Details for Patent: 7,015,315

Summary for Patent: 7,015,315

Title:	Gapped oligonucleotides
Abstract:	Oligonucleotides and other macromolecules are provided which have increased nuclease resistance, substituent groups for increasing binding affinity to complementary strand, and subsequences of 2′-deoxy-erythro-pentofuranosyl nucleotides that activate RNase H. Such oligonucleotides and macromolecules 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 oligonucleotide therapeutics.
Inventor(s):	Phillip Dan Cook, Brett P. Monia
Assignee:	Ionis Pharmaceuticals Inc
Application Number:	US08/465,866
Patent Claim Types: see list of patent claims	Compound;

United States Patent 7,015,315: Scope, Claims, and US Patent Landscape for Chimeric 2′-O-alkyl/2′-deoxy Oligonucleotides with Mixed Phospho(diester)/(thioate) Linkages

US Patent 7,015,315 claims chemically modified oligonucleotides designed for sequence-specific hybridization to single-stranded DNA or RNA using a multipart sugar architecture: (i) 2′-O-alkyl substituted nucleotides (with an alkyl group of at least 2 carbons in several claim sets) and (ii) 2′-deoxy nucleotides; while backbone connectivity is defined using phosphodiester and/or phosphorothioate internucleotide linkages, including mixed patterns across regions.

What the claims cover (core inventive structure)

1) Hybridization function and sequence specificity

All asserted claim groupings are framed as:

• “An oligonucleotide which is specifically hybridizable with single-stranded DNA or RNA” and
• “comprises a sequence of nucleotide units,” with the sequence divided into defined regions.

This restricts scope to sequence-defined probes/antisense-like oligos rather than generic modified nucleic acid polymers.

2) Two- (and three-) region sugar design

The claims repeatedly require:

• First region: nucleotide units with 2′-O-alkyl substitution, where the 2′-O-alkyl group has at least 2 carbon atoms (explicit in independent claims) and in dependent claims includes 2′-O-alkyl-O-alkyl motifs.
• Second region: nucleotide units with 2′-deoxy sugars.
• Optional third region: additional 2′-O-alkyl substituted units, with the second region positioned between first and third.

3) Backbone linkage logic (phosphodiester vs phosphorothioate)

The claim set is organized around whether each region’s internucleotide linkages are:

• phosphodiester (PO) only
• phosphorothioate (PS) only
• mixed across regions, where at least one of the regions is PS-connected.

The most central linkage patterns appearing across the claim set are:

• First region PS-connected + Second region deoxy region PS/PO-connected (varied across claims 1–4 and 28–30).
• For the three-region embodiment: first/third can be linked PO-only or PS-only, while the middle second region can be PS-connected (claims 8–15 and 21–27 and also claim 29).

4) Length constraints

Claims impose length windows in some independent/near-independent sets:

• 5 to 50 nucleotide units (claims 7, 14, 20, 27, 30).

5) Region size thresholds (dependent)

The second region has minimum size limits in multiple dependent claims:

• at least three nucleotide units (claims 5, 12, 18, 25, 26)
• at least five nucleotide units (claims 6, 13, 19, 26)

6) Specific sugar variability

A dependent claim explicitly specifies a more particular sugar substitution:

• at least one nucleotide in first region is a 2′-O-alkyl-O-alkyl nucleotide unit (claim 16; claim 22 repeats the concept for another independent family).

Claim-by-claim scope mapping (what each cluster adds)

Claims 1–7: Two-region oligonucleotide with mixed backbone at least one PS linkage

Claim 1 is the broadest two-region independent claim as provided:

• First region: 2′-O-alkyl, alkyl has ≥2 carbons
• Second region: 2′-deoxy
• At least one region includes nucleotide units connected by phosphorothioate linkages.
• No explicit fixed rule for PO vs PS within a region in claim 1 (it says PS linkages exist in at least one of the first/second regions).

Claim 2 narrows by requiring PS linkages between nucleotide units in both regions.

Claims 3 and 4 provide the two mixed PO/PS configurations:

• Claim 3: First region PO; Second region PS
• Claim 4: First region PS; Second region PO

Claims 5–6 add size requirements for the second region:

• at least 3, at least 5 nucleotide units

Claim 7 adds overall oligo length:

• 5 to 50 nucleotides

Business relevance: This cluster targets compositions where the deoxy block is PS-linked and/or the 2′-O-alkyl block is PS-linked, with the minimum deoxy block size and overall length acting as fallback narrowing points.

