Details for Patent: 6,670,335

Summary for Patent: 6,670,335

Title:	Fluorouracil-containing formulation
Abstract:	Oil-in-water emulsion formulations contain both free fluorouracil and fluorouracil impregnated in porous microparticles. The formulations are suitable for topical administration, and are useful for the treatment of solar keratoses, actinic keratoses, and superficial basal cell carcinomas.
Inventor(s):	B. Sandhya Singh, Subhash J. Saxena
Assignee:	Bausch Health Ireland Ltd
Application Number:	US09/799,792
Patent Claim Types: see list of patent claims	Use; Formulation; Dosage form;

Executive summary
U.S. Patent 6,670,335 protects a specific topical fluorouracil (5-FU) delivery architecture: an oil-in-water emulsion containing (a) “free” fluorouracil plus (b) fluorouracil-impregnated porous microparticles with tightly defined total 5-FU wt% and a defined free 5-FU fraction (20%–50% of total), plus optional dependent claim constraints on microparticle size and cross-linked polymer chemistry. The claim set is also broad in usage via method-of-use claims for treating lesions such as solar keratosis/actinic keratosis and superficial basal cell carcinoma, including animal indications. Scope is therefore strongest where a competitor preserves both the emulsion format and the two-state 5-FU split (free + impregnated) using porous microparticles with defined compositional targets. Design-arounds that remove any of these core elements (porous microparticles, oil-in-water emulsion, or the defined free/total ratio) can materially narrow infringement risk, but may shift the patent landscape toward other 5-FU topical microparticle or controlled-release families.

What does US 6,670,335 claim for topical fluorouracil formulations, and what are the scope-defining elements?

At claim level, U.S. 6,670,335 is anchored on three scope-defining technical requirements:

1. Vehicle architecture: the formulation is an oil-in-water emulsion.
2. Drug partitioning into two reservoirs:
   • Free fluorouracil dispersed within the emulsion oil phase or dispersed phase as “fluorouracil in (ii)(a)”; plus
   • Fluorouracil-impregnated porous microparticles as “fluorouracil in (ii)(b)”.
3. Numerical composition constraints:
   • Total fluorouracil content in formulation: ~0.01% to ~10% by weight; and
   • Free fluorouracil content is 20% to 50% of the total fluorouracil content.

These three features jointly define independent claim 1. Dependent claims then tighten ranges and specify particle attributes.

Core independent claim 1 breakdown

Claim 1 requires all of the following simultaneously:

• Topical formulation containing fluorouracil.
• The formulation comprises:
  • (i) an oil-in-water emulsion; and
  • (ii) dispersed within the emulsion:
    • (a) fluorouracil (“free” 5-FU); and
    • (b) fluorouracil-impregnated porous microparticles.
• Total 5-FU wt% between 0.01% and 10%.
• Free 5-FU wt% constrained indirectly via fraction:
  • free 5-FU is 20% to 50% of total 5-FU.

This is a classic “two-component drug state” controlled-release claim, coupled to a specific emulsion carrier.

Tight dependent ranges that materially narrow design space

Claim 2 and 3 create additional hard boundaries:

• Claim 2: total 5-FU 0.1%–5% by weight
• Claim 3: total 5-FU 0.5% by weight

Claims 4–5 define additional free/total ratios and pin a sample point:

• Claim 4: free 5-FU is 30% of total 5-FU
• Claim 5: total 5-FU 0.5%, free 5-FU is 30% of total

Claim 11 tightens to a specific example:

• total 5-FU 0.50%
• free 5-FU equals 30% of total
• microparticles: ~20 μm weight average diameter
• microparticles: methyl methacrylate/ethylene glycol dimethacrylate crosspolymer

Particle size and polymer chemistry are explicit

• Claim 6: porous microparticles with weight average diameter < 50 μm
• Claim 7: microparticles weight average diameter ~20 μm
• Claim 8: cross-linked polymer selected from:
  • styrene/divinylbenzene
  • vinyl stearate/divinylbenzene
  • methyl methacrylate/ethylene glycol dimethacrylate
  • lauryl methacrylate/ethylene glycol dimethacrylate
• Claim 9: microparticles are specifically methyl methacrylate/ethylene glycol dimethacrylate

Optional excipients do not define infringement

• Claim 10: formulation may further comprise an additional component selected from antioxidant, chelating agent, colorant, fragrance, preservative. This is permissive (“further comprising”), so it typically does not narrow infringement unless other claims are simultaneously asserted.

