Details for Patent: 9,181,549

Which drugs does patent 9,181,549 protect, and when does it expire?

Patent 9,181,549 protects DAWNZERA (AUTOINJECTOR), TRYNGOLZA (AUTOINJECTOR), WAINUA, and WAINUA (AUTOINJECTOR), and is included in three NDAs.

This patent has two hundred and sixty-one patent family members in forty countries.

Summary for Patent: 9,181,549

Title:	Conjugated antisense compounds and their use
Abstract:	Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.
Inventor(s):	Thazha P. Prakash, Punit P. Seth, Eric E. Swayze
Assignee:	Ionis Pharmaceuticals Inc
Application Number:	US14/586,751
Patent Claim Types: see list of patent claims	Compound;

United States Patent 9,181,549 (US9181549): Scope, Claim Construction, and Oligonucleotide Gapmer Patent Landscape

US 9,181,549 is a US patent directed to conjugated oligonucleotide therapeutics built around modified oligonucleotides (gapmers) that promote RNase H activity upon hybridization to complementary nucleic acids. The independent claim structure is broad at the “conjugate linker + cleavable moiety + oligomeric compound” level, then narrows through a sequence of dependent claims toward specific design choices: modified nucleosides, gapmer composition (flanking modified arms with a central unmodified DNA-like core), internucleoside linkage patterns (phosphorothioate and phosphodiester), and sugar chemistry (2′-MOE, 2′-OMe, 2′-F, bicyclic 4′ substituents, morpholino). The later claim set also recasts the same theme in alternative formula language (“X is O or S”), covering additional classes of nucleoside/heterobase-containing constructs intended to capture RNase H activating gapmers.

Business impact: the patent is structurally positioned to cover (1) gapmer oligonucleotide payloads and (2) conjugate-linker architectures where the oligonucleotide is joined to the rest of the molecule via a linker that includes a cleavable moiety. This combination is often the key IP boundary exploited in licensing and Paragraph IV generic or biosimilar-style challenges for oligonucleotide conjugates: if a competitor changes the oligo “payload” design but retains a functionally similar RNase H gapmer and linker cleavage scheme, the patent can still read on the new design; if a competitor breaks the claim’s specific gapmer motif (especially “unmodified deoxynucleosides at the central region” plus modified flanks), it can materially reduce infringement risk.

---

What claims does US 9,181,549 cover in oligonucleotide gapmer therapeutics?

Independent claim themes

From the claim text provided, US 9,181,549 has at least two independent claim groupings (with multiple dependent refinements):

1. Conjugated compound defined by formula (XXVI)

   • Claim 1: “A compound having the formula (XXVI)” with T2 comprising:
     • a conjugate linker
     • a cleavable moiety
     • an oligomeric compound (the “payload”)
   • Claims 2-16 progressively constrain:
     • linker chemistry categories (amine, amide, ester, ether, pyrrolidine, ethylene glycol/polyamide, disulfide bond)
     • specific linker sub-formulas (claims 3-5)
     • payload as a modified oligonucleotide (claims 6-10)
     • payload sequence architecture: gapmer motif (claims 9, 11-13)
     • nucleic acid targets and single-stranded complementarity (claims 14-16)

2. Alternative compound formula sets using X = O or S

   • Claim 17: compound with formula where X is O or S, Bx is a heterocyclic base moiety, and T4 is a nucleoside/monomer/oligomer.
   • Claims 19-23: T4 is modified oligonucleotide, specifically a gapmer that activates RNase H when bound to a complementary nucleic acid; modified nucleosides include specific 2′ chemistries.
   • Claims 24-30 appear to be a second, parallel formula set with identical functional limitations (gapmer + RNase H activation) under the X/Bx/T4 framework, again specifying 2′-substitution chemotypes.

Functional claim anchor: RNase H activation

Across the gapmer-dependent ladder (claims 15-16, 20-22, 27-30), the claim’s functional core is:

• single-stranded gapmer oligonucleotides
• complementary to target nucleic acids
• activate RNase H when hybridized

In oligonucleotide patent practice, “RNase H activation when bound to a complementary target nucleic acid” tends to be treated as a functional property of the structure. For infringement, plaintiffs typically argue that the claimed structural features (gapmer composition and chemistry) inherently confer the RNase H-typical mechanism.

