Details for Patent: 6,699,492

Summary for Patent: 6,699,492

Title:	Quinolone carboxylic acid compositions and related methods of treatment
Abstract:	The present invention relates to the use of quinolone carboxylic acid formulations in the treatment of ocular and periocular infections. The present invention also relates to sustained release compositions comprising specific quinolone carboxylic acid compounds. The invention also relates to quinolone carboxylic acid compositions and methods of preparing the same.
Inventor(s):	Samir Roy, Santosh Kumar Chandrasekaran, Katsumi Imamori, Takemitsu Asaoka, Akihiro Shibata, Masami Takahashi, Lyle M. Bowman
Assignee:	Bausch and Lomb Inc
Application Number:	US10/126,513
Patent Claim Types: see list of patent claims	Use; Composition; Delivery;

US Patent 6,699,492: Scope, Claims, and US Patent Landscape for Topical Ophthalmic Broad-Spectrum Quinolone-Carboxylic Acid/Carboxy-Polymer Sustained Release

What does US 6,699,492 actually claim at the composition level?

US Patent 6,699,492 claims topical ophthalmic broad-spectrum antibiotic compositions that combine (1) a quinolone carboxylic acid derivative (defined by a Markush-like Formula (I) with substituent constraints) in micronized form and (2) monodispersed particles (particle size constraint) of a crosslinked carboxy-containing polymer, with additional claim sets that narrow excipients, polymer composition, and sustained release behavior.

The independent claim family is composition-centric and adds method claims tied to treating ocular/periocular infections and to preparing the sustained release delivery system.

What is the core structural and formulation scope of the quinolone active (Formula I)?

Across claims, the “quinolone carboxylic acid derivative of formula (I)” is defined by substituent variables:

• R1: hydrogen, alkyl, aralkyl, or an ester residual group hydrolyzable in vivo
• R2: hydrogen or an amino group substituted by one or two lower alkyl groups
• X: hydrogen or halogen
• Y: CH2, O, S, SO, SO2, or N-R3
• R3: hydrogen or lower alkyl
• Z: oxygen or two hydrogen atoms
• The quinolone is a carboxylic acid derivative (carboxyl function is central)

The claim set also contains dependent claim embodiments that expressly identify two candidate quinolone carboxylic acids (and salts/hydrochlorides), which narrows interpretive risk for claim construction because they anchor what “formula (I)” covers in practice.

Which specific quinolone actives are explicitly enumerated?

Two specific free acids appear as dependent claims (examples of “formula (I)” embodiments):

1. Free acid (R)-(+):
   “7-(3-amino-2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid”
   plus salt thereof and hydrochloride (claims 10, 26, 43)
2. Another enumerated free acid:
   “8-chloro-1-cyclopropyl-6-fluoro-7-(2,3,4,5,6,7-hexahydro-5-oxo-1H-1,4-diazepin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid”
   plus salt thereof and hydrochloride (claims 11, 27, 44)

What is the core particulate and polymer scope (crosslinked carboxy-containing polymer)?

The independent composition claims require:

• A crosslinked carboxy containing polymer in the composition
• The composition includes monodispersed polymer particles with:
  • particle size of 30 μm and below
• The quinolone carboxylic acid derivative (formula I) is:
  • micronized (multiple independent/dependent claim versions)
• The formulation is positioned as:
  • topical ophthalmic and nonirritating to ocular tissue (explicitly in claim 1)

Several dependent claims then narrow polymer composition:

• Lightly crosslinked polymer of acrylic acid is a covered polymer class (claims 15, 18, 19/28/29/30)
• Acrylic acid polymer loading:
  • 0.1% to 6.5% by weight (claims 4, 21, 30 depending on which claim version)
  • preferred range shown: 0.5% to 1.0% by weight (claims 5/17/31)
• Polymer can contain up to:
  • 40% by weight of non-carboxyl-containing monoethylenically unsaturated monomers (claims 5, 22)

What are the independent composition claim “limiting features” you must map for freedom-to-operate?

