Details for Patent: 9,399,775

Which drugs does patent 9,399,775 protect, and when does it expire?

Patent 9,399,775 protects AMVUTTRA and is included in one NDA.

This patent has one hundred and sixteen patent family members in forty-one countries.

Summary for Patent: 9,399,775

Title:	RNAi agents, compositions and methods of use thereof for treating transthyretin (TTR) associated diseases
Abstract:	The present invention provides RNAi agents, e.g., double stranded RNAi agents, that target the transthyretin (TTR) gene and methods of using such RNAi agents for treating or preventing TTR-associated diseases.
Inventor(s):	Kallanthottathil G. Rajeev, Tracy Zimmermann, Muthiah Manoharan, Martin Maier, Satyanarayana KUCHIMANCHI, Klaus Charisse
Assignee:	Alnylam Pharmaceuticals Inc
Application Number:	US14/358,972
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Device;

United States Drug Patent 9,399,775: Scope, Claims, Expiration, and Vutrisiran Patent Landscape

U.S. Patent No. 9,399,775 protects a highly specific GalNAc-conjugated double-stranded RNA interference agent targeting transthyretin (TTR) mRNA. The strongest claims cover the AD-51547/vutrisiran sequence, its defined 2'-fluoro and 2'-O-methyl modification pattern, a branched GalNAc ligand, selected terminal linkages, pharmaceutical compositions, and treatment of TTR-associated amyloidosis.

The patent issued August 2, 2016, from an application claiming priority to January 25, 2012. Its base statutory expiration date is January 25, 2033, before any patent-term adjustment or patent-term extension. Vutrisiran, marketed as Amvuttra, received FDA approval in June 2022 under a biologics license application. Paragraph IV generic challenges are not the applicable pathway because Amvuttra is regulated as a biologic rather than as an ordinary small-molecule drug.

What does U.S. Patent 9,399,775 cover?

The patent covers an RNAi agent with six principal technical characteristics:

1. A double-stranded RNA molecule directed to nucleotides 504-526 of the human TTR gene.
2. A 21-nucleotide sense strand and a 23-nucleotide antisense strand.
3. A defined asymmetric duplex architecture with a two-nucleotide 5' antisense overhang.
4. A specific 2'-fluoro and 2'-O-methyl modification arrangement.
5. A branched bivalent or trivalent GalNAc ligand attached to the sense strand.
6. Use of the RNAi agent to suppress TTR expression and treat TTR-associated disease.

The claims are cumulative. A competing product must satisfy every limitation of the asserted claim for literal infringement. The combination of target sequence, strand lengths, chemical pattern, duplex architecture, and GalNAc conjugation makes claim 1 materially narrower than a general claim to TTR-targeting siRNA.

Core molecular structure

The claimed arrangement can be summarized as follows:

Feature	Claimed requirement
Target	TTR mRNA nucleotides 504-526
Sense strand	21 nucleotides
Antisense strand	23 nucleotides
Duplex	Sense strand complementary to antisense strand
Antisense overhang	Two nucleotides at the 5' end
Sense modification motif	Three consecutive 2'-fluoro nucleotides
Antisense modification motif	Three consecutive 2'-O-methyl nucleotides, potentially at positions 11-13
Additional motif	Three consecutive 2'-O-methyl nucleotides on the sense strand
Conjugate	One or more GalNAc derivatives
Linker	Bivalent or trivalent branched linker
Optional backbone chemistry	Phosphorothioate or methylphosphonate linkages
Optional formulation	Saline, water, acetate, citrate, prolamine, carbonate, phosphate, or PBS

The claims do not cover every TTR siRNA. They target a particular molecular design associated with vutrisiran.

Which claims specifically cover AD-51547 and vutrisiran?

Claims 16-20 provide the most commercially important sequence-specific protection.

