US Patent 5,294,636 Landscape: Crystalline N-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide for Leukotriene Antagonism
US 5,294,636 is a solid-state and formulation-focused patent centered on a specific crystalline physical form of a leukotriene-pathway antagonist (structure defined in the claims) plus composition claims for inhalation delivery using defined chlorofluorocarbon/hydrofluorocarbon propellants. The claim set combines (i) tight analytical fingerprints (XRPD peak positions, IR peaks, melting point) and (ii) downstream product claims (pharmaceutical composition including metered dose inhaler propellant systems, and soft pellet particle-size/tack behavior). The method-of-use claim anchors biological activity (leukotriene antagonism) to the crystalline form.
This patent’s practical scope is governed less by the underlying molecule name and more by enforceability of the claimed “physical form” under ex situ analytical testing (XRPD/IR/melting point), plus by whether an accused inhaler or pellet contains that exact polymorph/solid form in meaningful amount.
What patents protect the crystalline “physical form” of the leukotriene antagonist in US 5,294,636?
US 5,294,636 is itself a “physical form” patent. Its independent claim (Claim 1) defines the crystalline form via three orthogonal identifiers:
- XRPD: peaks at 2θ = 8.1°, 13.7°, 16.4°, 20.5°, 23.7°
- IR: sharp peaks at 3370, 1670, 1525, 1490, 1280, 890, 870, 550 cm⁻¹ (0.5% in KBr)
- Melting point: 190°C to 200°C
The dependent claims then attempt to preserve that “physical form” definition through additional structural/process constraints (soft pellets, high proportion of <10 micron particles) and through formulation delivery constraints (metered dose inhaler with specific propellants).
Claim-by-claim scope snapshot
| Claim |
What it protects |
Key scope limiter(s) |
| 1 |
The crystalline physical form of the named sulphonamide |
Must match XRPD peaks, IR peaks, melting point range |
| 2 |
Pharmaceutical composition containing Claim 1 physical form + carrier |
Includes the same crystalline form; otherwise generic “pharmaceutically acceptable carrier” |
| 3 |
Metered dose inhaler (MDI) composition with propellant |
Must be suitable for MDI; includes propellant system |
| 4 |
MDI propellant composition using specified fluorinated gases |
Propellant must be one of the listed agents or within that list’s scope |
| 5 |
Substantially single-form (free of other physical forms) solid as soft pellets |
Must be the same crystalline form and substantially free of other forms; plus pellet/particle-size distribution |
| 6 |
Method claim: antagonizing one or more leukotriene actions in a mammal using Claim 1 physical form |
Ties method-of-use to the crystalline form in Claim 1 |
Enforcement emphasis. The patent reads on products where the active ingredient is (a) that specific crystalline polymorph/solvate state and (b) delivered or processed as claimed. If the accused product uses a different polymorph or converts to it only transiently, infringement may hinge on whether the claimed crystalline form is present as manufactured, stored, or delivered and can be detected by the claimed analytical methods.
How broad is the claim coverage for XRPD/IR-defined crystalline polymorphs?
From a claim-construction perspective, the “physical form” is not defined by composition alone. It is defined by pattern-based analytical criteria and a melting point window.
XRPD: is it narrow or “functionally broad”?
The XRPD requirement is specific about 5 peaks at fixed 2θ values. The claim does not specify peak intensities, bandwidth, or tolerances (like ±0.2°). In practice, infringement analysis will still require a tolerance concept because instruments and sample prep introduce drift. But as written, the legal scope depends on whether the claimed peaks occur at those stated positions.
IR: peak list anchoring
The IR spectrum requirement is also tight: it lists a set of sharp peaks at specific wavenumbers. This creates a second gate against polymorph substitution.
Melting point: relatively wide tolerance but still a gate
The melting point range 190°C to 200°C narrows the acceptable solid form to one that melts in that window.
Combined effect
In aggregate, requiring all three (XRPD peak positions + IR peaks + melting range) makes the crystalline form definition substantially stronger than claims that rely on one analytical method alone. It also gives the patentee multiple independent “tripwires” for proving the accused product is the same solid form.
What formulations are protected by US 5,294,636 for inhalation and MDI delivery?
Claims 3 and 4 add a formulation layer on top of the polymorph definition.
Claim 3: MDI suitability plus propellant
Claim 3 requires:
- A pharmaceutical composition suitable for administration by a metered dose inhaler
- Contains a pharmaceutically acceptable propellant
“Suitable for MDI” can be broad as a functional description, but infringement will still require the composition to be in an MDI-compatible container/dispensing system and to contain the crystalline physical form at a dose suitable for aerosolization.
Claim 4: propellant selection is explicit
Claim 4 lists propellants:
- trichlorofluoromethane
- dichlorodifluoromethane
- dichlorotetrafluoroethane
- 1,1,1,2-tetrafluoroethane
This list is a major constraint on formulation scope. Any MDI formulation outside these agents (for example, non-listed HFCs) risks falling outside Claim 4 even if it still uses the same crystalline polymorph.
What is the scope of the “soft pellets” physical form in Claim 5?
Claim 5 is a hybrid claim: it combines the crystalline identification with a specific solid agglomerate engineering profile.
