US Patent 10,125,364: ALAS1 RNAi Claims, Givosiran Coverage, and Patent Landscape

US Patent No. 10,125,364 protects specific double-stranded RNA molecules targeting the ALAS1 gene, including the sequence-defined RNA duplex used in givosiran, marketed as Givlaari by Alnylam Pharmaceuticals. The patent covers the active RNA sequence, structural features, chemical modifications, GalNAc conjugation, pharmaceutical compositions, engineered cells and vectors, and treatment of acute hepatic porphyrias.

The patent issued on November 13, 2018. Its expected patent-term expiration is May 22, 2035, subject to any applicable patent-term adjustment or extension. Givlaari received FDA approval on November 20, 2019, for acute hepatic porphyria in adults and adolescents age 12 years and older.[1-4]

What does US Patent 10,125,364 protect?

The patent has broad claim categories, but its commercial center is a sequence-defined, GalNAc-conjugated siRNA against ALAS1.

Claim category	Claims	Protected subject matter
Core dsRNA	1, 32, 33, 36	Antisense sequence SEQ ID NO: 1296 paired with a sense strand derived from SEQ ID NO: 1295 or the ALAS1 target region
Chemical modification	2, 20, 30, 31, 34	2'-O-methyl, 2'-fluoro and other modified nucleotides
Duplex architecture	3-5, 28, 32	19-24 nucleotide strands, 15-30 base-pair duplexes, 3' overhangs and a blunt end
Targeted delivery	6, 7, 19, 21, 33, 35	Ligand-conjugated RNA, particularly GalNAc attached to the 3' end of the sense strand
Pharmaceutical composition	9	A composition containing the claimed dsRNA
Cellular and genetic tools	8, 16, 17	Cells and vectors containing the dsRNA or an encoded strand
Treatment methods	10-15, 18, 24-27	ALAS1 inhibition, porphyria treatment and reduction of ALA, PBG, porphyrins or porphyrin precursors

The independent claims are important because they do not rely solely on a broad functional description of RNA interference. Claims 1 and 32 require a specific antisense sequence and a defined relationship between the sense and antisense strands. Claim 33 uses a related formulation based on the ALAS1 target region and a GalNAc derivative.

What sequence is claimed by US 10,125,364?

Claim 1 requires an antisense strand comprising SEQ ID NO: 1296 and a sense strand comprising at least 15 contiguous nucleotides from SEQ ID NO: 1295. The duplex must contain a 15-30 base-pair duplex region.

Claim 33 separately requires a sense strand containing at least 15 contiguous nucleotides from SEQ ID NO: 1295 and an antisense strand complementary to nucleotides 871-889 of SEQ ID NO: 1. This creates two principal sequence-defined claim paths:

A claim centered on SEQ ID NO: 1296.
A claim centered on complementarity to ALAS1 nucleotides 871-889.

This drafting gives the patent two forms of sequence coverage. The first is exact or near-exact sequence coverage. The second is target-region coverage that may capture certain sequence variants or strand constructions if they satisfy the specified complementarity and structural limitations.

The "at least 15 contiguous nucleotides" limitation is material. A competing RNA with only partial overlap may avoid the claim if it does not contain the required contiguous sequence or does not meet the claimed duplex architecture. A competing RNA with the same target region may still face infringement risk if it uses a qualifying sense strand, antisense strand, duplex length and ligand configuration.

How broad are the structural claims?

The claims cover conventional siRNA design elements rather than one unmodified RNA sequence.

Claim 3 requires each strand to be 19-24 nucleotides long. Claims 4 and 5 address 3' overhangs, with claim 5 specifying a two-nucleotide overhang. Claim 28 requires one blunt-ended terminus. Claim 29 adds one or more phosphorothioate linkages.

Claim 32 combines several limitations in one product claim:

SEQ ID NO: 1296 antisense sequence;
a sense strand derived from SEQ ID NO: 1295;
a 15-30 base-pair duplex;
a 3' overhang;
one blunt end; and
2'-O-methyl or 2'-fluoro modification.