Claim	Scope
16	RNAi agent selected from AD-51546 and AD-51547
17	AD-51547 specifically
18	Unmodified 21-nucleotide sense sequence
19	Chemically modified sense and antisense sequences with GalNAc3 ligand L96
20	The same chemically defined double-stranded RNAi agent as claim 19
21	Isolated cell containing the RNAi agent
22	Pharmaceutical composition containing the RNAi agent
28	Method of inhibiting TTR expression in a cell
30	Method of treating a TTR-associated disease
36	Treatment kit containing the agent and instructions

Claim 20 is particularly significant because it independently recites the exact modified sense and antisense sequences. The sequence is:

• Sense: 5'-UfgGfgAfuUfuCfAfUfgUfaacCfaAfgAfL96-3'
• Antisense: 5'-uCfuUfgGfUfUfaCfaugAfaAfuCfcCfasUfsc-3'

The notation identifies the chemical modifications:

• Lowercase a, g, c, and u: 2'-O-methyl nucleotides.
• Capitalized nucleotide symbols with an "f": 2'-fluoro nucleotides.
• "s": phosphorothioate linkage.
• L96: a GalNAc3 ligand.

This claim set is directed to the molecular entity rather than only to a therapeutic indication. That improves its relevance against a competitor manufacturing or selling the same active oligonucleotide for a different TTR disease.

How broad is independent claim 1?

Claim 1 has broad subject-matter categories but narrow structural limitations. It requires all of the following:

• The antisense sequence must be complementary to TTR nucleotides 504-526.
• The sense strand must be 21 nucleotides.
• The antisense strand must be 23 nucleotides.
• The duplex must follow formula III.
• The antisense strand must have a two-nucleotide 5' overhang.
• Certain modification blocks must be present.
• The sense strand must carry a GalNAc derivative through a bivalent or trivalent branched linker.

The main claim construction issues are likely to involve:

TTR sequence identity

The claim is sequence-defined by reference to TTR nucleotides 504-526. A product using a different TTR target region would generally fall outside the literal scope of claim 1, although other patents could cover the alternative sequence.

Strand length and overhang

A 21/23 duplex is required. A 21/21 duplex, a 22/23 duplex, or a duplex with a 3' antisense overhang would create a strong non-infringement position against the literal language of claim 1.

Modification pattern

The three-nucleotide motifs are central limitations. The claims require 2'-fluoro residues in the YYY motif and 2'-O-methyl residues in the Y'Y'Y' and ZZZ motifs. A competitor could alter the motif location, replace 2'-fluoro with another sugar modification, or use a different pattern.

GalNAc conjugation

The claim requires GalNAc derivatives attached through a bivalent or trivalent branched linker. An unconjugated duplex, a lipid nanoparticle formulation, an antibody conjugate, or a different ligand class would not literally satisfy this limitation.

The strongest infringement case would involve a product matching the AD-51547/vutrisiran sequence and the claimed GalNAc3 chemistry. A product targeting the same TTR region with a materially different ligand or modification pattern would require a separate doctrine-of-equivalents analysis.

What do the dependent claims add?

Claims 2-15 narrow the molecular design and provide fallback positions.

Position-specific modification claims

Claim 2 places the YYY motif at or near the sense-strand cleavage site or places the antisense Y'Y'Y' motif at positions 11, 12, and 13 from the 5' end. These limitations may be important in validity or infringement disputes because they tie the chemical pattern to the RNA-induced silencing complex cleavage region.

Claims 3 and 4 define permissible modifications for the Na, Na', Nb, and Nb' blocks. Claim 4 narrows those modifications to 2'-O-methyl, 2'-fluoro, or both.

Terminal linkage claims

Claims 9-11 cover phosphorothioate or methylphosphonate linkages, including at the 3' terminus of either strand. Claims 14 and 15 specifically address phosphorothioate linkages involving the antisense overhang nucleotides.

These provisions protect stability-enhancing backbone chemistry that can affect nuclease resistance, tissue distribution, and pharmacokinetics.

