Details for Patent: 8,492,359

Which drugs does patent 8,492,359 protect, and when does it expire?

Patent 8,492,359 protects ONPATTRO and is included in one NDA.

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

Summary for Patent: 8,492,359

Title:	Lipid formulations for nucleic acid delivery
Abstract:	The present invention provides novel, stable lipid particles comprising one or more active agents or therapeutic agents, methods of making the lipid particles, and methods of delivering and/or administering the lipid particles. More particularly, the present invention provides stable nucleic acid-lipid particles (SNALP) comprising a nucleic acid (such as one or more interfering RNA), methods of making the SNALP, and methods of delivering and/or administering the SNALP.
Inventor(s):	Edward Yaworski, Kieu Lam, Lloyd Jeffs, Lorne Palmer, Ian Maclachlan
Assignee:	Arbutus Biopharma Corp
Application Number:	US13/253,917
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,492,359
Patent Claim Types: see list of patent claims	Composition; Compound;

US Patent 8,492,359 (Nucleic acid-lipid particle) Scope, Claim-by-Claim Coverage, and US Patent Landscape

US Patent 8,492,359 covers nucleic-acid (with explicit emphasis on siRNA) lipid nanoparticles (LNPs) defined by a quantitative lipid composition window: a cationic lipid at 50 to 65 mol%, a non-cationic lipid phase comprising phospholipid (3 to 15 mol%) plus cholesterol (30 to 40 mol%), and an aggregation-inhibiting conjugated lipid (0.5 to 2 mol%). The claims also narrow to siRNA attributes (modified nucleotides, 2’-O-methyl, 19 to 25 bp, 3’ overhangs) and specific lipid exemplars including DPPC/DSPC and PEG-lipid conjugates with specified PEG chemistries (PEG-DAG, PEG-DAA including PEG-DMA/PEG-DSA) and PEG molecular weight (~2,000 Da). A separate claim covers a pharmaceutical composition containing the covered LNP.

Because the exact issuance document text, prosecution history, priority claims, and the full family set are not provided in the prompt, the analysis below maps scope strictly to the claim language you supplied and identifies the competitive patent “landscape” categories that typically determine freedom to operate for this kind of LNP composition. Where specific US publication/patent numbers would normally anchor the map, the prompt does not provide them; the result is a category-level landscape rather than a confirmed citation-level one.

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What is the claim scope of US Patent 8,492,359 for nucleic acid-lipid particles?

Short answer: The patent claims an LNP defined by (1) nucleic acid, (2) a high fraction of cationic lipid, (3) a defined phospholipid plus cholesterol fraction in the non-cationic lipid component, and (4) a low fraction of a conjugated lipid that inhibits aggregation, with dependent claims locking onto siRNA and specific PEG-lipid chemistries.

Independent claim 1: composition and mol% boundaries

Claim 1 requires all of the following in one nucleic-acid-lipid particle:

1. Nucleic acid (unspecified in claim 1).
2. Cationic lipid: 50 to 65 mol% of total lipid.
3. Non-cationic lipid: a mixture of:
   • Phospholipid: 3 to 15 mol%
   • Cholesterol (or derivative): 30 to 40 mol%
4. Conjugated lipid that inhibits aggregation: 0.5 to 2 mol%

These mol% windows interact in a way that defines a narrow “formulation region.” Practically, the claim is not about any particular ionizable lipid alone, but about a specific ratio structure that is consistent with many cationic/ionizable LNP designs used for nucleic-acid delivery, with PEG-lipid added to reduce aggregation.

Independent claim 1: what the “mixture of phospholipid and cholesterol” does to scope

The “non-cationic lipid comprising a mixture of phospholipid and cholesterol or a derivative thereof” clause is a structural limitation. It bars formulations where cholesterol is absent, where cholesterol exists outside the stated 30 to 40 mol% range, or where the “non-cationic lipid” is not a mixture containing both phospholipid and cholesterol/derivative in the required mol% ranges.

A key implication: even if a competitor hits similar cationic lipid and PEG-lipid ranges, a shift in cholesterol and/or phospholipid mol% can move them outside claim 1.

Dependent claim 2 to 6: siRNA structural and modification limitations

Dependent claim 2 narrows claim 1 by specifying:

• Nucleic acid comprises siRNA.

Claim 3 adds:

• siRNA comprises at least one modified nucleotide.

Claim 4 narrows further:

• siRNA comprises at least one 2’-O-methyl (2’OMe) nucleotide.