This combination is narrower than claim 1 but maps closely to a therapeutic siRNA product with defined architecture and chemical stabilization.

Claims 30 and 31 are directed to extensive modification. Claim 30 requires at least 20 modified nucleotides selected from 2'-O-methyl and 2'-fluoro nucleotides. Claim 31 requires both modification types across the entire length of the sense and antisense strands. These claims can be relevant to manufacturing designs that alter the modification pattern while preserving the ALAS1 sequence.

What formulations are protected by the patent?

The most commercially significant formulation claims are the GalNAc-conjugated dsRNA claims.

Claims 6 and 7 cover a ligand-bearing dsRNA and identify GalNAc as the ligand. Claim 19 places the GalNAc ligand at the 3' end of the sense strand. Claim 21 requires attachment through a linker. Claims 33-35 provide a separate GalNAc-focused claim set.

GalNAc targets the asialoglycoprotein receptor on hepatocytes. That delivery mechanism is relevant because ALAS1 is expressed in the liver and because Givlaari is administered subcutaneously for hepatic delivery. A competing product could use the same ALAS1 sequence but a different delivery ligand, a different attachment position or a different linker. It would still need to avoid the broader dsRNA, sequence and treatment claims.

The provided claim text does not reproduce the structural drawings for claims 22 and 23. Those claims appear directed to a specified ligand-linker structure. The exact scope of those claims depends on the omitted chemical structure and cannot be determined from the text alone.

What diseases and treatment methods are covered?

Claims 11-15 and 18 target treatment of disorders related to ALAS1 expression. Claim 12 identifies porphyria, while claim 24 lists:

acute intermittent porphyria;
hereditary coproporphyria;
variegate porphyria;
ALA dehydratase deficiency porphyria; and
hepatoerythropoietic porphyria.

The patent also covers treatment timing and clinical outcomes. Claims 13 and 25 address administration before, during or after an acute attack and during a prodrome. Claims 14, 15, 18, 26 and 27 cover reduction of porphyrins, porphyrin precursors, ALA and PBG.

These method claims create infringement exposure even where a competing product is not identical to Givlaari in every formulation detail. A product that uses a different ALAS1-targeting siRNA could still face method-of-use issues if it practices a patented treatment step, although infringement would depend on the precise sequence, claim limitations, prescribing instructions and applicable law.

When does US Patent 10,125,364 lose exclusivity?

The listed expiration date is May 22, 2035. The date reflects the patent term associated with the underlying priority and filing history. FDA regulatory exclusivity is separate.

Event	Date or period
Patent issued	November 13, 2018
Givlaari FDA approval	November 20, 2019
Expected US patent expiration	May 22, 2035
FDA orphan-drug exclusivity	Seven years from approval, expected to run through November 20, 2026
Potential pediatric extension	Depends on FDA-approved written pediatric study requirements and the applicable regulatory record

Orphan-drug exclusivity prevents FDA approval of the same drug for the same orphan indication during the exclusivity period, subject to statutory exceptions. It does not prevent all competing products, and it does not replace patent protection.

What is the Orange Book status of Givlaari?

Givlaari is an FDA-approved orphan drug manufactured by Alnylam Pharmaceuticals. The FDA approval is for the treatment of adults and adolescents age 12 years and older with acute hepatic porphyria.[1]

The Orange Book is the principal source for approved drug patent listings and use codes. For a generic applicant, the relevant pathway would generally be an abbreviated new drug application if the product and regulatory classification permit that route. A Paragraph IV certification could challenge an Orange Book-listed patent before expiration.

For Givlaari, the regulatory barrier is more complex than a conventional small-molecule generic because the product is a chemically modified, ligand-conjugated siRNA. A follow-on applicant would need to address:

sequence identity and target-site selection;
GalNAc or alternative liver-targeting chemistry;
strand modifications;
duplex architecture;
impurity and conjugate profiles;
potency and off-target activity;
pharmacokinetic comparability;
immunogenicity and safety;
manufacturing consistency; and
patent certifications or litigation.

