Details for Patent: 10,478,500

Which drugs does patent 10,478,500 protect, and when does it expire?

Patent 10,478,500 protects OXLUMO and is included in one NDA.

This patent has seventy-six patent family members in forty-four countries.

Summary for Patent: 10,478,500

Title:	Compositions and methods for inhibition of HAO1 (Hydroxyacid Oxidase 1 (Glycolate Oxidase)) gene expression
Abstract:	The invention relates to RNAi agents, e.g. double-stranded RNAi agents, targeting the HAO1 gene, and method of using such RNAi agents to inhibit expression of HAO1 and methods of treating subjects having, e.g., PH1. Described herein are double-stranded RNAi agents which inhibit the expression of a HA01 gene in a cell, such as a cell within a subject, e.g., a mammal, such as a human having a HAO1 associated disorder, and uses of such double-stranded RNAi agents. In certain aspects of the invention, substantially all of the nucleotides of an iRNA of the invention are modified.
Inventor(s):	William Querbes, Kevin Fitzgerald, Brian Bettencourt, Abigail Liebow, David V. Erbe
Assignee:	Alnylam Pharmaceuticals Inc
Application Number:	US15/517,471
Patent Claim Types: see list of patent claims	Use; Composition;

United States Patent 10,478,500: Claim Scope, Lumasiran Coverage and HAO1 RNAi Patent Landscape

U.S. Patent No. 10,478,500 is a core Alnylam patent covering a chemically modified, GalNAc-conjugated double-stranded RNA interference agent directed to HAO1, the gene encoding glycolate oxidase. Its claims are narrowly anchored to specified sense and antisense sequences, but they extend across composition, conjugation chemistry, modified nucleotides, vectors, cells, pharmaceutical compositions and HAO1-silencing methods. The patent is directly relevant to lumasiran, marketed as OXLUMO for primary hyperoxaluria type 1.

The central infringement risk is a generic or competing RNAi product using the claimed SEQ ID NO:589/706 duplex, or a chemically corresponding embodiment covered by claim 19. A product using a different HAO1 sequence may avoid literal infringement of the principal composition claims but could encounter other HAO1 patent families, formulation claims, manufacturing claims or method-of-use claims.

What does U.S. Patent 10,478,500 cover?

The patent claims an HAO1-targeting siRNA duplex with five principal technical elements:

1. A sense strand and antisense strand forming a double-stranded RNAi region.
2. The specific sequences identified as SEQ ID NO:589 and SEQ ID NO:706.
3. Substantially all, or all, nucleotides chemically modified.
4. A ligand attached to the 3′ terminus of the sense strand.
5. A GalNAc-based ligand, preferably connected through a bivalent or trivalent branched linker.

The patent therefore does not claim every HAO1 inhibitor. It claims a defined sequence duplex and specific structural features surrounding that duplex.

Claim feature	Scope created
HAO1 inhibition	Requires an RNAi agent capable of suppressing HAO1 expression
Double-stranded RNAi agent	Covers a duplex, not a single-stranded antisense oligonucleotide
SEQ ID NO:589 and 706	Creates the principal sequence limitation
Modified nucleotides	Covers extensive chemical modification of both strands
3′ sense-strand ligand	Requires the conjugate position on the sense strand
GalNAc derivative	Covers hepatocyte-targeting ligand chemistry
Branched linker	Claims bivalent or trivalent GalNAc arrangements
Terminal phosphorothioate or methylphosphonate linkages	Adds stability and nuclease-resistance embodiments
AU base pair at antisense 5′ position	Defines a duplex-end configuration
Pharmaceutical composition	Extends coverage to drug products containing the claimed agent
Cell and vector claims	Covers research, delivery and cellular embodiments
HAO1 inhibition method	Covers contacting a cell and maintaining it until HAO1 mRNA degradation occurs

The sequence limitations are the principal boundary. A competing product that changes one or more nucleotides, uses a different HAO1 target site or moves the ligand to the opposite strand may have a noninfringement position against claims 1 through 18, although the total patent estate must be reviewed.

How strong is the patent estate for lumasiran?