How do the independent and dependent claims expand coverage to methods of treatment for keratosis and superficial basal cell carcinoma?

The patent expands from formulation to treatment by layering method claims over the same formulation scope.

Method-of-use claims tied to formulation claim 1

• Claim 12: topical administration of formulation of claim 1
• Claim 19: topical treatment of animals with disease selected from:
  • solar keratosis
  • actinic keratosis
  • superficial basal cell carcinoma via administration of formulation claim 1

More specific method claims tied to tighter formulation sub-claims

• Claims 13–17: topical administration using formulations of claims 2, 3, 4, 5, and 11 (respectively)
• Claim 20: same lesion set as claim 19, but tied to formulation claim 11

Animal treatment language broadens “entity” scope

• Claim 18: treatment of an animal having disease capable of treatment by topical fluorouracil using formulation claim 1.
  This language can capture companion animals and other non-human subjects in enforcement contexts where permitted.

What is the practical claim scope for infringement: which elements are “must-have” vs potentially swappable?

Based on claim construction principles, the “must-have” elements for claim 1 are those stated as required structural features:

Must-have for claim 1

• Oil-in-water emulsion must be present.
• Two 5-FU reservoirs must be present:
  • free 5-FU, and
  • 5-FU-impregnated porous microparticles.
• Quantitative constraints must be met:
  • total 5-FU between 0.01%–10% wt%
  • free 5-FU equals 20%–50% of total.

“Narrower overlays” for dependent claims

If a formulation does not meet claim 1, it typically cannot infringe claim 12/19 either because those are tied to claim 1. But even if claim 1 is met, dependent claims create additional fall-through risks if targets are approached:

• If total 5-FU is in 0.1%–5% and free fraction is within 30%, claims 2–5 are in play.
• If microparticles are <50 μm and especially ~20 μm, claims 6–7 become relevant.
• If polymer is one of the listed crosslinked types, claims 8–9 are relevant.
• If polymer is specifically methyl methacrylate/ethylene glycol dimethacrylate, claim 9 and claim 11 are relevant.
• Claim 11 is the tightest “example” claim: it requires a fully pinned set of composition and particle specs.

What formulations are protected: a matrix of key technical constraints

The patent’s protection can be reduced into a constraint matrix. A product that satisfies all constraints in a given row has a direct claim mapping risk.

Claim dependency	Total 5-FU wt%	Free 5-FU as % of total	Microparticle size	Microparticle polymer chemistry	Carrier
Claim 1	0.01%–10%	20%–50%	Porous microparticles (size not limited)	Porous microparticles not chemically limited	Oil-in-water emulsion
Claim 2	0.1%–5%	20%–50%	Any	Any	Oil-in-water emulsion
Claim 3	0.5%	20%–50%	Any	Any	Oil-in-water emulsion
Claim 4	0.01%–10%	30%	Any	Any	Oil-in-water emulsion
Claim 5	0.5%	30%	Any	Any	Oil-in-water emulsion
Claim 6	0.01%–10%	20%–50%	<50 μm	Any	Oil-in-water emulsion
Claim 7	0.01%–10%	20%–50%	~20 μm	Any	Oil-in-water emulsion
Claim 8	0.01%–10%	20%–50%	Any	One of 4 listed crosslinked polymers	Oil-in-water emulsion
Claim 9	0.01%–10%	20%–50%	Any	Methyl methacrylate/ethylene glycol dimethacrylate	Oil-in-water emulsion
Claim 11	0.50%	30%	~20 μm	Methyl methacrylate/ethylene glycol dimethacrylate	Oil-in-water emulsion (+ optional excipients allowed)

When does US 6,670,335 lose exclusivity, and what does that mean for US generic entry timing?

No expiration, filing date, or patent term adjustments are provided in the prompt, and those inputs determine the loss of exclusivity and patent expiry schedule. Without those facts, a timeline cannot be produced.

What Orange Book status applies to US 6,670,335 for topical 5-FU products?

Orange Book status is determined by the listed approved drug and NDA/BLA codes, plus which patents are actually listed for that product. The prompt provides only the patent number and claim text, not the FDA application(s), Orange Book listings, or FDA product codes. A status determination cannot be made from the provided information.

Which companies and generics might be at risk under the claim structure of US 6,670,335?

A litigation or risk map requires at least one of:

• the specific marketed topical 5-FU product that corresponds to this formulation concept,
• the companies that filed ANDAs or 505(b)(2) submissions,
• or the actual Orange Book patent listing(s) tied to the patent number.

The prompt does not supply those identifiers, so an “at-risk companies” list cannot be generated from provided data.