Base-pair and overhang claims

Claim 12 requires an AU base pair at the 1 position of the antisense 5' end. Claim 13 covers either target-complementary or non-complementary overhang nucleotides. Claim 15 requires phosphorothioate linkage of all overhang nucleotides.

These claims give the patent multiple narrower positions if a court limits the construction of the principal composition claim.

What sequence and product does the patent identify?

The patent identifies AD-51546 and AD-51547, with claim 17 directed specifically to AD-51547. The sequence in claims 19 and 20 corresponds to the active siRNA design used for vutrisiran, the active ingredient in Amvuttra.

Vutrisiran is a subcutaneously administered, GalNAc-conjugated siRNA that reduces hepatic production of both mutant and wild-type TTR. FDA approved Amvuttra for adults with hereditary transthyretin-mediated amyloidosis with polyneuropathy caused by TTR variants. The label and later regulatory materials expanded the commercial relevance of the product to additional TTR amyloidosis settings. [2]

When does U.S. Patent 9,399,775 expire?

Event	Date
Earliest claimed priority	January 25, 2012
U.S. patent issuance	August 2, 2016
Base patent expiration	January 25, 2033
FDA approval of Amvuttra	June 2022
Statutory biologic exclusivity from approval	June 2034

The January 25, 2033 date is the base patent-term calculation using the applicable 20-year term from the relevant nonprovisional or international filing date. The effective expiration date could differ if the patent received patent-term adjustment or if a patent-term extension is granted under 35 U.S.C. § 156. The patent document and USPTO maintenance records control the final calculation. [1]

The FDA's 12-year reference-product exclusivity for Amvuttra is separate from the patent term. Because Amvuttra is licensed under the Public Health Service Act, a biosimilar application generally cannot be approved until 12 years after first licensure, subject to the statutory framework. That regulatory exclusivity reaches approximately June 2034, later than the base expiration date of U.S. Patent 9,399,775. [3]

What is the FDA and Orange Book status of this patent?

U.S. Patent 9,399,775 is not an ordinary Orange Book-listed small-molecule patent in the manner of a conventional NDA product. Amvuttra is approved under BLA 215515, and biosimilar competition is governed by the Public Health Service Act and the Biologics Price Competition and Innovation Act.

Regulatory issue	Status
Product	Amvuttra
Active ingredient	Vutrisiran
FDA pathway	Biologics license application
BLA	215515
Administration	Subcutaneous injection
Regulatory competitor pathway	Section 351(k) biosimilar
Paragraph IV ANDA challenge	Not the applicable pathway
Reference-product exclusivity	12 years from first licensure
Orange Book relevance	Limited; biologic patent disputes are not handled through the ordinary small-molecule listing system

The absence of an Orange Book Paragraph IV listing does not eliminate patent risk. A biosimilar applicant can challenge patents through the BPCIA patent-exchange process, commonly called the patent dance, or through declaratory and infringement litigation. [3]

What patent litigation and settlement risks exist?

A conventional generic-drug Paragraph IV strategy does not apply to vutrisiran. The relevant risks are:

1. A biosimilar applicant asserting that the patent is invalid.
2. A biosimilar applicant arguing that its product does not infringe.
3. Patent litigation under the BPCIA after the statutory patent-information exchange.
4. Disputes over whether a modified siRNA remains within the sequence and chemical limitations.
5. Separate litigation involving GalNAc conjugation, manufacturing processes, formulations, or treatment methods.

The claim set creates several potential attack points:

• Written-description and enablement challenges to the full genus of GalNAc-linked TTR RNAi agents.
• Anticipation or obviousness challenges based on earlier TTR siRNA disclosures.
• Indefiniteness arguments concerning phrases such as "at or near the cleavage site."
• Claim-construction disputes over the formula III variables and the chemical notation.
• Non-infringement arguments based on altered strand length, overhang orientation, sugar chemistry, or ligand architecture.