The patent is strong against an exact-copy version of lumasiran because the independent claim combines sequence identity with the characteristic GalNAc-siRNA architecture used for liver delivery.

Its strongest characteristics are:

• Exact sequence protection.
• Coverage of both the duplex and drug-product context.
• Protection for the 3′ sense-strand GalNAc configuration.
• Dependent claims covering extensive nucleotide modification.
• Claims directed to phosphorothioate and methylphosphonate terminal linkages.
• A method claim tied to HAO1 mRNA degradation.
• A claim directed to a specifically enumerated chemical embodiment in claim 19.

The estate is narrower against a next-generation HAO1 RNAi agent. A competitor could attempt to design around the patent by:

• Selecting another HAO1 target sequence.
• Using a different antisense guide.
• Placing the GalNAc ligand at a different location.
• Using a non-GalNAc delivery ligand.
• Using a single-stranded or non-duplex modality.
• Altering the duplex-end base pair.
• Omitting the claimed sequence while retaining HAO1 activity.

Those changes would not automatically eliminate risk. Other Alnylam patents may cover alternative HAO1 sequences, conjugation structures, formulations, dosing regimens or manufacturing processes.

What are the key limitations in claims 1 through 19?

Claims 1 and 2: chemical composition

Claim 1 is the principal independent composition claim. It requires the exact sense and antisense sequences, substantially modified nucleotides on both strands and a 3′-terminal ligand on the sense strand.

Claim 2 narrows claim 1 by requiring every nucleotide on both strands to be modified. A product with one unmodified nucleotide may fall outside claim 2 while remaining within claim 1 if it satisfies the “substantially all” limitation.

The phrase “substantially all” introduces a fact-dependent infringement issue. Courts would likely examine the number, location and function of unmodified nucleotides. Chemical modifications that preserve RNAi activity would not ordinarily avoid the claim if most nucleotides remain modified.

Claim 3: permitted nucleotide modifications

Claim 3 lists a broad set of modifications, including:

• 2′-O-methyl nucleotides;
• 2′-fluoro nucleotides;
• 2′-deoxy nucleotides;
• locked nucleic acid residues;
• abasic residues;
• 2′-amino and 2′-alkyl modifications;
• morpholino and phosphoramidate structures;
• non-natural bases;
• 5′-phosphorothioate groups;
• phosphate mimics; and
• terminal cholesterol or dodecanoic acid bisdecylamide groups.

Because claim 3 depends on claim 1, these modifications do not replace the required sequence, duplex architecture and 3′ sense-strand ligand. They provide additional protected embodiments.

Claims 4, 6 and 7: GalNAc conjugation

Claim 4 focuses on one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. Claims 6 and 7 further specify attachment to the 3′ end of the sense strand and a conjugate schematic in which X is oxygen or sulfur.

These claims are commercially important because triantennary GalNAc conjugation is the delivery architecture used to direct siRNA to hepatocytes through the asialoglycoprotein receptor. A competing product using the same duplex and a materially equivalent 3′ GalNAc structure would present a high literal infringement risk.

Claim 5, as reproduced, is incomplete because it ends after “wherein the ligand is.” Its effective scope cannot be determined from the supplied text alone. The issued patent should control the analysis of that claim.

Claims 8 through 11: terminal backbone modifications

Claims 8 through 11 cover at least one phosphorothioate or methylphosphonate internucleotide linkage, including placement at:

• the 3′ terminus;
• the 5′ terminus; or
• both termini of one strand.

These limitations target stability and pharmacokinetic features common in therapeutic oligonucleotides. A product can avoid an individual dependent claim by omitting the specified linkage, but the omission does not avoid claim 1 if the remaining limitations are met.

Claim 12: antisense 5′-end base pair

Claim 12 requires an AU base pair at position 1 of the antisense strand’s 5′ end. This is a narrow duplex-end limitation. It may be significant in an infringement analysis because a single base-pair change could remove the product from claim 12 without changing the remainder of the molecule.

