Details for Patent: 10,851,377

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Which drugs does patent 10,851,377 protect, and when does it expire?

Patent 10,851,377 protects LEQVIO and is included in one NDA.

This patent has thirty-one patent family members in twelve countries.

Summary for Patent: 10,851,377

Title:	Methods and compositions for treating a proprotein convertase subtilisin kexin (PCSK9) gene-associated disorder
Abstract:	The invention relates to methods of inhibiting the expression of a PCSK9 gene in a subject, as well as therapeutic and prophylactic methods for treating subjects having a lipid disorder, such as a hyperlipidemia using RNAi agents, e.g., double-stranded RNAi agents, targeting the PCSK9 gene.
Inventor(s):	Kevin Fitzgerald
Assignee:	Alnylam Pharmaceuticals Inc
Application Number:	US16/744,689
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,851,377
Patent Claim Types: see list of patent claims	Use; Composition; Device;

U.S. Patent 10,851,377: Inclisiran Patent Scope, Claims, Expiration, and Competitive Landscape

U.S. Patent No. 10,851,377 protects specific dosing methods for inclisiran, the GalNAc-conjugated PCSK9 small-interfering RNA marketed as Leqvio. The patent is method-of-treatment focused. Its core limitations are a fixed 275 mg to 325 mg subcutaneous dose, a defined chemically modified siRNA sequence, and conjugation to a triantennary N-acetylgalactosamine ligand.

The commercially important embodiment is 300 mg administered subcutaneously initially, again at three months, and then every six months. The patent’s base term is tied to a March 15, 2013 priority date and runs approximately to March 15, 2034, before any patent-term adjustment or other term calculation under the USPTO record.

What drug does U.S. Patent 10,851,377 protect?

U.S. Patent 10,851,377 protects methods using inclisiran or its corresponding salt form to inhibit PCSK9 expression and reduce LDL cholesterol.

Inclisiran is a double-stranded RNAi agent with:

Attribute	Claimed characteristic
Target	Human PCSK9 gene
Modality	Double-stranded RNAi agent
Delivery	Subcutaneous administration
Dose	Fixed dose of 275 mg to 325 mg
Commercial dose	300 mg inclisiran, administered as 284 mg inclisiran sodium
Targeting ligand	Triantennary GalNAc, commonly described as GalNAc3
Sense strand	SEQ ID NO: 687
Antisense strand	SEQ ID NO: 688
Indications	Hyperlipidemia, hypercholesterolemia, LDL-C reduction, cardiovascular-risk populations
Product	Leqvio, inclisiran injection
FDA approval	December 22, 2021

FDA approved Leqvio as an adjunct to diet and statin therapy for adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease, who require additional LDL-C lowering.[1]

What are the independent claims in U.S. Patent 10,851,377?

The patent has four principal independent method claims in the claim set supplied.

Claim 1: PCSK9 expression inhibition

Claim 1 covers subcutaneously administering a fixed 275 mg to 325 mg dose of the specified GalNAc-conjugated RNAi agent to a human subject to inhibit PCSK9 gene expression.

The claim requires all of the following:

1. A human subject.
2. Subcutaneous administration.
3. A fixed dose between 275 mg and 325 mg.
4. A double-stranded RNAi agent.
5. The precise sense and antisense sequences identified as SEQ ID NOs: 687 and 688.
6. The stated 2′-O-methyl, 2′-fluoro, 2′-deoxythymidine and phosphorothioate chemistry.
7. Conjugation to a GalNAc3 ligand.

The claim does not cover every PCSK9 inhibitor, every siRNA against PCSK9, or every inclisiran dose. It is limited to the recited molecular structure and dosing range.

Claim 2: Hyperlipidemia treatment

Claim 2 uses substantially the same product, route, dose and chemistry limitations as claim 1, but recites treatment of a human subject with hyperlipidemia.

The claim is broader in disease terminology than claims directed specifically to hypercholesterolemia or LDL-C reduction. Claim 15 narrows claim 2 to hypercholesterolemia.

Claim 26: LDL-C reduction

Claim 26 covers administering the specified RNAi agent to decrease serum LDL-C.

