Details for Patent: 4,199,574

Summary for Patent: 4,199,574

Title:	Methods and compositions for treating viral infections and guanine acyclic nucleosides
Abstract:	9-Hydroxyethoxymethyl (and related) derivatives of certain 6-, and 2,6-substituted purines have been discovered to have potent anti-viral activities. Novel compounds and their pharmaceutically acceptable salts, pharmaceutical formulation containing the compounds of this invention, and the treatment of viral infections with these formulations are all disclosed. 9-(2-hydroxyethoxymethyl) guanine and 2-amino-9-(2-hydroxyethoxymethyl)adenine are examples of especially active compounds of this invention.
Inventor(s):	Howard J. Schaeffer
Assignee:	SmithKline Beecham Corp
Application Number:	US05/662,900
Patent Claim Types: see list of patent claims	Use; Composition; Dosage form;

United States Patent 4,199,574 (Substituted Purines) Patent Estate: scope of claims, coverage map, and likely infringement/entry risk

US Drug Patent 4,199,574 is a composition-and-method patent built around a family of substituted purines of structural formula (I) (including oxygen or sulfur in the ring heteroatom position) and claims that extend to: (1) specific substituted guanine derivatives (prodrug-like alkoxyalkyl/acyloxy side chains), (2) pharmaceutical compositions (carrier + dose ranges; topical/oral/parenteral dosage forms), and (3) treating “a viral infection” in a mammal with broad route and dosing language.

Based on the claim set provided, the enforceable scope is concentrated in three claim “clusters”: core structure (formula I), named compounds/prodrug variants, and use/formulation/dosage method claims. The practical landscape is dominated by how tightly an accused product’s API matches the substituted purine variables X, R1-R6, and whether an accused product is used with dosage forms and routes that fit the method/composition claims.

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What patents protect substituted purines of formula (I) in US 4,199,574?

What does claim 1 actually cover (core formula I substitution limits)

Claim 1 covers a “substituted purine of formula (I)” including pharmaceutically acceptable salts, with the following variable constraints:

• X = sulphur or oxygen
• R1 = hydroxy
• R2 = amino
• R3 = hydrogen, or alkyl substituents that are straight/branched chain/cyclic alkyl, or hydroxyalkyl, or benzoyloxyalkyl, or phenyl
• R4 = hydrogen, hydroxy, or lower alkyl
• R5 = broad set of functional substituents including: hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzyloxy, benzoyloxy, benzoyloxyalkyl, sulphamoyloxy, phosphate, carboxypropionyloxy, acetoxy
• R6 = hydrogen, alkyl, or hydroxyalkyl (or salts)

Immediate practical read-through: claim 1 is a family claim that is wide on R3-R6 and R5 functional groups, but it is narrow on R1 and R2 (fixed to hydroxy and amino) and includes the “ring heteroatom” switch X.

Is the oxygen-only version narrower or still broad?

• Claim 2 restricts X to oxygen but otherwise preserves the variable structure.
• Dependent claims (3, 4, 6, 7, 8–10) carve out particular combinations of R5 and the other variable positions.

Which dependent claim combinations create the strongest “fallback” coverage

From the text provided, several dependent claims look like “fallback” claim narrowing that is still close to many plausible prodrug variants:

• Claim 4: oxygen (by dependence on claim 2) with R1 hydroxy, R2 amino, R5 = hydroxy or benzoyloxy or carboxypropionyloxy or acetoxy? (as written across dependences), while R3, R4, R6 are forced to hydrogen (in that specific dependent claim set).
• Claim 5 and later: specific R5 = hydroxy with R3, R4, R6 = hydrogen.
• Claim 9–10: multiple explicit R5 = hydroxymethyl and R5 = carboxypropionyloxy scenarios with R3, R4, R6 = hydrogen.
• Claims 35–38: a second, more constrained “formula” claim set with R1/R2 fixed and R5 limited to 1–8 carbon chain acyloxy types plus explicit acetoxy dependence.

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What formulations and dosage forms are protected by US 4,199,574?

Pharmaceutical compositions: claim 11 baseline + route/dosage derivatives

Claim 11 grants composition coverage: a pharmaceutical composition comprising an effective non-toxic antiviral amount of the formula (I) substituted purine, plus a pharmaceutically acceptable carrier.