Claims 13 and 14: sequence repetition

Claims 13 and 14 repeat the SEQ ID NO:589/706 limitation. Claim 13 uses “comprises,” while claim 14 uses “consists of.” Claim 14 is narrower because it requires the listed sequences without additional sequence material within the claimed strands.

Claims 15 through 18: use and product context

Claim 15 covers a vector containing the claimed RNAi agent. Claim 16 covers a cell containing it. Claim 17 covers a pharmaceutical composition. Claim 18 covers a method of inhibiting HAO1 expression by contacting a cell and allowing sufficient time for HAO1 mRNA degradation.

Claims 15 and 16 are more relevant to research tools and delivery systems than to a conventional finished drug. Claim 17 is the principal product-level extension. Claim 18 may be relevant to commercial use of the agent in vitro, ex vivo or in certain therapeutic manufacturing and testing processes.

Claim 19: chemically defined embodiment

Claim 19 identifies a specific modified duplex:

• Sense strand: SEQ ID NO:213
• Antisense strand: SEQ ID NO:330
• 2′-fluoro and 2′-O-methyl residues
• Phosphorothioate linkages
• L96 GalNAc ligand defined as N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol

This claim is materially narrower than claim 1 but potentially more valuable in a product comparison because it identifies a detailed chemical structure corresponding to a therapeutic-grade GalNAc-siRNA design.

The supplied text contains a drafting issue: claims 1 and 14 refer to SEQ ID NO:589 and 706, while claim 19 refers to SEQ ID NO:213 and 330. The claims may be directed to related sequence representations or distinct embodiments. The issued patent’s sequence listings and prosecution history are necessary to determine whether those identifiers represent the same functional duplex, alternative sequences or a claim-drafting inconsistency.

When does U.S. Patent 10,478,500 lose exclusivity?

U.S. Patent 10,478,500 was granted on November 12, 2019. Its underlying patent term is expected to run into 2034, based on the earliest relevant nonprovisional filing and the 20-year patent-term framework. The operative expiration date should be taken from the USPTO patent record and any Orange Book listing because patent term adjustment, terminal disclaimers and patent-term extension can affect the final date.

OXLUMO received FDA approval on November 22, 2020, for the treatment of elevated plasma oxalate levels in adults and children with primary hyperoxaluria type 1. The product received orphan-drug exclusivity, which generally runs for seven years from approval and therefore reaches November 22, 2027, subject to the statutory scope of orphan exclusivity.[1]

Exclusivity or barrier	Relevant timing
FDA approval of OXLUMO	November 22, 2020
Orphan-drug exclusivity	Expected through November 22, 2027
U.S. Patent 10,478,500	Expected to run into 2034
Earlier possible ANDA entry	Dependent on patent challenges, settlement terms and regulatory exclusivity
Patent-free commercial entry	Not expected before the applicable 2034 patent term absent invalidity, noninfringement or license

Orphan exclusivity blocks FDA approval of the same drug for the same orphan indication, but it does not operate as a blanket prohibition on all competing HAO1 products. Patent rights provide the more substantial barrier after orphan exclusivity expires.

What is the Orange Book status of U.S. Patent 10,478,500?

U.S. Patent 10,478,500 is associated with the OXLUMO patent estate and is relevant to Orange Book analysis because its claims cover the active RNAi agent and pharmaceutical compositions containing it. The listing category and expiration date should be evaluated against the current FDA Orange Book entry for lumasiran.[2]

An Orange Book listing creates a Paragraph IV certification pathway for an ANDA applicant. The generic applicant may assert that:

• the patent is invalid;
• the patent is unenforceable; or
• the proposed product does not infringe.

A Paragraph IV notice would trigger patent litigation if Alnylam filed suit within 45 days. A timely suit ordinarily produces a 30-month stay of final FDA approval, subject to statutory exceptions and court developments.[3]

The patent’s exact sequence claims create a high litigation risk for an exact-copy lumasiran product. An ANDA applicant using a different duplex may have a stronger noninfringement position, but it would need to assess whether other listed patents cover the alternative sequence or product design.

Which companies are challenging lumasiran patents?