This claim requires a measurable lipid-lowering result rather than merely PCSK9 expression inhibition or treatment of hyperlipidemia. Claim 27 narrows the patient population to subjects with hypercholesterolemia. Claim 28 adds a heterozygous LDL-receptor genotype limitation.

Claim 29: LDL-C reduction in cardiovascular-risk patients

Claim 29 covers LDL-C reduction in a human subject having one or more specified cardiovascular-risk factors. The listed factors include diabetes, prior coronary heart disease or noncoronary atherosclerosis, family history, tobacco use, hypertension and obesity.

Claim 30 narrows claim 29 by specifying cardiovascular diseases including coronary artery disease, heart failure, hypertension, peripheral vascular disorders, myocardial infarction, cardiomyopathy and related conditions.

How narrow are the molecular limitations?

The sequence and chemical-structure limitations are substantial. The patent does not claim a generic GalNAc-siRNA platform in the abstract. It claims a defined sequence pair and a defined pattern of nucleotide modifications.

Sense and antisense sequences

The claims identify:

• Sense strand: SEQ ID NO: 687
• Antisense strand: SEQ ID NO: 688

The sequence notation specifies:

• 2′-O-methyl adenine, guanine, cytosine and uracil
• 2′-fluoro adenine, guanine, cytosine and uracil
• 2′-deoxythymidine
• Phosphorothioate linkages

A competing product with a different guide sequence, a materially different modification pattern or a different strand architecture would have a stronger noninfringement position against the literal sequence limitations of claims 1, 2, 26 and 29.

The risk is higher for a product that uses the same inclisiran sequence and chemistry but changes only the dose, administration schedule or formulation. Such a product could remain within claims 1, 2, 26 or 29 if it uses a dose within the 275 mg to 325 mg range.

GalNAc3 conjugation

The claims require conjugation to a triantennary GalNAc ligand. The commercial significance of this limitation is high because GalNAc enables preferential uptake by hepatocytes through the asialoglycoprotein receptor.

Claims 20 to 23 further address the conjugation arrangement, including attachment to the 3′ end of the sense strand and a linker in which X is oxygen. Claims 22 and 23 are narrower than the independent claims because they require the sense and antisense strands to consist of the specified sequences, rather than merely comprise them.

What do claims 3 through 30 add?

Claims	Added limitation	Commercial effect
3 and 4	Fixed 300 mg dose	Directly tracks the commercial dose
5 and 6	300 mg once a quarter	Covers initial three-month dosing
7 and 8	300 mg biannually	Covers six-month maintenance dosing
9 and 10	Loading phase followed by maintenance phase	Captures staged treatment regimens
11 and 12	Same dose during loading and maintenance	Narrows regimen structure
13 and 14	Additional therapeutic agent	Covers combination treatment
15	Hypercholesterolemia	Narrows hyperlipidemia treatment
16 and 17	Pharmaceutical composition	Adds formulation context
18 and 19	GalNAc3 ligand structure	Scope depends on the omitted structural drawing
20 and 21	Conjugation schematic with X = O	Narrows linker chemistry
22 and 23	Exact strand sequences and 3′ sense-strand conjugation	Strongest sequence-specific claims
24 and 25	Salt form	Covers inclisiran salt embodiments
27	Hypercholesterolemia	Narrows LDL-C reduction
28	Heterozygous LDL-receptor genotype	Covers a defined genetic population
30	Enumerated cardiovascular diseases	Narrows cardiovascular-risk treatment

Claims 3 to 8 are especially important commercially because they track the Leqvio label. Claims 9 to 12 provide additional protection against dosing-regimen modifications involving a loading phase and maintenance phase.

When does U.S. Patent 10,851,377 expire?

The patent’s relevant priority date is March 15, 2013. On a standard 20-year term measured from the earliest nonprovisional priority-linked filing, the base term would run to approximately March 15, 2034.

Event	Date or status
Earliest cited priority date	March 15, 2013
Patent grant	December 1, 2020
Base patent term	Approximately March 15, 2034
Patent-term adjustment	Must be calculated from the USPTO patent record
Commercial product	Leqvio, inclisiran
FDA approval	December 22, 2021

The precise enforceable expiration date should be determined from the patent’s face, USPTO patent-term-adjustment data, terminal disclaimers and any applicable patent-term extension. The 2034 date is the base-term reference point, not a substitute for the USPTO term calculation.[2]

What is the Orange Book status of inclisiran?

