Details for Patent: 11,446,380

Which drugs does patent 11,446,380 protect, and when does it expire?

Patent 11,446,380 protects OXLUMO and is included in one NDA.

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

Summary for Patent: 11,446,380

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 methods of using such RNAi agents to inhibit expression of HAO1 and methods of treating subjects having, e.g., PH1.
Inventor(s):	William Querbes, Kevin Fitzgerald, Brian Bettencourt, Abigail Liebow, David V. Erbe
Assignee:	Alnylam Pharmaceuticals Inc
Application Number:	US16/673,863
Patent Claim Types: see list of patent claims	Composition; Formulation; Compound;

United States Patent 11,446,380: Scope, Claim Coverage, and Patent Landscape for a HAO1-Directed dsRNAi With 2′-OMe/2′-F and GalNAc-L96 Conjugation

What is US 11,446,380 claiming in operational terms?

US Patent 11,446,380 claims a specific double stranded RNA interference (RNAi) agent that inhibits HAO1 expression in a cell. The core protected subject matter is the exact dsRNA sequence(s) and exact chemical modifications that define the sense strand and antisense strand, plus a specific ligand conjugate moiety at the 3′ end in dependent claim scope, and composition formats (buffered and unbuffered solutions).

Independent claim structure

• Claim 1: dsRNAi agent (or salt) with:
  • Sense strand = SEQ ID NO:213: 5′-gsascuuuCfaUfCfCfuggaaauauaL96-3′
  • Antisense strand = SEQ ID NO:330: 5′-usAfsuauUfuCfCfaggaUfgAfaagucscsa-3′
  • Base modifications:
  • a, g, c, u = 2′-O-methyl (2′-OMe) A, G, C, U
  • Af, Gf, Cf, Uf = 2′ fluoro A, G, C, U
  • s = phosphorothioate linkage
  • End group / conjugate on the sense strand:
  • L96 = N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol
• Claim 2: pharmaceutical composition containing the agent of claim 1.
• Claim 3: isolated cell containing the agent of claim 1.

Dependent claim structure that materially narrows/extends scope

• Claim 4: dsRNAi agent similar to claim 1 but with an added structural requirement that a ligand is conjugated to the 3′ end of the sense strand “as shown” (with X = O in schematic). This claim is written around a sense strand ending without the explicit L96 string in the sequence listing, but it still requires the same modification set and phosphorothioate linkage, and it is aligned to the same ligand-conjugation concept.
• Claims 5 and 6: pharmaceutical composition and isolated cell for claim 4.
• Claims 7-9 and 10-11 and 12-16: formulation-dependent coverage for unbuffered aqueous solution and buffered solution, specifying:
  • Unbuffered solution = water (claims 7-9) or saline (claims 9)
  • Buffered solution = buffer selected from acetate, citrate, prolamine, carbonate, phosphate, alone or in combination (claims 11 and 16).

How broad is the protection? (Claim-by-claim coverage map)

The patent’s scope splits into three layers: sequence and chemistry, conjugate architecture, and formulation.

Layer 1: Sequence + nucleotide chemistry (core scope)

Claims 1 and 3 are tight because they require:

1. Exact sense strand sequence (SEQ ID NO:213) including:
   • The exact pattern of 2′-OMe nucleotides (a/g/c/u)
   • The exact positions of 2′-fluoro nucleotides (Af/Gf/Cf/Uf)
   • The exact presence and placement of phosphorothioate linkages (s)
   • The exact 3′ end conjugate/terminus via L96 in the listed sense strand form
2. Exact antisense strand sequence (SEQ ID NO:330) with the same modification vocabulary

Practical infringement boundary:

• A product that changes even one base position, changes a modification class (2′-OMe vs 2′-F), or alters the phosphorothioate pattern would likely fall outside claims 1 and 3, unless it still literally meets the claim’s specific sequence definitions.

Layer 2: Ligand-conjugated 3′ end (adjacent/overlapping scope)

Claims 4-6 add a requirement that a ligand is conjugated to the 3′ end of the sense strand by reference to a schematic.

