mg composition claims can block specific branded or generic presentations at the unit strength level.
- Method claims can support clinical and labeling enforcement if the product is used in adults for KRAS G12C tumors in the listed categories.
Design-around pathways signaled by the claim structure
This is the inverse view: where a challenger can try to avoid literal infringement.
-
Switch solid-state form
- Use a different polymorph, amorphous form, hydrate, or solvated form
- The NMR fingerprint requirement can fail if the peaks differ
-
Change atropisomer identity
- Use the P atropisomer or a racemic mixture, if the competitor can meet the product spec without a “crystalline form of the M atropisomer” component
-
Alter formulation strength
- Avoid exactly 120 mg per tablet
-
Use different patient subset
- Avoid adult-only administration if a purely pediatric program exists (this is less common for KRAS G12C, but the adult limitation still matters for claim scope)
Key Takeaways
- US 12,398,133 is a form-identity patent built on crystalline M-atropisomer Compound 1 plus an explicit 19F solid-state NMR fingerprint.
- The NMR fingerprint is doing the heavy lifting: claim 1 requires two peaks (−109 and −120 ppm), while claims 2-3 add a 10-peak list and a 14 kHz rotor condition.
- Formulation claims are anchored to tablet and 120 mg strength, tightening literal infringement for specific marketed presentations.
- Method claims cover KRAS G12C cancer treatment across a wide tumor list, with dependent claims narrowing to NSCLC, colorectal, and pancreatic cancers, plus an adult limitation.
FAQs
1) Is the patent protected by a broad “KRAS G12C inhibitor” mechanism claim?
No. The method claims cover KRAS G12C cancers, but only when the administered compound is the specific crystalline M atropisomer with the 19F solid-state NMR fingerprint defined in claims 1-3.
2) Can a different solid-state form avoid the patent?
Yes in claim scope terms. The claims require a crystalline form and specific 19F solid-state NMR peak sets, so a different polymorph or non-matching NMR fingerprint can fall outside literal coverage.
3) Which claims are most sensitive to manufacturing analytics?
Claims 1-3. Identity depends on solid-state characterization and 19F NMR reporting, including spinning frequency at 14 kHz in claim 3.
4) Does the tablet claim require exactly 120 mg?
Yes. The composition claims specify that the tablet comprises 120 mg of the compound (for each claim family tied to claim 1, 2, or 3).
5) What tumor types are directly covered by the method-of-use claims?
The claims list a broad set of KRAS G12C cancers, including NSCLC, colorectal cancer, pancreatic cancer, plus numerous others as enumerated in claims 13, 23, and 33.
References
[1] United States Patent US 12,398,133 (claims as provided in prompt).
