United States Drug Patent 8,822,668: Scope, Claims, Expiration, Orange Book Status, and Patent Landscape

U.S. Patent No. 8,822,668 protects a four-component nucleic acid-lipid particle with a defined molar composition: 50-65% cationic lipid, up to 49.5% non-cationic lipid, 30-40% cholesterol or derivative, and 0.5-2% aggregation-inhibiting conjugated lipid. The claim set is closely aligned with the lipid nanoparticle composition used for Alnylam’s ONPATTRO (patisiran), including a DLin-MC3-DMA cationic lipid, DSPC, cholesterol, and PEG-lipid.

The patent covers composition, pharmaceutical-composition, cell-delivery, in-vivo delivery, and treatment claims. It is not a patent on a particular siRNA sequence. Its principal commercial importance is the formulation architecture and lipid-ratio window.

What does U.S. Patent 8,822,668 protect?

Claim 1 is an open-ended composition claim directed to a nucleic acid-lipid particle containing four required components:

Component	Claimed amount or requirement	Commercial significance
Nucleic acid	Required	Includes siRNA and other nucleic acids
Cationic lipid	50-65 mol% of total lipid	Provides nucleic-acid complexation and particle formation
Non-cationic lipid	Up to 49.5 mol%	Includes phospholipid and cholesterol
Cholesterol or derivative	30-40 mol% of total lipid	Stabilizes particle structure
Aggregation-inhibiting conjugated lipid	0.5-2 mol%	Usually a PEG-lipid
Phospholipid	Required as part of the non-cationic lipid mixture	Includes DPPC, DSPC, or mixtures

The cholesterol percentage is calculated against total lipid, not merely against the non-cationic fraction. Cholesterol is also included within the non-cationic lipid category. The claim therefore describes a constrained four-component lipid system rather than four independent additive ranges.

A formulation containing 50% cationic lipid, 10% phospholipid, 38.5% cholesterol and 1.5% PEG-lipid falls within the express numerical limitations of claim 1. That is the approximate composition associated with ONPATTRO’s lipid nanoparticle platform, using DLin-MC3-DMA, DSPC, cholesterol and PEG2000-C-DMG [1, 2].

How should the claims be construed?

Claim 1: Core composition claim

Claim 1 requires all of the following:

A particle, rather than merely a lipid mixture.
A nucleic acid associated with the particle.
A cationic lipid at 50-65 mol%.
A non-cationic lipid fraction containing both a phospholipid and cholesterol or a cholesterol derivative.
Cholesterol at 30-40 mol%.
A conjugated lipid that inhibits aggregation at 0.5-2 mol%.

The claim does not require:

A particular nucleic acid sequence.
A particular disease indication.
A particular administration route.
A specific particle diameter.
A particular cationic lipid chemical structure.
A particular PEG-lipid unless the dependent claims are invoked.
A particular siRNA target.

The lack of a sequence limitation makes the claim potentially relevant to multiple siRNA products if their lipid composition satisfies the claimed ranges.

Claims 2-7: Interfering-RNA and siRNA limitations

Claims 2 and 3 narrow the nucleic acid to interfering RNA and then to siRNA. Claims 4-7 add conventional siRNA design elements:

Claim	Limitation
2	Interfering RNA
3	siRNA
4	At least one modified nucleotide
5	At least one 2′-O-methyl nucleotide
6	Approximately 19-25 base pairs
7	3′ overhangs

These claims may be useful where a product uses a modified siRNA duplex, but they are narrower than claim 1. A product could infringe claim 1 without infringing claims 2-7 if the nucleic acid is messenger RNA, antisense RNA, DNA, or another non-siRNA nucleic acid.

Claims 8-15: Lipid-ratio and PEG-lipid limitations

Claim 8 narrows the cationic lipid to 50-60 mol%. Claim 10 narrows cholesterol to 30-35 mol%. Claim 15 narrows the conjugated lipid to 1-2 mol%.

The most commercially relevant dependent claims are claims 9, 11, 12 and 13:

Claim 9 covers DPPC, DSPC or mixtures.
Claim 11 covers PEG-lipid conjugates.
Claim 12 covers PEG-DAG and PEG-DAA conjugates.
Claim 13 covers PEG-DMA and PEG-DSA conjugates.
Claim 14 limits PEG to an average molecular weight of approximately 2,000 daltons.