No publicly established commercial competitor has displaced lumasiran in the HAO1 RNAi market. The relevant competitive groups are:

Competitor type	Product strategy	Risk to OXLUMO
Generic oligonucleotide manufacturer	Copy lumasiran through an ANDA	High patent and analytical-equivalence risk
RNAi developer	Alternative HAO1 siRNA	Moderate estate-design-around risk
Antisense developer	Single-stranded HAO1 suppression	Lower risk against this duplex patent
Enzyme or small-molecule developer	Reduce oxalate through another mechanism	Clinical substitution risk rather than direct patent infringement
Biosimilar manufacturer	Not applicable	Lumasiran is a synthetic oligonucleotide, not a biologic

A biosimilar pathway is not the relevant U.S. route for lumasiran. A competitor would generally consider an ANDA if it can establish pharmaceutical equivalence, or a 505(b)(2) application if it relies on different clinical, formulation or delivery characteristics.[4]

What formulation and method-of-use patents affect lumasiran?

U.S. Patent 10,478,500 is primarily a molecule and conjugate patent. It is not limited to a particular commercial vial concentration or administration schedule in the claims reproduced here.

The wider lumasiran landscape can include separate patents directed to:

• injectable pharmaceutical compositions;
• buffer and excipient systems;
• subcutaneous administration;
• dosing schedules;
• loading and maintenance regimens;
• treatment of primary hyperoxaluria type 1;
• reduction of urinary oxalate;
• use in pediatric patients;
• combination treatment with hydration, crystallization inhibitors or dialysis; and
• manufacturing and purification of GalNAc-siRNA conjugates.

A freedom-to-operate review should therefore separate four patent layers:

1. Sequence patents.
2. Conjugate and chemical-modification patents.
3. Formulation and dosing patents.
4. Manufacturing and process patents.

An alternative HAO1 sequence may avoid the first layer while remaining exposed to the third or fourth.

What patent litigation and settlement risks exist?

An ANDA Paragraph IV challenge to an exact lumasiran copy would likely focus on:

• written-description support for the claimed sequence;
• enablement of the full range of chemical modifications;
• construction of “substantially all” modified nucleotides;
• construction of “capable of inhibiting expression”;
• equivalence of GalNAc linker structures;
• whether claim 19 properly depends from claim 1;
• patent-term calculations; and
• the relationship between the SEQ ID NO:589/706 and SEQ ID NO:213/330 embodiments.

Potential invalidity theories would include anticipation or obviousness based on earlier HAO1 siRNA disclosures, GalNAc conjugation prior art and known 2′-O-methyl/2′-fluoro modification patterns. Alnylam’s counterargument would be that the claimed combination requires a specific sequence, specific chemical architecture and demonstrated HAO1 inhibition.

No settlement agreement can be reliably inferred from the patent claims alone. Any commercial settlement would require review of ANDA litigation dockets, FDA correspondence and publicly filed court documents.

How does lumasiran compare with other RNAi drugs?

Product	Target	Delivery	Modality	Biosimilar pathway
OXLUMO, lumasiran	HAO1	GalNAc conjugate	Synthetic siRNA	No
ONPATTRO, patisiran	TTR	Lipid nanoparticle	Synthetic siRNA	No
GIVLAARI, givosiran	ALAS1	GalNAc conjugate	Synthetic siRNA	No
Leqvio, inclisiran	PCSK9	GalNAc conjugate	Synthetic siRNA	No

Lumasiran’s competitive profile is defined by a rare-disease indication, liver-targeted delivery and a single-gene mechanism. The narrow patient population reduces broad generic volume but increases the commercial importance of orphan exclusivity, specialist distribution and reimbursement access.

What manufacturing and geographic barriers remain?

The patent covers selected molecular structures, but commercial entry also requires capabilities that are difficult to replicate quickly:

• solid-phase oligonucleotide synthesis;
• controlled incorporation of 2′-fluoro and 2′-O-methyl residues;
• stereochemical and positional control of phosphorothioate linkages;
• conjugation of the triantennary GalNAc ligand;
• removal of truncated sequences and process impurities;
• analytical characterization of duplex purity and identity;
• sterile injectable manufacturing; and
• validated stability and release testing.

