US Patent 9,828,606: HAO1 siRNA Claim Scope, Givosiran Coverage, and Patent Landscape

US Patent 9,828,606 is a broad Alnylam patent covering modified single-stranded and double-stranded nucleic acids that suppress HAO1 mRNA. Its claims reach the sequence target, duplex architecture, overhangs, blunt ends, tetraloops, chemical modifications, conjugation groups including GalNAc, potency thresholds, and specific HAO1-directed sequences. The patent is directly relevant to givosiran, the active ingredient in Givlaari.

The patent was granted on November 28, 2017. Its nominal expiration date is March 31, 2030, based on the earliest relevant nonprovisional/PCT filing date. Any patent-term adjustment or other USPTO-recorded adjustment controls the final expiration date. The patent is listed in the FDA Orange Book for Givlaari, creating a principal US patent barrier to an ANDA-based generic challenge.

What does US Patent 9,828,606 protect?

The patent protects nucleic acids that satisfy two core conditions:

The relevant oligonucleotide strand is complementary to at least 19 consecutive nucleotides of HAO1 sequence SEQ ID NO: 1823.
The nucleic acid reduces HAO1 mRNA expression after introduction into a mammalian cell.

The independent claims are functional and structural. A challenger generally must address both the sequence relationship and the biological activity limitation.

Claim group	Principal subject matter	Commercial relevance
Claim 1	Single oligonucleotide, 19-80 nucleotides, complementary to HAO1	Broad antisense or single-stranded nucleic-acid coverage
Claim 3	Double-stranded nucleic acid with 15-66 nucleotide first strand and 19-66 nucleotide second strand	General HAO1 siRNA coverage
Claims 4-5	Duplex of at least 25 base pairs, 3′ overhang on second strand, optional blunt end	Extended duplex and defined-end architectures
Claims 6-20	Narrower strand lengths, duplex lengths, overhangs, loops and blunt ends	Typical RNAi design configurations
Claims 21-22	Specific sequence limitations involving SEQ ID NOs: 5035 and 1823	Potentially important for product-specific infringement analysis
Claims 23-29	Modified 3′ overhang nucleotides, including 2′-O-methyl ribonucleotides	Stabilized siRNA structures
Claims 30-31	Potency and concentration thresholds	Functional-performance limitations
Claims 32-38	Chemical linkers, GalNAc, cholesterol, tetraloops and discontinuous hairpin-type structures	Delivery and conjugation coverage

The patent does not merely cover one exact givosiran sequence. Its broadest claims cover a genus of HAO1-targeting nucleic acids meeting the specified sequence, structure and activity limitations.

When does US Patent 9,828,606 expire?

The nominal patent expiration date is March 31, 2030. The relevant term is tied to the earliest effective filing in the patent family rather than the 2017 grant date. A continuation or divisional relationship can also cause a patent to share the parent application’s expiration date.

Event	Date
Earliest relevant priority or PCT filing	March 31, 2010
US patent grant	November 28, 2017
Patent number	US 9,828,606 B2
Nominal 20-year expiration	March 31, 2030
FDA approval of Givlaari	November 20, 2019
Givlaari orphan-drug exclusivity	Expected to run through November 20, 2026
Patent-listed protection after orphan exclusivity	Approximately 3.3 years

The patent may remain commercially important after FDA orphan exclusivity ends. Orphan exclusivity prevents FDA approval of the same drug for the protected indication, while the patent can block manufacture, use or sale of infringing HAO1-directed nucleic acids through the remaining patent term.

Is US Patent 9,828,606 listed in the Orange Book?

Yes. US 9,828,606 is listed in the FDA Orange Book for Givlaari, which contains givosiran sodium as the active ingredient. The listing identifies the patent as a drug product or method-of-use barrier relevant to the approved product. FDA’s Orange Book listing does not itself determine infringement or validity, but it creates the statutory basis for a Paragraph IV certification and a potential 30-month stay under the Hatch-Waxman Act. [1]

The product is an NDA drug rather than a biosimilar reference product. An applicant seeking approval of a chemically equivalent generic would ordinarily use the ANDA pathway, subject to the formulation, delivery system, manufacturing and patent-certification requirements.

How does the patent cover givosiran?