What this does to scope:

• Claim 4 is positioned to cover dsRNAi agents where the ligand-conjugation is present at the sense strand 3′ terminus, while maintaining the same 2′-OMe/2′-F and phosphorothioate constraints.
• If claim 4 is drafted to capture the same L96-type ligand structure via the “as shown” schematic, then it provides a second claim pathway to catch variants that satisfy the ligand-conjugation architecture even when the sense strand sequence presentation is slightly different in text form.

Layer 3: Formulation and solution environment (narrow but commercially relevant)

Claims 7-16 do not change the active agent; they cover where/how the agent is presented:

• Unbuffered solution:
  • Water (claims 7 and 12)
  • Saline (claims 9 and 13)
• Buffered solution:
  • Buffer composition includes any combination of:
  • acetate
  • citrate
  • prolamine
  • carbonate
  • phosphate
  • (claims 11 and 16)

Practical infringement boundary:

• If a competitor prepares a formulation in these specified aqueous buffers/unbuffered formats, those products are more likely to fall within the pharmaceutical composition claims even if some aspects of the active agent are contested.
• If a competitor uses a different buffer system not listed (or uses non-aqueous formulation not meeting “solution” framing), it may avoid the formulation-dependent claims, but still risk the active-agent independent coverage (claims 1-6).

What exact chemical “knobs” define the protected agent?

From the claim language, the agent is defined by four chemical knobs that competitors must match to land inside the literal claim:

1. 2′-O-methyl modified nucleotides: A/G/C/U represented as a, g, c, u
2. 2′-fluoro modified nucleotides: A/G/C/U represented as Af, Gf, Cf, Uf
3. phosphorothioate linkages: represented as s
4. 3′ end ligand conjugate on sense strand:
   • L96 = N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol
   • Claim 4 further requires the ligand-conjugation at sense 3′ end “as shown.”

These define the “shape” of the chemical entity. Even if a competitor keeps the same general length or targeting premise (HAO1), the modification pattern is typically make-or-break for literal infringement.

Competitive design-around analysis (where freedom-to-operate typically gets decided)

1) Sequence edits (highest-risk design changes)

• Keeping the same HAO1 target does not matter for claims 1 and 4 because the claims are sequence- and modification-specific (SEQ ID NO:213 and SEQ ID NO:330).
• Edits that shift base identity or position will likely remove literal coverage.

2) Modification class swaps (high-risk)

• Swapping 2′-OMe to unmodified ribonucleotides, or to 2′-H or 2′-MOE, changes the chemical definition.
• Swapping 2′-F positions (Af/Gf/Cf/Uf) also removes literal coverage.

3) Backbone changes (high-risk)

• Changing phosphorothioate linkages (“s”) to a different backbone chemistry would likely fall outside the claim language.

4) Ligand conjugate architecture at the 3′ end (high to medium risk depending on how claim 4 maps to L96)

• Claims 1 and 4 both require ligand-conjugation at the sense strand 3′ end, with claim 1 expressly listing L96.
• Design changes can reduce risk if the competitor avoids the exact L96 structure and also avoids satisfying the “ligand conjugated … as shown” constraint in claim 4.

5) Formulation (medium to low risk for avoiding active-agent infringement, high risk for composition claims)

• Moving away from water/saline unbuffered solutions or from the listed buffers may reduce exposure to claims 7-16, but not to the active-agent claims 1-6.

Claim scope summary table (what you can and cannot sell without touching this patent)

Claim	What is protected	Active agent requirements	Composition requirements
1	dsRNAi agent (or salt)	Sense = SEQ ID NO:213 with L96 at 3′ end; antisense = SEQ ID NO:330; a/g/c/u are 2′-OMe; Af/Gf/Cf/Uf are 2′-F; s = phosphorothioate	None
2	Pharmaceutical composition	Contains claim 1 agent	None specified beyond “pharmaceutical composition”
3	Isolated cell	Contains claim 1 agent	None
4	dsRNAi agent (ligand-conjugated sense 3′ end)	Same modification set; ligand conjugated to 3′ end of sense strand “as shown”	None
5	Pharmaceutical composition	Contains claim 4 agent	None specified beyond “pharmaceutical composition”
6	Isolated cell	Contains claim 4 agent	None
7-9	Formulation: unbuffered	Contains claim 2 agent	Unbuffered: water (7-8) and saline (9)
10-11	Formulation: buffered	Contains claim 2 agent	Buffered: acetate/citrate/prolamine/carbonate/phosphate (11)
12-16	Formulation tied to claim 5 agent	Contains claim 5 agent	Unbuffered or buffered with same sets (water/saline; listed buffer species)

