Details for Patent: 10,683,501

Which drugs does patent 10,683,501 protect, and when does it expire?

Patent 10,683,501 protects AMVUTTRA and is included in one NDA.

This patent has sixty-three patent family members in thirty-seven countries.

Summary for Patent: 10,683,501

Title:	Transthyretin (TTR) iRNA compositions and methods of use thereof for treating or preventing TTR-associated diseases
Abstract:	The present invention provides iRNA agents, e.g., double stranded iRNA agents, that target the transthyretin (TTR) gene and methods of using such iRNA agents for treating or preventing TTR-associated diseases.
Inventor(s):	Tracy Zimmermann, Amy Chan, Vasant R. Jadhav, Martin A. Maier, Kallanthottathil G. Rajeev
Assignee:	Alnylam Pharmaceuticals Inc
Application Number:	US16/223,362
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,683,501
Patent Claim Types: see list of patent claims	Use; Dosage form;

US Patent 10,683,501: Scope, Claims, Expiration, and Vutrisiran Patent Landscape

US Patent No. 10,683,501 protects prophylactic treatment of subjects at risk of transthyretin-associated disease using a defined, chemically modified TTR-targeting siRNA, including the GalNAc-conjugated agent used in vutrisiran. The patent is method-of-use focused. It does not broadly claim every TTR siRNA, every treatment of TTR amyloidosis, or the chemical compound independent of prophylactic use.

The highest-value claim is claim 21, which covers prophylactic administration of the exact modified duplex sequence with the L96 GalNAc ligand. Claims 1 through 20 provide broader sequence-variation and conjugation coverage, while claims 22 through 28 add patient, disease, route, self-administration, device, and chronic-treatment limitations.[1]

What drug and technology does US Patent 10,683,501 protect?

US 10,683,501 is directed to a TTR-targeting double-stranded RNA interference agent. The claimed sequence and chemistry correspond to vutrisiran, marketed by Alnylam Pharmaceuticals as AMVUTTRA for transthyretin-mediated amyloidosis in adults.[1,2]

The claimed duplex has:

Component	Claimed feature
Target	Human transthyretin, or TTR
Modality	Double-stranded RNAi agent
Sense strand	SEQ ID NO: 10
Antisense strand	SEQ ID NO: 7
Sugar chemistry	2'-O-methyl and 2'-fluoro nucleotides
Backbone chemistry	Phosphorothioate linkages at designated positions
Delivery ligand	Optional GalNAc ligand in claims 14-20; required L96 ligand in claim 21
Administration	Subcutaneous and other routes
Use	Prophylactic treatment of subjects at risk for TTR-associated disease

Vutrisiran is a subcutaneously administered, GalNAc-conjugated siRNA that reduces hepatic TTR production. The FDA approved AMVUTTRA in 2022 for hereditary transthyretin-mediated amyloidosis with polyneuropathy in adults and later expanded the label to cardiomyopathy associated with wild-type or hereditary TTR-mediated amyloidosis in adults.[2,3]

What are the independent claims in US 10,683,501?

The patent has two principal independent method claims.

Claim 1: sequence-variation prophylaxis claim

Claim 1 covers prophylactically treating a human subject at risk of developing a TTR-associated disease by administering a therapeutically effective amount of a double-stranded RNAi agent with:

1. A sense strand differing by no more than four modified nucleotides from SEQ ID NO: 10; and
2. An antisense strand differing by no more than four modified nucleotides from SEQ ID NO: 7.

The claim is broader than the exact vutrisiran sequence. It can reach certain sequence and chemical variants, subject to the four-modified-nucleotide limitation on each strand.

The claim also requires:

• A human subject;
• A prophylactic, rather than merely therapeutic, treatment objective;
• Risk of developing a TTR-associated disease; and
• Administration of a prophylactically effective amount.

Claim 21: exact L96-conjugated duplex claim

Claim 21 covers the exact modified sense and antisense strand sequences, with the sense strand conjugated to L96:

N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol.

The claim specifically requires the GalNAc-containing L96 ligand. This is the most product-specific claim in the patent because it combines the defined TTR siRNA duplex with the defined hepatocyte-targeting conjugate.

Claim 21 is narrower than claim 1 in chemical structure but may be commercially more important because it maps closely to the marketed vutrisiran product.

How do claims 1 through 20 divide the patent scope?

The first claim group creates a layered protection structure.

