Details for Patent: 9,169,214

Which drugs does patent 9,169,214 protect, and when does it expire?

Patent 9,169,214 protects ATTRUBY and is included in one NDA.

This patent has twenty-one patent family members in eighteen countries.

Summary for Patent: 9,169,214

Title:	Compounds and compositions that bind and stabilize transthyretin and their use for inhibiting transthyretin amyloidosis and protein-protein interactions
Abstract:	Disclosed herein are compounds and compositions thereof which find use in increasing stability of proteins particularly proteins that tend to misfold and form aggregates. Also provided herein are methods for using these compounds and compositions for increasing stability of proteins and thereby decreasing aggregate formation by these proteins. Also disclosed herein are heterobifunctional compounds that include a TTR binding compound connected to a targeting moiety via a linker, for use in disrupting PPIs of a target protein.
Inventor(s):	Isabella A. Graef, Mamoun M. Alhamadsheh
Assignee:	Leland Stanford Junior University
Application Number:	US13/830,731
Patent Claim Types: see list of patent claims	Use; Composition;

United States Patent 9,169,214: Scope, Claim Boundaries, and Patent Landscape for TTR Stabilizing Compounds

US Drug Patent 9,169,214 claims a broad genus of small-molecule compositions defined by “Compound (VI)” (with n = 3 in claim 1), plus specific structural embodiments (claim 2 and claims 20-27), and a large downstream method set centered on transthyretin (TTR) stabilization, inhibition of misfolding/dissociation, and decrease of amyloid fibril formation. The claims also expand into TTR binding assays using labeled versions of the same compounds, including distance-dependent energy transfer assays on the TTR tetramer.

What is the core invention scope in claim 1?

Claim 1 is a genus claim to a composition that includes a compound of Compound (VI) with the following variable-space:

Structural constraints in claim 1 (key genus boundaries)

Parameter	Claim 1 constraint
n	3
R1	short-chain alkyl with 1 to 4 carbons
R2	hydrogen
R3	short-chain alkyl with 1 to 4 carbons
Xa	C(R4)(R5), O, N-R5, or S
R4 and R5	independently from an enumerated set including H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkoxy, aryloxy, hydroxyl, heterocyclic groups, halogen, nitro, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, cyano
Ra	enumerated set including CHO, COOH, COOCH3, COOR6, CONR7R8, tetrazolyl, CONHOH, B(OH)2, CONHSO2Ar, CONHCH(R9)COOH, hydrogen, acyl, substituted acyl, carboxyl, alkoxycarbonyl, heterocyclic group, sulfonamide, sulfonyl fluoride, thioester, substituted alkoxycarbonyl
Rb	enumerated set including CHO, COOH, COOCH3, COOR6, CONR7R8, tetrazolyl, CONHOH, B(OH)2, CONHSO2Ar, CONHCH(R9)COOH, a halogen, or heterocyclic group
R6	alkyl, haloalkyl, cycloalkyl, or heterocyclyl
R7 and R8	independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl
R9	side chain of a naturally occurring α-amino carboxylic acid
Form	any pharmaceutically acceptable salt, ester, enol ether/ester, acetal/ketal/orthoester/hemiacetal/hemiketal, hydrate, solvate, or prodrug

Immediate implication

The claim is drafted as a TTR kinetic stabilizer / dissociation inhibitor scaffold with wide substitution tolerance at multiple positions, including heteroatoms and a large range of pendant functional groups. The claim does not restrict to a single binding chemotype; it restricts to the particular Compound (VI) core with broadly varying substituents.

How do claims 2 and 20-27 narrow the genus to specific embodiments?

Claim 2 locks a second explicit embodiment: “Compound (VIIc)” (or its pharmaceutically acceptable derivative forms). Claim 20 repeats n = 3 and provides a set of dependent feature selections that narrow the substituent set into commercially useful sub-genuses.

Dependent-claim narrowing map

Claim	Narrowing feature
2	compound of Compound (VIIc)
20	n is 3 (restating claim 1’s genus boundary)
21	Xa is O
22	R1 is methyl
23	R3 is methyl
24	Xa is O (with R3 methyl)
25	Ra is carboxyl
26	Rb is bromo/chloro/fluoro
27	Rb is fluoro

Scope effect

The dependent claims concentrate the substitution space into a smaller set of regulator-friendly chemical options (carboxyl Ra; halogen Rb; O as Xa; methyl at R1 and R3). These are the types of constraints that downstream competitors must evaluate when designing around by changing one site.

What therapeutic and formulation claims are covered?

