Details for Patent: 10,465,195

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Which drugs does patent 10,465,195 protect, and when does it expire?

Patent 10,465,195 protects OXLUMO and is included in one NDA.

This patent has thirty-two patent family members in twenty countries.

Summary for Patent: 10,465,195

Title:	Methods and compositions for the specific inhibition of glycolate oxidase (HAO1) by double-stranded RNA
Abstract:	This invention relates to compounds, compositions, and methods useful for reducing Glycolate Oxidase (HAO1) target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.
Inventor(s):	Bob D. Brown, Henryk T. Dudek
Assignee:	Novo Nordisk AS
Application Number:	US16/297,316
Patent Claim Types: see list of patent claims	Use; Composition;

US Drug Patent 10,465,195: Scope, Claim Construction, Exclusivity, and HAO1 Patent Landscape

US Patent No. 10,465,195 protects modified double-stranded nucleic acids directed to the HAO1 gene, including the siRNA active ingredient used in lumasiran, marketed as Oxlumo by Alnylam Pharmaceuticals. The patent covers the nucleic-acid structure, selected sequence relationships, chemical modifications, GalNAc conjugation, pharmaceutical compositions, and methods for treating primary hyperoxaluria type 1 (PH1) [1, 2].

The patent is composition-focused but includes method-of-use claims broad enough to reach administration of a qualifying HAO1-silencing dsNA to human PH1 patients. Its commercial relevance is highest for lumasiran products and follow-on HAO1 RNAi products using the claimed sequence architecture.

What does US Patent 10,465,195 cover?

The independent claims divide the patent into three protection categories:

Claim category	Claims	Principal subject matter
dsNA composition	1, 2-22	Modified double-stranded nucleic acid targeting HAO1
Pharmaceutical composition	23	dsNA combined with a pharmaceutically acceptable carrier
Therapeutic method	24-28	Reducing HAO1 mRNA, including treatment of human PH1

Claim 1 is the principal composition claim. It requires:

1. A first strand of 15 to 27 nucleotides;
2. A second strand of 19 to 27 nucleotides;
3. At least one modified nucleotide in each strand; and
4. Complementarity of the second strand to SEQ ID NO: 1823 over at least 19 consecutive nucleotides.

The claim uses "comprising," an open transitional term. A qualifying dsNA may therefore contain additional nucleotides, chemical modifications, conjugates, or structural features unless another claim limitation excludes them.

How should the core dsNA claim be construed?

First-strand limitations

The first strand must be 15-27 nucleotides long and must contain at least one modified nucleotide. Claim 15 narrows the first strand to SEQ ID NO: 1823. Claim 16 further limits the first strand to specified lengths from 21 through 27 nucleotides.

The claim set therefore contains both:

• A sequence-function limitation in claim 1, based on the second strand's complementarity to SEQ ID NO: 1823; and
• An exact sequence limitation in claim 15, based on inclusion of SEQ ID NO: 1823 in the first strand.

Claim 16 contains a repeated "25" in the supplied text. That appears to be a drafting or transcription duplication and does not change the operative length range.

Second-strand limitations

The second strand must be 19-27 nucleotides long and complementary to SEQ ID NO: 1823 across at least 19 consecutive nucleotides.

The second strand may include:

• A 3′ single-stranded overhang of 1-5 nucleotides;
• Two 3′ overhang nucleotides under claim 5;
• One or more phosphorothioate linkages;
• 21-27 nucleotides in specified embodiments; and
• 23 consecutive nucleotides of SEQ ID NO: 5035 under claim 10.

Claim 10 is commercially important because it moves beyond a purely functional complementarity limitation and identifies a defined sequence segment. A product with a second strand containing the specified 23-nucleotide sequence would face a more direct claim comparison than a product designed around a different HAO1-targeting sequence.

What chemical modifications are protected?

Claims 4, 20, and 21 cover ribose modifications. The principal protected modifications are:

Modification	Claim coverage
2′-O-methyl	Claims 4, 12, 20, 21
2′-fluoro	Claims 4, 20, 21
2′-methoxyethoxy	Claim 20
2′-allyl	Claim 20
2′-O-[2-(methylamino)-2-oxoethyl]	Claim 20
2′-amino	Claim 20
2′-O-(N-methylcarbamate)	Claim 20

Claim 19 creates a broad modification-density limitation. It covers dsNAs in which at least 10% to 95% or more of the nucleotides are modified. Because the claim recites multiple alternative thresholds, a molecule satisfying a higher threshold would also satisfy the lower thresholds.

