US Patent 10,369,154: Scope, Claim Structure, and Landscape for H3 K27M Glioma Using ONC201
United States Patent 10,369,154 claims method-of-treatment coverage for cancers defined by histone H3 K27M status and, in specific claim sets, DRD2/DRD5 expression patterns, using compound (1) or a compound of formula (10) (with ONC201 explicitly called out). The claim architecture is built to secure broad “treatment + biomarker” protection, then narrow by (i) tumor anatomic subtype, (ii) exact K27M residue and histone variants (H3.3 K27M or H3.1 K27M), (iii) which histone genes harbor the mutation, and (iv) receptor expression signatures.
What is the claim scope in plain terms?
The independent claim coverage is split across at least two functional claim families:
- Claim family A (compound (1)): focuses on gliomas with H3 K27M and includes an expression qualifier tied to DRD2 overexpression and/or DRD5 underexpression.
- Claim family B (compound of formula (10) / analogs; ONC201): expands beyond glioma-only by tying treatment to cancers having a histone H3 mutation, then includes a midline glioma subset and repeats the H3.3/H3.1 K27M + histone gene list framework. It also includes DRD2 overexpression as an expression qualifier.
The net effect is a landscape position where the patent can be used to police treatment approaches that combine:
- H3 K27M (H3.3 or H3.1) biomarker logic
- defined histone gene sources (H3F3A/H3F3B/HIST1H3A-J)
- and ONC201 or structurally described formula (10) compounds
- optionally plus DRD2/DRD5 expression selection
What do the key elements in the claims cover?
Which cancer types are covered?
A. Glioma-focused (Claim family A)
Claims 1-9 restrict to glioma and enumerate anatomic categories and exclusions:
- Glioma is specified to be one of:
- Diffuse intrinsic pontine glioma
- Diffuse midline glioma
- Spinal cord glioma
- Thalamic glioma
- Brainstem glioma
- Cerebellar glioma (Claim 2)
- There is also a carve-out:
- glioma is not a spinal cord tumor (Claim 3)
So claim family A supports both:
- a listed subtype basket (including spinal cord glioma), and
- a narrower basket excluding spinal cord.
B. Broader “histone H3 mutation” cancers (Claim family B)
Claims 10-20 introduce a broader tumor set tied to “cancer has a histone H3 mutation”:
Included cancers (Claim 11):
- Central nervous system tumor
- Brain tumor
- Peripheral nervous system tumor
- Pheochromocytoma
- Paraganglioma
- Adrenal cortical carcinoma
- Adrenal tumor
- Neuroendocrine tumor
This is then followed by multiple overlapping CNS tumor lists (Claims 12-13), including:
- Meningioma
- Ependymoma
- Glioma
- Neuroblastoma
- Diffuse intrinsic pontine glioma
and then among the glioma sublist:
- Diffuse midline glioma
- Spinal cord glioma
- Thalamic glioma
- Brainstem glioma
- Cerebellar glioma (Claim 13)
C. Midline glioma-specific (Claim family B narrowing)
Claims 21-30 explicitly narrow to a midline glioma and then enumerate the same subtype basket (Claim 22) and the spinal cord exclusion (Claim 23).
Which biomarker logic matters?
A. Histone residue and variant
Both families use a strict K27M structure:
- H3.3 K27M or H3.1 K27M (Claim 4 for family A; Claim 14 for family B)
- and they anchor to “histone H3 K27M mutation” language (Claims 1, 10, 21).
B. Histone gene sources
The claims specify a set of histone genes that can carry the K27M mutation:
- H3F3A, H3F3B
- HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G
- HIST1H3H, HIST1H3I, HIST1H3J (Claim 5 and Claim 15)
This reduces ambiguity versus a claim that only says “H3 K27M positive,” because it ties mutation assignment to defined gene loci.
Which expression signature is used?
Claim family A includes DRD2/DRD5 dual logic
- Cancerous tissue has:
- DRD2 is overexpressed, DRD5 is underexpressed, or both (Claim 6)
Claim family B includes DRD2-only logic
- Cancerous tissue has DRD2 overexpressed (Claim 16 and Claim 26)
This difference matters operationally: DRD5 status only appears in the narrower family A claim. Any lab-to-clinic biomarker decision tree that tests DRD2 alone may map more directly to family B.
Which subjects are covered?
Claims are not limited to humans; they include:
- Human (Claims 7 and 17; Claims 27)
- Domesticated pet (Claims 8 and 18; Claims 28)
- Pediatric subject (Claims 9 and 20; Claims 30)
This expands the enforcement surface beyond adult oncology cohorts.