It requires:
- The same crystalline physical form as Claim 1
- substantially free of other physical forms
- soft pellets consisting of agglomeration of particles:
- at least 90% of particles with diameter < 10 microns
- pellet diameter 50 to 900 microns
Practical enforcement implications
This claim is designed to prevent design-around via changing particle morphology to maintain crystallinity while altering powder properties. It also adds a “substantially free of other physical forms” limitation, which can matter if a manufacturing process yields a mixture of polymorphs, amorphous content, or different hydrates/solvates.
For litigation, pellet/powder characterization (laser diffraction for particle sizes, XRPD for polymorph fraction) becomes central. If the accused product has a different agglomerate distribution or contains measurable other forms, Claim 5 can be avoided without changing the core polymorph.
How strong is the method-of-use protection for leukotriene antagonism in Claim 6?
Claim 6 claims a method:
- antagonizing one or more leukotrienes in a mammal
- by administering an effective amount of the crystalline physical form of Claim 1
This is a classic tying of use to a specific active solid form. Even if a defendant argues the molecule is known for leukotriene antagonism, the patentee retains a path to argue infringement if the administered active is that specific polymorph.
Scope considerations
- The method claim is not limited by formulation (it incorporates the physical form administration).
- The trigger is the administration of that physical form. If the defendant uses a different crystalline form, the biological efficacy does not automatically create infringement.
What patent-expiration and exclusivity timelines apply to US 5,294,636?
US 5,294,636 is a granted patent; absent additional date context (filing date, maintenance status, terminal disclaimers, or priority), exact expiration and term adjustments cannot be computed from the claim text provided. If computed incorrectly, it would materially misstate competitive exposure. No expiration timeline is provided here.
Which companies are covered, and what generic entry risks exist under Paragraph IV-type theories?
The scope and claims provided do not identify:
- any named applicants, assignees, or licensees
- any NDA/ANDA product references
- any Orange Book listings or FDA approvals linked to this compound
- any litigation or settlement record
Without those identifiers, mapping Paragraph IV risk and “who is challenging whom” cannot be done reliably from the patent number alone using the information supplied.
How does US 5,294,636 compare with typical solid-form patents for inhaled leukotriene drugs?
Compared with broad small-molecule formulation patents, this one is structurally narrower but evidentially stronger:
- Narrowness: claim elements force the crystalline identity (XRPD/IR/melting point) and, for formulation, require specific propellants and (for Claim 5) defined pellet size distribution and “substantially free of other physical forms.”
- Strength: analytical criteria create concrete infringement “handles” and reduce ambiguity about what counts as the claimed solid form.
Common design-arounds in this design space (as a category) include:
- substituting an alternate polymorph/solvate
- using the same polymorph but changing particle engineering to fail pellet/particle distribution limits
- using the same crystalline active in an MDI but switching propellant to agents not listed in Claim 4
Those pathways are compatible with the structure of the claims and are the primary ways to contest infringement.
Key claim elements that determine infringement outcomes
| Claim element |
What an accused product must show to infringe |
| XRPD peaks at fixed 2θ values |
Accused crystalline form produces those peaks at those positions (with method- and tolerance-dependent matching) |
| IR sharp peaks at listed cm⁻¹ |
Spectral match to the listed peak set |
| Melting point 190°C–200°C |
Thermal behavior matches that window |
| For Claim 5: substantially free of other forms |
Accused solid is predominantly one form with low polymorph/solid-state impurities |
| For Claim 4: listed propellants |
Accused MDI uses one or more listed propellants |
| For Claim 5: soft pellets with defined particle/pellet size |
Particle-size distribution matches: ≥90% <10 µm and pellets 50–900 µm |
| For Claim 6: administration of claimed physical form |
The administered active is the claimed crystalline form |
Key Takeaways
- US 5,294,636 is a crystalline solid-form and inhalation formulation patent, anchored by XRPD peak positions, IR peak list, and a melting point range.
- Claims 3-4 materially narrow formulation scope to metered dose inhaler compositions using specified propellants.
- Claim 5 adds a manufacturing/product engineering gate: substantially single-form content plus soft pellet and particle-size distribution requirements.
- The method claim (Claim 6) ties leukotriene antagonism to administration of the same crystalline physical form, limiting enforceability against products using alternate polymorphs.
FAQs
1) Can a product infringe US 5,294,636 if it contains the same molecule but a different polymorph?
Claim 1 defines the protected subject as a specific crystalline physical form by XRPD/IR/melting point. A different solid form can avoid infringement if it fails the analytical criteria.
2) Does Claim 3 cover nebulizers and dry powder inhalers as well as MDIs?
Claim 3 is limited to compositions “suitable for administration by a metered dose inhaler,” which is narrower than nebulizers or dry powder inhalers by claim language.
3) What happens if an MDI uses a listed propellant but the crystalline form does not match XRPD/IR?
Even with a matched propellant system, infringement depends on whether the administered active matches the claimed crystalline physical form in Claim 1 (and pellet form if invoking Claim 5).
4) Is the “substantially free of other physical forms” language a hard numerical limitation?
The phrase is not numerically defined in the claim text provided; enforcement typically turns on analytical quantification thresholds, but the claim language still requires substantial freedom from other forms.
5) Does Claim 6 require a specific leukotriene receptor subtype or only “one or more actions of leukotrienes”?
The method is broad in biological target description: it covers antagonizing “one or more of the actions of leukotrienes,” without specifying a receptor subtype in the claim text provided.
References
No sources were provided in the prompt beyond the claim language.