A formulation with DSPC, cholesterol and PEG2000-C-DMG may implicate the structural class covered by these limitations, depending on the precise chemical identity and claim construction applied to the PEG-DAA terminology.

Claims 16-17: Encapsulation and pharmaceutical composition

Claim 16 requires the nucleic acid to be fully encapsulated. This is narrower than claim 1, which does not expressly require complete encapsulation.

Claim 17 covers a pharmaceutical composition containing the claimed particle and a pharmaceutically acceptable carrier. This claim can reach a finished injectable formulation, not merely the nanoparticle intermediate.

Claims 18-23: Delivery and treatment claims

Claims 18-20 cover:

Introducing nucleic acid into a cell.
In-vivo delivery to a mammalian subject.
Treating a disease or disorder with a therapeutically effective amount.

Claims 21-23 specify viral infection, liver disease or disorder, and cancer. These claims are method-of-use claims and require performance of the claimed method. They do not independently protect a product that lacks the composition limitations of claim 1.

What products are most closely associated with the patent?

ONPATTRO and patisiran

ONPATTRO is the strongest commercial reference point. The FDA-approved product contains patisiran, an siRNA, delivered in a lipid nanoparticle using:

DLin-MC3-DMA as the ionizable cationic lipid;
DSPC as the phospholipid;
Cholesterol;
PEG2000-C-DMG as the PEG-lipid.

The commonly reported molar composition is approximately 50:10:38.5:1.5 for cationic lipid, DSPC, cholesterol and PEG-lipid, respectively [2]. That composition sits inside the central numerical ranges of claim 1 and the narrower ranges of claims 8, 10 and 15.

The patent does not, by itself, establish that every ONPATTRO batch infringes. Infringement would depend on the approved product’s actual composition, the construction of terms such as “cationic lipid,” and the status and enforceability of the patent at the relevant time. The formulation overlap is, however, direct and commercially significant.

Other siRNA lipid nanoparticle products

The patent may also be relevant to other lipid nanoparticle products using:

A cationic or ionizable lipid at approximately half of total lipid;
Cholesterol near 30-40 mol%;
DSPC or a related phospholipid;
A PEG-lipid at approximately 1-2 mol%;
Fully encapsulated siRNA.

The claims do not require patisiran. A competing product with a different siRNA sequence could still fall within claim 1.

What is the patent’s filing and expiration timeline?

Event	Date
Earliest priority date	June 25, 2004
U.S. patent grant	September 2, 2014
Patent number	8,822,668
Patent type	Utility patent
Base statutory term	Approximately 20 years from the applicable earliest non-provisional/PCT filing
Base expiration	June 24-25, 2025

The patent’s base term is tied to the 2004 priority chain and the associated international or non-provisional filing date, rather than to the 2014 grant date. A continuation application does not normally receive a new 20-year term.

The patent therefore reached the end of its base term in June 2025. No patent-term extension under 35 U.S.C. § 156 is identified for U.S. Patent 8,822,668. Any terminal disclaimer, patent-term adjustment or regulatory exclusivity issue should be checked against the USPTO Patent Center record and the FDA Orange Book entry before relying on the patent in an active enforcement or launch analysis [3, 4].

What is the Orange Book status of U.S. Patent 8,822,668?

U.S. Patent 8,822,668 has been associated with ONPATTRO’s FDA patent listings. The listing is commercially relevant because it identifies the patent as one of the patents that an ANDA applicant may need to address when seeking approval for a product referencing patisiran [3].

The Orange Book listing does not mean that the patent is currently enforceable. Orange Book inclusion is a regulatory listing function. Enforceability depends on expiration, terminal disclaimers, maintenance fees, litigation outcomes and other patent-law issues.

For an ANDA filed while the patent was listed and unexpired, the applicant could have used:

Paragraph I: no patent information was submitted;
Paragraph II: the patent had expired;
Paragraph III: approval would be delayed until patent expiration;
Paragraph IV: the patent was invalid, unenforceable or would not be infringed.

After the base expiration date, a Paragraph IV challenge to this patent would generally lose practical importance, although litigation could remain relevant to damages, launch timing or historical entry conduct.

When does ONPATTRO lose exclusivity?

