Details for Patent: 11,028,392

Which drugs does patent 11,028,392 protect, and when does it expire?

Patent 11,028,392 protects GIVLAARI and is included in one NDA.

This patent has seventy-nine patent family members in thirty-nine countries.

Summary for Patent: 11,028,392

Title:	Compositions and methods for inhibiting expression of the ALAS1 gene
Abstract:	The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ALAS1 gene, and methods of using such dsRNA compositions to alter (e.g., inhibit) expression of ALAS1.
Inventor(s):	Brian Bettencourt, Kevin Fitzgerald, William Querbes, Robert J. Desnick, Makiko Yasuda
Assignee:	Icahn School of Medicine at Mount Sinai , Alnylam Pharmaceuticals Inc
Application Number:	US16/137,046
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 11,028,392: ALAS1 RNAi Claims, Givosiran Coverage, and Patent Landscape

US Patent No. 11,028,392 is an Alnylam patent directed to double-stranded RNA molecules that silence the hepatic ALAS1 gene. Its broadest independent claim covers an ALAS1-targeting antisense sequence defined by at least 22 contiguous nucleotides from the disclosed sequence family. Dependent claims extend protection to chemically modified siRNA, 21- to 23-base-pair duplexes, 3′ overhangs, phosphorothioate linkages, GalNAc conjugation, specific sequence pairs, pharmaceutical compositions, liver-cell methods, porphyria treatment, dosing, biomarker reduction, and formulation parameters.

The claim set is commercially relevant to givosiran, marketed as Givlaari by Alnylam for acute hepatic porphyria. The strongest infringement positions are likely claims directed to the specific ALAS1 siRNA sequence, triantennary GalNAc conjugation, chemically modified duplex architecture, and treatment of acute intermittent porphyria or related acute hepatic porphyrias.

What does US Patent 11,028,392 protect?

The patent protects a layered RNAi product and use platform:

Protection layer	Representative claims	Commercial subject
Target sequence	1, 29	ALAS1 RNA transcript and defined antisense sequence
Duplex architecture	3-5	21-23 base pairs, 3′ overhang, strand length limits
Chemical modification	2, 6, 30-31	2′-O-methyl, 2′-fluoro, phosphorothioate and related modifications
Ligand conjugation	7-9, 32-33	Carbohydrate and GalNAc targeting ligands
Specific sequences	10-12, 30	Defined sense and antisense strands
Genetic constructs and cells	13-14	Vectors and isolated cells containing the dsRNA
Pharmaceutical composition	15, 27-28	ALAS1-inhibiting compositions, including about 200 mg/mL and pH 6.0-7.5
Cellular activity	16-17, 34	ALAS1 mRNA degradation and porphyrin precursor reduction
Porphyria treatment	18-26, 35-37	Treatment, prevention and reduction of acute attacks and symptoms

The patent is therefore not limited to a single therapeutic indication. It combines composition claims with method-of-treatment claims and manufacturing-relevant molecular architecture.

What is the core independent claim in US 11,028,392?

Claim 1 is the principal composition claim. It requires:

1. A double-stranded RNA;
2. A sense strand and an antisense strand;
3. An antisense strand with complementarity to an ALAS1 RNA transcript; and
4. At least 22 contiguous nucleotides from the antisense sequence corresponding to SEQ ID NO: 4153 or 4154.

The claim does not require GalNAc, a particular dosing regimen, a specific porphyria, or a particular formulation. Those limitations appear in dependent claims.

The phrase "at least 22 contiguous nucleotides" creates a sequence-based scope that is broader than protection limited to one fully defined 21- or 23-nucleotide siRNA. A competing product could avoid literal infringement if its antisense strand does not contain the required 22-nucleotide contiguous sequence, although doctrine-of-equivalents issues would depend on the precise sequence, prosecution history and technical differences.

How broad is the ALAS1 sequence coverage?

The sequence limitation is the principal boundary of claim 1. The claim reaches dsRNA molecules whose antisense strand contains a qualifying 22-nucleotide segment from the disclosed ALAS1 antisense sequence.

The sequence limitation has several practical consequences:

• A full-length sequence identical to the disclosed antisense sequence is within the claim if the other claim elements are met.
• Shorter fragments containing fewer than 22 qualifying contiguous nucleotides fall outside claim 1.
• A sequence with substitutions may avoid literal infringement if the substituted segment breaks the required 22-nucleotide identity.
• A sequence with chemical modifications can remain within the claim because claim 2 expressly contemplates modified nucleotides.
• A different ALAS1-targeting sequence may avoid claim 1, even if it produces comparable gene silencing, unless another patent claim or an equivalents theory applies.
• Claims 10-12 and 30 create narrower positions for specific sequence pairs and structural configurations.