Claims	Principal scope
1	Prophylactic use of defined TTR siRNA sequence variants
2	Subject carries a TTR mutation
3	Enumerated TTR diseases
4	Broad administration-route list
5	Subcutaneous administration
6	Self-administration
7	Pre-filled syringe or auto-injector
8	Chronic administration
9	Up to three modified-nucleotide differences
10	Up to two modified-nucleotide differences
11	Up to one modified-nucleotide difference
12	Sense and antisense strands comprise the reference sequences
13	Sense and antisense strands consist of the reference sequences
14	RNAi agent includes at least one ligand
15	Sense strand is ligand-conjugated
16	Ligand is a bivalent or trivalent branched GalNAc derivative
17	Specific ligand limitation shown in the patent drawing
18	Ligand attached at the 3' end of the sense strand
19	Specific conjugate architecture
20	Conjugate uses oxygen at the specified X position

Claims 9 through 13 progressively narrow the sequence space. Claim 13 is the most exact sequence claim in the first group because it requires the strands to consist of the stated sequences, rather than merely comprise them.

Claims 14 through 20 add conjugation architecture. These claims are important because naked or unconjugated siRNA generally has different delivery characteristics from GalNAc-conjugated siRNA. A competing product using the same core sequence but a materially different ligand or attachment configuration would need a separate infringement analysis.

What does “differing by no more than four modified nucleotides” mean?

The phrase does not create an unrestricted four-base mismatch rule. It is tied to the patent’s defined modified-nucleotide framework.

The claim identifies:

• Lowercase a, c, g, and u as 2'-O-methyl nucleotides;
• Uppercase subscripted or marked bases as 2'-fluoro nucleotides; and
• “s” as a phosphorothioate linkage.

The practical scope can include certain substitutions, additions, or chemical modifications relative to the listed reference strands, but the claim must be interpreted with the patent specification, sequence listings, and prosecution history. A molecule that differs in four positions may still fall outside the claim if the changes alter the claimed strand structure, strand length, orientation, or required chemical features.

Claims 9 through 11 are valuable fallback positions because they reduce the permissible variation from four to three, two, or one modified nucleotide. Claim 13 provides the narrowest exact-strand position.

What diseases and patient populations are covered?

Claims 1 and 21 use the broad category of a subject at risk of developing a TTR-associated disease. Dependent claims identify:

• Senile systemic amyloidosis;
• Systemic familial amyloidosis;
• Familial amyloidotic polyneuropathy;
• Familial amyloidotic cardiomyopathy;
• Leptomeningeal or central nervous system amyloidosis; and
• Hyperthyroxinemia.

Claims 2 and 22 further cover subjects carrying a TTR gene mutation associated with disease development.

The prophylactic language is commercially significant. The claims are directed to preventing or delaying disease in an at-risk subject, including a genetically predisposed patient. They do not expressly require that the patient already have symptomatic amyloidosis.

The claims therefore have potential relevance to:

• Mutation carriers before overt polyneuropathy;
• Patients at risk of hereditary TTR amyloidosis;
• Patients at risk of hereditary or wild-type TTR cardiomyopathy;
• Patients receiving long-term treatment intended to suppress future TTR deposition; and
• Genetic screening and early-intervention treatment strategies.

The patent’s express disease list predates the current commercial labeling framework and does not itself determine the scope of the FDA-approved indication.

What administration methods and devices are protected?

Claim 4 lists several routes:

• Subcutaneous;
• Intravenous;
• Intramuscular;
• Intrabronchial;
• Intrapleural;
• Intraperitoneal;
• Intraarterial;
• Lymphatic;
• Cerebrospinal; and
• Combinations of those routes.

Claims 5 through 7 focus on the commercially relevant route and delivery format:

1. Subcutaneous administration;
2. Self-administration; and
3. A pre-filled syringe or auto-injector syringe.

These claims can create additional risk for a competing product that uses the same or substantially equivalent duplex and is supplied for patient self-injection. Device claims are not present as independent apparatus claims in the provided claim set. The patent instead captures the delivery device through method-of-treatment limitations.

Does the patent cover chronic treatment?

Yes. Claim 8 and claim 28 expressly cover chronic administration.

The chronic-treatment limitation is significant because TTR suppression is generally maintained through repeated dosing rather than a single curative administration. A generic or follow-on product marketed for recurring administration could implicate the chronic-use claims if the underlying agent and prophylactic indication satisfy the independent claim.

The claim does not specify a particular dosing interval, dose amount, treatment duration, or loading regimen. Those details may be relevant to infringement and validity, but they are not express limitations in the quoted claims.

What does the GalNAc limitation protect?

The GalNAc limitations protect a liver-targeting conjugate architecture.