Pharmaceutical composition coverage (claims 4, 6, 8, 10, 28)

The patent includes formulation claims built on the active-ingredient compositions of claims 1, 3, and 5, combined with conventional carriers/excipients:

• Claim 4: composition of claim 3 + pharmaceutically acceptable carrier/diluent/excipient/adjuvant
• Claim 6: composition of claim 5 + pharmaceutically acceptable carrier/diluent/excipient/adjuvant
• Claim 8 and 10: method variants where the contacting composition further includes carriers/diluents/excipients/adjuvants
• Claim 28: pharmaceutical composition of claim 1 + conventional formulation components

Composition claims for additional compound families (claims 3 and 5)

• Claim 3: compound of Compound (VIIa), with specific allowed Ra values and R6 restricted to straight or branched alkyl of 1 to 3 carbons.
• Claim 5: compound of Compound (VIIb), with specific allowed Ra values and the same R6 restriction.

This indicates the patent asserts multiple related structural families (VI, VIIa, VIIb, VIIc) under a shared functional theory for TTR kinetic stabilization and amyloid reduction.

What method claims define the therapeutic mechanism (stabilize TTR, reduce amyloid)?

The therapeutic portion of the claim set is direct and broad: “contacting” TTR with the claimed compound(s) to stabilize and reduce amyloid formation. The tissue or biological fluid scope is explicit.

Primary mechanism claims

Claim	Method scope
7	contacting TTR with composition of claim 1, stabilizes TTR and/or decreases TTR amyloid fibril formation
9	contacting TTR with composition of claim 2, stabilizes TTR and/or decreases TTR aggregation and amyloid fibril formation
11	method of inhibiting TTR misfolding by contacting TTR with a compound of claim 1
12	inhibiting dissociation of a TTR tetramer via kinetic stabilization of the native state
13	inhibiting protein-protein interactions by contacting TTR with a compound of claim 1
14	method of claim 13 where compound is a hetero-bifunctional molecule

What “kinetic stabilization” adds

Claim 12 frames the mechanism as kinetic stabilization of native-state tetramers to inhibit dissociation. That language can matter for both validity and infringement against competitors who argue a different mechanism (e.g., thermodynamic stabilization, receptor mediated clearance, or altered expression only).

What assay and diagnostic method claims expand the patent into measurement and screening?

The patent extends beyond treatment into labeled-compound binding assays on the TTR tetramer, including an advanced assay format using distance-dependent energy transfer between labeled species on two binding sites.

Labeled TTR measurement (claims 15-19)

Claim	Assay format
15	measure TTR tetramer levels by contacting with a labeled compound of claim 1
16	add labeled compound of claim 1 to sample, allow binding, measure presence/concentration
17	add labeled compound; measure distance-dependent energy transfer between a labeled compound bound to a T4 binding pocket and a labeled compound/peptide/protein bound to an orthogonal binding surface
18	determine efficacy of a candidate compound/method by contacting TTR in sample with labeled compound of claim 1 in the presence of candidate; measure labeled compound presence
19	efficacy with the same concept as claim 18, using distance-dependent energy transfer readout

Screening relevance

Claims 18-19 are written to capture:

• direct competitors’ candidates tested in the same labeled binding/energy-transfer framework, and
• candidates aimed at stabilization, dissociation decrease, amyloid fibril decrease, or TTR protein expression alteration.

That functional framing can broaden infringement risk for in vitro assay developers who adopt the claimed labeled reagent and readouts.

Is there a clear composition-to-method linkage?

Yes. Nearly every method claim is triggered by:

• contacting TTR (or the TTR tetramer) with a composition of claim 1 or a labeled compound of claim 1, and/or
• measuring binding or energy transfer involving the same labeled compound.

What is the practical “claim map” for infringement risk?

Likely infringement triggers

1. Any therapeutic using a compound within claim 1’s Compound (VI) space that stabilizes TTR and/or decreases amyloid fibril formation (claims 7, 11-13).
2. Any therapeutic using claim 2 compounds that stabilize TTR and/or decreases aggregation and amyloid fibril formation (claim 9).
3. Any therapeutic formulation using claim 1 or claim 3/5 actives with conventional carriers (claims 4, 6, 8, 10, 28).
4. Any diagnostic/assay where the labeled compound of claim 1 is used to quantify TTR tetramer levels (claims 15-17).
5. Any screening assay using labeled claim 1 compound in the presence of candidate compounds, with either presence/concentration readout or energy-transfer readout (claims 18-19).

Likely design-around levers (high-level)

• Substitution changes that move a candidate out of the Compound (VI)/(VIIa)/(VIIb)/(VIIc) frameworks are the first line.
• Altering specific dependent features (Xa = O; methyl R1/R3; Ra = carboxyl; Rb halogen/fluoro) can avoid dependent claim coverage, but claim 1’s genus breadth still dominates unless the overall scaffold falls outside Compound (VI).
• Avoiding use of a labeled compound that matches claim 1 chemistry and the specific binding-pocket/orthogonal-surface energy-transfer arrangement can reduce assay claim exposure.