Claim 5 narrows length:

• siRNA is about 19 to about 25 base pairs.

Claim 6 adds termini structure:

• siRNA comprises 3’ overhangs.

Scope effect: These dependent claims create a “ladder.” A generic LNP composition matching claim 1 but loaded with unmodified siRNA (lacking 2’-O-methyl) could avoid claims 2–6 while still potentially infringing claim 1 if the particle composition is within the mol% windows.

Dependent claim 7: tighter cationic lipid range

• Cationic lipid 50 to 60 mol% (subset of claim 1’s 50 to 65).

This is narrower than claim 1. A competitor with 61 to 65 mol% cationic lipid would avoid claim 7 but could still fall within claim 1.

Dependent claims 8–13: phospholipid identity and tighter mol% windows

Claim 8: phospholipid comprises DPPC, DSPC, or a mixture thereof.
Claim 9: phospholipid 4 to 15 mol%
Claim 10: phospholipid 4 to 12 mol%
Claim 11: phospholipid 5 to 12 mol%
Claim 12: phospholipid 6 to 12 mol%

Claims 13: cholesterol 30 to 35 mol% (subset of claim 1’s 30 to 40).

Scope effect: These are formulation “species” locks. A competitor that uses a different phospholipid (not DPPC/DSPC) or uses phospholipid mol% outside the narrower subranges can avoid these dependent claims while still being exposed on claim 1.

Dependent claims 14–18: PEG-lipid identity and PEG molecular weight

Claim 14: conjugated lipid inhibiting aggregation is a PEG-lipid conjugate.
Claim 15: PEG-lipid is PEG-DAG, PEG-DAA, or mixture.
Claim 16: PEG-DAA includes PEG-DMA or PEG-DSA or mixture.
Claim 17: PEG average MW about 2,000 Da.
Claim 18: conjugated lipid amount 1 to 2 mol% (subset of claim 1’s 0.5 to 2).

Scope effect: Claim 1 covers “a conjugated lipid” that inhibits aggregation, but dependent claims tie the identity to PEG-lipid chemistries and PEG MW. A non-PEG aggregation inhibitor could fall outside claims 14–18 while still potentially infringing claim 1 if it is still “a conjugated lipid that inhibits aggregation” and meets mol%. In practice, courts typically require a reasonable structural match to the dependent claims’ described concept unless claim 1 is interpreted broadly. The dependent claim set signals that the patentee intends PEG-lipid compositions as the core embodiments.

Claim 19 is a composition recitation:

• about 55 mol% cationic lipid
• about 11 mol% phospholipid
• about 33 mol% cholesterol
• about 1.6 mol% PEG-lipid conjugate

This is effectively a specific point within the claim 1 region and provides an easy infringement map for formulations matching those approximate values.

Dependent claims 20–21: encapsulation and pharmaceutical composition

Claim 20: nucleic acid is fully encapsulated.
Claim 21: pharmaceutical composition comprising the covered nucleic acid-lipid particle plus carrier.

Scope effect: A competitor could infringe claim 1 without “fully encapsulated” if its nucleic acid is partially associated but not “fully encapsulated,” depending on interpretation. Claim 21 extends directly to dosage form level, capturing compositions used in therapy.

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How strong is the patent estate for US 8,492,359 based on claim composition coverage?

Short answer: The strength is composition-ratio heavy. That tends to be strong against copycat formulations but vulnerable to design-around via mol% tuning, phospholipid/cholesterol selection, PEG-lipid replacement, and changes to siRNA chemistry/length/termini.

What makes the claims enforceable (vs. easy to design around)

1. All key formulation components are present with explicit mol% ranges.
   This is the “workhorse” for infringement because it reduces ambiguity over which formulation qualifies.

2. Dependent claims cover common formulation choices (DPPC/DSPC and PEG-lipid variants).
   This suggests the assignee anticipated real-world competitors using these typical materials.

3. The siRNA dependent claims map to widely used feature sets (2’-O-methyl and 3’ overhangs).
   Many commercial siRNA designs incorporate these features, which increases the chance that at least some product candidates overlap the dependent claims.

What makes the claims less bulletproof

1. “About” and range windows create wiggle room.
   If a competitor adjusts mol% slightly within plausible manufacturing variability, litigation turns on measurement protocol and whether “about” is interpreted as strict or tolerant.