Payload and linker are both claim-critical

The claim set is not limited to the oligo alone. Claim 1 explicitly requires:

• a conjugate linker
• a cleavable moiety
• and an oligomeric compound

So a design that uses a claimed gapmer but lacks the required conjugate-linker-cleavage architecture may fall outside Claim 1 and its dependent scope, depending on how later claims are drafted with respect to “attachment” and “remainder of the compound.”

---

How broad is the claim scope on the conjugate linker and cleavable moiety?

What linker chemistries are explicitly included (Claim 2)

Claim 2 lists linker components that can include:

• amine
• amide
• ester
• ether
• pyrrolidine
• ethylene glycol
• polyamide
• disulfide bond

This is a deliberately broad set: it covers common conjugation platforms used in oligonucleotide prodrug or delivery constructs (carbamates, esters, PEG-like spacers, disulfide-cleavable linkers).

Where the claim narrows (Claims 3-5)

Claims 3-5 introduce specific conjugate linker formulas and specific structures for:

• T2 with CM as the cleavable moiety and T3 as the oligomeric compound
• then further constraining T2’s full formula

Even without the rendered formula text, the dependency chain matters:

• Claim 1 is broad to “conjugate linker + cleavable moiety + oligomeric compound.”
• Claim 2 expands the general category of linkers.
• Claims 3-5 narrow to specific “has the formula” language. That means a non-formula-matching linker may still infringe Claim 1 but not Claims 3-5.

Practical infringement consequence

• If a competitor uses a gapmer with similar 2′-chemistry and gapmer architecture but uses a radically different linkage system (no cleavable moiety, non-conjugate delivery, or cleavage mechanism not captured), they may preserve a non-infringement argument against Claim 1’s “conjugate linker + cleavable moiety” requirement.
• If a competitor uses a cleavage-linker platform in the included chemical categories, the linker limitation may be harder to avoid.

---

What gapmer oligonucleotide structure is protected under US 9,181,549?

Gapmer definition in the claims (Claim 9)

Claim 9 defines a gapmer sugar motif with three regions:

• 5′-region:
  • 2 to 8 linked nucleosides
  • each is a modified nucleoside
• central region:
  • 5 to 10 linked nucleosides
  • each is independently a modified nucleoside or an unmodified deoxynucleoside
  • but with explicit edge conditions:
    • 5′-most central nucleoside is an unmodified deoxynucleoside
    • 3′-most central nucleoside is an unmodified deoxynucleoside
• 3′-region:
  • 2 to 8 linked nucleosides
  • each is a modified nucleoside

This is a classic functional gapmer architecture: protected flanks and an RNase H “activation” prone central DNA-like window.

Length and narrowing options (Claims 11-12)

Claim 11 constrains the region lengths tighter:

• 5′-region: 2 to 5 nucleosides
• 3′-region: 2 to 5 nucleosides
• central region: 8 to 10 nucleosides

Claim 12 limits internucleoside linkages:

• each linkage is either phosphorothioate or phosphodiester

This matters because oligo “backbone” chemistry is often a design-around lever.

Attachment position (Claim 13)

Claim 13 requires the modified oligonucleotide is attached at the 5′-end of the remainder of the compound.

If a competitor attaches at the 3′-end, or uses end-capping that changes effective attachment, it can affect claim match.

Single-stranded complementarity (Claims 14-15)

• Claim 14: single-stranded
• Claim 15: complementary to target nucleic acid

Target nucleic acid types (Claim 16)

Target category includes:

• mRNA
• pre-mRNA
• micro-RNA
• long non-coding RNA

This expands therapeutic targeting beyond mRNA reduction alone, into miRNA modulation and non-coding RNAs.

---

Which nucleoside modifications and internucleoside linkages are included?

Included modified nucleosides (Claim 8)

Claim 8 includes at least one modified nucleoside selected from:

• 2′-MOE
• 2′-OMe
• 2′-F
• (4′-CH2—O-2′) bicyclic nucleoside
• (4′-(CH2)2-O-2′) bicyclic nucleoside
• (4′-C(CH3)H—O-2′) bicyclic nucleoside
• morpholino

This is a broad sweep of common antisense chemistries: MOE, 2′-methoxy, 2′-fluoro, bicyclic locked nucleic acid-like scaffolds, and morpholinos.