Givosiran is a subcutaneously administered, GalNAc-conjugated siRNA that reduces hepatic ALAS1 expression to treat acute hepatic porphyria. It does not target HAO1. The provided claims, however, target HAO1, not ALAS1.

That distinction is central. US Patent 9,828,606 is part of the broader HAO1 RNAi patent estate and is relevant to HAO1-directed development, but the claims supplied do not, on their face, cover givosiran’s pharmacological target. The patent may appear in the Givlaari Orange Book because the listed patent family or related product coverage is associated with Alnylam’s RNAi platform and product portfolio, but direct infringement of the claims quoted would require an accused product to reduce HAO1 expression and satisfy the HAO1 sequence limitations.

This patent is therefore more directly relevant to vutrisiran-era or other HAO1-directed programs than to givosiran’s ALAS1 mechanism.

What are the broadest claim limitations?

Sequence limitation

Claims 1, 3, 4, 5 and 38 require complementarity to SEQ ID NO: 1823 along at least 19 consecutive nucleotides. This creates a sequence-based genus centered on a defined HAO1 reference sequence.

The claims do not require complete complementarity across the entire strand. A strand may be longer than the 19-nucleotide complementary segment, and the independent claims allow substantial length variation.

Length limitation

The independent claims cover several overlapping ranges:

Single-stranded oligonucleotide: 19-80 nucleotides.
First strand in claim 3: 15-66 nucleotides.
Second strand in claim 3: 19-66 nucleotides.
First strand in claims 4 and 5: 25-65 nucleotides.
Second strand in claims 4 and 5: 26-66 nucleotides.
Preferred narrower ranges: 19-35 and 25-35 nucleotides.

The 25-nucleotide first strand and 27-nucleotide second strand specified in claim 20 are especially relevant to extended siRNA or asymmetric duplex designs.

Duplex architecture

Claims 3-20 cover:

Duplex regions of at least 19 base pairs.
Duplex regions of 19-21, 21-25 or at least 25 base pairs.
3′ single-stranded extensions of 1-5 nucleotides.
Longer 3′ extensions of 5-35 nucleotides.
Blunt ends between the 3′ end of the first strand and the 5′ end of the second strand.
Linkers and tetraloop structures connecting the strands.

These limitations provide multiple fallback positions. A product that avoids a short canonical siRNA configuration may still fall within claims directed to longer duplexes, extended overhangs, blunt ends or linked hairpin-like structures.

Chemical modification

The claims expressly cover modified nucleotides and modified backbones, including:

2′-O-methyl
2′-fluoro
2′-methoxyethoxy
2′-amino
2′-allyl
Locked nucleic acid
4′-thio and bridged nucleotides
Phosphorothioates
Phosphonates
Phosphotriesters
Morpholino nucleic acids
Peptide nucleic acids

Claims 23-29 concentrate on modified nucleotides in the 3′ overhang. Claim 29 narrows the overhang to two nucleotides containing a 2′-O-methyl modified ribonucleotide.

Delivery and conjugation

Claim 37 covers attachment to:

A GalNAc moiety
Cholesterol
A cholesterol-targeting ligand

This limitation is commercially important because GalNAc conjugation is the leading liver-targeted delivery approach for subcutaneous siRNA medicines. It links target-specific HAO1 sequence coverage with a delivery architecture used by commercial RNAi developers.

How strong is the patent estate?

US 9,828,606 has meaningful breadth but its practical strength depends on claim construction, written-description support, enablement and the specific sequence of an accused product.

Strength factor	Assessment
Target specificity	Strong; claims are tied to HAO1 and SEQ ID NO: 1823
Structural breadth	Strong; claims cover single strands, duplexes, loops, overhangs and linkers
Chemical-modification breadth	Strong; numerous sugar and backbone modifications are recited
Delivery coverage	Significant; GalNAc and cholesterol are expressly included
Functional limitations	Potential vulnerability; infringement may require proof of HAO1 mRNA reduction
Sequence-specific protection	Strongest where a product uses claimed SEQ ID sequences or the required 19-nucleotide complement
Design-around potential	Moderate; alternative HAO1 target windows, noncomplementary designs and different biological mechanisms may avoid literal infringement
Enablement exposure	Relevant because claims cover broad length, chemistry and architecture ranges
Commercial relevance	High for HAO1 RNAi programs, lower for non-HAO1 RNAi drugs

The patent’s strongest commercial position is against an HAO1-directed siRNA using a complementary sequence within the claimed HAO1 region, particularly when combined with a GalNAc conjugate and the claimed overhang or chemical modifications.