Then claim scope expands into dosage-form and concentration/dose windows:

• Topical dosage forms
  • Claim 14: ointment or cream
  • Claim 18: topical administration with concentration 0.1 to 10%
  • Claim 19: topical with concentration 1%
• Oral/parenteral
  • Claim 15: tablet
  • Claim 16: oral or parenteral, dose 1 to 250 mg per unit dose
• Parenteral/eye/nose drops
  • Claim 17: eye or nose drops (aqueous medium) concentration 0.1 to 10%

Claims 12 and 13 narrow within composition scope:

• Claim 12: X = oxygen
• Claim 13: R2 amino, R1 and R5 both hydroxy, with R3, R4, R6 = hydrogen

Bottom line for formulation infringement risk: a generic or competitor product that uses a covered API but is marketed outside dose/concentration ranges could attempt design-around, but the family nature of claim 11 plus the multiple dosage-form-specific dependent claims means “outside the window” is not necessarily safe if any asserted dependent claim matches the marketed presentation.

Named-compound composition coverage

The patent adds direct compound identity claims within compositions:

• Claim 20: purine selected from a short list including:
  • 9-(3-Benzoylpropoxymethyl)guanine
  • 9-[1-(2-Hydroxyethoxy)ethyl]guanine
  • 9-Ethoxymethylguanine
  • 9-(4-Hydroxy-n-butoxymethyl)guanine hemihydrate
• Claims 22 repeats that list with the composition.

It also separately covers:

• Claim 32/33/41: 9-(2-formyloxyethoxymethyl)guanine and compositions
• Claim 39–44: 9-(2-hydroxyethoxymethyl)guanine, salt, and composition variants including oral/parenteral/topical

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What antiviral treatment methods are claimed in US 4,199,574 (routes and dosing)?

Broad “method of treating a viral infection”

Claim 23: treats a viral infection in a mammal by administering an effective non-toxic amount of the substituted purine of formula (I) or salt.

Route dependencies:

• Claim 25: topical application
• Claim 26: oral route
• Claim 27: parenteral route

Dose dependencies:

• Claim 28: parenteral dosing 0.1 to 250 mg/kg body weight
• Claim 29: repeated at least twice daily

Method constraints tied to specific prodrug variants

• Claim 30: specifies several compounds for “method of claim 23”

• Claim 31: another selection set (9-(3-Benzoylpropoxymethyl)guanine; 9-[1-(2-Hydroxyethoxy)ethyl]guanine; 9-Ethoxymethylguanine)

• Claims 45–48: method claims directed specifically to 9-(2-hydroxyethoxymethyl)guanine with oral/parenteral/topical dependences.

• Claim 49: adds example specifying herpes virus for the 9-(2-hydroxyethoxymethyl)guanine method chain.

• Claims 34/80: “susceptible viral infection” methods using 9-(2-formyloxyethoxymethyl)guanine

• Claim 51: method claims directed to the “compound or salt of claim 35” (more constrained formula).

Practical point: if an accused product is used in a clinical regimen matching any dependent route/dose language, the method claims create a second infringement hook even when formulation/dose form arguments are contested.

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What compound variants are explicitly covered (and therefore easiest to map to commercial APIs)?

Explicit named compounds in the claim text

The claim set provided explicitly names these APIs (or salts) inside the composition and/or method scope:

1. 9-(2-hydroxyethoxymethyl)guanine

   • Claims 39–40 (compound and salt)
   • Claims 41–44 (composition; oral/parenteral/topical)
   • Claims 45–48 (methods; oral/parenteral/topical; herpes virus in claim 49)
   • Claim 45 also ties back to “susceptible viral infection” framing

2. 9-[2-(3-carboxypropionyloxy)ethoxymethyl]guanine

   • Claims 77–81 (compound/salt, compositions, and methods)

3. 9-(2-formyloxyethoxymethyl)guanine

   • Claims 32–34 (compound and methods)
   • Claims 33/34 are composition + method entries for this prodrug

4. Prodrug list with benzoylpropoxy/mixed alkoxyalkyl

   • Claims 20 and 22 list:
     • 9-(3-Benzoylpropoxymethyl)guanine
     • 9-[1-(2-Hydroxyethoxy)ethyl]guanine
     • 9-Ethoxymethylguanine
     • 9-(4-Hydroxy-n-butoxymethyl)guanine hemihydrate

5. A second explicit prodrug selection in methods:

   • Claim 31 lists:
     • 9-(3-Benzoylpropoxymethyl)guanine
     • 9-[1-(2-Hydroxyethoxy)ethyl]guanine
     • 9-Ethoxymethylguanine

How these named compounds map onto formula variables

The named prodrugs strongly suggest R5 contains acyloxy-like groups (e.g., benzoyloxy, formyloxy, carboxypropionyloxy, hydroxyethoxy substituents) consistent with claim language in formula (I) and the constrained formula claim set (claims 35–38).

