| Abstract: | Novel compounds are provided that comprise esters of antiviral phosphonomethoxy nucleotide analogs with carbonates and/or carbamates having the structure --OC(R2)2 OC(O)X(R)a, wherein R2 independently is H, C1 -C12 alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro or OR3 in which R3 is C1 -C12 alkyl; X is N or O; R is independently H, C1 -C12 alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro, --O--, --N═, --NR4 --, --N(R4)2 -- or OR3, R4 independently is --H or C1 -C8 alkyl, provided that at least one R is not H; and a is 1 or 2, with the proviso that when a is 2 and X is N, (a) two R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, or (b) one R additionally can be OR3. The compounds are useful as intermediates for the preparation of antiviral compounds or oligonucleotides, or are useful for administration directly to patients for antiviral therapy or prophylaxis. Embodiments are particularly useful when administered orally. |
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Patent landscape, scope, and claims: |
United States Patent 5,922,695 (5,922,695) Scope, Claims Construction, and US Patent Landscape for Phosphonomethoxy Nucleotide Analog Antivirals
US Patent 5,922,695 claims a family of antiviral phosphonomethoxy nucleotide analog compounds and an integrated US IP set that covers: (i) broad chemical composition claims with variable stereochemistry and leaving-group-derived substituents, (ii) specific base identity within a nucleobase scaffold (purine and cytosine variants, including “aza” analogs), (iii) salt/hydrate/tautomer/solvate forms, (iv) oral therapeutic use, and (v) manufacturing routes based on esterification/derivatization reactions with nucleoside-like “L–CH(R2)O–C(O)X(R)n” fragments, including process constraints (equivalents, temperature, time) and downstream salt formation.
Because only the claim text was provided, this analysis focuses strictly on claim scope, likely claim construction outcomes (as they affect enforceability and design-around), and the practical US patent landscape implied by the claim categories in 5,922,695. No additional dataset (Orange Book listings, prosecution history, related-family patents, litigation dockets, or assignment records) is included here.
What compounds are covered by US Patent 5,922,695?
Core scope: “A compound having formula (1a)” with Z substituent(s) that incorporate an ester/amidate/acyloxy-amidate-like linkage to a residue “A” that is “the residue of an antiviral phosphonomethoxy nucleotide analog,” plus defined variable groups for X (N or O) and substituents R2 and R with binding constraints on a and linkage geometry.
Claim 1 structural elements that drive breadth
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Base “A” is fixed by function, not by a single literal formula
- “A is the residue of an antiviral phosphonomethoxy nucleotide analog.”
- This anchors the molecule to a specific antiviral pharmacophore class (phosphonomethoxy nucleotide analog residue), but the claim uses “residue” language, which often enlarges scope to derivatives where the nucleotide core is preserved while the substituent architecture around it varies.
-
Z is the main tunable variable
- Z is independently selected from:
- –OC(R2)2 OC(O)X(R)a
- an ester
- an amidate
- or –H
- At least one Z must be –OC(R2)2 OC(O)X(R)a.
- This means the claim includes multi-Z variants where some Z positions are hydrogen and at least one is the “OC(R2)2 OC(O)X(R)a” moiety, plus other acyl/amide forms via “ester” and “amidate” inclusions.
-
X and a define a nitrile/heteroatom-mediated branching option
- X is N or O
- a is 1 when X is O, or 1 or 2 when X is N.
- For X = N and a = 2, the claim includes special provisions:
- (a) two N-linked R groups together can form a carbocycle or oxygen-containing heterocycle
- (b) one N-linked R can additionally be –OR3
- (c) both N-linked R groups can be –H
- These provisions are important because they reduce the risk that the claim excludes intramolecular cyclization or linked R-group configurations.
-
R2 and R are broad substituent families
- R2: H, C1–C12 alkyl, C5–C12 aryl, C2–C12 alkenyl, C2–C12 alkynyl, C7–C12 alkenylaryl, C7–C12 alkynylaryl, or C6–C12 alkaryl; each can be unsubstituted or substituted with halo, cyano, azido, nitro, or –OR3.
- R: similar range, but with explicit inclusion of substitution with halo, cyano, azido, nitro, or –N(R4)2, and at least one R not equal to H.
-
Salts/hydrates/tautomers/solvates are explicitly included
- This is typical for maintaining infringement coverage even if the solid form differs.
Key implication for enforceability
Claim 1 is not limited to a single prodrug pattern. It is broad across:
- multiple Z states (H, ester, amidate, or the “OC(R2)2 …” moiety),
- either X = O (a single linkage) or X = N (including bifunctional possibilities with a = 2),
- wide freedom in R2 and R substitution patterns including cyclic or heterocycle formation under the defined N-linked constraints.
That breadth raises the bar for a clean design-around. A design-around must likely change at least one of: the phosphonomethoxy nucleotide residue “A” identity, the presence/positioning of the Z “at least one” constraint, or the X/a/R linkage rules.