Across claims 1, 19, and 32 (and method claim 33), the key limiting features are:

• Topical ophthalmic route (composition is “ophthalmic”)
• Broad spectrum antibiotic functional positioning
• Quinolone carboxylic acid derivative of formula (I) as active
• Active is micronized (claim 2/19/32 variants)
• Active concentration:
  • 0.005% to 10% by weight (claims 1, 19, 32, and method 33)
  • later narrowed dependent ranges (claims 6/7/39/40)
• Crosslinked carboxy-containing polymer
• Polymer is present as monodispersed particles:
  • particle size ≤ 30 μm
• Sustained release is explicitly required in certain dependent sets (claim 2 and claim 20, plus method claim 34)
• Nonirritating to ocular tissue is explicitly required in claim 1

These features are the tightest levers for claim-charting.

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How is sustained release and micronization layered across the claim set?

The claims separate “composition definition” from “performance”:

• Claim 1: includes the core composition elements plus nonirritating and polymer particle size ≤ 30 μm and polymer being crosslinked and carboxy-containing, but does not explicitly require sustained release.
• Claim 2: adds sustained release and requires that formula (I) particles are “prepared by micronization.”
• Claim 19: defines a composition that uses micronized active and polymer monodisperse particles ≤ 30 μm, positioning sustained release in dependent claim 20.
• Claim 32: independent variant that again anchors the micronized quinolone + polymer particle constraints.

So, sustained release is not uniformly present in every independent version. It becomes a dependent narrowing limitation, which matters in both infringement mapping and licensing negotiations.

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What are the key quantitative windows in the formulation?

Active loading

• Generic range: 0.005% to 10% (claims 1, 19, 32; methods 33/37-style)
• Dependent tightened ranges:
  • 0.007% to 5% (claims 6, 39)
  • 0.02% to 2.5% (claims 7, 40; and composition claim 23)

Polymer loading

• 0.1% to 6.5% by weight (claims 4, 21, 35)
• Preferred narrowing:
  • 0.5% to 1.0% by weight (claims 17, 31)
• Polymer particle size limitation:
  • ≤ 30 μm (claims 1, 19, 32, 33)

Polymer monomer content

• Up to 40% by weight of non-carboxyl-containing monoethylenically unsaturated monomers (claims 5, 22, 36)

Polymer is explicitly “lightly crosslinked acrylic acid”

• Claim path: claim 15 -> 16/17 (0.1%–6.5% and 0.5%–1.0%)
• Then multiple “identity” claims reiterate the polymer is lightly crosslinked acrylic acid (claims 18, 28, 29)

Average particle diameter

• Method claim 38 adds: “particles have an average diameter less than about 10 microns.”

That gives two different size constraints in the ecosystem:

• composition claims: ≤ 30 μm monodispersed polymer particles
• method claim: average diameter < 10 microns (could be interpreted as either polymer or composite particles depending on claim drafting context; as written, it ties to “said particles” in claim 33 framework)

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What excipients and delivery forms are captured?

Cyclodextrin solubilizer

• Solubilizer is expressly allowed (claim 12)
• Specific solubilizer: hydroxypropyl-β-cyclodextrin (claim 13)
• Loading window: 5.0% to 20.0% by weight (claim 14)

Delivery forms

• Method claim 37: composition is in the form of an ointment or instillant

The composition claims themselves do not hard-code ointment vs instillate, but the method claim does.

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What therapeutic and microbiology scope is claimed in the treatment method?

Method claim 33 covers delivering to ocular/periocular region to treat or prevent bacterial infection.