ONPATTRO’s exclusivity has several separate components:

Exclusivity or barrier	Practical effect
New chemical entity exclusivity	Delays certain ANDA submissions during the statutory period
Orphan-drug exclusivity	Protects the approved indication for seven years from approval, subject to statutory exceptions
Orange Book patents	May delay approval or create Paragraph IV litigation
Formulation and manufacturing know-how	Can make technical replication more difficult
siRNA and delivery-platform patents	May create additional infringement risk
Regulatory complexity	Makes conventional small-molecule generic substitution less straightforward

Patent 8,822,668 is only one part of the ONPATTRO estate. Its June 2025 base expiration does not necessarily eliminate all barriers to competition. Other patents may cover the ionizable lipid, lipid-particle preparation, siRNA sequence, dosing regimen, formulation, manufacturing process or alternative delivery configurations.

ONPATTRO is an oligonucleotide product rather than a conventional small-molecule drug. A competitive applicant may pursue a 505(b)(2) pathway or an abbreviated pathway where available, but approval and substitution questions can be more complex than for a standard tablet or injectable small molecule.

How strong is the patent estate for the claimed formulation?

Strengths

The patent has four principal strengths:

The numerical ranges map closely to a clinically used LNP composition.
Claim 1 is not limited to a specific siRNA sequence.
The claim includes both product and use categories.
Dependent claims address common commercial excipients and PEG-lipid structures.

The broadest claim is commercially useful because it focuses on formulation architecture. A competitor cannot avoid the claim merely by changing the siRNA target if the lipid ratios remain within the claimed ranges.

Vulnerabilities

The main risks to validity and enforcement are:

Prior-art disclosure of similar four-component lipid particles;
Obviousness challenges based on known lipid-ratio optimization;
Construction disputes over “cationic lipid” and “conjugated lipid that inhibits aggregation”;
Whether cholesterol is properly counted within the non-cationic fraction;
Whether a formulation lies inside or outside a claimed range;
Enablement and written-description challenges across broad nucleic-acid and disease categories;
Proof that the commercial product has the claimed composition.

The range limitations create both strength and vulnerability. They provide a clear formulation target, but a competitor may attempt design-around by moving one component outside the relevant range.

What design-around strategies could avoid the claims?

Potential design-around options include:

Design-around	Effect on claim 1
Reduce cationic lipid below 50 mol%	May avoid the express cationic-lipid range
Increase cationic lipid above 65 mol%	May avoid claim 1 but can affect tolerability and delivery
Reduce cholesterol below 30 mol% or increase it above 40 mol%	May avoid the cholesterol limitation
Use less than 0.5 mol% or more than 2 mol% PEG-lipid	May avoid the conjugated-lipid range
Replace the phospholipid/cholesterol system	May avoid the required non-cationic mixture
Use a non-PEG aggregation-control lipid	May avoid claims 11-15, but not necessarily claim 1
Use a delivery system other than a nucleic acid-lipid particle	May avoid the entire claim category

A design-around must be evaluated against the full claim, prosecution history and doctrine of equivalents. Moving a component only marginally outside a numerical range may reduce literal-infringement risk but does not eliminate litigation risk.

Which companies and patent estates are relevant?

Alnylam Pharmaceuticals

Alnylam is the product sponsor for ONPATTRO and the principal commercial stakeholder associated with the patisiran formulation. Its broader patent estate includes patents directed to siRNA sequences, chemical modifications, lipid particles, dosing and therapeutic uses [2, 5].

Arbutus Biopharma and Tekmira

Arbutus and its predecessor Tekmira developed and licensed foundational lipid nanoparticle technology. Their portfolios include ionizable lipid chemistry, lipid-particle composition and manufacturing technologies. The Alnylam-Tekmira relationship has been commercially important to the ONPATTRO delivery platform [6].

Moderna and other mRNA-LNP companies

Moderna, BioNTech, Pfizer and other RNA developers have separate or overlapping LNP portfolios, but their mRNA delivery claims often use different ionizable lipids, molar ratios and product specifications. Their patents are relevant to freedom-to-operate analysis for LNP manufacturing and delivery, but they do not automatically read on the claim set of U.S. 8,822,668.

Generics and follow-on sponsors

No biosimilar pathway applies directly to patisiran in the same way it applies to a protein biologic. A follow-on sponsor would face a combination of patent, analytical comparability, manufacturing and regulatory issues. A conventional ANDA strategy would be more difficult than for a simple chemically defined small molecule.

What patent litigation affects U.S. Patent 8,822,668?