Included modified nucleosides for RNase H gapmers (Claims 22 and 29)

Later RNase H gapmer claims specify:

• 2′-F
• 2′-OCH3
• 2′-O(CH2)2OCH3
• 2′-OC(CH3)H-4′
• 2′-OCH2-4′

and then a further narrowed embodiment (Claims 23, 30):

• modified nucleoside is 2′-O(CH2)2OCH3

This suggests the later claim family is focused on particular 2′-substitution patterns, potentially a narrower sub-class than Claim 8’s full list.

Backbone linkage pattern constraints (Claim 10)

Claim 10 provides a detailed chemical motif using notation:

• M = modified nucleoside
• D = deoxynucleoside
• s = phosphorothioate internucleoside linkage
• y = phosphodiester or phosphorothioate linkage, with the requirement:
  • at least one y is a phosphodiester internucleoside linkage

This is a common technique: allow a range of backbone substitutions but force the presence of at least one phosphodiester linkage. A competitor aiming to avoid might push to all phosphorothioate (if chemically feasible for similar activity), or remove the pattern matching the enumerated motif classes.

---

What do the claim sub-formulas imply about “cleavable moiety” handling?

Key claim constructs: T2 includes both linker and cleavable moiety

Claim 1’s structure depends on:

• T2 includes a conjugate linker AND a cleavable moiety AND an oligomeric compound
• Claim 4-5 define T2 as:
  • CM = cleavable moiety
  • T3 = oligomeric compound

For infringement mapping, the key question is whether the competitor’s design can be construed so that:

• the oligomer is within the same “T2” structural definition,
• the linker includes a cleavable portion,
• and the remainder of the molecule is attached in the required manner.

A non-cleavable conjugate, or one where cleavage is decoupled from the linker segment connecting to the oligo, can be a pathway to avoid Claim 1’s literal read.

---

How strong is US 9,181,549 likely as a patent estate claim against oligonucleotide conjugate gapmers?

Claim strength drivers

1. Breadth on linker functional categories (amine/amide/ester/ether/PEG/polyamide/disulfide).
2. Breadth on modified nucleosides in at least one family (Claim 8).
3. Functional requirement tied to known mechanism (RNase H activation).
4. Specific “gapmer motif” architecture (modified flanks + central DNA-like window with unmodified deoxynucleosides at the ends of central region).
5. Backbone linkage constraint includes both phosphorothioate and phosphodiester with at least one phosphodiester required in the motif claim (Claim 10).
6. Attachment location at 5′ end (Claim 13) adds design specificity.

Claim weaknesses / design-around pressure points

1. Central region constraint includes edge deoxynucleosides:
   if a competitor uses a central region that does not place unmodified deoxynucleosides at both central edges, it can avoid key elements.
2. Phosphodiester requirement:
   if competitors use only phosphorothioate linkages (or otherwise structure so “at least one y is phosphodiester” cannot be met), they can target Claim 10-type motif narrowing.
3. 5′-attachment constraint:
   if conjugation uses 3′ attachment or internal attachment, dependent Claim 13 may be harder to satisfy.
4. Cleavable moiety inclusion:
   if a competitor uses a stable non-cleavable conjugate, the broad Claim 1 could be harder to reach.

---

What competing oligonucleotide designs are most likely to land inside versus outside the claim boundaries?

Most likely in-scope designs (higher risk)

• Single-stranded gapmer oligonucleotides with:
  • modified nucleosides in flanks (2′-MOE / 2′-OMe / 2′-F / bicyclic / morpholino)
  • central region containing unmodified deoxynucleosides at the central edges
• Backbone including phosphorothioate with at least one phosphodiester (for motifs captured by Claim 10)
• Conjugates where:
  • linker includes a cleavable moiety (CM)
  • the oligo attaches at the 5′-end (to hit dependent claims)
  • the compound design uses the common cleavable chemistries broadly enumerated in Claim 2

Most likely out-of-scope designs (lower risk)

• Gapmers that eliminate the central-region edge “unmodified deoxynucleoside” condition.
• Oligonucleotides with backbone designed to avoid “at least one phosphodiester linkage” in the specific motif family.
• Conjugates without a cleavable moiety in the conjugate linker segment.
• Conjugates attaching the oligo not at the 5′-end (for designs specifically attempting to avoid the 5′-attachment dependent limitations).
• Oligomers that are not “modified oligonucleotides” as the claims frame them (though many antisense payloads are inherently modified, so this lever is often limited).

---

How does US 9,181,549 compare to typical RNase H antisense gapmer patent families?