2. The independent claim is nucleic acid-lipid particle, not a specific ionizable lipid identity.
   Competitors can potentially substitute alternative aggregation inhibitors (non-PEG conjugates) and still remain close to the claimed architecture.

3. Claim 2–6 add multiple siRNA chemistry/structure constraints.
   If a product uses unmodified siRNA or lacks 2’-O-methyl, it can fall outside claims 2–6 even if the particle composition matches claim 1.

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What types of competing patents overlap the same LNP composition space?

Short answer: In the US, nucleic-acid LNP landscapes are typically clustered by (a) ionizable/cationic lipid classes, (b) phospholipid/cholesterol ratio or specific phospholipid identities, (c) PEG-lipid identity/PEG MW and site/anchor chemistry, (d) manufacturing methods (microfluidic mixing, ethanol dilution, pH/charge conditions), and (e) the nucleic acid itself (siRNA sequence features, chemical modifications, length, overhang structure) or endosomal escape mechanisms.

Because the prompt does not include the full patent family or citation set for 8,492,359, the landscape below is structured as the categories most likely to collide with this claim set in US practice.

1) Ionizable/cationic lipid selection and ratio patents

• Patents in this cluster typically claim specific lipid structures and/or their use in LNPs for nucleic-acid delivery.
• If those patents also include composition windows, they can overlap claim 1’s cationic lipid fraction.

Design-around logic: use a different cationic lipid structure, or keep within/without particular mol% bands.

2) Phospholipid/cholesterol selection and mol% patents

• Claim 1 explicitly requires phospholipid 3–15 mol% and cholesterol 30–40 mol%.
• Dependent claims specify DPPC and DSPC and cholesterol 30–35 mol%.

Design-around logic: shift cholesterol outside 30–40 mol% or use a different phospholipid identity and/or mol%.

3) PEG-lipid anchored surface and PEG chemistry/size patents

• Claims 14–18 cover PEG-DAG and PEG-DAA with PEG-DMA/PEG-DSA and PEG MW about 2,000 Da.
• The PEG content window (0.5–2 mol% in claim 1; 1–2 in claim 18) is also tightly controlled.

Design-around logic: adjust PEG-lipid mol% outside 0.5–2 or change anchor chemistry/MW and potentially use non-PEG aggregation inhibitors.

4) Nucleic acid feature patents (siRNA chemistry/length/overhangs)

• Claims 2–6 are driven by: modified nucleotides, 2’-O-methyl, 19–25 bp length, and 3’ overhangs.

Design-around logic: change nucleotide modification profile (e.g., avoid 2’-O-methyl), alter strand length, or change overhang structure.

5) Encapsulation and formulation performance patents

• Claim 20 requires fully encapsulated nucleic acid.

Design-around logic: different loading/encapsulation metrics or particle architecture that results in partial association rather than “full encapsulation,” depending on test definitions.

6) Manufacturing method patents

Even if composition claims do not read, method patents can still restrict operations. Commonly litigated areas include microfluidic mixing parameters and “ethanol dilution to form LNPs” process steps.

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What freedom-to-operate risk exists for generic or follow-on siRNA-LNP products?

Short answer: The most direct risk is for follow-on LNP formulations that match (1) the lipid ratio windows of claim 1 and (2) siRNA feature sets of claims 2–6. The next highest risk is for “composition-only” copycats matching claim 1 but using nucleic acids that satisfy the dependent claims.

Risk tiering

1. Highest risk:
   LNP composition within claim 1 plus siRNA with modified nucleotides including 2’-O-methyl, 19–25 bp length, and 3’ overhangs.

2. Moderate risk:
   LNP composition within claim 1; siRNA is modified but not 2’-O-methyl or length/overhang falls outside claims 5–6.

3. Lower risk (but not zero):
   LNP composition slightly outside claim 1 windows. Still, infringement can occur if “about” is construed to overlap and if the formulation lab measurement supports inclusion.

Typical design-around levers mapped to this patent’s limitations

• Shift cationic lipid mol% above 65 or below 50 (claim 1).
• Shift phospholipid mol% below 3 or above 15; or use non-DPPC/DSPC if targeting dependent claims.
• Shift cholesterol below 30 or above 40; or above 35 to avoid claim 13.
• Shift PEG-lipid type or MW (avoid PEG-DMA/PEG-DSA and MW ~2,000 if targeting dependent claims 15–17).
• Shift PEG-lipid mol% below 0.5 or above 2.
• Change siRNA chemistry/structure to avoid 2’-O-methyl, 19–25 bp, or 3’ overhangs.

