Details for Patent: 6,451,991

Summary for Patent: 6,451,991

Title:	Sugar-modified gapped oligonucleotides
Abstract:	Oligonucleotides are provided which have increased nuclease resistance, substituent groups for increasing binding affinity to complementary nucleic acid strand, and subsequences of 2'-deoxy-erythro-pentofuranosyl nucleosides that activate RNase H. Such oligonucleotides are useful for diagnostics and other research purposes, for modulating the expression of a protein in organisms, and for the diagnosis, detection and treatment of other conditions susceptible to ooligonucleotide therapeutics.
Inventor(s):	Pierre Martin, Karl-Heinz Altmann, Phillip Dan Cook, Brett P. Monia
Assignee:	Novartis AG , Ionis Pharmaceuticals Inc
Application Number:	US08/802,331
Patent Claim Types: see list of patent claims	Compound;

United States Patent 6,451,991 Scope: What does the oligonucleotide claim cover, and how broad is the phosphodiester/phosphorothioate “mixed-backbone” protection?

US Drug Patent 6,451,991 claims a sequence-defined oligonucleotide that is specifically hybridizable to DNA or RNA and that uses a mixed backbone architecture: adjacent 2′-O–CH2–CH2–O–CH3 (a 2′-O-(2-methoxyethyl) type sugar motif) in one segment and 2′-deoxy sugars in another segment, with the linkages between nucleosides constrained to either phosphodiester and/or phosphorothioate depending on which subsequence is in which region. The core claim scope is driven by three levers: (1) hybridizability/sequence definition, (2) placement of the 2′-O–CH2–CH2–O–CH3 vs 2′-deoxy sugar segments, and (3) which backbone linkage type is assigned to each segment.

On the face of the claims you provided, the patent estate is structured to capture antisense/oligonucleotide constructs that mix (a) 2′-O-(2-methoxyethyl) (2′-MOE) or equivalent 2′ substituents and (b) deoxy gaps, while also specifying segment-level backbone chemistry using phosphorothioate vs phosphodiester. That is a common pattern in next-generation antisense chemistries designed to tune potency, nuclease stability, and binding.

What follows is a claim-by-claim scope dissection, then an impact-oriented landscape view focused on the legal/technical bottlenecks a competitor would face when designing around or asserting non-infringement.

---

What is the claim scope of US Patent 6,451,991 for mixed 2′-O–CH2–CH2–O–CH3 and 2′-deoxy oligonucleotides?

1) Claim 1: the foundational “two-subsequence, mixed linkage” architecture

Claim 1 is an independent claim with these required elements:

1. Oligonucleotide specifically hybridizable with DNA or RNA
   This is sequence-dependent. It implies a defined nucleobase sequence (or at least a sequence that confers specific complementarity to a target DNA/RNA).

2. Linear covalently-bound nucleoside units
   No circular/nucleic-acid analog format.

3. Two subsequences

   • First subsequence: contains adjacent 2′-O–CH2–CH2–O–CH3 sugar moieties
   • Second subsequence: contains adjacent 2′-deoxy sugar moieties

4. Backbone linkage assignment is restricted in one of three alternative ways
   Claim 1 contains three “either/or” linkage regimes:

   • Regime A (all phosphorothioate): nucleoside units in first and second subsequences are phosphorothioate-linked
   • Regime B (mixed): first subsequence phosphodiester, second subsequence phosphorothioate
   • Regime C (mixed): first subsequence phosphorothioate, second subsequence phosphodiester

Implication: Claim 1 does not require any specific length for either subsequence. It only requires that one region is 2′-O–CH2–CH2–O–CH3 adjacent residues and another region is 2′-deoxy adjacent residues, and that the backbone linkage type is allocated to those regions in one of the enumerated combinations.

2) Claims 2–4: specify which linkage regime applies

• Claim 2: both subsequences are phosphorothioate (Regime A).
• Claim 3: first = phosphodiester, second = phosphorothioate (Regime B).
• Claim 4: first = phosphorothioate, second = phosphodiester (Regime C).

Implication: Claims 2–4 are narrower fallback positions that lock the linkage allocation, but they also show the patent drafter anticipated at least two mainstream implementation patterns: thioate-stabilized segments and more “oxygenated” segments depending on which sugar region is present.

3) Claims 5–7: length constraints on the second subsequence and overall oligo

• Claim 5: second subsequence has at least 3 nucleoside units.
• Claim 6: second subsequence has at least 5 nucleoside units.
• Claim 7: overall oligonucleotide has 5 to 50 nucleoside units.

Implication: The main novelty isn’t just length. But the length limits can matter for design-around arguments: a competitor could attempt to use fewer than the claimed minimums, or push outside 5–50 if that is strategically feasible while maintaining function.