Which nucleobases are specified in dependent claim 2?
Claim 2 narrows Claim 1’s “A residue” content by specifying the nucleobase letter “B.” It lists:
- B = guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl
- plus “1-deaza, 3-deaza, or 8-aza” analogs of those purines
- or cytosin-1-yl.
Implication: Claim 2 covers the same prodrug/derivative families as Claim 1 but restricts to a defined set of purine/cytosine-like bases (including aza-variants). If a candidate competitor changes base identity outside this enumeration (eg different nucleobase or other heterocycles not encompassed), it may avoid Claim 2 but still fall within Claim 1 if “A residue” remains consistent.
Does US 5,922,695 cover stereoisomers and enantiopurity?
Yes. Dependent claims 11–12 and 24 address enriched/resolved stereochemistry.
- Claim 11: enriched or resolved at the carbon atom chiral center linked to R1.
- Claim 12: at least about 90% in the (R) configuration at R1.
- Claim 24: at least about 90% in the (S) configuration at R1.
Implication for product form: If the commercial candidate uses a specific enantiomer or substantially enantiopure mixture, it may still be captured by the stereochemical dependent claims even if the generic chemical scaffold variants are designed to match other elements.
Design-around pressure point: A competitor could attempt to use an opposite configuration outside the claimed enrichment threshold, but the presence of Claim 1’s broad chemical formula language means “no stereochemical limitation” likely still covers some portion unless Claim 1 is construed as encompassing racemate and/or all stereochemistry. In practice, the dependent enrichment claims indicate that stereochemistry is material to at least some embodiments.
What formulation-like embodiments are protected (salts, prodrugs, solvate)?
The claims explicitly include:
- salts
- hydrates
- tautomers
- solvates
Claim 1 also covers substituent states for Z that include ester and amidate categories, which are commonly prodrug-masking groups.
Implication: Even if a competitor changes the exact ester/derivative type while keeping the core formula satisfying Z requirements, it may still land inside literal scope. If they change to a non-ester/non-amidate prodrug linkage not encompassed in Z definition, they reduce literal risk.
What methods of treatment does US 5,922,695 claim?
Claim 25: A method comprising orally administering a therapeutically effective amount of a compound of claim 1 to a patient infected with virus or at risk of viral infection.
Implication for regulatory and infringement strategy:
- Orally administered prodrug forms are explicitly within scope.
- Treatment is viral infection broadly, which is wider than a single virus indication and can complicate non-infringement positions based on indication selection.
What manufacturing processes are claimed (composition + process constraints)?
US 5,922,695 includes a manufacturing “method for preparing” track that is detailed enough to create multiple infringement hooks even if a competitor sources intermediates differently.
Route in claim 26
Claim 26: React the diacid of a phosphonomethoxy nucleotide analog with:
- L–CH(R2)OC(O)X(R)n
where L is a leaving group, to form a compound of formula (1a).
Implied chemistry: This is consistent with derivatizing a diacid with a substituted amino- or oxy-alkyl carbonyloxymethyl fragment depending on X (N or O) and the n (a/R mapping).
Alternative route in claim 27
Claim 27: React a compound of formula (6) with:
- L–CHR2–O–C(O)–OR
and recover compound of formula (1), with B restricted as in claim 2 and with R/R1/R2/R8 defined.
Process parameters in claims 28–29
- Claim 28: use at least about 1.0 equivalent of the L–CHR2–O–C(O)–OR reagent.
- Claim 29: reaction in organic base, organic solvent, at ~4–100°C for ~4–72 hours.
These limitations provide enforceability even for “same endpoint different process” scenarios. A process that uses different base, solvent class, temperature band, or time scale may still be captured if literal elements are met, but it creates potential arguments for non-infringement if the competitor deviates from both the chemical steps and the process boundaries.
Salt formation in claims 30–31
- Claim 30: recover by forming a salt, precipitating, and recovering the precipitated salt.
- Claim 31: salts formed from sulfuric acid, phosphoric acid, lactic acid, or citric acid.
Implication: Competitors targeting free base isolation or different counterions may reduce literal coverage of claim 31, but claim 30 remains broader (any salt).
How narrow are dependent claims 3–24 relative to Claim 1?
The dependent claims create layered capture:
- Claim 3: R2 is H.
- Claim 4: R1 is CH3.
- Claims 5–6: R2 constraints including one CH3 and the other H.
- Claim 7–10: restrict R3 (e.g., C1–C6 alkyl or phenyl; or CH3/ethyl; and X = O or X = N with one R3 = H).
- Claims 13–18: restrict base B among adenin-9-yl and 2,6-diaminopurin-9-yl plus R “alkyl identity” patterns (ethyl, isopropyl, 3-pentyl/neopentyl, t-butyl/isobutyl).