Claims 6, 7, 13, and 14 cover phosphorothioate linkages. The strongest terminal-protection embodiments place the linkage at the final internucleotide linkage at either the 3′ or 5′ terminus. These modifications can improve nuclease resistance and are relevant to analytical comparison of a generic or follow-on RNAi product.

What overhang and duplex structures are protected?

The patent claims several structural configurations:

• A 3′ overhang on the second strand of 1-5 nucleotides;
• A two-nucleotide 3′ overhang;
• A 19-21 base-pair duplex region;
• A blunt end between the first-strand 3′ terminus and second-strand 5′ terminus;
• Modified nucleotides at positions 1, 2, and/or 3 from the first strand's 3′ terminus.

The overhang and blunt-end limitations create alternative claim pathways. A molecule may be exposed to claims directed to an overhang configuration while avoiding a blunt-end dependent claim, or vice versa. The presence of an overhang does not automatically avoid claim 1 because claim 1 does not require a blunt or overhanging end.

Does the patent cover GalNAc-conjugated lumasiran?

Yes. Claim 22 requires the 3′ terminus of the first nucleic acid to be conjugated to a GalNAc moiety. This is the limitation most closely aligned with the hepatocyte-targeted delivery design used by lumasiran.

GalNAc conjugation is commercially significant because Oxlumo is administered systemically but is designed to deliver the siRNA to hepatocytes through the asialoglycoprotein receptor pathway. A product that uses the claimed HAO1 sequence and a GalNAc conjugate could implicate claim 22 even if its carrier, dosage form, or manufacturing process differs from Alnylam's product [2].

The claim does not require a particular GalNAc valency, linker chemistry, attachment site beyond the recited terminus, or formulation excipient. Those issues would depend on the patent specification and prosecution history, not only the issued claims.

What methods of use does US 10,465,195 protect?

Claims 24-28 protect use of the claimed dsNA to reduce HAO1 mRNA in mammalian cells.

The method claim progression is:

Claim	Limitation
24	Contacting a mammalian cell with the dsNA in an amount sufficient to reduce HAO1 mRNA
25	The cell is in a subject
26	The subject is human
27	The human has PH1
28	Administration is intravenous, intramuscular, intraperitoneal, or subcutaneous

Claim 24 is broader than the PH1 treatment claims because it applies to mammalian cells without requiring a disease indication. Claims 26-28 are narrower but commercially more important because they track human therapeutic use.

The claims do not expressly require a reduction in urinary oxalate, preservation of kidney function, a particular dose, a dosing interval, or a specific clinical endpoint. A competing product that uses the claimed dsNA to reduce HAO1 expression in a human PH1 patient could face method-of-use exposure even if its label uses different efficacy language.

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

Oxlumo, the lumasiran product associated with the HAO1 RNAi program, received FDA approval in November 2020 for treatment of primary hyperoxaluria type 1 to reduce urinary oxalate levels in pediatric and adult patients [2].

US Patent No. 10,465,195 is relevant to the product's active siRNA and delivery architecture. The FDA Orange Book is the controlling source for whether the patent is listed against the approved drug, the listed use, and any pediatric exclusivity or patent-term information [3].

Exclusivity timeline

Event	Date or period
US Patent No. 10,465,195 issued	November 5, 2019
Oxlumo FDA approval	November 23, 2020
Five-year new chemical entity exclusivity	Through approximately November 23, 2025
Nominal patent term	Approximately 2034, subject to patent-term adjustment or extension
Earliest practical generic filing risk	After the applicable NCE and regulatory restrictions, subject to Paragraph IV certification
Commercial generic entry	Potentially before patent expiration only if the patent is invalidated, not infringed, disclaimed, or subject to an effective settlement

The patent's exact Orange Book expiry date should be taken from the current FDA listing because patent-term adjustment, patent-term extension, terminal disclaimers, and regulatory listing status can affect the operative date [3].

When does lumasiran lose exclusivity?

Lumasiran's regulatory exclusivity and patent exclusivity are separate.