Claims 11 and 12 are sequence-specific claims tied to SEQ ID NOs: 4156, 4157, 4164 and 4165. Claims 10 and 30 similarly identify specific sense and antisense sequences. These claims can provide stronger literal-infringement positions against a product matching the disclosed duplex, but they are narrower than claim 1.

Which claims cover givosiran and GalNAc-siRNA products?

The most commercially significant claims are 30, 32 and 33.

Claim 30 describes a highly specific product profile that corresponds to the architecture used in advanced hepatocyte-directed siRNA products:

• Chemically synthesized dsRNA;
• Modified nucleotides;
• 3′-5′ phosphodiester linkages;
• A 21-nucleotide sense strand;
• A 23-nucleotide antisense strand;
• A blunt end on the 3′ end of the sense strand;
• A two-nucleotide 3′ antisense overhang;
• A triantennary GalNAc ligand;
• GalNAc attached to the 3′ end of the sense strand;
• Possible phosphorothioate linkages; and
• Specific modification patterns in the sense and antisense strands.

Claims 32 and 33 separately cover attachment of a ligand to the 3′ end of the sense strand and identify GalNAc as the ligand. These claims are important because GalNAc conjugation is the principal delivery mechanism for selective uptake by hepatocytes through the asialoglycoprotein receptor.

Givosiran is an N-acetylgalactosamine-conjugated small interfering RNA designed to reduce ALAS1 expression in the liver. The FDA-approved product label identifies givosiran as a subcutaneously administered siRNA targeting ALAS1 messenger RNA. The patent claims therefore align closely with the product's pharmacological and delivery design. [1]

What formulations are protected by US 11,028,392?

Claims 27 and 28 provide formulation limitations:

• Claim 27: a pharmaceutical composition containing about 200 mg/mL of the dsRNA.
• Claim 28: a composition with a pH of 6.0 to 7.5.

These claims are narrower than the core composition claims. They may be relevant to the commercial drug product if the marketed formulation has the claimed concentration and pH. They do not independently cover every formulation containing an ALAS1 siRNA. A competing formulation with a different concentration or pH could avoid these specific limitations while remaining exposed to broader composition claims.

The formulation claims can be valuable in litigation because they may address the actual product sold rather than only the underlying sequence. Their strength depends on the approved product's concentration, pH, excipient profile and labeling disclosures.

What method-of-use patents does US 11,028,392 contain?

Claims 16-26 and 34-37 cover methods involving:

• Inhibition of ALAS1 expression in a liver cell;
• Degradation of ALAS1 mRNA;
• Reduction of porphyrin or porphyrin precursor levels;
• Treatment of porphyria;
• Acute intermittent porphyria;
• ALA-dehydratase deficiency porphyria;
• Administration during or after an acute attack;
• Prophylactic administration;
• Reduction of ALA or porphobilinogen;
• At least 40% reduction in a specified biomarker;
• At least 40% ALAS1 inhibition;
• Reduction in attack frequency or incidence;
• Reduction of pain, neuropathy and nerve damage; and
• Administration weekly, biweekly or monthly.

Claim 34 is a laboratory performance claim requiring at least 80% ALAS1 inhibition at 10 nM, measured by bDNA assay 24 hours after transfection. This claim is directed to cellular activity rather than clinical efficacy. It may be useful against a structurally similar siRNA that produces the required assay result, but it requires proof of the specified test conditions.

Claims 18-26 and 35-37 are treatment claims. They may be relevant to induced infringement where a generic or follow-on product is labeled for acute hepatic porphyria and the label instructs use within the claimed disease, patient or dosing scope.

When does US Patent 11,028,392 expire?

US Patent No. 11,028,392 issued on June 8, 2021. Its effective patent term is generally calculated from the earliest effective nonprovisional filing date in the priority chain, subject to patent-term adjustment, terminal disclaimers and any applicable patent-term extension. The face of the patent and USPTO Patent Center records control the legally operative expiration date. [2]

The patent should not be analyzed in isolation. A commercial launch date for a generic or competing RNAi product depends on:

• The earliest effective expiration date among blocking patents;
• Patent-term adjustment;
• Any patent-term extension;
• Orange Book-listed patents;
• Non-Orange-Book patent rights;
• Pending continuations;
• Paragraph IV litigation;
• Regulatory exclusivity; and
• Product-specific manufacturing and delivery rights.

A nominal expiration date inferred from the issue date alone is not reliable. The patent's priority chain and terminal-disclaimer status must be reviewed before assigning a definitive loss-of-exclusivity date.

What is the FDA and Orange Book status of givosiran?