---

What is the claim scope of US Patent 6,451,991 for three-subsequence “sandwich” designs (Claim 8)?

Claim 8: first and third MOE-like segments with a deoxy “middle block”

Claim 8 keeps the same key definition points, but changes the required topology:

1. Oligonucleotide specifically hybridizable with DNA or RNA.
2. Three subsequences arranged linearly:
   • First subsequence: adjacent 2′-O–CH2–CH2–O–CH3 sugars
   • Second subsequence: adjacent 2′-deoxy sugars
   • Third subsequence: adjacent 2′-O–CH2–CH2–O–CH3 sugars
3. Second subsequence positioned between first and third subsequences.
4. Backbone linkage types are assigned at the subsequence level:
   • nucleoside units within the first/second/third subsequences are covalently bound by phosphodiester or phosphorothioate linkages (no limitation in Claim 8 on which segments take which linkage types).

Claims 9–11: specify linkage allocation permutations in the sandwich

• Claim 9: first, second, third subsequences all phosphorothioate.
• Claim 10: first and third phosphodiester, second phosphorothioate.
• Claim 11: first and third phosphorothioate, second phosphodiester.

Implication: In Claim 8, linkage assignment could be “any of the two types” but the dependent claims explicitly cover two sandwich embodiments that are typical in medicinal chemistry: a thioated middle (or thioated outer blocks).

Claims 12–14: length of the deoxy middle block and total oligo length

• Claim 12: second subsequence has at least 3 nucleosides.
• Claim 13: second subsequence has at least 5 nucleosides.
• Claim 14: total oligonucleotide has 5 to 50 nucleosides.

Implication: For three-block “sandwich” architectures, the competitive design-around often turns on whether a functional deoxy block can be reduced below the claimed minima while preserving binding and potency.

---

What chemical features are legally “in” US 6,451,991, and what features can fall outside it?

Legally in-scope features (as written)

1. Two or three adjacent blocks of sugars

   • Adjacent residues with 2′-O–CH2–CH2–O–CH3 motif
   • Adjacent residues with 2′-deoxy motif

2. Backbone linkages are limited to phosphodiester and phosphorothioate

   • No allowance, in these claims, for other stereochemical variants or backbone modifications beyond these two linkage categories.

3. Hybridizable with DNA or RNA

   • Requires a sequence-specific property. Generic “binds to nucleic acids” is not the same as “specifically hybridizable.”

4. Total length 5–50 (only for claim 7/14, not in claim 1/8)

   • The base independent claims (1 and 8) do not impose the 5–50 limit.

Common ways to argue out of scope (design-around levers)

These are not legal conclusions, but they identify the mechanical boundaries embedded in the claim language:

• Avoid adjacentness: the claims require subsequences with “adjacent” sugar moieties. Introducing single “break” residues can be used to disrupt the “adjacent” pattern if the competitor’s chemistry is not literally a contiguous block.
• Replace the 2′-O–CH2–CH2–O–CH3 motif: substituting a different 2′-alkoxy (or 2′-substituent) can remove literal identity because the claim recites a specific sugar motif.
• Use different backbone linkage types: if the competitor uses backbone chemistries outside phosphodiester/phosphorothioate (for example, selenides or methylphosphonates), literal infringement risk shifts sharply, but this depends on whether any alternative is covered in the claim set beyond what you provided.
• Change subsequence topology: Claim 8 requires first and third MOE-like blocks with the deoxy block in the middle. A two-block design might avoid Claim 8 if it does not satisfy the required sandwich arrangement, but it could still hit Claim 1.

---

How strong is the patent estate for oligonucleotide “mixed backbone” claims like US 6,451,991?

Strength from claim drafting

• The claims are chemically specific (2′ sugar motif and deoxy adjacency) and backbone-specific (phosphodiester vs phosphorothioate) while still being flexible on sequence length in the independent claims.
• Dependent claims tighten length of the deoxy subsequence and total oligo length, which provides layered protection.

Strength limitation embedded in “specifically hybridizable”

• “Specifically hybridizable” is a functional limitation tethered to sequence complementarity. For infringement, the patent owner typically must tie an accused sequence to a target and show specific hybridization capability. That can create fact issues in litigation for oligos used in multiple targets or with engineered binding regions.

What this suggests for enforcement

• The most straightforward enforcement posture is against accused oligos that match:
  • a two-block (MOE-like followed by deoxy or vice versa) or three-block sandwich format, and
  • a backbone regime that is exactly one of the enumerated phosphodiester/phosphorothioate patterns, and
  • a deoxy block length meeting the dependent claim thresholds (if those are asserted).

---

Which product classes are most likely implicated by US 6,451,991?

Given the sugar and linkage language, the likely covered space is:

• Antisense oligonucleotides (ASOs) and related RNA/DNA-targeting reagents
• Hybridization-based nucleic-acid therapeutics with backbone compositions using phosphorothioate and phosphodiester and with 2′-O-(2-methoxyethyl) style motifs in one segment and 2′-deoxy in another.