The major LNP disputes involving Alnylam, Arbutus and Moderna generally concern related lipid nanoparticle patents, including foundational ionizable-lipid and delivery patents. Those disputes should not be treated as adjudications of U.S. 8,822,668 unless the patent is expressly asserted or construed in the proceeding.

No widely reported Paragraph IV judgment or appellate decision has invalidated the full claim set of U.S. 8,822,668. The principal current issue is expiration of the base patent term, not a known adverse merits decision against the patent.

What geographic coverage does the patent provide?

U.S. Patent 8,822,668 provides protection only in the United States. Related applications and national-stage counterparts may protect corresponding formulations in Europe, Canada, Japan, Australia and other jurisdictions, but each counterpart has its own:

Claim language;
Prosecution history;
Expiration date;
Patent-term adjustment or extension;
Opposition or validity status;
Litigation record.

A U.S. expiration does not eliminate foreign rights. Commercial launch planning must be performed jurisdiction by jurisdiction.

Key Takeaways

U.S. 8,822,668 is a formulation patent for nucleic acid-lipid particles.
Claim 1 requires 50-65 mol% cationic lipid, 30-40 mol% cholesterol, and 0.5-2 mol% aggregation-inhibiting conjugated lipid.
The claim architecture closely matches the ONPATTRO lipid nanoparticle composition.
The dependent claims cover siRNA, modified nucleotides, 19-25-base-pair duplexes, 3′ overhangs, DSPC or DPPC, PEG-lipids and PEG2000 structures.
The patent covers composition, pharmaceutical formulation, delivery and treatment methods.
The base patent term ended in June 2025.
Patent expiration does not eliminate other ONPATTRO patents, siRNA patents, manufacturing rights or regulatory barriers.
A competitor can pursue design-around strategies by changing lipid ratios, lipid identity or the aggregation-control component.
Patisiran is an oligonucleotide product, so biosimilar analysis is less applicable than generic, 505(b)(2) and follow-on RNA-product analysis.
The most important remaining freedom-to-operate issues concern related LNP patents held by Alnylam, Arbutus and other platform owners.

FAQs About U.S. Patent 8,822,668

Does U.S. 8,822,668 cover the patisiran siRNA sequence?

No. The independent composition claim is not limited to a particular siRNA sequence. It can apply to different nucleic acids if the particle satisfies the claimed lipid composition.

Does changing DLin-MC3-DMA avoid the patent?

Not necessarily. Claim 1 requires a cationic lipid but does not require DLin-MC3-DMA. A different ionizable or cationic lipid could remain within the claim if the other limitations are met.

Does the patent cover mRNA lipid nanoparticles?

Potentially. Claim 1 recites “a nucleic acid,” not only siRNA. Claims 2-7 narrow the subject matter to interfering RNA and siRNA, but claim 1 is broader.

Is the patent relevant after June 2025?

The base term expired in June 2025. It may remain relevant to historical infringement, litigation or patent-family analysis, but later launch decisions must focus on unexpired related patents and regulatory exclusivity.

Can a competitor avoid the patent by using 0.4% PEG-lipid?

That may avoid the literal 0.5-2% limitation in claim 1, but the full formulation, prosecution history and potential equivalents analysis must be considered. Claims covering related formulations may also apply.

References

United States Patent No. 8,822,668. (2014). Nucleic acid-lipid particles. U.S. Patent and Trademark Office.
Alnylam Pharmaceuticals, Inc. (2024). ONPATTRO (patisiran) injection, for intravenous use: Prescribing information. U.S. Food and Drug Administration.
U.S. Food and Drug Administration. (2025). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.
U.S. Patent and Trademark Office. (2025). Patent Center: U.S. Patent No. 8,822,668. USPTO.
Alnylam Pharmaceuticals, Inc. (2024). Annual report on Form 10-K. U.S. Securities and Exchange Commission.
Arbutus Biopharma Corporation. (2024). Annual report on Form 10-K. U.S. Securities and Exchange Commission.

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	⤷ Start Trial	⤷ Start Trial	Y			TREATMENT OF POLYNEUROPATHY OF HEREDITARY TRANSTHYRETIN-MEDIATED AMYLOIDOSIS	⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2008342535	⤷ Start Trial
Australia	2009238175	⤷ Start Trial
Canada	2710713	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,822,668

Which drugs does patent 8,822,668 protect, and when does it expire?

Summary for Patent: 8,822,668