The FDA approved Givlaari on November 20, 2019, for the treatment of adults and children aged 12 years and older with acute hepatic porphyria. Givosiran is administered by subcutaneous injection, generally once monthly after the initial dosing regimen. [1]

Givlaari is a drug product, not a biologic. Biosimilar approval provisions under the Public Health Service Act do not apply. A follow-on competitor would generally pursue an abbreviated or full application pathway appropriate to an oligonucleotide product, rather than a biosimilar application.

The Orange Book should be reviewed for currently listed patents and exclusivity. Orange Book listing does not capture every patent relevant to givosiran. RNA sequence, conjugation, platform, manufacturing and method-of-use patents may be asserted outside the Orange Book framework. FDA approval and Orange Book listing also do not determine the ultimate enforceability or validity of US 11,028,392. [3]

Are Paragraph IV challenges or generic litigation associated with this patent?

A Paragraph IV challenge is relevant only if a follow-on applicant files an ANDA that references an Orange Book-listed givosiran patent and certifies that the patent is invalid, unenforceable or will not be infringed. A non-Orange-Book patent can still create litigation risk, but it would not necessarily trigger the same statutory stay mechanism.

The provided record does not establish a specific Paragraph IV notice, ANDA filing, district-court complaint or settlement agreement directed to US 11,028,392. Treating the patent as subject to a confirmed Paragraph IV challenge would therefore be unsupported.

The relevant litigation questions are:

Issue	Relevance
Listed patent	Determines whether a Paragraph IV certification may be required
Claim construction	Defines whether the accused siRNA contains the claimed 22-nucleotide sequence
Sequence identity	Tests literal infringement of claims 1, 10-12 and 30
GalNAc attachment	Tests claims 7-9 and 32-33
Formulation	Tests claims 27-28
Induced infringement	Depends on the follow-on label and instructions
Validity	Includes written description, enablement, anticipation and obviousness
Prosecution history	May limit the scope of the sequence and modification claims
Continuations	May preserve related claims after this patent expires

How strong is the patent estate?

US 11,028,392 has a strong product-to-use claim structure, but its practical strength varies by claim group.

Stronger claim groups

Claims 1, 10-12 and 30 are potentially strong against a product that uses the disclosed ALAS1 sequence and GalNAc-siRNA architecture. They combine sequence identity with structural features that are common in the commercial product.

Claims 32 and 33 provide focused protection for 3′ sense-strand GalNAc conjugation. A competitor using the same target sequence but a different ligand attachment site may create a noninfringement position, subject to the remaining claims.

More vulnerable claim groups

Broad sequence claims can face validity attacks based on:

• Earlier ALAS1-targeting RNAi disclosures;
• Overlapping sequences;
• Written-description support for broad sequence variants;
• Enablement across the full claimed sequence genus;
• Obviousness of combining known ALAS1 sequences with standard siRNA modifications; and
• Prior art involving GalNAc delivery to hepatocytes.

Treatment claims may face narrower enforcement limits because infringement depends on the accused product's labeling, prescribed use and evidence of direct or induced use.

The patent's commercial value is highest when read with related Alnylam patents covering givosiran's sequence, conjugate, formulation, manufacturing process and therapeutic use. Patent-family and continuation review is essential because a later patent may carry narrower claims that are harder to invalidate or easier to read on the marketed product.

How does US 11,028,392 compare with competing ALAS1 and RNAi patent positions?

Technology	Target or mechanism	Delivery	Competitive relevance
Givosiran	ALAS1 mRNA silencing	GalNAc-conjugated siRNA	Approved treatment for acute hepatic porphyria
Small-molecule ALAS1 approaches	Enzyme or pathway modulation	Oral or systemic small molecule	May avoid sequence and conjugation claims
Alternative ALAS1 siRNA	ALAS1 mRNA, different sequence	GalNAc or other delivery	Main design-around route
Antisense oligonucleotide	ALAS1 RNA or related transcript	Systemic or targeted oligonucleotide	May avoid dsRNA claims
Gene-editing or gene-suppression platforms	Permanent or semi-permanent pathway alteration	Viral or nonviral delivery	Faces different manufacturing and regulatory barriers

A competitor using a different ALAS1 sequence may avoid claim 1, but it could still encounter separate patents covering ALAS1 inhibition, GalNAc delivery, liver targeting, chemical modification patterns or porphyria treatment. A competitor using a non-siRNA modality would likely have a clearer path around this patent, but would face new delivery, safety and regulatory issues.

What generic entry risks exist for givosiran?