Claim 16 refers to one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. Claim 18 places the ligand at the 3' end of the sense strand. Claims 19 and 20 define a more specific conjugation structure and identify the relevant atom as oxygen in claim 20.

Claim 21 narrows the ligand to L96. This creates a product-specific position around the marketed conjugate rather than around the entire universe of GalNAc-siRNA compounds.

A competitor could attempt design-around strategies involving:

• A different TTR-targeting sequence;
• A different GalNAc ligand;
• A different linker;
• A different attachment site;
• A non-GalNAc delivery system;
• A materially different chemical modification pattern; or
• A different indication or treatment objective.

Each strategy would require separate analysis under the patent’s literal language and equivalents doctrine.

What is the Orange Book status of US 10,683,501?

US 10,683,501 is associated with AMVUTTRA, Alnylam’s NDA-approved vutrisiran product. FDA’s Orange Book identifies patents submitted for approved drug products and may include method-of-use patents with corresponding use codes.[4]

The patent is relevant to the Orange Book because its claims are directed to a method of using the active siRNA product in a defined patient population. A generic applicant seeking approval before the listed patent term ends could face a Paragraph IV certification if the patent is listed for the relevant NDA and indication.

The Orange Book listing does not mean every claim automatically blocks every future product. The relevant questions are:

• Whether the proposed generic product is the same active ingredient;
• Whether the proposed label includes the claimed prophylactic use;
• Whether the product uses the claimed sequence and modification profile;
• Whether the listed patent remains enforceable;
• Whether the generic applicant uses a Paragraph IV certification; and
• Whether Alnylam files an infringement action within the statutory period.

FDA listing information should be checked against the current Orange Book edition because listing status, patent corrections, and use codes can change.[4]

When does US Patent 10,683,501 lose exclusivity?

The patent issued on June 16, 2020.[1] The enforceable expiration date depends on the earliest effective nonprovisional priority date, patent-term adjustment, any patent-term extension, terminal disclaimer, and USPTO term calculation.

The patent’s statutory term is not necessarily the same as AMVUTTRA’s FDA regulatory exclusivity period. The following protections must be separated:

Protection	Relevance
Patent term	Bars or exposes infringing conduct under the patent claims
FDA orphan-drug exclusivity	Can restrict approval of the same drug for the same disease or condition
New chemical entity exclusivity	Applies to the FDA approval framework if granted
Pediatric exclusivity	Can add six months to qualifying exclusivity or patent periods
Orange Book listing	Provides notice and supports ANDA certification procedures
Patent-term extension	May extend a qualifying patent for regulatory review time

The FDA approved AMVUTTRA in June 2022. The product’s regulatory exclusivity periods do not independently establish the expiration date of US 10,683,501.[2,3] The controlling patent expiration should be taken from the current USPTO Patent Center record and the current Orange Book entry rather than inferred from the grant date.

Are there Paragraph IV challenges to this patent?

An ANDA applicant must address listed patents through a Paragraph I, II, III, or IV certification, or a section viii statement for a use patent where permitted. A Paragraph IV certification asserts that the patent is invalid, unenforceable, or will not be infringed.

For US 10,683,501, the key litigation risk would arise from an ANDA directed to vutrisiran or an equivalent TTR siRNA that seeks approval for a use covered by the listed claims. The most likely dispute issues would include:

• Whether the proposed product has the same or materially equivalent sequence;
• Whether the product contains the claimed 2'-O-methyl and 2'-fluoro pattern;
• Whether the product contains the claimed phosphorothioate linkages;
• Whether its GalNAc ligand is L96 or falls within the broader ligand claims;
• Whether the ANDA label includes prophylactic treatment;
• Whether the claimed use is induced by the proposed labeling; and
• Whether the claims are enabled and adequately described across the claimed sequence variation.

No Paragraph IV litigation conclusion should be drawn solely from the existence of the patent. The relevant evidence is the Orange Book listing, the ANDA certification, any 30-month stay notice, and the docket filed under the Hatch-Waxman statute.

What patent litigation affects vutrisiran and TTR RNAi products?

The major competitive patent risk is not limited to US 10,683,501. A follow-on entrant could face overlapping patents covering:

• TTR-targeting sequences;
• GalNAc conjugates;
• Linker chemistry;
• Nucleoside modifications;
• Phosphorothioate placement;
• RNAi architecture;
• Formulations;
• Dosing schedules;
• Treatment of polyneuropathy;
• Treatment of cardiomyopathy;
• Manufacturing processes; and
• Delivery devices.