The claim language does not read like an siRNA duplex-specific construct. It reads like a single-strand oligonucleotide defined by its sugar blocks and backbone linkage assignments.

---

What design-around strategies are most likely for competitors facing US 6,451,991?

1) Block redesign

• Convert the deoxy segment into a non-deoxy sugar motif (break the “2′-deoxy adjacent” requirement).
• Break adjacency by inserting non-matching residues so the claimed “subsequence comprising adjacent” motif is not satisfied.

2) Topology redesign

• Avoid the three-block sandwich arrangement if targeting Claim 8. Use a different arrangement that still achieves potency but is not literally “first MOE, second deoxy in the middle, third MOE.”

3) Linkage pattern redesign

• Use different backbone linkage distributions so the claimed permutations in Claims 2–4 and 9–11 are not met.
• Use only phosphorothioate or only phosphodiester where claim coverage expects mixed segmentation tied to sugar motifs.

4) Length engineering

• If asserting the dependent claims, reduce the deoxy block length below the minimum (Claims 5–6 and 12–13) or move total length outside 5–50 (Claims 7 and 14). This can be an effective lever when potency can be maintained by altering sequence density rather than length.

---

What patents commonly co-exist in the same “oligonucleotide chemistry” landscape as US 6,451,991?

Without introducing unfounded specific patent numbers (not provided here), the landscape dynamics for this kind of chemistry usually includes:

1. Core nucleoside and backbone composition patents
   • Claims covering 2′-O-alkyl (including 2′-O-(2-methoxyethyl)) motifs and phosphorothioate linkages.
2. Chimera / mixed backbone patents
   • Claims directed to alternating or segmented placement of modified sugars and backbone linkage types.
3. Sequence and method-of-use patents
   • Particular sequences targeting particular genes plus delivery or dosing methods.

In that ecosystem, a patent like 6,451,991 is best read as a chemistry-architecture gate: it can be used to block or license competitors whose constructs match the segmented sugar/backbone pairing.

---

Timeline: when would the patent be expected to expire (US 6,451,991)?

No filing, priority, or prosecution data was provided with the patent number, so an exact expiration cannot be computed from the information in this prompt. Producing a date without record-level inputs would be inaccurate.

---

Key Takeaways

• US 6,451,991 claims sequence-defined oligonucleotides that target DNA or RNA via specific hybridization, with adjacent 2′-O–CH2–CH2–O–CH3 sugar blocks and adjacent 2′-deoxy blocks, and with backbone linkages limited to phosphodiester and/or phosphorothioate by subsequence.
• Claim 1 covers a two-subsequence architecture and three linkage-allocation regimes; Claims 2–4 lock the linkage regimes.
• Claim 8 covers a three-subsequence “sandwich” where the deoxy block is between two 2′-O–CH2–CH2–O–CH3 blocks; Claims 9–11 lock linkage allocations for that sandwich.
• Dependent claims add practical limits: deoxy block length (≥3 or ≥5 nucleosides) and overall length (5–50).
• The main design-around levers are embedded in the claim language: break adjacency, change the 2′-O motif, change backbone linkage types beyond phosphodiester/phosphorothioate, or alter block topology and length so the dependent thresholds are missed.

FAQs

1. Do Claims 1 and 8 require a specific order of subsequences for the sugar motifs?
   Claim 1 requires a first subsequence and a second subsequence but does not state that one must be first in the molecule beyond the term “first” and “second.” Claim 8 expressly requires the second (deoxy) subsequence to be positioned between the first and third subsequences.

2. Is the phosphorothioate/phosphodiester linkage assignment tied to the sugar type or can it be arbitrary?
   In the independent claims, linkage assignment is constrained to specific allocations by subsequence (Claims 1 and 8), and dependent claims further fix permutations.

3. Can an oligonucleotide with only phosphorothioate linkages still fall within Claim 1 or Claim 8?
   Yes. Claim 2 (for Claim 1) and Claim 9 (for Claim 8) expressly cover all-subsequence phosphorothioate linkage patterns.

4. What is the minimum deoxy block length protected by the dependent claims?
   Claims 5 and 12 protect deoxy subsequences with at least 3 nucleosides; Claims 6 and 13 protect deoxy subsequences with at least 5 nucleosides.

5. Does Claim 1 protect oligonucleotides outside the 5 to 50 nucleotide range?
   Claim 7 limits overall length to 5–50, but Claim 1 itself does not include that total-length constraint.

---

References

1. US Patent 6,451,991 (claims provided in prompt).

Drugs Protected by US Patent 6,451,991

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 6,451,991

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	267207
Australia	1955297
Australia	725262
Brazil	9707529