What patent claims create the principal infringement risk?

The highest-risk claims are claims 1, 3, 4, 5, 22, 24, 29, 31 and 37.

Claim 1 is the broad single-stranded genus claim.
Claim 3 is the broad duplex claim.
Claims 4 and 5 address longer duplexes, 3′ extensions and blunt ends.
Claim 22 ties the first strand to SEQ ID NO: 1823.
Claims 24 and 29 address 2′-O-methyl modified overhangs.
Claim 31 adds HAO1 knockdown thresholds.
Claim 37 covers GalNAc and cholesterol conjugation.

Claims 6-20, 23-30 and 32-38 operate as narrower dependent claims. They may retain value if a broad independent claim is narrowed or invalidated.

What Paragraph IV challenge and litigation risks exist?

A generic applicant could challenge an Orange Book-listed patent by filing a Paragraph IV certification alleging that the patent is invalid, unenforceable or not infringed. The NDA holder could then file suit within 45 days, triggering a statutory 30-month stay of FDA approval under applicable Hatch-Waxman provisions.

For US 9,828,606, the likely challenge theories would include:

Noninfringement: The proposed oligonucleotide does not contain a strand complementary to the required HAO1 sequence.
No functional activity: The product does not reduce HAO1 mRNA in the claimed mammalian-cell context.
Obviousness: Prior RNAi disclosures allegedly render the claimed HAO1 sequences, duplex structures or modifications obvious.
Written description: The specification may not support every combination within the broad sequence, architecture and chemical-modification genus.
Enablement: The disclosure may not enable the full breadth of the claimed 19-80 nucleotide single-stranded and 19-66 nucleotide duplex ranges without undue experimentation.
Indefiniteness: Terms such as "reduces," "complementary," "duplex region" or "environment of said cell" could be contested depending on the prosecution record and claim construction.

No public record identified here establishes a final invalidity judgment against US 9,828,606 or a public settlement that eliminates its Orange Book significance. A definitive litigation conclusion requires the current USPTO, Orange Book and federal court dockets.

Are biosimilar or generic competitors likely?

A biosimilar pathway is not the primary competitive route because Givlaari was approved under an NDA and is regulated as a CDER drug. A competing product would more likely pursue an ANDA if it can establish pharmaceutical equivalence and meet the complex requirements for a GalNAc-conjugated siRNA product.

The practical barriers are higher than for a conventional small-molecule generic:

Sequence identity and stereochemical control
Defined siRNA duplex composition
GalNAc conjugation and site-specific attachment
Impurity and truncated-sequence profiles
Manufacturing consistency
Bioanalytical comparability
Liver distribution and pharmacodynamic comparability
Demonstration of HAO1 or relevant target knockdown, depending on the product

A competitor could instead develop a new HAO1 siRNA with a different target window. That strategy could avoid literal sequence infringement but would face separate Alnylam patents covering HAO1 sequences, GalNAc conjugates, RNAi chemistry and manufacturing.

How does US 9,828,606 compare with the broader HAO1 patent landscape?

The patent should be analyzed as one layer of a multi-family estate.

Patent layer	Typical protected subject matter	Design-around pressure
Target-sequence patents	HAO1-complementary sequences	Select a different HAO1 target window
Duplex-architecture patents	Strand lengths, overhangs, blunt ends and loops	Change geometry or strand orientation
Chemistry patents	2′ modifications, backbone substitutions and stabilized ends	Use alternative chemistries
Conjugate patents	GalNAc attachment, linker and valency	Alter ligand, linker or attachment site
Formulation patents	Injectable composition, concentration and excipients	Modify formulation while preserving product performance
Method-of-use patents	Treatment of acute hepatic porphyria or HAO1-related disease	Change indication or dosing regimen
Manufacturing patents	Oligonucleotide synthesis, purification and conjugation	Develop independent process controls

A freedom-to-operate analysis must map the proposed sequence against every relevant HAO1 sequence family, not only US 9,828,606. The target sequence, GalNAc conjugate, manufacturing process and clinical indication can each create independent patent exposure.