Which compounds are claimed?
Two different “compound identifiers” appear:
- compound (1) used in Claim family A (Claims 1-9)
- compound of formula (10) or an analog used in Claim family B (Claims 10, 21)
In family B, the claims explicitly cover:
- ONC201 (Claim 19 and Claim 29)
Because Claim 10 and Claim 21 cover “compound of formula (10) or an analog,” the landscape position depends on how strictly analogs are interpreted in claim construction relative to formula (10) and known ONC201 analogs.
Claim-by-claim mapping to practical treatment scenarios
Claim family A: “Glioma + H3 K27M” with DRD2/DRD5 expression selection
| Claim |
Target disease constraint |
Biomarker constraint |
Expression constraint |
Compound constraint |
Subject constraint |
| 1 |
Glioma having histone H3 K27M mutation |
K27M + implied histone H3 |
None |
compound (1) |
None |
| 2 |
Specific glioma anatomical list (includes spinal cord) |
Same as Claim 1 |
None |
compound (1) |
None |
| 3 |
Same as Claim 1, but not spinal cord tumor |
Same |
None |
compound (1) |
None |
| 4 |
H3 variant specified: H3.3 K27M or H3.1 K27M |
Explicit |
None |
compound (1) |
None |
| 5 |
Histone gene list specified |
Explicit gene loci |
None |
compound (1) |
None |
| 6 |
Glioma with DRD2 overexpression and/or DRD5 underexpression |
Same |
DRD2/DRD5 |
compound (1) |
None |
| 7-9 |
Same as Claim 1 with subject type |
Same |
None (unless dependent) |
compound (1) |
Human / pet / pediatric |
Enforcement posture for family A: strongest where clinical protocols select patients by H3 K27M and then require DRD2↑/DRD5↓ as part of the population definition prior to treatment with compound (1).
Claim family B: “Cancer + histone H3 mutation,” then midline glioma subset with ONC201 and DRD2 overexpression
| Claim |
Target disease constraint |
Biomarker constraint |
Expression constraint |
Compound constraint |
Subject constraint |
| 10 |
Cancer with histone H3 mutation |
Histone H3 mutation (K27M specified later) |
None |
formula (10) or analog |
None |
| 11 |
Enumerated cancer list (CNS/PNS + neuroendocrine tumors) |
Same |
None |
formula (10) or analog |
None |
| 12-13 |
CNS tumor and glioma subtype lists |
Same |
None |
formula (10) or analog |
None |
| 14 |
K27M variant: H3.3 K27M or H3.1 K27M |
Explicit |
None |
formula (10) or analog |
None |
| 15 |
Histone gene list specified |
Explicit gene loci |
None |
formula (10) or analog |
None |
| 16 |
DRD2 overexpressed |
Still tied to histone H3 mutation |
DRD2 only |
formula (10) or analog |
None |
| 17-20 |
Subject variants |
Same |
None (unless dependent) |
formula (10) or analog |
Human / pet / pediatric |
| 19 |
ONC201 specifically |
Same |
None |
ONC201 |
None |
| 21 |
Midline glioma |
Tied to histone H3 mutation |
None |
formula (10) or analog |
None |
| 22-23 |
Midline glioma subtype list; includes non-spinal-cord constraint |
Same |
None |
formula (10) or analog |
None |
| 24-26 |
Variant + gene list + DRD2 expression |
K27M variant and gene loci plus DRD2↑ |
DRD2 only |
formula (10) or analog |
None |
| 27-30 |
Subject variants plus ONC201 dependency |
Same |
None (unless dependent) |
formula (10) or analog (ONC201 in 29) |
Human / pet / pediatric |
Enforcement posture for family B: strongest where treatment uses ONC201 or formula (10) analogs for H3 K27M (H3.3/H3.1) tumors, with at least some routes supported by DRD2 overexpression as a qualifier.
What is the scope of dependence and claim layering?
The claims are structured so that broad disease constraints get layered with narrower biomarker and molecular selection:
-
Disease anchor:
- Glioma + H3 K27M (Claim 1)
- Cancer + histone H3 mutation (Claim 10)
- Midline glioma + histone H3 mutation (Claim 21)
-
Biomarker tightening:
- K27M variant specificity (Claims 4 and 14, then 24)
- histone gene locus specificity (Claims 5 and 15, then 25)
-
Additional selection:
- DRD2/DRD5 dual expression (Claim 6)
- DRD2-only expression (Claims 16 and 26)
-
Patient population:
- Human/pet/pediatric (Claims 7-9, 17-20, 27-30)
-
Compound specification:
- ONC201 explicitly (Claims 19 and 29)
- analog coverage exists only in the family that uses “formula (10) or analog thereof” (Claim 10 and Claim 21)
This layered design targets both:
- direct “treat this defined biomarker-positive tumor with this defined agent” practice, and
- biomarker-stratified clinical trial enrollment.