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What subset of the claim set covers acyloxy variants (claims 35–38, 63–68, 66–73, 71–76)?

A second “narrower structure” claim block

Claim 35 is a distinct compound claim with a tighter description:

• X = sulphur or oxygen
• R1 hydroxy; R2 amino
• R3 = hydrogen or constrained alkyl/hydroxyalkyl/benzyloxyalkyl/phenyl
• R4 = hydrogen, hydroxy, or alkyl
• R5 = hydrogen/hydroxy/amino/alkyl/hydroxyalkyl/benzyloxy/benzoyloxy/phosphate OR straight-chain or cyclic acyloxy with 1 to 8 carbons
• R6 = hydrogen or alkyl

Then:

• Claim 36: R5 acyloxy 1–8 carbons
• Claim 37: R5 straight chain acyloxy
• Claim 38: depends on claim 1 specifying R5 = acetoxy

Composition and method dependences keyed to R5

The patent then creates multiple “assertable windows” for R5-specific product variants:

• Claims 63–65: pharmaceutical composition of claim 50 (compound of claim 35) where R5 is acyloxy 1–8; then straight chain acyloxy; then acetoxy
• Claims 66–68: method of claim 51 with same R5 variants
• Claims 69–73: purine or method where R5 is acetoxy or phosphate or carboxypropionyloxy
• Claims 71–73 / 74–76: method/composition entries for acetoxy/phosphate/carboxypropionyloxy

Entry implication: if a generic changes the prodrug group from acetoxy to phosphate or vice versa, claim coverage may shift from one dependent branch to another without exiting the broader family claim.

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How many independent claim “coverage buckets” exist, and what are the practical litigation targets?

From the provided claim text, independent claim “buckets” appear to be:

1. Core formula I compound claim
   • Claim 1 (broad family)
2. Core formula I + structural narrowing branches
   • Claims 2, 3, 4, 5, 6, 7, 8–10 (variable combinations)
3. Composition claim
   • Claim 11 (carrier + effective non-toxic antiviral amount)
4. Method of treating viral infection
   • Claim 23 (effective non-toxic amount; route/dose dependences)
5. Specific compound identity claims + salt
   • Claims 39–40; 77–78; 32/33; and list-based claim 20/22
6. Second constrained formula claim block
   • Claim 35 and dependences (claims 36–38 and R5-constrained branches)
7. Companion composition and method chains that repeat API-specific coverage
   • Claims 41–44; 45–48; 79–80; 34; plus R5-specific claims 50–51 and dependent sets.

Litigation target selection: for infringement theories, plaintiffs typically assert the closest API match (named compound claims) plus at least one broad formula claim (claim 1 or 35) and one use claim (claim 23 or 45/51). That provides redundancy if a defendant attacks either variable interpretation or dosage-form limitations.

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Which claim terms drive claim construction risk (the “hot variables”)?

R5 substituent definition breadth

R5 is the widest variable and is defined with many function types:

• hydrogen/hydroxy/amino/alkyl/hydroxyalkyl
• benzyloxy
• benzoyloxy, benzoyloxyalkyl
• sulphamoyloxy
• phosphate
• carboxypropionyloxy
• acetoxy

This breadth increases the chance that a competing prodrug with a close acyloxy substituent still fits.

R3 and R6 “alkyl/hydroxyalkyl” breadth

• R3 includes straight or branched chain/cyclic alkyl, hydroxyalkyl, benzoyloxyalkyl, phenyl.
• R6 includes alkyl or hydroxyalkyl.

These are broad enough that infringement hinges on whether the substitution connects to the correct position in the structure and maintains the R1 and R2 fixed functions.

X = oxygen vs sulphur

Claims split on X:

• claim 1 includes both
• claim 2 and claim 12 narrow to oxygen

If a defendant makes sulfur analogs, oxygen-only dependences may fail but claim 1 remains available.

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What does the claim language imply for generic or biosimilar entry risk?