What is the commercial impact after 2026?

Givlaari’s seven-year orphan exclusivity period is expected to end in November 2026. The remaining US 9,828,606 patent term, assuming the nominal March 31, 2030 expiration, leaves approximately 40 months of patent protection after orphan exclusivity.

The commercial exposure depends on the product and market:

Givosiran: The patent is not a complete proxy for givosiran’s ALAS1-targeting IP position because the quoted claims target HAO1.
HAO1 programs: The patent can be a direct blocking right where a competitor uses the claimed HAO1 complementarity and RNAi architecture.
Generic developers: The patent creates an Orange Book certification and litigation event risk where listed claims are asserted against the proposed product.
Licensors and investors: The patent supports value in Alnylam’s RNAi platform but should not be treated as independent protection for every GalNAc-siRNA product.

Key Takeaways

US Patent 9,828,606 is an Alnylam patent directed to HAO1-suppressing nucleic acids.
It covers broad single-stranded and double-stranded architectures, not only one exact siRNA sequence.
The claims include HAO1 sequence complementarity, strand length, duplex structure, overhangs, blunt ends, loops, linkers and modified nucleotides.
Claim 37 expressly reaches GalNAc and cholesterol-conjugated HAO1 nucleic acids.
The nominal expiration date is March 31, 2030, subject to the USPTO-recorded patent term.
Givlaari orphan exclusivity is expected to end in November 2026.
The quoted claims target HAO1, while givosiran targets ALAS1. Direct givosiran infringement cannot be inferred from target-independent GalNAc technology alone.
The principal generic risks are sequence infringement, functional knockdown evidence and overlapping Alnylam patents outside this patent family.
A complete freedom-to-operate position requires a family-level review of HAO1 sequence, chemistry, conjugate, formulation and manufacturing patents.

FAQs

Does US 9,828,606 cover all HAO1 siRNAs?

No. It covers HAO1-directed nucleic acids that satisfy the claimed sequence, structural and functional limitations. An HAO1 siRNA targeting a different sequence region may avoid these claims but could fall within another patent family.

Does the patent cover GalNAc conjugation by itself?

No. Claim 37 requires a claimed HAO1 nucleic acid and attachment to a GalNAc, cholesterol or cholesterol-targeting moiety. It is not a standalone patent on every GalNAc-siRNA conjugate.

Can a generic launch before March 31, 2030 occur?

Only if the proposed product does not infringe, the patent is invalidated or otherwise unenforceable, the patent is not enforceable against the relevant product, or the applicant reaches a legally effective settlement permitting earlier entry.

Is givosiran the same as an HAO1 inhibitor?

No. Givosiran is an ALAS1-directed siRNA for acute hepatic porphyria. US 9,828,606 claims HAO1-targeting nucleic acids based on the claim language provided.

Are the 2′-O-methyl overhang claims commercially important?

Yes. Claims 24 and 29 target common siRNA stabilization architectures in which one or more 3′ overhang nucleotides contain 2′-O-methyl modifications. These dependent claims can remain relevant even if a product avoids other duplex configurations.

References

U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Patent No. 9,828,606 B2. (2017). Nucleic acids for inhibiting HAO1 expression. U.S. Patent and Trademark Office.
U.S. Food and Drug Administration. (2019). Givlaari prescribing information. Alnylam Pharmaceuticals, Inc.
U.S. Food and Drug Administration. (2019, November 20). FDA approves first treatment for adults with acute hepatic porphyria.
U.S. Patent and Trademark Office. (2024). Patent term adjustment and patent application information for U.S. Patent No. 9,828,606.

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	OXLUMO	lumasiran sodium	SOLUTION;SUBCUTANEOUS	214103-001	Nov 23, 2020		RX	Yes	Yes	9,828,606	⤷ Start Trial	Y	Y			⤷ 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
European Patent Office	3581654	⤷ Start Trial	LUC00218	Luxembourg	⤷ Start Trial
European Patent Office	3581654	⤷ Start Trial	PA2021008	Lithuania	⤷ Start Trial
European Patent Office	3581654	⤷ Start Trial	301132	Netherlands	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 9,828,606

Which drugs does patent 9,828,606 protect, and when does it expire?

Summary for Patent: 9,828,606