- Claims 19–22: restrict R1 to H or CH2OH, and restrict B accordingly (adenin-9-yl or cytosin-1-yl).
- Claims 23–24: cytosin-1-yl plus (S)-enrichment at R1.
Practical effect: Dependent claims are more specific but also more enforceable because they match concrete product forms. A generic developer designing around Claim 1 might still inadvertently meet one dependent subset.
What does this claim set imply about the patent family and likely blocking coverage?
Even without the rest of the family, the internal structure of 5,922,695 indicates a typical “core compound + use + process + solid form” arrangement that often comes with continuation filings to broaden substitution patterns, stereochemistry, and salts.
From the claim set alone, the following “landscape clusters” are strongly implied as likely targets in related US filings:
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Compound variants
- alternate R2/R patterns
- different X = N vs O configurations
- additional Z embodiments that include ester/amidate/acyloxy forms
-
Nucleobase scope
- guanine/adenine/diaminopurine/aminopurine plus deaza/aza variants
- cytosine derivatives
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Stereochemistry
- explicit (R) and (S) enrichment claims suggest either:
- multiple active enantiomers in commercial development, or
- use of resolved intermediates driving different endpoints.
-
Oral prodrug use
- a broad oral method-of-treatment claim often accompanies composition claims to cover clinical dosing.
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Process and salt recovery
- equivalent and temperature/time bands
- specific acid counterions for salt formation
This combination typically leaves competitors fewer “safe harbors” across medicinal chemistry, process development, and solid-state formulation.
What design-around strategies are most likely blocked by the claim language?
-
Changing counterions
- Claim 30 broadly covers salt formation and precipitation in recovery steps.
- Claim 31 lists specific acids; using other acids could avoid literal claim 31 but not necessarily claim 30.
-
Avoiding Z = –OC(R2)2 OC(O)X(R)a
- Claim 1 requires at least one Z to be exactly that moiety.
- Removing that moiety or replacing it with an alternative masking group not meeting the Z definition is the most direct method to step outside claim 1.
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Switching between X = O and X = N
- Claim 1 includes both X = O and X = N. So switching may not avoid the claim unless the molecule fails other constraints such as a, R substitution rules, and the required Z moiety.
-
Stereochemical changes
- If a candidate uses the same scaffold but opposite stereochemistry, it may still fall within Claim 1 unless Claim 1 is construed to require specific absolute configuration. Dependent claims 12 and 24 give explicit enantiopurity thresholds, but they do not necessarily limit Claim 1.
-
Process changes
- Deviating from base/solvent selection or outside 4–100°C or 4–72 hours could help avoid claim 29, but it may not avoid product infringement under claim 1/2.
Key Takeaways
- US 5,922,695 is a broad antiviral composition patent anchored on a phosphonomethoxy nucleotide analog residue with wide substitution freedom in R2 and R, and with a hard requirement that at least one Z equals –OC(R2)2 OC(O)X(R)a.
- Claim 2 locks in nucleobase scope: guanine-9-yl, adenine-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl, the corresponding deaza/aza analogs, and cytosin-1-yl.
- The patent covers orally administered antiviral treatment (method claim 25), plus manufacturing routes via derivatization reactions (claims 26–29) and salt recovery using acids including sulfuric, phosphoric, lactic, and citric (claims 30–31).
- Enantiomeric control is enforced through dependent claims with ≥90% (R) or (S) configuration at the R1 chiral center, tightening capture of commercial-grade stereochemistry.
- The combination of compound, use, process-parameter, and salt recovery claims increases “cross-functional” blocking power across medicinal chemistry, process development, and formulation.
FAQs
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Does US 5,922,695 require a specific nucleobase for infringement of claim 1?
No. Claim 1 uses “A” as a phosphonomethoxy nucleotide analog residue. Claim 2 specifies nucleobase “B,” tightening scope only in that dependent claim.
-
Can a competitor avoid the patent by changing from a salt to a free base?
Claim 30 covers recovery by forming a salt and precipitating it. If a competitor avoids salt formation entirely in manufacturing recovery, it may reduce literal exposure, but product-level coverage in claims 1 and 2 remains.
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What is the most critical structural “gate” in claim 1?
The requirement that at least one Z equals –OC(R2)2 OC(O)X(R)a.
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Do the enantiomer-specific claims limit only the enriched stereoisomer products?
Dependent claims 12 and 24 cover compounds with ≥90% (R) or (S) configuration. They may still leave Claim 1 broadly applicable to other stereochemical distributions depending on claim construction.
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Is the manufacturing process claim limited to a single stoichiometric ratio or reaction window?
Claims 28 and 29 impose a minimum equivalent for the derivatizing reagent and define a temperature/time band and base/solvent conditions, but only within the process claims, not the composition claims.
References
- United States Patent 5,922,695. (Provided claim text).
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