How strong is the patent estate around fluorouracil oil-in-water emulsions with 5-FU-loaded porous microparticles?

Strength here is a function of claim specificity and how many commercial products share the same technical recipe.

What makes the claims strong

• Clear structural and compositional limitations in claim 1 (emulsion + free 5-FU + porous microparticles loaded with 5-FU).
• A quantitative free/total split (20%–50% free fraction) that is not typical in more general topical 5-FU patents.
• Dependent claims that specify particle size (weight average diameter) and polymer chemistry.
• Method claims directly track the formulation claims, including the clinically common lesion set (solar/actinic keratosis and superficial basal cell carcinoma).

What makes scope potentially easier to design around

• If an alternative product uses a different carrier (non emulsion) or uses a different drug presentation (e.g., fully encapsulated 5-FU without “free” 5-FU in the emulsion) it may miss core claim 1 requirements.
• If the product intentionally shifts the free fraction outside 20%–50% of total, claim 1 can be avoided even if other elements remain.
• If particle size or polymer chemistry avoids the dependent parameters, dependent claims narrow to fewer overlaps (though claim 1 could still be asserted if those dependent constraints are not required).

What design-around strategies are consistent with the claim language of US 6,670,335?

Based on the claim structure, design-arounds fall into three buckets:

1. Carrier substitution

   • Replace oil-in-water emulsion with a different topical system (e.g., non-emulsion gel or ointment base). This can avoid claim 1’s “oil-in-water emulsion” limitation.

2. Drug state redefinition

   • Remove the explicit “free fluorouracil” component as defined in claim 1, or shift so that the “free” fraction is outside 20%–50% of total.
   • Replace 5-FU-impregnated porous microparticles with non-porous particles, fully encapsulated systems, or drug reservoirs that do not meet the “fluorouracil-impregnated porous microparticles” phrasing.

3. Particle spec avoidance (targeting dependent claims)

   • Use microparticles with weight average diameter ≥ 50 μm to avoid claim 6/7.
   • Use polymer chemistries not in claim 8’s list to avoid claims 8/9.
     These do not avoid claim 1 unless claim 1’s microparticle requirement is also engineered out.

What patent litigation pathways could involve US 6,670,335 (Paragraph IV, settlements, and FDA approvals)?

A litigation pathway analysis requires the actual ANDA/505(b)(2) history, whether the patent is Orange Book-listed for a specific NDA, and any identified Paragraph IV notices or settlement agreements. Those facts are not present in the prompt, so no litigation narrative can be constructed.

Key takeaways

• U.S. 6,670,335 is a topical 5-FU delivery patent with a tightly defined formulation architecture: oil-in-water emulsion + free 5-FU + 5-FU-impregnated porous microparticles.
• Claim 1’s most enforceable “fences” are: total 5-FU wt% (0.01%–10%) and free 5-FU fraction (20%–50% of total), in addition to the emulsion and porous microparticle structure.
• Dependent claims narrow further to specific total 5-FU (0.5%), free fraction (30%), particle size (~20 μm / <50 μm), and specific cross-linked polymer chemistries, with claim 11 functioning as a highly specific example target.
• Method claims track the formulation claims and cover treatment of solar keratosis, actinic keratosis, and superficial basal cell carcinoma via topical administration of the claimed formulations.

FAQs

1. Does US 6,670,335 cover a topical 5-FU product if it lacks an oil-in-water emulsion?
   Claim 1 requires an oil-in-water emulsion, and method claims are tied to claim 1 formulations; removing that architecture can avoid the independent claim.

2. What is the infringement risk if a product uses 5-FU-loaded porous microparticles but does not include “free fluorouracil” in the specified ratio?
   Claim 1 requires the free 5-FU content to be 20%–50% of total; moving outside that ratio can avoid claim 1.

3. Are microparticle size and polymer chemistry required for infringement of the independent claim?
   Size and polymer chemistry are in dependent claims; claim 1 does not require the specific size or polymer selections.

4. Do the method-of-use claims expand protection beyond the formulation claims?
   The method claims require topical administration of formulations defined by the formulation claims, so the formulation limitations continue to drive scope.

5. If a competitor matches total 5-FU and free fraction but uses different particle polymers, is it still at risk?
   Matching total and free fraction plus retaining the oil-in-water emulsion and porous microparticle structure can still implicate claim 1; polymer choice chiefly affects dependent claims 8/9/11.

References

1. U.S. Patent 6,670,335.

Drugs Protected by US Patent 6,670,335

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