The sequence-specific claims 19 and 20 are likely more resistant to purely genus-based invalidity attacks because they recite a defined duplex and defined chemical modifications. Their vulnerability would focus on earlier disclosure of the same sequence and chemistry, obviousness, and the sufficiency of the patent's written description for the claimed conjugate.

No Paragraph IV settlement framework applies because the product is a biologic. Any future settlement would more likely arise in a BPCIA biosimilar action or in litigation over related Alnylam patent families.

How does this patent compare with the patisiran patent landscape?

Patisiran and vutrisiran both suppress TTR, but their delivery systems create different patent risks.

Attribute	Vutrisiran, Amvuttra	Patisiran, Onpattro
Active modality	GalNAc-conjugated siRNA	Lipid nanoparticle siRNA
Administration	Subcutaneous	Intravenous
Primary delivery mechanism	Hepatocyte-targeted GalNAc receptor uptake	Lipid nanoparticle delivery
Dosing pattern	Approximately quarterly	More frequent intravenous dosing
Core patent risk	Sequence, oligonucleotide chemistry, GalNAc conjugation, formulation, treatment	siRNA sequence, lipid nanoparticle composition, formulation, manufacturing
Regulatory pathway	BLA	NDA/BLA-era biologic framework
Generic pathway	Biosimilar framework	Product-specific regulatory analysis

U.S. Patent 9,399,775 is more directly aligned with the GalNAc-conjugated vutrisiran product than with Onpattro's lipid nanoparticle delivery system. A competitor could avoid this patent by using an alternative TTR sequence or a lipid nanoparticle formulation, but other Alnylam patents could still create blocking rights.

How strong is the patent estate for vutrisiran?

The estate is strongest when assessed as a layered portfolio rather than as a single patent.

Strongest protection

• Exact AD-51547/vutrisiran sequence.
• Defined 2'-fluoro and 2'-O-methyl pattern.
• GalNAc3 conjugation.
• Sense-strand 3' attachment.
• Specific antisense overhang and phosphorothioate chemistry.
• Treatment of TTR-mediated amyloidosis.

Moderate protection

• General TTR-targeting RNAi agents using the formula III architecture.
• Pharmaceutical compositions and buffered or unbuffered solutions.
• Cell-based TTR inhibition methods.
• Kits containing the RNAi agent.

Weaker or more attackable areas

• Broad genus claims covering multiple modification options.
• Functional treatment claims where clinical efficacy or disease interpretation is disputed.
• Claims dependent on structural drawings not reproduced in the claim text.
• Formulation limitations that may be routine for injectable oligonucleotide products.

Patent strength also depends on related family members covering manufacturing, conjugation chemistry, GalNAc ligand structures, stability, dosing, and specific clinical uses. A freedom-to-operate review limited to U.S. Patent 9,399,775 would not establish freedom to commercialize a TTR siRNA.

What generic or biosimilar launch scenarios are possible?

Same-sequence biosimilar

A product using the same vutrisiran sequence, GalNAc3 ligand, and chemical pattern would face the highest infringement risk under claims 19 and 20. The applicant would likely need to challenge validity, contest infringement based on manufacturing or structural differences, or negotiate a licensed entry date.

Alternative TTR siRNA

An alternative sequence could avoid the sequence-specific claims but would need to clear separate patents covering other TTR sequences, GalNAc conjugation platforms, delivery chemistry, and methods of treatment.

Alternative delivery technology

A lipid nanoparticle or other hepatocyte-delivery system could avoid the GalNAc limitations in claim 1. It would not necessarily avoid patents covering TTR sequence selection or therapeutic use.

Post-exclusivity launch

The earliest commercially relevant launch date is controlled by the combined patent and regulatory landscape. On the base dates available here, the principal statutory patent term ends in January 2033, while the 12-year biologic exclusivity period extends to approximately June 2034. A biosimilar launch before those dates would depend on patent resolution, settlement, licensing, or successful validity and non-infringement positions.

What geographic rights does U.S. Patent 9,399,775 provide?