Dependent method claims expand into microbiology and target organism lists:

• General bacterial categories:

  • Gram positive
  • Gram negative
  • mixed Gram positive/Gram negative (claim 45, and claim 47 for mixed explicitly)

• Extensive genus/species list (claim 46) includes organisms such as:

  • Escherichia coli
  • Salmonella typhi
  • Shigella flexneri
  • Klebsiella pneumoniae
  • Proteus vulgaris
  • Proteus rettgeri
  • Haemophilus influenzae
  • Pseudomonas aeruginosa
  • Serratia marcescens
  • Moraxella morganii, M. lacunata, M. catarrhalis
  • Bacillus subtilis
  • Staphylococcus aureus, S. epidermidis, S. haemolyticus, S. hominis, S. pyogenes
  • Streptococcus pneumoniae
  • Enterococcus faecalis
  • Micrococcus lysodeikticus
  • plus “combinations thereof”

For competitive landscape mapping, this is a broad clinical indication statement typical of antibiotic topical formulations, and it is written as a claim-accessible organism list, which can be used to argue infringement breadth if the formulation meets the physical constraints.

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What process scope is claimed (preparing the sustained release system)?

A separate method of preparation claim (claim 48) recites:

• Use of 0.005% to 10% quinolone carboxylic acid derivative
• Preparing a micronized topical ophthalmic broad spectrum antibiotic composition containing quinolone (formula I) and then combining that composition with a carboxy-containing polymer
• Dependent claim 49: polymer loading 0.1% to 6.5%
• Dependent claim 50: packaging step
• Claim 51: a specific tighter combination:
  • polymer is lightly crosslinked acrylic acid present 0.5% to 4.5%
  • active is 0.02% to 2.5%
  • and includes explicit identification of the two enumerated actives (free acid plus salt/hydrochloride)

Claim 53 additionally ties to:

• “particles having an average diameter less than about 10 microns”
• prepared by micronization of the quinolone carboxylic acid

This process claim is useful in landscape analysis because it can broaden infringement theories beyond end-product formulation into “how it was made,” depending on evidence.

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What are the most important claim dependencies that tighten coverage?

Nonirritating ocular tissue (claim 1)

• Only the earliest independent composition claim includes this explicit performance attribute.
• If a competitor argues irritation profile differences, this element becomes critical only for claims where it is actually recited.

Sustained release (claims 2 and 20 and 34)

• Dependent claim lines cover sustained release.
• If a competitor uses a non-sustained release formulation, infringement risk drops for those dependent claims but may remain for the core independent claim.

Micronization

• Active micronization is explicitly required in claim 2, claim 19, and claim 32 (and method claim 48/53).
• A competitor formulating the active in non-micronized particulate form could avoid these micronization-dependent limitations.

Polymer particle size and monodispersity

• Monodispersed particles with particle size ≤ 30 μm is in the independent composition claims.
• This is often a controllable manufacturing variable (polymer particle sizing and dispersity), and it is also measurable, which can become central evidence in enforcement.

Polymer chemistry (lightly crosslinked acrylic acid)

• A competitor can potentially substitute other carboxy-containing polymers (still crosslinked) to avoid the narrower acrylic acid polymer sub-claims (claims 15/18/28/29), while still risking broader generic “crosslinked carboxy containing polymer” claims (claims 1/19/32).

Specific solubilizer

• Hydroxypropyl-β-cyclodextrin is only in dependent claims.
• Avoiding it can narrow dependent claim exposure but rarely avoids independent claim coverage if solubilizer is optional (“further comprising”).

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US Patent Landscape: What this patent is likely protecting and how it sits in the broader topical quinolone sustained-release space

1) Likely protected “product format”

The patent is designed around a specific product format:

• Topical ophthalmic quinolone carboxylic acid derivative
• delivered with sustained release
• using a crosslinked carboxy polymer prepared as monodispersed particles ≤ 30 μm
• with micronized active (depending on claim version)
• optionally using hydroxypropyl-β-cyclodextrin to solubilize

This format is more specific than “topical antibiotic composition” and closer to a controlled-release particulate dispersion system.

2) Likely protected “dosage and excipient knobs”

The dependent claims lock in:

• active % windows (0.007%-5% and 0.02%-2.5%)
• polymer % windows (0.1%-6.5% and 0.5%-1.0%, plus 0.5%-4.5% in process claim)
• cyclodextrin 5%-20%

This means competitors face a real risk if they track formulation ratios, not just the API identity.