FDA approval does not itself establish freedom to operate. The Orange Book listing and the broader patent family must be reviewed separately.

What Paragraph IV challenges or litigation affect Givlaari?

Publicly available information through June 2024 does not establish a reported final Paragraph IV judgment or settlement specifically involving US 10,125,364. The absence of a public case does not eliminate future litigation risk.

A Paragraph IV dispute could involve:

invalidity based on anticipation, obviousness, written description or enablement;
noninfringement based on sequence, linker, ligand or modification differences;
patent-term calculations;
Orange Book listing eligibility;
claim construction relating to "comprising," sequence identity and structural limitations; or
regulatory questions concerning a follow-on siRNA pathway.

The strongest litigation positions are likely to differ by claim type. Sequence claims may be easier to test against an accused product but may be vulnerable to prior-art or written-description arguments if the specification does not support the full breadth asserted. Method claims may raise divided-infringement and induced-infringement issues. GalNAc claims may turn on the exact conjugate structure and attachment chemistry.

How strong is the patent estate for Givlaari?

US 10,125,364 is commercially significant because it combines product, formulation, delivery and method-of-use protection in one patent. Its strongest practical value is the overlap between:

the ALAS1 target sequence;
the specific dsRNA architecture;
hepatocyte-directed GalNAc delivery; and
porphyria treatment.

Strength factor	Assessment
Sequence specificity	High for products using the claimed antisense and sense sequences
Delivery coverage	High where the product uses 3' sense-strand GalNAc conjugation
Chemical modification coverage	Moderate to high, depending on the exact modification pattern
Method-of-use coverage	Broad for ALAS1-related porphyria treatment and biomarker reduction
Design-around potential	Possible through a different target sequence, ligand, linker or duplex architecture
Manufacturing barrier	High because GalNAc-siRNA production requires specialized conjugation and analytical controls
Biosimilar relevance	Limited; Givlaari is a synthetic oligonucleotide, not a biologic requiring a conventional biosimilar pathway

The estate should be assessed as a layered barrier rather than a single blocking patent. Related Alnylam patents may cover alternative ALAS1 sequences, conjugation chemistry, delivery systems, manufacturing processes and dosing regimens. A complete freedom-to-operate review therefore requires a live family search across US, PCT, European and other national records.

How does Givlaari compare with competing porphyria treatments?

Givlaari is differentiated by durable RNAi-mediated suppression of hepatic ALAS1. The principal pharmacologic alternative for acute hepatic porphyria is hemin, marketed in the United States as Panhematin. Hemin is used primarily to manage acute attacks and does not provide the same long-term RNAi mechanism.

Product	Active approach	Primary use	IP profile
Givlaari	GalNAc-conjugated ALAS1 siRNA	Long-term reduction of attack frequency in acute hepatic porphyria	Sequence, conjugate, formulation and method claims
Panhematin	Hemin	Acute attack management	Older small-molecule and formulation landscape
Investigational ALAS1 approaches	RNAi or antisense modulation	Prevention or treatment of porphyria	Program-specific sequence and delivery patents

The main competitive risk to Givlaari is not a conventional small-molecule generic. It is a next-generation ALAS1 silencing product with a noninfringing sequence or delivery design, or an alternative therapy that reduces ALA and PBG without practicing the patented dsRNA claims.

What generic launch scenarios exist?

A generic or follow-on launch before May 22, 2035 would face several possible scenarios:

Paragraph IV launch. The applicant certifies that the listed patent is invalid, unenforceable or not infringed and launches after providing notice. Alnylam could sue, triggering a statutory stay of approval for up to 30 months under applicable conditions.
Skinny-label strategy. The applicant removes a patented indication or method from labeling. This strategy is more difficult where the patented use is closely tied to the product's principal approved indication.
Sequence design-around. The applicant uses a different ALAS1 target sequence. This may avoid sequence claims but could encounter other Alnylam patents and requires new efficacy and safety evidence.
Delivery design-around. The applicant replaces GalNAc or changes the conjugation site. This may avoid certain formulation claims but could lose liver-targeting efficiency.
Post-expiration launch. The applicant waits for patent expiry and addresses any remaining regulatory exclusivity or other unexpired family patents.