Alnylam has historically maintained a broad RNAi platform estate. Its commercially relevant protection can therefore involve multiple patent families even where one patent contains the closest sequence claim.

The patent should be treated as one layer of a portfolio, not as the complete AMVUTTRA estate.

How does this patent compare with competing TTR therapies?

Product	Company	Modality	Primary target/use	Patent-risk relationship
AMVUTTRA, vutrisiran	Alnylam	GalNAc-siRNA	TTR-mediated amyloidosis	Directly aligned with US 10,683,501
ONPATTRO, patisiran	Alnylam	Lipid nanoparticle siRNA	TTR-mediated amyloidosis	Different delivery system and sequence; overlapping platform risk may remain
WAINUA, eplontersen	Ionis/AstraZeneca	Ligand-conjugated antisense oligonucleotide	Hereditary TTR amyloidosis with polyneuropathy	Different modality, chemistry, and sequence
TAFAMIDIS, tafamidis	Pfizer	TTR stabilizer	ATTR cardiomyopathy and polyneuropathy	No direct sequence or RNAi overlap
Diflunisal	Generic manufacturers	TTR stabilizer	Off-label ATTR treatment	No direct RNAi overlap

The strongest direct product comparison is with other TTR gene-silencing products. Vutrisiran and patisiran both reduce TTR production but use different delivery technologies. Eplontersen is an antisense product rather than a double-stranded RNAi agent. Tafamidis acts by stabilizing the TTR tetramer and does not directly implicate the claims of US 10,683,501.

Is there biosimilar risk for AMVUTTRA?

No conventional biosimilar pathway applies because vutrisiran is a chemically synthesized oligonucleotide drug rather than a protein biologic licensed under the Public Health Service Act.

The likely US follow-on route is an ANDA if FDA determines that the proposed product qualifies as a pharmaceutical equivalent or otherwise fits the abbreviated pathway. If the product cannot satisfy the ANDA framework, a 505(b)(2) application may be considered.

The regulatory pathway does not eliminate patent risk. A 505(b)(2) applicant can still face listed-patent certifications and patent litigation.

What manufacturing and IP barriers exist?

Manufacturing may create practical barriers beyond the sequence claims. A competing product may need to reproduce or establish equivalence for:

• Solid-phase oligonucleotide synthesis;
• Site-specific 2'-O-methyl and 2'-fluoro incorporation;
• Phosphorothioate stereochemical or positional control;
• Duplex annealing;
• GalNAc-linker synthesis;
• Conjugation at the 3' sense-strand position;
• Impurity control;
• Residual solvent and metal control;
• Particle, aggregate, and concentration specifications; and
• Sterile injectable production.

Some of these processes may be covered by separate manufacturing patents or trade secrets. US 10,683,501 is principally a use patent and should not be read as a complete manufacturing barrier.

How strong is the patent estate for US 10,683,501?

Strengths

• Claim 21 closely identifies the commercial L96-conjugated duplex.
• Claims 1 and 9-13 provide layered sequence coverage.
• Claims 14-20 add GalNAc and conjugation limitations.
• Claims 5-8 and 25-28 capture subcutaneous, self-administered, chronic use.
• The patent covers prophylactic use, which can be commercially important for genetically at-risk patients.
• The defined chemical modifications may make a literal infringement case clearer against a copy product.

Limitations

• The claims are method claims, not broad composition claims.
• A product using a different sequence or delivery ligand may avoid literal infringement.
• The prophylactic-use limitation may create label and induced-infringement issues.
• The claim language does not independently cover every therapeutic use of vutrisiran.
• The four-nucleotide variation language may face written-description, enablement, construction, or indefiniteness scrutiny depending on the specification and prosecution record.
• Claim 17 and claim 19 depend on structural drawings not reproduced in the supplied claim text, making the exact scope dependent on the issued patent figures.

What generic launch scenarios exist?

Scenario 1: Paragraph IV challenge to the listed method patent

A generic applicant challenges validity or noninfringement before patent expiration. Alnylam may bring an infringement action, potentially triggering a statutory stay of approval.

Scenario 2: Skinny-label strategy

A follow-on applicant omits prophylactic language and other patented uses where FDA permits a section viii statement. The risk would turn on the final label, product instructions, promotional conduct, and whether the remaining indication practices the claims.

Scenario 3: Non-infringing delivery design

A competitor uses a different ligand, linker, attachment site, or TTR sequence. This may avoid US 10,683,501 but could encounter other Alnylam or third-party patent families.

Scenario 4: 505(b)(2) entry

A sponsor uses the approved product’s safety and efficacy data while pursuing a modified formulation, delivery format, or dosing approach. Patent certifications and use-patent issues remain relevant.