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Claims 8–16: Three-region oligonucleotide with central deoxy block and defined PS linkage arrangement options

Claim 8 introduces a third region:

• First region: 2′-O-alkyl
• Second region (between): 2′-deoxy
• Third region: 2′-O-alkyl
• Total length: optional (claim 14) but at least structural layout is fixed.

Claim 9 adds backbone uniformity across all regions:

• first, second, third are connected by PS linkages

Claims 10 and 11 add mixed PO/PS patterns:

• Claim 10: first and third PO; second PS
• Claim 11: first and third PS; second PO

Claims 12–13 add minimum deoxy block size (≥3 and ≥5).

Claim 14 adds overall length (5–50).

Claim 15 offers an alternative linkage pattern:

• first region PO; second and third PS

Claim 16 adds substitution detail:

• at least one 2′-O-alkyl unit in first region is 2′-O-alkyl-O-alkyl

Business relevance: The three-region family is designed to capture common “flanking modifications” patterns around a deoxy core, with multiple fallback claim paths based on where PS resides.

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Claims 17–22: Two-region configuration where linkage types are fixed: first region PO, second region PS

Claim 17 is an independent claim that tightens linkage rules relative to claim 1:

• First region: 2′-O-alkyl
• Second region: 2′-deoxy
• First region connected only by phosphodiester linkages
• Second region connected only by phosphorothioate linkages

Claims 18–20 add size/length fallback:

• second region at least 3; at least 5; overall 5–50.

Claim 21 adds the three-region variant with the same central deoxy PS requirement logic:

• second (middle) region PS
• first and third 2′-O-alkyl blocks with unspecified PO/PS in claim 21, but dependent claims define PS/PO variations.

Claim 22 repeats the 2′-O-alkyl-O-alkyl dependent substitution in a three-region context.

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Claims 23–30: Linkage-pattern permutations and independent broadening around PS presence

Claims 23–24 specify the third region linkage type in the three-region family:

• Claim 23: third region connected by PS
• Claim 24: third region connected by PO

Claims 25–27 add second region size and overall length:

• second region ≥3, ≥5; overall 5–50.

Claim 28 is a structured independent claim with constrained linkage logic:

• First region 2′-O-alkyl (≥2 carbons)
• Second region 2′-deoxy
• PS exists in at least one of the first/second regions
• In addition, the first region is connected either only by PO or only by PS.

This claim is important because it constrains the internal linkage homogeneity within the first region, while still allowing PS in at least one region.

Claim 29 is an independent three-region claim:

• First and third regions: 2′-O-alkyl
• Second (middle): 2′-deoxy positioned between
• PS exists in at least one of first/second regions
• First and third regions’ internucleotide linkages are each either PO-only or PS-only (claim wording allows either only PO or only PS for “first region or third region,” while second-region PS presence is required).

Claim 30 is a tight two-region linkage configuration:

• First region PO-only
• Second region PS-only

Business relevance: Claims 28–30 function as additional entry points that may be easier for a design-around party to argue non-infringement based on linkage homogeneity and PS placement.

Practical infringement map (design space and likely boundary conditions)

High-probability “read” zones (within the literal claim language you provided)

An oligonucleotide is very likely to fall within the provided claim set if it satisfies these three conditions:

1. Sequence-specific binding to ssDNA or ssRNA
2. Region architecture: at least one defined segment uses 2′-O-alkyl (alkyl ≥2 carbons) and at least one defined segment uses 2′-deoxy
3. Backbone linkages: PS linkages occur in at least one required region, with certain claims requiring PO-only in a region and PS-only in another

Most common boundary levers

The claim set offers clear non-infringement levers:

• 2′-O-alkyl alkyl size: if the 2′-O-alkyl group does not meet “at least 2 carbon atoms” (where explicitly required), coverage narrows.
• Region definition: if the oligo is not cleanly divided into the claimed first/second (or first/second/third) regions.
• PS placement: several claims fix PS to the deoxy block and PO to the 2′-O-alkyl block (claims 17 and 30; and claim 10/15 style patterns).
• PS within regions: some independent claims allow PS to exist in at least one of the regions; others require PS-only connectivity for a region.

Why the “mixed PO/PS” structure matters competitively

The claims do not just cover “PS backbones” generally. They require PS/PO patterns mapped onto sugar-defined regions (2′-O-alkyl vs 2′-deoxy). That mapping is the scope-limiting feature that differentiates this patent from broader “PS-containing oligonucleotides” disclosures.