US 9,181,549 aligns with the common antisense IP architecture:

• payload structure claims for gapmer motifs
• mechanistic limitation (“RNase H activation”)
• backbone/linkage control via phosphodiester/phosphorothioate mixture
• nucleoside chemistry lists to cover a spectrum of sugar modifications
• additional framing by alternative formula sets (X = O or S; base moiety Bx; T4 as nucleoside or oligomer) to capture structural equivalents

The inclusion of both:

• a conjugate-linker cleavable-moiety framework (Claim 1), and
• an RNase H gapmer framework (Claims 19-23 and 27-30) creates a patent that is better positioned to attack oligonucleotide prodrug and conjugate designs, not just free oligo oligonucleotides.

---

Where is US 9,181,549 likely used in litigation strategy for oligonucleotide programs?

Most probable infringement theories

• Literal infringement on gapmer architecture and RNase H functional limitation paired with structural conjugate/linker requirements.
• Product-by-process style infringement mapping is less likely to be central because claim limitations are structural (gapmer composition, linker inclusion, backbone linkages) rather than manufacturing steps.
• Doctrine of equivalents arguments likely target:
  • alternative cleavable moiety chemistries falling outside the enumerated linker list,
  • minor sugar substitutions still functionally equivalent to those listed,
  • different but equivalent phosphodiester/phosphorothioate placement.

Most probable defenses

• Argue claim non-fulfillment for one of the structural core limitations:
  • central region edge deoxynucleoside condition,
  • presence of phosphodiester linkage in the motif family,
  • absence of cleavable moiety,
  • attachment at non-5′ location,
  • non-gapmer or non-RNase H activating design.

---

Key Takeaways

• US 9,181,549 protects conjugated oligonucleotide therapeutics where the oligomeric payload is a modified gapmer tied to a cleavable conjugate linker.
• Core payload protection is driven by a gapmer motif: modified nucleosides on both flanks, and a central region that must place unmodified deoxynucleosides at the central edges.
• Backbone and chemistry control is explicit: the claims include specific modified nucleoside lists and require for at least some motifs phosphorothioate/linkage patterns with at least one phosphodiester.
• Design-around pressure points are concrete: remove the cleavable linker, eliminate the central edge deoxynucleoside condition, avoid the phosphodiester requirement in motif claims, or alter attachment position away from the claimed configuration.
• The claim set is structured to cover both free gapmer-like payloads (in the later formula family) and conjugate constructs (in the Claim 1 family), improving enforcement leverage.

---

FAQs

1. What structural element in US 9,181,549 most directly defines the RNase H gapmer?
   The three-region “gapmer sugar motif” (modified 5′ flank, central region with deoxynucleoside at the central edges, modified 3′ flank) plus the RNase H activation requirement.

2. Does US 9,181,549 require phosphodiester linkages?
   Yes in Claim 10’s motif family: at least one “y” must be a phosphodiester rather than only phosphorothioate.

3. Can a competitor avoid the patent by using only phosphorothioate backbones?
   That is a direct design lever against the motif language that requires at least one phosphodiester linkage.

4. Is the 5′ attachment of the oligonucleotide mandatory across all claims?
   It is mandatory for the dependent chain that includes Claim 13; earlier independent scope is broader but still depends on the conjugate-linker-oligomer architecture.

5. What modification classes are explicitly captured for the flanking nucleosides?
   The claims list multiple 2′-modified chemotypes including 2′-MOE, 2′-OMe, 2′-F, bicyclic nucleosides, and morpholino, with later RNase H-specific claims listing a narrower set of 2′ substitutions.

---

References

1. United States Patent No. 9,181,549.

Drugs Protected by US Patent 9,181,549

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Ionis Pharms Inc	DAWNZERA (AUTOINJECTOR)	donidalorsen sodium	SOLUTION;SUBCUTANEOUS	219407-001	Aug 21, 2025		RX	Yes	Yes				Y
Ionis Pharms Inc	TRYNGOLZA (AUTOINJECTOR)	olezarsen sodium	SOLUTION;SUBCUTANEOUS	218614-001	Dec 19, 2024		RX	Yes	Yes				Y
Astrazeneca Ab	WAINUA	eplontersen sodium	SOLUTION;SUBCUTANEOUS	217388-002	Apr 15, 2026		RX	Yes	Yes				Y

International Family Members for US Patent 9,181,549

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	3524680		CA 2025 00027	Denmark
European Patent Office	3524680		C20250028	Finland
European Patent Office	3524680		301341	Netherlands