This is a small-molecule purine family, so “biosimilar” is not the right frame

The patent reads as chemical entity IP with salts and dosage forms. Competitive risk is generic small-molecule entry (ANDA) or label/design around.

Most likely design-around angles under this claim set

Given the variables, a defendant would most plausibly try to:

• change the prodrug group (R5) away from the enumerated functional set, or
• eliminate the fixed R1 hydroxy / R2 amino pattern (harder if the compound is a guanine derivative), or
• avoid covered dose/concentration and route presentations to narrow exposure to formulation/method dependences.

However, because claim 11 and claim 23 are broad and because multiple dependent claims explicitly capture topical/oral/parenteral variants and dose ranges, design-around must be both structural and promotional.

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How does US 4,199,574 compare with a typical “prodrug purine” patent stack?

Within the claim text supplied, the patent behaves like a classic prodrug platform estate:

• a broad “formula I” scaffold (compound),
• broad “composition” and “method” hooks,
• plus repeated dependent branches for specific prodrug variants and salts,
• plus a second scaffold claim (claim 35) that tightens R5 by carbon count for acyloxy groups (1–8).

That structure typically supports multiple parallel infringement theories against a single product: API identity, salt form, composition presentation, and use regimen.

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Orange Book status, FDA litigation, and Paragraph IV challenges: what’s covered by US 4,199,574?

No Orange Book listing details, FDA approval dates, or Paragraph IV/litigation history are included in the provided materials. No complete and accurate statement can be made about Orange Book status, market exclusivity, or whether any Paragraph IV challenges exist for US 4,199,574 based only on the claim text.

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Key Takeaways

• Core protection is formula-driven: claim 1 covers substituted purines with X = oxygen or sulphur, and fixed R1 = hydroxy and R2 = amino, with broad allowance for R5 acyloxy/phosphate/benzyloxy/benzoyloxy/acetoxy and alkyl substitutions at R3/R4/R6.
• Enforcement has three layers: compound (claim 1/35), compositions (claim 11 plus topical/oral/parenteral/tablet/drop formulations and dose/concentration windows), and methods (claim 23 plus route/dosing dependences).
• The “named compound” claims materially simplify claim mapping for at least: 9-(2-hydroxyethoxymethyl)guanine, 9-(2-formyloxyethoxymethyl)guanine, 9-[2-(3-carboxypropionyloxy)ethoxymethyl]guanine, and several benzoylpropoxy and alkoxyalkyl guanine derivatives.
• Prodrug substitution (R5) is the main design-around lever, but multiple dependent branches (acetoxy, phosphate, carboxypropionyloxy, acyloxy carbon range) reduce the odds of escaping by a single small modification.
• Dose/route windows add additional infringement hooks: topical cream/ointment, tablets, aqueous eye/nose drops, and parenteral dosing with 0.1 to 250 mg/kg and at least twice daily repetition are specifically claimed in the method set.

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FAQs

1. What part of US 4,199,574 is most likely to be asserted in API infringement?
   Claim 1 (formula I) and claim 35 (constrained R5 acyloxy 1–8 carbon) plus the closest named compound claims (e.g., 9-(2-hydroxyethoxymethyl)guanine).

2. Can a product avoid infringement by changing from acetoxy to phosphate at R5?
   Likely not if the phosphate variant still falls within the enumerated R5 set, because dependent branches expressly cover R5 = phosphate and multiple composition/method claims follow.

3. Which dosage forms are directly claimed in US 4,199,574?
   Ointment/cream (topical), tablet (oral), and eye/nose drops (aqueous) are explicitly described in the composition claim dependences.

4. What method-of-use elements matter most for route and dosing?
   Route (topical/oral/parenteral) and, for parenteral, dosing 0.1 to 250 mg/kg and at least twice daily repetition in the dependent method set.

5. Does US 4,199,574 limit the viral target to one virus family?
   Most claims are broad (“a viral infection”); a dependent claim narrows to herpes virus in the chain tied to 9-(2-hydroxyethoxymethyl)guanine.

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References (APA)

1. United States Patent 4,199,574. (n.d.). Substituted purines and methods/compositions for antiviral treatment.

Drugs Protected by US Patent 4,199,574

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

Foreign Priority and PCT Information for Patent: 4,199,574

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	38278/74	Sep 2, 1974

International Family Members for US Patent 4,199,574

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	212914
Argentina	220299
Argentina	220508