Patent landscape implications in the US (what this patent likely blocks or tolerates)

Landscape shape: “composition of modified nucleotides” with backbone-pattern claims

The structure of the claims indicates this patent sits in a crowded chemical space where competitor products often differentiate by:

• choice of 2′-O modification type (alkyl length, branching)
• whether PS is used at all
• whether PS is used uniformly or only in a subset of linkages
• whether PS is localized to the deoxy region versus distributed

Because this patent localizes PS to region(s) with specific sugar moieties, it is positioned to block a class of chimeric designs that use PS to tune stability while changing binding chemistry with 2′-O substituents.

Competitive design strategies that typically attempt to exit claim scope

Given the claim language provided, the most direct avoidance strategies in a US freedom-to-operate context are:

• Move to designs where PS linkages do not occur in the required region(s) and/or are not assigned to the sugar-defined region in the claimed way.
• Keep 2′-O substitution but change the substituent such that the claim’s “2′-O-alkyl substituent has at least 2 carbon atoms” requirement is not met in the relevant claims.
• Use PO-only backbones throughout or PS-only backbones throughout, then structure region definitions to avoid matching the specific PO/PS combinations that the claims lock in (claims 17, 30 for example).
• Change regional segmentation so that no “first region” and “second region” satisfy the defined sugar/moiety and linkage constraints concurrently.

Practical enforcement likely targets

If asserted, the patent’s claims (as provided) are well-suited to:

• enforcement against specific lead compounds used in antisense, siRNA-like hybrids, or hybridizable probes where the chemistry follows region-based PS localization; and
• enforcement where competitor compositions deliberately maintain PS in the deoxy block and use 2′-O-alkyl flanks.

Business-read takeaway on claim strength from the provided set

From the claim language alone, the patent is built with multiple layers:

• Structural independents: claims 1, 8, 17, 28, 29, 30 (as provided).
• Fallback dependents: multiple PS/PO permutations across regions, with length and minimum deoxy block size constraints.
• Substitution specificity: dependent claim on 2′-O-alkyl-O-alkyl.

This means the patent can maintain infringement leverage even if an accused product attempts to vary PS placement by region, as long as it lands within one of the enumerated backbone permutations.

Key Takeaways

• US 7,015,315 claims region-defined chimeric oligonucleotides that hybridize to ssDNA/ssRNA using 2′-O-alkyl (≥2 carbons) and 2′-deoxy nucleotide blocks.
• The scope is not “PS in general”; it is PS/PO linkage patterns mapped onto the 2′-O-alkyl vs 2′-deoxy regions.
• Independent claim entry points include:
  • PS present in at least one of the first/second regions (claim 1, plus related permutations),
  • a fixed PO-first/PS-second architecture (claims 17 and 30), and
  • a three-region flanking structure with PS/PO permutations (claims 8, 21, 29).
• Key non-infringement levers are PS placement (region-based), PO/PS linkage homogeneity requirements, and the “2′-O-alkyl ≥2 carbon atoms” constraint where explicitly required.

FAQs

1) Does the patent require that every linkage be phosphorothioate?

No. Some claims require PS in all regions (for example claim 9), but others require only that PS exists in at least one defined region (claim 1) or fix PO in one region and PS only in another (claims 17 and 30).

2) What is the minimum oligonucleotide length covered?

The claims provided that set length explicitly cover oligonucleotides with 5 to 50 nucleotide units (claims 7, 14, 20, 27, and 30).

3) Is the deoxy region required to be a minimum size?

Yes for multiple dependent claims: the second region must have at least three nucleotides (claims 5, 12, 18, 25) or at least five nucleotides (claims 6, 13, 19, 26), depending on the claim.

4) Can the oligonucleotide have a third region?

Yes. The three-region architecture is recited in claims such as 8, 21, and 29, with the second region positioned between the first and third regions.

5) What does “2′-O-alkyl-O-alkyl nucleotide unit” add?

It narrows a dependent claim (claims 16 and 22) by specifying that at least one first-region nucleotide uses a more particular 2′-O-alkyl-O-alkyl substitution pattern, beyond generic “2′-O-alkyl.”

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References

[1] United States Patent 7,015,315 (claims provided in user prompt).

Drugs Protected by US Patent 7,015,315

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 7,015,315

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	154947
Austria	159025
Austria	160353
Austria	168561
Austria	186072
Austria	187771