Patent landscape context: how US 11,446,380 typically fits

The landscape for HAO1 silencing dsRNAi generally clusters around:

• Sequence-defined dsRNAi constructs
• Chemical modification patterns (2′-OMe and 2′-F)
• Backbone chemistry (phosphorothioate)
• Targeted delivery ligands (GalNAc-based liver-targeting conjugates)
• Formulation buffers (especially aqueous buffer selections)

Within that landscape, US 11,446,380’s position is driven by its high specificity: it does not claim a broad class of “HAO1 siRNA” in general terms; it claims particular named SEQ ID constructs with particular modification patterns and a particular ligand-conjugated sense terminus, plus aqueous formulation subsets.

Enforcement posture implication

Because the claims anchor on:

• specific sense/antisense sequences (SEQ ID NO:213 and SEQ ID NO:330),
• specific chemical modifications (2′-OMe and 2′-F patterns),
• specific ligand construct L96 (claim 1), the patent’s enforceability tends to track exact-match competitors and minor-variant competitors that preserve the claim-defining chemistry.

Freedom-to-operate implication

A typical competitor risk assessment for this kind of claim set:

• Focuses on whether the candidate matches sequence + modification + ligand + backbone literally (claims 1 and 4).
• Separately checks whether the commercial drug product uses a covered aqueous presentation (claims 7-16) if the agent is already covered or likely to be contested under claims 1-6.

Key Takeaways

• US 11,446,380 protects a specific HAO1-directed dsRNAi agent defined by the exact sense strand SEQ ID NO:213 and antisense strand SEQ ID NO:330, with 2′-OMe and 2′-F nucleotide modifications and phosphorothioate linkages.
• Claim 1 is anchored by L96, a tris(GalNAc-alkyl) amidodecanoyl 4-hydroxyprolinol ligand moiety on the sense strand 3′ end.
• Claim 4 reinforces ligand-conjugation at the sense 3′ end via a schematic requirement, creating an alternate pathway to coverage under the same modification regime.
• Claims 7-16 cover aqueous formulation formats using water/saline and buffers from the set acetate, citrate, prolamine, carbonate, phosphate.
• The practical infringement boundary is tight: sequence position changes, modification-class swaps, backbone changes, or ligand architecture changes are the primary levers for design-around.

FAQs

1. Does this patent claim any dsRNAi that inhibits HAO1, regardless of sequence?
   No. The claims require specific sense and antisense sequences by SEQ ID NO definitions and specific nucleotide modification identities at defined positions.

2. What modifications are explicitly required?
   2′-O-methyl for nucleotides labeled a, g, c, u, 2′-fluoro for nucleotides labeled Af, Gf, Cf, Uf, and phosphorothioate linkages labeled s.

3. What role does the GalNAc-based ligand play?
   Claim 1 requires L96 on the sense strand 3′ end. Claim 4 requires that a ligand is conjugated to the sense 3′ end as shown in the schematic.

4. Do the formulation claims broaden the active-agent scope?
   No. They restrict coverage to pharmaceutical compositions where the active agent of the earlier claims is present in water/saline or in buffers from a defined list.

5. Which competitor changes are most likely to avoid these claims?
   Changes to sequence identity/position, switching 2′-OMe vs 2′-F patterns, altering phosphorothioate linkages, and using a different sense 3′ ligand architecture.

References

[1] United States Patent 11,446,380. Claims as provided in the prompt text (claims 1-16).

Drugs Protected by US Patent 11,446,380

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			Y	Y

International Family Members for US Patent 11,446,380

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