What geographic coverage matters?

US 10,125,364 has direct force only in the United States. Parallel rights may exist in jurisdictions that entered the relevant PCT or national phase, including major pharmaceutical markets. The effective landscape differs by country because of:

national prosecution outcomes;
patent-term adjustment or supplementary protection certificates;
claim amendments;
opposition proceedings;
regulatory exclusivity;
compulsory licensing rules; and
local standards for sequence-related patentability.

A global launch analysis must review the US, European Patent Office, United Kingdom, Japan, China, Canada and Australia separately. A US noninfringement position does not establish freedom to operate elsewhere.

Key Takeaways

US 10,125,364 is a core Alnylam patent for ALAS1-targeting dsRNA technology associated with Givlaari.
Claims 1 and 33 establish the principal sequence-based protection.
Claims 6, 7, 19, 21, 33 and 35 target GalNAc-conjugated liver delivery.
Claims 30-32 cover heavily modified, structurally defined siRNA products.
Claims 11-18 and 24-27 cover porphyria treatment, acute attacks, prodromes and reductions in ALA, PBG and porphyrins.
The expected patent expiration is May 22, 2035.
FDA orphan-drug exclusivity is distinct from patent protection and is expected to run through November 20, 2026.
A follow-on product would need to address sequence, conjugation, chemical modification, manufacturing and regulatory barriers.
The omitted structures for claims 22 and 23 prevent a complete assessment of those specific ligand-linker limitations.

FAQs

What drug is covered by US Patent 10,125,364?

The patent covers ALAS1-targeting dsRNA technology associated with givosiran, the active pharmaceutical ingredient in Givlaari.

Does the patent cover all ALAS1 siRNA products?

No. The claims require particular sequence relationships, duplex structures, chemical modifications or ligand configurations. A different ALAS1 siRNA may avoid this patent but could fall within another patent family.

Is Givlaari protected by orphan-drug exclusivity?

Yes. Givlaari received orphan-drug designation and approval for acute hepatic porphyria. Orphan exclusivity is separate from the patent term and does not provide the same scope as the patent claims.

Can a competitor use a different GalNAc linker?

Potentially, but the result depends on whether the alternative satisfies the broader dsRNA or ligand claims and whether related patents cover the alternative linker, attachment position or conjugate structure.

Is a biosimilar pathway available for Givlaari?

Givlaari is a synthetic, chemically modified siRNA product rather than a conventional protein biologic. A follow-on applicant would likely face a product-specific regulatory pathway rather than a standard biosimilar analysis.

References

U.S. Food and Drug Administration. (2019). FDA approves first treatment for acute hepatic porphyria.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Patent No. 10,125,364. (2018). RNAi agents for inhibiting ALAS1 gene expression. U.S. Patent and Trademark Office.
Alnylam Pharmaceuticals, Inc. (2024). Givlaari (givosiran) prescribing information.
U.S. Food and Drug Administration. (2024). Approved orphan-drug designations and approvals.

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	GIVLAARI	givosiran sodium	SOLUTION;SUBCUTANEOUS	212194-001	Nov 20, 2019		RX	Yes	Yes	⤷ Start Trial	⤷ Start Trial	Y	Y		TREATMENT OF ACUTE HEPATIC PORPHYRIA	⤷ 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
Argentina	090641	⤷ Start Trial
Argentina	129562	⤷ Start Trial
Australia	2013245949	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 10,125,364

Which drugs does patent 10,125,364 protect, and when does it expire?

Summary for Patent: 10,125,364