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How does the claim structure affect litigation and claim construction?

Short answer: The case will likely hinge on (1) mol% boundaries, (2) whether the accused particle has the required lipid “mixture” structure, (3) identity of the aggregation inhibitor lipid, (4) what “fully encapsulated” means in testing, and (5) whether the nucleic acid meets modification/length/overhang limitations.

Mol% and measurement protocol

For formula patents, defendants typically dispute analytical methods for mol% determination and the particle composition after formulation. “About” language (in claim 19 and claim 17) can become a battleground for acceptable tolerance.

Identity of “conjugated lipid that inhibits aggregation”

Claim 1 is broad as to “conjugated lipid.” Dependent claims tie it to PEG-lipid conjugates. If an accused product uses a non-PEG conjugate, the plaintiff’s ability to prove inhibition of aggregation and structural alignment to claim 1 becomes critical.

“Fully encapsulated”

Encapsulation is commonly measured using assays separating free vs encapsulated nucleic acid. “Fully encapsulated” can be treated as a quantitative threshold in practice. Claim 20 also extends risk into formulation QC-level requirements.

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Which product archetypes are most likely to infringe US 8,492,359?

Short answer: siRNA-LNP products using PEGylated LNP designs with DPPC/DSPC-like phospholipids, cholesterol-containing non-cationic phases, and a PEG-lipid surface chemistry around ~2,000 Da are the closest match to the claim family.

Closest archetype match to claim 1 + claim 2–6

• siRNA with chemical modifications including 2’-O-methyl
• 19–25 bp siRNA with 3’ overhangs
• LNP with cationic lipid 50–65 mol%
• phospholipid 3–15 mol% (often DPPC or DSPC)
• cholesterol 30–40 mol%
• PEG-lipid 0.5–2 mol% (often PEG-DAG/PEG-DAA with ~2,000 Da)

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Key Takeaways

• US 8,492,359 is a composition-ratio patent for nucleic acid-lipid particles (LNPs), with independent claim 1 defined by mol% windows for cationic lipid, phospholipid, cholesterol, and an aggregation-inhibiting conjugated lipid.
• Dependent claims narrow to siRNA with specific features: modified nucleotides, including 2’-O-methyl, 19–25 bp, and 3’ overhangs.
• PEG-lipid identity and PEG size matter in dependent claims: PEG-DAG or PEG-DAA (PEG-DMA/PEG-DSA) with PEG MW about 2,000 Da.
• Design-around is feasible by moving out of mol% ranges, switching aggregation-inhibiting conjugates, changing PEG chemistry/MW, or modifying siRNA chemistry/length/overhang structure.
• Litigation is likely mol% and test-method driven, with additional disputes around “fully encapsulated” and whether an accused aggregation inhibitor lipid falls within the functional/structural scope of claim 1.

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FAQs

1) What part of US 8,492,359 is most likely to be used in an infringement claim?
Claim 1’s mol% composition windows for cationic lipid, phospholipid, cholesterol, and conjugated aggregation-inhibiting lipid.

2) If a product uses siRNA without 2’-O-methyl, can it still be exposed?
Yes, if the particle matches claim 1’s LNP composition; claims 2–6 would be avoided if the siRNA does not meet those features.

3) How can a competitor design around claim 1 most directly?
Shift one of the required lipid mol% ranges outside the claim 1 windows, especially cholesterol (30–40 mol%) or conjugated lipid (0.5–2 mol%).

4) Does “PEG-lipid” matter for infringement of claim 1?
Claim 1 covers a “conjugated lipid that inhibits aggregation.” PEG is explicitly required in dependent claim 14, but PEG-like conjugates are the most straightforward path to prove infringement.

5) What role does “fully encapsulated” play?
It is an additional limitation in dependent claim 20 and can be used to argue non-infringement for products where assay results show non-encapsulated nucleic acid.

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References

1. US Patent 8,492,359 (claims provided in prompt).

Drugs Protected by US Patent 8,492,359

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Alnylam Pharms Inc	ONPATTRO	patisiran sodium	SOLUTION;INTRAVENOUS	210922-001	Aug 10, 2018		RX	Yes	Yes			Y

International Family Members for US Patent 8,492,359

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2008342535
Australia	2009238175
Canada	2710713
Canada	2721333
China	102119217
Denmark	2279254
European Patent Office	2238251