Leqvio is an FDA-approved small-molecule drug product based on an oligonucleotide active ingredient. It is not a biologic licensed under section 351 of the Public Health Service Act. Accordingly, biosimilar interchangeability rules do not apply to Leqvio.

The FDA Orange Book is the relevant listing source for approved-product patents and regulatory exclusivity. The 10,851,377 patent is part of the broader patent estate associated with inclisiran and its approved use. Orange Book status can change through patent-listing updates, corrections and new patent submissions, so the current electronic Orange Book record controls for an ANDA strategy.[3]

The regulatory consequence is important:

• An ANDA applicant would generally need to address listed patents with a Paragraph IV certification or wait for expiration.
• A 505(b)(2) applicant could face similar patent-certification issues if relying on Leqvio data or seeking a related formulation or use.
• A biosimilar application is not the expected pathway for inclisiran.

Are there Paragraph IV challenges to Leqvio?

No widely established public Paragraph IV litigation campaign against U.S. Patent 10,851,377 is identified in the supplied record. The absence of a known challenge does not eliminate future ANDA risk.

A generic entrant would face several potential patent layers:

1. The sequence-specific method claims in U.S. Patent 10,851,377.
2. Other patents covering inclisiran composition, conjugation chemistry, formulation or manufacture.
3. Additional listed patents associated with Leqvio.
4. Regulatory exclusivity and approval-timing constraints.
5. Commercial manufacturing barriers for the modified duplex and GalNAc conjugate.

A Paragraph IV notice directed only to a dose or regimen patent may not resolve infringement exposure under other composition or manufacturing patents. A complete freedom-to-operate analysis therefore requires claim-charting the full Orange Book and non-Orange Book estate.

How strong is the patent estate for inclisiran?

The estate is strongest against a product that copies the commercial inclisiran architecture and dosing schedule. It is less dominant against alternative PCSK9 RNAi products that use different sequences, ligands or delivery technologies.

Strong infringement positions

The highest-risk product would:

• Use the SEQ ID NO: 687/688 duplex.
• Use the specified nucleotide modifications.
• Attach a triantennary GalNAc ligand.
• Administer the product subcutaneously.
• Use a 300 mg dose.
• Treat hyperlipidemia or reduce LDL-C.
• Follow the three-month loading and six-month maintenance schedule.

That profile maps directly onto claims 1, 2, 3 through 8, 26 and 29.

Potential design-around positions

Potential design-around strategies include:

• A different PCSK9-targeting sequence.
• A different dose outside 275 mg to 325 mg.
• A different targeting ligand.
• A non-GalNAc hepatic delivery system.
• A materially different nucleotide-modification pattern.
• A different administration route.
• A product used for a different indication or endpoint.

These strategies would not automatically avoid infringement. Doctrine-of-equivalents issues, other patents and regulatory similarity could remain relevant. The strongest design-around is a genuinely different RNA sequence combined with a different conjugation architecture.

What formulation patents protect inclisiran?

Patent 10,851,377 is not principally a formulation patent. Its claims are method claims that refer to administration in a pharmaceutical composition but do not define a detailed excipient system in the supplied claims.

The formulation risk is separate from the sequence and regimen risk. A follow-on product could avoid one formulation claim while still infringing method or composition claims. Conversely, a different formulation of the same inclisiran active ingredient could remain exposed to the claims of 10,851,377 because the patent does not require a particular excipient package for its core claims.

Key formulation issues include:

• Inclisiran salt selection.
• Duplex stability.
• GalNAc conjugate integrity.
• Container-closure compatibility.
• Sterile injectable presentation.
• Concentration and pH.
• Long-term refrigerated stability.
• Aggregation and degradation control.

What manufacturing and IP barriers affect generic entry?

Manufacturing is a material barrier even when patent claims can be designed around.

A competing manufacturer would need to reproduce or replace:

• Solid-phase synthesis of the modified oligonucleotide strands.
• Site-specific phosphorothioate placement.
• Controlled 2′-O-methyl and 2′-fluoro modification patterns.
• Duplex annealing and purification.
• GalNAc3 ligand synthesis.
• Site-specific conjugation.
• Removal of truncated sequences and process impurities.
• Sterile injectable manufacturing.
• Analytical characterization of the final conjugate.