How does this shape the patent landscape for H3 K27M glioma therapies?
Core competitive wedge: ONC201/DRD2 pathway in H3 K27M settings
By tying treatment to H3 K27M and (in dependent claims) DRD2 overexpression, the patent sets up a competitive wedge around:
- identifying H3 K27M tumors (via K27M variant and gene loci),
- and selecting or justifying use of DRD2-linked agents.
Even where DRD2 testing is not required in the broadest claim text, the existence of dependent claims that explicitly require DRD2 overexpression makes it easier to argue infringement where labeling, patient selection criteria, or trial protocols incorporate DRD2 stratification.
Key land-grab for clinical trial design
The explicit inclusion of:
- H3.3 K27M or H3.1 K27M
- a defined histone gene list
- and midline glioma categories
supports trial designs that enforce biomarker inclusion/exclusion and region-specific targeting. The “not spinal cord tumor” language creates a second operational axis for population selection.
Enforcement surface is not limited to human oncology
Coverage explicitly extends to:
- domesticated pets and pediatric subjects.
This broadens the landscape beyond adult neurologic oncology and could matter where veterinary oncology or pediatric off-label use is considered in licensing.
Risk points for competitors (based on claim language structure)
1) If a protocol treats H3 K27M glioma with ONC201-like agents
The explicit ONC201 claim dependency (Claims 19 and 29) means any competing development that uses ONC201 or a close “formula (10)” analog for K27M-defined tumors risks mapping to at least the narrower claim sets:
- K27M variant (H3.3/H3.1)
- histone gene loci list
- and potentially DRD2 overexpression selection (Claims 16 and 26).
2) If a protocol uses DRD2 and DRD5 as biomarkers
Claim 6 specifically requires a combined logic:
- DRD2 overexpressed and DRD5 underexpressed, or both.
This is a technical risk if a competitor’s clinical protocol or companion diagnostic logic enforces the DRD5↓ portion while using compound (1) for H3 K27M glioma.
3) If a protocol includes spinal cord tumors
Family A has a dependent constraint excluding spinal cord tumors (Claim 3) and also has another claim that includes spinal cord glioma (Claim 2). Family B midline glioma claims likewise include a non-spinal-cord limitation (Claim 23). Competitors that segment by neuroanatomic location should consider whether their trial populations land in the include-only or exclude-only dependent sets.
Key takeaways
- US 10,369,154 is a biomarker-defined method-of-treatment patent for H3 K27M (H3.3 or H3.1) cancers, with glioma-focused coverage and a broader “histone H3 mutation” scaffold.
- The claim sets are built to cover ONC201 (explicit) and formula (10) analogs, with DRD2 overexpression as a key dependent qualifier and DRD5 underexpression appearing only in the glioma/compound (1) dependent set.
- The patent expands enforcement beyond humans to pediatric and domesticated pet use.
- The combination of (i) K27M variant, (ii) specific histone gene loci list, and (iii) DRD receptor expression logic is the practical basis for freedom-to-operate analysis in H3 K27M glioma trials.
FAQs
1) What tumors are explicitly included for glioma use?
The claims list diffuse intrinsic pontine glioma, diffuse midline glioma, spinal cord glioma, thalamic glioma, brainstem glioma, and cerebellar glioma, with dependent claims that also include an exclusion for spinal cord tumor. (Claims 2-3 and 22-23)
2) Does the patent require H3.3 K27M or H3.1 K27M?
Yes in dependent claims it specifies that the H3 K27M mutation is H3.3 K27M or H3.1 K27M. (Claims 4, 14, 24)
3) Which histone genes are named for K27M?
The claims name H3F3A, H3F3B, and HIST1H3A through HIST1H3J as the gene set. (Claims 5, 15, 25)
4) Is DRD5 part of the biomarker package?
Only in the glioma/compound (1) dependent claim: it requires DRD2 overexpression with DRD5 underexpression or both. (Claim 6)
5) Where does ONC201 appear in the claims?
ONC201 is explicitly recited as the administered compound in dependent claims for both the broader histone H3 mutation family and the midline glioma family. (Claims 19 and 29)
References
[1] United States Patent No. 10,369,154.