The five-year NCE period restricts submission of an ANDA for a drug relying on the reference product's safety and efficacy data, subject to statutory exceptions. That period is distinct from the patent term. After NCE exclusivity expires, an ANDA applicant may submit a Paragraph IV certification against listed patents.

The commercial loss-of-exclusivity date is therefore determined by the later of:

1. The end of applicable FDA regulatory exclusivity;
2. The expiration or successful challenge of listed patents;
3. Any enforceable pediatric exclusivity;
4. Any litigation stay under the Hatch-Waxman Act; and
5. Any settlement restrictions agreed between the patent holder and an ANDA applicant.

A generic applicant could file before patent expiry with a Paragraph IV certification. Filing does not itself establish an immediate launch right. Patent litigation can trigger a 30-month stay of approval if the statutory requirements are met.

How strong is the patent estate for lumasiran?

US 10,465,195 is strongest against products that reproduce the following combination:

• HAO1-directed sequence architecture;
• 19-21 base-pair siRNA duplex;
• 2′-O-methyl and/or 2′-fluoro modifications;
• Terminal phosphorothioate linkages;
• A two-nucleotide 3′ overhang;
• The SEQ ID NO: 1823 or SEQ ID NO: 5035 relationships; and
• GalNAc conjugation.

Its protection is narrower against:

• A noncomplementary HAO1 sequence;
• A different gene-silencing mechanism;
• An antisense oligonucleotide rather than a dsNA;
• A substantially different duplex length;
• A non-GalNAc delivery system;
• A product using different chemical modifications outside claims 4 and 20; or
• A product that avoids the specified terminal and overhang configurations.

The patent is more than a sequence patent. It combines sequence, length, duplex architecture, chemical modification, terminal stabilization, conjugation, formulation, and therapeutic-use limitations. That layered structure increases the number of design-around variables but also gives the patent holder multiple infringement theories for products closely modeled on lumasiran.

Which companies are challenging the patent?

No Paragraph IV challenger, ANDA litigation judgment, or settlement agreement can be established from the claim text alone. Public regulatory and court records must be reviewed separately for current challenger identity, filing date, asserted claims, district court venue, and any 30-month stay.

The relevant litigation questions are:

• Whether an ANDA applicant has filed a Paragraph IV certification;
• Whether Alnylam has sued within the statutory period;
• Whether claim 1, claim 15, claim 22, or claims 24-28 are asserted;
• Whether the challenge is based on anticipation, obviousness, written description, enablement, or noninfringement;
• Whether a settlement permits a fixed generic launch date; and
• Whether the settlement includes an authorized generic or license arrangement.

The patent record identifies the scope of the claims but does not by itself establish litigation status.

What manufacturing and IP barriers affect a follow-on product?

A competing lumasiran-like product would face both patent and technical barriers.

Manufacturing barriers

The principal manufacturing issues include:

• Controlled synthesis of chemically modified oligonucleotides;
• Stereochemical control of phosphorothioate linkages;
• Removal of truncated sequences and failure products;
• Duplex annealing and strand-ratio control;
• Reproducible GalNAc conjugation;
• Control of aggregation and particle formation;
• Analytical characterization of modified oligonucleotide impurities; and
• Establishment of comparability for a complex RNA therapeutic.

An ANDA applicant cannot rely solely on small-molecule bioequivalence concepts if the product's structure, conjugation, and manufacturing process raise complex-product issues. FDA may require extensive analytical and pharmacokinetic support under the applicable pathway.

Patent design-around options

Potential design-around strategies include:

Strategy	Principal risk
Change the HAO1 target sequence	May reduce activity or trigger separate sequence patents
Alter duplex length	Could affect potency and avoid some claims, but may implicate broader family claims
Remove GalNAc	May avoid claim 22 but materially alter liver delivery
Use alternative sugar modifications	May avoid selected claims while preserving RNAi activity
Use a different overhang architecture	May avoid claims 2, 3, and 5
Use antisense rather than dsNA	Changes mechanism and regulatory pathway
Use a different delivery ligand	May avoid GalNAc-specific coverage but requires new development

How does US 10,465,195 compare with other HAO1 patent categories?