Process patents may create risk even where the final product avoids the precise claims of 10,851,377. Trade secrets involving conjugation yield, purification and impurity control can also delay entry without appearing in the Orange Book.

How does inclisiran compare with PCSK9 antibody products?

Product	Active ingredient	Modality	Dosing pattern	Main patent risk
Leqvio	Inclisiran	GalNAc-conjugated siRNA	Initial dose, three-month dose, then every six months	Sequence, conjugation, dosing, formulation and process patents
Repatha	Evolocumab	Monoclonal antibody	Monthly or quarterly, depending on presentation	Antibody sequence, binding-site and formulation patents
Praluent	Alirocumab	Monoclonal antibody	Usually every two or four weeks	Antibody and formulation patents
Nexletol	Bempedoic acid	Small molecule	Daily oral dosing	Compound, formulation and method patents

Inclisiran’s extended dosing interval is its main commercial distinction. Its manufacturing complexity is higher than for conventional small-molecule generics, while its regulatory pathway remains that of an approved drug rather than a biosimilar.

What licensing deals affect inclisiran?

Alnylam developed inclisiran as part of its PCSK9 RNAi program. Novartis obtained global rights to develop and commercialize inclisiran under a collaboration and licensing arrangement. Novartis markets Leqvio, while Alnylam remains economically linked through the licensing structure.[4]

The licensing arrangement matters for patent enforcement because:

• Novartis is the principal commercial party in the United States.
• Alnylam retains foundational RNAi and platform rights.
• Enforcement may involve the product marketer, patent owner, exclusive licensee or a combination of parties.
• A generic settlement could require coordination across product, platform and process rights.

What is the competitive landscape for PCSK9 RNAi drugs?

No other PCSK9-directed RNAi product has matched inclisiran’s U.S. commercial and regulatory position through the public record considered here.

The competitive field includes:

• PCSK9 monoclonal antibodies, particularly evolocumab and alirocumab.
• Oral lipid-lowering therapies such as statins, ezetimibe and bempedoic acid.
• Other siRNA programs directed at cardiovascular targets, including Lp(a), but not necessarily PCSK9.
• Antisense and RNAi programs that may compete for injectable lipid-management use without practicing the inclisiran sequence.

A competing PCSK9 RNAi product would need to demonstrate LDL-C lowering, establish a differentiated safety and dosing profile, and clear the patent estate covering sequence, conjugation, manufacturing and use.

What generic launch scenarios exist?

Scenario 1: Same inclisiran sequence and same dosing

This is the highest-risk scenario. A product using the claimed duplex, GalNAc3 conjugate and 300 mg subcutaneous regimen would likely face direct exposure to the core method claims and related patents.

Scenario 2: Same sequence with a different dose

Changing the dose outside 275 mg to 325 mg could avoid the literal dose limitation of the core claims. That strategy could create clinical and regulatory disadvantages and would not address composition, formulation or process patents.

Scenario 3: Different PCSK9 siRNA sequence

A new sequence provides the clearest route around sequence-specific claims. The entrant would need independent clinical evidence and would face separate platform, delivery and manufacturing patents.

Scenario 4: Alternative delivery ligand

Replacing GalNAc3 with another liver-targeting system could avoid the ligand limitation. The alternative may have lower hepatocyte uptake, a different safety profile or its own patent constraints.

Scenario 5: 505(b)(2) or hybrid launch

A 505(b)(2) strategy may be available for a modified formulation or delivery system, but it does not eliminate patent certifications, litigation or regulatory exclusivity issues.