How should the patent landscape be assessed for US 9,169,214?

Key observation from claim drafting: this is a platform-style TTR chemistry + labeled assay IP

The claim set is not limited to one drug molecule. It covers:

• multiple related compound families (VI, VIIa, VIIb, VIIc),
• broad substitution patterns with multiple functional groups,
• and a labeled-assay framework including distance-dependent energy transfer across a T4 pocket and an orthogonal surface.

That structure usually correlates with a landscape where:

• multiple continuation filings and related family members exist around the same chemotype and binding-mode assay readouts,
• enforcement can extend to both therapeutics and assay reagent kits, and
• later entrants face overlapping risk not only on API structure but on diagnostic reagent use and screening methods.

Practical landscape axes for freedom-to-operate (FTO)

1. Chemotype overlap: whether the candidate compound falls within Compound (VI)/(VIIa)/(VIIb)/(VIIc).
2. TTR functional claims: whether the candidate’s mechanism is argued as kinetic stabilization of tetramers (claim 12).
3. Assay use: whether TTR quantification or efficacy screening uses labeled versions that meet claim 1’s chemistry and the energy-transfer geometry (claims 15-19).
4. Formulation: conventional excipient/cosolvent usage does not typically change infringement risk because formulation claims are carrier-based (claims 4, 6, 8, 10, 28).

What does the independent claim set suggest about priority and enforceability strategy?

The independent claims are:

• claim 1 (composition; Compound VI with n = 3 and large substitution freedom),
• claim 3 (composition; Compound VIIa, with narrower Ra and R6),
• claim 5 (composition; Compound VIIb, with narrower Ra and R6),
• method claims tied to claim 1 or claim 2 compositions, and
• assay claims tied to labeled claim 1 compounds.

This structure is consistent with a strategy to secure enforceable coverage across:

• drug molecule analogs,
• prodrugs/salts,
• therapeutic delivery,
• and assay toolchains.

Key Takeaways

• US 9,169,214 is a broad TTR stabilization IP covering a wide genus of small molecules anchored in Compound (VI) (with n = 3), plus related compound families (VIIa), (VIIb), (VIIc).
• The patent’s method claims cover therapeutic stabilization and anti-amyloid outcomes (misfolding, dissociation inhibition, reduced fibril formation) by contacting TTR with the claimed compositions.
• The patent expands materially into assays and screening, including labeled-compound binding quantification and distance-dependent energy transfer between a labeled compound in the T4 binding pocket and a labeled species on an orthogonal surface.
• Dependent claims narrow key substitution positions (Xa = O; R1 and R3 methyl; Ra = carboxyl; Rb halogen including fluoro), but claim 1’s genus remains the dominant infringement and design-around anchor.
• Landscape risk is likely two-sided: structural infringement on the API and operational infringement on assay reagent use and energy-transfer readouts.

FAQs

1. Which claim most broadly defines the small-molecule composition scope?
   Claim 1 defines the broad genus for Compound (VI) with n = 3 and multiple substitution freedoms.

2. Do the claims cover both treatment and diagnostic assays?
   Yes. The patent includes therapeutic methods (claims 7, 9, 11-14) and measurement/screening methods using labeled compounds (claims 15-19).

3. What assay readout is specifically claimed?
   Claims 17 and 19 claim distance-dependent energy transfer between labeled entities: one in the T4 binding pocket and another on an orthogonal binding surface.

4. What are the explicit dependent substitutions that narrow the genus?
   Claims 21-27 narrow key variables such as Xa = O, R1 = methyl, R3 = methyl, Ra = carboxyl, and Rb = fluoro (among other halogens).

5. Does the patent require a specific formulation component for infringement of the therapeutic method claims?
   No. Formulation claims (claims 4, 6, 28) require conventional carriers/excipients, while method claims (claims 7, 9, 11-14) are primarily triggered by contacting TTR with the claimed compositions; claims 8 and 10 add carrier language only as a further limitation.

References

[1] United States Patent No. 9,169,214. (Claim text as provided by user).

Drugs Protected by US Patent 9,169,214

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Bridgebio Pharma	ATTRUBY	acoramidis hydrochloride	TABLET;ORAL	216540-001	Nov 22, 2024		RX	Yes	Yes	9,169,214		Y			TREATMENT OF THE CARDIOMYOPATHY OF WILD-TYPE OR VARIANT TRANSTHYRETIN-MEDIATED AMYLOIDOSIS (ATTR-CM)

International Family Members for US Patent 9,169,214

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2934514		301323	Netherlands
European Patent Office	2934514		C20250016	Finland
European Patent Office	2934514		CA 2025 00013	Denmark
European Patent Office	2934514		PA2025512	Lithuania