Patent category	Typical protected subject matter	Relevance to lumasiran
Sequence patents	Specific HAO1-targeting sequences	Direct active-ingredient coverage
Chemistry patents	2′ modifications, phosphorothioates, backbone chemistry	Controls oligonucleotide composition
Conjugate patents	GalNAc linkers and ligand structures	Controls hepatocyte delivery
Formulation patents	Excipients, concentrations, stability, injectable formulations	Controls finished dosage form
Manufacturing patents	Synthesis, purification, annealing, conjugation	Raises production and supply barriers
Method-of-use patents	PH1 treatment, dosing, urinary oxalate reduction	Controls labeled or clinical use

US 10,465,195 is most accurately categorized as a combined HAO1 sequence and chemically modified dsNA patent with GalNAc and therapeutic-use subclaims. It should be analyzed alongside, rather than in isolation from, Alnylam's sequence, conjugate, formulation, manufacturing, and dosing patent families.

What are the main commercial risks for generic entry?

The principal risks are:

1. A generic product may fall within claim 1 even if it changes some terminal chemistry.
2. Claim 15 may capture products using SEQ ID NO: 1823 in the first strand.
3. Claim 10 may capture products containing the specified 23-nucleotide segment of SEQ ID NO: 5035.
4. Claim 22 may reach GalNAc-conjugated versions of the claimed dsNA.
5. Claims 24-28 may create method-of-use exposure for labeled PH1 treatment.
6. A noninfringement position may depend on multiple structural differences rather than one isolated modification.
7. Separate patents may remain relevant after this patent expires.

The most important diligence issue is therefore the complete patent family and Orange Book listing, not the expiration date of US 10,465,195 alone.

Key Takeaways

• US 10,465,195 covers modified dsNAs targeting HAO1, including structures associated with lumasiran.
• Claim 1 requires defined strand lengths, chemical modification in both strands, and complementarity to SEQ ID NO: 1823.
• Dependent claims add exact sequence, overhang, blunt-end, phosphorothioate, ribose-modification, duplex-length, and GalNAc limitations.
• Claim 22 is particularly relevant to GalNAc-conjugated liver-directed RNAi products.
• Claims 24-28 cover HAO1 mRNA reduction and treatment of human PH1 through specified administration routes.
• Oxlumo received FDA approval in November 2020, with five-year NCE exclusivity running approximately through November 2025.
• The patent has a nominal term extending to approximately 2034, subject to applicable patent-term adjustments or extensions.
• Generic entry depends on the complete Orange Book-listed estate, Paragraph IV activity, litigation outcomes, and any settlement terms.
• Manufacturing complexity and separate sequence, conjugate, formulation, and process patents may remain barriers even after this patent expires.

FAQs

Is US 10,465,195 a lumasiran composition patent?

Yes. Its claims cover HAO1-directed modified dsNAs, including structural features associated with lumasiran, but the patent claims are written to nucleic-acid characteristics rather than using the product name.

Does the patent require GalNAc conjugation?

No. Claim 1 does not require GalNAc. GalNAc conjugation is added by dependent claim 22, which provides narrower protection for a GalNAc-conjugated embodiment.

Can a different HAO1 siRNA avoid US 10,465,195?

Potentially, if it does not satisfy the claimed complementarity, sequence, length, modification, or other structural limitations. A different sequence may still implicate separate HAO1 or RNAi patent families.

Does the patent cover all treatments for primary hyperoxaluria?

No. The method claims require use of the claimed dsNA to reduce HAO1 mRNA. They do not independently cover unrelated drugs, antisense compounds, small molecules, or other PH1 therapies.

Is patent expiration the same as lumasiran loss of exclusivity?

No. Regulatory exclusivity, patent term, pediatric exclusivity, litigation stays, settlements, and additional listed patents can produce different dates for filing, approval, and commercial generic entry.

References

1. United States Patent and Trademark Office. (2019). US Patent No. 10,465,195, double-stranded nucleic acids for inhibiting HAO1 expression.
2. U.S. Food and Drug Administration. (2020). Oxlumo (lumasiran) prescribing information.
3. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.

Drugs Protected by US Patent 10,465,195

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	10,465,195		Y	Y		TREATMENT OF PRIMARY HYPEROXALURIA TYPE 1 (PH1)

International Family Members for US Patent 10,465,195

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	3581654		LUC00218	Luxembourg
European Patent Office	3581654		PA2021008	Lithuania
European Patent Office	3581654		301132	Netherlands