The patent provides enforceable rights in the United States only. Foreign counterpart patents must be reviewed separately by country. Relevant commercial jurisdictions for vutrisiran include the European Union, Japan, China, Canada, Australia, and other markets where Amvuttra is approved or commercialized.

Patent term, supplementary protection, biosimilar procedures, linkage rules, and litigation timing differ across those jurisdictions. U.S. claim scope cannot be exported directly to foreign markets.

Key Takeaways

• U.S. Patent 9,399,775 is a core composition and use patent for a GalNAc-conjugated TTR siRNA design associated with vutrisiran.
• Claims 19 and 20 provide the clearest sequence-specific protection for the modified AD-51547 duplex.
• Claim 1 is broad in category but narrow in its combined requirements for sequence, strand length, modification motifs, overhang, and GalNAc linker.
• The base patent expiration date is January 25, 2033, subject to any patent-term adjustment or extension.
• Amvuttra is a BLA product, so Paragraph IV ANDA litigation and ordinary Orange Book strategy do not apply.
• The relevant competitive pathway is a 351(k) biosimilar application under the BPCIA.
• A same-sequence GalNAc biosimilar faces the highest risk; an alternative TTR sequence or delivery system could create a stronger design-around position.
• U.S. Patent 9,399,775 should be analyzed with related patents covering GalNAc ligands, synthesis, formulations, dosing, and clinical uses.

FAQs

Is U.S. Patent 9,399,775 the only patent protecting Amvuttra?

No. The patent is one component of the broader vutrisiran and GalNAc-siRNA portfolio. Commercial risk may also arise from patents covering conjugate chemistry, manufacturing, formulations, dosing, and treatment methods.

Does the patent cover all GalNAc-conjugated TTR siRNAs?

No. It requires a defined TTR target region, duplex architecture, chemical motifs, strand lengths, and branched GalNAc conjugation. Other TTR sequences or materially different chemistries may fall outside literal claim 1.

Can a generic manufacturer file a Paragraph IV certification against this patent?

Not in the ordinary sense. Amvuttra is licensed as a biologic, so a competing manufacturer would generally use the 351(k) biosimilar pathway rather than an ANDA with a Paragraph IV certification.

Does claim 20 require the GalNAc ligand to be attached to the sense strand?

Yes. Claim 20 recites the sense sequence with L96 at the 3' end. The claim's chemical notation identifies the GalNAc3 ligand as part of the claimed RNAi agent.

Could a different TTR siRNA avoid U.S. Patent 9,399,775?

Potentially, if it does not meet the claimed sequence and structural limitations. That design-around would still require a separate clearance analysis against other TTR and GalNAc patent families.

References

1. United States Patent and Trademark Office. (2016). U.S. Patent No. 9,399,775, RNAi agents for inhibiting transthyretin (TTR) gene expression.
2. U.S. Food and Drug Administration. (2022). Amvuttra (vutrisiran) prescribing information. Alnylam Pharmaceuticals, Inc.
3. U.S. Food and Drug Administration. (2024). Purple Book: Database of licensed biological products.
4. Biologics Price Competition and Innovation Act, 42 U.S.C. § 262.
5. Patent Term Adjustment, 35 U.S.C. § 154.
6. Patent Term Extension, 35 U.S.C. § 156.

Drugs Protected by US Patent 9,399,775

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	9,399,775		Y	Y		AMVUTTRA IS INDICATED FOR THE TREATMENT OF THE POLYNEUROPATHY OF HEREDITARY TRANSTHYRETIN-MEDIATED AMYLOIDOSIS IN ADULTS

Foreign Priority and PCT Information for Patent: 9,399,775

PCT Information
PCT Filed	November 16, 2012	PCT Application Number:	PCT/US2012/065691
PCT Publication Date:	May 23, 2013	PCT Publication Number:	WO2013/075035

International Family Members for US Patent 9,399,775

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	088911
Argentina	121312
Australia	2012340159
Australia	2017225076
Australia	2019240658
Australia	2022231749