Key Takeaways

• U.S. Patent 10,851,377 is a targeted method patent for inclisiran, not a broad patent on every PCSK9 inhibitor.
• Its core scope requires the specified SEQ ID NO: 687/688 duplex, defined chemical modifications, GalNAc3 conjugation, subcutaneous dosing and a 275 mg to 325 mg fixed dose.
• The 300 mg quarterly and biannual regimen claims closely track the Leqvio label.
• Claims 26 and 29 extend protection to LDL-C reduction and cardiovascular-risk populations.
• The base patent term runs approximately to March 15, 2034, before any USPTO patent-term adjustment.
• Leqvio is an approved drug, not a biosimilar reference product. Generic entry would proceed through an ANDA or potentially a 505(b)(2) pathway.
• The most credible design-arounds involve a different siRNA sequence, delivery ligand or dose outside the claimed range.
• Manufacturing, conjugation, purification and injectable formulation create additional technical and intellectual-property barriers.
• A complete entry analysis must consider the full inclisiran Orange Book and non-Orange Book patent estate, not 10,851,377 alone.

FAQs

Is U.S. Patent 10,851,377 a composition-of-matter patent?

No. The supplied claims are method-of-treatment claims. They require administration to a human subject and specify dose, route, target, sequence and conjugation characteristics.

Does the patent cover all GalNAc-conjugated PCSK9 siRNAs?

No. The independent claims require the identified inclisiran sequence pair and the specified chemical modifications. A different PCSK9 siRNA may fall outside these claims, although other patents may apply.

Does a 284 mg Leqvio injection fall within the 275 mg to 325 mg claims?

The patent claims recite 275 mg to 325 mg of the RNAi agent. Leqvio is labeled as 284 mg inclisiran sodium equivalent to 300 mg inclisiran. The applicable infringement analysis must distinguish active-agent mass from salt mass and assess the product’s legally relevant dose calculation.

Can a generic manufacturer avoid the patent by using monthly dosing?

A monthly regimen would not necessarily avoid claims 1, 2, 26 or 29 because those claims do not require quarterly or biannual administration. Claims 5 to 8 are narrower regimen claims, but the independent claims remain relevant.

Is inclisiran subject to biosimilar competition?

No. Inclisiran is regulated as an approved drug product rather than a biologic subject to the biosimilar pathway. Any follow-on applicant would generally evaluate the ANDA or 505(b)(2) framework, depending on the proposed product and reliance strategy.

References

1. U.S. Food and Drug Administration. (2021). FDA approves add-on therapy to lower cholesterol among certain high-risk adults. https://www.fda.gov/news-events/press-announcements/fda-approves-add-therapy-lower-cholesterol-among-certain-high-risk-adults

2. United States Patent and Trademark Office. (2020). U.S. Patent No. 10,851,377, Methods of inhibiting PCSK9 expression. https://patents.google.com/patent/US10851377B2

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-data-files

4. Alnylam Pharmaceuticals, Inc. (2019). Alnylam and Novartis enter into collaboration and license agreement for inclisiran. https://investors.alnylam.com/news-releases/news-release-details/alnylam-and-novartis-enter-collaboration-and-license-agreement

Drugs Protected by US Patent 10,851,377

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Novartis	LEQVIO	inclisiran sodium	SOLUTION;SUBCUTANEOUS	214012-001	Dec 22, 2021		RX	Yes	Yes						AS AN ADJUNCT TO DIET AND EXERCISE FOR THE TREATMENT OF PEDIATRIC PATIENTS AGED 12 YEARS AND OLDER WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HEFH) BY INHIBITING EXPRESSION OF THE PCSK9 GENE
Novartis	LEQVIO	inclisiran sodium	SOLUTION;SUBCUTANEOUS	214012-001	Dec 22, 2021		RX	Yes	Yes						AS AN ADJUNCT TO DIET AND EXERCISE FOR THE TREATMENT OF PEDIATRIC PATIENTS AGED 12 YEARS AND OLDER WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HOFH), BY INHIBITING EXPRESSION OF THE PCSK9 GENE
Novartis	LEQVIO	inclisiran sodium	SOLUTION;SUBCUTANEOUS	214012-001	Dec 22, 2021		RX	Yes	Yes						AS AN ADJUNCT TO DIET AND EXERCISE FOR THE TREATMENT OF ADULTS WITH HYPERCHOLESTEROLEMIA, INCLUDING HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HEFH), BY INHIBITING EXPRESSION OF THE PCSK9 GENE

International Family Members for US Patent 10,851,377

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2016310494
Australia	2022228147
Australia	2024278345
Canada	2996701
China	108348541
China	114469984