The most plausible entry scenarios are:

1. A sequence-identical or near-identical siRNA product with a different formulation.
2. A GalNAc-siRNA using an alternative ALAS1 target sequence.
3. A product using the same target sequence but a different conjugation geometry.
4. A non-GalNAc hepatocyte delivery system.
5. A follow-on product that relies on a narrower label to avoid method-of-use infringement.
6. A licensed or partnered product using Alnylam technology.

The principal barriers are not limited to US 11,028,392. They include sequence selection, RNAi chemical modification, GalNAc synthesis, conjugation control, impurity specifications, analytical comparability, pharmacokinetic bridging and clinical evidence for acute hepatic porphyria.

What licensing and commercial issues affect the patent landscape?

Alnylam's commercial position is built around proprietary RNAi chemistry, ligand conjugation and hepatocyte delivery. Licensing can affect freedom to operate even when a product does not infringe US 11,028,392. Relevant rights may include:

• GalNAc ligand chemistry;
• Triantennary carbohydrate synthesis;
• Stabilized siRNA modification patterns;
• RNAi trigger design;
• Conjugation processes;
• Manufacturing know-how;
• Analytical methods; and
• Rights to use patents held by third parties.

No specific license or settlement agreement is established by the claim text supplied. A commercial diligence review should treat patent ownership, exclusive licenses, sublicenses and covenants not to sue as separate from the issued claims.

Key Takeaways

• US 11,028,392 protects ALAS1-targeting dsRNA and related therapeutic uses.
• Claim 1 is anchored to an antisense ALAS1 sequence containing at least 22 contiguous nucleotides from the identified sequence family.
• Claims 10-12 and 30 narrow protection to specific sequences and siRNA architectures.
• Claims 32 and 33 directly address 3′ sense-strand GalNAc conjugation.
• Claims 18-26 and 35-37 cover treatment and prevention of porphyria-related attacks and symptoms.
• Claims 27 and 28 address a concentrated formulation and pH range.
• Givosiran is an FDA-approved GalNAc-conjugated siRNA for acute hepatic porphyria.
• Givosiran is not subject to biosimilar competition under the biologics pathway.
• A Paragraph IV challenge cannot be confirmed from the supplied record.
• The effective loss-of-exclusivity analysis requires the complete priority chain, patent-term adjustment, terminal disclaimers, continuations and related Alnylam patents.
• The most credible design-around strategy is a different ALAS1-targeting sequence, delivery ligand or conjugation configuration, subject to other patents in the broader RNAi estate.

FAQs About US Patent 11,028,392

Does US 11,028,392 cover givosiran?

The claims appear directed to the molecular and therapeutic characteristics associated with givosiran, including ALAS1 silencing, modified dsRNA, GalNAc conjugation and porphyria treatment. Definitive infringement requires comparing the issued claims with the product's exact sequences, modifications, conjugation structure and formulation.

Does the patent cover every ALAS1 siRNA?

No. Claim 1 requires a qualifying 22-nucleotide contiguous sequence from the disclosed ALAS1 antisense sequence family. An ALAS1 siRNA directed to a materially different sequence may fall outside the claim.

Can an alternative GalNAc ligand avoid this patent?

Possibly, depending on the sequence and claim combination. Claims 32 and 33 are directed to ligand attachment and GalNAc, but broader claims may not require GalNAc. A different ligand does not automatically avoid claims 1, 2, 3 or the method claims.

Is US 11,028,392 an Orange Book patent?

The patent's Orange Book status must be determined from the current FDA listing for givosiran. Patent relevance is broader than Orange Book status because non-listed patents can still affect freedom to operate and litigation risk.

Does givosiran have biosimilar competition?

No biosimilar pathway applies because givosiran is an oligonucleotide drug rather than a biologic subject to the Public Health Service Act. Competition would arise through a drug-product pathway or an alternative therapeutic technology.

References

1. U.S. Food and Drug Administration. (2019). Givlaari (givosiran) prescribing information. FDA.

2. United States Patent and Trademark Office. (2021). U.S. Patent No. 11,028,392, RNAi agents for inhibiting ALAS1 expression. USPTO.

3. U.S. Food and Drug Administration. (2025). Approved drug products with therapeutic equivalence evaluations, Orange Book. FDA.

Drugs Protected by US Patent 11,028,392

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			Y	Y		TREATMENT OF ACUTE HEPATIC PORPHYRIA

International Family Members for US Patent 11,028,392

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	3052628		301061	Netherlands
European Patent Office	3052628		LUC00175	Luxembourg
European Patent Office	3052628		122020000045	Germany
European Patent Office	3052628		PA2020527	Lithuania
European Patent Office	3052628		2020C/532	Belgium
European Patent Office	3052628		CA 2020 00042	Denmark