Scenario 5: Post-expiration entry

The applicant waits until the relevant patent and regulatory exclusivities expire. This reduces litigation risk but sacrifices first-entry economics.

What licensing deals affect the patent landscape?

The commercial value of US 10,683,501 is tied primarily to Alnylam’s internally developed TTR RNAi and GalNAc platform. Publicly disclosed industry licensing transactions involving RNAi technology may affect freedom to operate at the platform level, but a license to a platform patent does not by itself establish a license to this specific patent or to AMVUTTRA commercialization rights.

A diligence review should distinguish:

• Patent ownership;
• Exclusive field-of-use rights;
• Sublicense rights;
• Royalty obligations;
• Territory;
• Improvements;
• Patent prosecution control; and
• Settlement licenses arising from litigation.

The patent record identifies the legal owner and assignment history. Commercial licensing rights may not be fully visible from the issued patent.

Key Takeaways

1. US 10,683,501 is a prophylactic method-of-use patent for TTR-targeting siRNA.
2. Claim 1 covers defined sequence variants within a four-modified-nucleotide limit.
3. Claim 21 most closely tracks vutrisiran because it requires the exact duplex and L96 GalNAc ligand.
4. Claims 5-8 and 25-28 cover subcutaneous, self-administered, chronic use.
5. The patent does not broadly claim all TTR therapies or all TTR siRNA compounds.
6. AMVUTTRA’s regulatory protection and patent protection are separate legal barriers.
7. No biosimilar pathway is expected; a follow-on sponsor would more likely pursue an ANDA or 505(b)(2) pathway.
8. The commercial patent risk must be evaluated with Alnylam’s broader sequence, conjugate, formulation, manufacturing, and method-of-use portfolio.
9. A generic launch would most likely involve Paragraph IV litigation, a skinny-label strategy, a design-around product, or delayed entry.
10. The controlling expiration and listing status should be taken from the current USPTO Patent Center and Orange Book records.

FAQs

Does US 10,683,501 claim vutrisiran itself?

No. The patent claims methods of prophylactically treating a subject using defined vutrisiran-related sequences and, in claim 21, the L96-conjugated duplex. It is not a standalone composition claim to all forms of vutrisiran.

Does the patent cover treatment of existing TTR amyloidosis?

The supplied claims require prophylactic treatment of a subject at risk of developing a TTR-associated disease. They do not expressly cover every treatment of established, symptomatic disease.

Can a different GalNAc ligand avoid US 10,683,501?

Potentially, depending on the remaining claim limitations. Claims 14-20 and 21 contain different levels of ligand specificity. A different ligand may avoid claim 21 but could still fall within a broader ligand or sequence claim, or another Alnylam patent.

Is AMVUTTRA protected by biologic exclusivity?

AMVUTTRA is an oligonucleotide drug, not a conventional protein biologic. The principal follow-on issues are expected to involve small-molecule-style abbreviated approval procedures, patent certifications, and FDA-specific treatment of oligonucleotide products.

What is the principal infringement risk for a competing TTR siRNA?

The highest risk arises from a product using the same or highly similar duplex, the claimed chemical modifications, a 3'-sense-strand GalNAc conjugate, and a label or promotional program that supports prophylactic treatment of TTR-associated disease.

References

1. United States Patent and Trademark Office. (2020). United States Patent No. 10,683,501, Methods of prophylactically treating TTR-associated disease.
2. U.S. Food and Drug Administration. (2022). FDA approves new treatment for patients with hereditary transthyretin-mediated amyloidosis.
3. U.S. Food and Drug Administration. (2024). AMVUTTRA (vutrisiran) prescribing information. Alnylam Pharmaceuticals, Inc.
4. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.

Drugs Protected by US Patent 10,683,501

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	AMVUTTRA	vutrisiran sodium	SOLUTION;SUBCUTANEOUS	215515-001	Jun 13, 2022		RX	Yes	Yes			Y	Y		AMVUTTRA IS INDICATED FOR THE TREATMENT OF THE POLYNEUROPATHY OF HEREDITARY TRANSTHYRETIN-MEDIATED AMYLOIDOSIS IN ADULTS

International Family Members for US Patent 10,683,501

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	3329002		301216	Netherlands
European Patent Office	3329002		PA2023505	Lithuania
European Patent Office	3329002		7/2023	Austria
European Patent Office	3329002		2023C/507	Belgium
European Patent Office	3329002		LUC00297	Luxembourg
European Patent Office	3329002		CA 2023 00008	Denmark