3) Likely protected “manufacturing and performance narrative”

The inclusion of:

• “nonirritating”
• “sustained release”
• micronization and polymer particle sizing creates a claim architecture where enforcement can lean on:
• formulation manufacturing records (micronization and polymer sizing)
• product performance testing (sustained release and irritation)

4) Likely “design-around” areas to prioritize in competitor analysis

Within the constraints of what the claims literally recite, the typical design-around levers are:

• change polymer particle size so it is not ≤ 30 μm monodispersed
• use a different polymer system not satisfying “crosslinked carboxy-containing polymer” or not “lightly crosslinked acrylic acid” (for acrylic-specific subclaims)
• avoid micronized active (where independent versions require it)
• avoid sustained-release behavior if only dependent claims are asserted
• replace hydroxypropyl-β-cyclodextrin if a dependent claim path is needed

These levers map to claim language and are measurable in development and in litigation.

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How do you read the landscape risk for investors and competitors?

Risk increases when a candidate matches multiple layers at once

In this patent, infringement likelihood generally increases if a competitor:

• uses one of the two enumerated quinolone actives (or a formula (I) embodiment)
• uses micronization
• uses a crosslinked carboxy polymer in monodispersed particles ≤ 30 μm
• targets sustained release ocular delivery
• uses similar % ranges and cyclodextrin where applicable

Matching two or three layers can trigger dependent claim exposure; matching all layers triggers broader exposure including independent claim reach.

Risk can drop sharply if a single “hard limiter” is missed

The strictest binary-looking limit is:

• polymer monodispersed particle size ≤ 30 μm The second is:
• micronization (in claim versions where required) Because these are construction elements of the claim, missing them tends to narrow exposure even if API identity overlaps.

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Key Takeaways

• US 6,699,492 protects a topical ophthalmic sustained/controlled-release formulation combining a micronized quinolone carboxylic acid derivative of formula (I) with crosslinked carboxy-containing polymer present as monodispersed particles ≤ 30 μm.
• The claim set is built around layered constraints: API identity (formula I plus two explicit free-acid embodiments), micronization, polymer chemistry, polymer particle size, loading ranges, and sustained release/nonirritating attributes.
• The treatment method claims extend to ocular/periocular delivery for Gram +/- and mixed infections, with a detailed organism list.
• The process claim adds a manufacturing angle via micronization and combining with a carboxy-containing polymer, plus packaging and particle size concepts.
• For landscape and freedom-to-operate, the most actionable technical points are polymer particle size/dispersity, polymer chemistry (acrylic vs other carboxy polymers), micronization status of the active, and whether the product is engineered to deliver sustained release.

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FAQs

1) Does US 6,699,492 cover any topical ophthalmic quinolone carboxylic acid, or does it require the Formula (I) structure?

It requires a quinolone carboxylic acid derivative of formula (I) with the specified substituent variable ranges and definitions.

2) Is “sustained release” required in every independent composition claim?

No. Claim 1 does not explicitly require sustained release, while claim 2 and claim 20 add sustained release as dependent limitations (and method claim 34 mirrors this).

3) What is the hardest particle-size limiter in the independent claims?

The polymer is defined as monodispersed particles with particle size 30 μm and below in the independent composition claim framework.

4) Are micronized particles required for the quinolone in every independent composition claim?

They are explicitly required in the independent versions that recite micronized active (e.g., claims 19 and 32, and claim 2 as a dependent addition to claim 1).

5) Does the patent restrict formulations to ointments only?

No. The method claim specifies ointment or instillant, but the composition claims cover topical ophthalmic compositions more generally.

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References

1. US Patent No. 6,699,492 (claims and claim text as provided).

Drugs Protected by US Patent 6,699,492

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 6,699,492

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	296093
Australia	2002322002
Australia	3920300
Australia	772228
Canada	2368637
Canada	2445408
Cyprus	1107259