The patent’s U.S. rights apply only in the United States. Corresponding rights in Europe, Japan, China and other markets depend on the national patent family, local prosecution, validity outcomes and term adjustments. A global launch therefore requires a jurisdiction-by-jurisdiction review rather than reliance on the U.S. patent number.

Key Takeaways

• U.S. Patent 10,478,500 is a core HAO1 siRNA patent associated with lumasiran and OXLUMO.
• Claims 1 through 14 focus on a specified HAO1 duplex, chemical modification and 3′ sense-strand ligand attachment.
• Claims 4, 6 and 7 are particularly relevant to GalNAc-conjugated liver delivery.
• Claim 17 extends protection to pharmaceutical compositions, while claim 18 covers HAO1 mRNA-degradation methods.
• Claim 19 defines a detailed 2′-fluoro, 2′-O-methyl, phosphorothioate and GalNAc embodiment.
• The patent is expected to remain relevant into 2034, while OXLUMO’s orphan exclusivity is expected to run through November 2027.
• An exact-copy lumasiran ANDA would face substantial Paragraph IV litigation risk.
• Lumasiran is a synthetic oligonucleotide, so biosimilar analysis does not apply.
• A competing HAO1 sequence may avoid the literal sequence claims but could encounter separate formulation, use, conjugate or manufacturing patents.
• The incomplete text of claim 5 and the differing sequence identifiers in claim 19 require reliance on the issued patent record for definitive claim construction.

FAQs About U.S. Patent 10,478,500 and Lumasiran

Does U.S. Patent 10,478,500 cover all HAO1 inhibitors?

No. The principal claims require specified sequences and a defined modified duplex architecture. Other HAO1 inhibitors may fall outside this patent while remaining exposed to other patent families.

Can a generic lumasiran product launch after orphan exclusivity expires?

Not necessarily. Orphan exclusivity is separate from patent protection. A generic applicant would still need to address listed patents, including through Paragraph IV certifications or a negotiated license.

Is lumasiran eligible for a biosimilar application?

No. Lumasiran is a chemically synthesized siRNA drug. The principal abbreviated pathway would generally be an ANDA or, for a materially different product, a 505(b)(2) application.

Does changing the GalNAc linker avoid the patent?

It may avoid a narrow conjugate limitation, but not necessarily the broader claim. The effect depends on whether the altered product still has the required 3′ sense-strand ligand and satisfies the sequence and modification limitations.

What is the main invalidity vulnerability of this patent?

The main technical issues are prior-art disclosure of the claimed HAO1 sequence, obviousness of the specific chemical combination, written description for the modification range and construction of the “substantially all” limitation.

References

1. U.S. Food and Drug Administration. (2020). OXLUMO (lumasiran) prescribing information.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Code, 21 U.S.C. § 355(j).
4. U.S. Food and Drug Administration. (2024). ANDA submissions: Refuse-to-receive standards and Paragraph IV certifications.
5. U.S. Patent and Trademark Office. (2019). United States Patent No. 10,478,500: RNAi agents for inhibiting HAO1 gene expression.
6. Alnylam Pharmaceuticals, Inc. (2024). Annual report on Form 10-K.

Drugs Protected by US Patent 10,478,500

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	10,478,500		Y	Y		TREATMENT OF PRIMARY HYPEROXALURIA TYPE 1 (PH1)

Foreign Priority and PCT Information for Patent: 10,478,500

PCT Information
PCT Filed	October 09, 2015	PCT Application Number:	PCT/US2015/054881
PCT Publication Date:	April 14, 2016	PCT Publication Number:	WO2016/057893

International Family Members for US Patent 10,478,500

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	3204015		301167	Netherlands
European Patent Office	3204015		PA2022004	Lithuania
European Patent Office	3204015		CA 2022 00011	Denmark
European Patent Office	3204015		2022C/509	Belgium
European Patent Office	3204015		LUC00252	Luxembourg
European Patent Office	3204015		122022000018	Germany
European Patent Office	3204015		C20220010 00364	Estonia